Tuberculosis: a comprehensive international approach

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ISBN: 0-8247-8121-X This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright © 2000 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

DEDICATION

This book is dedicated to four individuals who were giants in our field and have passed away in the last few years. Their contributions to the scientific literature, program management, and global tuberculosis control are without parallel. Stefan Grzybowski, a native of Poland, graduated from the University of Edinburgh and did postgraduate work at Brompton Hospital. He came to Canada in 1954, first working in Ontario and then moving to the University of British Columbia in 1964, ultimately as Professor and Director of Pulmonary Disease. The size and body of his work would have been enough to earn him an honored place among his peers, but it will be as a unique person that this vital, remarkable man will be remembered. He approached his life’s work with unquenchable energy, human concern, and infectious humor. His passing leaves a large void in the field of tuberculosis and he will be greatly missed by his many friends and colleagues. Among the numerous qualities that made Karel Styblo an exceptional person were his passion for truth and integrity, his care for human beings, and his indefatigable courage. His passion for truth meant that he spared no effort to obtain proof. Once he obtained that proof, nothing would make him depart from it. He strove very hard to obtain the means and monies to provide proper short-course chemotherapy for patients in developing countries and is considered the father of the now pervasive directly observed therapy short course (DOTS) strategy of the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD). The IUALD and the Royal Netherlands Tuberculosis Association (KNCV) were extremely important to him as they supported him in the demonstration, implementation, and propagation of his concept of tuberculosis control throughout the world. Guan-qing Kan was well known in the tuberculosis community especially as Honorary Director of the Beijing Research Institute for Tuberculosis Control, Honorary President of the Chinese Anti-Tuberculosis Association, and Chief Editor of the Bulletin of the Chinese Anti-Tuberculosis Association. Based on his international experience and China’s situation, he put forward China’s guidelines on tuberculosis control. In 1978, Kan promoted finding the source of TB infection as a top priority and began fully utilizing the powerful weapon of DOTS. These strategies opened a new page in tuberculosis control in China and gave Beijing the lowest prevalence of smear-positive cases in all of China. This

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Dedication

success attracted the attention of the WHO and the antituberculosis societies of many countries and paved the way for the successful World Bank loan to China. His death is a great loss to China’s medical community and tuberculosis physicians worldwide. Alexander G. Khomenko, who died in 1999 after a long illness, was a member of the Russian Academy of Medical Sciences, an honored scientist of the Russian Federation, and Director of the Central Tuberculosis Research Institute of the Russian Academy of Medical Sciences. A long-time member of the Executive Committee of the IUATLD, he was the leader in bringing new Western ideas, such as DOTS and evidence-based medicine, into the former Soviet Union and getting them widely accepted. It would be fair to state that he almost single-handedly prevented Russian Tuberculosis Care and Control from falling out of the mainstream of the world’s medical science. L. B. R. E. S. H. To the memory of my father, Dr. C. Sheppy Hershfield (1904–1989), whose concepts of social justice for all had a profound influence on my life. E. S. H.

INTRODUCTION

In her book A History of Medicine (1992), Lois N. Magner comments on the impact of Robert Koch’s announcement in 1882 that he had discovered the tubercle bacillus: “To understand the profound effect of Koch’s announcement requires an appreciation of the way in which this disease (tuberculosis) permeated the fabric of life in the nineteenth century.” In fact, in the 17th century, it was already “difficult to believe that anyone could reach adulthood without at least a touch of consumption.” Since 1950, biomedical research and public health concepts have considerably modified our perspective on tuberculosis. Indeed, no one should fail to recognize the remarkable progress that has benefited generations of people all over the world. However, as we enter a new millennium, it would appear that we are now complacent about tuberculosis, perhaps in great part because of our past successes. We are told that the prevalence of tuberculosis is increasing because, on the one hand, its incidence is going up, and, on the other hand, its treatments are not as effective as they were in the past. Indeed, regarding the latter, the theory and reality of drug resistance are now clearly established. In the United States, the government is responding by stimulating a renewed research focus on understanding drug resistance and also on developing new, effective therapeutic agents. With the tools and approaches in hand to address these research questions, we can be optimistic that answers will soon be found. The issue of complacency is greatly different because to successfully address it requires a “will” that is difficult to create. It is a sad state of affairs that public health matters have not improved as much as they could because the will, or the interest to do what could and should be done, is often lacking. This is not a problem specific to tuberculosis and to other communicable diseases. Indeed, the same problem exists in the control of chronic diseases. This book addresses a wide range of biological and clinical questions; it also discusses worldwide public health issues and what must be accomplished to address them. At the very least, we should make full use of what we know works. v

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Introduction

The editors, Lee B. Reichman and Earl S. Hershfield, are well-recognized experts in the study and control of tuberculosis. They, and a remarkable array of contributors, bring the reader up-to-date on the extent of the tuberculosis problem worldwide, and they propose solutions to combat its resurgence. The first edition, published in 1993, had a wide audience. This second edition is a tool for those who are concerned about tuberculosis and want to do something about it. The Lung Biology in Health and Disease series has included many unique volumes. This one is added to the list with the conviction that it will contribute to solving a problem that affects us all. As the executive editor of the series, I am grateful to Drs. Reichman and Hershfield for the opportunity to present this timely and most important contribution. Claude Lenfant, M.D. Bethesda, Maryland

PREFACE TO THE SECOND EDITION

This second edition of Tuberculosis: A Comprehensive International Approach appears only seven years after the debut of the first edition, which was the first textbook exclusively devoted to tuberculosis in over twenty years. In response, it exhausted three printings—unprecedented for a book devoted solely to tuberculosis. Because, since the publication of the first edition in 1993, so much more information has been forthcoming, the editors, executive editor, and publishers felt a revised and expanded edition was required. In 1993, concurrent with publication of the first edition, the World Health Organization publicly recognized, for the first time, that tuberculosis was a “global health emergency.” The year 1993 also marked the beginning of the reversal of the resurgence of tuberculosis in the United States, which was one of the greatest public health successes of the twentieth century. This reversal underscored the observation that political will is the most critical ingredient in tuberculosis control. Unfortunately, events since 1993 have demonstrated that without political will, tuberculosis will get worse and potentially become incurable. As we enter the new millennium, tuberculosis remains the leading killer among the infectious diseases. As this edition goes to press, one-third of the world’s population remains infected. A very ominous new problem is the vast increase in documented multiple drug resistant tuberculosis (MDRTB), which is always a man-made phenomenon. This book presents evidence that the inexpensive but effective directly observed therapy short course (DOTS), the World Health Organization/International Union Against Tuberculosis and Lung Disease standard of care, is not being utilized enough to prevent multidrug resistance. Furthermore, the increasing levels of MDRTB may jeopardize the worldwide use of DOTS, as DOTS may be ineffective in the presence of MDRTB and can actually compound drug resistance. This ominous scenario will increasingly require the use of expensive and more toxic drugs tailored to a patient’s individual drug susceptibility profile— known as DOTS-Plus—to control the epidemic. vii

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Preface to the Second Edition

This new edition is unique in that it is responsive to tuberculosis programs in both low- and high-prevalence countries. With the resurgence of tuberculosis and the recent huge amount of attention paid to this disease, this remains the only textbook that presents a comprehensive international approach. Once again we are proud to include contributions from many of the world’s leading authorities on tuberculosis. We are especially honored that the table of contents includes chapters from our mentors and teachers as well as our students. We would like to thank the contributors and their secretarial staffs for meeting our deadline. Jean Norwood and Janet Hayward were invaluable in organizing and coordinating the work. Our production editor, Moraima Suarez, was of great assistance in helping put the work together and carrying it through production. To Claude Lenfant, Executive Editor of the Lung Biology in Health and Disease series, we express our heartfelt thanks for his counsel, support, and encouragement. Finally, we acknowledge the support and patience of our wives, Rose Reichman and Betty Ann Hershfield, and our children, Daniel and Deborah Gar Reichman and Jeffrey, David, and Bryan Hershfield. Lee B. Reichman Earl S. Hershfield

PREFACE TO THE FIRST EDITION

Tuberculosis is an ancient disease. In the past it has been both feared and respected. Despite being glamorized in literature, drama, and opera, its effects have led to death, disfigurement, and disability. It has wiped out young people in the prime of their lives; it has devastated families. The history of tuberculosis parallels the socioeconomic ills of humankind. Endemic in many populations, it rose to epidemic proportions with the advent of overcrowding, undernutrition, lack of fresh water, and poor sewage disposal. When susceptible populations were exposed for the first time, the epidemic flourished. In the long fight against this disease, treatments often evolved from fear and ignorance. Individuals with tuberculosis were isolated, treated with various potions, and subjected to a variety of surgical interventions. The advent of the mass radiograph for early diagnosis and the development of potent antituberculous medications and highly effective treatment regimens raised the hope that eradication of this disease was possible. However, the inability of governments to develop appropriate national tuberculosis control programs has hindered the fight against this disease. The lack of patient adherence to prescribed regimens has led to the development of relapses, often with drug-resistant organisms. Finally, the appearance on the world scene of widespread human immunodeficiency virus infection has increased tuberculosis rates worldwide, in both developing and developed countries. It is against this background that we offer Tuberculosis: A Comprehensive International Approach. This book represents a complete consideration of this disease from the historical, theoretical, practical, and operational points of view. Hopefully the various chapters will provide the reader with valuable information so that appropriate treatment regimens and control programs can be developed to ensure that those infected fully benefit from the most recent advances. We are proud to include contributions from many of the world’s leading authorities on tuberculosis. Their combined knowledge forms the basis of the current principles and practices embodied in this volume. We are especially honored ix

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Preface to the First Edition

that the List of Contributors includes many of our mentors and teachers as well as our colleagues. We would like to thank the contributors and their secretarial staffs for their assistance in meeting our deadline. Ms. Jean Norwood and Ms. Janet Haywood were invaluable in organizing and coordinating the work. Our Production Editor, Elaine Grohman, was of great assistance in helping us put the work together and carry it to production. To Dr. Claude Lenfant, Executive Editor of the Lung Biology in Health and Disease series, we wish to express our heartfelt thanks for his most cheerful counsel and encouragement. We acknowledge the support and patience of our wives, Rose Reichman and Betty Anne Hershfield, and our children, Daniel and Deborah Gar Reichman, and Jeffrey, David, and Bryan Hershfield. Lee B. Reichman Earl S. Hershfield

CONTRIBUTORS

Nils Eric Billo, M.D., M.P.H. Executive Director, International Union Against Tuberculosis and Lung Disease, Paris, France Nancy J. Binkin, M.D., M.P.H. Associate Director, International Activities, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia Henry M. Blumberg, M.D. Associate Professor, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, and Hospital Epidemiologist, Grady Memorial Hospital, Atlanta, Georgia Naomi N. Bock, M.D., M.S. Medical Officer, Research and Evaluation Branch, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia W. Henry Boom, M.D. Associate Professor, Division of Infectious Diseases, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio Jaap F. Broekmans, M.D., M.P.H. Director, Royal Netherlands Tuberculosis Association (KNCV), The Hague, The Netherlands Emmanuelle Cambau, M.D. Assistant, Department of Bacteriology and Hygiene, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France Antonino Catanzaro, M.D. Professor, Department of Medicine, University of California, San Diego, San Diego, California Richard E. Chaisson, M.D. Professor, Department of Medicine, Johns Hopkins University, Baltimore, Maryland xi

xii Pierre Chaulet, M.D.* Algiers, Algiers, Algeria

Contributors Professor, Faculty of Medicine, University of

Cynthia Bin-Eng Chee, M.D., F.R.C.P.(Edin) Consultant, Tuberculosis Control Unit, Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore Daniel Chemtob, M.D., M.P.H., D.E.A. Director, National Tuberculosis and AIDS Unit, Ministry of Health, Jerusalem, Israel David L. Cohn, M.D. Professor, Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, and Associate Director, Denver Public Health, Denver, Colorado George W. Comstock, M.D., Dr.P.H. Professor, Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland Nancy D. Connell, Ph.D. Assistant Professor, Department of Microbiology and Molecular Genetics, New Jersey Medical School National Tuberculosis Center, UMDMJ–New Jersey Medical School, and International Center for Public Health, Newark, New Jersey Thomas M. Daniel, M.D. Professor Emeritus, Department of Medicine, Center for International Health, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio Anne L. Davis, M.D. Associate Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University Medical School and Bellevue Hospital Chest Service, New York, New York Jerrold J. Ellner, M.D. Hunterdon Professor of Emerging and Reemerging Pathogens, and Director, Infectious Diseases Division, Department of Medicine, UMDNJ–New Jersey Medical School, Newark, New Jersey Wafaa M. El-Sadr, M.D., M.P.H. Professor, Department of Medicine, Columbia University College of Physicians and Surgeons, and Chief, Division of Infections Diseases, Harlem Hospital Center, New York, New York Donald A. Enarson, M.D., F.R.C.P.(C), F.R.C.P.(Edin) Professor, Department of Medicine, University of Alberta, Alberta, Canada, and Director of Scien* Retired.

Contributors

xiii

tific Activities, International Union Against Tuberculosis and Lung Disease, Paris, France Sue C. Etkind, R.N., M.S. Director, Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Boston, Massachusetts Paul E. Farmer, M.D., Ph.D. Director, Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, Boston, Massachusetts Paul E. M. Fine, V.M.D., Ph.D. Professor, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, England Paula I. Fujiwara, M.D., M.P.H. Director and Assistant Commissioner of Health, Tuberculosis Control Program, New York City Department of Health, and Supervisory Medical Officer, Centers for Disease Control and Prevention, Atlanta, Georgia Karen E. Galanowsky, R.N., B.S.N., M.P.H. Nursing Consultant, Department of Tuberculosis Control, New Jersey Department of Health and Senior Services, Trenton, New Jersey Jacques Grosset, M.D. Professor, Department of Bacteriology and Hygiene, Faculté de Médicine Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France Earl S. Hershfield, M.D., B.Sc., F.R.C.P.(C) Professor, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Philip C. Hopewell, M.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, and Associate Dean, San Francisco General Hospital, San Francisco, California Jim Yong Kim, M.D., Ph.D. Director, Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, Boston, Massachusetts Kraig Klaudt Advocacy Campaign Coordinator, Program on Communicable Diseases, World Health Organization, Geneva, Switzerland

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Contributors

Barry N. Kreiswirth, Ph.D. Director, Tuberculosis Center, Public Health Research Institute, New York, New York, and International Center for Public Health, Newark, New Jersey Adalbert Laszlo, Ph.D. Director, WHO Collaborating Center for Tuberculosis Bacteriology Research, Health Canada, Ottawa, and Consultant Tuberculosis Bacteriology, International Union Against Tuberculosis and Lung Disease, Nepean, Ontario, Canada Philip A. LoBue, M.D. Medical Epidemiologist, Division of Tuberculosis Elimination, Field Services Branch, Centers for Disease Control and Prevention, San Diego, California Bonita T. Mangura, M.D. Associate Professor, Department of Medicine, New Jersey Medical School National Tuberculosis Center and International Center for Public Health, UMDNJ–New Jersey Medical School, Newark, New Jersey Richard I. Menzies, M.D., M.Sc., F.R.C.P.(C) Associate Professor, Department of Medicine and Department of Epidemiology and Biostatistics, Montreal Chest Institute, McGill University, Montreal, Quebec, Canada Bess Miller, M.D., M.Sc. Associate Director for Science, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia Carole D. Mitnick, Sc.M. Research Fellow, Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, Boston, Massachusetts Flor M. Muñoz, M.D. Assistant Professor, Department of Microbiology and Immunology and Department of Pediatrics, Baylor College of Medicine, Houston, Texas Sonal S. Munsiff, M.D. Director, Epidemiology and Surveillance, Tuberculosis Control Program, New York City Department of Health, New York, New York Eileen C. Napolitano, B.A. Deputy Director, New Jersey Medical School National Tuberculosis Center and International Center for Public Health, UMDNJ–New Jersey Medical School, Newark, New Jersey Edward A. Nardell, M.D. Associate Professor, Department of Medicine, Harvard Medical School, Chief, Department of Pulmonary Medicine, Cambridge

Contributors

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Hospital, and Tuberculosis Control Officer, Massachusetts Department of Public Health, Boston and Cambridge, Massachusetts Richard J. O’Brien, M.D. Chief, Research and Evaluation Branch, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia Frances R. Ogasawara, M.S., C.H.E.S.† Associate Managing Director, American Lung Association, New York, New York Sharon Perry, Ph.D. Staff Research Associate, Department of Medicine, University of California, San Diego, San Diego, California Willy F. Piessens, M.D. Professor, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, Massachusetts Mario C. Raviglione, M.D. Coordinator, Strategy Development and Monitoring of Endemic Bacterial and Viral Diseases, Communicable Disease Control, Prevention and Eradication, World Health Organization, Geneva, Switzerland Hans L. Rieder, M.D., M.P.H. Chief, Tuberculosis Division, International Union Against Tuberculosis and Lung Disease, Paris, France Camilo C. Roa, Jr., M.D. Professor, Department of Medicine, University of the Philippines College of Medicine, Manila, Philippines Rodrigo L. C. Romulo, M.D. Assistant Professor, Section of Infectious and Tropical Diseases, Department of Medicine, Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines Sara Rosenbaum, J.D. Harold and Jane Hirsh Professor, School of Public Health and Health Services, The George Washington University, Washington, D.C. Annik Rouillon, M.D., M.P.H. Honorary Executive Director, International Union Against Tuberculosis and Lung Disease, Paris, France Mona Saraiya, M.D., M.P.H. Medical Epidemiologist, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia

† Retired.

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Contributors

Holger Sawert, M.D., M.P.H. Medical Officer, Ministry of Public Health, World Health Organization, Bangkok, Thailand Patricia M. Simone, M.D. Chief, Field Services Branch, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia Jeffrey R. Starke, M.D. Associate Professor, Department of Pediatric Infectious Disease, Baylor College of Medicine, Houston, Texas Elizabeth J. Stoller, M.P.H.‡ Director, Francis J. Curry National Tuberculosis Center, San Francisco, California Elizabeth Tayler, M.B.B.S., M.R.C.P.(UK), M.F.P.H.M. Health Coordinator, Department of Health, Department for International Development (DFID), British High Commission, Abuja, Nigeria Ralph Timperi, M.P.H. Assistant Commissioner, Massachusetts State Laboratory Institute, Massachusetts Department of Public Health, Boston, Massachusetts Chantal Truffot-Pernot, D.Pharm. Assistant, Department of Bacteriology and Hygiene, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France Jaap Veen, M.D., Ph.D., D.T.P.H. Senior Tuberculosis Consultant, Royal Netherlands Tuberculosis Association (KNCV), The Hague, The Netherlands Yee-Tang Wang, M.D., F.R.C.P.(Edin) Senior Physician and Head, Tuberculosis Control Unit, Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore Daniel Weiler-Ravell, M.D. Director, Division of Respiratory Physiology and Medicine, Carmel Medical Center, Haifa, Israel Sheri Weiser, M.A. National Tuberculosis and AIDS Unit, Ministry of Health, Jerusalem, Israel Israel Yitzhak, L.V.N. Health Educator, National Tuberculosis and AIDS Unit, Ministry of Health, Jerusalem, Israel

‡

Current affiliation: Institute for Global Health, San Francisco, California.

CONTENTS

Introduction Claude Lenfant Preface to the Second Edition Preface to the First Edition Contributors Part One

PROGRAMMATIC BACKGROUND

1. A Historical Perspective on Tuberculosis and Its Control Anne L. Davis I. Early Perceptions and Practices II. Concepts from the Renaissance Through the Eighteenth Century III. Nineteenth- and Twentieth-Century Developments and Concepts References 2. Tuberculosis Control in Low-Income Countries Donald A. Enarson I. II. III. IV. V. VI. VII. VIII.

v vii ix xi

Introduction Objectives of Tuberculosis Control The Scientific Basis of Intervention Prevention Through Treatment Basic Principles of Tuberculosis Control Adaptations for Low-Income Countries Achieving Success in Low-Income Countries Effective Strategies for the Management of Tuberculosis

3 5 7 10 43 55 55 55 56 57 58 60 62 65 xvii

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Contents IX. Future Challenges References

3. Tuberculosis Control in Low-Prevalence Countries Jaap F. Broekmans I. The Prospect of Elimination II. Framework for Tuberculosis Control in Low-Prevalence Countries III. Surveillance IV. Program Monitoring References 4. Tuberculosis Laboratories: The Centerpiece of National Tuberculosis Control Programs Adalbert Laszlo I. II. III. IV. V. VI.

68 71 75 75 81 86 89 92

95

Introduction National Tuberculosis Programs Tuberculosis Diagnostic Services Tuberculosis Diagnostic Techniques The NTP National Tuberculosis Laboratory Network Structure and Function of the National Tuberculosis Laboratory Network VII. The National Tuberculosis Laboratory Network as a Source of Data VIII. The National Tuberculosis Laboratory Network as a Source of Operational and Epidemiological Information IX. Conclusion References

101

5. Evaluation of Applied Strategies of Tuberculosis Control in the Developing World Pierre Chaulet and Earl S. Hershfield

107

I. Introduction II. Prerequisites for Evaluating a Tuberculosis-Control Strategy III. Evaluation of the Strategies Applied in Tuberculosis Treatment IV. Evaluation of Strategies Applied in the Detection of Tuberculosis Cases V. Conclusion References

95 97 99 100 101

103 104 104 105

107 108 111 119 124 124

Contents Part Two

xix BASIC ASPECTS

6. Epidemiology of Tuberculosis George W. Comstock I. II. III. IV.

Introduction Etiological Epidemiology Administrative Epidemiology Conclusion References

7. Bacteriology of Tuberculosis Jacques Grosset, Chantal Truffot-Pernot, and Emmanuelle Cambau I. II. III. IV. V. VI. VII. VIII.

Introduction Biological Safety General Characteristics of Tubercle Bacilli Bacteriology for Diagnosis and Monitoring Treatment of Tuberculosis Strain Typing of M. tuberculosis Drug Activity Against M. tuberculosis Immunodiagnostic Tests for Tuberculosis Direct Detection of M. tuberculosis by Nucleic Acid Amplification References

8. Immunology of Tuberculosis Thomas M. Daniel, W. Henry Boom, and Jerrold J. Ellner I. Introduction II. Mycobacterial Protein Antigens III. The Mycobacterial Cell Wall: Mycobacterial Adjuvants and Mycobacterial Polysaccharides IV. Granuloma Formation V. Cell-Mediated Immunity VI. Humoral Immunity VII. Immune Spectrum and Immunoregulation VIII. HIV–M. tuberculosis Interactions IX. Conclusions References 9. Transmission of Tuberculosis Edward A. Nardell and Willy F. Piessens I. Aerobiology of Tuberculosis II. Epidemiology of Transmission

129 129 130 141 149 149 157 157 158 158 160 168 169 175 177 178 187 187 188 192 194 194 199 200 202 203 204 215 217 221

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Contents III. IV. V. VI. VII.

Infectious Dose for Humans Recent Outbreaks Preventing Transmission Governmental Recommendations: An Overview Preventing Transmission from Unsuspected Cases of Tuberculosis VIII. Engineering Approaches to Preventing Transmission References 10. Pathogenesis of Tuberculosis Willy F. Piessens and Edward A. Nardell I. Introduction II. Stage 1 (Week 1): Invasion III. Stage 2 (Weeks 2 and 3): Logarithmic Bacillary Growth and the Early Tuberculous Lesion IV. Stage 3 (After Week 3): Infection Control V. Stage 4 (Months to Years Later): Endogenous Reactivation and Transmission VI. Clinical Correlates of Immune Events in Human Tuberculosis VII. Conclusion References 11. Mycobacterial Strain Genotyping Nancy D. Connell and Barry N. Kreiswirth I. II. III. IV. V. VI.

Part Three

Introduction Methodologies Interpreting Genotypes International Applications of Molecular Fingerprinting Implications for Basic Research Clinical Applications of Molecular Fingerprinting References

225 227 228 229 230 231 236 241 241 242 248 249 252 254 255 255 261 261 262 265 267 269 270 270

CLINICAL ASPECTS

12. Tuberculin Skin Testing Richard I. Menzies

279

I. Introduction II. Technical Aspects

279 280

Contents

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III. Simple Cognitive Aspects: False-Negative and False-Positive Reactions IV. Complicated Cognitive Aspects: Interpreting Tuberculin Tests V. Conclusions References 13. Case Finding in High- and Low-Prevalence Countries Hans L. Rieder I. II. III. IV. V. VI.

Introduction Sources of Transmission and Other Cases Identification of Sources of Transmission Factors Modifying the Choice of Case-Finding Methods The Role of Case Finding in Tuberculosis Control Conclusions References

14. Diagnosis of Tuberculosis Philip A. LoBue, Sharon Perry, and Antonino Catanzaro I. II. III. IV. V. VI. VII. VIII.

285 296 310 311 323 323 324 325 331 332 333 334 341

Introduction Medical History and Physical Examination Routine Laboratory Tests The Tuberculin Skin Test Diagnostic Tests: Pulmonary Disease Extrapulmonary Tuberculosis Pediatric Tuberculosis Developments in Rapid Diagnosis: Nucleic Acid Amplification Tests X. Summary References

341 341 343 343 343 351 356

15. Contact Follow-Up in High- and Low-Prevalence Countries Sue C. Etkind and Jaap Veen

377

I. II. III. IV. V. VI.

Introduction Definitions Need for Contact Tracing Contact Tracing in Low-Prevalence Countries Contact Tracing in High-Prevalence Countries New Technology: The Role of Restriction Fragment Length Polymorphism Testing

356 363 363

377 378 379 380 389 391

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Contents VII. Challenges and Unanswered Questions VIII. Summary References

16. Treatment of Tuberculosis Paula I. Fujiwara, Patricia M. Simone, and Sonal S. Munsiff I. Introduction II. History of Tuberculosis Treatment in the Chemotherapeutic Era III. Antituberculosis Medications IV. Standard Antituberculosis Treatment Regimens in the United States V. Antituberculosis Treatment Regimens in Resource-Poor Countries VI. Methods Used to Diagnose Tuberculosis and Monitor Treatment VII. Special Clinical Situations VIII. Adherence to Treatment IX. The Future of Treatment References 17. Responding to Outbreaks of Multidrug-Resistant Tuberculosis: Introducing DOTS-Plus Paul E. Farmer, Jim Yong Kim, Carole D. Mitnick, and Ralph Timperi I. II. III. IV.

Introduction: Strengths and Limitations of DOTS What Is DOTS-Plus? Making DOTS-Plus Work: A Case Study Pitfalls in the Planning and Execution of DOTS-Plus Programs V. Conclusions: DOTS-Plus, We Can’t Afford Not to Try It References

18. Treatment of Latent Tuberculosis Infection David L. Cohn and Wafaa M. El-Sadr I. Introduction II. Treatment of Latent Tuberculosis Infection in Immunocompetent Hosts III. New Regimens for Treatment of Latent Tuberculosis Infection

394 395 396 401 401 402 405 415 418 420 423 432 435 436

447

447 453 455 462 466 466 471 471 472 481

Contents

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IV. Treatment of Latent Tuberculosis Infection in HIV-Infected Persons V. Treatment of Latent Tuberculosis Infection in Special Populations VI. Development of Disease Due to Resistant Organisms VII. Recommendations for Treatment of Latent Tuberculosis Infection VIII. Conclusions and Future Directions References 19. BCG Vaccines and Vaccination Paul E. M. Fine I. II. III. IV. V. VI. VII. VIII. IX. X.

Part Four

Introduction Historical Background BCG Vaccines Current BCG Policies The Protective Efficacy of BCG Protection Against Diseases Other Than Tuberculosis Adverse Reactions The Impact of BCG Vaccination Programs Improving Upon BCG Immediate Prospects for Vaccination Against Tuberculosis References

482 491 492 493 496 497 503 503 503 505 505 508 512 512 513 514 516 518

SPECIAL PROBLEMS

20. Tuberculosis and Human Immunodeficiency Virus Infection Philip C. Hopewell and Richard E. Chaisson

525

I. Risk of Tuberculosis in Persons with HIV Infection II. Prevalence of HIV Infection Among Patients with Tuberculosis III. Influence of HIV Infection on the Pathogenesis of Tuberculosis IV. Diagnosis of Tuberculosis Infection and Tuberculosis V. Treatment VI. Tuberculosis Caused by Multidrug-Resistant Organisms VII. Prevention VIII. Infection Control IX. Influence of Tuberculosis on the Course of HIV Infection

525 528 529 531 535 539 541 544 545

xxiv

Contents X. Necessary Changes in Approaches to Tuberculosis Control References

21. Tuberculosis in Children Flor M. Muñoz and Jeffrey R. Starke I. II. III. IV. V. VI.

Introduction Epidemiology Pathogenesis Clinical Forms of Tuberculosis Diagnosis of Tuberculosis in Children Treatment References

22. Case Management: The Key to a Successful Tuberculosis-Control Program Bonita T. Mangura and Karen E. Galanowsky I. II. III. IV. V. VI. VII. VIII. IX.

Part Five

Introduction Directly Observed Therapy Clinical Care and Public Health The Newark Experience The Nurse Case-Management Model Tuberculosis Therapy by Directly Observed Therapy Incremental Service Delivery Change and DOT The Interaction: Patient and Health Care Provider Impact on TB Control References

545 547 553 553 555 560 563 574 578 586

597 597 598 598 599 600 601 602 604 604 605

UNIQUE ASPECTS OF TUBERCULOSIS CONTROL

23. Tuberculosis Infection Control Henry M. Blumberg I. Introduction and Historical Overview II. Trends in Nosocomial Transmission of Tuberculosis III. Institutional Controls in the United States and Other Developed Countries IV. Hospital Discharge Planning and Standards V. OSHA Requirements for a Tuberculosis-Control Program VI. Institutional Controls in Developing Countries and Areas with Very Limited Resources References

609 609 610 617 630 631 631 636

Contents

xxv

24. Tuberculosis in Correctional Facilities Naomi N. Bock

645

I. II. III. IV.

Introduction Epidemiology of Tuberculosis in Correctional Facilities Transmission of Tuberculosis in Correctional Facilities Risk Factors for Tuberculosis Among Inmates in Correctional Facilities V. Correctional Facility Tuberculosis and the Community at Large VI. Controlling Tuberculosis in Correctional Facilities References 25. Tuberculosis Among Immigrants Mona Saraiya and Nancy J. Binkin I. II. III. IV. V. VI.

Introduction History of Migration of TB Definitions Epidemiology of TB Among Foreign-Born Persons Drug Resistance Contribution of Immigration to Transmission of TB in Low-Prevalence Countries VII. Approaches to TB in the Foreign-Born References 26. Coalition Building for Tuberculosis Control: The Philippine Experience Camilo C. Roa, Jr., and Rodrigo L. C. Romulo I. Coordinating Tuberculosis-Control Efforts: The Need for Coalitions II. TB Interest Groups III. Rallying Around a Common Goal IV. The Philippine Coalition Against Tuberculosis V. Formalizing and Expanding VI. Generating Resources VII. The Birth of PHILCAT VIII. Pushing Onwards IX. Developing a Unified Strategy: Identifying More Stakeholders X. National Consensus on Tuberculosis XI. Coalition Activities: Achieve Objectives and Maintain Member Enthusiasm

645 646 648 648 649 651 654 661 661 661 662 664 675 677 678 687

693

693 694 696 696 697 697 698 698 700 702 702

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Contents XII.

Summary References

27. Tuberculosis Education Eileen C. Napolitano and Elizabeth J. Stoller I. Introduction II. Evidence of the Need for Training and Education for Providers III. Current Training Initiatives IV. Health-Care Providers in Need of Education and Training V. Methods VI. Future Directions for Training VII. Topics for Further Discussion References 28. Political Will: The Singapore Tuberculosis Elimination Program Cynthia Bin-Eng Chee and Yee-Tang Wang I. Singapore: An Island City-State II. Tuberculosis in Singapore III. Rationale for the Singapore Tuberculosis Elimination Program IV. Organizational Structure of STEP V. Key Factors for the Success of STEP VI. Conclusion References 29. Medical Anthropology: An Important Adjunct to International TB Control Daniel Chemtob, Sheri Weiser, Israel Yitzhak, and Daniel Weiler-Ravell I. II. III. IV.

Introduction The Relevance of Social Science to Public Health Some Basic Concepts in Social Science Some Key Perspectives in the Social Science Literature on TB V. An Anthropological Study of TB Among Ethiopian Immigrants in Israel VI. The Contribution of Social Science to the New National Program for the Elimination of TB in Israel VII. Conclusion References

703 703 705 705 707 711 713 714 717 718 720

727 727 729 734 735 736 739 740

745

745 746 750 754 757 762 765 766

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30. The Role of Nongovernmental Organizations Annik Rouillon, Nils Eric Billo, and Frances R. Ogasawara I. Introduction II. National Tuberculosis Associations III. The International Union Against Tuberculosis and Lung Disease IV. Present Trends: Irreplaceable Partners V. Summary References 31. Economic Considerations for Tuberculosis Control Holger Sawert I. Political Commitment and Economic Arguments II. Economic Analysis: Basic Concepts III. Specific Points for the Analysis of Tuberculosis Control Interventions IV. Example: Improving Tuberculosis Control in Thailand References 32. The Impact of Managed Care on Tuberculosis Control in the United States Bess Miller and Sara Rosenbaum I. Introduction II. Tuberculosis Control in the United States: Current Organizational Structure III. The Advent of Managed Care and Its Impact on TB Control IV. Concerns of TB Health Officials About Managed Care V. Response of TB Health Officials to the Advent of Managed Care VI. Role of Contracts and Memoranda of Agreement VII. Conclusion References 33. The Impact of Health Sector Reform on Tuberculosis Control in Developing Nations Elizabeth Tayler I. II. III. IV.

Introduction Why Health Sector Reform Is Needed Impact of Health Sector Reform Upon TB Services Political Commitment

771 771 775 787 793 795 795 799 799 802 804 807 814

817 817 818 819 820 821 823 825 825

829 829 831 832 833

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Contents V. Case Finding and Diagnosis VI. Standardized Short-Course Regimen and Supervision of Therapy VII. Drug Supply VIII. Recording and Reporting IX. Conclusions References

34. Mobilizing Society Against Tuberculosis: Creating and Sustaining Demand for DOTS in High-Burden Countries Kraig Klaudt I. Assessment of the Current Response to the Global TB Epidemic II. The Role of Information, Education, and Communication, Advocacy, and Social Mobilization III. The C.A.U.S.E. Strategy for Mobilizing Society IV. The Main Components of Advocacy V. Potential Initiatives to Help Mobilize Society to Control TB VI. Conclusion References Part Six

Index

835 837 837 838 840

843

843 846 850 854 858 863 863

THE FUTURE

35. Tuberculosis in the Future Richard J. O’Brien and Mario C. Raviglione I. II. III. IV. V.

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Tuberculosis in the 1990s: Reasons to Be Hopeful Problems Looming at the End of the Twentieth Century TB in the New Millennium: Clues from Modelers The Promise of New Technologies Tuberculosis Elimination: An Impossible Dream? References

867 867 871 874 877 878 881 885

Part One PROGRAMMATIC BACKGROUND

1 A Historical Perspective on Tuberculosis and Its Control

ANNE L. DAVIS New York University Medical School and Bellevue Hospital Chest Service New York, New York

Since the first appearance of tuberculosis in humans probably some 8000 years ago (1–3), its control has continued to elude the brightest minds and to challenge both the human and economic resources of countries around the world. One third of the world’s population is estimated to be infected. If the trends of the 1990s continue, the annual number of new cases could exceed 8 million, and 30 million deaths will have resulted from the disease between 1990 and 2000 (4). As an indolent wasting, debilitating condition, “the Captain of the Men of Death” (5), or a highly lethal epidemic, “The Great White Plague” (6,7), it is different from most infectious diseases in the worldwide magnitude of its effects. From a constellation of elusive illnesses of hypothetical etiologies to its final recognition as a single disease caused by a specific microorganism, it has challenged the imagination and intellect of people from prehistory to the present. It has stimulated as well as snuffed out the creative and intellectual endeavors of those who have encountered it. It has enchanted the imaginations of writers, artists, musicians, philosophers, scientists, and most recently news reporters. It has spawned a global public health movement, called attention to the deplorable effects of poverty, overcrowding, and ignorance and raised awareness of the vital role of the nursing and other health professions, as well as veterinary medicine, in its control. The continuing ability of the disease to elude control has prompted re3

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strictive laws (8–11) and raised legal ethical issues as recently as the 1990s (12–16). Not only when but also how and where tuberculosis originated and spread is still the subject of debate. Some believe that it existed in animals long before it affected humans (1–3,17,18). When primitive agricultural practices permitted permanent settlements, cattle, swine, and sheep became domesticated and often shared the family’s dwelling space, making the spread between animals and humans possible but initially sporadic and endemic. Whether Mycobacterium tuberculosis evolved from Mycobacterium bovis is still unclear, but some believe that biological and historic evidence support such an evolution (1). The strong degree of DNA homology (19) and the immunological properties suggest that they are subspecies (20) and that M. tuberculosis evolved through genetic mutations from M. bovis in humans after the domestication of cattle (1). Concepts about where on the globe tuberculosis began and how it spread are also changing as new archeological discoveries and molecular technologies emerge (21–25). The distribution of infection and severity of the disease have varied with the time period and geographic location (3,26–31). The epidemiology has been imperfectly hypothesized from the spotty data available before the development of modern tools for more accurate identification of the disease and required reporting of cases. Even if one accepts that tuberculosis was endemically present in areas of Eurasia, Africa, India, China, Japan, and the Americas for perhaps several thousand or more years, the chronology of its devastating impact in the different populations of the world has yielded differing theories explaining the observed phenomena (1,32–34). In addition to exposure to infected cattle, their milk, and milk products (1,17,18,34–37), human “herd immunity” (38) and migration and immigration patterns, industrialization, poverty, poor nutrition, overcrowding, unhealthy lifestyle changes, and concomitant disease [e.g., human immunodeficiency virus (HIV) infection] have played a role. During the lengthy history of the disease there have been brief glimpses of enlightenment, but progress primarily had to await additional observations and discoveries beginning during the Renaissance but continuing with increasing acceleration to the present. The discovery and isolation of the etiological agent by Robert Koch in 1882 and subsequent developments in the first part of the twentieth century provided more accurate ways of detecting the disease, generated vigorous public health campaigns, introduced new treatment and prevention strategies, and renewed hope that tuberculosis could be prevented and even cured. Clinical and laboratory investigations burgeoned and have provided the background for the present application of sophisticated new tools to the persistent challenges retarding the conquest of tuberculosis into the next century. This chapter can only hint at the rich history of this ancient disease and highlight a few of the events and trends—particularly in the nineteenth and twentieth

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centuries—that have led to current concepts of tuberculosis and strategies for its potential control.

I. Early Perceptions and Practices Prehistoric humans thought that supernatural powers were responsible for all that they did not understand, including sickness. Diagnosis was unimportant because the treatment was the same: appeasing the supernatural spirit or scaring away the evil demons, evoked by magic. Herbs and animal parts, their secretions and excretions, were used therapeutically. Sometimes certain stones or colors (red, especially) were considered beneficial. The sun, moon, and stars were also believed to influence health. Transference of disease to another object or animal was practiced (18). A child with scrofula was passed through the hole of a tree or a rock with the belief that the disease would thus be transferred (39). Some of these superstitions regarding disease and health, that existed when Egyptian, Babylonian, Greek, Roman, Hindu, Chinese, and Japanese civilizations began, still exist among some populations in parts of the world where traditional healers still practice (26,40–42). Awareness of such customs is important for the development of successful control programs (40,41). The observations of ancient societies, as detailed in their skeletons, artefacts, drawings and paintings, and later in writings are remarkably recognizable as the clinical features of tuberculosis as we know it today. The bony deformities found in skeletons, drawings, and sculptures in Egypt, Peru, and other countries are very suggestive of Pott’s disease (39,44–47). Data from written sources, although scarce, also tend to support the hypothesis that tuberculosis has existed for a very long time (18,39,48), but some scholars are skeptical because perceptions of the symptoms and course of what we now call tuberculosis varied widely until the last decades of the nineteenth century when the unity of the disease was established. It was known as phthisis (“wasting disease”) or consumption as well as scrofula (the cervical swellings resembling cow’s udders), lupus vulgaris, lung hemorrhage, chronic diarrhea, and hectic fever. The Hindus alluded to consumption. Some historians believe that descriptions of consumption passed orally from generation to generation long before the Vedas were written (26,39). Hindu drugs were known to the Egyptians, who derived cotton from India, long before Hippocrates. Many Greek drugs had Sanskrit names. Hindu remedies were also mentioned in the Old Testament. Antedating by centuries many of the remedies still believed to be beneficial for consumption as late as the nineteenth and first half of the twentieth centuries, the Hindus recommended milk, especially from a lactating woman, many meats and vegetables, and avoidance of fatigue. The Yajur Vedas advised that “to mount and be carried on

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gentle horses makes an exercise which increases the flesh and blood and helps sleep. . . . A consumptive should go and live in high altitudes” (39). The Greeks apparently saw most forms of the disease and contributed detailed descriptions of the cardinal symptoms—age, incidence, and prognosis (18,43,49). The careful observations and interest in scientific inquiry by Hippocrates and his followers removed medicine from the realms of religion and philosophy and began to replace superstition with common sense. At the end of this era, Rome and subsequently Byzantium assumed importance, but little medical progress was made. When the Roman Empire eventually disintegrated about 600 A.D. and the Dark Ages ensued, the writings and teachings of Galen (130–200 A.D.), a Greek emigré to Rome, became authoritative in medicine for about the next 1400 years (43,50). The prior interest in keen observation and scientific inquiry exemplified by Hippocrates and others of the Greek Golden Age faded. Mystical explanations for natural phenomena again prevailed, and authority reigned as the source of knowledge. In summary, as these early civilizations developed, little progress was made in the understanding and control of phthisis. Diagnosis, at its best, was based almost solely on careful observations of the patient. Limited attempts at physical examination were made. References to râles and to succussion have been found in the Hippocratic Collection (18,43,49). Human dissection was not permitted, except transiently, in Alexandria around 332 B.C. (39). Sputum as a diagnostic or prognostic tool was barely mentioned, but Aretaeus did suggest that inspection of the sputum was of greater diagnostic value than testing it with fire or water (43). One Hippocratic aphorism stated that “in persons affected with phthisis, if the sputa which they cough up have a heavy smell when poured upon coals, and if the hairs of the head fall off, the case will prove fatal” (49). Without the benefit of pathological or microbiological studies, the causes and pathogenesis of these afflictions were highly speculative. An imbalance of the four humors, heredity, defluxions proceeding from the head, something exhaled in the patient’s breath. ulceration of the lung, which might be due to inflammation extending from the nose or throat, or even chilling of the lung or trauma were a few of the theories (43). The contagious nature of phthisis was not recognized (18). Although long before mycobacteria were identified, Aristotle had hinted at the possibility (39), and Galen (50) and Avicenna, the Arab physician, had suggested (43,51), it was not until the seventeenth century that measures were briefly put in place in Italy to quell the spread. Treatment continued to include many of the superstitious practices of earlier times as well as the old Hindu remedies. Bloodletting and cupping were also employed. Pliny the Elder (23–79 A.D.) commented that sea voyages were desirable especially for hemoptysis (39), and some specific therapeutic concoctions such as wolf’s liver boiled in wine or boiled crocodile for chronic cough were

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mentioned. Later “the King’s Touch” for scrofula instituted by King Clovis in 494 A.D. was considered beneficial (39,43), although the idea of healing by royal touch may have originated with Pyrrhus (318–272 B.C.), who cured disease of the spleen by the touch of his right toe. The Christian practice of “laying on of hands” to heal derives from this early belief in the royal healing power. During the Dark Ages, the Christian church and Arab physicians (Syrians, Persians, and Spaniards by virtue of their common language) determined the course of medicine, primarily by collecting and preserving the texts of the Greek physicians. II. Concepts from the Renaissance Through the Eighteenth Century After the invention of printing and the translation of the great Greek texts into Latin and their publication by the middle of the sixteenth century, discussions about possible causes for tuberculosis and controversies over contagion were revived. At last anatomical and pathological studies began to provide a basis for understanding the clinical features and pathogenesis of tuberculosis as we know it today. A. Contagiousness and Early Attempts to Control

A notable achievement in this period was the advancement, at least temporarily, of the notion of contagiousness of tuberculosis. Heironymous D. Fracastorius’s description in his book, De Contagione, in 1546 of three methods of infection— direct contact, fomites, and air—and his postulation of the existence of “seminaria,” imperceptible particles which he believed could exist outside the body for several years and still infect, were the most articulate and original enunciations up to this time of the modern germ theory of contagion (1). In phthisis he postulated that the “seminaria” could come not only from outside, but could arise within the body as well, from “putrefaction of the humors” (39). He believed that “the original germs generate and propagate other germs precisely like themselves and these in turn propagate others until the whole mass and bulk of humors is infected by them” (1,52). He also suggested that contagion was selective: some organs are affected while others may be spared, and “some bodies catch infections very easily, others either not at all or with difficulty” (52). He even suggested the idea of sterilization, which went unheeded for the next 300 years. In the initial stage of treatment, “pay attention to the germs only, for if these could be destroyed, by caustic means no more effective remedy could be employed” (52). Similar conclusions regarding control of tuberculosis with emphasis on detection, isolation, and prompt treatment of infectious tuberculosis followed in the twentieth century, but experience both before (53) and since the chemotherapy era has shown that tu-

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berculosis is more than a simple infectious disease and that its effective control requires combat on many fronts (27,54–57). During the seventeenth century the contagious nature of tuberculosis was accepted and dreaded throughout much of Europe, but by the latter half of the century those north of the Alps began touting hereditary or constitutional factors. In southern Europe the contagion notion persisted and resulted in strict measures to safeguard the public. In 1699 the The General Sanitary Council of the Republic of Lucca ordered that “the health of the human body shall not be harmed or imperiled by objects remaining after death of a person infected with the disease of phthisis” (58). Disinfection measures were promptly instituted, including replastering the entire house by the authorities, decontamination or burning of household goods, and removal of the poor sick to a hospital (59). Furthermore physicians had to report persons treated for or suspected of tuberculosis or they faced fines of 300 ducats or banishment for 10 years for a second offense (59). Although systematic recording of cases was not yet practiced, it is generally agreed that there was a sharp increase in cases of consumption in Britain and then throughout western Europe during the 1600s, especially in the overcrowded cities. Following Lucca’s attempts at record-keeping, compulsory notification was introduced by Ferdinand VI in Spain and in Naples. Parish registers from England quoted by Thomas Beddoes in his 1799 essay (60) indicate that over a 7- to 10-year period one in four deaths was ascribed to tuberculosis. Similar mortality statistics were available from New England in the United States (37). Both Florence (1754) and Naples (1782) subsequently passed edicts to control contagion, and for a while the latter’s rules were strictly enforced in Spain and tubercular patients were forbidden to emigrate (52). However, opposition finally prevailed, and the laws were removed or forgotten. Fears that the laws would evoke prejudice against the tubercular poor and create financial burden contributed to the demise of these early public health efforts (52,58,59). These arguments are reminisicent of those expressed against the pioneering public health laws in New York City at the turn of the twentieth century. B. Concepts of Etiology and Pathogenesis

Once Andreas Vesalius (1514–1564) had established the principal of dissecton and corrected Galen’s errors, correlation of post-mortem examination with clinical aspects began to demystify the puzzling constellation of symptoms and signs that we now call tuberculosis. It took more than 100 more years before the results of autopsies during the sixteenth and seventeenth centuries were published by Theophile Bonet in his Sepuchretum in 1679. Cavities (vomicae) were described in some of the lungs of cases from the leading Parisian physician, Jean Fernel

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(1497–1558), who had stated that these occurred frequently in consumptive patients (39). Symptoms of consumption were connected with pathological findings by Richard Morton in 1689 in his systematic treatise, Phthisiologica (39). Francis de le Boe (Sylvius) (1614–1672), a professor at Leyden, observed that tubercles were identified with the symptoms of phthisis. He noted their tendency to grow and gradually to suppurate and even to lead to cavities (61), but he misinterpreted their origin as being tiny lymph nodes (39,43,61). Thomas Willis (1621–1675) of Oxford first proposed the heretical idea that phthisis was possible without ulceration (43,51,61). He also noted the variations in the pathology and clinical course in different individuals, which up to this time had not been fully appreciated (51). William Stark (1741–1770), a meticulous Scotland-trained pathologist, observed structural changes in phthisis, which led him to believe, unlike his predecessors, that observed changes reflected variations in the speed and evolution of the pathologic process rather than different diseases (43,51). Of particular note is Benjamin Martin’s amazing book A New Theory of Consumption, More Especially of Phthisis or Consumption of the Lungs, written in 1719, 26 years after Leeuwenhoek’s opening of a new world of microscopical vistas. It was remarkable in its anticipation of the germ theory proposed and validated more than 100 years later. He believed that consumption was not only contagious, but that this infection was possibly due to “some certain Species of Animacula or wonderful minute living creatures that, by their peculiar shape or disagreeable parts are inimicable to our nature” (43,62). He goes on to suggest “the possibility of very minute animals being not only the original and essential cause of many distempers hitherto inexplicable; but that they are, perhaps, the very malignity so much complained of in many distempers but so little understood” (51,52,62). Marten also commented on the liklihood of tuberculosis contagion: “by habitual lying in the same bed with a consumptive patient, consistently eating and drinking with him or by frequently conversing so nearly as to draw in part of the breath he emits from the lung, consumption may be caught by a sound person. . . . I imagine that slightly conversing with consumptive patients is seldom or never sufficient to catch the disease.” (51,52,62). Marten predicted that his ideas would be scorned, and indeed they were for two centuries, until Villeman and Koch appeared. By the end of the eighteenth century, tuberculosis was rampant: early attempts at control had failed, the cause(s) was still speculative, and the treatments ineffective. Although the gross pathology had been described and the tubercles were believed to be associated with the disease, their origin was unknown, as was the relationship of their occurrence in different parts of the body.

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The observations and investigations of the next hundred years would establish the fact that the diverse clinical and pathological manifestations were indeed one disease, tuberculosis. They would revolutionize understanding of the cause, improve diagnostic accuracy, and lead to more rational attempts at therapy and control. The correlations of clinical symptoms and signs with specific pathology led to new interest in expanding techniques for eliciting physical signs of anatomical pathological changes. A. Percussion and Auscultation in Diagnosis

The use of percussion and of a new tool, the stethoscope, augmented information gained from symptoms alone, and this could be correlated with the history and pathological observations. Leopold Auenbrugger, an innkeeper’s son, had watched his father tapping wine casks to determine their full or empty state. He decided to apply the technique to his patients and to cadavers on which he experimented (43,51,52). Students of physical diagnosis today would be impressed with the scope of his work, as illustrated by his categorization of his observations in the book Inventum Novum ex Percussione Thoracis Humani, ut Sigmo Abstrusos Interni Pectoris Morvos Detegendi, published in 1761. It took another half century for medical clinicians to recognize the value of Auenbrugger’s approach to diagnosis. Only when Jean Nicholas Corvisart, Professor of Medicine at the College of France, discovered the work in 1797, translated and published the original text, and practiced the method did percussion begin to achieve acclaim (51). Laennec ( b. 1781) devised an indirect method of listening to the sounds generated in the chest. Direct auscultation and succussion, practiced by the ancient Greeks, was not practical in obese patients or women or when hospital vermin were common (39). He constructed a simple instrument to obviate these obstacles and first published his observations in 1819 in his Traite de l’Auscultation Mediate. The stethoscope was at first ridiculed as a mere mechanical toy, and critics considered it ludicrous that a “physician would proudly listen through a long tube applied to the patient’s thorax, as if the disease were a living being that could communicate its condition to the sense without” (39,63). Despite initial skepticism, auscultation and percussion remained the only methods of examination of the chest until Roentgen’s discovery of x-rays later in the century. Even with today’s more sophisticated tools, percussion and ausculation have not yet been discarded.

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B. Tuberculosis as One Disease

Bayle had dispelled some of the prevalent misconceptions in his Recherches sur la Phthisie Pulmonaire, published in 1810. On the basis of 900 autopsies—many of them on patients he had known at the bedside—he described phthisis on the basis of pathological injury rather than differences in symptoms or possible causes or complications. He described miliary and extrapulmonary lesions, but he was unable to recognize the etiological unity of his findings or to differentiate cases of bronchiectasis or lung abscess (43). His work attracted Laennec, and they were good friends until Bayle’s death in 1816 at the age of 42 (43). Laennec, in a second edition of his book in 1826, noted that “whatever be the form under which the tuberculous matter is developed, it presents, at first, the appearance of a grey semitransparent substance, which gradually becomes yellow, opaque and very dense. Afterwards it softens, and gradually acquires a fluidity nearly equal to that of pus: it being then expelled through the bronchi, cavities are left, vulgarly known by the name of ulcers of the lungs, but which I shall designate tuberculous excavations” (43,51). Although Stark and Bayle had imperfect glimpses of tuberculosis as possibly a single disease, Laennec noticed that tubercles found in various organs and in various varieties and stages of development seemed uniformly to characterize the disease. He traced its evolution from the tiny gray tubercle through successive eruptions and all its pathological manifestations, thus claiming for the first time the unity of the disease. Laennec’s accomplishments were not without their toll. His work was cut short, when he died from tuberculosis in 1826 at age 45 (43). The concept of the unity of tuberculosis which Laennec had so meticulously expounded was disputed until the bacteriological era confirmed it. Such eminent professors as Broussais and Virchow led the dissension. In the meantime, Johann Lukas Schonlein, Professor of Medicine in Zurich, embraced the idea of the tubercle being the fundamental anatomical lesion and suggested in 1839 that the word “tuberculosis” be used for all manifestations of phthisis (58,61). Clinical pathological studies continued throughout the nineteenth and into the twentieth century, with radiological correlations being added. The work of Parrot, Kuss, and Ghon (64) elucidated the characteristic changes of primary infection in children (and subsequently recognized at any age) and supported the theory that most tuberculosis is acquired by inhalation. The pathogenesis of generalized tuberculosis was demonstrated by Carl Weigert in 1882, and the mechanisms of such complications as laryngeal and intestinal tuberculosis, so common before chemotherapy, and of bronchogenic spread were also demonstrated (65). Ranke in 1917 attempted further clarification of the relationship of the primary complex and the later manifestations of tuberculosis. He proposed three stages of the disease and provoked much discussion about “endogenous” exacerbation ver-

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sus “exogenous” reinfection as the source of the third stage (43). In 1935 Opie summarized the then current views by noting that “there is no agreement concerning the relative frequency of endogenous and exogenous infection of adults” or whether or not first infection makes one more or less susceptible to a new infection (66). Discussion continues today as molecular techniques suggest that exogenous reinfection occurs more frequently than was previously believed (67–69), especially when prevalence in the community is high. C. Cause and Transmissibility in Animals and Humans

That tuberculosis is a specific infectious disease was not recognized until Jean Antoine Villeman’s astute observations. Working with military horses, he had observed that healthy young rural horses brought into crowded military depots often died of fulminating glanders (52,61). He also noted that military men stationed in barracks, not out in the field, and prisoners, industrial workers, and members of cloistered religious orders were more likely to have tuberculosis than the general population (52). Inocculation experiments had been performed by Kortum in 1789 and later by Cruveilhier, who considered tuberculosis not to be specific but to result from inoculation of a number of substances (39). In 1865 Villemin began his signal series of experiments. He inocculated products of the disease, such as sputum and gray and soft tubercles from the lung and other organs from humans to lower animals and from animal to animal and found that the disease developed in the inoculated animals (51,65). He concluded that tuberculosis is a specific disease the cause of which resides in an inoculable agent. He also went on to show that all forms of scrofula are really tuberculosis (70). Despite Villeman’s significant contribution, many in France and England continued to challenge it, claiming that he was just producing a foreign body reaction. His work, however, stimulated tuberculosis research elsewhere, especially in Italy and Germany, and by 1880 his conclusion was known and accepted (51,52). It was not until Robert Koch isolated the tubercle bacillus in 1882, however, that the unity and transmissibility of tuberculosis were finally confirmed. Experimenting within the new science of bacteriology, Koch developed a method of plate cultivation, which by permitting separation of colonies made possible isolation of individual strains (71). Koch demonstrated that the bacillus he had isolated inoculated into animals could reproduce the disease in them and that the organism could be recovered from those tissues and, when reinoculated into other animals, could again produce the disease (72). Koch’s postulates and his precise experiments to prove them have served as a model for infectious disease investigators ever since. Even though Koch’s demonstrations seem indisputable now, there were at the time still skeptics who clung to their preconceived notions or unproven hy-

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potheses. At Koch’s momentous presentation before the Physiological Society in Berlin, the audience looked to Virchow for comment. His silence was cutting. Virchow persisted to the end of his life in claiming that scrofula and pulmonary phthisis were not the same disease. He lectured that certain aspects of the disease in cattle known as “pearl disease” (so named because of the appearance of the lesions on the serous membranes) looked like lymphosarcomas. The peculiar distribution of these grape-like or potato-like lesions in the peritoneum or internal genitalia led to speculation that they must be related to nymphomania and satyriasis (65). Koch himself did not appreciate that there was a distinction between human and bovine tuberculosis. Between 1896 and 1898 Theobold Smith in the United States demonstrated that these were separate strains (73), but even as late as 1908 at the International Conference on Tuberculosis in Washington, D.C., there was still controversy over whether the disease in humans and that in cattle were caused by two different tubercle bacilli (65,74). Ravenel (75) of the United States, however, presented incontrovertible evidence that the bovine bacillus is responsible for most tuberculosis in cattle, a vital step in the subsequent eradication of tuberculosis from bovine herds and consequently preventing many cases of tuberculosis in humans as well. Proving which species of the organism was responsible for bovine tuberculosis took ingenuity. Because cattle can develop cavitary pulmonary lesions, the organism could be recovered from pulmonary secretions. Nocard, a French veterinarian, did this by grasping a cow’s tongue and swabbing the throat—when the cow coughed, he tried to catch the secretions. Ravenel more cleverly constructed a hood, which he put over the cow’s nose and mouth. At the bottom was a wooden platform upon which the cow’s coughed-up secretions would fall. He then collected and examined them for the tubercle bacillus (65). Although contagiousness of tuberculosis had long been suspected, considerable skepticism remained as to whether tubercle bacilli were the cause or merely a by-product of tuberculosis (76). Even those accepting the fact of its transmissibility did not agree about how the infection was transmitted. D. Modes of Transmission: Implications for Control

It was still hypothesized that tuberculosis might be transmitted through the ovum even after Koch’s announcement. Osler temporarily perpetuated the idea using silkworm infestation as an example, saying that even the silkworm egg can be invaded by a parasite, thus providing hereditary transmission. This notion was gradually eroded and finally discounted in Cornet’s statement that the tubercle bacillus would have to be straddling a spermatozoa as it enters the ovum, a situation thought to be too absurd to be believed (65). Theories of how tuberculosis might be transmitted helped to determine certain control measures (Fig. 1). Cornet, among others, was a proponent of the dust

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theory, namely that dust arising from expectorated sputum, which has dried and become pulverized, floats in the air and is inhaled (77). The belief that tuberculosis might also be transmitted by soiling hands or mouth helped to foster the idea that most tuberculosis started in childhood. That surfaces could be contaminated was demonstrated by strategically placing pans of water around to collect material emanating from the patient’s cough or by swabbing the floor. Inoculation of animals with such collected material produced tuberculosis (65). It was later confirmed that particles carrying M. tuberculosis can be transiently resuspended by an air current and become a possible reservoir for infectious respirable particles (78). This concept as a major mode of transmission was disputed by Flugge (77), who instead postulated that moist droplets produced by cough and sprayed into the air were the means. Considerable controversy prevailed during the 1880s and 1890s, but Cornet’s work was so persuasive that the environment was contaminated and the disease still so lethal that disinfection pervaded all of the early laws for tuberculosis prevention and control in the United States in the early 1890s and the first part of the twentieth century. Sulfur candles might be used, or, once a patient had died, the walls might be swept down with soft bread if they were whitewashed or papered or washed with carbolic acid or formalin solution if painted (65). It was not until the 1930s, extending into the 1960s, that the current understanding of transmission by droplet nuclei was demonstrated by Wells (79,80) and further elucidated by Richard Riley (81). Wells exposed animals to various concentrations of droplet particles and demonstrated that it is not the moist droplet particle that is the usual immediate means of transmission, but the particle that loses its content of moisture, leaving a single bacillus or small clump of bacilli to float freely in the air for considerable periods of time. Wells termed these lighter particles “droplet nuclei.” He noted that the heavier droplets, greater than several micrometers in diameter, generally fell to the floor and dried out and their organisms usually died off. Droplet nuclei produced by a single cough in Loudon’s and Robert’s experiments remained suspended in the air after 30 minutes (82). Such droplets could be readily inhaled and if they reached an alveolus could initiate primary infection (80,81). Riley and coworkers in Baltimore subsequently demonstrated how the dried nuclei may be airborne for some distances and still be capable of infecting animals (83). Such transmission was demonstrated in humans in the well-documented Figure 1. Antituberculosis campaign educational poster circa 1915. For some time transmission of tuberculosis was believed to be by fomites and dust particles. Disinfection was widely used until the work of Wells and Riley in the mid-twentieth century showed that airborne droplet nuclei were the means of transmission. (Courtesy of the American Lung Association, New York.)

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Navy submarine epidemic reported during the 1960s (84) and more recently in hospital outbreaks of multidrug-resistant tuberculosis (85). The work of Wells, Riley, and their colleagues, as reflected in a National Tuberculosis Association Committee Report in 1967 (86), has been crucial to the modern strategies of environmental tuberculosis control aimed at preventing infected droplet nuclei from entering the air, diluting their numbers by adequate number of air exchanges, preventing dissemination by maintaining negative pressure in the contaminated space relative to the adjoining areas, using devices to filter or “sterilize” the air leaving the room, and preventing persons entering the infectious patient’s room from inhaling infected particles by using particulate respirators (87–89).

E. Evolution of Public Health Campaign

Other events important to the history of tuberculosis were occurring during the nineteenth century. The first international medical congress, held in 1867 in Paris, included presentations on tuberculosis, including Villeman’s work. Subsequent international congresses devoted specifically to tuberculosis were held regularly until the end of the century and still meet periodically even today. Toward the end of the nineteenth century, national organizations composed of medical, lay, and government persons evolved to combat tuberculosis in Austria, Denmark, and France, with other countries in Europe and Canada rapidly joining the movement (43). Lawrence Flick in Philadelphia in 1892 organized the first voluntary society in the United States to combat a specific disease, the Pennsylvania Society for Prevention of Tuberculosis (90). He wanted to disseminate the idea of the communicability of tuberculosis and to stop its spread using education, legislation, research, and better patient care. Other voluntary associations began to arise and competed for the honor of representing the United States at the International Tuberculosis Congress in Paris in 1904. Adolphus Knopf urged the organization of a strong national scientific and popular organization against the disease. The National Association for the Study and Prevention of Tuberculosis, later called the National Tuberculosis Association and now known as the American Lung Association, was thus born in 1904 (90,91). By 1914, with the collaboration of its many grass-root affiliates, it had become a powerful force in the crusade against the disease (90). Through the innovative idea of a Danish postal worker, Einar Holboell, and the philanthropic efforts of Emily Bissell, a Delaware Red Cross volunteer, the sale of Christmas seals provided remarkable financial support for an expanding antituberculosis campaign (92). In 1902 an International Central Bureau for the campaign against tuberculosis under the emblem of the double-barred cross was established, with an office in Berlin and then Geneva. After World War I, it became the International Union

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Against Tuberculosis, now the International Union Against Tuberculosis and Lung Disease (IUATLD) (43). The antituberculosis campaign extended to other parts of the industrializing world: Asia, Africa, the Near East, and Latin America. In 1898 in Japan, Goto Shinpei petitioned the government to establish an office of sanitary police. Attention to epidemic control and water supplies would keep the population healthy and benefit Japanese imperialism (42). In China the YMCA organized city-wide health campaigns between 1915 and 1921, enlisting the cooperation of city officials, educators, churches, newspapermen, students, boy scouts, and the Chamber of Commerce, but tuberculosis was a low priority of the government despite the dismal statistics available in the early twentieth century. It was 1933 before the Chinese Medical Association held its first tuberculosis conference and an antituberculosis association was formed in Shanghai (42). In Korea the first tuberculosis sanatorium opened in 1928, the School of Hygiene was organized, and in 1932 the sanatorium became the seat of the new Korean Christmas Seal organization. Some historians feel that the campaign against tuberculosis has been driven primarily by “the need to protect the investment and profits of the owning class” (93). When labor was initially unskilled, cheap, and easily replaceable, employers had little concern for the health of individual workers. Only as the labor pool shrank and increased skills were required did employers realize the financial importance of not losing employees. Such motives may have hastened the institution of preventive measures in South Africa in the early twentieth century as the alarming rates of pneumococcal disease and tuberculosis in mine workers became known (94). The other catalyst in the campaign was the recognition by physicians that untreated, unsupervised poor people were a threat not only to themselves but to the larger public’s health as they came in contact with middle and upper class persons as their servants, repairmen, or in other capacities. During the recent resurgence of tuberculosis in New York City this threat resurfaced, caught the media’s attention and thus the public’s, and undoubtedly stimulated the rapid action of legislators and public health departments even beyond the United States. The time was also ripe for social activism. The belief in the importance of constitutional and hereditary factors in tuberculosis persisted throughout the nineteenth and even the twentieth century in North America and England, despite Koch’s isolation of the infectious agent. Toward the end of the nineteenth century vulnerability to tuberculosis was linked to immorality and lower social class. Adolphus Knopf in his 1907 prize-winning essay, “Tuberculosis as a Disease of the Masses and How to Combat It” (95), identified those most susceptible as the unfortunate poor, the ignorant or depraved, or the alcoholic. As large numbers of people moved from rural to urban areas and immigants flooded the larger cities, greedy landlords offered the worst of housing conditions: dark cramped quarters with inadequate water, sewage, or ventilation (Fig. 2).

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Figure 2. Tenement visit by visiting nurse in 1924. The nurse/social worker was an essential link in the antituberculosis campaign, educating families about tuberculosis, expectoration, disinfectation, importance of ventilation, good hygiene, and nutrition. She was a liaison between the community, medical facilities, and the health department, identifying those at risk or ill, referring to appropriate medical facilities, and monitoring their subsequent follow-up. The poverty and inadequate housing reflected here, believed to contribute to prevalence of the disease, are still with us. (Photograph Courtesy of the Bellevue Hospital Chest Service Archives, New York.)

Death rates from tuberculosis in the 1890s soared to more than 776 per 100,000 (93) in some districts. Xenophobia augmented the difficulties of controlling the disease. Many Americans feared being overwhelmed by aliens with different cultures and beliefs. New waves of immigrants and refugees in the latter part of the twentieth century stimulated similar sentiments in some areas, and many immigrants do not seek health care for sociocultural, economic, or other reasons, including fear of the consequences if they are undocumented (96,97). As Koch had predicted at the conclusion of his scholarly thesis in 1882, “when the conviction that tuberculosis is an exquisite infectious disease has become firmly established among physicians, the question of an adequate campaign

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against tuberculosis will certainly come under discussion, and it will develop by itself” (72). He was correct in predicting that such a campaign would evolve. In Edinburgh Sir Robert W. Phillip was a prime mover in establishing an organized system for the control of tuberculosis. In 1887, just 5 years after Koch’s announcement, Phillip opened the first tuberculosis dispensary in the world. It became the nucleus of the Edinburgh Anti-tuberculosis Scheme (37,43). Phillip’s dispensary was unique in its organization not only for the treatment of tuberculosis, but also in its prevention, case finding, record filing, sputum examinations, home visits by physicians, and specially trained nurses. Social service in the home, classification, triage, and aftercare of discharged patients was practiced, and education was freely dispensed (98). In the United States, Canada, and Germany the sanatorium movement preceded any generally organized antituberculosis effort (98). Phillip’s pioneering efforts led to the development of city chest clinics throughout the world, often integrating case finding and referral within a sanatorium or hospital system in collaboration with developing municipal antituberculosis structures (99,100) (Fig. 3). In the United States state health departments began to broaden their mandates from primarily sanitary water supplies, safe sewage, and garbage disposal to the control of transmissible diseases. Public health physicians began to replace sanitary engineers. In 1888 Commissioner of Health in New York City, Joseph D. Bryant, asked a group of consultants, including Herman Biggs, an 1883 graduate of the Bellevue Medical College, to issue a position paper on tuberculosis for the Board. The document asserted the validity of Koch’s findings and recommended the inspection of cattle to prevent consumption of infected meat and milk, public education regarding the dangers of pulmonary discharges from tuberculous individuals, and disinfection of rooms occupied or previously occupied by tubercular individuals. Since the report was not embraced by most of the medical community, a political campaign to educate the public was launched, with flyers distributed in several languages (93). By 1893 the Board of Health requested updated recommendations and accepted the first six of the following measures recommended by Biggs (101): 1. Educate the public via circulars and publications. 2. Require public institutions to notify the Department within 7 days of all persons suffering from pulmonary tuberculosis. 3. Appoint inspectors to ensure effective disinfection of contaminated premises. 4. In hospitals, separate tuberculosis patients from other patients. 5. Establish a hospital exclusively for tuberculosis patients. 6. Require the Board of Health to do diagnostic bacteriological sputum examination in every case of pulmonary disease of doubtful character, at the physician’s request.

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Figure 3. Tuberculosis clinic, Bellevue Hospital, early 1900s. The dispensary or TB clinic became an increasingly integral part of the tuberculosis-control effort. Because case rates were not declining as rapidly as mortality, more attention was directed to earlier identification of cases and prevention of transmission. The dispensary served as a diagnostic and triage center and provided social services, case management, and follow-up after hospital or sanatorium care in cooperation with the health department. James Alexander Miller established in New York this model organization, similar to that initiated by Dr. Phillip of Edinburg in 1888. Note the “No Spitting on the Floor” sign on the wall. (Photograph Courtesy of the Bellevue Hospital Chest Service Archives, New York.)

7. Insist that all physicians practicing in New York City notify the Board of all patients with pulmonary tuberculosis coming under their care. Just as in Naples in the 1700s, physicians resisted the “punitive” reporting laws. Physicians in New York and as far away as Philadelphia fought this suggestion on the basis that it would stigmatize such patients and make them outcasts of society and physicians would lose both medical control and a source of their income. Gradual enforcement of compulsory notification finally succeeded because of the political astuteness and sensitivity of the Board of Health and its advisors.

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Between 1898 and 1910 the numbers of reported cases increased from 8,559 to 32,065 and sputum examinations from 1,920 to 40,000 (93). In Britain, although Sir Robert Phillip advocated compulsory notification as early as 1890, 20 more years elapsed before it was finally enacted into law (43). In 1901 Robert Koch commended Biggs for the willingness of the American people to accept the limitation of their liberties in the interest of public health, and he recommended the New York model for the “study and imitation of all municipal sanitary authorities” (102). Biggs, writing on administrative measures for the control of tuberculosis in New York City, noted that Edinburgh and New York had more comprehensive plans than any other cities, and he gave great credit to Sir Robert Phillip for his innovative initiative in addressing tuberculosis control (98). The New York City Health Department became a model in the United States in the 1890s. A century later, in the recent upsurge of the disease, it again reacted aggressively to squelch the epidemic and serve as a resource for others, including a delegation from the World Health Organization, in anticipation of similar increases in cases and problems with drug resistance in other parts of the world. The reasons for the upsurge even in developed countries are multiple (12,55,56, 96,97,103,104), but complacency and diversion of resources to other priorities contributed (27,56,103,104). The sudden need to relearn and reinstitute the lessons of the past has been painful and costly. The importance of continuous monitoring of control strategies and provision of adequate resources to implement necessary measures has been illustrated repeatedly by the necessity for task forces and conferences to address the continuing problem of control (37,56,105,106). F. Treatment and Control: The Sanatorium Era from the Mid-1800s to the Mid-1900s

The increasing emphasis on fresh air, diet, rest, and exercise as a means of preventing miasmas, the rise of the Public Health Movement stimulated by the atrocious sanitary conditions related to increasing urbanization, and the socioeconomic effects of the Industrial Revolution all intertwined with the development of the sanatorium era of treatment beginning around the mid-1800s and reaching its prime during the first half of the twentieth century (107). Diseased people may have been segregated in ancient times, but the “modern” sanatorium movement began slowly with the efforts of a few widely separated pioneers, then spread at an accelerating pace throughout the world. The originator of the movement was George Bodington, a Warwickshire physician, who in 1840 rebelled against the popular “antiphlogistic” therapy and advocated fresh air, sensible diet, and gradually increasing exercise. He felt that a structured program under close supervision was superior to the benefits of just go-

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ing to a boarding house for the climate or change of scene. He instituted such a program in a house near his own (43). The Brompton Hospital in London in 1841 and the Channing Home in Boston in 1857 (43,108) took in consumptive patients out of humane concern, but it was Hermann Brehmer, his ex-patient Peter Dettweiler, and then Otto Walther who led the “more therapeutic” European sanatorium movement, which spread to the riverside and coastal areas of Great Britain, to the mountains of Switzerland, and after 1882 to America and other continents as well. Brehmer was aware of Rokitansky’s finding that 90% of those who died from other causes had healed tuberculous lesions within normal lung tissue, and he was curious about the reasons for such spontaneous cures. He thought that the pulmonary disease was due to deficient circulation of the blood to the lung, as manifested by the disproportion between the size of the phthisic lung and the small heart and aorta, and he strongly believed that tuberculosis was curable with exercise at high altitude and abundant food to stimulate the circulation and metabolism. Having experienced good results in his own case by application of his theory, by 1859 he managed to build a 40-room Kurhaus with entertainment rooms and a kitchen in Gobersdorf, a mountain valley 1715 feet above sea level in Silesia. By 1869 he had treated 958 patients (109). The later recognition that tuberculosis was infectious almost closed this first real sanatorium as patients were reluctant to congregate in an institution where they would be continuously exposed, but Brehmer developed a successful disinfection system to allay their fears. In addition he added chemistry and bacteriology laboratories and an observatory to monitor the meteorological conditions believed so important to the patients. The sanatorium flourished. By the time of Brehmer’s death in 1899 there were more than 300 sanatoria in Germany alone (110). In 1904 it was the largest in the world, able to accommodate about 300 patients (112). Brehmer’s ex-patient and assistant, Peter Dettweiler, later established his own sanatorium in Falkenstein, which became a mecca for visitors interested in sanatorium treatment. He advocated much closer medical supervision, patient education, rest with graduated exercise only as tolerated without fatigue, and openair treatment in all seasons. He introduced the reclining chair (Liegekur), which subsequently became a hallmark of “taking the cure,” and invented an “ingenious little cuspidor” to prevent spread of the disease. It was made of blue glass and could be hidden in the folds of a handkerchief and manipulated with one hand (111). Walther similarly opened a successful sanatorium in the Black Forest at Nordrach. His strict discipline and therapeutic regimen became popular in Britain and a prototype for many sanatoria that included Nordrach in their name (113). Carl Spengler’s establishment of a sanatorium in Davos (114) initiated a multiplicity of institutions—including Rollier’s for heliotherapy—hotels, and

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boarding houses, which transformed Switzerland into a major health resort and inspired Thomas Mann’s novel The Magic Mountain (107). In the United States the perception of beneficial effects of altitude and climate were evident in the mid- to late 1800s, but it was Edward L. Trudeau who led the American sanatorium movement with the establishment of the Adirondack Cottage Sanitarium in 1885 near the village of Saranac Lake, New York. Having tirelessly cared for his brother during his rapidly fatal tuberculosis, Trudeau himself developed a cold abscess during medical school, but the true nature of his illness was recognized only shortly after he entered practice in New York City. The diagnosis was essentially a death sentence to him. As his health deteriorated, friends urged him to go to the mountains. He reluctantly left his wife and two young children for an exhausting trip to Paul Smith’s hunting lodge in the Adirondack Mountains. He wrote that “the change, the stimulus of renewed hope, and the constant open air life had a wonderful effect on my health” (115). The value of rest in the treatment of tuberculosis was not yet appreciated in the United States, but Trudeau noticed that his health improved as he was reclining on balsam boughs and blankets much of the day while he was being rowed by a guide from place to place on one of the beautiful Saranac lakes looking for fish or wildlife. When Trudeau first went to the Adirondacks in 1873, tuberculosis was still considered largely hereditary. Only the seriously symptomatic wealthy had access to climatic treatment. Trudeau’s awareness of the European sanatoriums and his own personal experience stimulated him, with the financial help of his influential friends and donations from devoted guides, to purchase some land and begin construction of first one and then a number of cottages in order to test the principles of a structured supervised regimen. A cottage system would permit expansion as monies became available, and after Koch’s work became known separate cottages seemed plausible as a strategy to minimize transmission. When Trudeau first obtained an English translation of Koch’s remarkable findings, he was inspired to set up his own little laboratory in a room of his house to study the tubercle bacillus and other aspects of the disease. With the guidance of Koch’s paper, a few lessons from Dr. Prudden in New York, and his own ingenuity, Trudeau managed to grow the tubercle bacillus despite the inclemently cold Saranac nights (107). He was only the second person in America to grow pure cultures, and throughout his life he supplied cultures without charge to other scientists (115). He repeated Koch’s experiments and was then able to test for the bacillus in patient’s secretions and perform his own experiments to determine factors related to progression of the disease and the effects of different treatments. Trudeau spent parts of almost every day in the laboratory, hoping to find some “magic bullet” against tuberculosis. The Saranac laboratory was the first in the United States devoted to original investigations into tuberculosis. When the sanatorium finally closed almost 40 years after Trudeau’s death from tuberculosis, the new Trudeau Institute for Re-

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search was created in 1964 with financial help from the sale of the property, the fund-raising efforts of his only remaining son, Francis P. Trudeau, and his grandson, Francis B. Trudeau, Jr., and many devoted friends. Its contributions to the understanding of immunology and the interaction of dust diseases and tuberculosis and more recently the immune system in relation to other infectious diseases and cancer have extended far beyond the little village of Saranac Lake (107). Trudeau’s sanatorium treatment gained momentum only slowly, but when he reported the results of his first 165 patients at the opening of the Henry Phipps Institute in Philadelphia in 1903 (116) and noted that he had succeeded in educating the public as to the safety and value of sanatorium treatment (“phthisiophobia” was prevalent in some communities) (117), his influence began to spread. He participated in the medical and public health activities going on and evolving around him in 1904, became the first president of the newly organized National Association for the Study and Prevention of Tuberculosis (now the American Lung Association), and later president of the Congress of American Physicians and Surgeons (107). His protegés included Dr. Edward Baldwin, who was awarded the Trudeau Medal (the highest award of the National Tuberculosis Association) in 1927 for his research into immunological mechanisms; Dr. Lawrason Brown, who devised a system that set standards so that different centers could compare success rates and who founded the Journal of Outdoor Life in 1903 to disseminate information about the prevention and cure of tuberculosis to those seeking health through an outdoor life; Allen K. Krausse, a pathologist who went to Johns Hopkins as the first full-time teacher in the field of tuberculosis and subsequently was the first managing editor of the American Review of Tuberculosis (now the American Journal of Respiratory and Critical Care Medicine), first published in 1917 for promotion of clinical investigation, laboratory research, and discussion of scientific and philosophical issues; Esmond R. Long, a pathologist who later headed the Henry Phipps Institute in Philadelphia and contributed in collaboration with Florence Siebert to the additional understanding of immunological aspects of tuberculin; and James Alexander Miller, founder of the prestigious Bellevue Hospital Tuberculosis Service in New York City (now the Chest Service) (107). Trudeau’s epitaph—Guerir quelquefois, soulanger souvent, consoler toujours—is not only a tribute to the man, but exemplifies the caring spirit of Trudeau’s treatment center. From its simple beginning, it developed into a “tuberculosis university” (118), which included not only the Saranac laboratory for the study of tuberculosis, but a nurses’s training school, which opened in 1912 for ex-patient nursing students, and the internationally renowned Trudeau School for Tuberculosis, established in 1916 to provide postgraduate education in tuberculosis (107). Sanatoria proliferated throughout the United States and Canada. By 1904 there were 115 sanatoria in the United States with less than 8000 beds for tuber-

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culosis. By 1923 there were 656 such facilities with 66,000 beds, about half being under state, county, or municipal auspices (119). The number of institutions and beds continued to increase steadily, despite declining mortality (with morbidity only slowly following suit), so that by 1953 there were 839 facilities in the United States and its territories with 130,322 beds set aside for tuberculosis patients. Federal hospital and mental institutions as well as state penal institutions accounted for some of these (120). As sanatoria sprouted around the world, so did controversies about the components of good sanatorium treatment, the benefits of treatment in a sanatorium versus alternative care at home, and finally whether the era of sanatorium care contributed positively or negatively to overall progress against the recalcitrant disease tuberculosis (107). The structured, sheltered environment provided by sanatoria represented to some patients a haven from the stigma and realities of their previous situations. It provided a structure for education and psychological support. To others, it represented a time of imprisonment, isolation, and diversion from their responsibilities and achievement of their ambitions. The sanatorium system enabled physicians to observe closely the effects of tuberculosis at different stages and with different manifestations in vast numbers of demographically diverse individuals. During this era the natural history of the disease, its pathogenesis, and its pathology were further elucidated. The closed environment permitted a valuable reference base and population for the study of emerging diagnostic and therapeutic technologies. From the public health standpoint, the effect of sequestering thousands of infectious persons for several months to whole lifetimes is still uncertain. Mortality had already been declining (37,121,122), and improved living conditions, nutrition, and economics may have played a role (121,122). The lagging decline in new case rates, however, despite growing availability of sanatorium beds and declining mortality, implies that isolation was not sufficient to eradicate the disease (53). Alternatives to sanatorium care during this period were often innovative and ranged from tents on tenement roof tops (Fig. 4), or window tents within a room, to old streetcars and even ferry boats (Fig. 5). Provisions for children included a unique foster care system in France (123) and preventoria in the United States [the first opened in 1909 and became the only one in the country to have cribs for the isolation of infants from tuberculous parents (124)]. Special camps and fresh air schools were organized for children with tuberculosis believed to be at risk because of anemia and malnutrition. Although the prevalence of tuberculosis was particularly devastating to blacks and American Indians, it was not until the 1930s that the enormity of the problem was recognized by the Tuberculosis Movement in America and facilities became more available to such patients (90,124).

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Figure 4. Roof-top “cure” of tuberculosis, an alternative to sanatorium care. Beginning in the mid-1800s, before effective chemotherapy for tuberculosis, a structured, often strict regimen of fresh air, rest with specifically prescribed exercise, and abundant nourishment were the sole mainstays of treatment until adjunctive collapse therapies were introduced in the early twentieth century. (Photograph circa 1920. Courtesy of the Bellevue Hospital Chest Service Archives, New York.)

Initial enthusiasm during the period of sanatoria was supplanted by reality as statistics began to be examined around 1914–1920. Among nine sanatoria from which statistics were available for periods of up to 15 years, 51% of the discharged patients were dead at 5 years (125). Early data from Saranac Lake indicated that among those discharged as “cured” the death rate was still triple that of the general population (90,110). Relapse and reentry rates to sanatoria were as high as 50% in some cases (126), but not all (127,128). These discouraging results caused more attention to be paid to after-care and rehabilitation (129) (Fig. 6). Some sanatoria provided opportunities for learning new skills or for regaining lost ones, and abroad, model colonies were developed

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where patients could live and work with supervision and encouragement (130). In the United States state vocational rehabilitation services increased 176% between 1936 and 1940 (131). Clinic practice was surveyed and standards recommended (99). More organized efforts at case finding, isolation of active cases, and emphasis on follow-up were initiated, and collapse therapies and surgical procedures were added to sanatorium regimens in the 1920s and 1930s. Mortality, which had steadily declined in Western Europe and the United States during the nineteenth century, decreased even further (37,122).

Figure 5. Children receiving eggs and milk on Southfield ferry boat in New York City. Children at risk of tuberculosis because of poor nutrition, living in crowded tenements, or household exposure to tuberculosis often received nutritional supplements and attended fresh air schools, or day camps. Children might be sent to “preventoria,” or in France they were placed in foster care in the countryside to remove them from exposure and to improve their resistance. (Photograph 1909, Courtesy of Bellevue Hospital Chest Service Archives, New York.)

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Figure 6. Men enjoying occupational therapy or vocational rehabilitation. These activities, an integral part of improving compliance and better treatment outcomes before chemotherapy, helped break the monotony of “the cure,” which often lasted for months or even years. Retraining for physically less demanding work or providing work in a medically supervised sheltered environment might reduce relapses. Also, unfortunately, even after effective drugs many patients were left with crippling respiratory insufficiency from the extensive lung damage already sustained or from the collapse therapy and its sequellae. (Photograph circa 1930, Courtesy of the Bellevue Hospital Chest Service Archives, New York.)

G. Developments in Diagnosis: Laboratory Tests and X-Rays

After the causative agent of tuberculosis was known, more precise diagnosis was an early interest. Prudden and Trudeau applied examination of the sputum to clinical problems before the turn of the century, but Grancher and Gerhardt in 1890 each cautioned about the late appearance of the bacilli in the sputum in comparison to the physical signs (132). Relevant even today in the AIDS era is Riviere’s comment: “Disastrous is it to wait for the advent of tubercle bacilli to establish a diagnosis; still more disastrous to regard a negative sputum examination as evi-

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dence that the patients’ disease is not tuberculous.” Riviere advocated repeated deep cough specimens (132). Other mycobacteria were known to exist before 1900, and with continuing advances in microbiological and molecular techniques and clinical experience it is now known that some are pathogenic and others not and that tuberculosis disease can be caused by M. tuberculosis complex, which presently includes not only M. tuberculosis and M. bovis, but also M. microti and M. africanum. By the early 1900s culture techniques and biochemical tests began to permit separation of these mycobacterial species by their growth rate, colonial and microscopic morphology, biochemical characteristics and behavior in experimental animals (73,75,133). By the 1940s and 1950s nontuberculous mycobacteria were being increasingly identified around the world (134). Rosenberger in 1908 was the first to describe acid-fast rods in blood, but their significance was disputed because animal tests did not confirm their pathogenicity. Riviere wrote: “So far as the early diagnosis of tubercle is concerned, the detection of bacilli in the blood offers as yet no practical assistance; we await with interest the appearance of further developments in this direction” (132). Riviere’s conclusion is of interest in view of the current availability of the peripheral blood-based PCR assay (135) and recovery of mycobacteria from blood with the use of the isolator tube (Wampole) (136). Experiments with other diagnostic tests such as the tuberculo-opsonic index initiated by Wright in 1905 and complement fixation methods in the early 1900s were abandoned. Throughout the twentieth century other immunological assays using various antigens from the tubercle bacillus were attempted (137,138). The recent upsurge of tuberculosis begining in the late 1980s has hastened the development of modifications and innovative culture techniques to improve the rapidity of diagnosis and detection of resistant organisms, such as the Bactec system, the Septi-chek AFB (BBL), and the Mycobacteria Growth Indicator Tube (MGIT,BBL), which are described elsewhere (136). Most exciting and promising, however, has been the recent application of nucleic acid probes to the earlier identification of mycobacterial species (139,140), and DNA fingerprinting, which has helped to identify clusters of disease and outbreak patterns and aided in the understanding of transmission and spread of resistant organisms in the community (21,68) and laboratory cross-contamination (141). Their usefulness and validity in the management of patients, however, is still being debated and evaluated (141–143). New technologies such as fiberoptic bronchoscopy and bronchoalveolar lavage have, in the last quarter of the twentieth century, enhanced diagnosis and improved understanding of pathogenesis and host immunological responses at different stages of tuberculosis (143a). They are discussed elsewhere. Even after Koch’s discovery, detection of disease continued to depend primarily on symptoms or physical findings and only seldom on radiographic tech-

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niques. When Konrad Roentgen discovered x-rays in 1895, their value in diagnosis was, like many previous innovations, received with caution or ridicule. A London firm allegedly advertised the sale of x-ray–proof underclothing (43). The use of x-rays in the diagnosis and management of tuberculosis was apparently ignored except for a brief note in 1896 in Lancet (43). In Boston, Francis H. Williams, without knowledge of their physical findings, performed fluoroscopic examinations on more than 100 patients with pulmonary tuberculosis and reported correspondence between physical signs and xray examination in a considerable number, but in some the disease was more extensive than the physical examination indicated. In others, x-ray detected increased density before it could be discerned clinically (43). Valuable investigations were also going on in France and Britain. The Trudeau and Loomis Sanatoria were the first in the United States to apply this technique routinely (43). Even in the 1930s some senior and influential physicians, for fear of jeopardizing their reputations, which had been built on their physical diagnostic prowess, were reluctant to admit the value of the tool. By the 1930s x-ray examination of patients with pulmonary tuberculosis was routine, and in the middle of the twentieth century mass x-ray screening became a major thrust in the control of tuberculosis (Fig. 7). Agreement on the meaning of findings discovered on x-ray was certainly not uniform, just as it is not today. Additional pathological investigations were necessary to clarify the pathogenesis of the disease and facilitate roentgenological interpretation. Around the 1920s there was interest in the “early pulmonary infiltrate,” frequently recognized by roentgenological examination in adults who presented with tuberculosis but with few or no symptoms or typical apical “crackles” (65). Worldwide interest in the significance of this early infitrate stimulated many investigations through the 1940s. Medlar (144) and other eminent pathologists studied postmortem material from accident victims and those dying unexpectedly of unknown causes. The early lesions were shown to be small areas of exudative bronchopneumonic tuberculosis. They were typically found in the upper posterior part of the lung near the pleural surface. By the time they were visible radiologically, they were usually necrotic at the center, and with repeated culturing of gastric contents they were found frequently to be discharging tubercle bacilli. Communication with a small bronchus was usually demonstrated, but discharge of tubercle bacilli could be intermittent if the bronchiole became plugged with the semisolid caseous material. Hope of discovering this early infiltrate in order to detect the disease at its earliest stages to prevent spread prompted the mass x-ray surveys so popular in the mid–twentieth century (65). Even when x-ray screening was abandoned in the 1970s as case rates dropped, radiological examination of patients admitted to hospitals or clinics or doctors’ offices was considered productive (145). Developments in computed tomography and magnetic resonance imaging and the use of contrast material and nuclear medicine techniques have improved differential diagnosis and detection and helped guide management. With the re-

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Figure 7. Mass x-ray screening mid-twentieth century. Once x-ray was accepted as a valuable diagnostic tool and more was learned about pathogenesis of tuberculosis from clinical, pathological, and radiological studies, mass screening was instituted in the 1940s in hope of detecting and treating cases earlier but was later abandoned as the drop in new cases made it less cost-effective. In many developing countries such surveys were not feasible. In such cases sputum smear has been used to detect disease, and when possible tuberculin testing has been used to detect distribution and prevalence of infection and to identify candidates for BCG vaccination. (Photograph Courtesy of the American Lung Association, New York.)

cent changes in the epidemiology of tuberculosis, the prevalence of impaired immune response, and more widespread mycobacterial drug resistance, the role of radiological tools has expanded rather than diminished. H. Adjunctive Therapies: Collapse Procedures and Surgical Resection

Better understanding of the pathology of tuberculosis and the ability through Roentgen’s discovery to see cavities during life spurred interest in mechanical methods of treating tuberculosis. Traction on the walls of cavities from elastic re-

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coil augmented with respiration, and reduced blood and lymph flow to the upper zones from upright posture were thought to impair healing. The idea of collapsing the lung to “rest” the lung and promote healing was first suggested by Edmund Bourru in Paris as early as 1770. The history of collapse therapy has been described elsewhere (43,146,147). Carlo Forlanini of Pavia in 1894 was the first to induce pneumothorax successfully through the chest wall. John B. Murphy in Chicago independently applied pneumothorax in tuberculosis in 1897; he was the first to do it under x-ray control (146,147). Trudeau was treated with therapeutic pneumothorax before he died in 1915 (107). It became a major adjunct to bedrest during the latter part of the sanatorium era, sometimes used in conjunction with other surgical procedures (148). Hans Christian Jacobeus’s invention of the thorascope in 1911 and his thorascopic cauterization of adhesions (intrapleural pneumonolysis), which often prevented effective collapse, enhanced the usefulness of therapeutic pneumothorax (149). Experience after 1912 and particularly in the 1920s and 1930s indicated that artificial pneumothorax was effective in about one third of patients in whom it was attempted (150–152) and was best in patients with unilateral disease not responding to rest alone, although there were heated debates about the indications. Complications included mild serofibrinous pleurisy in about 80–90% of patients, chronic pleural changes leading to “trapped lung” in some, empyema occasionally, bronchopleural fistula rarely, and air embolism very rarely (152). Other procedures to aid cavity closure included avulsion or crushing of the phrenic nerve to induce hemidiaphragmatic paralysis. Pneumoperitoneum was occasionally used in intestinal and peritoneal tuberculosis, and in 1933 Vadja reported possible benefit in patients with pulmonary tuberculosis. About 50% of patients showed radiological cavity closure, and sputum conversion occurred in slightly fewer. It was used in patients with bilateral, far-advanced cavitary disease to elevate the diaphragm (107). Thoracic surgery began to flourish during this period. In Europe during the 1880s ribs were removed to bring the chest wall down to the lung. Estandler first used the term “thoracoplasty” in 1879, and de Cerenville in 1885 first applied the procedure to collapse a tuberculous cavity. John Alexander refined the technique and wrote the first of his famous textbooks at Trudeau’s sanatorium while curing his own vertebral tuberculosis (148,153). A number of variations on the procedure subsequently were developed, and collapse of the lung was occasionally achieved by introduction of oil, paraffin, or plastic spheres into an extraperiosteal pocket (plombage thoracoplasy) in an attempt to minimize deformity and pulmonary function impairment. Thoracoplasy could achieve cavity closure and sputum conversion in as many as 80% of selected patients. With collapse therapy mortality rates ranged from 14 to 27% after 1–20 years, but without collapse therapy patients with cavitary disease had an average survival time of less than 2 years. On the other hand, such therapy sometimes led to longer

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sanatorium stays, serious impairment of pulmonary function, and increased mortality (107). Resection of diseased lung was first performed by Block in 1883 with fatal consequences (148). Even though Tuffier in 1891 successfully resected an apical tuberculous nodule, resection was considered so dangerous that it was not until 1934 that the first lobectomy and pneumonectomy were accomplished successfully for tuberculosis. However, before effective drugs against the disease and the technological developments that have markedly improved surgical outcomes, spread of disease, fistula formation, and empyema were common. In 1943 morbidity from such procedures was 50% or more and mortality 20–40% (153). In the 1950s with chemotherapy, resection for localized disease was rather common until the results of drug therapy proved it to be unnecessary in most cases. However, in selected multidrug-resistant patients resection is still occasionally performed. I. Tuberculin as Therapy, Method of Detection of Infection and Window to Understanding Immunity and Host Defenses

Koch followed many leads from the immunological studies of Jenner and Pasteur before him. He observed in guinea pigs that prior experience with tubercle bacilli, living or dead, altered the animal’s response to the new innoculation of tubercle bacilli and allowed the animal to survive. Much of what has become the science of cellular immunology has derived from Koch’s work (71,154). Koch later prepared a sterile filtrate of cultured organisms, subsequently termed “old tuberculin” (OT), and found that the same “Koch phenomenon” occurred. Koch’s great mistake was that he prematurely reported the use of this preparation as a remedy. It became widely used until it was soon recognized that it killed more patients than it helped (154,155). Koch’s observation of the delayed reaction to this material, however, spawned the term “delayed hypersensitivity,” and his observations of the difference in the effects of OT in patients infected with the tubercle bacillus versus noninfected patients formed the basis for the use of tuberculin as a diagnostic agent (156). Veterinarians were the first to recognize and demonstrate the potential diagnostic use of tuberculin. Tuberculosis was common in cattle, but symptoms, physical examination, and recovery of tubercle bacilli usually detected advanced disease. Professor Eber of Berlin and Leonard Pearson, an American who had worked in Koch’s laboratory in 1890, tested tuberculin in cattle as early as 1891 (157,158). It became evident early from clinical pathological correlations that the test could identify clinically inapparent infections. To control the spread of disease to other cattle and to humans, tuberculin-positive animals were slaughtered in large numbers (17,18). In the United States in 1917 the economic loss to the cattle industry and the serious threat of bovine tuberculosis to the public’s health prompted establishment of a national program to eliminate tuberculosis in cattle.

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The positive tuberculin reaction rate in cattle approached 5% in 1918. Systematic testing was instituted, along with prompt disposal of infected cattle, adequate disinfection, and regulations governing movement of animals. Pasturization of milk assured further protection for humans (17,36,37). By 1974 tuberculin reactor rates were 0–0.03% in the United States (18). Various control measures have been used in other countries, where infection rates have been as high as 70–90%, with 30–40% having disease on slaughter (18). Eradication of bovine tuberculosis worldwide requires continued vigilence, public and legislative support, and adequate availability of veterinarians. Von Pirquet first demonstrated that reactions to OT in humans could be induced by cutaneous injection and that a response was indicative of prior tuberculous infection (156). His observations were published in 1907 and 1908. In the early 1900s a patch test, percutaneous test, conjunctival test, and subcutaneous test had been tried, but the intracutaneous test of Charles Mantoux introduced in 1908 persisted as the preferred method because the dose could be most precisely controlled and the reaction, measured in millimeters of induration, could be more readily quantitated (158). Tuberculin is still used as a major method of detecting tuberculosis infection, but experience during much of this century has prompted a variety of changes in its preparation, its method of administration, and its interpretation. As testing was extended beyond herds suspected of the disease, doubts began to occur regarding the specificity of the test because some cattle reacted to tuberculin but had no signs of tuberculosis infection at post-mortem examination. Although variations in administering or reading the test or overlooking a small lesion might have accounted for the reactions, E. G. Hastings believed by 1924 that sensitization by some other organism or organisms was the cause of these false-positive reactions (158). By the mid-1920s nontuberculous mycobacteria were recognized to be widespread, and by the 1930s veterinarians had concluded that false-positive tuberculin reactions were due to nontuberculous mycobacteria (158). As tuberculin testing was extended to apparently healthy humans, the need for a standardized tuberculin more reliable than Koch’s OT became apparent. The development of a purified protein derivative (PPD), which was a potent stable tuberculin without sensitizing properties, was prepared by Florence Siebert of the Henry Phipps Institute in Philadelphia in 1934, and in 1941 Siebert and Glenn made a single large lot of ammonium sulfate–precipitated PPD (lot 349608) from a single strain of human tubercle bacilli, which was deposited as the International Standard of mammalian tuberculin (PPD-S) (159). Even with PPD-S, problems with specificity and sensitivity have continued. Pulmonary calcification had been considered diagnostic of tuberculosis, but the presence of calcification in tuberculin nonresponders noted in the 1930s raised questions about its specificity. Studies by Carol Palmer beginning in 1943 (160) and subsequent studies confirmed the likelihood of a fungal (histoplasmosis) origin (161,162).

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Concerns then arose about the sensitivity of the test. Quantitative studies showed that if sufficiently high doses of tuberculin were used, almost everyone would respond, while most patients with tuberculosis and known contacts reacted to a relatively low dose. Without a history of tuberculosis or known contact, only higher doses would elicit a response, so the author concluded that reactions to higher doses were probably not due to M. tuberculosis (163). Palmer, using what appeared to be the ideal dose of 0.0001 mg (5 TU), based on Furcolow’s studies, and 0.005 mg (250 TU) in student nurses found that with 5 TU the percentage of reactors correlated with the degree of exposure to tuberculosis and not place of residence, while with 250 TU the frequency of reactions correlated with geographical area of residence and not contact history. He concluded, like the veterinarians, that tuberculin sensitivity was not dependent on a single source but that antigenically related organisms prevalent in certain geographic environments could elicit a response to higher doses (158). Further Mantoux testing of general populations around the world indicated that sensitivity to 5 TU of PPD is quite uniform among tuberculous individuals, but in certain areas a bimodal distribution of reactions was apparent, with positive reactors having 6–26 mm induration (peak 14–15 mm), and those with reactions
5 mm were considered to be uninfected (164). In still other areas no clear-cut separation existed. The probability that these small reactions represented cross-reactions to tuberculin because of sensitization to other microorganisms was considered in the 1940s and 1950s (164,165). Between 1958 and 1970 further studies with some tuberculous mycobacterial antigens in Navy recruits demonstrated that reactions of 4–12 mm of induration and false-positive reactions to PPD-S appear to be related to prevalence of certain nontuberculous mycobacteria in the environment (166–169). In the 1960s false-negative results in bacteriologically proven cases of tuberculosis began to be reported (170,171). Adsorption of tuberculo-protein onto glass and plastic surfaces was believed to be a factor, and Tween R 80 detergent was subsequently added to help stabilize the material. Other recommendations coming from the advisory panel called by the NIH in 1972 related to timing of preparation in relation to infection and demonstration of bioequavalency of PPD tuberculin to 5 TU of PPD-S in phosphate buffer without polysorbate (158). Another problem affecting tuberculin test diagnostic reliability and interpretation was the “booster phenomenon,” an increase in the size of the reaction to a second tuberculin test compared to the reaction to the first test, first described by Steele and Willis (172). Two-step testing was then recommended for those undergoing serial testing to minimize errors in interpretation (173,174). Von Pirquet in 1908 had observed that the tuberculin test was almost always positive in patients moderately sick with tuberculosis but often negative in those with more severe or rapidly progressive disease (154). He used the terms “allergy” and “anergy” to describe the type of response elicited. For many years tuberculin reactivity was considered an indicator of protective immunity until Rich and Mc-

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Cordick in 1929 (175) challenged this view and Wilson later showed that animals could be made tuberculin negative without losing their immunity (176). Koch’s initial investigations of tuberculin have spawned numerous questions and further studies. Tuberculin testing has enhanced knowledge about distribution and other epidemiological aspects of mycobacterial, nonmycobacterial, and fungal diseases and the role of environmental antigens, but more specific tests for tuberculosis based on more specific mycobacterial components are still being pursued. Demonstration of cellular transfer of cutaneous hypersensitivity to tuberculin by Merrill Chase in 1945 (177) and others led to the recognition of the pivotal role of the lymphocyte in cellular hypersensitivity, and Mackaness’s work at the Saranac Laboratory began to elucidate the interaction between cellmediated immune response and macrophage activation (178). Host and mycobacterial factors in delayed hypersensitivity and protective immunity and their relationship are still the subject of ongoing research, as is the meaning of skin test anergy. Several editorials in the 1970s addressed these issues and reflect the understanding at that time (179,180,181). Since the AIDS epidemic the meaning of a negative tuberculin skin test and its relationship to protective immunity and to anergy are still disputed (182,183) as the complex interplay of many factors in tuberculin skin test sensitivity and host immune responses continues to be explored (184). J. Vaccine Development

Ever since Koch’s discovery of the microbial etiology, there has been interest in developing an effective vaccine to prevent tuberculosis. After 1882 many attempts using killed or chemically treated tubercle bacilli generally failed. In 1891 Trudeau found that a strain of M. tuberculosis became attenuated for the guinea pig after repeated subcultures on a serum glycol medium. The RI strain elicited protective immune responses in the animal, but it was not tried in humans. His studies established that living attenuated tubercle bacilli gave greater protection than killed bacill. A live vaccine appeared then to be needed (59). Albert Calmette, a scientist at the Pasteur Institute in Lille, and Camille Guérin, a veterinary school graduate and associate of Calmette, were working with a virulent bovine type tubercle bacillus previously isolated from a heifer’s udder by Nocard in 1902. Serendipitously they found that adding ox bile to the medium to prevent clumping, and subculturing of the microorganism lowered its virulence. Between 1906 and 1919 after 231 3-weekly transfers, they had a microorganism that failed to produce progressive tuberculosis when injected into guinea pigs, rabbits, cattle, or horses. In 1921 it was first given to a human, a newborn child whose mother had died of tuberculosis a few hours after the birth (185). In 1924 oral vaccinations had been given to 664 infants and an additional 114,000 were vaccinated by 1928 without serious consequences. It began to be used in

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Spain, Germany, and Scandinavia, but some British and U.S. authorities were skeptical about it. In 1928 the League of Nations announced the safety of the bacille CalmetteGuérin (BCG) for vaccination of humans and animals, but the deaths of 72 and infection of 135 of 250 children orally vaccinated in Lübeck, Germany, in 1929–1930 halted general acceptance of the vaccine until after World War II. It turned out that the children had inadvertently received a virulent strain. After 20 months of criminal proceedings the Lübeck doctors were imprisoned and BCG was exonerated (185). Even after most countries embraced the use of the vaccine, the United States and the Netherlands were not proponents of its use, and only in the late 1940s did England and Australia begin widespread use (186). In 1948 the first International BCG Congress in Paris stated that BCG was effective in preventing tuberculosis and that the BCG strain stably maintained its residual virulence (187). The Danish Red Cross had begun vaccination campaigns in war-ravaged Europe because of the serious tuberculosis situation, and in 1948 a joint enterprise with three Scandanavian voluntary organizations and UNICEF was initiated (188). In 3 years this International Tuberculosis Campaign had effected testing of almost 30 million persons and vaccination of 14 million. After mid-1951 this work was continued and expanded under joint WHO/UNICEF auspices. By the end of 1956 an additional 160 million people had been tuberculin tested and 60 million had been vaccinated (188). The preparation of the vaccines, the details of the animal experiments, the immunological aspects, the variable results from 0 to 80% effectiveness, and possible reasons for the differences have been discussed by others (189–193). The methodological aspects have also been evaluated (188,194–196). BCG vaccine trials have provided some of the best and most complete information on tuberculosis in human populations and have been invaluable in the development of vaccine trial methodology. The past failures of BCG in terms of variable and unpredictable efficacy and yet its remarkable success in terms of the magnitude of its worldwide use can point the way to future success with new vaccines. The 1949 international campaign was the first large-scale centralized public health campaign conducted with the WHO structure and was a forerunner and model for subsequent campaigns, including the eradication of smallpox (188). BCG has evoked endless discussions about the relationship between cellmediated immunity and delayed hypersensitivity. It has stimulated research into host immune mechanisms in mycobacterial infection. It has served as a vehicle for the introduction of other antigens in the hope of creating a single multiantigenic vaccine for use in developing countries (197). It has also led to a number of investigations of immunostimulation in neoplasia, especially in the therapy of bladder cancer. Attempts to develop better vaccines with novel molecular genetic approaches are accelerating and will be discussed elsewhere.

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A search for an effective therapy began almost immediately after the causative bacillus was identified. Koch’s tuberculin had failed, but Ehrlich’s magic bullet for syphilis stimulated interest in other chemical agents for tuberculosis. A number of these had been tried in animals and some in selected human patients. Amberson’s clinical trial of gold in 1931 is historically important in that randomization was utilized for the first time. Randomization was between a group of patients and a group of controls matched “as close as possible” (198). The study represents a transition from the matched to modern randomized clinical trials. The paper is also notable for Amberson’s meticulously detailed critique of previously reported clinical studies. A number of trials of sulfanilamide and other related compounds were performed in the late 1930s and early 1940s in experimental animals and humans with some favorable results, but often with significant associated toxicity (199). Waksman’s Nobel Prize–winning isolation of streptomycin in 1944 together with Schatz’s crucial astute laboratory observations (200) and Feldman’s and Hinshaw’s first clinical application ushered in the momentous era of modern chemotherapy of tuberculosis (43,201). Within 12 months of its announced isolation, William Feldman, professor of comparative pathology at the Mayo Foundation of Experimental Medicine, and H. Corwin Hinshaw, a bacteriologist and subsequent consultant physician at the Mayo Clinic, together demonstrated unequivocably streptomycin’s antituberculosis action in vitro and in vivo (43,201). A number of clinical trials ensued, including cooperative investigations by the Army and Navy and U.S. Veterans Administration (202–204) with liasons with the American Trudeau Society, the Mayo Clinic group, and Walsh McDermott’s group studying toxicity at Cornell University Medical College. Details are summarized elsewhere (199). It was apparent by 1947 not only that streptomycin was the most effective therapeutic agent so far against experimental tuberculosis in guinea pigs, but also that it produced promising results in certain types of pulmonary and extrapulmonary tuberculosis in humans. Rapid development of drug resistance and some toxicity became early concerns, however. Although Max Pinner had commented, in relation to evaluation of chemotherapy that “the therapeutic effects of a truly efficacious chemotherapeutic agent are not likely to depend for proof on elaborate control series” (205), the British Medical Research Council decided that studies using their precious allocation of streptomycin should be rigorously planned and use concurrent controls. Their trial, begun in 1947 (206), was a model for subsequent trials not only in the United Kingdom, but overseas as well, and was the first to incorporate all of the elements of the modern, randomized clinical trial (207). Many attempts to prevent or delay bacterial resistance by varying dosage, duration, or frequency of medication were, however, to no avail.

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The second important landmark in understanding chemotherapy of tuberculosis was the recognition that a two-drug regimen could prevent the emergence of resistance. Jorgen Lehman, following up on earlier studies indicating that benzoic acid and salicylic acids stimulated oxygen uptake by pathogenic strains of M. tuberculosis, was searching for competitive inhibitors of these acids. He discovered that para-aminosalicylic acid (PAS) had demonstrable bacteriostatic activity in vitro against M. tuberculosis. Animal experiments and a small clinical trial were begun in 1944. His favorable report in 1946 (208) paved the way for subsequent trials. The Medical Research Council study of three concurrent regimens—PAS alone, streptomycin alone, and the combination of streptomycin and PAS—reported in 1949 and 1950 (209) demonstrated unequivocably the reduction in risk of developing streptomycin resistance when both were used and broadened the potential application of such treatment. Nevertheless, chemotherapy was not yet accepted as definitive therapy except in tuberculous meningitis and miliary tuberculosis. The drugs at first tended to be used adjunctively with bedrest, collapse therapy, or surgical resection (210). Until the appearance of isonicotinic acid hydrazide (isoniazid) in 1951 and subsequent laboratory and clinical experience with this new “miracle drug” (211), it was not appreciated that chemotherapy alone might cure tuberculosis. Many additional clinical trials were carried out with various combinations, dosages, frequencies of administration, and durations of these initial three drugs and others as they became available in the 1950s and 1960s. By the 1970’s experience had dictated that ethambutol, rifampin, and pyrazinamide be added to the list of first-line drugs against tuberculosis (201). The large clinical trials conducted by the U.S. Public Health Service and by the VA–Armed Forces Study Units in the United States, the collaborative studies in East Africa, Hong Kong, Singapore, and Madras under the joint auspices of the British Medical Research Council and WHO (199), together with others such as the International Union Against Tuberculosis (IUAT) (212), have provided invaluable information to guide therapy today. Information gained from these trials revolutionized the treatment of tuberculosis around the world. It led to abandonment of sanatoriums and emphasis on ambulatory therapy, discontinuation of collapse therapy, and sparing use of surgery for very selected patients. It changed the careers of sanatorium doctors and led to an emphasis on other aspects of pulmonary medicine and the neglect of tuberculosis in the medical curriculum. The trials taught that relapse rates tend to be a better endpoint in evaluating therapy than radiological findings and that failure of cavities to close did not always mean drug failure (199). Bed rest and sanatorium care did not add to the benefits produced by chemotherapy (203,213,214,). The eradication of tuberculosis was now deemed possible if drug therapy was applied vigorously to persons with disease and preventive therapy was given to those who were already infected but

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without disease, as recommended by an expert group convened at Arden House by the American Lung Association (105). Ambulatory domiciliary care was feasible, as shown in Hong Kong and Madras (213,214) (Fig. 8). Short-course and intermittent regimens (204), stimulated by the problems of noncompliance with older standard regimens, drug costs, and availability of medical services in their countries of origin, were also effective elsewhere (199). Nine-month regimens were effective with inclusion of rifampin, and pyrazinamide permitted further shortening to 6 months. The importance of supervised and especially directly observed therapy (DOT) had long been appreciated from trials in other countries (215) but except for isolated instances was slow to be widely promoted in the United States until the problems of high noncompletion rates and multidrug resistance became alarmingly apparent in the late 1980s and early 1990s. L. Chemoprophylaxis

Once isoniazid, an effective, inexpensive oral medication with relatively low toxicity, was available, its usefulness in preventing tuberculosis was considered, especially in preventing the sequellae of infection (i.e., tuberculosis disease, which fosters transmission and stalls eradication). Controlled trials of chemoprophylaxis were carried out in a number of groups with various risk factors for developing disease; these are reviewed by Ferebee (216). In the United States isoniazid was shown to be effective, inexpensive, and relatively non-toxic in appropriately selected populations and was therefore preferred over BCG vaccination as a preventive strategy. BCG was not consistently shown to be effective except in preventing serious complications such as miliary tuberculosis and meningitis in children, and it has not been widely embraced in the United States, to the consternation of some (57). Because of the relatively low risk of acquiring infection in the United States, the diagnostic value of the tuberculin test has been considered important, and BCG would negate its reliability. Farer has also reviewed some of the personal and public health issues and the epidemiological and scientific background related to the use of chemoprophylaxis (217). In view of the competing risks of tuberculosis and isoniazid-associated hepatitis (218), lack of recent data from controlled trials, the possibility of drug-resistant infection, and the problems of distinguishing initial infection, exogenous superinfection, long-standing infection, and in some cases latent versus active disease, the recommendations regarding indications and choice of prophylactic therapeutic regimen continually change (219–223). While during the sanatorium era and beyond much attention was focused on practical therapies for tuberculosis, fortunately basic research was carried out simultaneously in a number of institutions around the world. In 1954 investigators from research institutes and medical school departments from the United States, the United Kingdom, France, Switzerland, and Denmark participated in a sympo-

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Figure 8. Patient in Madras receiving ambulatory directly observed therapy. The British Medical Research Council clinical trials of antituberculosis chemotherapeutic agents proved that sanatorium or hospital care was not necessary and that domiciliary or ambulatory treatment could be successful. This finding had important implications for TB control not only for the developing world, but for all countries. Directly observed therapy in an outpatient setting is now a major control strategy of WHO. (Photograph Courtesy of the American Lung Association, New York.)

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sium on the nature of the tubercle bacillus and the reactions of the host tissues. Arnold Rich’s prophetic remarks regarding the importance of fundamental research for long-range victory are as relevant now as they were almost 50 years ago (224): “In other spheres we know that superior weapons do not guarantee a permanent end of hostilities, and that for the surest preservation of security it is, in addition, essential to understand thoroughly the nature, designs and potentialities of the enemy and our own reaction toward, and human capacity to resist that type of nature; for new and superior defensive weapons can alone rarely if ever be relied upon to ensure enduring safety. Too often they are neutralized or surpassed by the development of new countermeasures by the enemy.” M. The Latter Half of the Twentieth Century

New tools and major technological developments have greatly accelerated knowledge about many aspects of tuberculosis. Max Lurie developed strains of animals that were genetically resistant or susceptible to M. tuberculosis and then studied the role of hereditary factors in the immunological responses in tuberculosis. Since then other animal models, including “knockout” mice and transgenic animals, improved cell culture techniques, development of specific monoclonal antibodies, and methods of isolating and identifying genes and gene products are among many tools facilitating research into the fundamental aspects of tuberculosis. The recent elucidation of the M. tuberculosis genome (225) opens up a whole array of prophylactic and therapeutic possibilities and may at last be another strategic milestone in humanity’s long struggle against this “captain of the men of death.” Despite the many advances in our understanding and ability to detect, diagnose, treat, and prevent tuberculosis and despite repeated admonitions of tuberculosis experts and lung association and other task forces, external societal factors persisting or resurfacing from the past, such as poverty, inadequate housing, poor nutrition, and ignorance, together with overpopulation, new waves of immigrants from countries of high prevalence of tuberculosis, drug abuse, emergence of the HIV epidemic, and increased problems with drug resistance have all combined to obstruct or delay tuberculosis control in the twentieth century. The unexpected (apparently transient in the United States) increase in tuberculosis in the late 1980s and early 1990s led to a revamping of the public health infrastructure so carefully constructed in the past. Case finding, isolation of infectious persons, and prompt appropriate treatment to completion under directly observed therapy—even in locked facilities, if necessary—became important issues. Education of a whole new generation of medical students, faculty, hospital and public health staff, and governmental officials as well as the public became imperative. Screening of high-risk populations and new guidelines for prophylactic treatment were issued. The race for faster methods of diagnosis, a more reliable

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method of detecting infection, and for new effective therapies and vaccines based on new knowledge of host and mycobacterial responses became more compelling. After thousands of years the twenty-first century may bring eradication closer to fruition. References 1. Haas F, Haas SS. The origins of Mycobacterium tuberculosis and the notion of its contagiousness. In: Rom WR, Garay S, eds. Tuberculosis. Boston: Little, Brown and Company, 1996:3–19. 2. Ayvazian LF. History of tuberculosis. In: Reichman LB, Hershfield E, eds. Tuberculosis. A Comprehensive International Approach, 1st ed. New York: Marcel Dekker, 1993:1–20. 3. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993; 77:1205–1217. 4. Report on the tuberculosis epidemic, 1997. Global TB Programme. Geneva: World Health Organization, 1997. 5. Dubos R, Dubos J. The White Plague: Tuberculosis, Man and Society. Boston: Little, Brown, 1952:8. 6. Weisse AB. Tuberculosis: why “the white plague”? Perspect Biol Med 1995; 39:132–138. 7. Holmes OW. Medical Essays, 1842–1882. 2d ed. Boston: Random House, 1892:353. 8. Lerner BH. Public health then and now. Temporarily detained: tuberculous alcoholics in Seattle, 1949–1960. Am J Pub Health 1996; 86:257–265. 9. Gostin LO. Controlling the resurgent tuberculosis epidemic: a 50-state survey of TB status and proposals for reform. JAMA 1993; 269:255–261. 10. Centers for Disease Control and Prevention. Tuberculosis control laws—United States, 1993. MMWR 1993; 42(suppl RR-15):1–28. 11. Oscherwitz T, Tulsky JP, Roger S, Sciortino S, Alpers A, Royce S, Lo B. Detention of persistently non-adherent patients with tuberculosis. JAMA 1997; 278(10): 843–846. 12. Singleton L, Turner M, Haskal R, Etkind S, Tricarico M, Nardell E. Long-term hospitalization for tuberculosis control. Experience with a medical-psychosocial inpatient unit. JAMA 1997; 278:838–842. 13. Dubler NN, Bayer R, Landesman S, White A. The Tuberculosis Revival: Individual Rights and Societal Obligations in a Time of AIDS. A Special Report. New York: United Hospital Fund of New York, 1992. 14. The dual epidemics of tuberculosis and AIDS: health care policy, professional practice, law and ethics. A Conference for World AIDS Day, New York, American Society of Law, Medicine and Ethics, Columbia University School of Public Health, Albert Einstein School of Medicine and Montefiore Medical Center, New York City Department of Health, and United Hospital Fund, Dec. 4–5, 1992. 15. Annas GJ. Control of tuberculosis—the law and the public’s health. N Engl J Med 1993; 328:585–588.

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Ravenel MP. The intercommunicability of human and bovine tuberculosis. Medicine 1902; 8:529–546. The bacillus tuberculosis and the contagiousness of phthisis. Boston Med Surg J 1883; 108:235–236. Chapin CV. Sources and Modes of Infection. New York: John Wiley and Sons, 1910:252–255. Smith PG, Moss AR. Epidemiology of tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection, and Control. Washington, DC: American Society for Microbiology, 1994:47–59. Wells WF. On air-borne infection: II. Droplets and droplet nuclei. Am J Hyg 1934; 20:611–618. Wells WF. Airborne Contagion and Air Hygiene. Cambridge, MA: Harvard University Press, 1955. Riley RL, O’Grady F. Airborne Infection: Transmission and Control. New York: Macmillan, 1961. Loudon RG, Roberts RM. Droplet expulsion from the respiratory tract. Am Rev Respir Dis 1967; 95:435–442. Riley RL, Mills CC, O’Grady F, Sultan LU, Wittstadt F, Shivpuri DN. Infectiousness of air from a tuberculosis ward. Am Rev Respir Dis 1962; 85:511–525. Houk VN, Baker JH, Sorensen K, and Kent DC. The epidemiology of tuberculosis infection in a closed environment. Arch Environ Health 1968; 16:26–35. Edlin BR, Tokars JI, Grieco MH, Crawford JT, Williams J, Sordillo EM, Ong KR, Kilburn JO, Dooley SW, Castro KG, Jarvis WR, Holmberg SD. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992; 326:1514–1521. Infectiousness of tuberculosis: a report of the National Tuberculosis Association ad hoc Committee on Treatment of Tuberculosis in general hospitals. Am Rev Respir Dis 1967; 96:836–837. Nardell E, Keegan J, Cheney SA, Etkind SC. Airborne infection. Theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991; 144:302–306. Riley RL, Nardell EA. State of the art. Clearing the air. The theory and application of ultraviolet air disinfection. Am Rev Respir Dis 1989; 139:1286–1294. Guidelines for preventing the transmission of tuberculosis in health-care settings, with special focus on HIV-related issues. MMWR 1990; 39:RR-17. Shyrock RH. The National Tuberculosis Association 1904–1954. New York: National Tuberculosis Association, 1957. Knopf SA. A History of the National Tuberculosis Association. The Anti-Tuberculosis Movement in the United States. New York: National Tuberculosis Association, 1922. Hodges LM. The People Against Tuberculosis: The Story of the Christmas Seal. New York: National Tuberculosis Association, 1942. Haas F, Haas. S. The sociopolitical response to the discovery of mycobacterium tuberculosis. In: Baum GL, Crapo JD, Celli BR, Karlinsky JB, eds. Textbook of Pulmonary Diseases. 6th ed. Philadelphia: Lippincott-Raven Publishers, 1998: 3–21.

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Long ER. A History of the Therapy of Tuberculosis and the Case of Frederic Chopin. Lawrence: University of Kansas Press, 1956:54. Trudeau EL. An Autobiography. National Tuberculosis Association. New York: Doubleday, 1944. Trudeau EL, The history of the tuberculosis work at Saranac Lake, New York. Med News NY 1903; October 24:1–12. Knoph SA. Are sanatoriums for consumptives a danger to the neighborhood? Med Rec 1896; 1(4):82–83. Skavlem JH. The closing of the Trudeau sanatorium (editorial). Am Rev Tuberc Pulm Dis 1955; 71:163–164. Growth of the sanatorium movement. J Outdoor Life 1923; 20:255. Tuberculosis Hospital and Sanatorium Directory. New York: National Tuberculosis Association, 1954:184–185, 188–189. Frost WH. The age selection of mortality from tuberculosis in successive decades. Am J Epidemiol 1995; 141:4–9. McKeown T. The Role of Medicine: Dream, Mirage or Nemesis? London: The Nuffield Provincial Hospitals Trust, 1976. Armand Delille P. The campaign against infantile tuberculosis in France and the preservation of childhood against its ravages by the system of the “Oeuvre Grancher.” Am Rev Tuberc 1918–1819; II(7):435–448. Teller ME. The Tuberculosis Movement: A Public Health Campaign in the Progressive Era. Westport, CT: Greenwood Press, 1988. Weisner DE. Sanatorium follow up studies. Am Rev Tuberc 1922; VI:320–326. Goldstein SE. After the sanatorium what? J Outdoor Life 1914; 11:266–268. Mitchell RS. Mortality and relapse of uncomplicated advanced pulmonary tuberculosis before chemotherapy: 1,504 consecutive admissions followed for fifteen to twenty five years (parts I and II). Am Rev Tuberc 1955; 72:487–501, 502–512. Stephens MG. Follow-up of 1,041 tuberculosis patients. Am Rev Tuberc 1941; 44: 451–462. Siltzbach LE. Medical aspects of the rehabilitation of the tuberculous. The experience of a quarter century with 964 patients at Altro Work Shops. Am Rev Tuberc 1942; 46:489–504. Woodhead GS, Varrier-Jones PC. Experiences in colony treatment and after-care. Lancet 1917; 2:779–785. Willis S. Perspectives and treatment in tuberculosis. Am Rev Tuberc 1944; 50: 251–256. Riviere C. The Early Diagnosis of Tubercle. 3rd ed. London: Oxford Medical Publications, 1921:197, 222. Grange JM. The mycobacteria. In: Topley & Wilson’s Principles of Bacteriology, Virology and Immunity. Parker MT, Duerden BI, eds. 8th ed. Vol. 2. Philadelphia: BC Decker, Inc., 1990:73–101. Runyon EH. Anonymous Mycobacteria in pulmonary disease. Med Clin North Am 1959; 43:273–290. Condos R, McCune A, Rom WN, Schluger NW. Identification of patients with active tuberculosis using a peripheral blood-based polymerase chain reaction assay. Lancet 1996; 347:1082–1085.

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2 Tuberculosis Control in Low-Income Countries

DONALD A. ENARSON University of Alberta Alberta, Canada, and International Union Against Tuberculosis and Lung Disease Paris, France

I. Introduction The importance of tuberculosis to public health can hardly be questioned. In the first meeting of specialists in internal medicine held in Paris in 1867, it was noted that tuberculosis was the most frequent condition with which the specialists had to deal, and for this reason a series of scientific meetings was initiated that led to the establishment of the International Union Against Tuberculosis and Lung Disease. More than a century later, in 1993, tuberculosis was reported as the most frequent cause of death from a single agent among persons aged 15–49 years (1) and has been declared a global emergency. Anyone today may become infected with tuberculosis simply by breathing the air in a space through which a tuberculosis patient has passed. Because of its frequency, its potential effects, and the fact that it can be spread to the general public, tuberculosis has a significance to public health greater than most other disease conditions. II. Objectives of Tuberculosis Control Because tuberculosis is caused by a microorganism whose principal reservoir is the human population and because it represents such a danger to public health, the 55

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objective of activities directed against this disease should be nothing short of its elimination from the human population. Some would argue that this is an unrealistic objective. Nevertheless, it may be a reasonable one because of the inefficiency of the dynamics of tuberculosis (2). Beyond this are the strategic implications of aiming at elimination; this objective clarifies the obstacles in the way of achieving it and an agenda for action. The folly of thinking that tuberculosis can be reduced to a level beyond which it is no longer a concern to the public without eliminating it has been dramatically illustrated by the resurgence of this contagious disease where it was previously thought to be controlled (3). III. The Scientific Basis of Intervention A. The Dynamics of Transmission

Tuberculosis involves a dynamic process (4). Understanding this process is essential to interventions for its control; transmission of the causative microorganism from one person to another is the key component. To become infected with tuberculosis, a biologically effective dose of the microorganism is required; this is achieved primarily by inhalation. The microorganism enters the environment as an aerosol, a susceptible individual is exposed, becomes infected, and may subsequently develop disease, which may be contagious, thus passing the organism to others. The individual remains contagious for a limited period of time, during which transmission may occur. This period is limited either by the death of the individual or the suppression of growth of the microorganism in the body (as when the patient is cured). The key transitions in maintaining the cycle are (1) from exposure to infection, (2) from infection to disease, (3) from disease to exposure. B. Determinants

Key determinants in the transition from exposure to infection are the concentration of microorganisms in the environment, the degree of susceptibility of the exposed, and the duration of exposure (5). The key determinant in the transition from infection to disease is the state of the immune system of the individual infected. Key determinants in the transition from disease to being contagious are the numbers of bacteria in the lung and their access to the airways. The stages in the transmission cycle increase its inefficiency. C. Probabilities

In enhancing or retarding transmission, the probability of transition from one state to another must be modified. An understanding of the “base” probabilities (the

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probabilities of transition in the absence of the intervention) is essential to evaluate the impact of any intervention. Base probabilities can be derived from studies of individuals in contact with those with active tuberculosis (5). The probability of transition from exposure to infection varies, on average, from slightly more than 25% in a person living in the same household as a case with sputum smear positive tuberculosis to about 12% for someone who is a friend or colleague of such a case. The probability of transition from infection to disease in this setting is less than 15%. Finally, the probability of a case of tuberculosis being highly contagious, if the case is an adult, is approximately 50%. Thus, the combined probability (if a susceptible person lives in the same household with a highly contagious case of tuberculosis) is 0.25 times 0.12 times 0.50, which is 1.5%. This is clearly an inefficient cycle of transmission, which makes it theoretically possible to consider elimination a reasonable objective. A strategy for elimination needs to take account of the fact that Mycobacterium tuberculosis remains dormant in a high proportion of those infected; the low probability and long latent period between infection and disease means that most of those infected do not have the disease but retain the possibility of developing the disease throughout their lifetime. Thus, an elimination strategy focused on the sources of infection must be sustained over a long period of time. IV. Prevention Through Treatment A. Failure of a Vaccine Strategy

The most promising strategy for elimination of a disease is vaccination, as with smallpox. A vaccine was one of the earliest tools developed for the control of tuberculosis following the identification of the causative organism (6). This vaccine is capable only of limiting the dissemination of the microorganism within the body after infection (7) and does not prevent infection. In addition, the most frequent schedule of administration (shortly after birth) prevents those forms of tuberculosis that are not highly contagious (8) and so has limited impact on the transmission cycle. B. Preventive Therapy as a Secondary Prevention Strategy

Shortly after the development of effective chemotherapy for treatment, it was used to treat latent bacteria in those who had been infected but who had not yet developed disease (9). It was clearly effective in reducing the probability of developing subsequent tuberculosis. However, the number of persons who needed treatment to prevent a contagious case, and the duration of such treatment made this strategy cumbersome to apply at a population level.

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Enarson C. Evidence for Case Management as an Effective Preventive Tool

The possibility that chemotherapy could permanently cure a patient with tuberculosis was convincingly demonstrated in the early 1960s in Edinburgh (10). Prior to that time, many did not believe that tuberculosis could be cured, only that it could be suppressed, to reactivate at a later time in life. Evidence that chemotherapy could curtail infectiousness of a patient was provided by a study in India of the contacts of patients whose treatment was domiciliary as compared with those who received wholly ambulatory treatment (11); the proportion infected by exposure to the case was not different in the two groups. The ability of chemotherapy of tuberculosis cases to arrest infection of succeeding generations of children in the community has been more difficult to demonstrate. The evidence for its impact has been summarized (12). Supportive evidence includes the demonstration that the rate of decline in prevalence of infection in military recruits in the Netherlands was hastened after the introduction of chemotherapy (13), but it had been declining for some time prior to this period and was already at a relatively low level prior to the initiation of this treatment. More compelling evidence has been provided from intensive intervention in Inuit communities where the rate of tuberculosis was extremely high (14). The rates were very rapidly reduced primarily through the rapid identification and treatment of cases of tuberculosis in the community, but this was accompanied by an extensive application of preventive chemotherapy. V. Basic Principles of Tuberculosis Control A. Results of Chemotherapy

Chemotherapy of tuberculosis was associated with an immediate and dramatic effect on fatality: patients who would have clearly died of their disease remained alive. The trend in tuberculosis mortality after introduction of chemotherapy was illustrated in Norway (Fig. 1); the greatest reduction occurred immediately following the introduction of drugs before modern, multidrug chemotherapy was used. Subsequently it was conclusively shown that patients did not relapse if they had diligently completed the multidrug treatment prescribed (15). Chemotherapy, while saving the lives of patients, reduced the period of time of being contagious and prevented patients from again becoming contagious, removing them from the cycle of transmission. B. Effective Means of Case-Finding

Following the second world war, periodic radiographic examination of large proportions of the general population was performed in the belief that such active

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Figure 1. Trend in mortality from tuberculosis in Norway, 1925–1970, in relation to the introduction of chemotherapy. (Adapted from Ref. 59.)

measures would remove the infectious cases from the community and prevent further spread of tuberculosis. In an extensive field trial evaluating the components of the emerging strategy for tuberculosis control, Styblo and colleagues (16) in the Kolin district of Czechoslovakia showed convincingly that where routine services are regularly provided, periodic examinations are not efficient in identifying further cases of tuberculosis in the community, especially the most contagious cases. Studies in Kenya (17) indicated that patients identified on screening examinations had most likely attended the health service (in many instances on numerous occasions) where they had not been diagnosed. An international, multicenter evaluation of the ability of tuberculosis specialists to correctly identify active cases of tuberculosis using chest radiographs (18) demonstrated a striking degree of nonconcordance in the examination results. The most appropriate means of case detection was bacteriological examination of those presenting with compatible symptoms in routine health services.

C. Impact of Chemotherapy on Tuberculosis Control

In addition to saving the lives of tuberculosis patients, adequate multidrug chemotherapy rapidly reduced the numbers of tuberculosis patients in the community by quickly curing the long-term ( prevalence) cases, leaving primarily new, previously undiagnosed cases as the only patients in the community, and even these could be quickly rendered bacteriologically negative (Fig. 2).

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Figure 2. Impact of chemotherapy on prevalence of infectious cases, incidence of infectious cases, and prevalence of resistant cases of tuberculosis in Edinburgh in relation to the introduction of chemotherapy. (Adapted from Ref. 10.)

D. Rationalization of Tuberculosis Services

From the elements outlined above, a model was proposed for tuberculosis services as a full-scale public health program (19). It included government responsibility for tuberculosis control activities, ambulatory chemotherapy of tuberculosis patients using a standardized multidrug regimen under the supervision of a specialist, case detection based on examination of individuals presenting themselves to the general health services with symptoms compatible with tuberculosis, bacteriological monitoring of the course and outcome of treatment, periodic evaluation of activities, and the use of BCG vaccination. Application of this approach in many industrialized countries was followed by rapid reduction in the number of tuberculosis cases. VI. Adaptations for Low-Income Countries A. Constraints in Providing Tuberculosis Services

Attempts to reproduce the results achieved in industrialized countries using the same methods were successful in a few other countries, such as Cuba, Libya, Al-

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geria, Uruguay, and Chile. The poorest countries, where the majority of the cases lived, faced marked constraints. Infrastructure for providing services was in most instances nonexistent, financial resources were inadequate to deal with the disease burden, populations were scattered, and communication was insufficient to ensure accessibility to such services as did exist. Only few of the elements of the model developed in industrialized countries could be implemented promptly in the poorest countries. Vaccination was the easiest and was extensively applied; other elements were incompletely implemented due to the constraints encountered. B. The Need to Focus Interventions

The need to set priorities was evident. In addition to the experimental work supported by the World Health Organization (WHO) undertaken in the Kolin district of Czechoslovakia, a broad program of research was undertaken, primarily in India (20), which provided a scientific basis for discussion. A number of modifications were proposed. One of the earliest modifications was the use of isoniazid alone in the treatment of tuberculosis. This approach had been evaluated at the initiation of chemotherapy (21) and was shown to be effective in increasing the proportion of patients who could be cured, and the long-term outlook for those cured was not different from that for those whose disease was arrested using multidrug chemotherapy. It was clearly cheap and easy to apply and received enthusiastic support from many experts, including Johannes Holm, the executive director of the International Union Against Tuberculosis, an action praised by Halfdan Mahler, Director General of the World Health Organization (22). This policy led to the proliferation of resistance to isoniazid and ultimately to the present problem of multidrug resistance. Another recommendation was based on mathematical models applied to the transmission cycle for tuberculosis (23). The importance of case finding was stressed by the models because it was noted that if one could achieve a relatively modest level of success of treatment in a large number of cases, it would be much more effective in reducing the burden of disease in the community than if a high level of success of treatment was achieved in a limited number of cases. From this came a focus on case finding as the key activity of tuberculosis services. A formal recommendation was developed by WHO in 1964 for the development and implementation of national tuberculosis programs (24) and reiterated in a revision 10 years later (25). The report identified the need for a program that is countrywide, permanent, responsive to the felt needs of the population, integrated within the existing health services, and within the reach of the resources available. As a consequence of these recommendations, most governments instituted a national tuberculosis program.

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Enarson VII. Achieving Success in Low-Income Countries A. Impact of Applied Interventions

Within a few years of the recommendation of this strategy, millions of cases of tuberculosis were reported to WHO (26). The number of notified cases of tuberculosis declined in successive reports, which was interpreted as indicating success of the strategy. A more critical evaluation of the evidence, however, suggested that the number of cases of tuberculosis reported to WHO seriously underestimated the real number of cases that existed and that, instead of declining, the number of cases may actually have been increasing (27). Far from being successful, the interventions were shown to have been contributing to a worsening of the tuberculosis situation (28), an analysis initially presented to the annual meeting of the International Union Against Tuberculosis in 1973. Subsequent information from the national prevalence surveys periodically carried out in East Asia [particularly in Korea (29) and China (30)] indicated that more than half the sources of transmission of tuberculosis were cases known to the health services that had received treatment but had not been cured. Moreover, the majority of these cases harbored drug-resistant microorganisms. Instead of bringing the problem under some semblance of control, the ineffective treatment of the cases was actually making the epidemiological situation far worse than if the patients had never been treated. The conclusion of this evaluation was that it was far better to do nothing at all than to treat the cases badly! This information had already been available from the first years of chemotherapy in Edinburgh (Fig. 2) as well as from community studies in India (31), but the message had not been heeded. The immediate consequence of the lack of success was a decline in priority given to tuberculosis and an emphasis on improving general health services through a focus on “primary health care” and mobilization of the general population for health following the successful examples of services in China and of specific projects in India and Indonesia. It was felt that, when such services were established, it might be possible to revisit the focused intervention against tuberculosis (32). B. Redefining the Strategy

The failure of attempts to successfully address the tuberculosis problem in low-income countries was very much evident in Beijing in 1978, when Kan and Zhang (33) set out to introduce a revised strategy for management of tuberculosis in that municipality of 10 million inhabitants. Their program emphasized diagnosis based on bacteriological examination, treatment employing direct observation of a regimen of 12 months of chemotherapy including streptomycin, isoniazid, and para-aminosalicylic acid for one month, followed by twice-weekly streptomycin

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and isoniazid for 11 months, with an emphasis on the successful treatment of newly diagnosed cases, a separate treatment regimen for patients failing to respond to initial treatment, and BCG vaccination of newborns. Over the subsequent decade, the program was expanded from several model areas, where it had proved successful, to cover the entire population of the municipality. Childhood tuberculous meningitis virtually disappeared, and subsequent evaluation of tuberculin reactivity in a cohort of unvaccinated children showed that transmission of tuberculosis has been dramatically reduced. The reduction in transmission paralleled the decline in prevalence of tuberculosis cases in adults whose numbers were rapidly reduced through the implementation of directly observed chemotherapy, even though rifampicin-containing regimens were not used. The success in the model areas at the outset of the program was sufficient to convince the authorities of the municipality to provide full funding as the program was expanded to the whole population, and this treatment has been provided to the entire population free of charge through the resources of the local government. The constraints on implementing successful tuberculosis services were equally in mind in 1977 when the government of Tanzania invited representatives of the International Union Against Tuberculosis, WHO, and the Tanzania Anti-tuberculosis Association to a Meeting on the National Tuberculosis Control Program, financed by the Swiss Association against Tuberculosis, in an attempt to consolidate the sporadic successes achieved in certain parts of the country over the preceding years (34). After this meeting a process was commenced that included the establishment of a panel of national and international participants and a workshop, from which resulted a plan and the establishment of a national committee. The proposal was approved by the Ministry of Health in May 1977 (35). The principles of this program followed those of the Ninth Report of the WHO Expert Committee. Other key components were: A defined structure, with implementation in district health services, a designated health worker responsible to ensure that policies are followed, with support from both an intermediate and central level in order to ensure a regular supply of necessary materials, liaison with other relevant bodies, planning, monitoring, and evaluating services. Standardization of technical policies, including ambulatory treatment with different treatment regimens for new and previously treated patients, procedures for bacteriological monitoring of the results of treatment, case finding focusing on microscopic examination of sputum specimens from patients presenting with symptoms to the routine health services, and vaccination with BCG as part of the expanded program on immunization.

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Enarson Routine evaluation, monitoring activities, and their results using standardized instruments for recording and reporting as an integral part of the routine activities of the program. An in-built program of research as an essential component of the activities and included in the routine budget of the program.

This program was introduced after intensive training of existing health service personnel and with a concentrated effort of supportive visits to the district medical officers who had responsibility for its implementation. At the outset, treatment of cases never previously given chemotherapy involved a daily regimen lasting 12 months: 2 months of isoniazid, streptomycin, and thioacetazone, followed by 10 months with isoniazid and thioacetazone. Early results of the program were disappointing: success in treatment, at the outset just over 30% of sputum smear–positive cases, rose to 56% within the first several years but stabilized at that level. The failure to achieve a higher level of success was primarily caused by a high proportion of patients who failed to complete their treatment. By 1982, it was clear that the results achieved by the program would not be satisfactory if the current strategy was not revised. At this point, it was decided to introduce a rifampicin-containing chemotherapy regimen for the treatment of new cases who were sputum smear positive, consisting of 8 months of treatment: 2 months of isoniazid, rifampicin, pyrazinamide, and streptomycin followed by 6 months of isoniazid and thioacetazone daily. This was administered under very careful supervision, requiring patients to be admitted to the hospital for direct observation of swallowing of medications in the initial intensive phase of treatment while rifampicin was being given. Results in the first groups of patients were very encouraging, with 89% the patients successfully treated. With the progressive extension of this policy, the overall success rate for the whole country in the treatment of new sputum smear–positive cases approached 80% within several years and has remained at this level ever since. The most important component of success in treatment was a reduction in the proportion of patients failing to complete the full course of their treatment. The proportion of patients dying while taking treatment was already very low (6%) even when the success rate of treatment was low, and this changed very little as the success of treatment improved. There was a decline in the proportion of patients in whom the sputum remained or became again smear positive while taking treatment, but this proportion was relatively small (5%) even at the outset. The decline in proportion of cases failing to complete the full course of treatment was the determining factor in the improvement in treatment results. No systematic evaluation was made of the reasons for the decline in failing to complete treatment. The decline did not begin immediately but lagged 18–24 months after introduction of the revised strategy (36). Patients treated in the pro-

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gram pointed out that the community, at the outset, did not believe that tuberculosis was a curable disease, but that it could be controlled only to a certain extent and the moment of death merely delayed. The interaction of groups of patients at various stages in their treatment course at the time that they were in hospital or came together to the ambulatory clinic for the directly observed treatment demonstrated to the patients, their families, and the community that individuals were improving and being permanently cured. This factor was determinative in the increasing proportion of patients who followed their treatment to completion. The health education provided by patient-to-patient interaction was much more powerful than the same health education given by a health worker. Moreover, the daily interaction of patients for directly observed medications provided the opportunity for this interchange. Periodic evaluation of drug susceptibility in a representative sample of patients was undertaken (37). Among patients never previously treated, the proportion of cases resistant to isoniazid was low (
10%) and did not change over the three decades evaluated; resistance to both isoniazid and rifampicin (multidrug resistance) was essentially nonexistent and had not appeared in the community by 1988. The most important factor in preventing the emergence of drug resistance, even while using the medications throughout the country, was undoubtedly the policy to ensure that rifampicin was used only in the initial intensive phase of treatment, along with at least three other medications, and to use thioacetazone, along with isoniazid, in the continuation phase. This minimized the period of directly observed treatment and ensured that rifampicin was never used alone with isoniazid in patients in whom initial resistance to isoniazid was not rare. VIII. Effective Strategies for the Management of Tuberculosis A. Generalization of the Strategy

The success achieved in Tanzania was received with some skepticism; the commitment of the government to health care as a priority, the centralized organization of the health service, and the general accessibility of the health service were thought to be reasons for the success. Clearly, the generalizability of the strategy was not accepted. In consequence, and in collaboration with a number of partners, the strategy was extended during the following 5 years to a number of other lowincome countries: Malawi, Senegal, Mozambique, Benin, Nicaragua, Yemen, Mali, and parts of Kenya (areas with nomadic populations). Similar results were obtained in Malawi (38), Mozambique (39), Kenya (40), Benin (41), and Nicaragua (42). The other countries failed to achieve satisfactory results: in Mali, the failure to extend the services into the periphery compromised accessibility; in Senegal, simple failure to follow the principles (in particular, directly observed

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treatment) compromised the results of treatment; in Yemen, both of these errors resulted in equally inadequate results in spite of strong financial inputs. A critical evaluation of the results, particularly those in Tanzania, as part of a larger project termed the “health sector priorities review” undertaken by the World Bank and published in 1989 (43) demonstrated the success of these programs and pointed out their cost-effectiveness. Based on information obtained from Tanzania for patients commencing treatment in 1986, the estimated costs of this treatment were: per case treated, $123 using the 12-month regimen not containing rifampicin and $168 for the 8-month regimen containing rifampicin; $368 and $314 per case cured; $569 and $514 per death averted. The detailed analysis was extended to include Malawi and Mozambique (44). Average costs per case treated using 8-month chemotherapy were $160–217 with hospitalization and $139–196 for ambulatory treatment. The conclusion of this evaluation was that chemotherapy for sputum smear–positive tuberculosis patients is cheaper than other cost-effective health interventions such as immunization against measles and oral rehydration therapy. Further comparison was made and published in the annual report of the World Bank in 1993 (1). In this report, 47 health interventions were compared for cost and effectiveness: chemotherapy for smear-positive tuberculosis was estimated to cost $1–3 per disability-adjusted life-year saved as compared with a cost of more than $10 for measles vaccination; it was estimated to be among the three most cost-effective of the 47 interventions. B. The “Policy Package”

At the time of the retirement of Dr. Styblo as director of scientific activities, a review of the experience of the International Union Against Tuberculosis and Lung Disease (IUATLD) in the collaborative tuberculosis programs was made (45). Up to that point (1988), a total of 109,691 cases of sputum smear-positive tuberculosis who had never previously received chemotherapy had been evaluated in collaborative programs in Tanzania, Malawi, Mozambique, Nicaragua, and Benin. Among these, 52,840 had been given treatment with the 8-month daily regimen containing streptomycin, isoniazid, rifampicin, and pyrazinamide in the initial 2 months of treatment followed by 6 months of daily isoniazid and thioacetazone. The rifampicin was always directly observed to be swallowed (given combined with isoniazid in the same tablet), and the isoniazid and thioacetazone was also provided as a combined preparation. Of these patients, 80% were successfully treated compared with only 56% of those given the 12-month regimen not containing rifampicin. The conditions necessary for achieving success in these programs were: 1.

Political commitment on the part of government, reflected by the establishment of an adequate structure. This included a designated manager within the district (serving, on average, 100,000 population), an in-

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3.

4.

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termediate-level manager to support the district manager and a central unit for supervision, materials management and training, consisting of a full-time coordinator, as well as logistical support for administration and transport. A secure supply of drugs and materials, including the amount of medications and diagnostic supplies required for regular use as well as a stock (6 months equivalent at central, 3 months equivalent at region, and 3 months equivalent at district levels) to ensure that the supply was never interrupted. A network of microscopy centers with a system of quality control consisting of a binocular microscope and a trained microscopist who, among other duties, carried out sputum smear examinations. Each center was located at the same site as the district manager. Proper recording and reporting of cases, using a standard set of forms and registers: the numbers of cases newly diagnosed and the results of their treatment were recorded and reported on a quarterly basis, based on the “cohort” of patients registered within the same calendar quarter.

In addition, requirements for the introduction of rifampicin-containing treatment regimens were outlined: 1.

2.

3.

Adequate supervision of drug taking during the initial intensive phase, consisting of observing the swallowing of every dose of medication during the period in which rifampicin was being administered. Proper training and supervision of health workers: initial training in the technical policies of the national tuberculosis program was followed by quarterly supportive visits from officers of the program, focusing on the records of patients and interviews with selected individual patients. Step-wise introduction of rifampicin-containing regimens, not at a single point in time. The sites selected for initial introduction were those most likely to achieve success (showing the best results using the 12-month regimen) and gradually but progressively expanded to other sites are thus the majority of patients in the country. Patients unable to participate in direct observation of the swallowing of medications were not given a rifampicin-containing treatment regimen.

This experience was reviewed once again in 1995 (46). From 55,561 cases in 1990 at a total cost of $3.5 million ($63 per case) of donor support, the collaboration increased to include 129,889 cases in 1994 in 26 low-income countries at a cost of $3.0 million ($23 per case). The reduction in cost was primarily due to a reduction in the price of medications obtained through centralized drug procurement with international tender and competitive bidding.

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Enarson C. The Importance of Action Beyond Medication

While these results were encouraging, they were not sufficient to stimulate an adequate response to address the global problem. The most important achievement was the recognition of tuberculosis as a priority among decision makers and their commitment to providing resources to address it. Three important developments helped to promote this recognition and commitment. The first, and probably most important, was the recognition in the popular press, particularly in the United States, of the threat posed by tuberculosis (47). This recognition had an impact far beyond the borders of the United States and extended to decision makers in low-income countries. The second important development was the evaluation by the World Bank of tuberculosis as a high priority, the management of which was among the most cost-effective of any health intervention in low-income countries. The third was the designation by WHO of tuberculosis as a “global emergency.” Recognition of the cost-effectiveness of interventions in tuberculosis led the World Bank to provide loans to a number of countries, many of which, such as China, India, and Bangladesh, have large numbers of tuberculosis cases. These loans have set in motion revised programs based on the experience of the IUATLD collaborative programs and have reported a high degree of success (48). The priority given by WHO has led to a series of actions that have been indispensible to the extension of tuberculosis services in low-income countries. The declaration of a global emergency raised the visibility of tuberculosis in the various regions where the disease is particularly frequent. The acceptance of the thesis that a great deal can be achieved using existing technology (49) has stressed immediate action. The adoption of the principles of the IUATLD collaborative programs, first in the form of the framework for effective tuberculosis control (50), prepared under the leadership of Dr. Petra Graf, and subsequently, under the user-friendly brand name DOTS, has advanced the awareness of the strategy. Subsequently, the Global Tuberculosis Program of the World Health Organization has been markedly expanded in personnel, budget, and activities and has provided the credibility and leadership that had previously been lacking and that can only be provided by an official, governmental organization if it is to gain the attention of political leaders and other decision-makers. IX. Future Challenges A. Feasibility of Elimination

The objective of tuberculosis services is the elimination of tuberculosis; this identifies the strategy to be employed and the methods of evaluation to be undertaken. Is there good evidence that the application of the strategy has reduced the problem of tuberculosis in low-income countries?

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To date there is no incontrovertible evidence that the strategy has dramatically reduced transmission of M. tuberculosis infection in a low-income country. Indirect evidence of the effectiveness of the strategy comes from the experience previously noted in Beijing Municipality, where periodic surveys have shown that the prevalence of cases of tuberculosis has declined rapidly; one can only assume that this must be associated with a decrease in transmission of infection. As expected, the prevalence has declined more rapidly than the rate of newly diagnosed cases. Other indirect evidence comes from Nicaragua (51), where the case-notification rate has declined steadily over the past decade. What is the situation in sub-Saharan Africa? In the countries that have been involved in the IUATLD collaborative programs, case notification has not declined. Indeed, in a number of countries, case rates have risen alarmingly. This is due in large part to the epidemic of acquired immunodeficiency syndrome (AIDS) in these countries (see Chap. 20) (52). The dire predictions of a mathematical model of the impact of the AIDS epidemic on tuberculosis rates in countries of sub-Saharan Africa (53) have been shown to be disturbingly accurate. The impact of AIDS on the global situation of tuberculosis will be substantial as the epidemic spreads in the countries of the Indian subcontinent and Southeast Asia. The only bright spot is that, in spite of the rapid rise in the numbers of tuberculosis cases, it has been possible to maintain a high rate of success of treatment in smear-positive cases. B. Economic Sustainability

While tuberculosis services have been clearly shown to be cost-effective, the increasing economic crisis in many low-income countries has seriously jeopardized the possibility that these services can be routinely provided and sustained over the long term. This situation is leading to increasing donor dependence at a time of “donor fatigue.” If the strategy is donor-dependant, it will not be sustainable in the long term because it calls for efficient application for the duration of a full generation if it is to be effective. Moreover, the increasing reliance on bank loans will only compound the economic crisis as inflation and currency devaluation follow the decline in productivity over the short term. C. Maintenance of the Health Services

The economic crisis affecting many low-income countries and accompanying health sector reform (see Chap. 33) has reduced the number of health care workers, peripheralized decision making, and encouraged privatization of health services. The usual structure of tuberculosis services in the successful models may require revision. This is particularly true where the numbers of cases of tuberculosis are rapidly rising and accessibility to services is already compromised in consequence. Whether cost-effective tuberculosis services can be provided by the

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private sector in low-income countries is not clear. Moreover, the support required from central and regional levels for quality assurance of services in peripheral health facilities may be increasingly difficult to provide as the health sector reform process proceeds. D. Drug Resistance

The wide distribution of resistance, first to isoniazid (54) and then to both isoniazid and rifampicin (55), in low-income countries will be a threat to continued success of the tuberculosis services because cost-effective alternative treatment strategies are simply not available, nor are they expected in the near future. The importance of rapidly implementing the present strategy as a means of preventing further development and spread of drug resistance cannot be overemphasized (56). The ability of the strategy, and particularly the rigorous observation of administration of medications, to prevent the appearance of multidrug resistance has been shown where the strategy has been followed (57). The strategy incorporates specific measures to protect rifampicin, including never using it alone with isoniazid (unnecessary where thioacetazone is used in the continuation phase) (Fig. 3), always using it combined with isoniazid in preparations of proven bioavailability, and observing the swallowing of every dose of medication where rifampicin is given. This is in contrast with the situation where the strategy has not been followed (58). Where case rates can be expected to rise rather than decline, the least that can be done is to ensure that the development of multidrug resistance is minimized. It is highly unlikely that new medications will become available for use in low-income countries in the near future.

Figure 3. Balance of recommended regimens for treatment of new and retreatment cases of tuberculosis, outlining the medications in retreatment not previously used for new cases. Principles are as follows: Assume H resistance, always a companion to R never previously used alone with H. Assume that the patient is incurable when resistant to both H and R.

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References 1. World Development Report 1993: Investing in Health. Oxford: Oxford University Press, 1993. 2. Enarson DA. Why not the elimination of tuberculosis? Mayo Clin Proc 1994; 69: 85–86. 3. Brudney K, Dobkin J. A tale of two cities: tuberculosis control in Nicaragua and New York City. Sem Respir Inf 1991; 6:261–272. 4. Enarson DA, Rouillon A. The epidemiological basis of tuberculosis control. In: Davies PDO, ed. Clinical Tuberculosis London: Chapman Hall Medical, 1993:19–32. 5. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Un Tuberc 1975; 50:90–106. 6. Calmette A, Negre L, Boquet A. Essai de vaccination du lapin et du cobaye contre l’infection tuberculeuse. Ann Inst Pasteur 1922; 36:625–635. 7. Sutherland I, Lindgren I. The protective effect of BCG vaccination as indicated by autopsy studies. Tubercle 1979; 60:225–231. 8. Styblo K, Meijer J. Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem. Tubercle 1976; 57:17–43. 9. Ferebee SH, Mount FW. Tuberculosis morbidity in a controlled trial of the prophylactic use of isoniazid among household contacts. Am Rev Respir Dis 1962; 85: 490–510. 10. Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32:643–653. 11. Kamat SR, Dawson JJY, Devadatta S, Fox W, Janardhanam B, Radhakrishna S, Ramakrishnan CV, Somasundaram PR, Stott H, Velu S. 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. 12. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57:275–299. 13. Bleiker MA, Griep WA, Beunders BJW. The decreasing tuberculin index in Dutch recruits. KNCV Selected Papers 1964; 8:38–49. 14. Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976; 57 (suppl. 4):S1–S58. 15. Nakielna EM, Cragg R, Grzybowski S. Lifelong follow up of inactive tuberculosis: its value and limitations. Am Rev Respir Dis 1975; 112:765–772. 16. Styblo K, Dankova D, Drapela J, et al. Epidemiological and clinical study of tuberculosis in the district of Kolin, Czechoslovakia. Bull WHO 1967; 37:819–874. 17. Nsanzumuhire H, Lukwago EW, Edwards EA, Stott H, Fox W, Sutherland I. A study of the use of community leaders in case-finding for pulmonary tuberculosis in the Machakos district of Kenya. Tubercle 1977; 58:117–128. 18. Lotte A (rapporteur). Results of the multiple radiophotography reading trial performed in 1963. Bull Int Union Tuberc 1965; 38:61–72.

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19. National Tuberculosis Association. Recommendations of the Arden House Conference on tuberculosis. Am Rev Respir Dis 1960; 81:482–484. 20. International work in tuberculosis 1949–1964. Geneva: World Health Organization, 1965. 21. United States Public Health Service Tuberculosis Therapy Trials. Long-term consequences of isoniazid alone as initial therapy. Am Rev Respir Dis 1960; 81:824–830. 22. Halfdan Mahler. “Posthumous” letter to Dr. Holm. Bull Int Union Tuberc 1990; 65 (4):82. 23. Waaler H, Geser A, Andersen S. The use of mathematical models in the study of the epidemiology of tuberculosis. Am J Public Health 1962; 6:1002–1013. 24. World Health Organization. WHO Expert Committee on Tuberculosis, Eighth Report. Geneva: WHO Technical Report Series 290, 1964. 25. World Health Organization. WHO Expert Committee on Tuberculosis, Ninth Report. Geneva: WHO Technical Report Series 552, 1974. 26. Bulla A. World health statistics report: tuberculosis patients—how many now? WHO Chron 1977; 31:35–40. 27. Styblo K, Rouillon A. Estimated global incidence of smear-positive pulmonary tuberculosis. Unreliability of officially reported figures on tuberculosis. Bull Int Union Tuberc 1981; 56:118–126. 28. Grzybowski S, Enarson DA. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc 1978; 53:70–75. 29. Report on the Third Tuberculosis Prevalence Survey in Korea. Seoul: Korean National Tuberculosis Association, 1975. 30. Nationwide random survey for the epidemiology of pulmonary tuberculosis conducted in 1979. Chin J Respir Dis 1981; 5:67–71. 31. Frimodt-Moller J. Changes in tuberculosis prevalence in a south Indian rural community following a tuberculosis control programme over a seven years’ period. Ind J Tuberc 1962; 9:187–191. 32. International Union Against Tuberculosis/World Health Organization. Tuberculosis Control. Geneva: World Health Organization Technical Report Series 671, 1982. 33. Zhang L-X, Kan G-Q. Tuberculosis control programme in Beijing. Tuber Lung Dis 1992; 73:162–166. 34. L Stirling. Address to the National TB Workshop, Arusha, Tanzania, February 24, 1977. 35. International Union Against Tuberculosis. Tanzania National Tuberculosis Programme. Bull Int Union Tuberc 1977; 52:53–64. 36. Enarson DA, Hopewell PC. Treatment of tuberculosis in low income countries. In: Gangadharam PRJ, Jenkins PA, eds. Mycobacteria II: Chemotherapy. New York: Chapman and Hall, 1997:161–182. 37. Chonde TM. The role of bacteriological services in the National Tuberculosis and Leprosy Programme in Tanzania. Bull Int Union Tuberc 1989; 64:37–39. 38. Nuyangulu DS, Nkhoma WN, Salaniponi FML. Factors contributing to a successful tuberculosis control programme in Malawi. Bull Int Union Tuberc Lung Dis 1990/1991(suppl); 66:45–46. 39. Salomao MA, Parkkali LM. Case-finding and treatment results of pulmonary tuberculosis in Mozambique, 1985–1988. Bull Int Union Tuberc Lung Dis 1990 /1991 (suppl); 66:47–49.

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40. Idukitta GO, Bosman MCJ. The tuberculosis Manyatta Project for Kenyan nomads. Bull Int Union Tuberc Lung Dis 1990/1991(suppl); 66:44–47. 41. Gninafon M. The antituberculosis programme of Benin. Bull Int Union Tuber Lung Dis 1990/1991(suppl); 66:57–58. 42. Arguello L. Results of the tuberculosis control programme in Nicaragua in 19841989. Bull Int Union Tuberc Lung Dis 1990 /1991(suppl); 66:51–52. 43. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990; 65:2–20. 44. Murray CJ, DeJonghe 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. 45. Enarson DA. Principles of IUATLD Collaborative National Tuberculosis Programmes. Bull Int Union Tuberc Lung Dis 1991; 66:195–200. 46. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuber Lung Dis 1995; 76:95–99. 47. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991; 144:741– 742. 48. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996; 347:358–362. 49. Styblo K. The epidemiological situation of tuberculosis and the impact of control measures. Bull Int Union Tuberc 1983; 58:179–186. 50. World Health Organization. Framework for effective tuberculosis control. Geneva: WHO / TB/CARG(4)/94.3, 1994. 51. Cruz JR, Heldal E, Amadottir T, Juarez I, Enarson DA. Tuberculosis case finding in Nicaragua: evaluation of routine activities in the control programme. Tuber Lung Dis 1995; 75:417–422. 52. Chum HJ, O’Brien RJ, Chonde TM, Graf P, Rieder HL. An epidemiological study of tuberculosis and HIV infection in Tanzania, 1991–1993. AIDS 1996; 10:299–309. 53. Schulzer M, Fitzgerald JM, Enarson DA, Grzybowski S. An estimate of the future size of the tuberculosis problem in sub-Saharan Africa resulting from HIV infection. Tuber Lung Dis 1992; 73:52–58. 54. Kleeberg HH, Olivier MS. A World Atlas of Initial Drug Resistance. 2d ed. Pretoria: Tuberculosis Research Institute of South African Medical Research Council, 1984. 55. World Health Organization. Anti-tuberculosis drug resistance in the world. Geneva: WHO / TB/97.229, 1997. 56. Chonde TM. The role of bacteriological services in the National Tuberculosis and Leprosy Programme in Tanzania. Bull Int Union Tuberc 1989; 64:37–39. 57. Anagonou SY, Gninafon M, Kinde-Gazard D, Tawo L, Trebucq A, Boulahbal F. Etude de resistance primaire des mycobacteries tuberculeuses aux antibacillaires: une enquete nationale au Benin 1995–1997. Int J Tuber Lung Dis 1997; 5(suppl.):S28. 58. Rodier G, Gravier P, Sevre J-P, Binson G, Omar CS. Multidrug-resistant tuberculosis in the horn of Africa. J Infect Dis 1993; 168:523–524. 59. Bjartveit K. The tuberculosis situation in Norway. Scand J Respir Dis 1978, 102:28–35.

3 Tuberculosis Control in Low-Prevalence Countries

JAAP F. BROEKMANS Royal Netherlands Tuberculosis Association (KNCV) The Hague, The Netherlands

I. The Prospect of Elimination A. Elimination in the Indigenous Population

Tuberculosis remains one of the world’s major public health challenges, causing more than 2 million (mostly young) adult deaths per year. The scale of the problem is such that in 1993 the World Health Organization (WHO) was forced to declare tuberculosis a “global emergency.” This somber picture hides the overall success of tuberculosis-control efforts in most of the industrialized countries. After the Second World War, most industrialized countries successfully moved from high to low tuberculosis prevalence in little more than a generation by effectively treating infectious cases in well-established tuberculosis networks. For example, in the Netherlands the decline in the risk of infection was 4–5% per year between the two world wars, and with the introduction of modern chemotherapy this decline further increased to 13% per year after World War II (Fig. 1) (1). Case rates followed suit (Fig. 2) (1b,2). The tremendous impact of these measures on the tuberculosis situation in the Netherlands is best understood by observing the estimated prevalence of Mycobacterium tuberculosis by age in the indigenous population of the Netherlands in 1940, 1970, 2000, and 2030. In 2030 the prevalence of infection in the Dutch 75

Figure 1 1a.)

Annual risk of tuberculous infection: the Netherlands, 1910–1979. (From Ref.

Figure 2 Annual risks of tuberculous infection and incidence of new active tuberculosis in subjects aged 0–14, 15–19, 20–24, and 25–29 years, the Netherlands, 1952–1970. (From Refs. 1b,2.)

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Figure 3 Estimated prevalence of tuberculous infection prevalence by age, the Netherlands, 1940, 1970, 2000, 2030. (From Ref. 3.)

population will be less than 1% and the incidence of smear-positive tuberculosis is expected to be below 1 per million, the conventional limit of elimination (Fig. 3) (3). Further evidence as to the prospect of elimination can be derived from the decline in the incidence of new bacillary pulmonary cases in the Netherlands. The rates of such cases (foreigners excluded) from 1973–1976 to 1993–1995 declined from 3.7 per 100,000 to 2.4 per 100,000 (Table 1). Moreover, age-specific rates show a marked shift to higher age group, consistent with the underlying shift to higher age groups of the prevalence of infection (Fig. 4). An emerging international consensus defines a low-prevalence country as a country with a reliable case rate (all cases) of 20 per 100,000 and declining. Most industrialized countries fit in this category, although some countries like Spain and Portugal still have rates higher than 40 per 100,000 (Fig. 5). Thus, countries with case rates of 20 per 100,000 and declining can be considered to be in the elimination phase of the disease. However, elimination in low-

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Table 1 Average Annual Notification Rates of Bacteriologically Confirmed Pulmonary Tuberculosis (New Cases Only, Foreigners Excluded) per 100,000 Population, The Netherlands, 1973–1996

Male Female All a b

1973–1976a (P/100,000)

1977–1980a (P/100,000)

1981–1984a (P/100,000)

1993–1996b (P/100,000)

4.9 2.6 3.7

3.9 2.4 3.2

3.5 2.0 2.7

2.6 1.6 2.1

Source: Ref. 3a. Source: Ref. 4.

prevalence countries, given the extent of the underlying high prevalence of infection in older age groups, will take at least another 30–50 years, for which period tuberculosis-control activities, preferably in the context of a national program, must be maintained. B. The Impact of Migration on Low-Prevalence Countries

Since 1992 more than half of all tuberculosis cases in the Netherlands have been among foreigners (Fig. 6). DNA fingerprint technology made it possible to study the impact of migration on the native Dutch tuberculosis situation. From a study

Figure 4 Age-specific rates of infectious cases (Dutch), by age, the Netherlands, 1973–1984 and 1993–1996. (From Ref. 4.)

Figure 5

Incidence rate of notified tuberculosis, 1995, WHO European region. (From Ref. 11.)

Tuberculosis Control in Low-Prevalence Countries 79

80

Figure 6 Ref. 4.)

Broekmans

Notified tuberculosis cases (all forms), the Netherlands, 1974–1996. (From

in 1993–1995 involving all infectious pulmonary cases, it has been concluded that (1) 17% of native Dutch cases can be attributed to recent transmission from a foreign source, (2) 15% of native Dutch cases can be attributed to recent transmission from a native Dutch source, and (3) 68% of cases had a unique DNA fingerprint (or were assigned as the source case of a cluster) and could be attributed to exacerbation of latent infection and not from recent transmission (Fig. 7).

Figure 7

Dutch tuberculosis cases by transmission category.

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In addition to the excess transmission from foreign sources, native cases in low-prevalence countries occur due to infection acquired during travel in highprevalence countries. For example, it is reported that 61 (2%) of 3070 Dutch cases reported in 1993–1996 most likely were due to infection acquired outside the Netherlands (4). An extremely rare situation occurred in 1993–1997 in the Netherlands, when a single infectious source from outside the country caused at least 400 infections and more than 50 bacteriologically confirmed secondary cases. This ongoing cluster epidemic, which could only be studied with DNA fingerprint technology, is characterized by an unusually long patient’s and doctor’s delay in diagnosing the source case, which was a rather asymptomatic illness (5). The initial patient’s social life was extremely active. From the above it can be concluded that migration from countries with a high disease prevalence influences cases rates in low-prevalence countries and even has a distinct effect on transmission. Given the underlying trend in the prevalence of infection in the indigenous population, however, such migration at current rates is unlikely to delay elimination more than a few years. C. Impact of HIV Transmission

The effect of HIV transmission on the elimination of tuberculosis in low-prevalence countries will depend on the “overlap” between the prevalence of tuberculous and that of HIV infection in the population studied. In the Netherlands, the general population younger than 50 years of age is virtually free of tuberculous infection. The prevalence of tuberculous infection for those aged 15–54 years—the age group most vulnerable for HIV transmission—was only 7.1% in 1985 and 2.7% in 1995 (Fig. 3). Although excess cases of tuberculosis will occur due to HIV transmission, this will not result in a subsequent distinct deterioration of the tuberculosis situation in the Netherlands as a whole. In 1993–1996 116 (4.1%) of 2885 Dutch and 146 (4.3%) of 3411 foreign tuberculosis patients were reported to be HIV positive (4). However, because HIV testing is not encouraged, these data are not representative, and the precise interaction between the HIV epidemic and the tuberculosis situation in the Netherlands is not well documented. II. Framework for Tuberculosis Control in LowPrevalence Countries In 1993 WHO published the “Framework for Effective Tuberculosis Control,” which essentially encapsulates the DOTS (directly observed therapy, short course) strategy for high-prevalence countries. No such framework document exists for low-prevalence countries. The decline in disease incidence, the health sec-

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tor reforms, and the shift towards outbreak management of tuberculosis control have major consequences for network maintenance and control activities. A. Consequences of the Decline in Disease Incidence

In a low-prevalence country tuberculosis essentially becomes a rare disease. At the level of the health care provider, a decline in practical experience will result in a decline of expertise in both the clinical and public health management of the disease. At programmatic level a categorical tuberculosis network becomes unsustainable and for this reason needs to be integrated with other public health programs (e.g., other infectious disease programs). A multifunctional approach after such an integration has a diluting effect on the expertise, especially in the public health management of the disease (Fig. 8). In the Netherlands 400 chest physicians and 40 tuberculosis control officers take care of 800 infectious cases annually. After integration in the infectious disease departments of the Municipal Health Services in the early 1990s, 80 multifunctional public health nurses (instead of 40 previously assigned to tuberculosis cases only) became responsible for approximately the same number of tuberculosis patients. B. Consequences of the Health Sector Reform

Most industrialized countries experienced health sector reforms resulting in a decentralization of responsibilities and funding of the management of public health programs. Such developments fragment national tuberculosis networks (Fig. 9). In the Netherlands health sector reform carried out in the early 1990s decentralized funding (from an earmarked national subsidy to a nonearmarked, multipurpose municipal grant) and responsibilities for the tuberculosis program management to 45 administratively autonomous Municipal Health Services.

Figure 8

Consequences of the decline of disease incidence.

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Figure 9

83

Consequences of health sector reform.

C. Consequences of the Shift Toward Outbreak Management

Three distinct but very much interrelated developments elucidate a marked shift towards a more focused public health response during the elimination phase of the disease, best described as shifting away from passive case finding and toward outbreak management (Fig. 10). Occurrence of Microepidemics

In the elimination phase, in which the great majority of the younger population is virtually free of tuberculosis infection, the occurrence of microepidemics becomes a discernible epidemiological event. Microepidemics require a highly specialized public health response, based on the “stone in the pond principle.” Such outbreaks are often characterized by a single source of infection with a marked patient and/or doctor’s delay. A specific institutional environment (e.g., discotheque, school, or prison) may facilitate transmission to a multitude of contacts (see Chap. 15).

Figure 10 Consequences of shift towards outbreak management.

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During the elimination phase, in which the great majority of the young population is virtually free of infection, specific high-risk groups tend to be characterized by a higher prevalence of infection and/or disease than the general population. Such high-risk groups are often characterized by socially marginalized conditions. In the Netherlands, drug abusers, homeless persons, prisoners, and the foreign-born from high-prevalence countries have been found to have higher rates of tuberculosis. Identifiable high-risk groups thus become accessible for active case finding. In the Netherlands a high-risk group is characterized by a registered tuberculosis incidence (all cases) of 50 per 100,000 or more (6). Active case finding in such groups becomes the policy of choice where the following conditions are met: Passive case finding well organized Favorable treatment results (80%) in patients diagnosed by passive case finding Built-in evaluation of coverage and yield of the target population Treatment outcome monitoring Activities in accordance with ethical and legal regulations The importance of active case finding in high-risk groups is illustrated by the coverage and yield of screening asylum seekers on entry in the Netherlands in 1993–1996 (Table 2) (7). Introduction of DNA Fingerprint Technology

DNA fingerprint technology may revolutionize tuberculosis control in low-prevalence countries because of its ability to detect recent transmission (see Chap. 11). The application of this technology in a control program clarified and elucidated the epidemiological situation in the country as a whole, as well as the emergence Table 2 Tuberculosis Among Asylum Seekers Screened on Entry, The Netherlands, 1993–1996 Asylum seekers Examined Year 1993 1994 1995 1996

N

%

31,578 (90%) 42,939 (95%) 24,424 (97%) 17,919 (90%)

Source: Ref. 7.

Tuberculosis cases on entry

Total

All cases

Infectious PTB

N

N

p/100,000

N

p/100,000

35,000 45,202 25,089 19,868

137 149 94 52

434 347 385 290

46 61 40 26

146 142 164 145

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85

of high-risk groups and so-called cluster epidemics in particular. The specific “added value” of the application of this technology in routine program management is still limited, but its potential in identifying outbreaks in special settings, only suspected to occur in earlier decades, makes it potentially an extremely powerful new tool in tuberculosis control in low-prevalence countries. The great challenge to program management will be to demonstrate the specific role of this technology in the actual control of cluster epidemics. The occurrence of microepidemics, the emergence of high-risk groups, and the ability to substantiate recent transmission by DNA fingerprint technology are characteristic for the shift towards outbreak management that is due to occur in the elimination phase of tuberculosis. Away from but definitively not excluding the emphasis on passive case finding, this shift toward outbreak management constitutes a paradigm shift in control technology. D. Program Support and Coordination

Declining expertise due to declining incidence and integration of services, the danger of fragmentation of the tuberculosis network, and, moreover, the unmistakable shift toward outbreak management require urgent reassessment as to maintain an adequate tuberculosis network during the elimination phase of the disease (Fig. 11). In the Netherlands the national support and coordination functions were reexamined against that background. Key (government) functions and supportive (nongovernmental) functions were delineated (Table 3). Key functions are vital for the support and coordination of the tuberculosis network. Supportive functions add value to the activities of the tuberculosis network. Within the network itself it is of major importance to continue to have identifiable and accountable staff (e.g., tuberculosis control officers, public health nurses) to guide and execute program implementation.

Figure 11 Key issues within the tuberculosis network in the elimination phase.

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Key and Supportive Functions for Program Maintenance

Key functions for program maintenance: Consensus-based technical and policy guidelines Consensus-based system of quality assurance Surveillance Program monitoring Technical support by national consultants Supportive functions for program maintenance: Graduate/Postgraduate training Development of health-education material Research Documentation center International collaboration

E. Legal Framework

There exists a growing awareness of the importance of a legal framework to guide program policies. In most industrialized countries such a legal framework underlies most tuberculosis control activities. Surveillance, specific interventions such as screening of foreigners on entry, prisoners, sailors etc., mandatory isolation of noncompliant infectious patients, and even the specific functions of a tuberculosis clinic are often written in special laws or other official government documents. The distinct importance of a transparent and, from the public health point of view, up-to-date legal framework is not very well known. Research in this area is urgently needed for this reason as well as for the benefit of the implementation of WHO DOTS strategy in high-prevalence countries.

III. Surveillance A. Surveillance of Infection

The annual tuberculosis infection rate is the best single indicator for evaluating the tuberculosis problem and its trend in developed and developing countries. It is an index that expresses the attacking force of tuberculosis within a given population and, unlike disease notification rates, is not linked directly to the case-finding and treatment measures of the tuberculosis program. In the Netherlands the decline of the risk of infection was 13% annually in 1956–1965, 10.4% in 1966–1979, and 8.3% in 1979–1991 (Fig. 12). It is estimated that the annual rate of infection in the Netherlands was less than 10 per 100,000 in the mid-1990s.

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Figure 12 Prevalence of tuberculous infection and annual risk of tuberculous infection, the Netherlands, 1956–1991. (From ITSC/TSRU, unpublished.) B. Surveillance of Recent Transmission

Introduction of DNA fingerprint technology in control programs in low-prevalence countries enables the identification of cluster epidemics and may open the way to control the size of these clusters (Table 4). The use of DNA fingerprint Table 4

The Four Largest Cluster Outbreaks, The Netherlands, 1991–1997

Number of cases with identical DNA fingerprint from January 1, 1991 66 55 50 41 Source: Ref. 8.

Notification of first source case

Cluster growth in 1997

July 1991 March 1993 July 1993 December 1992

11 10 6 13

Nature of cluster (proportion attributed) Homeless/Drug abusers (77%) Related to foreign source (92%) Homeless/Drug abusers (60%) Asylum seekers (Ethiopia/ Somalia) (95%)

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technology often validates routine contact examinations and contributes to the identification of epidemiological links previously unsuspected (8). C. Surveillance of Disease

Notification of New and Relapse Cases

The notification rates of new and relapse cases in low-prevalence countries are of greatest value in evaluating the overall epidemological situation. In general, significant intracountry differences exist in the trend and level of notification. Resurgent tuberculosis in central Harlem in New York City was attributed to the effects of HIV transmission, homelessness, and the premature disintegration of the tuberculosis program. Implementation, at great cost, of standard control measures redressed the situation effectively. Even in a small country like the Netherlands, notification rates may differ from 25–35 (all cases) per 100,000 in major metropolitan areas to 5–10 (all cases) per 100,000 in more rural areas. Notification Rates for Infectious Pulmonary Tuberculosis

Notification rates of infectious pulmonary tuberculosis provide a sensitive measure for the occurrence of sources of infections in the population and its trend towards elimination (Table 1 and Fig. 4). Surveillance of Drug Resistance

Systematic surveillance of initial drug resistance in new cases and acquired resistance in retreatment cases may be of importance for both epidemiological surveillance as well as a measure of program performance. A special study concluded that in the Netherlands three quarters of all drugresistant cases occur in foreign-born persons (9). The great majority of these patients were infected or poorly treated in their country of origin. Thus, the rates of drug resistance in tuberculosis cases in the foreign-born in the Netherlands do not reflect the actual program performance in the Netherlands (Table 5). In the same Table 5

Drug-Resistant Pulmonary Tuberculosis, The Netherlands, 1993–1995

Isoniazid Streptomycin Rifampicin Other anti-TB drugs Any drug resistance Source: Ref. 4.

Asylum seekers, N  351 (%)

Other foreigners, N  786 (%)

Dutch N  1089 (%)

14 14 3 4 22

8 9 2 1 15

3 3 1 1 6

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study it was observed that in Dutch patients both acquired and primary drug resistance were rare. The high mean age of Dutch patients with drug-resistant tuberculosis suggests that this level of drug resistance mostly reflects program performance of a more distant past (9). D. Surveillance of Mortality

In low-prevalence countries, mortality rates are of only historical value in indicating the extent of the tuberculosis problem and its trend. With the introduction of effective chemotherapy after World War II, mortality rates have been reduced to very low levels. IV. Program Monitoring A. Surveillance of Diagnostic Measures

Patient and Doctor Delay

Patient and doctor delays in the diagnosis of sources of infection, an inevitable phenomenon of a case-finding and treatment program, is of importance because it contributes to transmission and microepidemics. Routine surveillance data from the Netherlands, compared with earlier studies, suggest an increased patient and doctor delay for Dutch patients. This observation may be consistent with the fact that tuberculosis is becoming a rare disease for Dutch patients and Dutch physicians. The comparatively shorter delays for foreign-born patients could be consistent with active case finding among foreigners and/or greater awareness among physicians that tuberculosis is still a problem among foreign-born persons (Table 6). Further studies are necessary to validate these findings. Table 6 Patient and Doctor Delay Bacteriologically Confirmed Pulmonary Tuberculosis Patients, The Netherlands, 1973–1996 1973–1976a Months

N

1–2 1346 3–4 713 5 or more 468 Total 2527 No 78 information a b

Source: Ref. 3a. Source: Ref. 4.

1977–1980a

1981–1984a

1993–1996b Dutch

1993–1996b Foreigners

%

N

%

N

%

N

%

N

%

53 28 19 100 3

1136 601 450 2187 52

52 27 21 100 2

996 469 374 1839 77

54 26 20 100 4

326 203 217 746 142

44 27 29 100 16

455 187 165 807 156

56 23 20 100 16

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Mode of Detection, The Netherlands, 1993–1996 1993–1996

Case finding Active case finding (screening) Passive case finding (complaints) Other/Unknown Total

N

%

1671 4482 492 6645

25 67 7 100

Source: Ref. 4.

Mode of Detection

In low-prevalence countries, in addition to passive case finding among self-reporting suspects, active case finding by screening of risk groups and the containment of microepidemics and cluster epidemics has become progressively more important. For example, in the Netherlands in 1993–1996, 25% of cases were detected by active case finding (Table 7). In the Netherlands in 1993–1996, 50% of patients were diagnosed by chest physicians, 21% by other clinical specialists, and 29% by tuberculosis control officers of a Municipal Health Service (Table 8) (4). B. Surveillance of Treatment Measures

Treatment-Outcome Monitoring of Infectious Pulmonary Cases

The first aim of a tuberculosis program is to cure all (or nearly all) sources of infection. To what extent the treatment results achieved in a tuberculosis program approximate the results obtained in controlled clinical trials is the most important issue in the surveillance of treatment measures.

Table 8 Mode of Detection, The Netherlands, 1993–1996 1993–1996 Diagnosing physician Chest physician Other specialist TB control officer Total Source: Ref. 4.

N

%

3294 1448 1903 6645

50 21 29 100

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Table 9 Treatment Outcome Monitoring of Infectious Dutch Cases, The Netherlands, 1993–1996

Treatment result Total (N) Cured/Completed Interrupted Died (TB) Died (non-TB) Transferred out

1993 (%)

1994 (%)

1995 (%)

1996 (%)

(329) 74.5 7.9 3.3 12.5 1.2

(410) 81.2 5.9 1.7 11.2

(368) 80.4 4.3 3.0 11.7 0.5

(410) 84.4 2.0 3.7 10.0

Total N

%

1517 1224 74 44 171 4

100 80.3 4.9 2.9 11.2 0.4

Source: Ref. 4.

In the Netherlands the treatment success rate in Dutch infectious pulmonary cases was 80% for the period 1993–1996 (Table 9). The treatment success rate would be substantially higher if it was corrected for the relatively high case fatality due to other diseases than tuberculosis. The treatment success rate in nonDutch infectious pulmonary cases (Table 10) was 83% in the same period, with a markedly higher interrupted rate of 9.1% than in the Dutch cohort 4.9%. The importance of treatment outcome monitoring in specific subgroups is demonstrated by the fact that among asylum seekers 10% interrupted treatment in 1993–1996 (Table 11) (4). Directly Observed Treatment

The great majority of patients in low-prevalence countries are treated by medication self-administration. With an increasing proportion of patients coming from Table 10 Treatment Outcome Monitoring of Infectious Non-Dutch Cases, The Netherlands, 1993–1996 Total

Treatment result

1993 (%)

1994 (%)

1995 (%)

1996 (%)

N

Total (N) Cured/Completed Interrupted Died (TB) Died (non-TB) Transferred out

(429) 79.7 11.2 1.2 3.3 4.4

(453) 78.4 12.4 0.7 2.2 6.4

(401) 85.8 6.5 0.5 1.5 5.7

(420) 86.9 6.0 0.7 1.4 5.0

1703 1411 155 13 36 88

Source: Ref. 4.

% 100 82.6 9.1 0.8 2.1 5.4

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Table 11 Treatment Outcome Monitoring of Infectious Asylum Seekers Only, The Netherlands, 1993–1996

Treatment result Cured/Completed Interrupted Died (TB) Died (non-TB) Transferred out Total

1993 (N)

1994 (N)

1995 (N)

1996 (N)

90 11 1

116 18 1

128 13

112 10

7 109

6 141

1 2 144

3 125

Total N

%

446 52 2 1 18 519

85.9 10.0 0.4 0.2 3.5 100

Source: Ref. 4.

specific risk groups and proportionally more patients detected by active case finding, direct observed treatment becomes an increasingly important intervention (see Chap. 16). Based on a special survey, it was observed that in 1996 at least 78 (4.6%) of 1678 cases reported in the Netherlands were put on direct observed treatment (10). References 1. Styblo K, Meijer J, Sutherland I. The transmission of tubercle bacilli. Its trend in a human population. Tuberculosis Surveillance Research Unit Report No. 1. Bull Int Un Tuberc 1969; 42:5–104. 1a. Sutherland I, Bleiker MA, Meijer J, Styblo K. The risk of tuberculous infection in The Netherlands from 1967 to 1979. Tubercle 1983; 64:241–253. 1b. Styblo K. Epidemiology of Tuberculosis. In: Selected papers, Vol. 24, KNCV, The Hague, The Netherlands. 2. Styblo K, Meijer J. Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem. Tubercle 1976; 57:17–43. 3. Styblo K. The elimination of tuberculosis in the Netherlands. Bull Int Un Tuberc 1990; 65:49–55. 3a. van Geuns HA, Hellinga HS, Bleiker MA, Styblo K. Surveillance of diagnostic and treatment measures in The Netherlands. Comparison between the periods 1971–1976, 1977–1980, and 1981–1985. Tuberculosis Surveillance Research Unit of the International Union Against Tuberculosis. Progress Report 1987; 1:60–81. 4. Index Tuberculosis 1993–1996. Netherlands Tuberculosis Register (NTR/KNCV). The Hague, The Netherlands, 16 Feb 1998. 5. Kiers A, Drost AP, Soolingen D van, Veen J. Use of DNA fingerprinting in international source case finding during a large outbreak of tuberculosis in the Netherlands. Int J Tuberc Lung Dis 1997; 1:239–245. 6. Tuberculosis Control in High Risk Groups in The Netherlands. Netherlands Tuberculosis Policy Committee/KNCV, The Hague, The Netherlands, 1997.

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7. Annual Reports 1993–1996 Tuberculose-screening asielzoekers in opvangcentra. Regio Noord en Zuid Nederland, Municipal Health Service Tilburg and Municipal Health Service Lelystad. 8. Data from KNCV/RIVM Surveillance Project, The Hague/Bilthoven, The Netherlands. 9. Lambregts-van Weezenbeek CSB. Drug-resistant tuberculosis in the Netherlands: trifle or threat? Thesis, University of Amsterdam, 1998. 10. Verhagen M. DOT in Nederland. Ervaringen met en meningen over directly observed therapy bij door Nederlandse GGD’en georganiseerde tuberculosebestrijding. Venlo, The Netherlands, 1998. 11. Euro TB Surveillance of Tuberculosis in Europe. Report on the feasibility study (1996–1997). Tuberculosis cases notified in 1995. European Centre for the Epidemiological Monitoring of AIDS (CESES) and Royal Netherlands Tuberculosis Association (KNCV), Saint Maurice, 1997.

4 Tuberculosis Laboratories The Centerpiece of National Tuberculosis Control Programs

ADALBERT LASZLO Health Canada, Ottawa, and International Union Against Tuberculosis and Lung Disease Nepean, Ontario, Canada

I. Introduction By March 1882, when Robert Koch reported his momentous discovery to the monthly meeting of the Berlin Physiological Society, tuberculosis in Europe had already been in decline for over a generation. In spite of wars and economic depressions, this decline was further accentuated during the first half of the twentieth century, probably fueled by improving socioeconomic conditions and the isolation of infectious cases in sanatoria. The end of World War II marked a turning point in tuberculosis prevention and control programs. In the late 1940s and early 1950s, mass radiography campaigns and bacille Calmette-Guérin (BCG) vaccination programs were introduced almost concurrently with the beginning of the chemotherapy era in industrialized countries as well as in some developing countries. Because the majority of tuberculosis cases are pulmonary, chest x-rays have, from the beginning, played an important role in tuberculosis case finding and in the assessment of the severity of disease. Despite the fact that no chest radiographic pattern is characteristic of tuberculosis and that a scar is not indicative of active disease, certain configurations are still considered by some as highly suggestive of tuberculosis. These assumptions did not apply to as many as one third of patients diagnosed with pulmonary tuberculosis who, even before the HIV/AIDS 95

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era, were found to have “atypical” chest x-ray patterns. Furthermore, observer error of interpretation of chest radiography films, extensively studied in the late 1940s and early 1950s, was found to be invariably and unacceptably high, with rates of underreading of up to 43% (1). By the early 1970s, periodic radiographic screening campaigns of entire populations were shown to be an inefficient tool of tuberculosis control because of low yields (only 20% of new cases were being discovered) (2). This was explained by the fact that infectious cases develop faster than repeated screening can logistically and economically follow up (3). Case finding by the detection of acid-fast bacilli in sputum, on the other hand, was less prone to misinterpretation and much less expensive than chest radiography. Although Ziehl-Neelsen (ZN) sputum smear microscopy can detect only about 60% of all adults with pulmonary tuberculosis, its specificity is at least 90%, especially in developing countries. Due to the fact that it provides actual proof of the presence of bacilli, that it can give a measure of the extent of disease, and provide an indication of the progress of chemotherapy, sputum smear microscopy is an important diagnostic tool in developed countries (4) and the diagnostic cornerstone of national tuberculosis programs (NTPs) in developing countries (5). Disparity in the results obtained in BCG controlled trials during the 1950s prompted organization by the Indian Council of Medical Research in cooperation with the World Health Organization (WHO) and the Centers for Disease Control, U.S. Public Health Service, of a large-scale controlled BCG trial in south India. Starting in 1968, it included 260,000 participants, but the first results in 1979 (6) showed that there had been no protective effects. Indiscriminate mass BCG vaccination campaigns had been superseded by mass vaccination of newborns and young children, but by the mid-1970s it became evident that this tuberculosis-prevention measure would not substantially improve the overall epidemiological situation (7). The main reason for this was that more than 95% of reported tuberculosis cases among children are smear negative, and it has been shown that smear-negative patients are much less infectious than smear-positive ones. Furthermore, the protection afforded by BCG vaccination was found to be transient at best. In the late 1950s, in spite of early scepticism, it became evident that adequate chemotherapy was the best available tool to achieve high cure rates (8) and to control tuberculosis in the community. Adequate chemotherapy accelerated the decline in the risk of infection by 10–14% in developed countries, whereas in developing countries, which today carry 95% of the world’s burden of tuberculosis, the annual decrease rates were very low during the last four decades—as low as 1 or 2% in certain African countries such as Tanzania (9). This could be ascribed mainly to poor chemotherapeutic services in these countries. Therefore, the picture emerging in 1964 when the rationale for the WHO national tuberculosis program was being formulated and in 1974 when it was further refined by a WHO expert committee (10) was that tuberculosis control as well as

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prevention could be achieved by adequate chemotherapy and that the detection of contagious sources of tuberculosis in the community could best be attained by inexpensive bacteriological means. By that time, tuberculosis in developed countries was perceived as virtually eradicated, and it was only in some developing countries that the principles of tuberculosis control and prevention described in the 1974 WHO document were formally adopted and implemented, with varying degrees of success. Since the late 1970s, the focus of the International Union Against Tuberculosis and Lung Disease’s (IUATLD) activities with respect to tuberculosis has been the development of an appropriate model for the NTPs of developing countries (11). This model was developed in Tanzania and subsequently applied to six other countries in Africa as well as to Nicaragua and Vietnam. In 1989, this model was evaluated by the Health Sector Priority Review of the World Bank and assessed as being among the most cost-effective of any health intervention strategy in developing countries. II. National Tuberculosis Programs The major sources of infection in the community are smear-positive pulmonary tuberculosis patients (2,12); smear-negative, culture-positive patients are much less infectious. The rapid discovery of infectious cases is a high priority, because it usually leads to the cure of the individual and the elimination of a source of infection in the community. Where resources are scarce, case-finding methods are limited to activities that have been shown to bring the highest rewards at the lowest possible cost. In most low-income countries, passive case finding for smear-positive cases, active case finding for contacts, and the simultaneous raising of community and medical profession awareness have become the method of choice for their tuberculosis control programs (13). Experience from recent decades indicates no improvement of tuberculosis rates in developing countries without a well-run NTP. The rationale for a NTP is based on the following facts (14): 1. Tuberculosis can be controlled with available tools under any socioeconomic circumstances because the infectious agent has only one major reservoir—the diseased patient—who can quickly be rendered noninfectious. This is particularly true for epidemiologically significant M. tuberculosis infections, which are almost exclusively confined to humans and captive primates (15,16). 2. Since there is a natural balance between the tubercle bacillus and the human host, any reduction of sources of infection will inevitably improve the epidemiological situation. A sputum smear–positive patient, if left untreated, will infect on average 10–15 close contacts per year; if

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The principles for the NTPs reviewed and expanded in the Ninth Report of the Expert Committee on Tuberculosis (10) are the following: 1. The distribution of tuberculosis cases is fairly even, and since populations in developing countries, in spite of rapid urbanization, are still predominantly rural, the program has to be delivered countrywide. Due to the disease’s transmissibility and the high mobility of populations, solutions must be found for the entire community; failing this, the part of the population without coverage will keep transmitting the disease to the part of the population receiving coverage. This is one condition that is often difficult to fulfill because of inadequate primary health service coverage in most developing countries. Fragmentation of tuberculosis control efforts in many countries between different governmental agencies and nongovernmental organizations poses a severe problem because of lack of uniformity in diagnostic and treatment guidelines. This lack of uniformity inevitably leads to poor treatment practices and to less than ideal program performance. 2. Most of the population in developing countries has been infected with tubercle bacilli and the risk of infection remains high, therefore the program must be permanent. Tuberculosis infection is chronic in character, with the possibility of endogenous reactivation many years after infection. This implies that once established, the NTP should be continued until tuberculosis is under control. Nowhere did the potential of modern tuberculosis-control measures became more apparent than in the Yukon Territory, Canada, where the Inuit (Eskimo) population’s rates of infection and disease in 1950 were among the highest ever reported and where by the 1970s the incidence of new infection was too low to be determined with accuracy (18,19). 3. To satisfy the demand of the populations, the program should provide universal accessibility and be effective enough to maintain credibility. Nothing can hurt the credibility and reputation of a NTP more than an interruption of tuberculosis-control activities leading to poor treatment practices and the creation of multidrug resistance. 4. To meet these requirements, the program must be integrated within the community health-delivery structure. Diagnosis and treatment of tuber-

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culosis should be conducted at the district level with supervision, training, monitoring, and leadership provided by the NTP (19). These principles were subsequently adapted and reformulated by WHO as the DOTS (directly observed therapy, short course), an appropriate model for tuberculosis control in developing countries (20). The DOTS strategy for tuberculosis control in developing countries is meant to provide short-course chemotherapy under direct observation to at least all identified smear-positive tuberculosis cases. Its targets are 1) to cure 85% of new detected cases of sputum smear–positive pulmonary tuberculosis worldwide and 2) to detect 70% of existing cases of sputum smear–positive pulmonary tuberculosis. The success of this strategy depends on the implementation of the five following points: political will, passive case finding, short-course chemotherapy for all smear-positive pulmonary tuberculosis cases, regular, uninterrupted supply of all essential antituberculosis drugs, and a monitoring system for program supervision and evaluation. The DOTS network has expanded from 11 countries in 1992 to 96 countries in 1997; patients under effective tuberculosis therapy consistent with the DOTS approach have increased 10-fold from fewer than 100,000 in 1993 to about 1 million in 1997 (21). III. Tuberculosis Diagnostic Services Tuberculosis bacteriology is a complex and demanding branch of clinical microbiology. Unlike in some other infectious diseases, the tuberculosis clinical laboratory plays a critical role, not only in the diagnosis of the disease and the management of the patient, but also in control and elimination strategies. Laboratory results are used to: Detect and confirm cases with diagnostic smear microscopy. Follow-up treatment by performing control smear at the end of the initial phase of treatment to verify significant reduction in the population of bacilli, at the middle of the continuation phase to check patient evolution and to detect possible treatment failure, and at the end of treatment to verify cure. Increase case finding by the introduction of culture once smear microscopy has reached its maximum case-finding capability. Guide the treatment of relapses and treatment failures by providing drug-resistance information on these cases. Measure the success of treatment strategies and adjust treatment policies by monitoring trends in drug resistance in the community. Define outbreaks by establishing relationships between M. tuberculosis isolates.

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Tuberculosis laboratory diagnostic services must be closely coordinated with the administrative, epidemiological, and clinical components of the NTP. They must be developed jointly and concurrently with the other NTP components in order to achieve the widest possible coverage by integrating activities within the structure of the general health services in a country or region. The bacteriological diagnostic services must work as part of the integrated NTP, and the NTP managers along with the managers of the general health laboratory programs must determine the organization of these services while observing the following principles: National standards for methods, procedures, and laboratory techniques Executive decentralization down to the least complex diagnostic levels Effective supervision and quality assurance from the immediately superior level Interdependence of the various diagnostic levels with full reciprocal access and feedback between them In the context of a developing country’s NTP, case finding refers to the diagnosis of sputum smear–positive disease and passive case finding, where the first move toward diagnosis is made by the patient, is the method of choice. From the NTP’s perspective, the order of priority for the TB laboratory network diagnostic bacteriological techniques is direct sputum smear examination, culture of sputum specimens, and drug susceptibility of M. tuberculosis complex isolates.

IV. Tuberculosis Diagnostic Techniques Direct sputum smear bright-field microscopy examination with ZN staining is recommended for peripheral laboratories. The use of fluorescence microscopy can be justified if large numbers of smears are examined (i.e., more than 50 per day), a situation that is only likely to happen in intermediate or in central laboratories. Culturing of clinical specimens in addition to smear microscopy will increase case finding by 20–30%. Since this mode of diagnosis is considerably more expensive than smear microscopy, it will probably be introduced when smear microscopy alone has reached the limit of its diagnostic capability, i.e., when the number of smears needed to diagnose a case of tuberculosis becomes too large and when increasing the number of smear examinations per tuberculosis suspect is no longer cost-effective. Culturing is obviously a prerequisite for drug susceptibility testing; it also can be used to confirm cure. Decontamination using 4% NaOH (22) and inoculation on egg-based media are time-honored, recommended procedures. Drug susceptibility testing capability is needed for laboratory-based surveillance of primary and acquired drug-resistant tuberculosis. The proportion method performed on egg-based Loewenstein-Jensen (LJ) medium is the most widely used drug susceptibility testing method for M. tuberculosis.

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V. The NTP National Tuberculosis Laboratory Network Implicit in the organization principles enunciated above is the concept of the national tuberculosis laboratory network as a tool for delivering tuberculosis diagnostic services. This laboratory network consists of a structure in which various laboratories, working at different levels of complexity of service, are united by the common objectives of the NTP. This unity manifests itself mainly through a common set of standards, information systems, goods and services offered, and quality assurance. A network provides a structure within which many laboratories are linked by information, supplies, supervision, and quality assurance programs. The network is necessary because smear microscopy must be carried out in accordance with standards, as near as possible to the patient’s home, and with an assurance of quality. In turn, the network will provide information at all levels required for the planning and the evaluation of the NTP. This information essentially refers to: 1.

2.

3.

4.

5.

Tuberculosis suspects: periodic and continuing information on the number of people presenting with chest symptoms examined by the network makes it possible to evaluate case-finding activities and to identify possible difficulties that may arise and the places where they may occur, in order to take remedial action. Case finding: if coverage is good, the trend in tuberculosis cases detected by smear microscopy is known to be the best indicator of the NTP’s diagnostic effectiveness. Cases diagnosed and treated: comparison of information in the tuberculosis laboratory register, the district tuberculosis register, and the patient’s treatment cards. Trends in bacteriological confirmation: a good operational indicator of the quality of the NTP—the higher it is, the better the NTP is likely to be. Cure rate: negative bacteriology at the end of treatment is the best indicator of the NTP’s efficacy and efficiency.

VI. Structure and Function of the National Tuberculosis Laboratory Network Ideally, a TB laboratory network would consist of the following levels: A. The Central Level (Type I or A) Laboratory

A central, national tuberculosis reference laboratory for the whole country, staffed with highly qualified personnel working in an adequate physical environment,

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with up-to-date equipment and quality reagents, represents the highest level of technical complexity and excellence in the field. It should be able to: Elaborate national guidelines for diagnostic, quality assurance, and biosafety procedures and techniques Perform direct smear microscopy and culture for its catchment area, drugsusceptibility testing, and species identification of the M. tuberculosis complex Coordinate the activities of the laboratory network Supervise, evaluate, and provide a program of quality assurance for the diagnostic services of the NTP Train technical/scientific personnel in all aspects of the network’s activities Certify TB laboratories of the private sector and promote the incorporation of new laboratories into the network Advise health professionals and institutions of this sector on available diagnostic technologies and on the interpretation of results Evaluate and introduce new diagnostic technologies for use in the network Collect and help evaluate the laboratory data obtained within the network and participate in epidemiological research of interest to the NTP B. The Intermediate-Level (Type II or B) Laboratory

Regional or provincial laboratories reflecting the political, administrative, or health structures of the country. Their main functions are: To coordinate the activities of the laboratories under their jurisdiction To provide logistic support (supplies and reagents) to the laboratories under their jurisdiction To perform smear microscopy and culture for their catchment area To train, supervise, and evaluate the local or peripheral laboratories under their jurisdiction To refer smear microscopy slides to the national reference laboratory for quality-control purposes, to perform quality control of smear microscopy, and to implement quality-improvement measures in the laboratories of their jurisdiction To refer cultures to national reference laboratory for drug-susceptibility testing To generate and provide laboratory-based surveillance data to the national reference laboratory. C. The Peripheral-Level (Type III or C) Laboratory

These laboratories, at the local or district level, are usually located in hospital health centers or posts and are staffed with at least one clinical laboratory tech-

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nologist, who should be able to: Collect samples during regular laboratory opening hours Collect samples from specimen collecting units Perform smear microscopy for the area (district) of jurisdiction Refer specimens for further testing to the corresponding intermediate laboratory Participate in the network smear microscopy quality-assurance program Specimen-collecting units are health establishments that do not possess a laboratory; they collect clinical specimens for referral to the district laboratory.

VII. The National Tuberculosis Laboratory Network as a Source of Data An increasing number of countries are following recommendations developed by IUATLD and adopted by WHO on recording and reporting of tuberculosis suspects and cases. Proper recording and reporting will facilitate budgeting and planning, provide better understanding of the epidemiology of tuberculosis, and assist in developing hypotheses about phenomena observed in the descriptive epidemiology of tuberculosis case-finding and treatment activities. A tuberculosis laboratory register is kept in all laboratories of the network. The IUATLD tuberculosis laboratory register (11) assigns a single line to each person examined and should contain the serial number of each consecutive sputum smear starting with #1 each year. The date of examination, the name, address, gender, and age of the patient, the name of the health unit requesting the examination, the purpose of the examination (diagnosis or treatment follow-up), and the result of the examination should be noted. Two additional columns provide space for the technologist’s signature and for remarks. The laboratory register therefore provides the following information: Number of examinees Number of tuberculosis suspects examined Number of diagnostic smears per suspect Number of new smear-positive cases detected Number of patients with follow-up Number of follow-up smears per patient Number of smear-negative patients at the end of the initial phase of treatment Number of smear-negative patients at the middle of the continuation phase of treatment Number of smear-negative patients at the end of treatment

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The laboratory register can provide useful information on the laboratory workload, performance, and demographic characteristics of the examinees (23), for example: The number of smears examined per working day The relative smear microscopy diagnostic laboratory workload The proportion of smear-positive cases among suspects The proportion positive on first sputum smear examination The incremental yield with second sputum smear examination The incremental yield with third examination The proportion of patients with follow-up The number of smears examined per case The relative treatment-control smear microscopy laboratory workload The gender-specific proportions of suspects by age The gender-specific proportions of cases by age The age-specific ratios by gender

IX. Conclusion There probably is no contagious disease that relies more for its control and prevention on laboratory-generated test results than tuberculosis. A tuberculosis laboratory network functioning in concert with a model NTP is an essential tool providing efficient, yet inexpensive, support for the diagnostic and treatment activities of the NTP. Laboratory diagnostic services used intelligently with the support of simple yet efficient information systems, such as those afforded by the District Tuberculosis Register, the Tuberculosis Laboratory Register, the Register for TB Suspects, as well as the Patient’s Treatment Card, provide all the elements required for program evaluation without which a modern NTP cannot exist. Results derived from the tuberculosis laboratory network can also be used to obtain laboratory operational indicators that are needed to improve the overall quality of the NTP. They can also be used to obtain essential tuberculosis epidemiological information about the population covered by the NTP. Drug-susceptibility testing services, by measuring the extent and trend of drug-resistant tuberculosis, can predict the efficiency of treatment and help guide treatment policy by adjustment of chemotherapeutic regimens. In spite of their importance to the NTP, tuberculosis laboratory support activities have all too often been neglected in many countries. This circumstance could be the main reason for the poor performance of these

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NTPs, since it can be noted that no successful NTP is without an efficient tuberculosis laboratory network. References 1. 2. 3.

4. 5.

6. 7. 8. 9.

10. 11. 12. 13.

14.

15. 16. 17.

Toman K. Tuberculosis case-finding and chemotherapy. Questions and answers. Geneva: World Health Organization, 1979. Meijer J, Barnett GD, Kubík A, Sty´blo K. Identification of sources of infection. Bull Int Union Tuberc 1971; 45:5–50. Sty´blo K., Danˇková D, Drápela J, Galliová J, Jez´ek Z, Krˇivánek J, Kubík A, Langerová M, Radkovsky´ J. Epidemiological and clinical study of tuberculosis in the District of Kolin, Czechoslovakia, Report of the first 4 years of the study (1961–64). Bull WHO 1967; 37:819–874. Shinnick TM, Good RC. Diagnostic mycobacteriology laboratory practices. Clin Infect Dis 1995; 21:291–299. Githui W, Kitui F, Juma FS, Obwana DO, Mwai J, Kwamanga D. A comparative study on the reliability of the fluorescence microscopy and Ziehl-Neesen method in the diagnosis of pulmonary tuberculosis. East Afr Med J 1993; 70:263–266. Tuberculosis Prevention Trial. Trial of BCG vaccines in south India for tuberculosis prevention Bull WHO 1979; 57:819–827. Sty´blo K, Meijer J. Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem. Tubercle 1976; 57:17–43. Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32:643–653. Bleiker MA, Chum HJ, Nkinda SJ, Sty´blo K. Tanzania National Tuberculin Survey, 1983–1986. In: Tuberculosis and Respiratory Diseases. Singapore: Professional Postgraduate Services, 1987. WHO Expert Committee on Tuberculosis. Ninth report. Tech. Rep. Ser. 552. Geneva: WHO, 1974. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuberc Lung Dis 1995; 76:95–99. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954; 69:724–732. International Union Against Tuberculosis and Lung Disease. Tuberculosis Guide for High Prevalence Countries. 2d ed. Paris: International Union Against Tuberculosis and Lung Disease/Misereor, 1991. Sty´ blo K. Tuberculosis control and surveillance. In: Flenley DS, Petty TL, eds. Recent Advances in Respiratory Medicine. Edinburgh: Churchill-Livingstone, 1986:77–108. Francis J. Bovine Tuberculosis Including a Contrast with Human Tuberculosis. London: Staples Press Ltd, 1947:220. Thoen CO, Richards WD, Jarnagin JL. Mycobacteria isolated from exotic animals. J Am Vet Med Assoc 1977; 170:987–990. Comstock GW. Tuberculosis—a bridge to chronic disease epidemiology. Am J Epidemiol 1986; 124:1–16.

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18. Grzybowski S. Tuberculosis in the third world. Thorax 1991; 46:689–691. 19. Tuberculosis Control Programme: Report of the first meeting of the coordination, advisory and review group. Geneva: WHO, WHO/TB Carg (C1)/1991. 20. Kochi A. The role of the World Health Organization in tuberculosis. In: Reichman LB, Hershfield ES, eds. A Comprehensive International Approach, 1st ed. New York: Marcel Dekker, 1993:699–717. 21. WHO: Ad Hoc Committee on the Tuberculosis Epidemic Report, London, 1998. 22. Petroff SA. A new and rapid method for the isolation and cultivation of tubercle bacilli from the sputum and feces. J Exp Med 1915; 21:38–42. 23. Enarson DA, Rieder HL, Arnadottir T, Trébucq A. In: International Union Against Tuberculosis and Lung Disease, ed. Tuberculosis Guide for Low Income Countries. 4th ed. Frankfurt: pmi Verlagsgruppe GmbH, 1996:1–65. 24. Rieder HL, Arnadottir T, Tardencilla Gutierrez AA, Kasalika AC, Salaniponi FLM, Ba F, Diop AH, Anagonou S, Gninafon M, Ringdal T, Trébucq A, Enarson DA. Evaluation of a standardized recording tool for sputum smear microscopy for acid-fast bacilli under routine conditions in low income countries. Int J Tuberc Lung Dis 1997; 1:339–345.

5 Evaluation of Applied Strategies of Tuberculosis Control in the Developing World

PIERRE CHAULET

EARL S. HERSHFIELD

University of Algiers Algiers, Algieria

University of Manitoba Winnipeg, Manitoba, Canada

I. Introduction It is currently estimated that 95% of cases of tuberculosis and 98% of deaths due to tuberculosis worldwide occur in the developing world annually (1). The evolution of the global tuberculosis epidemic is therefore dependent on the tuberculosis-control strategies that are applied in developing countries and on their ability to respond to the needs of the most vulnerable sections of the population in each country during the next 20 years. It seems clear that in the year 2020 tuberculosis will still be, as it is today, seventh on the list of diseases principally responsible for the burden of mortality worldwide, and that during 2000–2020 the gap between rich and poor countries will only increase (2). As a result, a careful evaluation of the tuberculosis control strategies that are applied is of crucial importance, in order both to adopt the most efficient methods of containing, and then reducing, tuberculosis, and to measure the impact of these strategies. At the beginning of the 1990s, the World Health Organization (WHO) proposed two goals to be achieved by the year 2000: to cure at least 85% of smearpositive pulmonary tuberculosis cases and to detect at least 70% of existing infectious cases (1). Apart from in countries such as Tanzania, Peru, Vietnam, or Morocco, these goals (particularly the latter) will most likely not be reached by 107

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2000 (3), mainly due to insufficient health coverage of the populations in poorer countries and to the fact that tuberculosis-control activities are not included in the “minimum package of health activities” at the district level. The current challenge is to create a global surveillance system in order to measure the evolution of the results obtained by applying these strategies and to determine exactly when—between 2000 and 2020—the WHO objectives will be achieved in each country. Since the first research activities were conducted in Africa in conjunction with the British Medical Research Council (4–6) and then under the aegis of the International Union Against Tuberculosis and Lung Disease (IUATLD) in its Mutual Assistance Program (7–9), the methods of evaluation have been refined and actively promoted on an international scale by WHO, which has for the last 2 years published the results of the applied strategies from countries that reported their data (10,11). II. Prerequisites for Evaluating a Tuberculosis-Control Strategy There are three prerequisites for evaluating a tuberculosis control strategy at the national level: the existence of a clearly defined control strategy, the existence of a network of laboratories capable of performing tuberculosis microscopy in all the country’s districts, and the implementation of an information system (registers and quarterly reports), which is essential for supervising and evaluating the activities. A. A Clearly Defined Control Strategy

Evaluation of results can only be done by respecting the norms set for the tuberculosis diagnosis and case-finding procedures and for the recommended chemotherapy regimens. The national tuberculosis program’s (NTP) technical manual should take into account the strategy recommended by WHO (1): priority given to detection of infectious cases, diagnosed by microscopic examination of the sputum of respiratory symptomatic individuals presenting spontaneously to the health services, standardized treatment of all tuberculosis cases identified using short-course chemotherapy regimens (of 6 or 8 months) under direct observation at least during the initial intensive phase of treatment and at least for infectious patients. Long-term chemotherapy regimens (of 12 months or more) no longer have a role in the modern revised strategy (13). B. A Network of Efficient, Quality-Controlled Laboratories for Smear Microscopy

In order to identify infectious cases and to monitor cure after treatment, it is essential that the patients and/or the health personnel have access to laboratories

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where routine, reliable smear microscopy is performed for tuberculosis. These laboratories can be located in hospitals or clinics that do not necessarily need to specialize in tuberculosis—they are for the most part multipurpose laboratories where 10–40 samples are examined per week. In general, a laboratory should be located no further than 15–20 km from the patients’ homes (or from the health post that collects the patients’ smear samples) for easy accessibility. One microscopy laboratory per 100,000 inhabitants in rural areas, or 200,000 in urban areas, can handle the needs of NTPs in high-prevalence countries. The laboratory technicians should be supervised by a technician from a higher level (intermediate, provincial, or regional level, depending on the country), and a permanent system of quality control is essential for guaranteeing the reliability of the results. C. The Information System

The information system perfected by the IUATLD and recommended by WHO should be implemented in all districts in the country, even if the revised program has not yet been set up. This information system can provide proof of the need to apply the revised strategy rapidly, as it gives better results than traditional methods. The information system is based on registers and quarterly reports (12). In the district tuberculosis register, all tuberculosis cases that begin treatment (new and retreatment cases) are recorded in chronological order. For each patient, site of disease, initial bacteriological status, and standardized chemotherapy regimen are entered. During treatment and at its completion, results of smear testing and the patient’s final status are recorded in the register, which also serves as a basis for the evaluation. In the laboratory register, patients for whom smear microscopy tests are requested (for initial diagnosis and for treatment monitoring) are recorded, as are their results before they are sent to the health service. A comparison of the results recorded in the laboratory register and the district tuberculosis register is an important task for the tuberculosis coordinator during quarterly supervisory visits in order to check or complete the data. The quarterly reports are completed every 3 months, based on data recorded in these two registers. The annual evaluation of the tuberculosis program is done by adding the results together. 1.

The report on tuberculosis case finding provides basic data for epidemiological analysis (Table 1) and allows the different rates and indicators of the case-finding activities to be calculated. 2. The report on treatment outcome analyzes the results of the treatments applied to two groups of patients: new cases of smear-positive pul-

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Table 1

Case Notification: Data to Be Collected

Pulmonary tuberculosis Smear-positive: new cases; retreatment cases (relapses, failures, retreatment after interruption) Smear-negative Smear not done Extrapulmonary tuberculosis Total tuberculosis, all forms Distribution of new smear-positive cases by age and sex (absolute number) Age groups: 0–14, 15–24, 25–34, 35–44, 45–54, 55–64, 65 Source: Ref. 12.

monary tuberculosis recorded one year previously during the same quarter and cases of smear-positive pulmonary tuberculosis enrolled for retreatment during the same period. The patients are classified according to the six possible outcome categories observed (Table 2). The cure and success rates (addition of cases cured and cases having completed treatment without a final microscopy examination) are calculated according to the number of cases recorded the previous year. 3. The report on program management provides a synthesis of the information on the application of the program (distribution of recorded tuberculosis cases according to type of treatment, rate of smear conver-

Table 2 Definitions of Treatment Outcome in Smear-Positive Pulmonary Tuberculosis Patients Cure Treatment completed Treatment failure Died Treatment interrupted (default) Transfer out Source: Refs. 11, 12.

Patient who is smear-negative at (or one month prior to) the completion of treatment and on at least one previous occasion Patient who has completed treatment but without bacteriological proof of cure Patient who remains or becomes again smear-positive at 5 months or later during treatment Patient who dies for any reason during the course of treatment Patient whose treatment was interrupted for 2 months or more any time after registration Patient who has been transferred to another reporting unit and for whom the treatment outcome is not known

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sion at the second or third month for initially positive cases) and on the stocks of antituberculosis drugs and laboratory reagents used. III. Evaluation of the Strategies Applied in Tuberculosis Treatment A. Basic Method: Patient Cohort Analysis

The basic method of evaluation is cohort analysis of patients with pulmonary tuberculosis. Patients with extrapulmonary tuberculosis do not form a homogeneous enough group, because the criteria for diagnosis and cure differ depending on the site of the disease. The cohort consists of all patients recorded consecutively with smear-positive pulmonary tuberculosis who have received (or should have received) the same chemotherapy regimen. This is why, when the chemotherapy regimens are standardized, at least two patient cohorts are analyzed: New patients who have never been treated or who have received treatment for less than one month, and who have been prescribed a primary treatment regimen of 6 or 8 months, depending on the national program guidelines Previously treated cases (failures, relapses, or retreatment after interruption) who have been prescribed the 8-month retreatment regimen recommended by the national program When regimens other than short, standardized chemotherapy are used, they are analyzed separately. In the cohort analysis performed to evaluate the treatment strategies applied in an NTP, several points need to be highlighted: Contrary to the evaluation of a chemotherapy regimen, where cohort analysis excludes those patients who have not received treatment as prescribed, thus reducing the number of different rates to only those cases that can be analyzed, the evaluation of a treatment program (cure rate, success rate) uses the number of cases recorded in the district tuberculosis register one year before as the denominator of all the indicators (10). The patients recorded who have not begun treatment and are not known to have died or to have been transferred are classified as “defaulters before treatment” (13). Treatment Outcome

The results of treatment are interpreted according to the patients’ final status and the duration of treatment. The basic criteria are the cure rate (proportion of pa-

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tients recorded who can be defined as cured at the end of treatment) and the success rate (proportion of patients who correspond to the definitions “cured” and “treatment completed without smear examination at the end of treatment”). The other rates (failure, death, default, and transfer) are used to identify the priority measures that need to be taken in order to improve the success rate. The main interest of the cohort analysis is to provide, for each district, a complete evaluation of the results of tuberculosis treatment based on the addition of the individual results observed for each patient. As described and recommended by WHO this permits a comparison of the results obtained within a country as well as between countries or groups of countries. Supervision Enhances the Validity of the Method

When the district coordinators are left to their own devices and are required to report the data collected in the registers (which they themselves have filled in), certain types of bias can appear in the patient cohort analysis: Bias in patient selection due to errors in recording (smear-negative mistakenly recorded as smear-positive, or vice versa) or errors in classification into treatment category (old cases and new cases). Bias in the data on the treatment actually received by the patients (treatment cards not completed; errors of dosage in the prescriptions; minor interruptions in taking treatment; absence of interviews with the patients by an external observer from the district). Bias in the final distribution of results into the six groups: confusion between “cured” and “treatment completed” and between “treatment interrupted” and “transferred out.” These errors are more frequent when the evaluation results might be perceived to have an influence on health staff assessment and eventual professional promotion or advancement (14). These different types of bias can be corrected or minimized when the district coordinators receive regular visits from supervisors from a higher administrative level (department or province) and when the data recorded in the district register and the laboratory register and the treatment cards are checked at least quarterly. Another bias may be due to the uneven quality of the results provided by the microscopy laboratory in the districts. This bias can be reduced by organizing a permanent, centralised system of quality control for smear examination. The effect of supervisory visits on treatment results was demonstrated in Algeria (15), where the results observed in two groups of districts equal in size and population coverage were compared. In the districts that were supervised regularly, not only was case finding more effective, but treatment success rate reached 83%, compared to a rate of only 70% in the districts that were not supervised (Table 3).

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Table 3 Treatment Results: Evaluation of a National Representative Sample of 719 New Smear-Positive Tuberculosis Cases Treated with a 6-Month Regimen in Algeria Patient status 6 months after end of treatment Patients assessed

Cured

Completed treatment

Failed

Died

Lost

Transferred out

503 216 719

69.8 48.5 63.3

13 22.2 16

2.5 2 2.3

2.2 2.3 2.2

6.5 12 8.2

6 13 8

Districts supervized Districts not supervized Total districts Source: Ref. 15.

Results International

In 1997, 181 of the 212 WHO member states reported their treatment results for patient cohorts recorded in 1995; 97% of the world’s population lives in these countries, and all of the most populated countries (more than 40 million inhabitants) provided data. Of these 181 member states, 164 are developing countries (11). Approximately half of the countries provided interpretable results and had implemented the WHO-recommended strategy more or less fully. Of the 96 countries that adopted the WHO strategy, 91 are developing countries. In 1995 in all countries and in all regions of the world there were zones where the WHO strategy was applied and others where it was not yet applied. One can observe that where the WHO strategy was applied (Table 4) the majority of recorded cases are evaluated (94% versus 55%), with a success rate of 78%, as opposed to only 45% in zones where it was not applied. Developing Countries

Data collected during the period 1995–1997 in certain countries where HIV prevalence among tuberculosis patients is high (Ivory Coast, Democratic Republic of Congo), moderate (Guinea, Djibouti), or low (Morocco, the Philippines) (16–21) confirm worldwide trends (Table 5). Success rates of 78–86% are observed in zones where the strategy is applied and are lower in Djibouti, where a large proportion of the population is highly mobile (50% of patients are foreigners from neighboring countries). A variety of surveys (in Djibouti, Congo, and the Ivory Coast) have shown that the death rate is higher in HIV-positive than among HIVnegative tuberculosis patients. A success rate of 85% can therefore be obtained in program conditions in developing countries except when HIV seroprevalence is very high (12), in which case the success rate is about 75–80%.

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WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO

AFR

105, 245 71, 312 53, 517 74, 945 18, 138 28, 302 4, 732 28,702 26, 574 291, 836 152, 274 143, 970 360, 480 639, 067

15 8 8 57 1 2 13 14 4 68 1 22 6 45

Not evaluated 52 38 69 22 69 51 50 60 66 4 89 43 72 23

Cured (%) 10 19 8 10 13 23 19 7 8 25 2 26 6 22

Treatment completed (%) 10 14 6 6 9 15 7 4 12 1 2 5 6 5

Defaulted (%) 1 2 1 1 1 5 2 7 2 0 1 1 1 1

Failed (%) 7 6 5 2 2 1 7 6 4 0 2 2 4 2

Died (%)

5 14 3 2 5 4 2 2 4 1 3 2 3 3

Transferred out (%)

62 57 77 31 83 73 69 57 74 29 91 68 78 45

Treatment success rate (%)

AFR  Africa Region; AMR  America Region; EMR  Eastern Mediterranean Region; EUR  European Region; SEAR  Southeast Asia Region; WPR  Western Pacific Region. Source: Ref. 11.

Global

WPR

SEAR

EUR

EMR

AMR

Strategy used

Number of smear-positive cases registered

Treatment outcome

Treatment Outcome by WHO Region and Applied Strategy of Tuberculosis Control, 1995

WHO region

Table 4

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WHO HIV HIV Total WHO (pilot areas)

WHO

a HIV seroprevalence in patients  39%. Source: Refs. 16–21.

Philippines (1996–1997)

8052 8195 2158

WHO non-WHO WHO

550 5636 7086 769

14 621

63.5

7221a

non-WHO

52.4 64.7 63.8 82.3

79.2

63.9 46 58

Cured (%)

Strategy applied

No. of smear-positive cases assessed

7 6.5 6.6 1.4

6.8

15.9 23 20

6

Treatment completed (%)

Treatment outcome

11.1 2.1 2.8 2.6

2

5.5 5.2 7

4.4

Died (%)

0.5 0.9 0.8 2.2

1

1.4 1.3 3

1.5

Failed (%)

Treatment Outcomes in Certain Countries by Tuberculosis-Control Applied Strategy

Ivory Coast (1995) Dem. Rep. of Congo (1995) Guinea (1994) Morocco (1994) Djibouti (1990–1995)

Country

Table 5

29 25.8 26 8.2

5

8.3 11.2 10

17.6

Treatment interrupted (%)

3.3

6

5 13.3 3

7

Transferred out (%)

59.4 71.2 70.4 83.7

86

79.8 69 78

69.5

Treatment success rate (%)

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Chaulet and Hershfield B. Surveillance of Mycobacterium tuberculosis Resistance to Antituberculosis Drugs

An indirect method of evaluating the tuberculosis-treatment strategies applied is to monitor the evolution of bacterial resistance to antituberculosis drugs in representative patient samples on a regular basis. A direct link exists between the quality of chemotherapy applied in the community (efficacy of the regimens selected and quality of patient monitoring during treatment) and the rate of drug resistance (22). The more ineffective and poorly observed the chemotherapy regimens are, the higher are the rates of acquired drug resistance among previously treated patients who present after treatment failure, relapse, or premature interruption of treatment. The higher the proportion of already (and poorly) treated patients in the community, the greater will be the risk of transmission of resistant bacilli to new patients, and consequently the risk of witnessing the appearance of high rates of primary resistance among never-treated patients. These facts have once again been demonstrated in the WHO/IUATLD study of the surveillance of drug resistance in the world (23). Treatment Strategies and Evolution of Drug Resistance in Korea

The results of treatment were monitored in Korea for all smear-positive pulmonary tuberculosis patients treated by the public health services from 1983 to 1995 (24). In 1983–1984, the main primary treatment consisted of an 18-month regimen combining isoniazid and ethambutol, with a daily or intermittent supplement of streptomycin. From 1985 to 1990, primary treatment consisted of a 9month regimen with isoniazid, rifampicin, and ethambutol. Since 1991, the primary treatment generally applied is a 6-month regimen combining isoniazid and rifampicin, supplemented by pyrazinamide and streptomycin (or ethambutol) during the first 2 months. The success rates increased from 61–65% in the first period to 69–78% in the second, and reached 82% in the final period. The failure rates fell gradually from 10% in 1983 to 2% since 1989, as did the default rate. At the same time, the proportion of already treated patients among all smear-positive cases started on treatment fell from 47.2% in 1980 to 25.4% in 1994. The prevalence of primary drug resistance (23.8% in 1980, 5.8% in 1995), measured during the prevalence surveys (25), fell as the treatment strategy improved in efficiency (Table 6). Treatment Strategies and Evolution of Drug Resistance in Algeria

In Algeria, a similar pattern was observed (26–28). From 1965 to 1970, the chemotherapy routinely applied was not standardized, and the regimen that was generally prescribed consisted of isoniazid, PAS (para-aminosalicylic acid), and streptomycin for 12–18 months.

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Prevalence of Drug Resistance in Korea

Prevalence survey

Old cases tested

1975 1980 1985 1990 1995

45 55 70 35 28

Resistant strains n

(%)

New cases tested

33 41 41 19 7

(73.3) (74.5) (58.6) (54.3) (25.0)

143 63 100 78 103

Resistant strains n

(%)

39 15 19 12 6

(27.3) (23.8) (19.0) (15.4) (5.8)

Source: Ref. 25.

From 1970 treatment was standarized, using the same drugs for 12 months, until 1980 (rifampicin was used exclusively for retreatment cases). From 1980, short-course chemotherapy was applied nationwide and consisted of 6 months of daily isoniazid and rifampicin, supplemented with streptomycin and pyrazinamide during the first 2 months. The success rates, measured by cohort analysis, rose from 54% in 1971 (28) to 65% in 1977, 78% in 1983, and 84% in 1988 (27), with a corresponding drop in the failure and default rates. During this time drug resistance prevalence was monitored in the national reference laboratory. The fall in resistance rates, which had begun as soon as treatment was standardized, accelerated when the more effective short-course chemotherapy came into general use (Table 7). A Complementary Method

Drug-resistance surveillance is a method of epidemiological surveillance that provides information on the treatment strategy applied in the community in recent

Table 7

Prevalence of Drug Resistance in Algeria

Years

Old cases tested

1965–1970 1971–1979 1980–1985 1986–1990 Source: Refs. 26, 27.

858 1490 606 408

Resistant strains n

(%)

New cases tested

703 917 145 86

(81.9) (61.5) (35.7) (21.0)

145 825 805 1111

Resistant strains n

(%)

217 83 51 58

(15) (10.1) (6.3) (5.2)

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years. As a result it complements cohort analysis and provides confirmation of the results. However, the implementation of this kind of surveillance system is not simple. It requires close coordination between the tuberculosis program and the national reference laboratory, and a rigorous methodology: quality control of susceptibility testing, selection of a representative patient sample, and reporting of reliable information on previous treatment by the clinicians (23). Finally, the impact of a good treatment strategy on the rate of primary resistance becomes apparent only 3–5 years after its implementation. C. An Alternative Method: The Prospective Survey

To evaluate the applied treatment strategy with more precision, it is possible to conduct community-based prospective surveys. These surveys, which are more costly and can be conducted at intervals of 5–10 years, confirm or clarify the results of cohort analyses performed regularly during the running of the program. They provide more complete information on the quality of initial diagnoses, on drug resistance prevalence, on the quality and regularity of treatment, and on treatment results (depending on the regimens used and the results of initial susceptibility testing) at the end of treatment and after follow-up. The main measurement consists of centralizing, in a reference laboratory, all sputum smear samples collected before, during, and after treatment (samples taken in addition to those examined locally) in order to obtain complete, comparable results (including culture and susceptibility testing). X-rays taken before and after treatment are also centralized and interpreted by an independent reader. This method was applied in Algeria under routine conditions to evaluate two short-course regimens of different durations (6 and 8 months). The bacteriological data collected in a single reference laboratory were analyzed. The survey continued for 4 consecutive years in 30 districts, covering a population of about 4 million (29,30). The cure rate 2 years after completion of treatment by 2218 patients was 86.5%, with no major differences observed between the two regimens. The percentage of patients who needed an additional course of chemotherapy was 2.3%, and the rate of persistent positive cultures (chronic cases) was only 1.5% (Table 8). Despite its usefulness, this type of survey has a number of limitations: Districts participating in the study must have access to a central reference laboratory. Sufficient health staff must be available (clinicians, bacteriologists, local surveyors, secretarial staff) to undertake the coordination of the survey and district supervision. It needs adequate financing to cover the costs of coordination and supervision.

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Table 8 Results of Evaluation of Smear-Positive New Cases Initially Treated by Short-Course Chemotherapy Regimens Under National Programme Conditions Regimen initially prescribed Results 2 years after end of chemotherapy Negative cultures After 18th month Between end of treatment and 18th month Completed treatment without control since end of treatment Positive cultures when last seen after end of treatment Deaths Total

6 months

8 months

Patients analyzed

n

%

n

%

678 (16)

69

810 (18)

66

1488 (34)

174 (3)

18

258 (4)

20

432 (7)

19.5

7

101 (1)

8

167 (1)

7.5

66

13 (2) 46 977 (21)

1 5 100

22 (7) 50 1241 (30)

2 4 100

n

35 (9) 96 2218 (51)

% 67

1.5 4.5 100

Numbers in parentheses refer to patients who have received an additional course of chemotherapy for failure, relapse, or development of a nonpulmonary lesion. Source: Refs. 29, 30.

In the evaluation of treatment strategies, cohort analysis performed routinely for all tuberculosis cases recorded is therefore the essential, and the optimal, method, which can be applied in all situations in the developing world. IV. Evaluation of Strategies Applied in the Detection of Tuberculosis Cases Evaluation of the strategies applied in case detection is generally based on data collected by the public health services and by approved health structures that have adopted the same system of notification. In many countries it is unusual for the profit-making private sector to report tuberculosis cases detected in private clinics. A. Sources of Information

Three information sources need to be consulted in each district: 1. The consultation registers in the primary health services, where all care seekers are recorded by age, sex, and reason for their visit

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Chaulet and Hershfield 2. The register of the laboratory where tuberculosis microscopy is performed, in which are recorded the numbers of suspects for whom one or more smear tests have been requested for diagnosis 3. The district tuberculosis register, in which all identified tuberculosis cases are recorded

Based on these registers, the quarterly reports on tuberculosis case finding and program management are completed every 3 months. By adding together the quarterly reports, the annual incidence of tuberculosis cases can be calculated, as can the different rates and indicators associated with case-finding activities. B. Indicators

The indicators that need to be collected are used not only to show the results of case finding, but also to analyze the procedures leading to case detection, which involves all of the basic health services. The data that should be collected on a quarterly and annual basis are the following: The number of patients seeking care The number of adults presenting with respiratory symptoms The number of adults with respiratory symptoms suggestive of tuberculosis The number of smear microscopy tests performed for tuberculosis suspects The number of cases of pulmonary (smear-positive or smear-negative) and extrapulmonary tuberculosis recorded. From this information two series of indicators can be calculated. Indicators of the case-finding process consist of: 1. The proportion of adults (aged 12 years or 15 years) presenting with respiratory symptoms among the totality of care seekers. This varies from 15 to 30% in developing countries; it is higher among children under 5 years. 2. The proportion of tuberculosis suspects among the totality of adults presenting with respiratory symptoms (this proportion differs according to whether or not x-ray is used for selection of tuberculosis suspects). 3. The proportion of tuberculosis suspects, among all of the tuberculosis suspects selected, who have undergone three sputum smear examinations. This proportion should be over 90%, to increase the chances of detecting infectious cases. These indicators reflect the ability of the staff of the basic health services to identify tuberculosis suspects and to send the necessary samples to the laboratory for diagnosis of pulmonary tuberculosis.

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Performance indicators in case detection (12) consist of: 1. The proportion of smear-positive cases among all tuberculosis suspects. This proportion can vary depending on the criteria used to identify suspects: duration of the symptoms presented by the patients, confirmation by the number and type of medical examinations (e.g., x-ray). If the respiratory symptoms presented by the patient are the only criterion for inclusion as a tuberculosis suspect, the proportion will be on average 10% (range 5–15%). 2. The proportion of new smear-positive pulmonary cases out of all new pulmonary cases (smear-positive, smear-negative, and smear not done) recorded. This should be at least 65% of cases. If it is less than 65%, the diagnosis of pulmonary tuberculosis (by microscopy and/or radiology) is of poor quality. The proportion can reach 80% (range 75–85%) if radiological facilities are used appropriately and if smear microscopy is repeated (at least two series of three smear examinations for those tuberculosis suspects who have three negative smears in the first series). A lower proportion can be observed in HIV-positive patients, particularly at later stages of AIDS. However, even in African countries with high HIV prevalence, the overall proportion of smear-positive cases is frequently over 65%. 3. Ratio of new smear-positive cases to new smear-negative and extrapulmonary cases. This ratio is approximately 1:1 in the developing world, due to the large numbers of extrapulmonary cases. 4. Reported case-notification rate for new smear-positive cases (per 100,000 population). This rate is usually calculated annually. The numerator is the number of new smear-positive cases registered in a year from within a defined population (district, region, or country). The denominator is the estimated total midyear population of that district, region, or country. An estimated incidence rate is used in program planning (e.g., to estimate drug needs). The reported case-notification rate of new smear-positive cases by age and sex is the number of new smear-positive cases detected in specific age and sex groups per 100,000 population; it provides information on the trend of tuberculosis in a specific country over the years. C. Results

At the global level, as at a national level, the notification of tuberculosis cases of all forms has only an indicative value: the wide variations from one year to the next have a number of explanations, and in general, radiology is used more for diagnosis than as a means of selection (11).

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Nevertheless, in regions where there are a number of developing countries, the proportion of new smear-positive cases among the totality of newly notified cases of pulmonary tuberculosis can be compared. It can therefore be observed that in countries or regions where the WHO strategy has been applied, the proportion of new smear-positive pulmonary cases is higher than in those where it has not (Table 9). Regular supervision of case-finding activities in the districts can have a considerable impact on results (15). During a retrospective study of a representative sample of 52 districts in Algeria for the year 1984, case-finding results were compared. It was observed that the public health services were delivered in out-patient clinics at the same rate to patients in both groups of districts (one regularly visited for supervision of activities, and the other not visited); however, in the supervised group, individuals with suspected tuberculosis were selected at a much higher rate, the number of smear examinations was 46% higher, and the number of cases identified was twice that of the nonsupervised districts (Table 10). D. How to Detect 70% of Existing Infectious Tuberculosis Cases

Although the aims of the treatment strategy are simple, those of the detection strategy are much more difficult both to reach and to measure. Reaching the case-de-

Table 9 Proportion of New Smear-Positive Pulmonary Cases Out of All New Pulmonary Cases by Region, 1996

WHO region AFR AMR EMR SEAR WPR

Tuberculosis-control strategy

No. of new smear-positive cases notified

New smear-positive/New pulmonary cases (%)

WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO WHO non-WHO

155, 146 93, 833 52, 220 81, 773 21, 651 36, 499 51, 075 322, 044 206, 582 146, 592

65 32 70 64 76 45 64 25 68 27

AFR  Africa Region; AMR  America Region; EMR  Eastern Mediterranean Region; SEAR  Southeast Asia Region; WPR  Western Pacific Region. Source: Ref. 11.

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Table 10 Influence of Supervision Activities of Health Staff on Case-Detection Results Health districts (n  52)

Population covered Adjusted population Outpatients attending health services (per year) Number of smear examinations performed in suspects Number of smear-positive pulmonary tuberculosis cases identified

With periodic supervision of activities (n  27)

Without periodic supervision of activities (n  25)

3.4 million 100,000

3.2 million 100,000

68,578

65,713

1,910

1,302

47

24

Source: Ref. 15.

tection rate of 70% of infectious cases depends on a number of variables, particularly the health coverage of the population, the population’s means of communication with and accessibility to the health services, and the ability of health workers to select tuberculosis suspects and to identify cases of smear-positive pulmonary tuberculosis. Estimation of Existing Cases from the Annual Risk of Tuberculous Infection

Until recently this estimation was based on data published in 1993 by the World Bank (31), with adjustments for those countries that had more recent information available (11). It is based on tuberculin surveys conducted in different countries, at different times, using different methodologies (the threshold of positivity of tuberculin reactions varied from one period to the next, due to the growing use of BCG vaccination). Tuberculin surveys that are done well are still an important tool for monitoring the trend of tuberculosis in a country (32). However, they rarely provide a clear picture of the situation at the provincial or district level, and as a result they can only estimate case-finding objectives on a national basis. Furthermore, the spread of the HIV/AIDS epidemic in many African countries has resulted in a considerable increase in numbers of cases, well above the numbers that were predicted, based on the annual risk of tuberculous infection (33,34).

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While awaiting the creation of new epidemiological methods that will allow us to calculate, country by country, the number of cases expected annually for the next decade, a pragmatic approach has been adopted in several developing countries, based on the demonstration and training areas where the WHO strategy has been implemented. We know that in all countries the incidence varies from 1 to 4, depending on the district. Based on the make-up of the districts of a particular country (urban/rural, high/low population density, accessibility and effectiveness of the health services), we can establish goals for case detection for a limited period, based on the results of case-finding activities in the most efficient districts in each group of similar districts. This pragmatic approach means that realistic goals can be set and that the WHO strategy can be extended from those that were initially selected as demonstration and training areas for the program (12). V. Conclusion The strategies for tuberculosis control that are applied in the developing world are still quite varied. They are gradually being simplified and standardized as the WHO strategy becomes more widely accepted and implemented. However, the aims of tuberculosis control cannot be reached if a broader sectorial approach to health activities is not envisaged (35). As long as health coverage extends to no more than 50% of the population, as occurs in many developing countries, it is an illusion to imagine that rapid progress can be made in tuberculosis control. As long as the activities defined by national tuberculosis programs are not fully integrated into the “minimum package of health activities,” it will be impossible to detect and treat tuberculosis patients in rural and periurban areas that are neglected, and particularly in the most vulnerable sections of the population. As long as peripheral district health activities do not receive support from the intermediate and central levels, with a strong technical structure and an adequate budget, so-called integration will remain an empty concept, devoid of any meaning. References 1.

WHO Tuberculosis Programme. Framework for Effective Tuberculosis Control. WHO/TB/94.179. Geneva: WHO, 1994. 2. 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. Cambridge, MA: Harvard University Press, 1996. 3. Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of worldwide tuberculosis control. Lancet 1997; 350:624–629.

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4. Kenyan-British Medical Research Council Cooperative Investigation. Tuberculosis in Kenya: a third national survey and a comparison with earlier surveys in 1964 and 1974. Tubercle 1989; 70:5–20. 5. Tanzanian-British Medical Research Council Cooperative Investigation. Tuberculosis in Tanzania: a national survey of newly notified cases. Tubercle 1985; 66:161–178. 6. Bignall JR, Leal Gonsalves A, Cabral J, Anastasatu C, Mihailescu P, Gartner A, Chaulet P. Enquêtes nationales sur les résultats du traitement de la tuberculose en pratique quotidienne. Bull Union Int Tuberc 1979; 54:37–48. 7. Broekmans JF. Control strategies and programme management. In: Porter JDH, McAdam KPWJ, eds. Tuberculosis, Back to the Future. Chichester: John Wiley and Sons, 1994:171–188. 8. International Union Against Tuberculosis and Lung Disease. Type of collaboration provided by IUATLD to national tuberculosis programmes in developing countries. In: IUATLD Tuberculosis Surveillance Research Unit Progress Report. The Hague: TSRU, 1987; Vol. 2:138–140. 9. Styblo K. IUATLD assisted National Tuberculosis Programmes in developing countries. In: IUATLD Tuberculosis Surveillance Research Unit Progress Report. The Hague: TSRU, 1987; Vol 2:102–105. 10. World Health Organization Global Tuberculosis Programme. Global Tuberculosis Control Report 1997. Geneva; WHO, 1997 (WHO/TB/97.225). 11. World Health Organization Global Tuberculosis Programme. Global Tuberculosis Control, WHO Report 1998. Geneva: WHO, 1998 (WHO/TB/98.237). 12. World Health Organization Global Tuberculosis Programme. Managing tuberculosis at national level. Geneva: WHO, 1996 (WHO/TB/96.203). 13. Maher D, Chaulet P, Spinaci S, Harries AD. Treatment of Tuberculosis: Guidelines for National Programmes. 2d ed. Geneva: World Health Organization, 1997 (WHO/TB/97.220). 14. Chaulet P, Zidouni N. Evaluation of applied strategies of tuberculosis control in the developing world. In: Reichman LB, Hershfield ES, eds. Tuberculosis, A Comprehensive International Approach. 1st ed. New York: Marcel Dekker, Inc., 1993:601–627. 15. Berkani M, Aït-Khaled N, Bouchahda K. Les mesures techniques de la lutte antituberculeuse. In: Chaulet P, ed. L’organisation de la lutte antituberculeuse en Algérie. Soc Alger Pneumophtisiologie 1985:75–77. Ed Un Med Alg, 1985. 16. Revue du programme de lutte antituberculeuse en République de Côte d’Ivoire. Abidjan-Genève: WHO, 1997. WHO/TB/98. 17. Programme antituberculeux intégré de la République Démocratique du Congo. Données statistiques du Bureau Central de la Tuberculose, Kinshasa, 1997. 18. Revue du programme de lutte antituberculeuse de la République de Guinée. ConakryGenève: WHO, 1995. WHO/TB/96/201. 19. Revue du programme de lutte antituberculeuse au Maroc. Rabat-Genève: WHO, 1996. WHO/TB/96/206. 20. Revue du programme de lutte antituberculeuse de la République de Djibouti. WHO/TB/97/226. Geneva: WHO, 1996. 21. Results of DOTS strategy in demonstration areas. Tuberculosis Control Services, Department of Health, Manila, Philippines, 1997.

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22. Chaulet P, Boulahbal F, Grosset J. Surveillance of drug resistance for tuberculosis control: why and how? Tubercle Lung Dis 1995; 76:487–492. 23. World Health Organization Global Tuberculosis Programme. Antituberculosis drug resistance in the world. The WHO/IUATLD Global project on antituberculosis drug resistance surveillance 1994–1997. Geneva: World Health Organization, 1997 WHO (WHO/TB/97.229). 24. Hong YP, Kim SJ, Lew WJ, Lee SH, Lee EK. Cohort analysis of the treatment of smear-positive pulmonary tuberculosis patients under programme conditions in Korea, 1983–1994. Int J Tuberc Lung Dis 1998; 2:365–371. 25. Hong YP, Kim SJ, Lew WJ, Lee EK, Han YC. The seventh nationwide tuberculosis prevalence survey in Korea. Int J Tuberc Lung Dis 1998; 2:27–36. 26. Boulahbal F, Khaled S, Tazir M. The interest of follow-up of resistance of the tubercle bacillus in the evaluation of a programme. Bull Int Union Tuberc Lung Dis 1989; 64(3):23–25. 27. Chaulet P. Tuberculose et transition épidémiologique: le cas de l’Algérie. AnnInstitut Pasteur–Actual 1993; 4:181–187. 28. Cheikh El Ghanami Z. L’organisation de la chimiothérapie de la tuberculose en Algérie. Résultats d’une enquête nationale menée en 1971. Thèse de Doctorat en Médecine, Université d’Alger, Algiers, 1971. 29. Algerian Working Group/British Medical Research Council cooperative study. Short course chemotherapy for pulmonary tuberculosis under routine programme conditions: a comparison of regimens of 28 and 36 weeks’ duration in Algeria. Tubercle 1991; 72:88–100. 30. Zidouni N, Chaulet P. Evaluation of the treatment results of pulmonary tuberculosis in a community survey in Algeria, including the comparison of two (6-month and 8month) short course chemotherapy regimens. In: IUATLD Tuberculosis Surveillance Research Unit. Progress report. Vol. 1. The Hague: TSRU, 1991:29–44. 31. World Bank. World Development Report 1993. Investing in Health. New York: Oxford University Press, 1993:3491. 32. Arnadottir T, Rieder HL, Trébucq A, Waaler HT. Guidelines for conducting tuberculin skin test surveys in high-prevalence countries. Tuberc Lung Dis 1996; 77(suppl 1):1–20. 33. Rieder HL. Methodological issues in the estimation of the tuberculosis problem from tuberculin surveys. Tuberc Lung Dis 1995; 76:114–121. 34. Menzies D. Tuberculin surveys—Why? Int J Tuberc Lung Dis 1998; 2:263–264. 35. Chaulet P. After health sector reform, whither lung health? Int J Tuberc Lung Dis 1998; 2:349–359.

Part Two BASIC ASPECTS

6 Epidemiology of Tuberculosis

GEORGE W. COMSTOCK School of Hygiene and Public Health Johns Hopkins University Baltimore, Maryland

I. Introduction Tuberculosis is still a leading contender for the dubious distinction of being the most important plague of humankind. The World Health Organization (WHO) has estimated that in 1990 7.5 million people had tuberculosis and that there were 2.5 million deaths due to tuberculosis (1). Accentuating the impact of tuberculosis 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. As noted in Chapter 1, tuberculosis has been exacting a toll for many centuries. Of particular interest from an epidemiological point of view is the reported frequency of skeletal lesions suggestive of tuberculosis among pre-Columbian populations of North America (2). While such lesions were occasionally noted in skeletons of the Late Woodland peoples (800–1050 A.D.), their successors, the Mississippians, had a much higher frequency of tuberculosis-like bony lesions, associated with their coming together in larger and relatively permanent settlements. That tuberculosis and crowding go together is now so generally accepted that the reason(s) for the association is rarely considered. Is it solely because crowding increases the risk of becoming infected if infectious cases are present? 129

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Is it because there is something associated with crowding that makes it more likely that an infected person will develop tuberculous disease? Is it some combination of these sets of risks? Answers to these questions comprise the etiological epidemiology of tuberculosis. This chapter will first address etiological epidemiology by reviewing what is known about risk factors for becoming infected with tubercle bacilli, 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. This approach is consistent with the oft-stated goals of tuberculosis control: (1) prevent the uninfected from becoming infected; (2) prevent the infected from developing tuberculous disease; and (3) prevent relapse, disability, and death among those who have tuberculosis. Administrative epidemiology will then be reviewed. This aspect of epidemiology deals with the occurrence of tuberculosis based on routine reporting or special surveys. These data are vital for tuberculosis control workers and other persons interested in health policy, who must know the distribution of cases by time, place, and personal characteristics regardless of the cause of these distributions. II. Etiological Epidemiology A. Risk of Becoming Infected with Tubercle Bacilli

Causes of Tuberculous Infection

Three related organisms—Mycobacterium tuberculosis, M. africanum, and M. bovis—are the necessary causes of tuberculosis. 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. The probability of having been infected with one of the three tubercle bacilli is assessed by the size of induration caused by the tuberculin test (see Chap. 12). Risk of Infection by Time and Place

The best estimate of the decrease in the risk of becoming infected for residents of the United States comes from the extensive and carefully standardized tuberculin testing of Navy recruits (3,4). Among white males aged 17–21 years, the proportion of positive reactors fell from 6.6% in 1949–51 to 3.1% in 1967–68. 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 (5). While the mean age of recruits had probably changed little since 1950, the two later study populations included sizable proportions of nonwhites, who in the earlier study had much higher proportions of infected persons than the white recruits. In addition, the

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positive reactors throughout this entire period undoubtedly included some who were infected with nontuberculous mycobacteria 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 (4). 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 come from the first Health and Nutrition Examination Survey in 1971–1972. Among 1494 adults aged 25–74 years, 16.1% were classified as reactors (6). The likelihood of having been infected among household contacts of infectious cases of tuberculosis has also declined with time, at least in the United States (7). In Williamson County, Tennessee, in the period 1931–55, 67% of household contacts aged 5–9 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 tuberculosis cases were positive tuberculin reactors (8). It is believed that the risk of becoming infected has been declining throughout most of the world, most rapidly in industrialized nations and least in sub-Saharan Africa and the Indian subcontinent, where the annual rate of decline is estimated to be less than 3% per year (9). Reasonably good estimates can be obtained in countries where there are enough children and young adults who have not been vaccinated with bacille Calmette-Guérin (BCG) to allow the risk to be estimated (10,11). 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 decrease during the next 20 years. Similar findings were reported from a rural area of South India (12). Among children 1–4 years of age at the initial examination, the average annual risk of infection during the next 4 years was estimated to be 2.8% with some evidence of a decrease during the 4-year period. The most dramatic decrease in the risk of infection was documented among the Inuit residents of the Yukon and Kuskokwim river deltas in Alaska (13). In 1949–51, 62% of children aged 0–6 years were infected with tubercle bacilli, 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 1963–64, only 2.4% were infected, and in 1969–70 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 tuberculosis is a communicable disease primarily spread by the airborne route, it is not surprising that the risk of an uninfected person becoming infected

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is strongly associated with the probability of coming in contact with someone with infectious tuberculosis, 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. The Navy recruit testing program illustrates the risk associated with urban or rural residence for white males aged 17–21 years (3). Lifetime residents of metropolitan areas had a prevalence of positive tuberculin reactions of 4.2%; lifetime residents of farms, 2.8%; and lifetime residents of other nonmetropolitan areas, an intermediate 3.6%. 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 (14). 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 intimate (e.g., household associates or sweethearts) than if it was casual (e.g., other friends, fellow employees). If sputum of the source case contained so many tubercle bacilli 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 (15). Other characteristics of the source case are related to the prevalence of positive tuberculin reactions among children who are household contacts (14). Extent of pulmonary involvement was strongly associated with infectivity: 62% of contacts of cases with far advanced disease were reactors compared to only 16% reTable 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

Intimate (n  1012) 44.7 27.7 25.7

White children

Casual (n  619)

Intimate (n  1873)

Casual (n  3,031)

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: Ref. 14.

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actors 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 (16). Duration of Exposure

Duration of exposure is important in comparing the infectiousness of tuberculosis with other communicable diseases. Although an occasional tuberculous patient can be as infectious as a child with measles (17), in most instances the proportion of exposed contacts who become infected with tubercle bacilli 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 tuberculosis 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 for guinea pigs (18). Isoniazid-resistant organisms also have decreased virulence for guinea pigs (19). Until recently, however, the possibility of strain resistance has not been seriously considered in the pathogenesis or epidemiology of human tuberculosis. During 1994–1996, 21 cases of tuberculosis developed in a small rural community in the midwestern part of the United States (20). 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 later index case were also tuberculin reactors and converters. Environmental investigations revealed no explanation for these high infection rates. The strain of tubercle bacilli responsible for the outbreak was initially reported to be more virulent than the standard virulent Erdman strain. However, subsequent laboratory investigations have not been able to confirm this finding (Cynthia L. Kelley and Arthur M. Dannenberg, Jr., personal communications, 1998). Whether or not M. tuberculosis varies in its virulence for humans remains uncertain. Foreign Residence

There is little evidence that a period of foreign residence is associated with an important risk of infection for persons born in the United States. Navy recruits who had lived abroad at a time when tuberculosis was common even in many developed countries were only slightly more likely to be tuberculin reactors than lifetime residents of this country (3). 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 Americans, most of whose exposures must have occurred in public places and have been very short in duration.

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Age

There is some evidence that the risk of acquiring infections increases with age during the period from infancy to early adult life (21), probably because of increasingly numerous contacts with other persons. Although tuberculin sensitivity, once acquired as a result of infection with tubercle bacilli, persists for many years, the prevalence of positive tuberculin reactions tends to level off at around 50–60 years of age. In some populations, there is even a decreased prevalence in older ages, possibly because the infecting bacilli in some persons 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 (22). This sex difference was clearly illustrated in a large tuberculin testing program among New York City school employees (23,24). 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 (23,24). Among high school students in Washington County, Maryland, large tuberculin reactions typical of those resulting from tuberculous infection were much more common among students living in crowded, inadequate housing (25). 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 (17,26,27). 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 (28). 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 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 also been shown to be associated with an increased risk of becoming infected with tubercle bacilli. In a continuing 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 tuberculosis cases in the home within the previous

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3 years (29). 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 persons (30). Using the two-step procedure at the time of initial testing will identify many of the conversions due to “boosting” (anamnestic reaction), which might otherwise be subsequently classified as new infections (30–32). Identification of new tuberculosis infections among persons 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 (32,33). A conversion from a negative to a positive test within the week or two interval in two-step testing is highly likely to be a boosted reaction. A subsequent conversion at a semi-annual or annual retest among persons 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 (34,35). Since that time, tuberculosis has been recognized as a serious threat because of gross overcrowding in correctional institutions and the ease of airborne spread of infection (33,34). A growing problem concerns tuberculosis transmission in homeless shelters. The presence of an untreated infectious case of tuberculosis in these often crowded, poorly ventilated buildings confers a considerable risk of infection upon the other clients and the shelter personnel (36). 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 (37). 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 (38). 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 persons who are still negative tuberculin reactors after a lifetime of caring for tuberculosis patients. B. Risk of Developing Tuberculosis Following Infection

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

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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 tuberculosis following the initial infection with M. tuberculosis (39). As noted in Chapter 20, 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 initial infection and that it declines thereafter. Findings from a controlled trial of isoniazid prophylaxis among contacts of active tuberculosis cases and a trial among mental hospital patients can be combined to yield a reasonable estimate (40). In these two trials, 1472 persons allocated to the placebo regimen converted from a negative to a positive tuberculin reaction at some time within the first study year. Sixty-four percent of the 29 new cases that developed during a 7-year follow-up period occurred during that first year, the year in which they became reactors. Twenty-two percent developed during the next 3 years, and 13% during the last 3 years. In South India, the risk of developing tuberculosis was 2.6% within the first year after tuberculin conversion, and only 0.5% during the next 3 years (41). Incidence of tuberculosis among tuberculin reactors varies by place, probably related to intensity of exposure. Among 265,488 tuberculin reactors with negative chest radiographs who participated in a mass campaign in 1950–52 in Denmark (exclusive of Copenhagen), the average annual incidence over the next 12 years was 29 per 100,000 (42). At the other extreme was the Inuit population in the Yukon-Kuskokwim river delta of Alaska, where the average annual incidence rate from 1957–64 was more than 500 per 100,000 persons with initially negative chest radiographs, virtually all of whom were tuberculin reactors (43). In Denmark in the 1960s, rural tuberculin reactors 15–44 years of age had a risk of subsequently developing tuberculosis that was only 60% of the risk for their urban counterparts (42). Personal Characteristics Age

Among tuberculosis contacts in British Columbia and Saskatchewan, Canada, who had positive tuberculin reactions, the frequency of active tuberculosis dis-

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covered during a 6-month period following diagnosis of the index case varied markedly with the age of the contact (14). The inverse association with age held true for total active cases as well as those whose diagnosis was confirmed by sputum examination. A similar pattern by age was observed in South India (41). 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 tuberculosis among tuberculin reactors by age was investigated as a by-product of a controlled trial of BCG vaccination in Puerto Rico (44). Among 82,269 tuberculin reactors aged 1–18 years who were followed for 18–20 years, 1400 cases of tuberculosis were identified. As shown in Figure 1, there were two peaks of incidence. One occurred among children in the 1- to 4year 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

Figure 1 Incidence of tuberculosis among Puerto Rican children who were reactors to tuberculin, by age when tuberculosis was first diagnosed. (From Ref. 44.)

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(45). The cause of increased incidence at this age, even for persons 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 tuberculosis during the lifetime of infected persons. For this reason, life expectancy becomes a major determinant of the lifetime risk of developing tuberculosis among tuberculin reactors. Sex

In seven studies that reported sex- and age-specific incidence rates among positive tuberculin reactors, female rates were higher during their child-bearing ages than male rates; at older ages, male rates were higher (22). An exception to this pattern occurred in the large BCG trial in the Chingleput area of South India (12). Among persons with tuberculin reactions of 12 mm or larger, males had higher incidence rates than females at all ages. 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 (46) or among Navy recruits (47). 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 (14). Dosage of Infection

The findings shown in Table 2 also bear on the relationship of dosage of infection to the risk of developing tuberculosis (14). 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

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  352)

Casual (n  169)

Intimate (n  412)

Casual (n  216)

14.4 5.1 3.0

10.0 3.9 0

14.0 5.0 2.3

8.2 6.2 0

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

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those with the closest contact, the conclusion seems inescapable that persons infected with larger numbers of tubercle bacilli 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 infections (48). Size of Tuberculin Reaction

It has been known for several decades that infections with nontuberculous mycobacteria often cause tuberculin sensitivity but rarely result in disease, and also that cross-reactions to tuberculin caused by these organisms are usually smaller than those caused by M. tuberculosis (49). 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 bacilli 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 (50). Children with reactions measuring 16 mm or more in diameter to 1 tuberculin unit (TU) of a purified tuberculin had a subsequent risk of tuberculous disease more than five times greater than children with reactions of 6–10 mm following a test with 10 TU of a purified tuberculin. The prognostic importance of this widely available risk factor has recently been recognized in recommended standards for tuberculosis control (51). Immunosuppression

The fact that the great majority of persons do not develop tuberculosis 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 to eradicate them. Treatment with immunosuppressive agents can upset this balance, as can infections with the human immunodeficiency virus (HIV). Tuberculosis is reported to be rampant in populations throughout the world who have dual infections with both the tubercle bacillus and HIV. An illustration of the enormous magnitude of this risk is afforded by a longitudinal study among intravenous drug users in New York City (52). No cases of tuberculosis were observed among 298 reactors who were HIV-negative, compared to 8 among 215 HIV-positive persons. Seven of the 8 tuberculosis 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 8,000 per 100,000. The well-documented, temporary loss of tuberculin sensitivity following measles has been equated with immunosuppression and hence increased susceptibility to activation of a latent tuberculosis infection. However, a careful review of the pertinent literature failed to substantiate the widespread belief that measles predisposes tuberculin reactors to the development of tuberculous disease (53).

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Relative Weight

Among the few benefits of being overweight is its association with protection against tuberculosis. 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 tuberculosis than those who were 10% or more overweight (54). Socioeconomic Status

There is almost no evidence on the relationship of social and economic factors to the development of tuberculous disease among tuberculin reactors. In Muscogee County, Georgia the incidence of tuberculosis among reactors during the period 1950–62 showed no association with the quality of their housing as recorded in a private census in 1946 (46). 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 etiological 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 resulted in an almost miraculous improvement in the prognosis for persons who develop tuberculosis. Conscientious adherence to an appropriate regimen even in the earlier days of chemotherapy came close to guaranteeing a lasting cure (55). 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 (56–58). Presence of drug-resistant tubercle bacilli is also an important risk factor for relapse. In 12 controlled trials of short-course chemotherapy, patients with bacilli resistant to streptomycin or isoniazid were much more likely to relapse than patients with bacilli sensitive to these drugs (59). Even though Fox considered completion of an appropriate regimen to come close to guaranteeing a cure (55), close is not perfection. As one example, among 582 patients who completed a 6-month regimen with isoniazid and rifampin throughout and pyrazinamide plus either ethambutol or streptomycin for the first 2 months and were followed for 5 years, the relapse rate was 3.4% (60). This rate is equivalent to an average annual rate of 680 per 100,000. Life-table reanalysis of the data from the USPHS tuberculosis short-course chemotherapy trial 21 showed a relapse rate of approximately 600 per 100,000 per year for the two regimens combined (61).

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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% (62). 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 (63,64); after chemotherapy was introduced, relapses were less likely during the year or two following adequate treatment (61,64). Long-term risk after adequate chemotherapy is not known. Age, Sex, and Race

Relapse rates by age do not show a consistent pattern. In untreated persons whose disease was judged to be inactive or fibrotic at the time of diagnosis, reactivation was less likely with increasing age (63,65). Among persons whose disease became inactive after treatment, relapse rates went up with age in Denmark (62) and showed no significant trend with age in India (66). There was a tendency for relapse rates to be somewhat higher in males than females (62,65,66), though not in all populations (67). Reactivation rates were more common among Canadian Indians than other Canadians (68) and, in the state of Georgia, more common among blacks than whites (63). 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 (63). Another indication that socioeconomic factors might play a role came from a geographic comparison of relapse rates in Denmark (62). Relapse rates among residents of Copenhagen were higher than among persons living in the more rural areas of Denmark. Extent of Disease

In the state of Georgia (United States) and in Europe, reactivation in untreated persons was much more likely among persons with extensive fibrotic disease than among those with only minimal lesions (63,69). A similar finding was reported among previously treated patients in Wisconsin and South Africa (56,70). III. Administrative Epidemiology Information on tuberculosis morbidity and mortality is voluminous compared to that available for etiological epidemiology. Even so, most of it is based on official

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reports and can be related only to time, place, race, sex, and age. Hard data on other risk 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 reported incidence of tuberculosis in the United States had been declining at an average rate of 5.9% per year for several decades until 1985 (71) (Fig. 2). 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 7.4 in 1997 (72). The so-called resurgence of tuberculosis 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 (73; G.W. Comstock, unpublished data). Seven states (California, Nevada, New Jersey, New York, Texas, Utah, and Washington) showed average annual increases of 4–17% during the period 1984–1991. Table 3 shows the case rates for the years 1984, 1992, and 1996 for these seven states, the rest of the United States, and the entire country (74–76). For the seven

Figure 2 Tuberculosis case rates, United States, 1975–1997, all ages. (Adapted from Ref. 72.)

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Table 3 Tuberculosis Cases per 100,000 Population for 1985, 1992, and 1996 for the Total United States, Seven States with Highest Average Annual Increases 1984–1991, and the Rest of the Country

Total Seven statesa Rest of United States

1985

1992

1996

9.4 11.2 8.5

10.5 16.8 7.4

8.0 11.9 6.2

a

Seven states with average annual increases in tuberculosis case rates of 4% per year or higher. See text for details. Source: Refs. 74–76.

states, the 1992 rates at the peak of the resurgence were 50% higher than in 1984; by 1996, their average rate was almost as low as it had been in 1984 and this trend has continued through mid-1999 (CDC, personal communication, 1999). 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 tuberculosis rates after 1985, and some even showed slight increases (73). A notable exception was Finland, where the decrease in case rates accelerated after 1985. In Eastern European countries, case and death rates from tuberculosis are higher than in Western Europe, but in most of these countries, reported tuberculosis case rates were still declining up to 1992. In only a few, however, were tuberculosis death rates going down (77). In Southeast Asia and in sub-Saharan Africa, where dual infections with HIV and tuberculosis are becoming increasingly more common, tuberculosis case rates are increasing to an alarming degree (1,78). Various factors have been suggested as the cause of the resurgence in the United States (79). These include HIV infection, poverty, homelessness, drug abuse, immigration, and, usually last, decreased funds for tuberculosis control. However, the only one of these factors to have changed in a favorable direction since 1985 was the considerable increase in tuberculosis control funds during the 1990s, which led to a revitalization of tuberculosis-control activities in critical areas (80). In Southeast Asia and sub-Saharan Africa, there is little doubt that dual infections with HIV and tuberculosis are the major cause of increasing case rates, but even in Africa the increase has been mitigated where tuberculosis control activities are more effective (78). Tuberculosis is more common in large cities than in rural areas (75,81). In the United States in 1996, metropolitan statistical areas with populations greater than 500,000 had 74% of the new cases, for a case rate of 9.6 per 100,000. In the less populous areas, the rate was only 5.5 per 100,000. Forty-six percent of the 3143 U.S. counties reported no cases in 1996; most were located in the northern plains and Rocky Mountain areas (76).

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An influx of immigrants from areas where the prevalence of tuberculosis is high can also affect temporal trends in some areas. In British Columbia, Canada, tuberculosis case rates decreased from 1970 to 1985 except for the city of Vancouver (82). 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. 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 20.3–72.8 (83). The Netherlands and four of the Scandinavian countries had the lowest rates. Rates in England and Wales ranged from 3.1 in Anglia to 37.0 per 100,000 in some boroughs of London in 1983 (81), while among the 50 United States the case rate in 1996 ranged from 0.7 in Vermont to 16.9 in Hawaii (76). Unfortunately, interpretation of geographic variations is more difficult than generally recognized. Within the United States in 1992, the percentage of pulmonary cases not bacteriologically confirmed varied from 0 to 35.4% among states with 25 or more reported cases (84). Considerable variations between nations in both the extent and nature of cases of pulmonary tuberculosis have also been recorded (85). B. Age, Race, and Sex

The numbers of reported tuberculosis cases among ethnic groups in the United States are shown in Figure 3 for the years 1980 through 1996 (8,33,71,72, 74,76,84,86–94). For all ethnic groups there was a downward trend until 1985. For American Indian/Alaskan natives, the general downward trend continued to 1996. All other ethnic groups showed an increase until 1992; for Asian/Pacific Islanders, however, numbers of cases increased until 1995. In the United States in 1996, case rates were low in infancy and decreased somewhat during early childhood (76). After the age of puberty, they showed a generally steady increase with age (Fig. 4). For all ethnic groups, rates among females are lower than among males. White rates are the lowest at all ages, and Asian/Pacific Islanders are the highest. Rates among blacks, Hispanics, and American Indian/Alaskan Natives are intermediate, except that rates among adult black males are appreciably higher than the other two groups except at the oldest ages. In under-developed countries, the highest reported rates are among young adults (11,48). C. Socioeconomic Status

The association of tuberculosis with poor socioeconomic status has long been noted (3,95) and perhaps is even stronger today. Decades ago, homeless men in New York City were found to have high rates of tuberculosis (96); a similar ex-

Figure 3 Reported tuberculosis cases by race/ethnicity group, United States, 1980–1996. *Up to 1993, Hispanics are also included in one of the other groups. (Adapted from Refs. 74–76, 84, 86, 87, 91, 92, 94.)

Figure 4 Tuberculosis case rates, United States, 1996, by race/ethnicity and age groups. A  American Indian/Alaskan Native; A/P  Asian/Pacific Islander; B  black; H  Hispanic; W  white; M  male; F  female. (Adapted from Ref. 76.)

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cess was noted among unmarried men living in central Copenhagen (97). The situation has been aggravated recently by the increase in homeless persons and the continued high frequency of tuberculosis among them (98). Further aggravation comes from the tendency of poor immigrants to crowd into large cities (82,99). Their tuberculosis risk reflects the prevalence of the disease in their native countries; the risk decreases with their duration of stay in their adopted homes (87,100–102). Based on a survey from 29 states in 1984–1985, occupational status was strongly associated with tuberculosis case rates (103). Executives and professionals had the lowest rates, and laborers, farm workers, and household servants had the highest rates. Health care workers had rates of tuberculosis 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 tuberculosis 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 bacilli as other employees (104). D. Institutional Living

Because poverty is associated with both crime and tuberculosis, it is not surprising that tuberculosis is often a problem among inmates of correctional institutions. Various surveys have estimated the frequency of tuberculosis to be increasing among such populations and to be three to six times higher than expected from rates in the general population (33,105). Tuberculosis among persons living and working in nursing homes and other facilities providing long-term medical care has only recently been recognized as a problem (29). 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 (90,105) (see also Chap. 24). E. Special Medical Situations

A variety of medical conditions are associated with tuberculosis. Although these risk factors are presumably limited to persons 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 human immunodeficiency virus (88,106) (see also Chap 20). Other causes of immunosuppression also accompanied by an increased tuberculosis 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 (107).

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Silicosis has long been linked with tuberculosis, so much so that silico-tuberculosis is an accepted disease entity. Although the causal nature of this association is largely based on uncontrolled reports (108), silica dust has long been known to have an adverse effect on tuberculosis in animals (39). Diabetes, too, has long been accepted as a risk factor for tuberculosis (109). 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 (110,111). Alcoholism and drug addiction are also associated with tuberculosis, although it is not clear whether these diseases increase susceptibility to tuberculosis or whether conditions conducive to substance abuse are similar to those leading to tuberculosis. In any case, alcoholism was well known to physicians in tuberculosis sanatoria, since 10–30% of patients were reported to be alcoholics (3). Current surveys also show a high prevalence of tuberculosis among alcoholics and drug addicts (112). Multiple drug resistance, currently defined as resistance to at least isoniazid and rifampin, has become a major problem in many areas throughout the world (113). Although multiple drug–resistant tubercle bacilli have been involved in many outbreaks of tuberculosis 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 persons 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 tuberculosis-control programs. F. Infection with HIV

The greatly increased risk of clinical tuberculosis among persons infected with M. tuberculosis and HIV has been clearly demonstrated in this country and abroad (52,78,106,114). Only in the study by Selwyn et al. (52) 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 tuberculosis cases among groups at high risk of developing tuberculosis. Many of these persons were known to be HIV-positive. In these clusters, a very high proportion of cases were found to have tubercle bacilli with the same restriction fragmentlength polymorphism pattern, strongly suggesting that all cases came from a single source, probably recent (115,116). 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 tuberculosis is the result of reactivation of latent infection.

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Two features distinguish the epidemiology of HIV-associated tuberculosis. First is the speed with which clinical disease becomes manifest following exposure. In two outbreaks among HIV-infected persons, attack rates of 16.7 and 29.4% were observed within somewhat less than a 2-year period (117,118). For comparison, during the first 2 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 tuberculosis (40). The likelihood of developing manifest tuberculosis depends on the stage of the HIV infection. Most cases of tuberculosis 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 (119). The other feature is that HIV-related tuberculosis under usual circumstances appears to be somewhat less infectious than tuberculosis not associated with HIV infection (120). Although this decreased infectiousness might appear to be related to the tendency for HIV-infected persons 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 nineteenth century, it was commonly believed that tuberculosis was a hereditary disease (121). In the early part of the twentieth century, Karl Pearson and Raymond Pearl each attempted to disentangle the hereditary and environmental factors that led to the familial concentration of tuberculosis (109), investigations that were continued in the Williamson County Tuberculosis Study by Ruth Puffer (122). Subsequent studies of monozygotic and dizygotic twins indicated that some degree of susceptibility was inherited (123). Because of these indications of genetic susceptibility, investigators have looked for associations of tuberculosis with various genetic markers. Among Inuits in Alaska, tuberculosis was more prevalent among persons with blood groups B and AB than among those with blood groups 0 or A (124). Although various human leukocyte antigen types have also been suspected of playing a role in tuberculosis susceptibility, no consistent associations have been found (125,126). H. Nontuberculous Mycobacterial Infections

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 tuberculosis (127). Evidence of protection was also found among British adolescents who reacted only to the 100 TU dose of tuberculin and U.S. Navy recruits who reacted to antigens prepared from M. avium-intracellulare or M. scofulaceum but not to the intermediate dose of PPD-tuberculin (128,129). These findings were not confirmed in a large study in Puerto Rico (50),

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although it is possible that the nonreactors to the strong dose of tuberculin were like some of Palmer’s guinea pigs who showed some evidence of protection even after failing to develop hypersensitivity after two injections of nontuberculous mycobacteria. Although the question is unsettled, there is a strong possibility that human infections with nontuberculous mycobacteria do confer some protection against tuberculosis. 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 tuberculosis literature that psychological, social, and economic stresses have an adverse effect on tuberculosis (130–132). 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 (47). White, black, and Filipino recruits who were tuberculin reactors on entry to the Navy had very similar housing, diet, and income during the first 4 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. 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 30–40 years ago. Of concern is the current risk of disease following tuberculous infection in a variety of populations. Some way of reliably identifying persons who continue to harbor tubercle bacilli after having been infected would allow tuberculosis 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 tuberculosis back under control and, in developed countries, could even lead to its elimination in the near future. References 1. Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995; 273:220–226. 2. Buikstra JE, Cook DC. Pre-Columbian tuberculosis in west-central Illinois. prehistoric disease in biocultural perspective. In: Buikstra JE, ed. Prehistoric Tuberculosis

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22. 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. 23. Reichman LB, O’Day R. Tuberculous infection in a large urban population. Am Rev Respir Dis 1978; 117:705–712. 24. Comstock GW, O’Brien RJ. Tuberculosis. In: Evans AS, Brachman PS, eds. Bacterial Infections of Humans. Epidemiology and Control. 2d ed. New York: Plenum, 1991:745–771. 25. Kuemmerer JM, Comstock GW. Sociologic concomitants of tuberculin sensitivity. Am Rev Respir Dis 1967; 96:885–892. 26. 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. 27. Riley RL, Moodie AS. Infectivity of patients with pulmonary tuberculosis in inner city homes. Am Rev Respir Dis 1974; 110:810–812. 28. Snider DE Jr, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection and disease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli. Am Rev Respir Dis 1985; 132:125–132. 29. 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. 30. 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. 31. 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. 32. Thompson NJ, Glassroth JL, Snider DE Jr, Farer LS. The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 1979; 119:587–597. 33. Centers for Disease Control and Prevention. Prevention and control of tuberculosis in correctional institutions: Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1996; 45(No. RR-8):1–27. 34. 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. 35. Stead WW. Undetected tuberculosis in prison. JAMA 1978; 240:2544–2547. 36. 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. 37. 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. 38. 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. 39. Rich AR. The Pathogenesis of Tuberculosis. Springfield, IL: Charles C Thomas, 1944:779–810. 40. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1970; 17:28–106.

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41. Krishna Murthy VV, 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. 42. 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. 43. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95:935–943. 44. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 45. Sutherland I. The evolution of clinical tuberculosis in adolescents (abstr). Tubercle 1966; 47:308. 46. Comstock GW, Palmer CE. Long-term results of BCG vaccination in the southern United States. Am Rev Respir Dis 1966; 93:171–183. 47. Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity in the U.S. Navy: its distribution and decline. Am Rev Respir Dis 1974; 110:572–580. 48. Raj Narain, Naganna K, Murthy SS. Incidence of pulmonary tuberculosis. Am Rev Respir Dis 1973; 107:992–1001. 49. Palmer CE, Edwards LB, Hopwood L, Edwards PQ. Experimental and epidemiologic basis for the interpretation of tuberculin sensitivity. J Pediatr 1959; 55:413– 429. 50. Comstock GW, Livesay VT, Woolpert SF. Evaluation of BCG vaccination among Puerto Rican children. Am J Public Health 1974; 64:283–291. 51. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990; 142:725–735. 52. 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. 53. Flick JA. Does measles really predispose to tuberculosis? Am Rev Respir Dis 1976; 114:257–265. 54. Edwards LG, Livesay VT, Acquaviva FA, Palmer CE. Height, weight, tuberculous infection, and tuberculous disease. Arch Environ Health 1971; 22:106–112. 55. Fox W. The John Barnwell Lecture. Changing concepts in the chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1968; 97:767–790. 56. Stead WW, Jurgens GH. Productivity of prolonged follow-up after chemotherapy for tuberculosis. Am Rev Respir Dis 1973; 108:314–320. 57. Kopanoff DE, Snider DE Jr, Johnson M. Recurrent tuberculosis: Why do patients develop disease again? Am J Public Health 1988; 78:30–33. 58. 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. 59. 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. 60. 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.

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61. Combs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Int Med 1990; 112:397– 406. 62. Horwitz O. Public health aspects of relapsing tuberculosis. Am Rev Respir Dis 1969; 99:183–193. 63. Comstock GW. Untreated inactive pulmonary tuberculosis: risk of reactivation. Public Health Rep 1962; 77:461–470. 64. Edwards LB, Doster B, Livesay VT, Ferebee SH. Risk of tuberculosis in persons with not active-not treated lesions. Bull Int Un Tuberc 1972; 47:151–156. 65. Springett VH. Tuberculosis risk in persons with “fibrotic” lesions. Bull Int Un Tuberc 1972; 47:157–159. 66. Pamra SP, Prasad G, Mathur GP. Relapse in pulmonary tuberculosis. Am Rev Respir Dis 1976; 113:67–72. 67. 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. 68. Nakielna EM, Cragg R, Grzybowski S. Lifelong follow-up of inactive tuberculosis: its value and limitations. Am Rev Respir Dis 1975; 112:765–772. 69. 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. 70. Cowie RL, Langton ME, Becklake MR. Pulmonary tuberculosis in South African gold miners. Am Rev Respir Dis 1989; 139:1086–1089. 71. Centers for Disease Control. Tuberculosis, final data—United States, 1986. MMWR 1988; 36:817–820. 72. Centers for Disease Control and Prevention. Tuberculosis morbidity—United States, 1997. MMWR 1998; 47:253–257. 73. Comstock GW. Variability of tuberculosis trends in a time of resurgence. Clin Infect Dis 1994; 19:1015–1022. 74. Centers for Disease Control. 1985 Tuberculosis Statistics. States and Cities. HHS Publication No. (CDC) 87-8249. Atlanta: Public Health Service, 1986. 75. Centers for Disease Control and Prevention. 1992 Tuberculosis Statistics in the United States. Atlanta: Public Health Service, 1994. 76. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 1996. Atlanta: Public Health Service, 1997. 77. Raviglione MC, Rieder HL, Styblo K, Khomenko AG, Esteves K, Kochi A. Tuberculosis trends in Eastern Europe and the former USSR. Tuberc Lung Dis 1994; 75:400–416. 78. Cantwell MF, Binkin NJ. Impact of HIV on tuberculosis in sub-Saharan Africa: a regional perspective. Int J Tuberc Lung Dis 1997; 1:205–214. 79. 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. 80. U.S. Congress, Office of Technology Assessment. The Continuing Challenge of Tuberculosis, OTA-H-574. Washington, DC: U.S. Government Printing Office, 1993. 81. 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.

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7 Bacteriology of Tuberculosis

JACQUES GROSSET, CHANTAL TRUFFOT-PERNOT, and EMMANUELLE CAMBAU Faculté de Médecine Pitié-Salpêtrière Université Pierre et Marie Curie Paris, France

I. Introduction Although a search for acid-fast bacilli (AFB) on stained sputum smear, and culture and drug-sensitivity testing on enriched agar or egg-based medium are still the basic methods for the laboratory diagnosis of tuberculosis, they are far from being accurately implemented or performed in a majority of countries in the world, and a complete set of new technologies is now available. The use of a radiometric detection system for mycobacterial growth permits a reduction of the time required for obtaining the results of culture and drug-sensitivity tests. Nonisotopic probes for the identification of pure cultures and DNA fingerprinting of Mycobacterium tuberculosis for strain typing are important new developments. In addition, the application of nucleic acid–amplification techniques to the direct detection of M. tuberculosis in clinical specimens and the direct detection of drug resistance, especially to rifampin, is offering new tools, although they are still relatively expensive and sophisticated. The purpose of this chapter is to present conventional and modern methods for the laboratory diagnosis of tuberculosis in a pragmatic approach for developed as well as for developing countries. 157

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Laboratories processing specimens that could contain tubercle bacilli should ensure that safety measures are appropriately implemented and controlled (1–3). Even more rigorous safety measures should be followed by technicians performing identification and drug-susceptibility testing since they work with large inocula of pathogenic mycobacteria. Workers in the mycobacteriology laboratory are particularly exposed to infectious aerosols generated by manipulations of tubercle bacilli. Therefore, manipulations, even the crucial direct sputum smear that is often the only possible laboratory diagnostic method performed in developing countries, must be performed in a dedicated room. The room should be under some kind of negative pressure and equipped with a biological safety cabinet, either a class I negative pressure or a class II laminar-flow safety cabinet, which should be regularly checked. Centrifugation should be carried out in sealed centrifuge cups to prevent aerosols in case of leakage. Workers must wear a laboratory coat or gown. An autoclave should be available in an adjacent room, and infectious waste should be removed and decontaminated frequently. All work surfaces should be cleaned with appropriate disinfectant such as fresh 3% dilution sodium hypochlorite or 2% alkaline glutaraldehyde. Personnel working in a mycobacteriology laboratory should have annual health exams including tuberculin testing with appropriate chest x-rays and preventive therapy. III. General Characteristics of Tubercle Bacilli The tubercle bacillus belongs to the Mycobacterium genus, the only genus of the Mycobacteriaceae family. It includes four species, namely M. tuberculosis, M. bovis, M. africanum, and M. microti, which constitute the M. tuberculosis complex. A. Physical and Chemical Characteristics

Microscopy

M. tuberculosis is a thin rod with rounded extremities, 2–5 m long and 0.2–0.3 m thick. Nonmotile, without capsule or spore, and true branching, it is difficult to stain with the usual methods, although it belongs to the gram-positive bacteria. But stained with the reference carbol fuchsin or Ziehl-Neelsen method, it resists decolorization with strong mineral acids and alcohol, hence is an acid-fast bacillus, appearing under microscope examination as a slightly curved or straight, small red or pink rod.

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Cell Wall

The mycobacterial cell wall is composed of a peptidoglycan, as in other bacteria, linked to a specific lipopolysaccharide made of arabinogalactan esterified at its distal end with fatty acids containing 60–90 carbon atoms, named mycolic acids (4). Mycolic acids play a major role in the acid-fastness of mycobacteria (5). In addition to the above components, a wide variety of other complex molecules are found within the outer layer of mycobacterial cell wall (6), e.g., sulfatides, trehalose-dimycolate, mycosides, and waxes Because of its thickness and high lipid content, the mycobacterial cell wall is much more impermeable to hydrophilic molecules than that of other bacteria (7,8). The penetration of hydrophilic molecules, at least small ones, might depend upon wall-associated proteins that play the same role as porins in gram-negative bacteria (9). The high lipid content of the cell wall is also responsible for the resistance of mycobacteria to chemical injury, in other words, to decontamination procedures with acids, sodium hydroxide, and/or detergents. However, M. tuberculosis is as susceptible as other bacteria to heat, x-rays, UV rays, and alcohol. M. tuberculosis remains viable for weeks at 4°C and for years at 70°C. Mycobacterial Antigens

Soon after the discovery of the tubercle bacillus, Robert Koch prepared a concentrated sterile filtrate from heat-killed liquid culture (10), which he named “tuberculin.” It soon became apparent that tuberculosis patients reacted to the injection of tuberculin more rapidly and intensely than uninfected persons, and the intradermal skin test with tuberculin became part of the diagnosis of tuberculosis infection. Among all antigens of M. tuberculosis and M. bovis that have been described, neither polysaccharides nor phenolglycolipids are specific to the tubercle bacilli. B. Nutrition and Growth

M. tuberculosis has two main growth characteristics. First, it does not grow on ordinary culture media, but only on enriched media. However, the absence of growth on ordinary culture media is not related to any particular requirement for a growth factor or vitamin, even though various compounds potentiate the in vitro growth. This is the case for bovine serum albumin, egg yolk, and even catalase. Second, it has a slow rate of growth, the generation time of the cells in the best conditions of culture being 13–20 hours on solid as well as in liquid medium. M. tuberculosis is a strict aerobe equipped with catalase, peroxidase, and superoxide-dismutase, the growth rate of which is highly dependent upon the oxygen concentration. When oxygen concentration is high, as in the tuberculosis cav-

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ity of the lung, M. tuberculosis multiplies freely; when it is much lower, as in the caseous foci of the lung, M. tuberculosis multiplies slowly or not at all (11). Up to 8% carbon dioxide either as NaHCO3 /Na2CO3 in the medium or as CO2 in the gas phase above the medium considerably improves the growth of isolates from clinical specimens (12). M. tuberculosis can oxidize an extremely wide range of compounds. The preferred carbon sources for growth are, by order of preference, glycerol, pyruvate, and glucose. The growth of M. bovis, a species closely related to M. tuberculosis, is favored by 0.2% pyruvate but inhibited by a high concentration (5%) of glycerol. Asparagine is usually considered as the preferred source of nitrogen for growth of M. tuberculosis. In addition to carbon and nitrogen sources, M. tuberculosis requires four major inorganic elements for growth—potassium, magnesium, sulfur, and phosphorus—and a variety of trace elements, such as iron, zinc, and probably manganese (12). All of these elements are present in common semisynthetic culture media as well as in the human body. IV. Bacteriology for Diagnosis and Monitoring Treatment of Tuberculosis A. Specimen Collection and Transport

A number of clinical specimens may be submitted to the laboratory for detection of mycobacteria. The majority of these are from the respiratory tract, but sterile body fluids, urine, and tissues, and even blood and stools from AIDS patients are also submitted. The quality of the results depends in large part on the quality of their collection and transport, their repetition, and sometimes their conservation. Specimens must be collected before chemotherapy begins. The collection containers should be sterile if the specimen is taken from a closed cavity (cerebrospinal fluid, pleural effusion, abcess, etc.) and should not contain any fixative or preservative. The collected clinical specimens should be delivered to the laboratory as soon as possible. If delays in delivery or processing are anticipated, specimens should be kept at 4°C to avoid overgrowth by contaminants and to preserve the viability of mycobacteria. In case of transportation, the collection container must be sealed to prevent leakage and cushioned to prevent breakage according to regulations. Sputum or Sputum-Containing Specimens

Three spontaneously produced specimens of sputum are usually collected in clean but not necessary sterile containers. If satisfactory sputum samples, distinct from saliva or nasopharyngeal discharge, cannot be produced, specimens can be obtained by either nebulization with sterile hypertonic saline or gastric lavage or laryngeal swabs. Bronchofibroscopy for collection of aspirates, brushing, or

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lavages may be necessary for some patients (13). The collection of sputum-containing specimens, especially by nebulization or bronchoscopy, should be performed in a special area and by qualified personnel to minimize the risk of infectious aerosols. Non–Sputum-Containing Specimens

Most specimens from extrapulmonary tuberculosis (pleural, pericardial, spinal, synovial, and ascitic fluids, blood and bone marrow samples, surgical biopsies, etc.) are normally free of organisms other than mycobacteria and usually contain a limited number of tubercle bacilli. Therefore, it is necessary to collect the largest possible volume aseptically and in sterile containers in order to avoid the decontamination procedure, which threatens the viability of bacilli. Special emphasis should be given to the collection of blood for culture of mycobacteria in subjects suffering from HIV infection. Blood may be collected using the Isolator LysisCentrifugation System (Vampole Laboratories, Cranbury, NJ) or the BACTEC 13A bottle (Becton-Dickinson Diagnostic Instruments System, Cockeysville, MD), both of which contain lysing agents that allow the release of intracellular bacilli (14). Specimens expected to be contaminated (i.e., urine, stools, pus from an open abcess) may be collected in containers similar to those used for sputum specimens. Urine specimens should be collected after appropriate cleaning of the external genitalia. Early morning midstream specimens collected on three consecutive days provide the best results. B. Microscopy

Microscope examination of the stained smear is the first step in the search for tubercle bacilli in the laboratory. Direct smear prepared from necrotic or bloodtinged particles of the specimen, usually sputum, is done in most laboratories worldwide. Often, especially when all specimens are processed for culture, a portion of the digested, decontaminated specimen is used for preparing a concentrated smear. The property of acid-fastness is used to detect mycobacteria. A variety of acid-fast staining procedures are available (13). The most classic is the carbol fuchsin procedure or Ziehl-Neelsen stain. After staining, the smear is examined under the 100 oil immersion objective of a light microscope equipped with a 10 ocular lens. Acid-fast bacteria (AFB) appear as pink-red thin rods against a blue background when methylene blue is used as a counterstain. In laboratories that have a large number of smears to scan daily, fluorescent staining procedures may be used with auramine O or auramine-rhodamine as the primary fluorochrome dye. After decolorization with an acid-alcohol preparation, the smear is counterstained with either potassium permanganate, acridine orange, or thiazine

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red, and scanned at a lower magnification with a 25 dry objective and a fluorescent microscope (13). AFB appear as yellow-green or orange fluorescent thin rods against a dark background. In these conditions, the examination is easier, more rapid, and finally more sensitive (15). Once detected on the stained smear, AFB should be reported using a 10-fold quantitative scale in order to assess the severity of the disease at the time of diagnosis and monitor the patient response to therapy (16). Though search for AFB on the stained smear is the easiest and most rapid procedure for the detection of the most infectious tuberculosis patients, it has several limitations. First, its sensitivity is relatively weak: more than 5,000–10,000 bacilli must be present per milliliter of specimen before the bacilli can be detected under the microscope. Second, because acid-fast artifacts may be present in a smear, especially after fluorochrome stain, it is necessary to carefully control bacillary morphology and to consider as doubtful any number of AFB less than 3 by fuchsin stain observed at a total magnification of 1000 or 10 by fluorochrome stain observed at 250 (13). Third, all mycobacterial species being acid-fast, the observation of AFB in a stained smear under the microscope is only evidence of mycobacterial disease, not necessarily of tuberculosis. C. Culture

Although microscopy is an essential tool in today’s tuberculosis-control programs, culture is much more sensitive than microscopy and enables specific identification and drug-sensitivity testing of the mycobacterial pathogen. Digestion and Decontamination

Most specimens submitted for culture, except those collected from closed aseptic lesions, are contaminated with more rapid growing organisms and should be decontaminated to eliminate these organisms before culture is attempted. They must be decontaminated by mixing with chemical compounds (acid, alkali, quaternary ammonium) that kill contaminant organisms more rapidly than tubercle bacilli. As tubercle bacilli are frequently included in organic debris, for example, mucus globules in the sputum, specimens must first be liquefied or digested with detergents or enzymes. In practice, both liquefaction and decontamination are accomplished simultaneously using either a single compound with both capacities, e.g., sodium hydroxide (NaOH), or a mixture of two compounds, e.g., N-acetyl-L-cysteine (NALC) and NaOH, sodium dodecyl sulfate (sodium lauryl sulfate) and NaOH, or benzalkonium chloride and trisodium phosphate (13). At the end of the procedure, decontaminated specimens are generally neutralized with a dilute acid solution and centrifuged to concentrate the tubercle bacilli. Then the supernate is decanted and the sediment inoculated onto culture medium.

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Whatever digestion-decontamination procedure is used, the procedure must be critically timed to minimize the killing of tubercle bacilli by the decontaminating agent, and great care must be taken to avoid laboratory cross-contamination (17). No one method of digestion-decontamination is ideal for all specimens and all laboratories, but the most widely used is the NALC-NaOH, which is compatible with the BACTEC culture system and molecular biology tests (18). Some procedures, using slow-acting compounds, such as pancreatin-desogen or cetylpiridinium chloride–sodium chloride, can be used for the digestion-decontamination of specimens that must be transported for several days before culture (19). Quality control methods should ensure that the specimens are being decontaminated adequately without killing excessive numbers of mycobacteria. A simple control is given by the percentage of contaminated cultures: 5% indicates that the digestion-contamination procedure is insufficient,
2% indicates that the procedure is too strong and will likely kill too many mycobacteria. All digestion-decontamination procedures, even critically done, kill 50–90% of the tubercle bacilli present in clinical specimens. Because body fluids from closed cavities usually contain small numbers of mycobacteria, these fluids should be collected aseptically and inoculated without decontamination. Culture Medium

The numerous culture media presently available may be simply classified into solid and liquid media. Solid Media

The most commonly used solid media are egg or agar based (13). Egg media (modified Löwenstein-Jensen, American Trudeau Society, Ogawa, Petragnani, etc.) are more laborious to prepare but are less expensive and have a longer shelf life than agar media. They do not require additional CO2-enriched atmosphere to initiate primary growth of mycobacteria and consequently may be placed in screw-capped tubes. The morphology of mycobacterial colonies is more typical. Conversely, agar media are easier to prepare, enable a more rapid detection of growth, but require a CO2-enriched atmosphere to initiate primary growth of mycobacteria and therefore should be placed in plates (Petri dishes) and not in screwcapped tubes. For all these reasons, egg media are more commonly used in countries where tuberculosis is still highly prevalent. On the other hand, agar media, which are better standardized than egg media, are often required for scientific work. Selective drug-containing media, either 7H10 agar based or LöwensteinJensen based, have been proposed to control contamination on primary isolation. Although useful in some circumstances, such as isolation of mycobacteria from stools (20), these media are not used in routine practice.

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Whatever the solid medium used, two to six tubes or plates should be inoculated with 0.1–0.5 mL of the decontaminated or aseptically processed specimen. The number of tubes or plates to be inoculated depends on many factors, among which are the space available in the incubator and the clinical importance of the specimen [e.g., cerebrospinal fluid (CSF)]. In countries where M. bovis and/or M. africanum is suspected, one or two tubes or plates of 0.2% pyruvate-containing medium may be inoculated in supplement, because sodium pyruvate enhances the growth of both organisms. All media should be incubated at 35–37°C. They should be examined within 3–5 days after inoculation to enable early recognition of rapidly growing mycobacteria and of contaminated cultures, followed by once-weekly examination for at least 6 weeks, at most 3 months, before being discarded as negative. Culture is reported as positive as soon as colonies of characteristic morphology constituted of acid-fast bacilli are recognized. The report of culture should contain the amount of growth (number of colonies) recorded in a semi-quantitative way (e.g., no colonies, exact number if less than to 50, 50–100, 100–200, or 200 colonies in case of confluent growth. This is of importance for monitoring patient response to therapy (21). Liquid Media

Numerous liquid media have been developed for the culture of M. tuberculosis. Among them, only the Middlebrook 7H12 broth is routinely used for the primary isolation of mycobacteria in conjunction with the BACTEC TB 460 System (Becton-Dickinson Instrument Systems, Sparks, MD). The system is based upon the semi-automated measurements of 14CO2 produced by the growth of tubercle bacilli in the headspace of a 7H12-containing vial that has 14C-labeled palmitic acid as the only carbon source (22). In practice, 0.5 mL aliquots of the decontaminated specimen are added to vials containing 4 mL Middlebrook 7H12 broth (BACTEC 12B vial) along with an antibiotic mixture. The vials are incubated at 37°C for a total of 6 weeks (23). They are read three times a week for the first 2 or 3 weeks and weekly thereafter. As soon as a significant amount of 14CO2 is produced, a smear is performed to determine if the vials contain AFB. Because an increase in the 14CO2 amount is more rapidly detected than colonies on a solid medium, the time to detection for positive growth with the BACTEC system is significantly shorter than that with solid media; on average, 8 days with AFB smear–positive specimens and 14 days with AFB smear–negative specimens (24,25). The 7H12 broth has also been reported to yield more positive cultures from clinical specimens than solid media (26,27). The BACTEC 460 TB system may also be used to recover mycobacteria from blood and to test drug susceptibility. However, it has several limitations: inability to observe colony morphology, difficulty in recognizing mixed cultures, overgrowth by contaminants, cost, radioisotope disposal, and extensive use of needles (3).

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To reduce the difficulties inherent in the use of radioisotopes, new nonisotopic liquid media, all modified Middlebrook 7H9 broth-based, have been developed. The SeptiCheck (Roche Diagnostics Systems Inc., Nutley, NJ) and MBCheck systems (Hoffman-LaRoche, Basel, Switzerland) are broth plus solid media biphasic systems. The rates of recovery for M. tuberculosis with these systems are similar to that of BACTEC 460 system. The average time to detection is longer than with the BACTEC system but shorter than with solid media (28,29). The mycobacterial growth indicator tube, or MGIT (BBL, Becton-Dickinson, Cockeysville, MD), is a culture broth that contains a fluorescence quenching–based oxygen sensor. Under UV light, bright orange fluorescence at the bottom of the inoculated tube indicates microbial growth. In two studies, the average time to detection of M. tuberculosis was similar between MGIT and the BACTEC 460 TB system, whereas the rate of recovery was slightly inferior with MGIT (27,30). A fully automated system, the BACTEC 9000 MB system, can monitor fluorescence levels and detect the growth of microorganisms from blood and other specimens (31). Three other nonisotopic liquid media are in development. The ESP culture system II (Difco Laboratories, Detroit, MI) and the MB/Bact T (Organon Teknika Corp., Durham, NC) are fully automated, continously monitoring systems whose technology is based on detection of pressure changes in the headspace above the broth culture (32) or color changes of a sensor under the effect of CO2 release (33), respectively. With the MB Redox medium (Biotest, Dreieich, Germany), growth is monitored by a macroscopically sensible color change (34,35). Tubes are ready to use and reading is possible without any additional aid. Initial results obtained with these three systems are attractive. D. Identification of the Isolated Mycobacterial Strain

Because numerous mycobacterial species other than M. tuberculosis complex are frequently recovered from human sources in the clinical laboratory, speciation of the isolated mycobacteria is of prime importance. Identification of the Tuberculosis Complex

The careful observation of growth properties and colonial morphology on solid media directs the identification of the isolated mycobacteria. The mycobacteria belonging to the tuberculosis complex grow slowly and produce colonies after incubation for 3–6 weeks at 35–37°C. Typical colonies of M. tuberculosis, the prominent species of the tuberculosis complex and the organism responsible for human tuberculosis, are well-developed (eugonic) with a rough surface and headed up with a characteristic buff color. Colonies of mycobacteria other than those of the M. tuberculosis complex, i.e., “atypical” or nontuberculous my-

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cobacteria (NTM), may produce pigment after exposure to light (photochromogens, such as M. kansasii and M. marinum) or even when grown in the dark (scotochromogens, such as M. gordonae and M. xenopi). Some, referred as to “rapidly growing mycobacteria,” are able to grow in less than 7 days. Others, especially those belonging to nonphotochromogenic species, such as M. terrae complex and M. avium complex (MAC), have unpigmented, sometimes rough colonies that may be easily confused with colonies of M. tuberculosis complex. Three conventional biochemical tests enable differentiation between M. tuberculosis complex and NTM: the heat-stable (68°C) catalase test, a niacin test, and growth on 0.5 g/mL para-aminosalicylic acid (PAS). M. tuberculosis complex has heat-labile catalase and is PAS susceptible; in addition, the species M. tuberculosis is niacin-test positive. With few exceptions, NTM give opposite results. Two other differential tests are now commonly used: the DNA probe assay and the BACTEC NAP test. DNA probes complementary to rRNA of M. tuberculosis complex, MAC, M. avium, M. intracellulare, M. gordonae, and M. kansasii (AccuProbe; GenProbe, San Diego, CA) are commercially available. These probes can be used to identify isolates on solid culture media and in broth culture. Because the results of probe assays are obtained in about 2 hours with excellent sensitivity and specificity and low cost, DNA probes have supplanted conventional biochemical tests. Cultures of M. tuberculosis complex in the Bactec vial can also be identified with the p-nitro- -acetylamino- -hydroxypropiophenone (NAP) test. Growth of M. tuberculosis complex is affected by NAP, whereas growth of any NTM is not. Speciation Among the M. tuberculosis Complex

Within the M. tuberculosis complex, DNA probes do not differentiate between M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, and M. microti. Although closely related to M. tuberculosis, M. microti is responsible for naturally acquired tuberculosis in the vole and never encountered in the clinical laboratory. M. tuberculosis, M. bovis, M. bovis BCG, and M. africanum have clear-cut cultural, biochemical, and epidemiological differences but on the basis of DNADNA hybridization could be considered simple varieties of a single species, M. tuberculosis (36). Differentiation between them (Table 1) relies upon colony morphology, rate of growth, niacin production, and nitrate reduction as well as growth in medium containing 2 g/mL of thiophene-2-carboxylic acid hydrazide or TCH (37), and sometimes susceptibility to cycloserine and guinea pig inoculation. At isolation, colonies of M. bovis do not develop before one month of culture, are smooth, tiny (dysgonic), and white. However, after several in vitro subpassages, the small (dysgonic) colonies of M. bovis often give rise to large rough colonies having a morphology similar to those of M. tuberculosis. Colonies of M.

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Table 1 Speciation Among the Mycobacterium tuberculosis Complex

Mycobacteria M. tuberculosis M. bovis M. bovis BCG M. africanum M. microti

Growtha Colonies rate (weeks) Morphology Pigmentation 3–4 ≥4 ≥4 ≥4 3–4

Re Sd Re Rd Re

Buff White Buff Matte Buff

Niacin production

Nitrate reduction

Growth on cycloserine (30 mg/L)

    to  

    to  

    ?

Growth on Virulenceb TCHb for (2 mg/L) guinea pig     to  

    

a

For primary isolation on solid media. For strain susceptible to isoniazid. R  rough; S  smooth; e  eugonic; d  dysgonic;   positive;   negative; TCH  thiophene-2-carboxylic hydrazide.

b

bovis BCG have growth and morphology characteristics similar to those of M. tuberculosis. Different geographic varieties of M. tuberculosis have been observed. In Europe and the United States the organisms grow slowly in culture into well-developed (eugonic), rough colonies with a characteristic buff color. In Southeast Asia, colonies of M. tuberculosis are small and smooth like those of M. bovis but with the characteristic M. tuberculosis buff color. M. africanum strains often grow poorly and slowly as minute flat and rough colonies with a matte color. M. bovis and M. bovis BCG neither accumulate niacin nor have nitrate reductase. Their growth is generally inhibited by TCH except when the strains are isoniazid resistant. They are naturally resistant to pyrazinamide. M. africanum strains may or may not have nitrate reductase activity and accumulate more or less niacin. Their growth may or may not be inhibited by TCH. In eastern regions of Central Africa (Rwanda variety), they have characteristics close to those of M. tuberculosis, but in West Africa (Dakar variety), they are closer to those of M. bovis. They are often resistant to thiacetazone. Inoculation into the guinea pig enables one to assess the virulence of the different strains of the M. tuberculosis complex. Lack of virulence is a crucial characteristics of M. bovis BCG, and decreased virulence is a characteristic of the normally virulent M. tuberculosis and M. bovis when they are resistant to isoniazid. Identification of Atypical or Nontuberculous Mycobacteria

Elaborate species differentiation of atypical mycobacteria is accomplished with a series of tests, including growth at different temperatures, pigment production, biochemical properties and drug susceptibility; for details on the identification procedures, the reader should consult specialized references (3,13). However, it should be emphasized that the identification of NTM has benefited from the development of specific DNA probes (GenProbe, San Diego, CA) and the determi-

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nation of the mycolic acid pattern (38). The latter method, particularly useful for the identification of difficult-to-identify NTM, requires high-performance liquid chromatography, thin-layer chromatography, or gas-liquid chromatography and, therefore, is still reserved to large reference laboratories.

V. Strain Typing of M. tuberculosis Typing of M. tuberculosis strains is of great epidemiological value for tracing transmission of M. tuberculosis in the community, deciding whether relapse of tuberculosis in a given patient is due to endogenous reactivation or exogenous reinfection, and demonstrating laboratory contamination of specimens or even of laboratory workers (see Chap. 11). Since the beginning of drug therapy for tuberculosis, unusual drug-susceptibility patterns have been used for epidemiological purposes but with great limitations. The development of a phage-typing system based on the use of 12 mycobacterial phages raised many expectations (39). Unfortunately, only four phage types were officially recognized: Ao, Aox, B, and C. Type B was common in Europe and the United States, type A was more common in Japan and Hong Kong. No relationship existed between phage typing and drug resistance. More recently, a method based on the study of DNA polymorphism caused by an insertion sequence (IS) 6110 or 986 (40) integrated at various sites in the chromosome and specific of the M. tuberculosis complex has been developed (41). The M. tuberculosis chromosome is first digested into DNA fragments of different sizes by a restriction endonuclease. DNA fragments are then transferred and hybridized with an IS 6110 probe. Thus, only the restriction fragments carrying the IS are revealed (Fig. 1). This method is referred to as restriction fragmentlength polymorphism (RFLP) or DNA fingerprinting (42). As the distribution of IS 6110 is variable from one strain to another in the number of copies (1–20) and their integrations sites, the banding patterns differ from one DNA to another. If two patients were infected with the same strain, the banding pattern of their DNA would be similar; if they were infected with different strains, the banding pattern would usually be different. Identical or similar patterns are generally observed in case of relapse (44). Analysis and comparisons of RFLP patterns need the use of a computer-assisted method when more than 10 strains are compared (45). DNA fingerprinting is at present the most elaborate technique used to characterize individual strains of M. tuberculosis and conduct scientifically based epidemiological studies, thus to trace strains in the community. Standardization of the method (reference strains used as markers, standardization of all steps of the technique, universal computer-assisted method) means that it is now possible to compare strains isolated around the world.

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Figure 1 IS 6110-based DNA fingerprint of 13 Mycobacterium tuberculosis complex isolates. The sizes of restriction fragments are given in kilobases (kb) on the left. Lane 1 corresponds to the Mt 14323 reference strain. Other lanes are from isolates of different patients. Note similar patterns between lanes 6 and 8 and between lanes 12 and 14 that are, respectively, from epidemiologically related patients. (Courtesy of W. Sougakoff and N. Lemaitre.)

A new method, “spoligotyping,” which is easier and more rapid, is currently under investigation (46). VI. Drug Activity Against M. tuberculosis Since the beginning of the antibiotic era, assessing the activity of different compounds against M. tuberculosis and conversely the susceptibility of different strains of M. tuberculosis to a given compound became common. Well-defined in

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vitro methods have been developed to measure the minimal inhibitory concentration (MIC) of drugs with known activity and of compounds with unknown activity against M. tuberculosis. The activity of a drug or a combination of drugs can also be assessed in vivo in an experimental animal model. Even more important, several methods have been devised to test, in the clinical laboratory, the susceptibility of M. tuberculosis to the drugs that are routinely used in the chemotherapy of tuberculosis. A. In Vitro Assessment of Drug Activity (MIC Determination)

The MIC determination may be performed on solid or liquid culture media. When solid media are used, the following protocol may be recommended. The drug to be tested is initially dissolved, subsequently diluted with distilled water, and incorporated into 10% oleic acid albumin dextrose catalase–enriched 7H10 or 7H11 agar medium, with twofold diluted final concentrations that may range from 16 to 0.03 g/mL. The reference H37Rv strain of M. tuberculosis is subcultured in Tween 80–containing 7H9 broth at 37°C for 7 days; then the turbidity of the resultant suspension is adjusted with distilled water to match that of a standard suspension of 1 mg/ml M. bovis BCG (similar to a McFarland 1 standard) and 0.05 mL of 103 and 105 mg/mL of the diluted suspensions are plated, respectively, on the drug-free and drug-containing media. The MIC is defined as the lowest drug concentration that inhibits more than 99% of the bacterial growth, as compared with the growth on drug-free medium, after incubation at 37°C for 21–28 days. Among liquid media, 7H9 broth without Tween 80 (which may enhance the antimicrobial activity of the test drug) and BACTEC broth are recommended. As with solid media, the drug to be tested should be dissolved, diluted, and incorporated into the broth, with twofold dilutions. Then the drug-free and drug-containing broths are inoculated with the H37Rv strain and incubated at 37°C. The MIC is also defined as the lowest drug concentration that inhibits bacterial growth, as compared with the growth in drug-free broth. B. In Vivo Assessment of Drug Activity in the Animal Model

Because of its great susceptibility to M. tuberculosis infection, the guinea pig has been used for many years in the clinical laboratory to detect the presence of tubercle bacilli in clinal specimens. It has also been used to assess the airborne transmission of tuberculosis (47), the comparative virulence of differents strains of M. tuberculosis (48), and the protective value of M. bovis BCG (49). It might be the experimental animal of choice for all these purposes. Although it has been used to test the antituberculous activity of several drugs (50,51), the model of choice for experimental chemotherapy is the mouse (52–55) because it is a small and robust animal that is easy to reproduce and handle, even though it is far from being as

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sensitive as the guinea pig to M. tuberculosis. Furthermore, the course of the disease that follows experimental infection with M. tuberculosis is different from that of the disease in humans. However, the mouse model is able to reproduce bacillary populations of comparable size to those observed in the lung cavity of human tuberculosis (54), and the infection can be treated with antimicrobial drugs used at equipotent (56) dosages to those given to humans (for a vast majority of drugs, with the noticeable exception of rifampin, the equipotent dosages are 12 times larger in the mouse than in humans). With the exception of aminoglycosides, which should given subcutaneously, drugs are given orally with an esophageal cannula (gavage) to each individual animal, thus mimicking human treatment. If used with great care, the mouse model provides responses to treatment that are predictive of the responses in humans (56). Because the aim of experimental chemotherapy is to obtain results that can be extrapolated to human beings, there is no need to use inbred mice such as BalbC, C57BL6, or C3H; the most frequently strain of mice used is the common outbred “Swiss” mouse. As in clinical trials, a sufficient number of mice should be used to compensate for individual variations. Inbred mice are, however, of great interest when factors other than drugs must be excluded. Mice are usually infected by the intravenous route with a standard amount of tubercle bacilli (56). The aerogenic route (57), more closely mimicking clinical infection than the intravenous route but requiring special devices and sophisticated safety measures, is more useful for testing the host-parasite relationship than for chemotherapy studies (58). The reference H37Rv strain of M. tuberculosis, the virulence of which is maintained through regular passages in the mouse and which is naturally susceptible to all antituberculous drugs, is the strain of choice. After intravenous infection with about 5  106 colony-forming units (CFU), up to 90% of mice die within the first month after infection from overwhelming tuberculosis with more than 108 CFU in the lungs and 107 CFU in the spleen (59,60). When the inoculum is smaller (about 5  103 CFU) mice are able to contain and control the initial multiplication of bacilli in such a way that the infection remains chronic and nonfatal, the size of the bacillary population not exceeding 106 CFU. A still more limited population of M. tuberculosis can be obtained if mice are vaccinated with M. bovis BCG one month before they are infected with a small inoculum (61). The activity of a single drug or a combination of drugs is monitored by the survival/mortality rate, the evolution of body weight, the extent of gross lesions, and the enumeration of CFU in the organs (spleen, lung) before, during, and after the course of treatment. Experimental chemotherapy had contributed to the assessment of all antituberculosis drugs, of standard streptomycin plus isoniazid long-course therapy, and also of short-course therapy with the combination of isoniazid, rifampin, and pyrazinamide. It enabled the demonstration in vivo of the bactericidal activity of the new fluoroquinolones, especially ofloxacin, lev-

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ofloxacin, and sparfloxacin, against M. tuberculosis (59,62). It permitted the study of the role of the rifamycin derivatives in preventive and curative treatments of tuberculosis, emphasizing the potential role of rifapentine, a long-lasting rifamycin derivative, in directly observed intermittent preventive therapy (63). C. The Drug-Susceptibility Test

In tuberculosis, drug resistance appearing during treatment designated as acquired or secondary resistance is the consequence of monotherapy; it results from the selection and multiplication of resistant mutants preexisting in the tubercle bacillus population before therapy. Multiple drug resistance is the consequence of sequential monotherapies. Drug resistance observed before treatment, designated as primary resistance, is the consequence of exposure to a drug-resistant source of infection. As the emergence of secondary drug-resistant M. tuberculosis strains and even of multidrug-resistant strains, particularly in AIDS patients (64), is increasingly reported from many countries (65), it is essential to determine the drug sensitivity of isolates from previously treated patients in order to design an effective treatment regimen. At least in theory it is less essential to determine the drug sensitivity of isolates from newly diagnosed, previously untreated patients because these patients usually harbor drug-susceptible organisms and are started on standard therapy well before the results of the pretreatment drug susceptibility test might be known. However, newly diagnosed patients may have developed disease with primary drug-resistant organisms. They also may have been previously treated, and the previous treatment may have remained undetected because it was not disclosed by the patients (66) or was forgotten by them. For these reasons, the American Thoracic Society (ATS) recommended that initial isolates from all patients be tested for drug susceptibility to confirm the anticipated effectiveness of chemotherapy or to choose the best combination of active drugs (67). In addition, ATS recommended that the tests be repeated if cultures were still positive after 2 months of treatment. Of course, such recommendations are only applicable to those countries having the potential to perform cultures for all cases of tuberculosis. For other countries, the priority should be given to isolates from previously treated patients. The antituberculous drugs that should be tested in priority include the firstline drugs isoniazid, rifampin, ethambutol, and streptomycin. Although pyrazinamide is also a first-line drug, it is not included in the priority list because its susceptibility is difficult to test. Pyrazinamide, a drug active only at an acid pH, should be incorporated in a culture medium in which the pH has been lowered to 5.5; at such a low pH, only 1–10% of the colonies grow in a control medium compared to the number of colonies growing at the usual pH 6.8. Despite the inclusion

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of control media at pH 6.8 and 5.5, the results of pyrazinamide-susceptibility testing cannot be interpreted in two frequently observed instances: when there is no growth in the control at pH 5.5 and in the pyrazinamide-containing medium or when there is extensive growth in both controls at pH 6.8 and at pH 5.5 and in the pyrazinamide-containing medium. Further susceptibility tests should be performed if resistance to the main drugs isoniazid and rifampin is suspected because of previous treatment history or infection with multidrug-resistant organisms. Secondary drugs for testing include pyrazinamide, ethionamide, kanamycin or amikacin, capreomycin, cycloserine, and at least a fluoroquinolone. The Standard Procedures

Four methods have been described for determining the antimicrobial susceptibilities of M. tuberculosis: the proportion method, the radiometric or BACTEC method, which is based on the same principle as the proportion method, the absolute concentration method, and the resistance ratio method (68). The proportion method and the BACTEC method are the most generally used. The proportion method is performed either on a solid egg-based or agarbased 7H10 medium containing an uniform, specified concentration of drug (“critical concentration”) (69). The BACTEC method (70) is performed in 12B broth vials also containing a critical drug concentration (68). The critical concentration (Table 2) is that which inhibits the growth of susceptible organisms without affecting the growth of the drug-resistant mutants. With the proportion method, the enumeration of M. tuberculosis colonies growing on drug-free and on drug-containing media inoculated with different dilutions of M. tuberculosis suspension enables the calculation of the proportion of drug-resistant mutants. If the proportion is less than the “critical proportion” that Table 2 Critical Concentration of Drugs for Susceptibility Testing with the Proportion Method on 7H10, 7H11, or Loewenstein-Jensen (LJ) Media or with the BACTEC Method Drug concentration (mg/L) Drugs

7H10

7H11

LJ

Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin PAS

0.2 1 25 5 2 2

0.2 1 ? 7.5 2 8

0.2 40 200 2 4 0.5

BACTEC 12B broth 0.1 2 100 2.5 2 4

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defines drug resistance, the strain is considered susceptible; if it is greater, the strain is considered resistant. Using 7H10 agar, the critical proportion is 1% for all drugs (71); using Löwenstein-Jensen medium, it is 1% for isoniazid, rifampin, streptomycin and PAS and 10% for other drugs (69). With the BACTEC method, drug-containing vials are inoculated with a suspension of the primary culture, the turbidity of which has been adjusted to a McFarland 0.5 standard. A 1:100 dilution of the inoculum is used as control. As soon as the growth index (GI) of the control is positive, the drug-susceptibility test is ready for interpretation: if the GI of the control vial is greater than the GI of the drug-containing vial, the strain is susceptible; if it is less, the strain is resistant. The solid medium may be directly inoculated with the decontaminated smear-positive specimen (direct susceptibility test) or with a suspension prepared from the primary culture (indirect susceptibility test). In the direct test, the specimen is diluted according to the number of AFB observed in the stained smear (Table 3) and two dilutions are inoculated. In the indirect test, a well-dispersed suspension of the primary culture is diluted to 103 and 105 mg wet weight per mL. In both cases, two dilutions are inoculated under the volume of 0.1 or 0.2 mL onto drug-containing (at the critical concentration) and drug-free media to provide a valid interpretation of the proportion of drug-resistant CFU. Due to the time required for the growth of colonies, the results of susceptibility tests on solid media are obtained after 3–6 weeks of incubation at 37°C. If a direct susceptibility test has been performed from the patient’s specimen, the results are available at the same time as those of culture, 3–6 weeks after inoculation (68). Those of an indirect susceptibility test are obtained 2 or 3 months after the inoculation of the patient’s specimen. Using the BACTEC 460 TB system, the results of drug-susceptibility testing can be obtained in as little as 5 days, depending on the inoculum size. The 14 CO2 is measured in drug-containing vials and in drug-free (control) vials (100fold lower inoculum). When the amount of 14CO2 in the drug-containing vial is equal or greater to the amount of 14CO2 in the control vial, at least 1% of the bacilli are resistant to the drug and the strain is considered resistant. The method is reliTable 3 Dilutions of Decontaminated Specimen for Inoculation in Direct Drug Susceptibility Testing by the Proportion Method No. of AFB observed per field Suspensions to be inoculated Undiluted and 102 101 and 103 102 and 104 Source: Adapted from Ref. 68.

Niehl-Neelsen (100)

Fluorochrome (40)


1 1–9 10

1–9 10–99 100

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able and at present widely used to test the susceptibility of M. tuberculosis to the first-line drugs, including pyrazinamide (72,73). It is not yet standardized for the second-line drugs. M. tuberculosis drug-susceptibility tests can be performed by comparing the fluorescence of a drug-containing MGIT with that of a growth-control MGIT without drug. The evaluation of the system is in progress (74). A newer, more elegant method for testing drug susceptibility is based on the use of a luciferase reporter mycobacteriophage (75). As only viable mycobacteria can multiply specific mycobacteriophages, drug resistance results in the production of light by organisms first cultivated in the presence of a given antimicrobial and then submitted to luciferase reporter mycobacteriophages. Detection of Mutations Associated with Drug Resistance

The genes encoding for the target of the first-line antituberculosis drugs as well as the mutations responsible for the resistant phenotypes have been identified (76–80). Because the mutations are localized in limited regions of the genes encoding for the drug target, they can be detected. After PCR amplification, the mutation is identified by sequencing the PCR products or by submitting them to simpler methods. One of these is the single strand conformation polymorphism method or PCR-SSCP (81). After denaturation of the PCR product, the single strands of DNA are subjected to electrophoresis on polyacrylamide gel. Their position on the gel, which depends on the presence or absence of mutations, is then characterized. In theory, the method is simple and rapid (48–72 hr) and may be applied to smear-positive specimens. In practice, the method is costly, rather sophisticated, and above all does not permit detection of all mutations conferring resistance, especially to rifampin. Another method that is much easier to perform is the Line Probe Assay, or LIPA (82). After denaturation of the PCR product, the single strands are hybridized with nine probes immobilized at known locations on a membrane strip. Five of these hybridize exclusively with wild-type sequences and each of the four others with a sequence carrying a particular mutation (Fig. 2). The presence of hybrids is revealed by an enzymatic color reaction. The method, which is available as a commerical kit, Inno-LIPA RIF.TB (Immunogenetic NV Zwijndrecht, Belgium) for the detection of rifampin resistance, is relatively simple and cheap and may be applied to smear-positive specimens. It gives promising results although it is not able to detect all mutations conferring rifampin resistance (83,84). VII. Immunodiagnostic Tests for Tuberculosis The tuberculin skin test (see Chap. 12) is well established as an immunodiagnostic test for tuberculosis infection. However, it can distinguish neither between ac-

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Figure 2 Rifampin susceptibility testing of Mycobacterium tuberculosis complex with the Line Probe Assay (LIPA). Lane 1: rifampin-susceptible strain (hybridization with the five susceptible sequences of the rpoB gene and no hybridization with any of the four resistant sequences of the rpoB gene); Lanes 2–6: rifampin-resistant strains with mutations at different sites of the gene. (Courtesy of W. Sougakoff and N. Lemaitre.)

tive tuberculosis disease and latent infection nor between M. tuberculosis infection and infection with other mycobacteria (85). Because of the common antigens shared by all species of the genus Mycobacterium, numerous efforts have been made to obtain and purify antigens specific to the M. tuberculosis complex. In addition, the most sophisticated procedures to detect corresponding antibodies, such as immunoelectrophoresis, hemagglutination tests, fluorescent antibody tests, radioimmunoassays, and enzyme-linked immunosorbent assays (ELISA), have been used. Despite all efforts, increased specificity often resulted in decreased sensitivity (86–88). Even with the

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most purified antigens, specificity remains about 96% and sensitivity is no better than 70% (89). Specificity and sensitivity are increased if ELISA results obtained with a set of purified antigens are combined (88,90). Although, for the present time, no immunodiagnostic test can be recommended for clinical use, research efforts should continue in order to develop an immunological test which enables the discrimination of patients with active disease among the sputum smear-negative, symptomatic patients suspected of having tuberculosis.

VIII. Direct Detection of M. tuberculosis by Nucleic Acid Amplification Because of the lengthy time required for cultivating M. tuberculosis, the application of nucleic acid amplification for the rapid detection of M. tuberculosis nucleic acids in clinical specimens has been extensively studied (3). Of the multiple PCRbased (18,91) and non–PCR-based (92–96) amplification procedures developed, three have been made commercially available: the Gen-Probe Amplified Mycobacterium tuberculosis Direct Test, or MTD (Gen-Probe Incorporated, San Diego, CA), the AMPLICOR Mycobacterium tuberculosis Test (Roche Diagnostic Systems, Inc., Branchburg, NJ), and the LCX Probe System (Abbott Laboratories, Diagnostic Division, Chicago). With these tests, and for smear-positive and smear-negative clinical specimens, the sensitivity has been demonstrated to be 95–96% and 48–53%; the specificity to be 100% and 96–99%; and the positive predictive value to be 100% and 24–58%, respectively (18,92,93,97–101). These values are in favor of the clinical use of MDT, AMPLICOR, and LCX in smear-positive specimens (102,103). In these specimens, the nucleic acid amplification tests may rapidly confirm the diagnosis of tuberculosis or identify the presence of nontuberculous mycobacteria, information of clinical value especially for HIV-infected patients (104,105). In smear-negative specimens, the nucleic acid amplification tests would, in spite of their relatively high specificity, add a relatively limited number of tuberculosis cases but a relatively high number of false-positive results because of the low prevalence of M. tuberculosis complex in these specimens. As a consequence, the U.S. Food and Drug Administration (FDA) stated in 1996 that the sole indication of nucleic acid amplification in the diagnosis of tuberculosis was the “smear-positive respiratory tract specimens from patients who have not been on antituberculosis medication for seven or more days; or have not been treated for tuberculosis within the last twelve months” (106). Of course, what holds true for respiratory tract specimens holds true also for extrarespiratory specimens because of the still lower prevalence of M. tuberculosis complex in extrarespiratory than in respiratory specimens (107,108).

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Although the wise recommendations of FDA emphasize the amount of care clinicians should take in prescribing and interpreting the nucleic acid–amplification tests for a rapid diagnosis of tuberculosis, these tests remain full of potential (109). In particular, it is likely that the future lies in the use of amplification tests for sputum-negative patients suspected of tuberculosis. All research efforts should be made for that future to occur as soon as possible. References 1. Kent PT, Kubica GP. Public Health Mycobacteriology: A Guide for the Level III Laboratory. Atlanta: Centers for Disease Control, U.S. Department of Health and Human Services, 1985. 2. Cernoch PL, Enns RK, Saubolle MA, Wallace RJ, Jr. Cumitechs 16A. Washington, DC: American Society for Microbiology, 1994. 3. Nolte FS, Metchock B. Mycobacterium. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, ed. Manual of Clinical Microbiology, 6th ed. Washington, DC: American Society for Microbiology, 1995:400–437. 4. Connell ND, Nikaido H. Membrane permability and transport in Mycobacterium tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection, and Control. Washington, DC: American Society for Microbiology, 1994:333–352. 5. Barsdale L, Kim KS. Mycobacterium. Bacteriol Rev 1977; 41:217–372. 6. Minnikin DE. Lipids: complex lipids, their chemistry, biosynthesis and roles. In: Ratledge C, Stanford J, eds. The Biology of the Mycobacteria. Section 3. Vol. I. London: Academic Press Ltd., 1982:95–184. 7. Jarlier V, Nikaido H. Permeability barrier to hydrophilic solutes in Mycobacterium chelonae. J Bacteriol 1990; 172:1418–1423. 8. Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 1994; 123:11–18. 9. Trias J, Jarlier V, Benz R. Porins in the cell wall of mycobacteria. Science 1992; 258:1479–1481. 10. Koch R. Weitere Mitteilung über das Tuberkulin. Dtsch Med Wochenschr 1891; 17:1189–1192. 11. Wayne LG. Dynamics of submerged growth of Mycobacterium tuberculosis under aerobic and microaerophilic conditions. Am Rev Respir Dis 1976; 114:807–811. 12. Ratledge C. Nutrition, growth and metabolism. In: Ratledge C, Stanford J, eds. The Biology of the Mycobacteria. Section 5. Vol. I. London: Academic Press Ltd., 1982:186–271. 13. Kubica GP. Clinical microbiology. In: The Mycobacteria: A Sourcebook. Part A. Section 7. New York: Marcel Dekker, 1984:133–175. 14. Gill VJ, Park CH, Stock F, Gosey LL, Witebsky FG, Masur H. Use of lysis centrifugation (Isolator) and adiometric (Bactec) blood culture systems for the detection of mycobacteremia. J Clin Microbiol 1985; 22:543–546. 15. Strumpf IJ, Tsang AY, Sayre JW. Reevaluation of sputum staining for the diagnosis of pulmonary tuberculosis. Am Rev Respir Dis 1979; 119:599–602.

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79. Honoré N, Cole S. Streptomycin resistance in mycobacteria. Antimicrob Agents Chemother 1994; 38:238–242. 80. Scorpio A, Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to antituberculous drug pyrazinamide in tubercle bacillus. Nature Med 1996; 2:662–667. 81. Telenti A, Imboden P, Marchesi F, Schmidheini T, Bodmer T. Direct, automated detection of rifampin resistant Mycobacterium tuberculosis by polymerase chain reaction and single stand conformation polymorphism analysis. Antimicrob Agents Chemother 1993; 37:2054–2058. 82. De Beenhouver H., Lhiang Z, Jannes G, Mijs W, Machtelinckx L, Rossau R, Traore H, Portaels F. Rapid detection of rifampicin resistance in sputum and biopsy specimens from tuberculosis patients by PCR and line probe assay. Tubercle Lung Dis 1995; 76:425–430. 83. Cooksey RC, Morlock GP, Glickman S, Crawford JJ. Evaluation of a Line probe assay kit for characterization of rpo mutations in rifampin-resistant Mycobacterium tuberculosis isolates from New-York City. J Clin Microbiol 1997; 35:1281–1283. 84. Rossau R, Traore H, De Beenhouwer H, Mijs W, Jannes G, De Ruk P, Portaels F. Evaluation of the InnoLipa Rif TB Assay, a reverse hybridization assay for the simultaneous detection of Mycobacterium tuberculosis complex and its resistance to rifampin. Antimicrob Agents Chemother 1997; 41:2093–2098. 85. Chaparas SD. Immunologically based diagnostic tests with tuberculin and other mycobacterial antigens. In: Kubica GP, Wayne LG, eds. The Mycobacteria: A Sourcebook. Part A. Section 9. New York: Marcel Dekker, 1984:195–220. 86. Daniel TM, Dehanne SM. The serodiagnosis of tuberculosis and other mycobacterial diseases by enzyme linked immuno-assay. Am Rev Respir Dis 1987; 158:678–680. 87. Chan SL, Reggiardo Z, Daniel TM, Guilling DJ, Mitchison DA. Serodiagnosis of tuberculosis using an ELISA with antigen 5 and a hemagglutination assay with glycolipid antigens. Am Rev Respir 1990; 142:385–390. 88. Verbon A, Weverling GJ, Kuijper S, Speelman P, Jansen HM, Kolk AHJ. Evaluation of different tests for the serodiagnosis of tuberculosis and the use of likelihood ratios in serology. Am Rev Respir Dis 1993; 148:378–384. 89. Bothamley GH, Rudd RM. Clinical evaluation of a serological assay using a monoclonal antibody (TB72) to the 38 kDa antigen. Eur Respir J 1994; 7:240–248. 90. Simonney N, Molinard M, Oksen Hendler E, Perronne C, Lagrange PH. Analysis of the immunological humoral response to Mycobacterium tuberculosis glycolipid antigens (DAT, PGLTB1) for diagnosis of tuberculosis in HIV seropositive and seronegative patients. Eur J Clin Microbiol Inf Dis 1995; 14:883–891. 91. Moore DF, Cuirry JI. Detection and identification of Mycobacterium tuberculosis directly from sputum sediments by Amplicor PCR. J Clin Microbiol 1995; 33:2686–2691. 92. Bodmer T, Gurtner A, Schopper, Matter L. Screening of respiratory tract specimens for the presence of Mycobacterium tuberculosis by using the Gen-Probe amplified Mycobacterium tuberculosis test. J Clin Microbiol 1994; 32:1483–1487. 93. Ausina V, Gamboa F, Gazapo E, Manterola JM, Lonca J, Matas L, Manzano JR, Rodrigo C, Cardona PJ, Padilla E. Evaluation of the semi automated Abbott Lex My-

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brispinal fluid, other nonrespiratory and respiratory specimens. J Clin Microbiol 1996; 34:834–841. 108. Gamboa F, Manterola JM, Vinado B, Matas L, Gimenes M, Lonca J, Manzano JR, Rodriguo C, Cardona PJ, Padilla E, Domingues J, Ausina V. Direct detection of Mycobacterium tuberculosis complex in nonrespiratory specimens by Gen Probe Amplified Mycobacterium Direct Test. J Clin Microbiol 1997; 35:307–310. 109. Barnes PF, Rapid diagnostic tests for tuberculosis. Progress but not gold standard. Am J Respir Crit Care Med 1997; 155:1497–1498.

8 Immunology of Tuberculosis

THOMAS M. DANIEL and W. HENRY BOOM Case Western Reserve University School of Medicine and University Hospitals of Cleveland Cleveland, Ohio

JERROLD J. ELLNER UMDNJ–New Jersey Medical School Newark, New Jersey

I. Introduction When 39-year-old Robert Koch announced to a stunned audience at the Berlin Physiological Society on March 24, 1882, that he had discovered the cause of tuberculosis (1), he opened a new era in microbiology. Not long thereafter, in 1891, he described what has become known as the Koch phenomenon (2) and in so doing similarly opened a new era in immunology. Koch reported that an animal with prior experience with the tubercle bacillus dealt with the introduction of virulent organisms by walling off and containing the infection, something that naive animals could not do. Perhaps this observation led him to his ill-conceived recommendation of tuberculin injections for the treatment of tuberculosis. This therapy certainly paved the way for von Pirquet’s observation that delayed tuberculin skin reactions were an indicator of tuberculous infection. The subsequent story of the development of the tuberculin skin test as a well-accepted hallmark of tuberculin cellular hypersensitivity and immunity is familiar to many and has been well recounted in review articles (3,4). Pathologists had long recognized granulomas as the central histopathological lesions of tuberculosis, and the role of granulomas in containing the spread of disease was recognized from studies of clinical pathological material. Koch’s ob187

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servations provided experimental support for this view. Mackaness and coworkers demonstrated that tuberculous immunity depended on the activation of macrophages, the central cells of granulomas, and that some aspects of this macrophage activation were not antigen-specific (5). The elegant studies of Warren and colleagues, who worked primarily with schistosomiasis, demonstrated the immunological nature of infectious tissue granulomas and the dependence of these granulomas on immunologically specific T lymphocytes (6). To Merrill Chase (7) goes credit for observing that delayed hypersensitivity could be transferred by lymphocytes, thus establishing the central memory function of these cells; as noted below, we now recognize diverse subsets of lymphocytes with specific functions in regulating cellular immunity. Subsequent seminal work by David and coworkers (8) led to the demonstration that immunologically competent lymphocytes produce soluble factors—lymphokines—that are responsible for the proliferation and activation of other immunoactive cells, a story that has subsequently unfolded to reveal an extraordinarily complex and highly regulated immune system. Not only by reason of history but also because of the elegant nature of the clinical model it produces, tuberculosis has become the paradigm for diseases mediated by cellular immunity. In this chapter we will review the immunology of tuberculosis, beginning with the organism that causes tuberculosis and induces the immunity and hypersensitivity characteristic of this infection. We will then move from the organism to the host and the highly regulated cellular immune system responsible for the host’s responses to tuberculous infection. II. Mycobacterial Protein Antigens Immunologically competent cells of the human host recognize Mycobacterium tuberculosis by its antigens, and scores of antigens of this organism have now been described. Indeed, when compared with other pathogens, mycobacteria have an extraordinarily large panoply of antigens. This may be related to the fact that these bacteria are rich in adjuvants, as noted below, so that many minor protein constituents are presented to host cells under circumstances that favor antigenicity. Following the description of an expression library for the entire genome of M. tuberculosis by Young and colleagues (9) and the cloning of genes for mycobacterial antigens in many laboratories, there has been a rapid increase in the number of antigenic proteins available for characterization and study. The elucidation of the entire DNA sequence of the M. tuberculosis genome will result in the identification of further increasing numbers of antigens. Banks of monoclonal antibodies have provided important reagents facilitating their characterization (10,11). We will not attempt a comprehensive review of mycobacterial antigens; we will, however, discuss several protein antigens about which a substantial body of

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knowledge exists. Readers interested in more detail about mycobacterial antigens will find the reviews by Young and coworkers (12) and Anderson (13) useful. A. The 65,000 Dalton Heat-Shock Protein Antigen

A 65,000 dalton antigen of M. tuberculosis and other mycobacteria has been extensively studied and found to be a heat-shock protein with substantial homology with other well-known heat-shock proteins, including the Escherichia coli GroEL protein (14,15). Heat-shock proteins are widely distributed in nature and highly conserved with substantial structural similarity crossing taxonomic lines. Named because they are produced in increased quantity by cells growing under stressful culture conditions such as high temperature, they are thought to have important functions in maintaining cell integrity and are produced by bacteria under many conditions of culture that are less than optimal. Similar proteins are produced by plant and higher animal, including mammalian, cells. The gene for the 65,000 dalton antigen has been cloned (16,17), and its structure is well known. This protein may exist in polymeric form in mycobacteria. The 65,000 dalton unit contains considerable helical structures and hydrophobic regions, characteristics typical of highly antigenic proteins. Studies with monoclonal antibodies have demonstrated that this protein has multiple epitopes (18), many of which are widely shared among mycobacteria, some of which appear to be species specific. Some epitopes appear to be shared with epitopes of mammalian proteins; these have been implicated in adjuvant arthritis and might be related to human autoimmune diseases (19). Because of the prominence of its nonspecific epitopes, this antigen has evoked less interest among investigators studying the immunology of tuberculosis than have more specific antigens. B. The 38,000 Dalton Species-Specific Antigenic Protein of M. tuberculosis

The goal of isolating a species-specific antigenic protein from M. tuberculosis has been elusive, yet hotly pursued by many investigators. Daniel and Anderson used immunoabsorbent affinity chromatography to isolate an antigen referred to as antigen 5 (20). Originally considered to have a molecular weight of 35,000 daltons, this protein was subsequently shown to be identical with the 38,000 dalton antigen later studied by Anderson and by Young, among others (21). With Ellner and others, the immunobiology of this protein was studied extensively, and it was found to be restricted to M. tuberculosis and M. bovis (22). This antigen elicited T- and B-lymphocyte responses in sensitized guinea pigs and infected humans, and it displayed substantial species-specificity in its reactions in guinea pigs. When used to skin-test populations of human subjects, it displayed less species specificity than had been observed in guinea pigs (23). This antigen formed the basis of a serodiagnostic ELISA test with excellent diagnostic test characteristics

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(24,25), and again patients with nontuberculous mycobacterial disease were found to display reactivity to this antigen (26). Thus, despite substantial evidence of species-specificity, this potent antigen was not completely specific in infected humans. Ivanyi and colleagues developed a serodiagnostic ELISA test based on inhibition of a monoclonal antibody designated TB-72 (27,28). In contrast with the studies of Daniel and colleagues cited above, a high degree of mycobacterial species specificity was obtained in this test. Young used immunoabsorbents prepared from similar monoclonal antibody TB-71 to purify a protein reactive with TB-71 and TB-72, each monoclonal antibody apparently reacting with a distinct epitope of the same protein (29). The eluted protein was found to be the 38,000 dalton antigen. Anderson and Hansen also purified and characterized the 38,000 dalton protein, designating it antigen b (30). Anderson and coworkers later proposed that this protein is necessary for phosphate metabolism of the organism (31). Haslov and colleagues considered this protein to be immunodominant in 5 of 7 strains of in-bred guinea pigs (32). Kadival et al. described preparing a less specific 38,000 dalton antigen by immunoabsorbent affinity chromatography using a monoclonal antibody-derived absorbent (33). What is currently known about the 38,000 dalton antigen of M. tuberculosis is sufficient to conclude that it is not a major component of this organism but that it is secreted by growing mycobacterial cells, available on the cell surface, and highly antigenic. It is a leading candidate for species specificity, an important characteristic favoring its use for immunodiagnosis and perhaps also for immunization. C. Antigens of the 85 Complex: Alpha Antigen

Harboe, Wiker, and colleagues used elegant crossed immunoelectrophoretic techniques to show close immunological relationships between three antigens designated by them 85 A, B, and C (34–37). While these three antigens share epitopes and have many similar properties, they appear to be encoded by three separate genes (36,37). The best known of these antigens is 85B, which had been previously described as -antigen (38), antigen a2 (39), antigen 6 (40), and MPB59/MPT-59 (34,35). The designation -antigen has historic precedence and has come into widespread current use. With a molecular weight of 30,000 daltons, this antigen is secreted by growing mycobacteria (34,35,41), and it is the predominant antigen in culture medium from mycobacteria growing in stationary cultures. It binds fibronectin (42), raising the question of whether this property is important in mycobacterial recognition and ingestion by macrophages. The gene for the 30,000 dalton antigen has been cloned from M. bovis and M. kansasii, and its base sequence and corresponding amino acid sequence are known (43). This antigen is

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present in all mycobacteria that have been tested (44,45), and there is substantial evidence that the molecule contains both species-specific and shared epitopes (46). The 30,000 dalton antigen has been shown to be a mycolyltransferase that may be important in mycobacterial cell wall synthesis, suggesting that this molecule might be a potential chemotherapeutic drug target (47). The 30,000 dalton antigen evokes strong skin test responses in sensitized animals with somewhat more specificity of reactivity than tuberculin purified protein derivative (PPD) (46). Measuring IgG antibody to the 30,000 dalton antigen provides the basis for a good serodiagnostic test for active tuberculosis (48). The 30,000 dalton antigen also elicits in vitro correlates of cell-mediated hypersensitivity, and it is of considerable interest that T lymphocytes of healthy M. tuberculosis–infected individuals react strongly to this antigen whereas those of patients with active tuberculosis do not (49,50). This might suggest that decreased T-lymphocyte responsiveness to the 30,000 dalton antigen is a feature of the immune regulation in active tuberculosis, or it might mean that individuals who do not mount T-lymphocyte responses are predisposed to development of disease. This antigen induces in vitro production of interferon- and tumor necrosis factor- , an effect mediated in part through its fibronectin binding property (51). Perhaps no other antigen of M. tuberculosis has been as extensively studied as the 30,000 dalton protein antigen. It is an important constituent of mycobacteria with a major role for the microbial cell in cell-wall biosynthesis. It is equally important to the infected host, probably serving a major role in recognition of the pathogen by host defenses and induction of immune responses. It is expressed on the mycobacterial cell surface, where it is a dominant antigen recognized by all infected individuals. Thus, it is a strong candidate antigen for vaccine development. Other members of the 85 complex of antigens are less well studied. The 85A component, also known as antigen P32 (52) and MPT44 (36,37), is also a fibronectin-binding, secreted protein. It has a molecular weight of 31,000–32,000 daltons (53). Its gene has been cloned and has a high degree of homology with the gene of the 85B antigen. This antigen evokes antibodies in patients with tuberculosis (53). Currently ongoing studies with DNA vaccines using gene sequences for members of the 85 antigen complex should provide further information about the protective role of these antigens. D. The Low Molecular Weight ESAT-6 Antigen

Sorensen and colleagues purified a low molecular weight antigen from short-term, shake cultures of M. tuberculosis, which they designated ESAT-6 (54). When studied by physical chemical means and identified by the use of a specific monoclonal antibody, it was heterogeneous with respect to molecular mass, with identification of the antigenic epitope in constituents of estimated molecular weights ranging from 3,000 to 31,000 daltons. It is not glycosylated, and the molecular

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heterogeneity is presumed to reside with the antigenic protein itself. The molecular weight deduced from its amino acid sequence is 9975 daltons. It is difficult to be certain with which constituents of preparations containing ESAT-6 protective immunity resides, and it is possible that the epitope by which this antigen is identified is expressed on a number of peptides and small proteins or that the structure is polymeric. ESAT-6 is prominently recognized by memory effector T lymphocytes in mice and guinea pigs and appears to have a major role in the recall of protective immunity in these animals, sharing this important characteristic with the 30,000 dalton -antigen described above (55). Its amino acid sequence has been determined, and two major epitopes that induce interferon (IFN)- production by T lymphocytes have been defined. ESAT-6 is secreted by growing cells of multiple strains of M. tuberculosis and M. bovis, but it is not produced by bacille CalmetteGuérin (BCG) (56). III. The Mycobacterial Cell Wall: Mycobacterial Adjuvants and Mycobacterial Polysaccharides The mycobacterial cell wall is a complex structure with many elements of immunological importance. The external aspect of the cell-wall surface comprises unique lipids containing long-chain mycolic aids. These are esterified to arabinogalactan, the principal structural element of the cell wall. Interiorly, linked to the arabinogalactan by phosphodiester bonds, is muramyl dipeptide. Each of these three major elements—mycolic acid lipid, arabinogalactan, and muramyl dipeptide—has importance to the immunology of tuberculosis. Brennan, whose laboratory has contributed so much to our recent knowledge of the mycobacterial cell wall, has provided a very helpful review of this topic that should be consulted by readers interested in pursuing this subject in depth (57). A. Arabinogalactan D-Arabino-D-galactan

serves as the backbone of the mycobacterial cell wall of mycobacteria and other actinomycetes and corynebacteria (57). An arabinofuranosyl side chain of arabinogalactan contains a major epitope that is identical among all organisms possessing arabinogalactan (58). This same side chain is also present on cell wall–associated arabinomannan. Arabinogalactan readily elicits antibodies in immunized experimental animals (58,59), but this polysaccharide induces and elicits few or no cellular immune responses. B. Lipoarabinomannan

Phosphorylated lipoarabinomannan (LAM) has been extensively studied by Hunter, Brennan, and their colleagues and shown to be antigenic (57,60–62). The

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carbohydrate structure of this polysaccharide was originally elucidated by Misaki, and it was shown to share an epitope-bearing polyarabinose side chain with arabinogalactan, which is the principal structural polysaccharide of the mycobacterial cell wall (63). Circulating antibodies to lipoarabinomannan are easily demonstrated in experimentally immunized animals (59) and are found in the majority of patients with active tuberculosis (62,64,65). Delayed-type hypersensitivity (DTH) reactions are not induced or evoked by this compound. Lipoarabinomannan from virulent strains of M. tuberculosis selectively induces immunosuppressive cytokines, including transforming growth factor (TGF)- but not tumor necrosis factor (TNF)- . C. Mycobacterial Adjuvants

In early but elegant and historically important studies, Raffel demonstrated that the adjuvant properties of mycobacterial cells resided in their lipids (66). Among these lipids, cord factor, a lipid associated with cording of mycobacterial colonies growing in liquid media and originally thought to be associated with virulence, was found to be of major importance as an adjuvant (67). This activity was further localized to the trehalose esters of mycolic acid, particularly trehalose dimycolate. The immune responses, both cellular and humoral, to any protein antigen are greatly potentiated when the antigen is administered in emulsions containing these mycolate adjuvants. Arabinogalactan, together with the underlying peptides phosphodiesterified to it, is a water-soluble adjuvant capable of potentiating a wide variety of immune responses (68,69). At the same time, it has major immunosuppressive properties (70). Cultured peripheral blood mononuclear cells from healthy tuberculin-positive donors had depressed responses to mycobacterial antigens when cocultured with arabinogalactan. This effect was mediated by monocytes, associated with their increased production of prostaglandin E2, and reversible with indomethacin or antibody to arabinogalactan. Immunoabsorption studies provided data suggesting that circulating arabinogalactan, possibly bound in immune complexes, might be responsible for the known immunosuppressive activity of some tuberculous plasma. The search for the minimal adjuvant unit in the water-soluble adjuvant led to the identification of muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine) as an extremely potent adjuvant (71). This small peptide is phosphodiesterified to cell-wall arabinogalactan, with which it forms water-soluble adjuvant. The extensive studies of analogs of muramyl dipeptide by many workers have explored the structural features of this small molecule that confer upon it adjuvant properties. Striking among these studies is the observation of Chedid and coworkers (72) that substitution of the D isomer for L-alanine created an immunosuppressive compound.

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If one phenomenon can be thought of as central among the multiple manifestations of the immunology of tuberculosis, it is the formation of tubercles—hypersensitivity granulomas. These lesions, which characterize and distinguish the tissue response to mycobacteria, are chiefly composed of macrophages activated in response to mycobacterial antigens and adjuvants. Mackaness demonstrated that macrophages became activated in response to contact with mycobacteria, although this activation lacked the specificity usually associated with immunological events (73). He hypothesized that monocytes, the circulating form of tissue macrophages, entered tissues at the site of tuberculous infection in response to chemotactic cytokines. Once aggregated in granulomas, monocytes transform to become the palisading histiocytes or epithelial cells characteristic of granulomas, and some of these cells fuse to form Langhans’ giant cells. In an elegant set of studies of the pathogenesis of schistosomiasis, Warren and colleagues (74,75) demonstrated the essential immune nature of granuloma formation. They showed that granuloma formation is antigen specific, that it is characterized by anamnesis, that it can be transferred by lymphocytes but not serum, and that it is dependent upon intact thymic but not bursal lymphocytes. Having thus firmly established granuloma formation as an immunological event in schistosomiasis, Boros and Warren extended their studies to tuberculin antigens and confirmed the immunological nature of the granulomas induced by these mycobacterial antigens (75). V. Cell-Mediated Immunity Natural immune mechanisms—macrophages, natural killer (NK) cells, neutrophils—likely have an important role in the primary response to M. tuberculosis and may suffice to control infection before development of the acquired immune response in few individuals (76). However, in the majority of infected persons the acquired immune response is responsible for control of M. tuberculosis infection. T cells, as antigen-recognition units, have critical regulatory and effector roles in the immune response to M. tuberculosis, as demonstrated by studies in animal models and in humans with cellular immune deficiencies (77–81). The traditional model for the role of T cells in tuberculosis is one in which macrophages present antigens obtained from phagocytosed bacilli to T cells. Antigen-activated T cells then secrete cytokines such as IFN-, which in turn stimulate macrophages to become more effective in controlling mycobacterial growth. Recent observations in basic immunology and in studies of the human immune response to mycobacteria require a revision of this simple model. First, besides the central role of CD4 T cells, other T-cell subsets such as  T cells and CD8 T

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cells are activated by mycobacteria and have complementary roles to those of CD4 T cells (49,82). Second, T cells also serve as cytotoxic effector cells against M. tuberculosis–infected macrophages (83,84). Third, macrophages, upon exposure to mycobacteria, produce a large number of cytokines such as interleukin (IL)-10, IL-12, IL-15, IL-18, TNF- , IL-1, IL-6, and TGF- . Secretion of cytokines with immunoregulatory properties extends the macrophage’s role beyond that of antigen-presenting cell and inhibitor of mycobacterial growth (85,86). A. CD4 ␣␤ T Cells

CD4 T cells recognize peptide antigen fragments presented to their T-cell receptors by class II major histocompatibility (MHC) molecules on antigen-presenting cells (87). The CD4 T-cell molecule interacts with a constant domain of the class II MHC molecule while the T-cell receptor (TCR), consisting of an and a chain, recognizes short peptide fragments held within a groove of the class II MHC molecule. These antigenic peptide fragments are generated by proteolytic digestion of large protein antigens by antigen-presenting cells such as macrophages and dendritic cells in an orderly process called antigen processing. Class II MHC molecules are recognized by CD4 T cells, and the antigen-processing mechanisms differ for each one of these antigen-presenting molecules. In humans, successful containment of primary infection is characterized by a strong cutaneous DTH response (tuberculin reaction), mediated primarily by CD4 T cells. In addition, these sensitized individuals retain in vitro CD4 Tcell proliferative responses and brisk IFN- production to soluble mycobacterial protein antigens such as PPD (50). These memory CD4 T cells not only are responsible for controlling quiescent foci of infection but probably also provide protection against exogenous reinfection with the tubercle bacillus. Failure of CD4 T cells, as seen in persons infected with the human immunodeficiency virus (HIV), results in progressive primary infection, reactivation of endogenous mycobacteria, or enhanced susceptibility to reinfection (81,88). In a murine model, CD4 T cells transferred from immune mice to naive animals provided protection from challenges with both BCG and virulent M. tuberculosis (80,89). In vivo depletion of CD4 T cells by monoclonal antibody treatment reduced resistance to mycobacterial infections (90,91). CD4 T cells were the major source of IFN- and cytolytic effector function during the course of sublethal infection with M. tuberculosis (92). Recent studies in mice, in which the genes for class I and class II MHC molecules were inactivated by gene-targeting methods, reconfirmed the central role of CD4 T cells in the protective immune response to mycobacteria (93). CD4 T cells exert their influence in the immune response to M. tuberculosis through secretion of cytokines and cytotoxicity for M. tuberculosis-infected

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macrophages. Through cytokines (IFN-, GM-CSF, TNF- / ), CD4 T cells enhance the effector function of macrophages and regulate the IL-2–mediated expansion of  and CD8 T cells. Soluble protein antigens, such as those found in PPD and culture filtrates of M. tuberculosis, are strong stimuli for CD4 T cells. The majority of CD4 T cells produce large amounts of IFN- and varying amounts of IL-2, IL-4, IL-5, and IL-10 (94–96). Recent studies have demonstrated that CD4 T cells can directly help macrophages control intracellular growth of M. tuberculosis, both through secretion of cytokines and through a cell contact–dependent mechanism (97). These CD4 T cells do not fall into a clear-cut Th-1 and Th-2 dichotomy and are more accurately classified as Th-0. Classification of T-helper cells as Th-1 and Th-2 has been used in murine studies based on patterns of cytokine secretion, with Th-1 cells secreting IFN- and IL-2 and Th-2 cells producing predominantly IL-4 and IL-5. These cytokine phenotypes are associated with different functions, including macrophage activation and help for Bcell antibody production. In general, in humans the dichotomy among CD4 T cells is less clear-cut than the one observed among murine CD4 T cells, and in the human T-cell response to M. tuberculosis the Th-1 and Th-2 dichotomy does not enhance our understanding of the immune deficiency responsible for development of clinical tuberculosis. When cytotoxic effector function is evaluated, cytotoxicity is observed readily in healthy tuberculin individuals; it is mediated by CD4 T cells in response to M. tuberculosis–infected macrophages. Both CD4 T-cell clones and bulk T-cell populations stimulated with either PPD or live mycobacteria are efficient cytotoxic effector cells (95,98–100). Strong tuberculin skin test responses (DTH) and IFN- production coupled with cytotoxic effector function by CD4 T cells in response to macrophages are characteristic of the CD4 T-cell responses of healthy tuberculin positive donors and prototypic for the cellular immune response to intracellular bacterial pathogens. In patients with active pulmonary tuberculosis evidence for diminished CD4 T-cell function is reflected in decreased proliferative and IFN- responses to soluble protein antigens of M. tuberculosis, as well as diminished or absent tuberculin skin test responses in some patients. These diminished responses are not due to deviation of CD4 T-cell responses towards a Th-2 like pattern but due to secretion by macrophages of cytokines such as TGF- and IL-10, which inhibit CD4 T-cell function (85,86,101). Most studies of the human immune response are performed with peripheral blood T cells and do not address the nature of the CD4 T-cell response in the site of active infection in the lung. One recent study demonstrated that M. tuberculosis–specific CD4 T cells are readily detected in the alveolar spaces of healthy tuberculin-sensitized persons (102). The major antigens of M. tuberculosis recognized by CD4 T cells remain poorly defined despite the availability of a number of recombinant or purified na-

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tive antigens and numerous studies performed with them during the last 15 years (12). From these studies and others in which subfractions of M. tuberculosis bacilli or culture filtrates were tested, a number of general conclusions can be drawn. First, no single immunodominant antigen has emerged so far. Second, there is marked diversity in CD4 T-cell responses to mycobacterial antigens among individuals and most respond to a large rather than a restricted number of antigens (12,50,103,104). Third, there is significant cross-reactivity with antigens from other mycobacterial species or unrelated bacterial species. Thus no antigen recognized by CD4 T cells has been identified to date that is specific for infection with M. tuberculosis, although there may be some epitopes restricted to the M. tuberculosis group of organisms. Fourth, most T-cell antigens identified so far are expressed by M. bovis BCG, the vaccine strain considered suboptimal. Clearly further characterization of antigens recognized by CD4 T cells is necessary to define the T-cell repertoire and identify protective antigens. B. ␥␦ T cells

The other major T-cell subset that may have an important role in the cellular immune response to M. tuberculosis is the  T-cell receptor (TCR)–bearing T cell (105). Gamma delta TCR–expressing T cells ( T cells) form a distinct subset of T lymphocytes, comprising 5% of T cells in lymphoid organs and 1–5% of circulating blood T lymphocytes. Gamma delta T cells express CD3, as do all T cells, but are CD4-negative, and fewer than 5% express low levels of CD8. The  TCR consists of  and chains, which are distinct from the and chains of the TCR on CD4 and CD8 T cells. How  T cells recognize antigens and how antigens are processed and presented to them by antigen-presenting cells is still unknown.  T cells do not use the class I and II MHC molecules, which are used for antigen presentation to CD4 and CD8 T cells. There is strong evidence both in humans and in animal models that  T cells participate in the immune response to mycobacteria. Mice exposed to mycobacterial antigens in footpads or lungs or to live bacteria in the peritoneum had an expansion of  T cells (106–108). Studies with  T-cell knock-out mice in which expression of  TCRs has been blocked suggest that  T cells have a role in granuloma formation to M. tuberculosis. In humans, whole intact, in particular live mycobacteria induce expansion of human  T cells and the V 2/V9 TCR subset (106–108). The activation of  T cells by M. tuberculosis is dependent on antigen-presenting cells, and bloodderived monocytes are particularly effective in this regard (109). In addition, alveolar macrophages also can serve efficiently as antigen-presenting cells for  T cells, suggesting that  T cells can be directly activated in the human lung (110). Studies in tuberculosis patients suggest a diminished ability to activated T cells in response to M. tuberculosis (108). On the other hand, individuals sensitized to my-

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cobacterial antigens have a greater ability to activate T cells in response to M. tuberculosis than tuberculin-negative persons (49). Functionally,  T cells are very similar to CD4 T cells. They secrete as much IFN-, possibly more on a per cell basis, and are equally cytotoxic for macrophages as CD4 T cells (84). They produce less IL-2 than CD4 T cells, which may explain their dependence on CD4 T-cell help for their expansion in vitro (111). In the last few years, substantial insight has been gained into the mycobacterial antigen(s) recognized by V 2  T cells. Increasing evidence suggests that the V 2  T cells are activated by phosphate-containing molecules (112–114). The first of these antigens to be identified were four TUBags isolated from M. tuberculosis, described by Constant et al., which are small (/500 dalton) phosphorylated molecules (112). Two of these (TUBag4 and TUBag3) contain both phosphate and nucleotide (thymidine in TUBag4 and uridine in TUBag3). In addition, Tanaka et al. have proposed isopentenyl pyrophosphate (IPP) and related prenyl phosphates as possible antigens for V 2 T cells (115). Others have described a larger protease-sensitive antigen (10–14 kDa) from heattreated M. tuberculosis bacilli, which also is sensitive to phosphatase treatment, suggesting a carrier molecule for the small phosphate ligands (116). C. CD8 T Cells and Other T-Cell Subsets

Until recently, the role of CD8 T cells in the human immune response to M. tuberculosis was largely undefined. In murine studies a minor role for CD8 T cells was suggested by cell transfer and antibody blocking studies. Studies with gene knock-out mice in which CD8 T-cell development has been arrested due to the absence of class I MHC molecules ( 2-microglobulin knock-out mice) revealed a heightened sensitivity to both M. tuberculosis and M. bovis BCG (82,93). The lung appeared to be the most susceptible organ for progressive M. tuberculosis infection in CD8 T-cell–depleted mice. Consistent with these observations were recent studies in which class I MHC restricted CD8 T cells specific for M. tuberculosis were found in the alveolar spaces of healthy tuberculin skin test–positive persons. These CD8 T cells were found to be efficient cytotoxic effector cells and to secrete IFN- (102). Little is known about the specific antigens recognized by CD8 T cells or their role in protective immunity to M. tuberculosis in humans. Alpha beta TCR T cells, which do not express CD4 or CD8, make up less than 1% of circulating T cells and can use the nonpolymorphic MHC-like molecule CD1 as antigen-presenting molecule (117). Expression of CD1 on macrophages is dependent on IL-4 and GM-CSF. Recent studies have demonstrated that some of these TCR, CD4, CD8 T-cell clones recognize mycobacterial mycolic acids and LAM in the context of CD1 (118). Mycolic acids are complex glycol-

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ipids unique to mycobacterial cell walls. The role of this unique T-cell subset in the immune response to mycobacteria remains to be defined. Studies of the immune response to M. tuberculosis in humans and animal models have increased our understanding of the complex roles of T-cell subsets in protection against tuberculosis. Although CD4 T cells remain the dominant and critical T-cell subset, others such as  and CD8 T cells have complementary roles. Since all three subsets are sources of IFN- and competent cytotoxic effector cells, in vivo kinetics and differences in antigen processing/recognition likely will define how each T-cell subset functions in different phases of the immune response to M. tuberculosis (119). Future studies in animal models, with human cells obtained from sites of infection such as lung or lymph node, characterization of the antigen repertoire, and longitudinal immuno-epidemiological studies should define more clearly how different T-cell subsets contribute to protection against M. tuberculosis. Such studies will determine how failure of T-cell subset function results in reactivation or progressive primary tuberculosis. VI. Humoral Immunity It is important to recognize that the pathogenesis of tuberculosis is almost exclusively determined by host T-lymphocyte–mediated cellular immune responses. At the same time, one must acknowledge that B-lymphocyte–mediated humoral responses to mycobacterial antigens occur in patients with tuberculosis, although these responses have no clearly demonstrated role in disease pathogenesis. Levels of immunoglobulin-G (IgG) antibody detectable by enzyme-linked immunosorbent assay (ELISA) or other immunoassay are usually an indicator of active tuberculous disease. Studies with many antigens using many techniques have found that few control subjects have measurable IgG antibody levels (120). Asymptomatic primary infection (121) and minimal pulmonary disease (122) usually are not sufficient to induce a significant antibody response. During the course of treatment, antibody levels rise somewhat for the first 1 or 2 months, falling thereafter but remaining detectable for up to several years (123). Patients with remote healed tuberculosis do not have readily detected IgG antibody to mycobacterial antigens. Many investigators have proposed serodiagnostic tests based upon the identification of IgG antibody to mycobacterial antigens, and new tests are being proposed almost daily. From the extensive work that has been done, one can state with reasonable confidence that it is possible to devise simple serodiagnostic tests using any of several antigens, but that the choice of antigen is a major determinant of diagnostic test specificity and predictive accuracy. Crude mycobacterial cell lysates and culture filtrates and tuberculin PPD do not provide as satisfactory diagnostic tests as do more highly purified antigens. No test has come into

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widespread clinical use, however, probably because the sensitivity and specificity of serological tests has not exceeded that of the sputum smear. VII. Immune Spectrum and Immunoregulation Leprosy is the classical example of a granulomatous disease caused by a facultative intracellular pathogen in which the host immune response shows a predictable linkage to bacterial load in tissues and disease manifestations. At the tuberculoid end of the spectrum, there are vigorous granulomatous hypersensitivity, active Tcell immune reactivity, little in terms of antibody response, few bacilli, and localized disease. At the lepromatous end of the spectrum there are few and poorly formed granulomas, specific hyporesponsiveness of T cells to mycobacterial antigens, high titers of antibody, and multibacillary disease. There have been several attempts to define a spectrum of disease manifestations similar to that of leprosy in patients with tuberculosis (124,125). These classification schemes have not been entirely convincing, often requiring clinical and pathological distinctions that are not easily made. A few general comments concerning the immune spectrum of tuberculosis are, however, supportable. Healthy tuberculin skin test–positive donors express vigorous DTH and have low titers of antibody directed against mycobacterial products. Pulmonary tuberculosis, at least in the United States, usually is characterized by relative hyporesponsiveness to tuberculin; 20–25% of individuals with acute tuberculosis have a negative tuberculin skin test, and hyporesponsiveness to PPD in vitro is two to three times more common (126,127). Miliary tuberculosis and tuberculous meningitis are associated with a greater frequency of skin test anergy and more systemic signs and symptoms than localized disease (128). The local immune response in tuberculous pleurisy is of some interest since clinical and epidemiological evidence indicates that it is capable of initial selfcure (129). The pleural fluid is enriched in highly antigen-reactive CD4CDw29 lymphocytes (130), apparently the result of in situ expansion rather than sequestration of such cells from the circulating pool (131). Pleural fluid also contains 5- to 30-fold increased levels of IFN- and TNF relative to serum (130). Based on the data from tuberculous pleurisy, the hyporesponsiveness of peripheral blood mononuclear cells to PPD in pulmonary tuberculosis is not readily explained by shifts in the compartmentalization of antigen-responsive T cells. Likewise the ratio of CD4/CD8 lymphocytes is preserved in tuberculosis (126,132). Similarly, in pulmonary tuberculosis anergy is accompanied by reduction in CD4 lymphocytes in correlation with reduction in total lymphocyte counts (127). Active and specific immunosuppression is a factor in the depression of Tcell blastogenic responses and expression of IL-2 in response to PPD (85,133).

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The mechanism of suppression appears to be unique. Monocytes primed during the course of infection are stimulated directly by PPD or bacterial lipopolysaccharide to increased production of cytokines such as IL-1 (134), TNF (135,136), and IL-6 (136), and of immunosuppressive factors such as the receptor for IL-2 (101), IL-10, and TGF- . Recent studies demonstrate a profound depression of PPD-stimulated production of IFN- in patients with moderately and far-advanced tuberculosis. Two mechanisms appear to be involved: a transient overproduction of IL-10 and TGF and a longer-lasting primary T-cell defect. The T-cell defect may represent compartmentalization of antigen-reactive cells to sites of inflammation and/or selective cell depletion, possibly by apoptosis. Immunotherapy with IL-2 restored IFN- production; it was not clear whether this occurred by reversal of a defect in CD4 T cells or by recruitment of additional CD4 cells. The response to certain protein antigens of M. tuberculosis seems to be selectively suppressed in patients with tuberculosis. For example, despite comparable responses to sonicates of M. tuberculosis, 84% of healthy household contacts and only 52% of treated and 48% of untreated patients with tuberculosis responded to the MTP40 (14,000 dalton) antigen (137). Similarly, tuberculosis patients showed selective hyporesponsiveness to the 30,000 dalton antigen. Seven of eight healthy tuberculin reactors and none of six tuberculosis patients (post 6–20 weeks of treatment) were responsive to the 30,000 dalton antigen (138). Interpretation of these findings is complicated by the consistent finding that tuberculosis patients in the United States are hyporesponsive to PPD (139). Supportive observations are, however, available from Mexico City. None of 10 patients with newly diagnosed pulmonary tuberculosis and 73% of 21 household contacts showed responses to the 30,000 dalton antigen of M. tuberculosis, whereas responses to mycobacterial sonicates were comparable in both groups (140). These results raise two possibilities. First, the absence of response to the 30,000 dalton antigen may be a stable characteristic, perhaps genetically determined, and may predispose individuals to the development of tuberculosis. Second, the 30,000 dalton antigen may activate immunosuppressive pathways, possibly through direct stimulation of monocytes. The anergy occurring in patients with pulmonary tuberculosis is specific in some and nonspecific in other individuals. In fact, it may be appropriate to assume that patients with pulmonary tuberculosis usually show specific superimposed on nonspecific anergy. Specific anergy has been addressed above; the mechanism of nonspecific anergy is not well understood. It is of interest, therefore, that mycobacterial polysaccharides such as D-arabino-D-mannan and D-arabino-D-galactan stimulate monocyte-dependent suppression of blastogenesis induced by nonspecific mitogens (70,141), Detailed studies, in fact, suggest that the underlying mechanism involves circulating immune complexes containing polysaccharides that stimulate monocyte production of immunosuppressive prostaglandin E2 (70).

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The finding that a polysaccharide antigen, presumably a major target of the antibody response to tuberculosis itself, suppresses T-cell reactivity is of interest as it may contribute to the inverse and reciprocal relationships between T-cell responses and B-cell responses in tuberculosis as considered above. Therapeutic intervention to modulate the spectral immune response in tuberculosis for the benefit of patients is a topic of increasing recent interest. Thalidomide and pentoxifylline are drugs known to ameliorate the adverse effects of TNF- , and as of this writing both drugs are being studied for their potential as therapeutic agents in tuberculosis. Mycobacterium vaccae, a nonpathogenic mycobacterium originally isolated from soil in Uganda, has been proposed as an immunogen potentially capable of augmenting beneficial protective immune responses in tuberculous patients (142,143). Early trials in Romania in which M. vaccae was administered to patients during the course of treatment show small but statistically significant results in the bacteriological response of patients being retreated for chronic disease but not significant effects in patients receiving treatment for the first time (145). Additional trials in Africa, which include HIV-infected patients, are underway as of this writing. VIII. HIV–M. tuberculosis Interactions HIV infection is the strongest known risk factor for the reactivation of a latent tuberculous infection. In a prospective study of a cohort of tuberculin skin test–positive intravenous drug users in a methadone-maintenance program in New York, the risk of developing tuberculosis was 7.9% per year during a 2-year period of follow-up (146). Studies in Africa yielded similar results, albeit with somewhat lower risk figures (147,148). This must be compared to the risk of developing tuberculosis in M. tuberculosis–infected, HIV-uninfected persons, which is estimated to be 5–10% per lifetime. It also is clear that primary infection with M. tuberculosis is likely to progress rapidly to active tuberculosis in HIV-infected persons. The current outbreaks of multidrug-resistant tuberculosis in HIV-infected persons (149) are clear evidence of this phenomenon. HIV infection increases the likelihood of a negative tuberculin skin test in M. tuberculosis–infected persons. For example, HIV-infected healthy women in Uganda were less likely to show reactions of over 3 mm to Old Tuberculin (48% vs. 82%) and had smaller reaction sizes (7.5 mm vs. 10.6 mm induration) as compared to HIV-negative age-matched post-partum females (150). The relationship between DTH reactions and CD4 counts in HIV-infected persons also has been studied using panels of nonmycobacterial antigens. Cutaneous anergy was infrequent (
10%) in individuals with a CD4 count 500/L; below this level, however, the frequency of anergy varied inversely with the CD4 count and was 2/3 for CD4
200 and 80% for CD4
50 (151). Studies in Zaire demonstrated anergy as

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defined using the CMI-Multitest in 46% of 50 HIV-infected individuals (152). Importantly, 36% of HIV-infected tuberculin-positive persons had active tuberculosis as compared to 8% of the tuberculin-negative persons. The notion that tuberculosis may boost tuberculin reactivity rather than further depress it in the presence of HIV infection is further supported by recent observations from Uganda. Sixty-eight percent of HIV-positive tuberculosis patients were tuberculin skin test–positive with reaction sizes of 10 mm, as compared to 18% in the unmatched cohort of HIV-positive post-partum women discussed above (153). Tuberculosis is often an early event in the course of AIDS, occurring a mean of 6–9 months before other AIDS-defining conditions (154). Atypical radiographic presentations, often suggesting primary tuberculosis, are frequent and are related to low CD4 cell counts (155). The T-cell dysfunction of HIV-infected individuals is similar to but much more pronounced than the T-cell defect seen in HIV-uninfected patients with acute forms of tuberculosis. HIV infection not only accelerates the course of tuberculosis, but tuberculosis also accelerates the course of HIV disease (156). This effect requires active disease rather than latent M. tuberculosis infection and is related to anergy and CD4 lymphopenia (157,158). Bronchoalveolar lavage studies have found the HIV viral burden to be higher in lavaged cells from HIV-infected patients with pulmonary tuberculosis than from HIV-infected patients free of pulmonary disease (159). These clinical observations can be correlated with the laboratory demonstration that M. tuberculosis cells and PPD heighten the expression of HIV in cultured human monocytoid and lymphoid cell lines (160). On the basis of both in vivo and in vitro evidence, it is reasonable to believe that the immune activation that is a consistent concomitant of active tuberculosis activates cells harboring latent HIV infection to promote viral replication and disease progression. This notion, if substantiated by additional immunological, virological, and epidemiological data, would have profound impact on public health policy. Certainly, the potential benefits from preventive therapy for tuberculosis would be enhanced if, besides preventing tuberculosis, it prolonged the survival of HIV-infected individuals. IX. Conclusions Progress towards understanding the immune response to mycobacteria has accelerated in the last decade, but it remains for this progress to be translated into practical advances relevant to the control of tuberculosis. Although existing means of diagnosis and prevention clearly are generally satisfactory as currently applied, new understanding of the immunology of tuberculosis offers the promise of new and advanced modalities. It is reasonable to expect the pace of progress to continue to increase, driven by the magnitude of the global problem compounded by the pandemic of HIV infection and outbreaks of multidrug-resistant tuberculosis.

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9 Transmission of Tuberculosis

EDWARD A. NARDELL

WILLY F. PIESSENS

Harvard Medical School Cambridge Hospital and Massachusetts Department of Public Health Cambridge and Boston, Massachusetts

Harvard School of Public Health Harvard Medical School Boston, Massachusetts

From the perspective of the organism Mycobacterium tuberculosis, both transmission and pathogenesis are essential for survival and propagation. However, this intracellular bacillus has exhibited itself as an entrenched, opportunistic pathogen, against which our best defenses and control strategies have thus far proven inadequate. Figure 1 depicts many of the biomedical factors known to be important in the propagation of tuberculosis (TB). Not shown are the equally important biosocial factors affecting propagation, such as crowded living conditions, malnutrition, and limited access to health care and effective treatment. This scheme will serve as an overview for this discussion of transmission and pathogenesis. Transmission begins with a human source, almost always a person with cavitary, pulmonary tuberculosis. The pathogenic process of liquefaction (caseating) necrosis is the destructive end result of ongoing delayed-type hypersensitivity (DTH) in response to overwhelming infection. Caseous foci erode into adjacent bronchi, where organisms find favorable aerobic conditions, multiply rapidly, cause characteristic local and systemic symptoms, and gain access to the environment. A variety of known and unknown factors influence transmission source strength, i.e., the number, viability, and infectivity of organisms put into the air by the source. These factors include a propensity to lung cavitation, cough strength 215

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Tuberculosis propagation—biomedical model.

and frequency, and poorly defined characteristics of respiratory secretions that permit effective aerosolization and preserve the viability and infectiousness of organisms. Effective chemotherapy is the single most important factor in reducing infectiousness at any stage of the disease. Organisms that have developed resistance to the most effective chemotherapeutic agents (multidrug-resistant, or MDRTB) are difficult to control both in the individual and in the community. MDRTB can be lethal for the host, but death is often preceded by prolonged infectiousness, assuring propagation in the community (1,2). Tubercle bacilli are spread as droplet nuclei, the dried residue of larger respiratory droplets. Fluid lining the respiratory tract and any microorganisms contained in it may become aerosolized by high-velocity airflow during coughing, sneezing, and other forced expiratory maneuvers. Aerosolization (take off), aerial transport, and implantation (landing) of the tubercle bacilli in a suitable host is thought to be lethal for the vast majority of microbes, accounting in some part for the much lower infectiousness of tuberculosis compared, for example, to measles (3). The physical and chemical characteristics of respiratory secretions may be more or less conducive to droplet formation and, during aerial transport, variably protect tubercle bacilli from dehydration, oxygen injury, natural irradiation, and other environmental stresses such as air pollutants (4–6). Rehydration on inhalation is another critical environmental stress. Strains of tubercle bacilli undoubtedly vary in their innate resistance to environmental stresses, but these aspects of TB aerobiology have not been investigated. Transmission occurs most efficiently

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in enclosed environments where the source, infectious droplet nuclei, and potential hosts are concentrated. The upper respiratory tract, where most airborne droplet nuclei greater than 5 m in diameter are likely to impact, is highly resistant to TB infection (7). Tuberculosis begins as an infection of the alveolar macrophage, and this requirement defines the size of infectious droplet nuclei as approximately 1–3 m in diameter. Upon landing on an alveolar surface, tubercle bacilli are engulfed by resident macrophages, which have variable, inherited and acquired, innate (nonimmunological) microbicidal capacity. If organisms survive and replicate in the macrophage, cell-mediated immunity and delayed-type hypersensitivity are triggered, resulting in the arrest of infection at a subclinical stage or progression to active disease. If organisms are destroyed before they replicate to 10–15 generations, infection is aborted without an immunological record (tuberculin skin test negative). How often this occurs is, by definition, unknown. Successful infection can progress to clinical disease after a 4- to 8-week incubation period (primary or progressive primary TB) or reactivate after a prolonged period of latency (postprimary TB). Reactivation disease may occur at the site of implantation in the lung but more often occurs at a site of hematogenous dissemination in any organ, most commonly in the vulnerable upper lung zones where a propensity to cavitation assures continued propagation of the disease. I. Aerobiology of Tuberculosis A. Historical Perspective

Airborne spread of tuberculosis (TB) was a controversial theory for decades before it was proven 40 years ago. Earlier in this century, little credence was given to the risk of airborne transmission. For example, Hans Castorp, hero of Thomas Mann’s 1924 Nobel Prize–winning novel, The Magic Mountain, travels to the renowned international sanatorium Berghof at Davos, in the Swiss Alps, anticipating a 3-week visit with his cousin, Joachim, a patient with pulmonary tuberculosis (8). Mann was inspired by his own 3-week visit to Davos where his wife was evaluated and found not to have the disease. For uninfected persons, living, dining, and socializing for weeks with dozens of patients with infectious pulmonary TB would have been quite dangerous in the era before chemotherapy. In the novel, ironically, Castorp soon discovers that he had arrived at Davos not only infected, but febrile with active disease, and he joined his ill-fated cousin as a long-term patient. So common was TB in Europe and other industrialized countries in previous centuries that infection was presumed to be nearly universal, unavoidable, possibly hereditary, and difficult to link to so many potential exposures. Relative immunity derived from infection early in life (i.e., herd immunity), and the often long latency period between infection and reactivation further blurred the association between exposure and disease. Precautions to prevent transmission were un-

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known in that era, although sanatoria treatment effectively served to isolate many patients from the general population. Contrast the cavalier risk perception evident in Mann’s novel with the 132-page, 1994 Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Facilities, intended to prevent even one health-care worker from becoming infected (9). Perhaps because TB infection is now uncommon in industrialized countries, the general public as well as the medical community have come to fear it. Concern escalated following well-publicized outbreaks of highly drug-resistant TB in congregate settings in the United States and Europe, leading to some deaths among patients, residents, and workers (10). Loss of herd immunity in low-prevalence populations makes such outbreaks more likely when exposures occur, however uncommon. In addition, the disciplines of occupational medicine and industrial hygiene have evolved over the years, and health expectations on the part of workers in resource-rich countries have increased (11). In resource-poor countries, however, complacency about the risk of TB infection still occurs, which is attributable to high prevalence rates, limited resources for better control, herd immunity, low health expectations, and inadequate education about the risk. Outbreaks of multidrug-resistant (MDR) TB among institutional patients and workers in developing countries is gradually changing that view, increasing awareness of the risk of airborne transmission of a potentially lethal infection (12). This chapter will review some of what is currently known about the aerobiology and epidemiology of TB transmission and the means available for control. B. History of Droplet Nuclei Transmission

Approximately 50 years after Koch’s discovery of the tubercle bacillus in 1882, William Firth Wells, working initially at Harvard University and later at the University of Pennsylvania, unraveled the mechanisms by which airborne infections spread (13). A sanitary engineer, Wells was under contract to the Massachusetts Department of Public Health to investigate the potential for respiratory illness among workers exposed to contaminated water that was aerosolized to keep the dust down in New England textile mills. Employing the air centrifuge he had earlier developed, Wells recovered culturable bacteria from the air as particles small enough to remain airborne and to be inhaled deeply into the lungs. From this observation, his brilliant intellectual leap was postulated: Respiratory droplets generated by human coughs and sneezes would also desiccate before impacting on surfaces, becoming particles so small they remain airborne as “droplet nuclei,” carrying infectious human pathogens from person to person. Working with Wells on the textile mill investigation was another sanitary engineer, Edward Riley, and his brother, Richard, then a medical student at Harvard. In the preface to his 1955 comprehensive monograph on the subject, Airborne Contagion and Air Hygiene, Wells shared credit with Richard Riley and Theodore Hatch for “the basic dis-

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tinction between infective droplet nuclei and germ-laden dust” (14). Wells, Riley, and their coworkers not only conceptualized droplet nuclei transmission, they conducted extensive quantitative laboratory and field tests that established the foundation of our current understanding of airborne infection and air disinfection. Riley’s 1961 monograph, Airborne Infection, summarized and updated Wells’s earlier work (3). In the 1960s, Loudon’s group focused on cough and the behavior of airborne mycobacteria. Experiments using a rotating drum established that the half-life of aerosolized virulent tubercle bacilli (H37Rv) is about 6 hours (15). As detailed below, Riley’s research on ultraviolet air disinfection continued through the 1970s, but there has been little basic work on the aerobiology of TB and its control since that time. However, recent outbreaks of MDRTB have stimulated new research focused on air disinfection. Although investigations on the aerobiology of TB stagnated, the aerobiology of other microorganisms has advanced steadily. A great deal more is known about factors that influence the take-off, transport, and landing of certain aerosolized viruses, fungi, and common test bacteria (Escherichia coli, Serratia, and Klebsiella) than is known about TB (4–6). For example, despite the striking prevalence of TB in tropical climates, the influence of temperature and humidity on TB transport remains completely unknown! Under experimental conditions it has been shown that aerosolized E. coli are adversely effected at high humidity, unless aerosolized in certain protective solutes. There are also data to suggest that high humidity protects some airborne microorganisms from natural irradiation, ozone, and other potentially lethal environmental factors. The mechanisms underlying these phenomena have been explored and mathematical models derived that correlate well with experimental data (4–6). These data have potential practical importance for TB control. Vulnerability of microorganisms during airborne transport relates directly to air-disinfection strategies, germicidal irradiation in particular. More basic research on the aerobiology of tuberculosis is needed if the institutional spread of TB worldwide is to be better controlled. C. Air Sampling for TB

Aerobiology research on TB has been greatly hampered by the slow growth rate of M. tuberculosis in culture. Using standard air-sampling methods and selective culture media, M. tuberculosis and M. bovis species can be recovered from room air only if artificially aerosolized at relatively high concentrations (16). From human sources, viable tubercle bacilli are few and far between in room air, and if captured by air sampling even highly selective culture media become overgrown with the much more numerous and rapidly growing ambient airborne fungi and bacterial species. Recently, pilot experiments have shown that it is possible to capture M. tuberculosis generated by highly infectious patients by having the patient cough into a box, thereby preventing dilution of droplet nuclei in room air (17).

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Nucleic acid–amplification technologies have also been applied to air sampling for TB, with limited success (18). As already noted, it is believed that the vast majority of airborne tubercle bacilli are inactivated due to the stresses of aerosolization, transport, and air sampling, but it is difficult to judge viability, much less infectivity, by current molecular detection methods. However, a much older technology, guinea pig air sampling, has provided information much closer to the infectiousness of airborne TB for humans. This technique was employed by Riley and coworkers four decades ago to demonstrate and quantify the infectivity (for guinea pigs) of patients with symptomatic pulmonary TB residing on a six-bed experimental ward in the Baltimore Veterans Administration Hospital (19). The results of those classic experiments remain the best source of quantitative information on TB infectivity, its variability, the impact of chemotherapy, and the potential benefits of air disinfection (in ventilation ducts) with ultraviolet irradiation. D. The Wells-Riley Experimental Ward

Previous laboratory experiments by Ratcliff and Palladino had established that guinea pigs are extraordinarily susceptible to airborne M. tuberculosis (20). Guinea pigs became infected with TB by breathing aerosolized solutions of virulent human TB. Using quantitative culture methods, aerosols were made so dilute that inhalation of more than a single infectious droplet by test animals was statistically unlikely. Autopsies of the infected animals revealed single foci of infection in the periphery of lungs. For guinea pigs, TB infection correlated with inhalation of just one infectious droplet nucleus, which also correlated with a single colony on culture. Knowing how much air each animal breathed (on average, 240 cubic ft per month), Wells devised an experiment (later published by Riley) using guinea pigs as quantitative air samplers for human TB (19). Because of their small size, however, the practical application of this sampling method required more than 100 guinea pigs breathing the air exhausted from a six-bed ward housing patients with potentially infectious TB. These experimental conditions have been established only once, during the remarkable 4-year study at the Veterans Administration Hospital in Baltimore during the late 1950s and early 1960s. The results established five important facts about TB transmission and its control: (1) TB is a true airborne infection, requiring only air contact for transmission; (2) patients vary greatly in infectiousness; (3) infectiousness is rapidly reduced by effective treatment; (4) the average concentration of infectious droplet nuclei is low, on the experimental ward averaging 1 in 11,000 cubic feet of air; and (5) ultraviolet germicidal irradiation in the exhaust duct was a highly effective method of air disinfection (19,21–24). The study had limitations. Among 61 untreated patients with drug-susceptible organisms, only 8 infected any guinea pigs, and among 6 untreated patients

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with drug-resistant organisms, only 2 proved infectious to guinea pigs. From a total of 40 patients under chemotherapy, only 2 infected guinea pigs. Thus, the infectivity of many tuberculosis patients with positive sputum was too low to be detected in the Baltimore study. On the other hand, a patient with laryngeal TB infected 15 guinea pigs in 3 days. By calculation, the concentration of infectious particles in the air at that time was about 1 in 200 cubic ft, or more than 50 times the average concentration of 1 in 11,000 cubic ft of air. Then, as now, our attention is called to what Riley called “disseminators,” individuals who for various reasons infect a high proportion of their contacts (24,25). Although often the subject of epidemiological investigations, it is unclear how much these unusually infectious sources contribute to TB propagation in the community compared to the more common, less infections cases, which are never reported in the literature. As already noted, extensive transmission can result from a variety of factors, alone and in combination: source strength, exposure duration, environmental conditions, strain hardiness, virulence, and host susceptibility. While many of these factors were controlled in the guinea pig–exposure experiments, they are harder to separate in the epidemiological studies discussed below. II. Epidemiology of Transmission A. Historical Studies

TB infection rates among nurses in training and doctors were studied extensively in the 1930s and 1940s (26,27). As reported by Israel, about a third of student nurses began training at Philadelphia General Hospital already TB infected, using 5 mm reactions to 1 tuberculin unit as criteria for infection. This rate was a good indicator of household exposure risk at the time for the age and socioeconomic cohort represented by nursing students. The number of students infected increased each year, with nearly all infected by the end of 3 years of training, and about 10% developing clinical disease. These investigations provided an estimate of exposure intensity on general hospital wards in the prechemotherapy era, largely from unsuspected cases, as TB patients were commonly transferred to sanatoria upon diagnosis. Riley calculated that the infection rate of student nurses could be approximated by exposure to the average concentration of infectious droplet nuclei on his experimental ward, assuming that humans, like guinea pigs, became infected by a single infectious droplet nucleus. If, as now seems likely (see Sec. III), more than one inhalation may be required for innately resistant individuals, the infection rate among student nurses would have required higher concentrations than Riley’s guinea pig air samplers were able to detect. Of course, none of the patients on the experimental ward were unsuspected, and most were on therapy, greatly reducing infectivity. Insights into the behavior of airborne TB organisms have been gained over the years through epidemiological investigations of outbreaks, experiments of na-

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ture, such as was the case on board the Navy vessel, U.S.S. Byrd (28). Sixty-six men shared one bunking compartment with the index case, who had a large cavity in his lung. Eighty-one men, with minimal direct contact with the others, shared a second compartment in which three quarters of the ventilation came through interconnecting ducts from the first compartment. Eighty percent of the men in the first compartment converted the tuberculin test from negative to positive, and 54% of the men in the second compartment converted. The rate of conversion in the first compartment was nearly the same as the expected rate based on the proportion of ventilation coming from the first compartment (0.75  0.8, or 0.6 vs. 0.54). In this inadvertent experiment, the men in the two compartments were infected roughly proportionally to the amount of contaminated air they breathed. But direct contact with the index case occurred only in the first compartment. Thus, close contact did not greatly increase the likelihood of infection. Under more ordinary exposure conditions, this observation suggests that close proximity to an infectious source may add little to the risk of exposure in the same breathing space. Despite intensive investigation by the Navy, no evidence for transmission from environmental sources could be found after the infectious cases had been removed. Airborne droplet nuclei from the source constituted the only mechanism of transmission, and shared air, rather than proximity per se, the principal environmental risk. B. Mathematical Models of Transmission

In a report on a measles outbreak in a suburban elementary school, the quantitative assessment of airborne infection was further refined (29). The results are directly applicable to TB transmission because both diseases are spread by droplet nuclei. The issue of infectious dose must be introduced here as it is relevant to any quantitative discussion. It is discussed again in more detail in the next section. The number of infectious droplet nuclei required to infect humans with any airborne infection is unknown, in contrast to TB in guinea pigs where one culturable bacillus is sufficient. To circumvent this obstacle, Wells coined the term “quantum” of infection to mean an infectious dose, which could be one or more than one inhaled infectious particle, usually referring to the same exposure. As discussed below, we have extended the definition of dose for TB to include repeated inhalations during one or more exposure until one inhalation results in infection. The Wells-Riley ward data had confirmed epidemiological observations that TB is much less infectious than most of the airborne viral infections, in part because average concentrations of infectious droplet nuclei are so low that infection during ordinary exposures is statistically unlikely. Poisson’s law of low-probability events comes into play. Even when highly susceptible guinea pigs were exposed experimentally to concentrations of tubercle bacilli low enough that each animal should inhale no more than an average of one droplet nucleus, only 63.2%

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became infected (some animals, by chance, inhaling more than one droplet nuclei), whereas 36.8% escaped infection. Thus, a quantum of infection is that dose that results in the infection of 63.2% of exposed subjects. For humans, it is clear that infectious dose for tuberculosis will vary with the resistance of exposed persons and the virulence of the TB strain. However, for the purpose of mathematical modeling, we will use Wells’s “quanta” of infection, understanding that for humans a quantum of infection for TB and most other infections cannot be converted to numbers of droplet nuclei inhaled over one or many exposures. This convenience, however, permits useful quantitative insights into transmission and its control. In studying the school measles outbreak in upstate New York, Edward Riley expanded and modified Wells’s use of the Soper mass balance equation for epidemiological investigations to allow for low-probability events and multiple generations of infection, as occurs in measles. The equation for a single generation of infection is: C  S(1  eIqpt/Q) where: C  number of new cases S  number of susceptibles exposed e  natural logarithm I  number of infectious sources q  number of quanta (infectious doses) generated per unit min p  human ventilation rate (L/min) t  exposure duration Q  infection-free ventilation (L/sec) Ideally applied to a single room or enclosed space, the model has been applied with less validity to spaces served by the same heating, ventilating, and air conditioning (HVAC) system. The larger the space, the less convincing the assumption of complete room air mixing. Other assumptions include uniform susceptibility of exposed persons to infection and uniform virulence of organisms from one outbreak to another. In analyzing successive generations of the measles epidemic, C, S, I, p, t, and Q were either known or estimated for each room throughout the school, and the value of q was calculated. The infectiousness, q, of the index case was found to be 5580 quanta per hour, about 10 times that of secondary cases appearing in the next generation. Measles patients thus showed great variability in infectiousness, as was seen in tuberculosis patients on Riley’s experimental ward, but the rate of production of infectious airborne particles was much higher. The mathematical model developed to analyze the measles outbreak has been applied to several episodes of TB transmission, of which two instructive examples will be men-

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tioned here: a prolonged exposure in an office building and a brief but explosive exposure in a hospital intensive care unit. A 30-year-old woman returned sick to her duties from a month-long holiday, but she continued to work in a welfare office for an additional month before she was diagnosed with cavitary, sputum smear–positive TB, at which time contact with fellow employees ended (30). Of 67 coworkers initially tuberculin skin test negative, 27 (40%) had conversions to positive upon repeat testing 3 months later. One noninfectious secondary case resulted in a worker who had declined treatment of latent infection. The office building had been the subject of repeated air-quality complaints, and several air-quality assessments had been done before and after the TB exposure. A mathematical analysis of the exposure was prompted by the suspicion of several workers that inadequate ventilation was responsible for the large number of infected workers. As in the measles outbreak, all values of the Wells-Riley equation were known or estimable except q, the number of infectious quanta generated by the source case. By calculation, the source generated 13 infectious quanta per hour, compared to an average of only 1.25 for the entire six-bed experimental ward and a high value of 60 for the case of laryngeal TB studied by Riley. Further calculations showed that outdoor air ventilation at the low end for acceptable air quality (15 cubic feet per minute per occupant, based on average room CO2 values of 1000 ppm) contributed to transmission. However, the model indicated that doubling ventilation would reduce the risk of infection only by approximately half (Fig. 2). Thirteen workers would still have been infected, according to the model. Moreover, an additional doubling, to an unrealistic 60 cfm per occupant, would again reduce risk by half, leaving approximately 6 workers unprotected. Both the potential of a moderately infectious patient to infect many contacts over a prolonged period and the limitations of building ventilation to prevent transmission were demonstrated, within the assumptions and limitation of the model. Catanzaro applied the Wells-Riley equation to an episode of transmission in an intensive care unit where an unsuspected patient, initially smear negative for TB, underwent intubation and bronchoscopy (31). During the 21⁄2 hours of the procedures, 10 of 13 susceptible room occupants became infected (31). By calculation, the source produced a remarkable 250 quanta per hour (compared to 1.25/hr for the experimental ward, and 13/hr for the office building). However, the ventilation rate in the intensive care unit was extremely low, and further calculations predicted substantial improvements by increases in ventilation that were achievable (Fig. 2). The episode illustrates the ever-present risk of the unsuspected case, the wide range of infectivity, and the potential for environmental controls to greatly reduce transmission when existing ventilation is low. Recently, mathematicians have endeavored to further refine the Wells-Riley model. However, the results differ only slightly from those using the original model, and given the nature of the assumptions and estimates necessary to apply modeling to real-world situations, it is unclear that embellishments of the model

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Figure 2 Two different situations of extensive transmission are represented. In both cases I was 1 and p was assumed to be 0.353 cfm, a constant. Thereafter the transmission factors for the Nardell and Catanzaro exposures were, respectively, q  13 and 250 qph; t  9600 and 150 minutes; and Q  1450 and 150 cfm.

at the expense of simplicity will serve any practical purpose (32). Although derived from an epidemiological model, the Wells-Riley equation has much in common with engineering mass balance equations, some of which have been validated by experimental measurements of airborne contaminant concentrations, such as the concentrations of airborne antigens in an animal facility (33). Epidemiological models predicting infection and disease rates, mortality, drug resistance, and financial consequences in response to demographic changes and other factors have become highly sophisticated (34). For epidemiological purposes, the details of transmission at the level of the room or building are not considered. It is assumed that populations interact in ways that permit the transmission of infectious diseases, whatever the mechanisms (35). III. Infectious Dose for Humans The concept of an infectious dose is somewhat different for tuberculosis than for some of the other common respiratory infections. For example, thousands of potentially pathogenic oral-pharyngeal bacteria are routinely aspirated without caus-

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ing pneumonia—apparently cleared by lung defenses. In guinea pigs and susceptible strains of inbred rabbits, however, experimental exposure studies using dilute aerosols (confirmed by culture) have shown that a single inhaled droplet nucleus, estimated to carry no more than three organisms, was sufficient to cause infection, manifested by a tuberculin skin test conversion and a single peripheral lung lesion (20). In humans, resistance to initial tuberculosis infection appears to be variable, among different individuals and among different populations, due to acquired and inherited resistance. This observation suggests that inhalation of more than one droplet nucleus, possibly many, may be necessary to cause infection in resistant individuals. Because the concentration of droplet nuclei in the air under ordinary exposure conditions is believed to be extremely low, averaging only 1 in 11,000 cubic feet in the air exhausted from Riley’s experimental tuberculosis ward over a 4-year period, multiple or recurrent inhalations are unlikely unless exposure is prolonged or the source strength is unusually strong (22). In the bronchoscopy exposure discussed above, a concentration of approximately 1 quanta in 70 cubic feet was estimated, making multiple inhalations likely (31). Whereas multiple pulmonary foci of infection are seen in persons exposed to high concentrations of histoplasmosis spores, primary tuberculosis on chest radiographs is almost always a single focal site. Thus, for tuberculosis an infectious dose may require repeated inhalations over time until one implantation results in infection. The dose of droplet nuclei required to cause infection depends on the probability of a successful defense by alveolar macrophages in each encounter with those tubercle bacilli reaching the alveoli. A successful defense depends on the microbicidal capacity of the macrophage relative to the virulence of inhaled tubercle bacilli (see Chap. 10). In theory, the infecting dose will be high in persons whose macrophages generally have great microbicidal capacity or where bacilli are of low virulence. In contrast, persons whose macrophages generally have relatively little microbicidal capacity or where bacilli are fully virulent even hypervirulent, the infecting dose will be low, probably as little as a single droplet nucleus. Chance plays an important role in several ways: (1) the variable innate microbicidal capacity of alveolar macrophages that happen to be in the vicinity of the bacillary implantation site, (2) the low likelihood of inhaling even one droplet nucleus during most exposures, and (3) the relatively low probability that inhaled droplet nuclei will reach the especially vulnerable apical or subapical region of the lung. Subapical implantation may be more important for exogenous reinfection than for initial infection, since previously infected persons have highly effective cell-mediated immunity to reinfection (36–38). The belief that TB infection is caused by the chance implantation of single infectious droplet nuclei containing few organisms does not explain epidemiological observations over the years that more extensive disease has been associated with situations of high exposure. For example, in Canada, Grzybowski and col-

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leagues observed among both Caucasians and indigenous peoples, that household contacts of smear-positive tuberculosis cases not only had higher rates of infection, but were almost three times more likely to go on to active disease (39). Earlier, Grzybowski had also shown more extensive calcifications of primary lesions (more disease) among children infected through household contact (greater exposure) than children infected outside the home (40). IV. Recent Outbreaks The resurgence of TB in North America and Western Europe between 1985 and 1992 was characterized by numerous well-publicized outbreaks in congregate setting, including homeless shelters, residential AIDS facilities, prisons, and, most strikingly, health-care facilities (41–48). Among the earliest and best studied outbreaks were those in Miami and New York City, epicenters of AIDS-associated MDRTB among intravenous drug users and their contacts (47). The availability of RFLP fingerprinting as well as well-characterized drug-resistance patterns permitted a new level of epidemiological tracing of cases, for example, throughout the New York State prison system (43). A new assumption was proposed that cases clustered by RFLP pattern represented recent transmission, while unclustered cases were more likely the result of reactivation of remote infection (49) (see Chap. 11). Based on this assumption, studies in New York City and elsewhere suggested that as many as 30–40% of new cases were recently transmitted, whereas it had previously been believed that reactivation of old foci accounted for 90% of active TB in low-prevalence countries like the United States. Among RFLP-linked MDRTB in New York City, epidemiological investigations showed remarkably focal transmission, primarily associated with a small number of hospitals (50). Molecular markers were also used in the investigation of an extensive outbreak in a rural setting, providing evidence that organisms of increased virulence may have been responsible (25). While these outbreaks added relatively little to our understanding of the basic aerobiology of M. tuberculosis, they do teach many lessons about its spread in communities and congregate settings. Health-care providers, institutional administrators, and even infection-control practitioners had grown lax about the potential for transmission in close communities, where most exposed persons are now fully susceptible to infection. Moreover, no one could have predicted the potentiating effect of HIV co-infection on TB transmission, where newly infected persons progressed rapidly and almost invariably to secondary, infectious disease. Ineffective treatment due to drug resistance further accelerated transmission. Unfortunately, awareness of these intertwined factors was achieved only slowly as transmission episodes were investigated (51). Early in the resurgence, for example, it was common to administer aerosolized pentamidine, an effective agent

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for preventing pneumocystis pneumonia, to groups of AIDS patients in the same room. Coughing, a common side effect of such treatments, effectively helped spread TB from unsuspected, infectious cases to other immunocompromised patients (47). In persons with HIV infection, cough, fever, weight loss, and lung infiltrates are common and have a low predictive value for TB, whereas lung cavities and positive skin tests characteristic of TB were less often present in those with both diseases. Among HIV-infected persons, new TB cases were not suspected isolated, diagnosed, or treated early, but remained infectious on hospital wards for days or weeks. Prior to the recent resurgence, methods for TB isolation had not been defined in great detail—particularly respirator usage and the maintenance and testing of isolation rooms. Surgical masks permitted extensive faceseal leakage, and upon testing, many negative pressure isolation rooms were found to be under positive pressure relative to hallways and adjacent rooms, potentially contributing to transmission. The use of upper room ultraviolet germicidal air disinfection to prevent transmission, a popular technology in the 1940s and 1950s had never been fully defined or field-tested, and expertise on its use was lacking. Even conventional room ventilation and air filtration were not optimally applied and maintained. Older guidelines had suggested that after 2 weeks of effective treatment, isolation procedures could be relaxed. Patients with unsuspected MDRTB were often allowed to mingle with other patients after 2 weeks of what would turn out to be inadequate treatment. Laboratory results showing drug resistance and continued sputum smear positivity were often slow to return to the chart, further prolonging exposure. Once these and other lapses were brought to the attention of the medical community and governmental agencies, meetings were held, interventions debated, and infection control guidelines developed, disseminated, and broadly implemented (9). Since 1992, TB case rates have continued to fall, and reports of outbreaks have also declined. Improved TB control both in the community and in institutions has been credited with this reversal (50,52). V. Preventing Transmission Because some of the early, extensive MDRTB outbreaks occurred in New York City and Miami, much of the initial response to the renewed treat of institutional TB transmission happened in the United States. As outbreaks were recognized elsewhere, other countries formulated their own responses, often influenced by events in the United States. By 1990, the U.S. Centers for Disease Control (CDC) revised its guidelines for preventing transmission in health-care facilities. These were again revised, expanded, and published in their current form in 1994 (9). The U.S. National Institute for Occupational Safety and Health (NIOSH) became fully involved in the choice of personal respirator protection for health-care workers in

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1992, ultimately revising its testing and classification of respirators to the current system in 1995 (53). The American College of Chest Physicians and The American Thoracic Society held a consensus conference on the subject of institutional TB transmission in 1993 and issued an official joint statement in 1995 (54). The Occupational Health and Safety Administration (OSHA) began enforcing compliance of health-care facilities with CDC guidelines, under the General Duty Clause of the OSHA Act, in the absence of a specific tuberculosis standard to guide enforcement. However, at the request of several labor unions, the process of developing a tuberculosis standard was set in motion, culminating in the publication of a draft standard in November, 1997, followed by public hearings, which were concluded in June 1998. A final OSHA TB standard is expected to adhere closely to the 1994 CDC guidelines (9). A review of currently available guidelines, including those from Canada and the United Kingdom, has been published (55). VI. Governmental Recommendations: An Overview Although the CDC guidelines (9) have been applied to a variety of acute and chronic health-care facilities, their main focus has been the control of TB transmission in acute care hospitals. These recommendations, their rationale, and extensive supporting materials cannot be presented here in detail. In essence, the guidelines suggest that institutions assess their risk status for TB transmission based on the rate of known TB admissions, the TB risk of the specific population served, and evidence of TB transmission in the facility. Based on the risk assessment, institutions are expected to formulate comprehensive TB infection–control plans, with clear lines of administrative accountability. In the 1994 CDC guidelines (9), five levels of risk are defined, ranging from minimal to high, with increasing control measures recommended for each risk level. Staff TB risk-awareness training at all levels is recommended, including knowledge of the signs and symptoms of TB, to encourage prompt identification of suspect cases. Administrative controls, including identification and triage of suspect cases, is the cornerstone of the CDC control strategy. Suspects are to be identified promptly and placed in special TB isolation rooms. Engineering controls for isolation and procedure rooms include negative pressure (relative to adjacent hallways and rooms) to assure directional airflow into contaminated spaces. Air disinfection in rooms to protect workers is primarily by dilutional ventilation, supplemented where needed by high-efficiency particulate air (HEPA) filtration, or ultraviolet irradiation. A controversial part of the CDC guidelines (9) has been the role of personal respiratory protection (56–58). Although generally considered least desirable in the hierarchy of controls in industrial settings, the inability to effectively eliminate

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risk by administrative and environmental controls has resulted in a prominent role for respirators in the CDC strategy. Two analyses of the protection provided by respirators have recently been published (59,60). The latter study analyzed the protection afforded by various levels of respiratory protection relative to ventilation under various exposure scenarios, and concluded that against most exposures achievable levels of ventilation and modest levels of respirator protection provide near maximal benefit. Only under extraordinary exposure conditions was the highest level of respiratory protection needed. The cost-effectiveness of routine respiratory use in hospital under low-prevalence conditions has been challenged (56,58). Fortunately, NIOSH has developed a new certification method for disposable respirators appropriate for droplet nuclei-size particles in clean, nonindustrial settings. The result has been the introduction to the market of a variety of respirators similar in appearance, cost, and comfort to ordinary, tight-fitting surgical masks. While the original concerns over the cost and practicality of industrial-type respirators in health-care facilities have been allayed, the issue of mandatory fit testing remains controversial. Good industrial hygiene practice views qualitative fit testing as a minimal requirement for an acceptable respirator program, with periodic refitting to assure that workers can use respirators effectively (61,62). Many hospital infection-control experts, however, find the practice burdensome and unlikely to be very effective when applied to disposable respirators that inherently have relatively large percentages of face-seal leak. Critics argue that good respirator educational program alone, without formal fit-testing, would lead to comparable protection (63). There are no scientific studies on either side of the argument, and the fit-testing requirement is likely to remain under the OSHA standard. Although several hospitals have reported fewer skin test conversions after the implementation of vigorous infection control plans (see Chap. 23), the contribution of each of the components—education, early detection, triage, isolation, skin testing, air disinfection, and respirator use—is not known (64,65). VII. Preventing Transmission from Unsuspected Cases of Tuberculosis In the view of many experienced observers, unsuspected cases of infectious, pulmonary TB have always been and remain the principal source of transmission in institutions (66,67). At the height of the resurgence, one study from two medical centers in Washington, DC, found that 49 (58%) of 85 hospitalized cases were missed initially, 22 (26%) had their diagnosis delayed 4 weeks, 17 (20%) were not diagnosed or treated while in the hospital, and 7 (8%) died with TB diagnosed at autopsy (68). Of the infection-control interventions mentioned, only increased surveillance and general air disinfection addresses the risk of transmission from

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unsuspected cases (67). The nonspecificity of the signs and symptoms of TB, against a background of extremely common symptoms due to other respiratory illnesses, together with often insensitive and nonspecific diagnostic tests assures that both underdiagnosis and overdiagnosis will persist as obstacles to effective and efficient TB infection control in the future, especially as cases decline. Increased surveillance results in fewer missed cases and less risk of transmission, but at the price of overisolation. Scott and colleagues estimated that in a low-prevalence, Midwest setting, 92 patients without TB are isolated in order to identify just one patient with the disease (69). Isolation rates as high or higher are common throughout the United States, and the rate of overisolation should continue to climb as TB case rates fall, due to the unchanging high background rate of respiratory illnesses. Lowering the index of suspicion for TB isolation is the appropriate response to falling cases rates, but it is certain to result in additional missed cases. There are no immediate solutions to the dilemma of over- and underdiagnosis of low-prevalence diseases with common presenting symptoms as long as screening and diagnostic tools have low predictive value (70). Fortunately, progress has been made, and more progress is expected in the near future (71). VIII. Engineering Approaches to Preventing Transmission A. Industrialized Countries

Identifying and isolating every potentially infectious TB case, however desirable, will be increasingly impractical in years to come, unless rapid, sensitive, and highly specific diagnostic tests are developed that can be utilized for every patient with TB risk factors and respiratory symptoms consistent with TB. Even then, often subtle respiratory symptoms in patients with other medical problems would have to be recognized to apply such a test. The dilemma of unsuspected cases and susceptibles moving freely within buildings led Riley to consider the value of engineering controls throughout environments where transmission occurs, such as enhanced air disinfection in emergency rooms, shelters, and jails (72). Dilution of infectious droplet nuclei within surrounding air, with subsequent removal by passive or active ventilation, is the mainstay of general air disinfection in most institutions in resource-rich countries (73). However, as noted above, dilutional ventilation is inherently limited, even under optimal conditions, producing an exponential decline in the concentration of air contaminants (30). Ventilation is further constrained by practical engineering issues, such as incomplete air mixing, energy costs, drafts, and noise. However, in operating rooms, procedure rooms, and special isolation rooms, it is possible to achieve more than 10 air changes per hour, which should offer substantial protection under ordinary circumstances against all but the most intensive exposure to airborne infection. Templeton and

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colleagues have reported transmission during a 3-hour autopsy that was so intense that it is doubtful that any environmental controls would have been substantially protective (74). Under these circumstances, highly effective personal respiratory protection is needed (60). Supplemental Air Disinfection

Because it is often cost-prohibitive to greatly increase mechanical ventilation in older buildings, supplemental air disinfection using air filtration or ultraviolet irradiation has been recommended (9). Although air filters less efficient than HEPA should be highly effective in retaining airborne particles in the range of 1–5 m in diameter, HEPA has become the standard for air disinfection in clinical and laboratory settings (75). HEPA filters can be used in the return ducts of central ventilating systems, but this adds greatly to flow resistance, requiring larger, louder fans or blowers to maintain airflow. Moreover, air filtration is most effective when applied close to the source of contamination. In the building’s general ventilating system, where droplet nuclei have been greatly diluted, large volumes of mostly infection-free air must be filtered to protect occupants. Where air is filtered close to the source of contaminants (e.g., an infectious TB patient), air disinfection is more efficient. Thus, HEPA filtration is being used in free-standing air-disinfection room units and even more efficiently in booths and partial enclosures designed for sputum induction and aerosol therapy. In large rooms, free-standing airfiltration units require high flow rates and good room air mixing to substantially increase the number of air changes per hour. Tests of particle clearance rates using room units of various design have generally shown rapid and effective air disinfection (75). In practice, as with building ventilating systems, motor noise, drafts, noise, and design issues limit the number of equivalent room air changes and, therefore, the practical benefit of filtration as a means of general air disinfection. The exponential decay curve in Figure 2 suggests that doubling room ventilation, in general, reduces the risk of infection by approximately half. Depending on the baseline conditions in a room, it may or may not be possible to double or quadruple ventilation through room air-filtration units, and the expected reductions by half to a quarter in the risk of infection may or may not be a satisfactory level of protection. Ultraviolet Germicidal Irradiation

DNA absorbs irradiation predominantly in the vicinity of 260 nm wavelength (UV-C, or germicidal UV). Living cells exposed to such irradiation are killed or inactivated due to damage to DNA, producing pyrimidine dimers, and due to damage to other essential proteins (76). Sublethal genetic mutations may also occur, some of which are reversible. As depicted in Figure 1, exposure to natural environmental irradiation is believed to be one of the stresses that limits airport trans-

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port of microorganisms (5). However, indoors, where person-to-person transmission of infection is most likely, natural radiation in the germicidal range is nearly absent. This is because short-wavelength UV irradiation is so readily absorbed that it is almost entirely removed from sunlight as it passes through the earth’s atmosphere. Because it cannot pass through ordinary window glass, whatever solar radiation is present in enclosed spaces is the more penetrating, but much less biologically active, longer-wavelength UV (UV-A and, to a lesser extent, UV-B). Fortunately, germicidal UV is easily produced indoors by inexpensive lamps that resemble ordinary fluorescent lamps but are made of quartz or fused silica glass that permits transmission of short-wavelength UV. Using a common mercury source, germicidal lamps produce a narrow spike of radiation at 253.7 nm wavelength, close to the 260 nm peak of the germicidal action spectrum. The availability of inexpensive germicidal irradiation provides another attractive supplement to room ventilation and filtration as a means of air disinfection. Whenever radiation is considered, human safety concerns are raised, and these are discussed first. Because short-wavelength UV is so biologically active, it is nearly completely absorbed by the outer, dead layer of human skin—the stratum corneum (77). Skin overexposure to germicidal UV can result in significant erythema but not tanning or the potentially severe sunburn associated with UV-A and UV-B in sunlight. Whereas the 8-hour exposure limit for less penetrating germicidal UV is 6 mJ, 4 hours of mid-day sunbathing can result in an estimated 740 mJ exposure of more penetrating, longer-wavelength UV (78). Thus, while airborne microorganisms are highly vulnerable to germicidal UV, human exposure has few or no serious health consequences, especially when compared to other common sources of UV exposure. Germicidal UV is classified as a potential human carcinogen because intensive exposure has caused skin cancer in hairless mice, but in an unpublished presentation at the National Centers for Disease Control in Atlanta, Urbach calculated that human skin cancer under the current exposure limits would require more than 300 years (79). Likewise, short-wavelength UV cannot penetrate the eye to reach the lens, so cataracts associated with longer-wavelength UV are not a complication of germicidal UV exposure. The human cornea, having no protective covering, is the organ most vulnerable to germicidal UV (80). Corneal irritation, called photoconjunctivitis, is a transient but painful response of the eye to UV overexposure. Corneal repair is nearly complete by 48 hours, and there are no known long-term consequences to germicidal or, much more common, solar UV corneal irritation. Most photoconjunctivitis due to UV-C occurs due to accidental direct exposure to high-intensity lamps, most often among maintenance and other workers. Because the onset of symptoms is delayed for hours, early photoconjuctivitis is not a useful warning sign. Well-designed fixtures, proper installation, metering with a sensitive 254 nm instrument, warning labels, and worker education are the most important ways to assure safe use of germicidal UV.

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The efficacy of germicidal UV in killing or inactivating a wide range of microorganisms is well established, having been quantified by countless experiments over more than 50 years (81). How best to apply germicidal UV in buildings to prevent airborne transmission, however, remains controversial. UV has been employed in ventilation ducts in an effort to reduce the recirculation of infectious airborne organisms and has the advantage over HEPA filtration of adding little flow resistance to the system. While UV air disinfection in ducts avoids exposure of room occupants, this application has limitations similar to those of ventilation and air filtration. That is, it is necessary to move enough air through the system to substantially increase the number of equivalent air changes over baseline conditions. For large-volume spaces, such as emergency rooms and homeless shelters, noise and drafts due to the high flow rates required are significant limitations. Another approach to the application of germicidal UV is upper room air disinfection. The advantages of upper room UV air disinfection have been appreciated for over 50 years (82). Much of the upper room is used to kill or inactivate slowly moving microorganisms carried into the irradiated zone by convection currents generated by body heat and a variety of other forces. Several room studies have demonstrated that passive air movement can result in air-disinfection rates well in excess of what is practical by forced air-disinfection systems, depending on the UV susceptibility of the test organism (16,83–85). Because the system is passive, it is inexpensive, quiet, and draftless relative to comparable forced-air systems. Although the potential for occupant UV exposure exists, this is not a serious limitation, as noted above. Perhaps the greatest limitation of upper room UV air disinfection is the uncertainty over the equivalent germ-free ventilation produced under field conditions, because this depends on the extent of room air mixing, which is not controlled. Details on the application of upper room UV air disinfection are beyond the scope of this chapter, but have been published recently in the engineering literature (86,87). These guidelines reflect current practice based on decades of experience and experiments. However, several universities are engaged in new research intended to fill in missing gaps in our current understanding, particularly with regard to optimal fixture design and deployment in rooms in relation to mechanical ventilation. In addition to bench-scale and room-scale experiments on such factors as the effects on high humidity, a multicenter, placebocontrolled trial of upper room UV air disinfection in homeless shelters is underway. This field trial tests two hypotheses at once: whether any air disinfection makes a difference to infection rates in a highly complex community, and whether upper room UV is an effective means of air disinfection. The results of such studies are essential if the technology is to be used where it is most needed—in many parts of the developing world where institutional transmission of multidrug-resistant TB is common and where alternative technologies are either unaffordable or unavailable.

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B. Transmission in High-Prevalence Countries

Although the recent TB resurgence focused attention on institutional TB transmission in North America and Europe, there is good reason to believe that more extensive transmission, increasingly of MDRTB, is occurring in high-prevalence countries. Outbreaks have occurred, for example, in an AIDS health-care facility in Argentina, in prisons in Russia (see Chap. 24), and in an entire community outside of Lima, Peru (2,88,89). In South Africa, workers are convinced that patients recovering from drug-susceptible TB are becoming reinfected with drug-resistant organisms shed by patients sharing the same open wards (90). WHO has recently published recommendations for practical interventions to prevent transmission (12,91). They focus on prompt diagnosis and treatment rather than on generally unavailable technologies such as negative pressure isolation rooms and personal respirators. Clearly there are no easy solutions to the problem of transmission in overcrowded places where an uninterrupted supply of first-line medications cannot be assured. However, there are approaches that should reduce transmission at little additional cost. In many high-prevalence countries TB patients spend far longer in hospitals than is required medically. Because drug susceptibility testing is usually unavailable, the first clue to drug resistance often is clinical failure. By the time treatment failure becomes obvious, patients and staff have been exposed. By reducing unnecessary hospitalization, the number of potential exposures can be reduced greatly, because both potential sources and potential victims are fewer. Still, there will always be congregate settings where transmission occurs from known TB cases and from unsuspected cases. For known infectious cases, effective treatment remains the most important infection-control intervention, especially when treatment occurs primarily in the community (2). In high-prevalence countries, respiratory isolation is often difficult but may be possible in some settings. For unsuspected cases the options are few, as in low-prevalence countries. General air disinfection, by dilution in the volume of the occupied space and through natural ventilation, is the most commonly available intervention. As noted, transmission of drug-resistant TB is increasingly being recognized in developing countries (12). The general unavailability of individualized treatment based on culture and drug susceptibility studies means that cases remain infectious for prolonged periods, generally until they die. Molecular and conventional epidemiology studies on cultures obtained from patients who have failed treatment in a poor region section of Lima, Peru, have proven transmission within households, within the community, and in health-care facilities. A unique program of community-based treatment for persons with MDRTB, based on individual susceptibility studies (see Chap. 17), is reducing transmission through effective treatment and also by keeping patients out of hospitals while they are being treatment (2). Several other pilot projects utilizing a similar strategy, called “DOTS-Plus,” are being initiated by WHO in other focal areas of MDRTB (92). A current barrier are

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the considerable financial resources needed to diagnose and effectively treat MDRTB in developing countries. References 1. Farmer P. Social scientists and the new tuberculosis [see comments]. Soc Sci Med 1997; 44(3):347–358. 2. Farmer P, Kim J. Community based approaches to the control of multidrug resistant tuberculosis: introducing “DOTS-plus.” BMJ 1998; 317:671–674. 3. Riley R, O’Grady F. Airborne Infection. New York: The Macmillan Company, 1961. 4. Cox C. Roles of water molecules in bacteria and viruses. Origins of Life and Evolution of the Biosphere 1993; 23:29–36. 5. Cox C. The Aerobiological Pathway of Microorganisms. Chichester: John Wiley and Sons, 1987. 6. Cox C. Airborne bacteria and viruses. Science Prog (Oxon.) 1989; 73:469–500. 7. Riley RL. Airborne infection. Am J Med 1974; 57(3):466–475. 8. Mann T. The Magic Moutain. New York: Alfred A. Knopf, 1924. 9. Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, 1994. Centers for Disease Control and Prevention. MMWR 1994; 43(RR-13):1–132. 10. Jarvis WR. Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis. Am J Infect Control 1995; 23(2):146–151. 11. Gerberding JL. Occupational infectious diseases or infectious occupational diseases? Bridging the views on tuberculosis control [editorial]. Infect Control Hosp Epidemiol 1993; 14(12):686–688. 12. Harries AD, Maher D, Nunn P. Practical and affordable measures for the protection of health care workers from tuberculosis in low-income countries. Bull WHO 1997; 75(5):477–489. 13. Wells W. On air-borne infection: II. Droplets and droplet nuclei. Am J Hyg 1934; 20:611–618. 14. Wells W. Airborne Contagion and Air Hygiene. Cambridge, MA: Harvard University Press, 1955. 15. Loudon RG, Bumbarna LR, Lacy J, Coffman GK. Aerial transmission of mycobacteria. Am Rev Respir Dis 1969; 100:165–171. 16. Riley R, Knight M, Middlebrook G. Ultraviolet susceptibility of BCG and virulent tubercle bacilli. Am Rev Respir Dis 1976; 113:413–418. 17. Fennelly K, Martyny J. Isolation of viable airborne Mycobacterium tuberculosis: a new method to study transmission. (abstract). Am J Respir Crit Care Med 1998; 157:A706. 18. Mastorides S, Oehler R, Greene J, Sinnott J, Sandin R. Detection of airborne Mycobacterium tuberculosis by air filtration and polymerase chain reaction. (letter). Clin Infect Dis 1997; 25:756–757. 19. Riley R, Mills C, Nyka W. Aerial dissemination of pulmonary tuberculosis—a two year study of contagion in a tuberculosis ward. Am J Hyg 1959; 70:185–196.

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20. Ratcliff H, Palladino V. Tuberculosis induced by droplet nuclei infection; intial homogeneous response of small mamals (rats, mice, guinea pigs and hamsters) to human and bovine bacilli, and the rate and pattern of tubercle development. J Exp Med 1953; 97:61. 21. Riley R, Wells W, Mills C, Nyka W, McLean R. Air hygiene in tuberculosis: quantitative studies of infectivity and control in a pilot ward. Am Rev Tuberc Pulmon Dis 1957; 75:420–431. 22. Riley R, Mills C, O’Grady F. Infectiousness of air from a tuberculosis ward—ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 1962; 84:511–525. 23. Riley R. Aerial dissemination of pulmonary tuberculosis—The Burns Amberson Lecture. Am Rev Tuberc Pulmon Dis 1957; 76:931–941. 24. Sultan L, Nyka C, Mills C, O’Grady F, Riley R. Tuberculosis disseminators—a study of variability of aerial infectivity of tuberculosis patients. Am Rev Respir Dis 1960; 82:358–369. 25. Valway SE, Sanchez MP, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis [see comments] [published erratum appears in N Engl J Med 1998; 338(24):1783]. N Engl J Med 1998; 338(10):633–639. 26. Israel H, Hetherington H, Ord J. A study of tuberculosis among student nurses. JAMA 1941; 117:839. 27. Amberson J, Riggins H. Tuberculosis among student nurses: a five-year study at Bellevue Hospital. Ann Int Med 1936; 10:156. 28. Houk V, Kent D, Baker J, Sorensen K. The epidemiology of tuberculosis transmission in a closed environment. Arch Environ Health 1968; 16:26–35. 29. Riley E, Murphy G, Riley R. Airborne spread of measles in a suburban elementary school. Am J Epidemiol 1978; 107:421–432. 30. Nardell E, Keegan J, Cheney S, Etkind S. Airborne infection: theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991; 144:302– 306. 31. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis 1981; 123:559–562. 32. Gammaitoni L, Nucci MC. Using a mathematical model to evaluate the efficacy of TB control measures. Emerg Infect Dis 1997; 3(3):335–342. 33. Swanson M, Campbell A, O’Hallaren M, Reed C. Role of ventilation, air filtration, and allergen production rate in determining concentrations of rat allergens in the air of animal quarters. Am Rev Respir Dis 1990; 141:1578–1581. 34. Anderson R, May R. Infectious Diseases of Humans: Dynamic and Control. Oxford: Oxford University Press, 1992. 35. Blower SM MA, Porco TC, Small PM, Hopewell PC, Sanchez MA, Moss AR. The intrinsic transmission dynamics of tuberculosis epidemics. Nature Med 1995; 1(8):815–821. 36. Nardell E, McInnis B, Thomas B, Weidhaas S. Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 1986; 315:1570–1575. 37. Smith D, Wiengeshaus E. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis 1989; 11:S385–S393.

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38. Balasubramanian V, Wiegeshaus E, Taylor B, Smith D. Pathogenesis of tuberculosis: pathway to apical location. Tubercle Lung Dis 1994; 75:168–178. 39. Grzybowski S, Barnett G, Styblo K. Contacts of cases of active pulmonary tuberculosis. Selected Papers of the Royal Netherlands Tuberculosis Association 1975; 16:90–99. 40. Bentley F, Grzybowski S, Benjamin B. Calcification of primary lesions. In: Tuberculosis in Childhood and Adolescence: With Special Reference to the Pulmonary Forms of the Disease. London: The National Association for the Prevention of Tuberculosis, 1954. 41. Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and HIV-infected patients in an urban hospital—Florida. MMWR 1990; 39(40):718– 722. 42. Guerrero A, Cobo J, Fortun J, et al. Nosocomial transmission of Mycobacterium boyis resistant to 11 drugs in people with advanced HIV-1 infection [see comments]. Lancet 1997; 350(9093):1738–1742. 43. Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system—New York, 1991. MMWR 1992; 41(28):507–509. 44. Tuberculosis transmission in a state correctional institution—California, 1990–1991. MMWR 1992; 41(49):927–929. 45. Edlin BR, Tokars JI, Grieco MH, et al. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome [see comments]. N Engl J Med 1992; 326(23):1514–1521. 46. Coronado VG, Beck-Sague CM, Hutton MD, et al. Transmission of multidrug-resistant Mycobacterium tuberculosis among persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis. J Infect Dis 1993; 168(4):1052–1055. 47. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988–1991. MMWR 1991; 40(34):585–591. 48. Sepkowitz KA. Occupationally acquired infections in health care workers. Part I. Ann Intern Med 1996; 125(10):826–834. 49. Alland D, Kalkut G, Moss A, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994; 330:1710–1716. 50. Frieden T, Sherman L, Maw K, et al. A multi-institutional outbreak of highly drugresistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996; 276:1229– 1235. 51. Beck-Sague C, Dooley SW, Hutton MD, et al. Hospital outbreak of multidrug-resistant Mycobacterium tuberculosis infections. Factors in transmission to staff and HIVinfected patients. JAMA 1992; 268(10):1280–1286. 52. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333(4):229–233. 53. Centers for Disease Control. NIOSH Guide to the Selection and Use of Particulate Respirators Certified Under 42 CFR 84. Cincinnati, OH: National Institute for Occupational Safety and Health, HHS, CDC, 1996: i–ix, 1–22. 54. Institutional control measures for tuberculosis in the era of multiple drug resistance. ACCP/ATS Consensus Conference. American College of Chest Physicians and the American Thoracic Society. Chest 1995; 108(6):1690–1710.

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55. Nardell E. Tuberculosis. In: Abrutyn E, Goldman D, Scheckler W, eds. Saunders Infection Control Reference Service. Philadelphia: W.B. Saunders Co., 1998:195–224. 56. Adal KA, Anglim AM, Palumbo CL, Titus MG, Coyner BJ, Farr BM. The use of high-efficiency particulate air-filter respirators to protect hospital workers from tuberculosis. A cost-effectiveness analysis [see comments]. N Engl J Med 1994; 331(3):169–173. 57. Jarvis WR, Bolyard EA, Bozzi CJ, et al. Respirators, recommendations, and regulations: the controversy surrounding protection of health care workers from tuberculosis. Ann Intern Med 1995; 122(2):142–146. 58. Nettleman MD, Fredrickson M, Good NL, Hunter SA. Tuberculosis control strategies: the cost of particulate respirators [see comments]. Ann Intern Med 1994; 121(1):37–40. 59. Barnhart S, Sheppard L, Beaudet N, Stover B, Balmes J. Tuberculosis in health care settings and the estimated benefits of engineering controls and respiratory protection. J Occup Environ Med 1997; 39(9):849–854. 60. Fennelly K, Nardell E. The relative efficacy of respirators and room ventilation in preventing occupational tuberculosis. Inf Control Hosp Epidemiol 1998; 19:754–759. 61. Qian Y, Willeke K, Grinshpun SA, Donnelly J. Performance of N95 respirators: reaerosolization of bacteria and solid particles. Am Ind Hyg Assoc J 1997; 58(12):876–880. 62. Willeke K, Qian Y. Tuberculosis control through respirator wear: performance of National Institute for Occupational Safety and Health-Regulated Respirators. Am J Infect Control 1998; 26(2):139–142. 63. SHEA’s response to proposed OSHA TB exposure rule [news]. Infect Control Hosp Epidemiol 1998; 19(4):288. 64. Blumberg HM, Watkins DL, Berschling JD, et al. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122(9):658–663. 65. McGowan JE, Jr. Nosocomial tuberculosis: new progress in control and prevention. Clin Infect Dis 1995; 21(3):489–505. 66. Moran GJ, McCabe F, Morgan MT, Talan DA. Delayed recognition and infection control for tuberculosis patients in the emergency department. Ann Emerg Med 1995; 26(3):290–295. 67. Nardell EA. Interrupting transmission from patients with unsuspected tuberculosis: a unique role for upper-room ultraviolet air disinfection. Am J Infect Control 1995; 23(2):156–164. 68. Mathur P, Sacks L, Auten G, Sall R, Levy C, Gordin F. Delayed diagnosis of pulmonary tuberculosis in city hospitals. Arch Intern Med 1994; 154:306–310. 69. Scott B, Schmid M, Nettleman M. Early identification and isolation of inpatients at high risk for tuberculosis. Arch Intern Med 1994; 154:326–330. 70. Nardell E. Needles in haystacks: diagnosing tuberculosis under low prevalence conditions. Tuberc Lung Dis 1996; 77:389–390. 71. Foulds J, O’Brien R. New tools for the diagnosis of tuberculosis: the perspective of developing countries. Int J Tuberc Lung Dis 1998; 2:778–783. 72. Riley R. Ultraviolet air disinfection: rationale for whole building irradiation. Infect Control Hosp Epidemiol 1994; 15:324–325.

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73. Nardell E. The role of ventilation in the nosocomial transmission of tuberculosis. Int J Tuberc Lung Dis 1998; 2(suppl 1):S110–S117. 74. Templeton G, Illing L, Young L, Cave D, Stead W, Bates J. The risk of transmission of Mycobacterium tuberculosis at the bedside and during autopsy. Ann Intern Med 1995; 15:955–956. 75. Miller-Leiden S, Lobascio C, Nazaroff WW, Macher JM. Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control. J Air Waste Manage Assoc 1996; 46(9):869–882. 76. Shechmeister I. Sterilization by ultraviolet irradiation. In: Block S, ed. Disinfection, Sterilization, and Preservation. 4th ed. Philadelphia: Lea and Febiger, 1991:553–565. 77. Bruls W. Transmission of human epidermis and stratum corneum as a function of thickness in the ultraviolet and visible wavelengths. Photochem Photobiol 1984; 40:485–494. 78. Sterenborg H. The dose-response relationship of tumorgenesis by ultraviolet radiation of 254 nm. Photochem Photobiol 1988; 47:245–253. 79. Cancer IAfRo. IARC Monographs on the Evaluation of Carcinogenic Effects to Humans: Solar and Ultraviolet Light. Lyons, France: World Health Organization, 1992. 80. Sliney D. Ultraviolet radiation and the eye. In: Grandolfo M, ed. Light, Lasers and Synchrotron Radiation. New York: Plenum Press, 1990:237–242. 81. Riley R, Nardell E. Clearing the air: the theory and application of ultraviolet air disinfection. Am Rev Respir Dis 1989; 139:1286–1294. 82. Luckiesch M. Application of Germicidal, Erythemal, and Infrared Energy. New York: D. Van Nostrand, 1946. 83. Riley R, Permutt S, Kaufman J. Conection, air mixing, and ultraviolet air disinfection in rooms. Arch Environ Health 1971; 22:200–207. 84. Riley R, Permutt S. Room air disinfection by ultraviolet irradiation of upper air–air mixing and germicidal effectiveness. Arch Environ Health 1971; 22:208–219. 85. Riley R, Permutt S, Kaufman J. Room air disinfection by ultraviolet irradiation of upper room air. Arch Environ Health 1971; 23:35–40. 86. First M, Nardell E, Chaission W, Riley R. Guidelines for the application of upperroom ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part I: basic principles. ASHRAE Trans 1999; 105. In press. 87. First M, Nardell E, Chaission W, Riley R. Guidelines for the application of upperroom ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part II: design and operations gudidance. ASRAE Trans 1999; 105. In press. 88. Ritacco V, DiLonardo M, Reniero M, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997; 176:637–642. 89. Banatvala N. Big problems in Moldova: eBMJ (website:htp://www.bmj.com/cgi/ eletters/317/7159/671), 1998. 90. Koornhof HJ, Fourie PB, Weyer K, Blumberg L, Pearse J. Prevention of the transmission of tuberculosis in health-care workers in South Africa. Infect Control (South Africa) 1996; 1(1):6–9. 91. Control of tuberculosis transmission in health care settings. A joint statement of the WHO Tuberculosis Programme and the International Union Against Tuberculosis and Lung Disease (IUATLD). Wkly Epidemiol Rec 1993; 68(50):369–371. 92. Pablos-Mendes A, Raviglione M, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. N Engl J Med 1998; 338:1641–1649.

10 Pathogenesis of Tuberculosis

WILLY F. PIESSENS

EDWARD A. NARDELL

Harvard School of Public Health Harvard Medical School Boston, Massachusetts

Harvard Medical School Cambridge Hospital and Massachusetts Department of Public Health Cambridge and Boston, Massachusetts

I. Introduction Host immune responses determine to a large extent the ultimate outcome of infection with Mycobacterium tuberculosis in at least two disparate ways: by participating in the resistance to the pathogen and by contributing to the development of disease. Thus, a better understanding of the cellular and molecular components of the immune system that mediate and regulate these beneficial and deleterious phenomena should lead to improved and novel approaches to the diagnosis, prevention, and control of human tuberculosis. In this chapter the mechanisms of innate and acquired resistance to M. tuberculosis, various strategies used by tubercle bacilli to survive in this hostile environment, and the nature of host immune responses with pathogenic potential are reviewed. The emphasis of this chapter is on studies done in human beings or with cells and materials from human donors. Data from animal models are reviewed only when similar studies have not yet been, or cannot be, performed in humans or to highlight contrasts between animal and human data that illustrate the inherent limitations of animal models of tuberculosis. The chapter also describes some of the changes in host immune responses to tubercle bacilli resulting from coinfection with HIV. However, it is not intended to be a comprehen241

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sive review of the complex interplay of these two life-threatening infections (see Chap. 20). For simplicity and convenience, we have used the chronology of a prototypical infection to organize the topics reviewed in this chapter. Educated readers will easily recognize that our outline follows the conceptual framework of the pathogenesis of tuberculosis first described by Dannenberg (1), to whom we dedicate this chapter. II. Stage 1 (Week 1): Invasion Tuberculosis infection can be initiated by ingesting, inoculating, or inhaling virulent mycobacteria, but inhalation of droplet nuclei containing tubercle bacilli is by far the most common route of infection. Ordinarily, large droplets are efficiently excluded from the lower respiratory tract, as they land on the ciliated epithelium of the airways, are carried up the mucociliary escalator, swallowed, and rendered harmless. The bronchial epithelium also appears highly resistant to infection by M. tuberculosis. Thus, in most cases virulent mycobacteria must reach the alveolar surface to begin infection through inhalation of droplet nuclei that are small enough (~1–2 m) to reach the lower respiratory tract. Three main factors determine whether exposure to tubercle bacilli results in infection: the infecting dose, the strength of innate host resistance, and the virulence of the infecting mycobacteria. The outcome of the initial contest between the host and M. tuberculosis determines whether infection occurs. If the bacilli are inhibited or killed by the alveolar macrophage that ingested it, infection is aborted. If not, ingested bacilli multiply, kill the alveolar macrophage, and initiate infection. A. Infecting Dose

This subject is discussed in greater detail in Chapter 9. In contrast to many other respiratory infections, the infecting dose needed to initiate human tuberculosis is largely unknown. Experimentally, a single inhaled droplet nucleus containing no more than one to three virulent organisms is sufficient to cause infection in guinea pigs and susceptible strains of inbred rabbits (2,3). It is unknown whether the same is true in human tuberculosis. A single droplet nucleus might cause infection if it contains fully virulent mycobacteria and is implanted in a site where perchance local innate resistance is low, such as in the vulnerable apical or subapical region of the lungs (see below). On the other hand, it has been assumed that inhalation of many droplet nuclei may be necessary to cause infection in innately resistant individuals. Multiple or recurrent inhalations are unlikely, however, unless exposure is prolonged or at close range or the source case is unusually infectious. Under ordinary exposure conditions the concentration of droplet nuclei in the air is extremely low: it averaged only 1 in 312 cubic meters in air exhausted from a tuberculosis ward over a 4-year period (4).

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B. Innate Host Resistance

Resident alveolar macrophages derived from blood monocytes are the first line of defense against pulmonary tuberculosis. These phagocytic cells scavenge the alveolar surface and ingest inhaled organisms and particles. The innate bacteriostatic and bacteriocidal activities of alveolar macrophages vary with the cells’ state of activation, which in turn is influenced by the genetics of the host and by multiple factors in the cells’ milieu. Mycobacteria are ingested by alveolar macrophages via conventional receptor-mediated phagocytosis, in which cellular pseudopodia move circumferentially around the bacilli and then fuse, leaving M. tuberculosis in a membranelined vacuole, the phagosome. The bacillus is a passive participant in the invasion process. Alveolar and other types of mononuclear phagocytes possess many different receptors involved in phagocytosis of various particles and pathogens. IgG antibody–coated mycobacteria can be ingested via Fc receptors on macrophages, but when the host has no antibodies to M. tuberculosis, the principal receptors that mediate phagocytosis of tubercle bacilli by human monocytes and macrophages are the receptors for complement (CR1, CR3, and CR4) and for mannose (5). Lung macrophages secrete complement proteins into the alveolar fluid (6). Complement receptors interact with C3 deposited on M. tuberculosis when the bacterial surface glycolipid trehalose dimycolate (cord factor) activates the alternative complement pathway or when pathogenic mycobacteria recruit C2a directly to form a C3 convertase (7,8). Mannose receptors interact with terminal mannosyl units on the major bacterial surface lipoglycan, lipoarabinomannan (LAM) (9). It has been shown that LAM can also bind to the endotoxin receptor CD14 and that sulfatides from M. tuberculosis can bind to scavenger receptors, but it is unclear whether these receptors by themselves can mediate phagocytosis of tubercle bacilli by alveolar macrophages. Cooperation between distinct types of receptors may be required for optimal binding and ingestion of tubercle bacilli. Which receptors are used for phagocytosis of M. tuberculosis may also be influenced by the state of differentiation and activation of the macrophage. The expression of CR4 and mannose receptors increases and the abundance of CR3 decreases as monocytes mature into tissue and alveolar macrophages. In addition, several host molecules modulate the interaction of complement and mannose receptors with their ligands and therefore can augment the baseline activity of alveolar macrophages. Some of these molecules are present before acquired immunity develops and thus modulate innate resistance. For example, human surfactant protein A (SP-A), which regulates the level of lung surfactant, enhances phagocytosis of M. tuberculosis by alveolar macrophages (10). SP-A is a member of the collectin family of proteins that participate in various aspects of innate resistance (11). Activation of macrophages by cytokines from M. tuberculosis–specific T cells will be discussed below in the context of acquired immunity.

244 Table 1

Piessens and Nardell Bactericidal Effector Mechanisms of Phagocytes

1. Oxygen-dependent mechanisms: The respiratory burst generates superoxide anion, hydrogen peroxide, singlet oxygen, and hydroxyl radicals. The efficiency of hydrogen peroxide as a microbicidal agent is increased in the presence of halide and peroxidase. [If Cl is present, hypochlorite (bleach) is formed.] 2. Lysosomal mechanisms: Lysosomes contain hydrolytic enzymes and other ill-characterized antimicrobial substances. 3. Peptide antibiotics: These proteins and peptides kill bacteria in a manner that does not depend on enzymatic activity. The group includes defensins, cationic antimicrobial proteins, bactenecins, and permeability-increasing protein. 4. Iron chelators: Molecules such as lactoferrin and transferrin inhibit the growth of intracellular pathogens by sequestering intracellular iron. 5. Polyamines: Oxidative deamination of polyamines such as spermine and spermidine produces the toxic molecules aminoaldehyde, ammonia, and hydrogen peroxide. 6. Tryptophan degradation: Enzymatic degradation of tryptophan depletes an essential nutrient and produces picolonic acid, which acts synergistically with IFN- to activate macrophages. 7. Reactive nitrogen oxides (RNOs) and intermediates (RNIs): Enzymatic conversion of Larginine into citrulline generates nitric oxide and related nitrogen intermediates. Their biological effects are similar to those of reactive oxygen intermediates.

Mononuclear phagocytes have a large repertoire of mechanisms that can kill intracellular organisms. It has not been unequivocally demonstrated that human macrophages can kill or inhibit the replication of M. tuberculosis in vitro, but some of the effector mechanisms implicated by studies in animal models can be activated in human macrophages and, therefore, may contribute to antitubercular activity in vivo. Table 1 lists the major types of antibacterial effector mechanisms of phagocytic cells. A detailed review of these mechanisms and of the evidence for or against their involvement in antitubercular activity has been published recently (12), but some points deserve emphasis. First, while important in mice, the role of reactive nitrogen intermediates (RNIs) in the antibacterial activity of human macrophages remains controversial. Antimicrobial effector mechanisms are also considerably redundant (Table 1), and it is likely that different combinations of them act in concert to control a given pathogen. The dominant effector mechanism in human tuberculosis also may change over time and in different settings depending on the phenotypes of both the mycobacteria and the mononuclear phagocytes change. Indeed, M. tuberculosis isolates vary in their susceptibility to hydrogen peroxide and RNIs, and the state of differentiation and activation of blood-derived alveolar macrophages affects the cells’ ability to control the growth of virulent pathogens.

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C. Bacillary Virulence

Virulent tubercle bacilli have evolved a wide range of mechanisms to resist hostdefense mechanisms. Historically, many different criteria have been used to define the virulence of nycobacteria. Most relevant to the early phase of infection are factors and mechanisms that allow mycobacteria to survive within alveolar macrophages. Several of these have been described (Table 2) (13,14). A DNA fragment of M. tuberculosis that is associated with entry and survival of bacilli inside nonphagocytic cells has been identified and cloned (15). Its mode of action is unknown, but different parts of the “invasion gene” encode the factors responsible for entry and survival. Mutation of a different gene causes loss of virulence in a strain of the M. tuberculosis complex (16). Particles phagocytosed by macrophages normally are routed to acidic lysosomal compartments for degradation. Mycobacteria avoid this fate in several ways. Sulfatides and other cell-surface components of M. tuberculosis can inhibit the fusion of lysosomes with phagosomes (17). Tubercle bacilli also selectively inhibit the fusion of phagocytic vacuoles with vesicles containing the proton-ATPase (which is involved in phagosomal acidification) and thus prevent the normal evolution of a phagosome into an acidified hydrolase-rich compartment in which engulfed pathogens ordinarily are digested (18). Other studies suggest that M. tuberculosis escapes from fused phagolysosomes into nonfused vesicles or the cytoplasm, where virulent but not avirulent bacilli are able to multiply (19). Mycobacteria also resist digestion by scavenging O2 with LAM, by inducing detoxifying enzymes such as catalase and superoxide dismutase and protective heat-shock proteins, and by resisting RNIs via unknown mechanisms (12,20,21). Mycobacterial LAM interferes with cell signaling pathways, inhibits macrophage activation by interferon (IFN)-, and stimulates the production of cy-

Table 2

Mechanisms of Intracellular Survival of Mycobacteria

1. Invasion gene: A DNA fragment associated with entry and survival of M. tuberculosis inside cells has been cloned. Its mode of action is unknown. 2. Inhibition of lysosome-phagosome fusion: Both complete and selective inhibitions of lysosome-phagosome fusion have been reported. 3. Escape into the cytoplasm: Both avirulent and virulent M. tuberculosis appear capable of escaping from phagolysosomes, but only virulent bacilli multiply in the cytoplasm. 4. Inactivation of toxic effector molecules: LAM scavenges O 2; virulent bacilli induce detoxifying enzymes such as catalase and superoxide dismutase and protective heatshock proteins and resist RNIs. 5. Macrophage deactivation: LAM blocks macrophage activation by IFN- by stimulating the production of inhibitory cytokines such as transforming growth factor (TGF- ) and interleukin (IL)-10.

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tokines such as transforming growth factor (TGF- )- and interleukin (IL)-10, which inhibit macrophage functions (22,23). Infected macrophages also poorly present mycobacterial antigens to T cells and thereby promote suboptimal immune responses or even immune tolerance (24). D. Innate Resistance and Variation in Susceptibility to Tuberculosis

Studies on familial clustering and twins suggest that susceptibility to tuberculosis has a genetic component, but the biological basis of the increased risk remains unknown. It is also well known that certain populations suffer disproportionately from tuberculosis. Often this can be explained by high exposure to the pathogen (as in nosocomial infections) or a high rate of progression to active disease due to a variety of circumstances that impact on acquired immunity (as in AIDS). The basis of other empirical observations remains controversial. It has been reported, for example, that the high incidence of tuberculosis among African Americans has a biological basis, namely that it reflects racial differences in susceptibility to initial tuberculosis infection (25). Others contest this explanation because it is difficult to separate biological from socioeconomic and demographic risk factors associated with race (26–28). This is perhaps best illustrated by the finding that racial differences in susceptibility to infection were observed among elderly residents of nursing homes but not during an outbreak of tuberculosis in a primary school (25,29). Nevertheless, evidence that genetic variation in innate resistance may contribute to racial differences in the prevalence of tuberculosis is accumulating. The natural resistance of mice to infection with several intracellular pathogens is controlled by a single autosomal dominant gene, Bcg (30). Mice with the resistant allele of the gene (Bcgr ) control the growth of BCG Montreal during the first 3 weeks of infection. This form of innate resistance occurs before acquired immunity develops and does not require BCG-specific T cells. In mice with the sensitive phenotype, the initial growth of BCG Montreal is unchecked, but the infection is controlled at a later stage by T-cell–dependent immune effector mechanisms. The mouse gene, which has been renamed the gene for natural-resistanceassociated macrophage protein 1 (Nramp 1), encodes an integral membrane protein that is expressed only in a late endocytic subcellular compartment. Upon phagocytosis, the protein is recruited to the membrane of the phagosome and remains associated with this structure as it matures into a phagolysosome. The Nramp 1 protein is part of a group of ion transporters or channels; it may eliminate divalent cations from the phagosomal interior and thereby deplete this compartment from essential cofactors for many enzymes (30). Humans have a homolog of the mouse gene on chromosome 2q35. Four polymorphisms in the human NRAMP1 gene are significantly associated with

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susceptibility to tuberculosis in West Africa (31). One of the variant NRAMP1 alleles associated with susceptibility to tuberculosis is very uncommon in European populations. This may explain in part the higher prevalence of tuberculosis among African Americans than among whites in the United States. The possibility of a Bcgs gene–like effect in human macrophages had been previously suggested by the observation that virulent tubercle bacilli replicate faster within unstimulated macrophages of African American than of white donors (32). However, the differential permissiveness observed in vitro may have a phenotypic rather than a genetic underpinning, because the difference is magnified when the cells are cultured in medium supplemented with autologous serum, and the permissiveness of macrophages from African American donors is corrected by addition of 1, 25OH 2 D3, a hormonally active form of vitamin D, to the in vitro cultures. In mice, the Bcg gene also controls early growth of M. lepraemurium, M. intracellulare, and two other intracellular pathogens, Salmonella typhimurium and Leishmania donovani, but not of BCG Pasteur or of virulent M. tuberculosis. Thus, variation in macrophage activity is not the only biological basis for the differential susceptibility of mouse strains to infection with various mycobacteria. Innate resistance of mice to M. tuberculosis is dependent on the presence of the Tbc-1 gene, the function of which remains unknown (33). A recent report associates an HLA-DQ allele with clinical tuberculosis, but this phenotype is likely to influence acquired rather than innate resistance to infection (34). Of note, the biological basis for the differential resistance of inbred rabbit strains developed by Lurie is unknown (2). E. Initial Infection Among HIV-Infected Persons

Several outbreaks of tuberculosis (TB) in which transmission from an index case within a known period of exposure could be documented have been reported. These outbreaks clearly show that some persons immunocompromised by HIV infection who secondarily become infected with TB progress rapidly to clinical disease, often with multiorgan involvement (35–38). This extraordinarily rapid rate of progression to active disease may reflect the inability of HIV-infected individuals to develop immune resistance to tuberculosis (39). However, these outbreaks also document higher-than-expected infection rates (actual intensity of exposure was not measured or estimated in the reports) and thus suggest that HIV infection also lowers the host’s innate resistance to a primary infection with tubercle bacilli. A report on airborne nosocomial transmission of M. bovis is consistent with this hypothesis (40). HIV has pleotropic effects on virus-infected macrophages that affect the cells’ phenotype and functions during progression of HIV infection (39,41). The virus alters the pattern of cytokine production, impairs the ability of monocytes and macrophages to serve as accessory cells for T-cell proliferation, and affects the elaboration by resident macrophages of proinflammatory leukotrienes and other 5-lipoxygenase metabolites of arachidonic acid (42,43). The resulting decrease in

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macrophage activating cytokines (e.g., IL-12) and the concomitant increase in deactivating cytokines (e.g., IL-10) combined with defects in chemotaxis, receptormediated phagocytosis, and oxidative burst activity (44,45) may very well reduce innate resistance of alveolar macrophages and thereby increase the risk of primary infections with M. tuberculosis in HIV-infected subjects (see also Chap. 20). III. Stage 2 (Weeks 2 and 3): Logarithmic Bacillary Growth and the Early Tuberculous Lesion A. Logarithmic Bacillary Growth

When the innate microbicidal capacity of alveolar macrophages fails to destroy the initial few M. tuberculosis of the droplet nucleus, the tubercle bacilli replicate within the macrophage and cause the cell to rupture. Released bacilli are then taken up by other macrophages in the vicinity. Monocytes in the circulation are attracted to the focus and develop into immature macrophages. The latter cells readily ingest the released tubercle bacilli but appear incapable of killing virulent M. tuberculosis or inhibiting their growth. Thus, the bacillary multiplication cycle is repeated within immature phagocytes. In both innately resistant and susceptible inbred rabbits, tubercle bacilli grow logarithmically during the first 3 weeks after infection until about 10 4 organisms are present and local cell-mediated immune responses are triggered (2). In both immunized and nonimmunized guinea pigs, bacillary growth is unimpeded for about 2 weeks until approximately 103 organisms are present. At this point, growth is inhibited in vaccinated animals but continues in nonvaccinated animals until a larger antigenic stimulus triggers cell-mediated immunity that controls the infection (46). B. The Early Tuberculous Lesion

Successive waves of intracellular multiplication followed by lysis of the infected macrophages lead to the formation and enlargement of the primary lesion. Early lesions consist mostly of concentric layers of immature macrophages containing mycobacteria. Mice, hamsters, guinea pigs, rabbits, and humans all develop histologically similar reactions to inhaled virulent or avirulent strains of tubercle bacilli during the first 3 weeks of infection (47). C. Bacillary Dissemination

During the stage of uncontrolled growth, some mycobacteria are transported to draining lymph nodes where the pathological process is repeated. The initial lesion and its inflamed draining lymph nodes form the so-called primary complex of tuberculosis. Bacilli also widely disperse to distant metastatic sites via the bloodstream. The propensity of human tubercle bacilli for hematogenous dissem-

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ination to the spleen and lungs in guinea pigs is considered a measure of intrinsic virulence of M. tuberculosis isolates. IV. Stage 3 (After Week 3): Infection Control A. Control of Bacillary Growth

After about 3 weeks, the growth of tubercle bacilli rather suddenly ceases in both susceptible and resistant rabbits and in other animals infected via aerosol. This coincides with the development of acquired immune resistance and the formation of characteristic tuberculous granulomas. Traditionally, the terms of cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH) have been used to describe two distinct processes. CMI refers to the cell-mediated immune process that results in the accumulation of large numbers of activated microbicidal macrophages around solid caseous tuberculous foci. Delayed-type hypersensitivity refers to the cytotoxic immune process that kills the nonactivated immature macrophages that permit intracellular multiplication of tubercle bacilli (48). Despite much debate over details, the prevailing view in the past was the CMI is the main effector mechanism of acquired immunity and that DTH is the major cause of lung damage in tuberculosis (49,50). Advances in basic and applied immunology indicate that this classic concept is only partially correct. Cell depletion and reconstitution studies and observations in animals with spontaneous or genetically engineered defects [so-called gene knock-outs (gKO)] in specific components of the immune system clearly indicate that, at least in mice, acquired immunity to M. tuberculosis is mediated by two different effector pathways (51–53). The first pathway, intracellular killing of M. tuberculosis by macrophages that have been activated by cytokines, corresponds to the traditional CMI process. The major source of macrophage-activating cytokines are Th1-like, CD4 CD8 T-helper cells. These lymphocytes produce the cytokines when activated by the binding of mycobacterial antigen to the cells’ specific T-cell receptor for antigen (TCR) plus an appropriate second signal from the antigen-presenting cell. Neutralization and gKO experiments indicate that both IFN- and TNF- are essential cytokines for resistance of mice to primary mycobacterial infections and that intracellular killing in this model is mediated primarily by NO/RNIs (53). Recent reports of disseminated mycobacterial infections in children with IFN- receptor 1 deficiency suggest that this cytokine is important in the control of human tuberculosis as well (54,55). IFN- has been used with success to treat human tuberculosis and nontuberculous mycobacterial infections (56,57). However, the in vivo activity of IFN- may be due to effects other than the activation of macrophages by the cytokine, because IFN- inconsistently stimulates the ability of human macrophages mycobacteria in vitro (58–60). As noted earlier, the role of RNIs in the killing of M. tuberculosis by human macrophages remains uncertain.

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In the second pathway, M. tuberculosis–infected macrophages are killed by cytolytic T lymphocytes (CTL). This DTH-like process benefits the host by destroying immature macrophages that provide a permissive environment for bacillary growth. The liberated tubercle bacilli can survive for many years extracellulary, but they are unable to multiply in the solid caseous necrotic material that forms the center of the developing granuloma. Released bacilli can also be ingested and killed by T-cell–activated macrophages in the vicinity and killed intracellularly. Several types of M. tuberculosis–specific CTL have been described. Some are classic CD4 CD8 CTL that recognize mycobacterial antigens presented by infected macrophages in the context of class I major histocompatibility complex (MHC) determinants. Other CTL are CD4 CD8 killer T cells, which appear to be more common in mycobacterioses than in other infections with intracellular pathogens (61). CD4 CTL recognize bacterial antigens, including the 65 kDa heat-shock protein of M. tuberculosis, that are complexed to MHC class II determinants on the target macrophages. The cells kill infected target cells by inducing Fas-mediated apoptosis; the latter process also can reduce the viability of intracellular M. tuberculosis (62). Yet another CTL subset recognizes antigen in the context of CD1, a MHC-like surface molecule with a unique ability to present nonpeptide antigens to T cells, including mycobacterial lipids. CD4 CD8 CD1restricted CTL induce apoptosis of infected macrophages but have no effect on the viability of the mycobacteria. CD8 CD1-restricted CTL lyse infected macrophages by a granule-dependent mechanism that also kills the mycobacteria (63). Because CD1-restricted T cells lack CD4, they are not infectable with HIV and therefore may play an important role in patients with AIDS (64). Of note, infected alveolar macrophages are relatively resistant to CTL (61). Other cells, including T cells with the variant of the TCR and natural killer (NK) cells, may contribute to the overall strength of acquired immunity to tuberculosis. However, studies in mice suggest that these cell populations are not essential for resistance to primary M. tuberculosis infections. These cells may play an immunoregulatory role by promoting Th0 to Th1 development of T-helper cells and thus expanding the pool of T cells capable of producing macrophage-activating cytokines (65). Alternatively, T cells influence local cellular traffic to tuberculous lesions by promoting the influx of monocytes and lymphocytes and limiting the inflow of other inflammatory cells that do not contribute to protection but may cause tissue damage (66). Observations in animal models suggest that the relative importance of activated macrophages and CTL in the control of primary tuberculosis may vary over time. Whether the same is true in human tuberculosis is unknown. Regardless of the underlying mechanisms, the bacillary population in the normal host remains stable, as growth is counterbalanced by bacillary destruction and inhibition. It is believed that the primary complex and most of the metastatic sites gradually become sterile over time. However, in “vulnerable” regions of the lungs (67) and other or-

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gans, caseation necrosis reduces the bacillary population to a low level of organisms that remain dormant and viable, but the immune response does not sterilize the lesion. This leaves behind bacilli that may later reactivate (68). The biological mechanisms leading to latency in M. tuberculosis remain poorly understood (69). B. The Caseous Tuberculous Granuloma

In a typical tuberculous granuloma, activated “mature” macrophages accumulate around a caseous lesion and prevent its further extension (2,70). Tuberculin-like products secreted by intracellular bacilli are thought to be important early stimulants of caseous necrosis, which involves several poorly defined processes in addition to the so-called DTH reaction that kills immature infected macrophages of the early lesion. Some processes implicated in caseous necrosis are listed in Table 3, but direct evidence supporting their postulated role in the process is scant. The activated macrophages within tuberculous granulomas are derived from bloodborne monocytes. Turnover rates of these cells are high in early lesions and decline over time as the reaction subsides and a steady state is reached. The chemotactic stimuli leading to macrophage extravasation into tuberculous granulomas have not yet been identified, but they likely include chemokines such as monocyte chemoattractant protein (MCP)-1 and IL-8, which are secreted by monocytes and alveolar

Table 3

Mechanisms Implicated in Caseous Necrosis

1. “Targeted” killing of infected host cells: Exuberant killing of infected macrophages presenting mycobacterial antigens by M. tuberculosis–specific CTL. 2. “Bystander” killing of host cells: Uninfected cells can be killed by locally high concentrations of cytokines with cytotoxic potential (e.g., TNF- , TGF- ) or bacteriostatic effector molecules (e.g., NO). Caseating necrosis is present in mice treated with antisera to TNF- , even though the number of organisms in the lesions is only marginally increased. The possible therapeutic use of thalidomide, a specific inhibitor of TNF- mRNA expression, is under investigation. Alternatively, cells in the center of the granuloma degenerate because they are exposed to concentrations of cytokines that are too low to suppress mycobacterial growth. 3. Ischemia from thrombosed blood vessels: Activated macrophages produce procoagulant factors; so-called tissue factors released by damaged host cells can also activate the clotting system. 4. Complement-mediated cell damage: Locally formed antigen-antibody immune complexes may trigger this reaction. 5. Cell and tissue digestion by enzymes: Hydrolytic proteases and lipases released by activated macrophages and other dying host cells may damage surrounding tissues. 6. Cytopathic effects: Some components of M. tuberculosis (e.g., cord factor, M. tuberculosis virulence gene product) may be toxic for host cells.

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epithelial cells infected with M. tuberculosis (71–73). Levels of IL-8 are elevated in bronchoalveolar lavage fluid from patients with pulmonary tuberculosis (74). Caseous granulomas in the lung are microscopic or barely visible during the first 4 or 5 weeks of infection. Lung lesions in resistant rabbits contain relatively few bacilli, some lymphocytes, many activated macrophages (also called mature epithelioid cells), multinucleated giant (Langhans’) cells, and relatively little necrosis. Lesions in susceptible rabbits contain many bacilli and few activated macrophages and are more necrotic (2,48). At the sites of lymphohematogenous dissemination, accelerated tubercle formation in resistant rabbits rapidly controls the metastatic foci with minimal necrosis, whereas bacillary growth leads to progressively caseating foci in susceptible animals. Ultimately, susceptible rabbits died of disseminated tuberculosis, not unlike tuberculosis patients with AIDS. Studies of tuberculous adenitis in HIV-infected persons confirm the important role of T cells in granuloma formation (75). When CD4 counts exceed 200/L, epithelioid and giant cells (i.e., activated macrophages) are present in the granulomas. When CD4 counts are lower, the lesions are less organized, more necrotic, and contain foamy macrophages. Memory CTL and NK cells present in normal granulomas are replaced with virgin CD8 cells and granulocytes in the necrotic lesions. Studies in gKO mice indicate that TNF- and IFN- are essential for granuloma formation. These cytokines are not sufficient, however, because their levels are elevated in SCID mice that do not develop tuberculous granulomas (53). Administration of exogenous TNF receptor 1 not only prevents the formation but also causes the disappearance of established granulomas in mice, an observation that might have therapeutic implications for the future (76). Thalidomide treatment decreases TNF- production by monocytes from tuberculosis patients and reduces the systemic toxicity of the cytokine without inhibiting CMI (77). Mice with gKO of ICAM-1 are unable to form granulomas but are resistant to primary infection with M. tuberculosis, suggesting that intercellular adherence through this molecule is required for the morphogenesis of a typical tuberculoid granuloma (78). V. Stage 4 (Months to Years Later): Endogenous Reactivation and Transmission A. Tissue Liquefaction and Cavitation

Liquefaction, the end stage of caseation, is believed to result mainly from the progressive hydrolysis of protein, lipid, and nucleic acid components of caseated tissues by hydrolytic enzymes from host cells and/or mycobacteria. Exactly what triggers the onset of liquefaction is unknown, but mycobacterial “toxins” are believed to play an important role (79). Observations in mice are consistent with this notion. In contrast to normal control mice, mice with gKOs of CD8 or IFN- fail to control infection and empty their tuberculous lesions into bronchi much in the same manner as Lurie’s rabbits. Host factors also contribute to tissue damage.

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Langhans’ and epithelioid cells in tuberculous granulomas express mRNA for TGF- . Thus, local production of TGF- may directly cause immunopathology (80). It has also been suggested that tubercle bacilli increase the sensitivity of host cells to the cytolytic effect of TNF- , and thereby predispose to tissue damage via a mechanism akin to the Koch phenomenon (81). When a liquefied caseous lesion discharges its contents into a nearby bronchus, a cavity is formed—the characteristic radiographic and pathological presentation of tuberculosis and other chronic, granulomatous infections. The local inflammatory response to the sudden spillage of necrotic, highly antigenic, infectious liquid within the lungs is recognized clinically as a tuberculous pneumonitis. Cavitation is largely responsible for the transmission and perpetuation of human tuberculosis. B. Resumption of Bacterial Growth

In most infected persons, the immune response maintains the bacillary population in “reactivatable sites” in a steady-state dormant level. The continuous release of small amounts of mycobacterial antigens from caseated granulomas presumably maintains both tuberculin reactivity and protective immunity, which are separate phenomena (82). When some event—stress, treatment with steroids or chemotherapeutic drugs, HIV infection, alcohol, malnutrition, etc.—perturbs this equilibrium, liquefaction of the caseous center of the granuloma permits extracellular growth and multiplication of M. tuberculosis. Several cytokines and other host factors can “deactivate” macrophages and thereby promote mycobacterial growth (Table 4). Presumably, host defenses are inoperative within liquefied necrotic tisTable 4 Effect of Cytokines and Other Mononuclear Cell Products on Macrophage Activation for M. Tuberculosis Control Activating molecules

Deactivating molecules

IL-2 IL-4 IL-7 IL-12 GM-CSF TNFTFNIFN1,25-(OH)2D3 (Calcitriol)

IL-1 IL-3 IL-6 IL-10 TGFProstaglandin E2

Information shown is based on a variety of models for human tuberculosis. Source: Adapted from Refs. 22, 85, 86.

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sue, but the cavitary fluid permits extracellular multiplication of mycobacteria, of which large numbers accumulate in tuberculous cavities (108 in Lurie’s rabbits). Given the baseline mutation rate in mycobacteria, this favors the emergence of drug-resistant tubercle bacilli. VI. Clinical Correlates of Immune Events in Human Tuberculosis In most immune-competent persons, primary tuberculosis is a subclinical infection or a mild self-limited illness that does not proceed past the third stage in the pathogenic scheme described in this chapter. Although progressive primary disease occasionally leads to cavitary tuberculosis, this outcome usually results from a second (postprimary) phase of disease activity that occurs months to decades after apparent recovery from the initial infectious process. As was noted above, it is unclear what event triggers this endogenous reactivation at the cellular and molecular level, but many known risk factors for development of clinical tuberculosis adversely affect the human immune system. Once a subject of considerable debate, “fingerprinting” mycobacteria by genetic methods (see Chap. 11) clearly indicates that exogenous (re)infection can also lead to cavitary tuberculosis. The relative frequency of endogenous reactivation and exogenous reinfection as the cause of cavitary tuberculosis is likely to vary with the local prevalence of infection, the former being more common in situations of low prevalence and vice versa. Even though they lead to the same clinical endpoint, distinguishing the two pathogenic pathways may be important for optimal management of tuberculosis. Primary tuberculous lesions occur throughout the lungs but are most common in the lower lobes because of the air flow distribution; postprimary disease occurs most commonly in the upper parts of the lung (83). To explain the existence of this so-called “vulnerable region,” Medlar postulated that foci in the apical region of the lung are incompletely sterilized by lung defenses, whereas other sites elsewhere become sterile (67). Smith and coworkers later hypothesized that tubercle bacilli reach the upper lung through lymphohematogenous dissemination that occurs during the primary infection. During subsequent reinfection, inhaled bacteria are destroyed by long defenses, except if they are implanted directly into an airspace in the lung apex, where resistance is weak (68,84). In the guinea pig model on which this hypothesis is partially based, BCG does not protect against a primary infection but reduces the resultant bacillemia. If the same is true in human tuberculosis, BCG should reduce the odds of cavitary tuberculosis (and of metastatic extrapulmonary disease) due to endogenous reactivation but not to exogenous reinfection, a prediction consistent with the results of some human BCG trials. Liquefaction necrosis is of major public health importance because the resulting cavitation connects the infected site with the environment and thus pro-

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motes transmission of mycobacteria. It is also likely that some of the molecular components of the process that leads to cavitation (e.g., TNF- , and I1-1 from activated macrophages) contribute to the systemic symptoms of fever, weight loss, and anorexia that are associated with cavitary disease. VII. Conclusion The human immune response to M. tuberculosis is a complex reaction that is both beneficial and deleterious to the infected individual. It requires the interaction of several types of cells that cross-regulate each other’s activities via mixtures of soluble cytokines. The latter often must act in concert or sequentially to stimulate a given cellular function and may have opposing effects on different cell types. Virulent tubercle bacilli dysregulate this delicate balance and pervert some host responses to ensure their own survival. Much of our knowledge of host responses to mycobacteria is based on in vitro and animal studies. Advances in basic biology now render it possible to directly analyze immune responses in infected or diseased human tissues and body fluids. This approach should permit a reappraisal of concepts based on the older models and improve our understanding of the pathogenesis of human tuberculosis infection and disease. In turn, this should spawn improved and novel approaches to the prevention and control of tuberculosis by manipulating the host immune response to this formidable pathogen. References 1. Dannenberg AM, Jr. Pathogenesis of pulmonary tuberculosis. Am Rev Respir Dis 1982; 125:25–29. 2. Lurie MB. Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defensive Mechanisms. Cambridge, MA: Harvard University Press, 1964. 3. Ratcliffe HL. Tuberculosis induced by droplet nuclei infection: pulmonary tuberculosis of predeterminded initial intensity in mammals. Am J Hyg 1952; 55:36–48. 4. Riley RL, Mills CC, O’Grady F, Sultan LU, Wittstadt F, Shivpuri DN. Infectiousness of air from a tuberculosis ward. Am Rev Respir Dis 1962; 85:511–525. 5. Ernst JD. Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998; 66:1277–1281. 6. Fels A, Cohen ZA. The alveolar macrophage. J Appl Physiol 1986; 60:353–369. 7. Ramanathan VD, Curtis J, Turk JL. Activation of the alternative pathway of complement by mycobacteria and cord factor. Infect Immun 1980; 29:30–35. 8. Schorey JS, Carroll MC, Brown EJ. A macrophage invasion mechanism of pathogenic mycobacteria. Science 1997; 277:1091–1093. 9. Schlesinger LS, Hull SR, Kaufman TM. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J Immunol 1994; 152:4070–4079.

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43. Coffey MJ, Phare SM, Kazanjian PH, Peters-Golden M. 5-Lipoxygenase metabolism in alveolar macrophages from subjects infected with the human immunodeficiency virus. J Immunol 1996; 157:393–399. 44. Smith PD, Ohura K, Masur H, Lane HC, Fauci AS, Wahl SM. Monocyte function in the acquired immune deficiency syndrome. Defective chemotaxis. J Clin Invest 1984; 74:2121–2128. 45. Spear GT, Kessler HA, Rothberg L, Phair J, Landay AL. Decreased oxidative burst activity of monocytes from asymptomatic HIV-infected individuals. Clin Immunol Immunopathol 1990; 54:184–191. 46. Smith DW, Harding GE. Animal model of human disease. Pulmonary tuberculosis. Animal model: experimental airborne tuberculosis in the guinea pig. Am J Pathol 1977; 89:273–276. 47. Ratcliffe HL, Palladino VS. Tuberculosis induced by droplet nuclei infection. Initial homogeneous response of small mammals (rats, mice, guinea pigs, and hamsters) to human and to bovine bacilli, and rate and pattern of tubercle development. J Exp Med 1953; 97:61–68. 48. Dannenberg AM, Jr. Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis [see comments]. Immunol Today 1991; 12:228–233. 49. Rich AR. The Pathogenesis of Tuberculosis. Springfield, IL: Charles C Thomas, 1951. 50. Youmans GP. Tuberculosis. Philadelphia: W.B. Saunders, 1979. 51. Kaufmann SHE. In vitro analysis of the cellular mechanisms involved in immunity to tuberculosis. Rev Infect Dis 1989; 11 (suppl):S448–S454. 52. Orme IM. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J Immunol 1987; 138: 293–298. 53. Bloom BR, Flynn J, McDonough K, Kress Y, Chan J. Experimental approaches to mechanisms of protection and pathogenesis in M. tuberculosis infection. Immunobiol 1994; 191:526–536. 54. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996; 335:1941–1949. 55. Jouanguy E, Altare F, Lamhamedi-Cherradi S, Casanova JL. Infections in IFN R-1deficient children. J Interferon Cytokine Res 1997; 17:583–587. 56. Condos R, Rom WN, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol [see comments]. Lancet 1997; 349:1513–1515. 57. Holland SM, Eisenstein EM, Kuhns DB, et al. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report. N Engl J Med 1994; 330:1348–1355. 58. Rook GA, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57:159–163. 59. Flesch I, Kaufmann SH. Mycobacterial growth inhibition by interferon-gamma-activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis. J Immunol 1987; 138:4408–4413.

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60. Denis M. Killing of Mycobacterium tuberculosis within human monocytes: activation by cytokines and calcitriol. Clin Exp Immunol 1991; 84:200–206. 61. Tan JS, Canaday DH, Boom WH, Balaji KN, Schwander SK, Rich EA. Human alveolar T lymphocyte responses to Mycobacterium tuberculosis antigens: role for CD4 and CD8 cytotoxic T cells and relative resistance of alveolar macrophages to lysis. J Immunol 1997; 159:290–297. 62. Oddo M, Renno T, Attinger A, Bakker T, MacDonald HR, Meylan PR. Fas ligandinduced apoptosis of infected human macrophages reduces the viability of intracellular Mycobacterium tuberculosis. J Immunol 1998; 160:5448–5454. 63. Stenger S, Mazzaccaro RJ, Uyemura K, et al. Differential effects of cytolytic T cell subsets on intracellular infection. Science 1997; 276:1684–1687. 64. Gong J, Stenger S, Zack JA, et al. Isolation of mycobacterium-reactive CD1-restricted T cells from patients with human immunodeficiency virus infection. J Clin Invest 1998; 101:383–389. 65. Havlir DV, Ellner JJ, Chervenak KA, Boom WH. Selective expansion of human gamma delta T cells by monocytes infected with live Mycobacterium tuberculosis. J Clin Invest 1991; 87:729–733. 66. D’Souza CD, Cooper AM, Frank AA, Mazzaccaro RJ, Bloom BR, Orme IM. An antiinflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J Immunol 1997; 158:1217–1221. 67. Medlar EM. The pathogenesis of minimal pulmonary tuberculosis: a study of 1225 necropsies in cases of sudden and unexpected death. Am Rev Tuberc 1948; 58:583– 611. 68. Smith DW, Wiegeshaus EH. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis 1989; 11 (suppl):S385–S393. 69. Parrish NM, Dick JD, Bishai WR. Mechanisms of latency in Mycobacterium tuberculosis. Trends Microbiol 1998; 6:107–112. 70. Dannenberg AM, Jr. Roles of cytotoxic delayed-type hypersensitivity and macrophage-activating cell-mediated immunity in the pathogenesis of tuberculosis. Immunobiology 1994; 191:461–473. 71. Kasahara K, Tobe T, Tomita M, et al. Selective expression of monocyte chemotactic and activating factor/monocyte chemoattractant protein 1 in human blood monocytes by Mycobacterium tuberculosis. J Infect Dis 1994; 170:1238–1247. 72. Zhang Y, Broser M, Cohen H, et al. Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components. J Clin Invest 1995; 95:586–592. 73. Lin YG, Zhang M, Barnes PF. Chemokine production by a human alveolar epithelial cell line in response to Mycobacterium tuberculosis. Infect Immun 1998; 66:1121– 1126. 74. Law KF, Jagirdar J, Weiden MD, Bodkin M, Rom WN. Tuberculosis in HIV-positive patients: cellular response and immune activation in the lung. Am J Respir Crit Care Med 1996; 153:1377–1384. 75. Muller H, Kruger S. Immunohistochemical analysis of cell composition and in situ cytokine expression in HIV- and non-HIV-associated tuberculous lymphadenitis. Immunobiology 1994; 191:354–368.

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76. Senaldi G, Yin S, Shaklee CL, Piguet PF, Mak TW, Ulich TR. Corynebacterium parvum-and Mycobacterium bovis bacillus Calmette-Guerin-induced granuloma formation is inhibited in TNF receptor I (TNF-RI) knockout mice and by treatment with soluble TNF-RI. J Immunol 1996; 157:5022–5026. 77. Kaplan G. Cytokine regulation of disease progression in leprosy and tuberculosis. Immunobiology 1994; 191:564–568. 78. Johnson CM, Cooper AM, Frank AA, Orme IM. Adequate expression of protective immunity in the absence of granuloma formation in Mycobacterium tuberculosis-infected mice with a disruption in the intercellular adhesion molecule 1 gene. Infect Immun 1998; 66:1666–1670. 79. Dannenberg AM, Jr., Sugimoto M. Liquefaction of caseous foci in tuberculosis. Am Rev Respir Dis 1976; 113:257–259. 80. Toossi Z, Gogate P, Shiratsuchi H, Young T, Ellner JJ. Enhanced production of TGFbeta by blood monocytes from patients with active tuberculosis and presence of TGFbeta in tuberculous granulomatous lung lesions. J Immunol 1995; 154:465–473. 81. Rook GA, Stanford JL. The Koch phenomenon and the immunopathology of tuberculosis. Curr Top Microbiol Immunol 1996; 215:239–262. 82. Orme IM, Collins FM. Adoptive protection of the Mycobacterium tuberculosis-infected lung. Dissociation between cells that passively transfer protective immunity and those that transfer delayed-type hypersensitivity to tuberculin. Cell Immunol 1984; 84:113–120. 83. Sweany HC, Cook CE, Kegerreis R. A study of the position of primary cavities in pulmonary tuberculosis. Am Rev Tuberc 1931; 24:558–582. 84. Balasubramanian V, Wiegeshaus EH, Taylor BT, Smith DW. Pathogenesis of tuberculosis: pathway to apical localization [see comments]. Tuber Lung Dis 1994; 75: 168–178. 85. Sieling PA, Sakimura L, Uyemura K, et al. IL-7 in the cell-mediated immune response to a human pathogen. J Immunol 1995; 154:2775–2783. 86. Zhang M, Gately MK, Wang E, et al. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest 1994; 93:1733–1739.

11 Mycobacterial Strain Genotyping

NANCY D. CONNELL

BARRY N. KREISWIRTH

New Jersey Medical School National Tuberculosis Center and and International Center for Public Health UMDNJ–New Jersey Medical School Newark, New Jersey

Tuberculosis Center Public Health Research Institute New York, New York and International Center for Public Health Newark, New Jersey

I. Introduction Historically, the microbiological tools used to differentiate or subspeciate clinical isolates of Mycobacterium tuberculosis were based on phage and/or drug susceptibility patterns (1). The comparison of strains has evolved from analysis of protein products (phenotyping) to the analysis of genetic content (genotyping). DNAbased fingerprinting of M. tuberculosis was introduced in 1990. In the ensuing years, more than 30,000 strains have been analyzed and cataloged, and thousands of unique patterns have been identified. Molecular fingerprinting is used in a wide range of epidemiological, clinical, and basic studies to demonstrate foci of transmission in cites (6–8), nosocomial outbreaks (9–11), and congregate settings (12–14); to study transmission among high-risk populations such as HIV-positive and homeless persons (16,17); to evaluate cross-contamination in the clinical laboratory (18–20); and to analyze sequence changes as they reflect rates of molecular evolution (21,22). On the basis of restriction enzyme analysis (23), hybridization with random DNA probes (24), and, most recently, direct sequencing (21), the DNA sequence of M. tuberculosis shows strikingly little variation (see below). It is surprising that within this homogeneous background there are several variable genetic elements. 261

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One of these, IS6110, is an ideal genotyping tool, able to discriminate among thousands of clinical isolates worldwide. II. Methodologies A. DNA Fingerprinting

DNA fingerprinting is based on the distribution (both in number and location) of the target sequence in the chromosome of M. tuberculosis complex strains. Total DNA from the sample strain is digested with a restriction enzyme that cuts outside of the element, resulting in a collection of DNA fragments. Among this collection are a finite number of fragments of various lengths containing the target sequence restriction fragment length polymorphism (RFLP). The fragments are separated by size, and those fragments bearing the target sequence are identified by Southern blot analysis. Each strain contains a distinct pattern of different-sized bands marked by the target sequence, although some caveats must be invoked (see below). The most commonly used target sequence is the bacterial insertion element, IS6110 (4). This mobile genetic element is 1355 bp in size, has an imperfect 28 bp inverted repeat, and generates a 3- to 4-bp target duplication upon insertion. It is present in 0–30 copies in the M. tuberculosis complex genome. In San Francisco, clinical strains of M. tuberculosis lacking IS6110 are estimated to occur at a frequency of less than 1% (25). The laboratory strain H37Rv, whose genome has been sequenced (26), contains 17 copies of IS6110. The IS6110 RFLP pattern of H37Rv is illustrated in Figure 1, lane 20. Pulsed field gel electrophoretic analysis and physical mapping of IS6110 copies in the chromosome of strain H37Rv have provided evidence that these insertions are randomly dispersed around the chromosome (26,27). The genomic context of these elements is the subject of several recent studies and will be discussed below. Other genetic markers used for RFLP analysis include a second insertion element, IS1081, first identified in M. bovis and shown to be present in members of the M. tuberculosis complex strains (28). Also useful are the repeated elements such as the DR (direct repeat) locus (29) (see spoligotyping, below), MPTR (major polymorphic tandem repeats) (30), and PGRS (polymorphic GC-rich repetitive sequence). B. Polymerase Chain Reaction

There are a number of fingerprinting techniques that exploit polymerase chain reaction (PCR) amplification. Using nucleotide primers of sequence derived from IS6110, for example, yields products using template concentrations as low as 10 pg. The DNA sequence of these products reveals priming from one of the IS6110 elements at one end and nonspecific sites in the chromosome at the other (17,31). PCR with random primers has also been used to analyze clustered cases (24).

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Figure 1 IS6110-based DNA fingerprint patterns from the collection of isolates of Mycobacterium tuberculosis maintained by the Public Health Research Institute, New York. Molecular weight makers are along the right margin. Lanes 1–12 are examples of the W strain group from various locales, as follows: 1–2, Singapore; 3–7, Russia; 8, Kenya; 9–11, New York City; 12, New Jersey. Lanes 13–19 are strains reflecting the range of RFLP fingerprint patterns found in New York City, with the exception of lane 14, the U strain, which is from New Jersey. Lane 20 shows the fingerprint pattern of Mycobacterium tuberculosis H37Rv, a laboratory strain.

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The analysis of drug-resistant isolates of M. tuberculosis on the basis of comparing the sequence of resistance genes has proven to be a very precise genotyping tool. Single-strand conformational polymorphism (SSCP) has distinguished strains on the basis of differences in the rpoB region among rifampin-resistant strains (32) and gyrA among quinolone-resistant strains (33) A more direct method uses PCR amplicons derived from drug-resistant isolates followed by automated sequencing. The finding that 21 rpoB genes sequenced from W-type strains have identical base pair changes supports the notion that these strains are clonal and are derived from a common ancestor (see below). D. Spoligotyping (Spacer Oligotyping)

This technique is based on sequence variation within a specific region of the M. tuberculosis chromosome, the highly polymorphic DR (direct repeat) locus (34). Its structure is a series of 36-bp imperfectly matched DR elements interrupted by spacer sequences. The DR elements vary in size from 35 to 41 bp and the spacers are 5–7 bp. In addition, the number of spacers is variable: BCG has 49 DR spacers and M. tuberculosis (H37Rv) has 39. PCR is used to amplify the DR region from each strain, and the PCR products are hybridized to membranes containing hundreds of immobilized random oligonucleotides. Each strain has a characteristic series of spacer regions in its DR locus, which is then reflected in the patterns detected by spoligotyping. Although the sequences vary, strains can be grouped on the basis of their spoligotype pattern. An advantage of this technique is that the first step is PCR amplification and can be applied directly to clinical samples without waiting for expansion of the culture. IS6110 fingerprinting becomes less differentiating as a strain’s copy number decreases. Clinical strains with fewer than five copies of IS6100 are generally analyzed by alternate means (see below). Several direct comparisons of spoligotyping and IS6110-based RFLP indicate that the DR locus can discriminate among strains containing as few as one copy of IS6110 (34–36). In addition, there was an occasional splitting of a group of high-copy-number strains by spoligotyping (37,38). E. Variable Number Tandem Repeat

A recent technique analyzed genetic loci containing tandem repeat sequences (39) Eleven variable number tandem repeat (VNTR) loci in the M. tuberculosis genome were examined. Two types of repeat loci were identified. Five of the loci were major polymorphic tandem repeat (MPTR) loci and contained 15-base-pair variable repeats. The remaining six loci were exact tandem repeat (ETR) loci and contained identical sequences in large adjacent repeats. Spacer regions do not in-

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terrupt these tandem repeat loci, as in the DR loci discussed above. Primers were designed that recognize the termini of the repeat sequences, and the 11 loci were analyzed by PCR. The number of repeats present in each locus determined the length of the PCR product. These lengths were then compared among 48 strains. Seven of the 11 tandem repeat loci showed discriminating polymorphisms. For example, 22 of 25 M. tuberculosis strains and 5 of 23 M. bovis BCG strains had distinct allele profiles. This technique should be useful for both strain differentiation and evolutionary analyses. F. Direct DNA Sequencing

Finally, the application of automated sequencing techniques has permitted the analysis of several genes from large numbers of clinical strains (21,40). In addition, the complete H37Rv genome sequence has been annotated and published (26). The circular chromosome contains 4,411,529 base pairs with 3,918 proteincoding regions. Most of these genes contain recognizable sequences, unlike gene sequences from other organisms, suggesting the function of their gene products. However, approximately 600 of the genes are entirely unknown. The availability of this information has significantly increased the pace of tuberculosis research. The applications of this approach are discussed below. III. Interpreting Genotypes The molecular subtyping of bacterial isolates has proven to be a necessary tool in the identification, control, and monitoring of nosocomial transmission. Specific for M. tuberculosis, IS6110 DNA fingerprinting has become the prototype molecular tool in the study of bacterial molecular epidemiology. This robust Southern blot hybridization method has been standardized among laboratories throughout the world leading to the creation of three large networks (Public Health Research Institute in New York and Baylor College of Medicine in Texas, Houston, Texas) and in Europe (RIVM in the Netherlands, BA Bilthoven, The Netherlands) to track on an international basis the spread of this airborne pathogen. In general, these tools are able to determine whether the isolates recovered from a localized outbreak of disease are the same or different strains and support short-term or local epidemiology. It is currently accepted that two or more isolates with an identical IS6110 DNA fingerprint pattern but cultured from different patients are genetically related as a consequence of recent spread. Examples of related and unrelated IS6110 DNA fingerprint patterns are illustrated in Figure 1. Lanes 1–12 are W strains from Singapore, Russia, Kenya, and New York City. Their similarity is in marked contrast to the remaining patterns in the gel (lanes 13–19), which illustrate the range of RFLP patterns exhibited by clinical strains found among those collected in New York City and environs. Although this subtyping approach has been suc-

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cessful in outbreak investigations on a local level and in identifying laboratory contamination, it is clear that use of IS6110 alone has limitations. The molecular epidemiology among strains with limited copies of IS6110 (
5 insertions) requires additional subtyping methods (41). As discussed above, secondary tools such spoligotyping, VNTR, and PGRS hybridization have all proved useful in either discriminating or verifying the IS6110 grouping. These methods have become necessary in understanding the epidemiological significance among related strains from geographically diverse regions. A further limitation in IS6110 subtyping is reflected in large outbreak studies in assessing the relatedness among selected isolates. For example, the largest characterized multidrug-resistant outbreak occurred in New York City during the early 1990s (7,8). One clone, termed strain W, with a unique 18-band IS6110 pattern caused disease in more than 350 patients. In the same outbreak investigation, eight additional multidrug-resistant strains were identified that shared the majority of IS6110 bands with the W pattern but were not identical. Were the members of this second group related to the W outbreak? To address this question it was necessary to use additional genotyping methods. In this instance the multidrug phenotype provided an additional approach as resistance target genes in M. tuberculosis have been identified and sequenced. Svreevatsan et al. (42) determined the sequence of the pncA locus in 67 pyrazinamide-resistant and 51 pyrazinamide-susceptible isolates recovered from diverse geographical localities and anatomical sites. The pncA gene encodes pyrazinamidase, which converts pyrazinamide to the active form pyrazinoic acid. Surprisingly, the wild-type alleles of all 51 susceptible strains were identical: this restricted alellic variation among strains M. tuberculosis is discussed below. In the 67 resistant strains, mutations all along the length of the pncA locus were found. The majority (72%) were mutations that altered the primary amino acid sequence of the enzyme, and a number of new mutations were found, including upstream mutations, missense changes, nucleotide insertions and deletions, and termination mutations. DNA sequence analysis of six genes with mutations conferring antibiotic resistance (katG—isoniazid; rpoB—rifampin; embB—ethambutol; rpsL—streptomycin; pncA—pyrazinamide, rrs—kanamycin) in large samples of W isolates confirmed the clonal relationship of these organisms by showing that all isolates had the identical mutation in each of the six genes (Table 1) (8). This same array of six mutant alleles is found in the eight MDR strains with IS6110 profiles differing from the W pattern by one or two hybridizing bands. This secondary typing approach confirmed the relatedness of the W strain and those with related IS6110 fingerprint patterns that we have called the W-MDR family. Further confirmation of the relatedness of the W-MDR family was found using other secondary typing methods. This family is now defined based on all of

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Table 1 Antibiotic Resistance Loci Used to Confirm Genetic Relatedness of RFLP DNA Fingerprint Group W Strains Antibiotic Isoniazid Rifampin Ethambutol Streptomycin Pyrazinamide Kanamycin

Genetic locus

Alterationa

Ref.

katG rpoB embB rpsL pncA rrs

315:ST 526:HY 306:MI/V 43:KR 47:TA A1400Gb

8 8 43 8 42 44

a

The affected codon is indicated, followed by the specific amino acid change from susceptible to resistant. b The nucleotide A at position 1400 is changed to G in resistant strains.

the following molecular properties: 18–20 band W-like IS6110 pattern (8) Common spoligotype pattern (45) IS6110 insertion in the dnaA-dnaN intergenic region (46) Two IS6110 head-to-tail insertions in NTF (8) Unique dinucleotide change in codon 315 in katG (8) IV. International Applications of Molecular Fingerprinting The transposition of IS6110 is a time-dependent process: the degree of polymorphism among a collection of strains should represent the degree of divergence and reflect the length of time that has elapsed since that divergence. Several groups have noted that among strains originating in Africa there appeared to be significantly fewer polymorphisms when compared to strains collected in the Netherlands (47–49). Similarly, an analysis of clinical M. tuberculosis strain genotypes was carried out with isolates obtained from the People’s Republic of China and Mongolia (50). More than two thirds of the strains evaluated exhibited closely related IS6110 profiles. The similarities observed in RFLP lengths were analyzed by IS6110 hybridization and were confirmed when further analyzed by two secondary genotyping methods, using IS1081 and spoligotyping. Limited polymorphisms were found associated with other repetitive DNA elements such as the polymorphic GC-rich sequence and the direct repeat. Furthermore, strains related to this group were located in neighboring countries such as Thailand, Mongolia, and South Korea, in contrast to the low prevalence of these genotypes in unrelated

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countries. The group was named the Beijing family, since the majority of the strains were isolated from patients living in that city. In addition, dissemination of the Beijing strain to other countries is described. Computer analysis (48) found that genotypes of members of the W-MDR and W-SUS (susceptible) families had many comigrating bands, suggesting genetic relatedness among these strains (46). Further examination of the specific insertion sites of copies of IS6110 in these groups confirmed their similarity. These specific insertion sites are discussed below. There is a very large global pool of individuals infected with the tubercle bacillus, and considerable chromosomal heterogeneity is suggested by the large number of RFLP patterns detected among the world’s M. tuberculosis strain collections. In striking contrast to the strain diversity observed by IS6110 subtyping, DNA sequencing of drug targets has revealed that there are very few specific changes in the DNA sequence. Even substitutions that would result in no change to the actual protein sequence (synonymous nucleotide substitutions) appear to be extremely rare. Musser and colleagues studied this phenomenon by comparing sequences (2 million base pairs) among 26 different genes in 842 clinical M. tuberculosis complex strains representing 40 countries on every continent (21). Three phylogenetic groups of M. tuberculosis were identified on the basis of two polymorphisms that occur at high frequency in the genes encoding catalase-peroxidase and the A subunit of gyrase enzyme. The products of these two genes are involved in the resistance to isoniazid and the quinolones, respectively. Each of the three phylogenetic groups has distinct characteristics (see Table 2). For example, Group 1 is closely related to M. bovis and appears to be evolutionarily old. A subset of this group, exhibiting closely related RFLP patterns, contains a copy of the IS6110 insertion sequence integrated in a region of the chromosome required for initiation of DNA replication. RFLP genotypes and detailed

Table 2 Genotypic Groups Mycobacterial Strains on the Basis of Specific Genetic Alterations Group

Species

1

2

M. microti M. africanum M. tuberculosis M. tuberculosis

3

M. tuberculosis

M. tuberculosis strains

Codon changes

W, Houston

katG463 CTG (leu) gyrA95 ACC (thr)

C, Houston Erdman H37Rv, H37Ra

katG 463 CGG (arg) gyrA95 ACC (thr) katG463 CGG (arg) gyrA95 AGC (ser)

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epidemiological profiles for each case are available for 6000 isolates from New York and Houston. These data are interpreted to suggest that Groups 1 and 2 are disproportionately represented among clustered cases of tuberculosis. The trivial explanation that Group 3 organisms are not found in these populations at a large enough frequency to be included among the clusters was ruled out. Among the strains included by Musser et al. in Group 1 are the W superfamily, common throughout Asia, including China, South Korea, Thailand, and the Philippines (51–53). These organisms are also causes of disease in New York and Houston and are responsible for relatively large (30 patients) case clusters (7,8,54,55). It is reasonable to speculate that the Beijing isolates identified in the United States were introduced by human population migration and should be found in regions with a relatively high percentage of people with Chinese ethnicity. These strains are rarely found in west Texas, Mexico, Guatemala, Honduras, Peru, Trinidad-Tobago, Israel, Romania, Kenya, the Netherlands, elsewhere in Europe, Tunisia, Pakistan, and Tanzania (48,56–59). On the other hand, group 1 genotypes were found in 16 of 49 (33%) isolates from Singapore, a city with approximately 40% ethnic Chinese. Scrutiny of the New York and Houston epidemiological databases reveals that the majority of the isolates belonging to group 1 are of Chinese and Vietnamese ethnicity, respectively. The group 1 strains (W-SUS, W-MDR, Beijing family, and N family) were further studied at the molecular level by identifying the precise chromosomal insertion sites of 5 of the 18 copies of IS6110 (40). Such analyses are aided by the recent availability of the entire DNA sequence of two M. tuberculosis genomes (26,60,61). None of the five insertion sites was in an open reading frame, suggesting that the insertion element does not interrupt gene expression in these five instances. However, one site was located in the origin of replication. A total of 722 strains was evaluated for precise sequence of insertion of the five IS6110 copies. The insertion-site mapping in this study identified the 537-base-pair region between the genes encoding dnaA and dnaN as a hot spot for IS6110 insertion. Ten different insertions in this region were identified, and the transposon was found in both orientations. Comparison of the specific sequences suggests further that there are small hairpin motif structures flanking the IS6110 insertion sites (46,62). A recent computer-based analysis also indicates that the M. tuberculosis genome contains hot spots for IS6110 insertion (63). V. Implications for Basic Research Taken together, the restricted nucleotide sequence variation and extensive IS6110 polymorphism provide strong evidence that transposition of IS6110 occurs at a greater frequency than unselected nucleotide changes. This has led to the proposition that transposition of IS6110 and other repetitive elements might be an im-

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portant mechanism to alter gene expression (21). The hypothesis remains largely unexplored in M. tuberculosis pathogenesis. Variance in pathogenic behavior has been attributed to insertion sequence-based alterations in gene expression in Yersinia pestis (64) and in Neisseria meningitidis (65). Among the few studies of the chromosomal context of IS6110 insertion in clinical strains of M. tuberculosis (46,62), only one describes a copy of IS6110 interrupting an open reading frame (66). The site, mtp40, was originally identified as a region found in strains of M. tuberculosis but not in BCG (67). mtp40 was eventually shown to be a portion of an operon with two open reading frames (mpcA and mpcB) encoding proteins homologous to hemolytic phospholipases (20). Remarkable polymorphism was found among the mtp40 regions of 100 clinical strains of M. tuberculosis, including insertion of a copy of IS6110 in one strain in the 3 end of the mtp40 region (66). The effect of this insertion on phospholipase expression or on any other parameter, such as virulence, has not been examined (66). VI. Clinical Applications of Molecular Fingerprinting The new molecular tools and the kinds of analyses they provide are changing the face of tuberculosis epidemiology on an international scale (68,69). A comprehensive epidemiology of the disease will lead to better identification of index cases and efficient treatment methodologies. These techniques will enable the study of the interaction between M. tuberculosis and the human immunodeficiency virus (10,70–72). Population-based studies of transmission will help define the risk factors for transmission within communities and within and among countries. Finally, the behavior of drug-resistant strains can be monitored and analyzed. In a recent report issued by the World Health Organization–International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance, drug-resistant tuberculosis was identified in all 35 countries surveyed (73). Acknowledgment Publication No. 66 from the Tuberculosis Center, Public Health Research Institute. References 1. Gruft H, Johnson R, Claflin R, Loder A. Phage-typing and drug-resistance patterns as tools in mycobacterial epidemiology. Am Rev Respir Dis 1984; 130:96–97. 2. Hermans PW, van Soolingen D, Dale JW, et al. Insertion element IS986 from Mycobacterium tuberculosis: a useful tool for diagnosis and epidemiology of tuberculosis. J Clin Microbiol 1990; 28:2051–2058.

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3. McAdam RA, Hermans PW, van Soolingen D, et al. Characterization of a Mycobacterium tuberculosis insertion sequence belonging to the IS3 family. Mol Microbiol 1990; 4:1607–1613. 4. Thierry D, Cave MD, Eisenach KD, et al. IS6110, an IS-like element of Mycobacterium tuberculosis complex. Nucleic Acids Res 1990; 18:188. 5. Thierry D, Brisson-Noel A, Vincent-Levy-Frebault V, Nguyen S, Guesdon JL, Gicquel B. Characterization of a Mycobacterium tuberculosis insertion sequence, IS6110, and its application in diagnosis. J Clin Microbiol 1990; 28:2668–2673. 6. Alland D, Kalkut GE, Moss AR, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods [see comments]. N Engl J Med 1994; 330:1710–1716. 7. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996; 276:1229–1235. 8. Bifani PJ, Plikaytis BB, Kapur V, et al. Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family [see comments]. JAMA 1996; 275:452–457. 9. Lemaitre N, Sougakoff W, Truffot-Pernot C, et al. Use of DNA fingerprinting for primary surveillance of nosocomial tuberculosis in a large urban hospital: detection of outbreaks in homeless people and migrant workers. Int J Tuberc Lung Dis 1998; 2:390–396. 10. Cohn DL, O’Brien RJ. The use of restriction fragment length polymorphism (RFLP) analysis for epidemiological studies of tuberculosis in developing countries. Int J Tuberc Lung Dis 1998; 2:16–26. 11. Nivin B, Nicholas P, Gayer M, Frieden TR, Fujiwara PI. A continuing outbreak of multidrug-resistant tuberculosis, with transmission in a hospital nursery. Clin Infect Dis 1998; 26:303–307. 12. Mangura BT, Napolitano EC, Passannante MR, McDonald RJ, Reichman LB. Mycobacterium tuberculosis miniepidemic in a church gospel choir. Chest 1998; 113:234–237. 13. Braden CR. Infectiousness of a university student with laryngeal and cavitary tuberculosis. Investigative team. Clin Infect Dis 1995; 21:565–570. 14. Cummings KC, Mohle-Boetani J, Royce SE, Chin DP. Movement of tuberculosis patients and the failure to complete antituberculosis treatment. Am J Respir Crit Care Med 1998; 157:1249–1252. 15. Angarano G, Carbonara S, Costa D, Gori A. Drug-resistant tuberculosis in human immunodeficiency virus infected persons in Italy. The Italian Drug-Resistant Tuberculosis Study Group. Int J Tuberc Lung Dis 1998; 2:303–311. 16. Segal SP, Gomory T, Silverman CJ. Health status of homeless and marginally housed users of mental health self-help agencies. Health Soc Work 1998; 23:45–52. 17. Dwyer B, Jackson K, Raios K, Sievers A, Wilshire E, Ross B. DNA restriction fragment analysis to define an extended cluster of tuberculosis in homeless men and their associates. J Infect Dis 1993; 167:490–494. 18. Segal-Maurer S, Kreiswirth BN, Burns JM, et al. Mycobacterium tuberculosis specimen contamination revisited: the role of laboratory environmental control in a pseudo-outbreak. Infect Control Hosp Epidemiol 1998; 19:101–105.

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19. Van Duin JM, Pijnenburg JE, van Rijswoud CM, de Haas PE, Hendriks WD, van Soolingen D. Investigation of cross contamination in a Mycobacterium tuberculosis laboratory using IS6110 DNA fingerprinting. Int J Tuberc Lung Dis 1998; 2:425–429. 20. Johansen KA, Gill RE, Vasin ML. Biochemical and molecular analysis of phospholipase C and phospholipase D activity in mycobacteria. Infect Immun 1996; 64:3259– 3266. 21. 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; 94:9869–9874. 22. Fang Z, Morrison N, Watt B, Doig C, Forbes KJ. IS6110 transposition and evolutionary scenario of the direct repeat locus in a group of closely related Mycobacterium tuberculosis strains. J Bacteriol 1998; 180:2102–2109. 23. Collins DM, De Lisle GW. DNA restriction endonuclease analysis of Mycobacterium bovis and other members of the tuberculosis complex. J Clin Microbiol 1985; 21:562–564. 24. Palittapongarnpim P, Chomyc S, Fanning A, Kunimoto D. DNA fingerprinting of Mycobacterium tuberculosis isolates by ligation-mediated polymerase chain reaction. Nucleic Acids Res 1993; 21:761–762. 25. Agasino CB, Ponce de Leon A, Jasmer RM, Small PM. Epidemiology of Mycobacterium tuberculosis strains in San Francisco that do not contain IS6110. Int J Tuberc Lung Dis 1998; 2:518–520. 26. Philipp WJ, Poulet S, Eiglmeier K, et al. An integrated map of the genome of the tubercle bacillus, Mycobacterium tuberculosis H37Rv, and comparison with Mycobacterium leprae. Proc Natl Acad Sci USA 1996; 93:3132–3137. 27. Zhang Y, Mazurek GH, Cave MD, et al. DNA polymorphisms in strains of Mycobacterium tuberculosis analyzed by pulsed-field gel electrophoresis: a tool for epidemiology. J Clin Microbiol 1992; 30:1551–1556. 28. Collins DM, Stephens DM. Identification of an insertion sequence, IS1081, in Mycobacterium bovis. FEMS Microbiol Lett 1991; 67:11–15. 29. Hermans PW, van Soolingen D, Bik EM, de Haas PE, Dale JW, van Embden JD. Insertion element IS987 from Mycobacterium bovis BCG is located in a hot-spot integration region for insertion elements in Mycobacterium tuberculosis complex strains. Infect Immun 1991; 59:2695–2705. 30. Hermans PW, van Soolingen D, van Embden JD. Characterization of a major polymorphic tandem repeat in Mycobacterium tuberculosis and its potential use in the epidemiology of Mycobacterium kansasii and Mycobacterium gordonae. J Bacteriol 1992; 174:4157–4165. 31. Ross BC, Raios K, Jackson K, Dwyer B. Molecular cloning of a highly repeated DNA element from Mycobacterium tuberculosis and its use as an epidemiological tool. J Clin Microbiol 1992; 30:942–946. 32. Telenti A, Imboden P, Marchesi F, Schmidheini T, Bodmer T. Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 1993; 37:2054–2058. 33. Takiff HE, Salazar L, Guerrero C, et al. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 1994; 38:773–780.

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34. Kamerbeek J, Schouls L, Kolk A, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 1997; 35:907–914. 35. Cousins D, Williams S, Liebana E, et al. Evaluation of four DNA typing techniques in epidemiological investigations of bovine tuberculosis. J Clin Microbiol 1998; 36:168–178. 36. Sola C, Horgen L, Maisetti J, Devallois A, Goh KS, Rastogi N. Spoligotyping followed by double-repetitive-element PCR as rapid alternative to IS6110 fingerprinting for epidemiological studies of tuberculosis. J Clin Microbiol 1998; 36:1122–1124. 37. Goyal M, Shaw RJ, Banerjee DK, Coker RJ, Robertson BD, Young DB. Rapid detection of multidrug-resistant tuberculosis. Eur Respir J 1997; 10:1120–1124. 38. Goguet de la Salmoniere YO, Li HM, Torrea G, Bunschoten A, van Embden J, Gicquel B. Evaluation of spoligotyping in a study of the transmission of Mycobacterium tuberculosis. J Clin Microbiol 1997; 35:2210–2214. 39. Frothingham R, Meeker-O’Connell WA. Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology 1998; 144:1189–1196. 40. Kapur V, Li LL, Iordanescu S, et al. Characterization by automated DNA sequencing of mutations in the gene (rpoB) encoding the RNA polymerase beta subunit in rifampin-resistant Mycobacterium tuberculosis strains from New York City and Texas. J Clin Microbiol 1994; 32:1095–1098. 41. Braden CR, Templeton GL, Cave MD, et al. Interpretation of restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates from a state with a large rural population. J Infect Dis 1997; 175:1446–1452. 42. Sreevatsan S, Pan X, Zhang Y, Kreiswirth BN, Musser JM. Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob Agents Chemother 1997; 41:636–640. 43. Sreevatsan S, Stockbauer KE, Pan X, et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 1997; 41:1677–1681. 44. Alangaden GJ, Kreiswirth BN, Aouad A, et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998; 42:1295–1297. 45. Goyal M, Saunders NA, van Embden JD, Young DB, Shaw RJ. Differentiation of Mycobacterium tuberculosis isolates by spoligotyping and IS6110 restriction fragment length polymorphism. J Clin Microbiol 1997; 35:647–651. 46. Kurepina NE, Sreevatsan S, Plikaytis BB, et al. Characterization of the phyogenetic distribution and chromosomal insertion sites of five IS6110 elements of Mycobacterium tuberculosis: non-random integration in the dnaA-dnaN region. Tubercle Lung Dis 1998; 79:31–42. 47. Borgdorff MW, Nagelkerke N, van Soolingen D, de Haas PE, Veen J, van Embden JD. Analysis of tuberculosis transmission between nationalities in the Netherlands in the period 1993–1995 using DNA fingerprinting. Am J Epidemiol 1998; 147:187–195. 48. Hermans PW, Messadi F, Guebrexabher H, et al. Analysis of the population structure of Mycobacterium tuberculosis in Ethiopia, Tunisia, and The Netherlands: usefulness of DNA typing for global tuberculosis epidemiology [see comments]. J Infect Dis 1995; 171:1504–1513.

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49. van Soolingen D, Hermans PW, de Haas PE, Soll DR, van Embden JD. Occurrence and stability of insertion sequences in Mycobacterium tuberculosis complex strains: evaluation of an insertion sequence-dependent DNA polymorphism as a tool in the epidemiology of tuberculosis. J Clin Microbiol 1991; 29: 2578–2586. 50. van Soolingen D, Qian L, de Haas PE, et al. Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia. J Clin Microbiol 1995; 33:3234–3238. 51. Huh YJ, Ahn DI, Kim SJ. Limited variation of DNA fingerprints (IS6110 and IS1081) in Korean strains of Mycobacterium tuberculosis. Tuberc Lung Dis 1995; 76:324–329. 52. Lim EM, Rauzier J, Timm J, et al. Identification of Mycobacterium tuberculosis DNA sequences encoding exported proteins by using phoA gene fusions. J Bacteriol 1995; 177:50–65. 53. Torrea G, Levee G, Grimont P, Martin C, Chanteau S, Gicquel B. Chromosomal DNA fingerprinting analysis using the insertion sequence IS6110 and the repetitive element DR as strain-specific markers for epidemiological study of tuberculosis in French Polynesia. J Clin Microbiol 1995; 33:1899–1904. 54. Moss AR, Alland D, Telzak E, et al. A city-wide outbreak of a multiple-drug-resistant strain of Mycobacterium tuberculosis in New York. Int J Tuberc Lung Dis 1997; 1:115–121. 55. Edlin BR, Valway SE, Onorato IM. Clusters of multidrug-resistant tuberculosis [letter]. Ann Intern Med 1993; 118:77. 56. Yang ZH, de Haas PE, van Soolingen D, van Embden JD, Andersen AB. Restriction fragment length polymorphism Mycobacterium tuberculosis strains isolated from Greenland during 1992: evidence of tuberculosis transmission between Greenland and Denmark. J Clin Microbiol 1994; 32:3018–3025. 57. Yang ZH, Mtoni I, Chonde M, et al. DNA fingerprinting and phenotyping of Mycobacterium tuberculosis isolates from human immunodeficiency virus (HIV)seropositive and HIV-seronegative patients in Tanzania. J Clin Microbiol 1995; 33:1064–1069. 58. Sechi LA, Zanetti S, Delogu G, Montinaro B, Sanna A, Fadda G. Molecular epidemiology of Mycobacterium tuberculosis strains isolated from different regions of Italy and Pakistan. J Clin Microbiol 1996; 34:1825–1828. 59. Sola C , Horgen L, Goh KS, Rastogi N. Molecular fingerprinting of Mycobacterium tuberculosis on a Caribbean island with IS6110 and DRr probes. J Clin Microbiol 1997; 35:843–846. 60. TIGR. TIGR releases EST data publicly [news]. Nat Biotechnol 1997; 15:397. 61. TIGR. HGS-TIGR splits, opportunity knocks [editorial]. Nat Biotechnol 1997; 15:693. 62. Mendiola MV, Martin C, Otal I, Gicquel B. Analysis of the regions responsible for IS6110 RFLP in a single Mycobacterium tuberculosis strain. Res Microbiol 1992; 143:767–772. 63. McHugh TD, Gillespie SH. Nonrandom association of IS6110 and Mycobacterium tuberculosis: implications for molecular epidemiological studies. J Clin Microbiol 1998; 36:1410–1413.

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64. Simonet M, Riot B, Fortineau N, Berche P. Invasin production by Yersinia pestis is abolished by insertion of an IS200-like element within the inv gene. Infect Immun 1996; 64:375–379. 65. Hammerschmidt S, Hilse R, van Putten JP, Gerardy-Schahn R, Unkmeir A, Frosch M. Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable genetic element. Embo J 1996; 15:192–198. 66. Vera-Cabrera L, Howard ST, Laszlo A, Johnson WM. Analysis of genetic polymorphism in the phospholipase region of Mycobacterium tuberculosis. J Clin Microbiol 1997; 35:1190–1195. 67. Del Portillo P, Murillo LA, Patarroyo ME. Amplification of a species-specific DNA fragment of Mycobacterium tuberculosis and its possible use in diagnosis [see comments]. J Clin Microbiol 1991; 29:2163–2168. 68. Roth A, Schaberg T, Mauch H. Molecular diagnosis of tuberculosis: current clinical validity and future perspectives. Eur Respir J 1997; 10:1877–1891. 69. Staneck JL. Impact of technological developments and organizational strategies on clinical laboratory cost reduction. Diagn Microbiol Infect Dis 1995; 23:61–73. 70. Gampper SN, George JA, Carter EJ, et al. Co-infection with Mycobacterium tuberculosis and HIV in high risk clinical care setting in Rhode Island. AIDS Care 1998; 10:221–229. 71. Johnson JL, Vjecha MJ, Okwera A, et al. Impact of human immunodeficiency virus type-1 infection on the initial bacteriologic and radiographic manifestations of pulmonary tuberculosis in Uganda. Makerere University-Case Western Reserve University Research Collaboration. Int J Tuberc Lung Dis 1998; 2:397–404. 72. Jansa JM, Serrano J, Cayla JA, Vidal R, Ocana I, Espanol T. Influence of the human immunodeficiency virus in the incidence of tuberculosis in a cohort of intravenous drug users: effectiveness of anti-tuberculosis chemoprophylaxis. Int J Tuberc Lung Dis 1998; 2:140–146. 73. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization-International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance [see comments]. N Engl J Med 1998; 338:1641–1649.

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12 Tuberculin Skin Testing

RICHARD I. MENZIES Montreal Chest Institute McGill University Montreal, Canada

I. Introduction Among tests presently used in clinical medicine, the tuberculin skin test is one of the few that was developed in the last century. Given such a long history of use it may seem surprising that the interpretation of this test remains controversial. However, this reflects the changing epidemiology, clinical features, investigation, and management of tuberculosis. In industrialized countries new problems have arisen in the interpretation of the tuberculin skin test in certain high-risk populations because of aging, HIV infection, intravenous (IV) drug use, and other phenomena. The first tuberculin test material was prepared by Robert Koch, who filtered heat-sterilized cultures of Mycobacterium tuberculosis grown on veal broth and then evaporated the filtrate to 10% of the original volume (1). This became known as old tuberculin (OT). Koch tried this unsuccessfully as a therapeutic agent, but in 1907 von Pirquet recognized its potential value for detection of persons infected with tuberculosis (2). The next year, Mantoux introduced the intradermal technique, which still bears his name (3). Old tuberculin proved unreliable and nonspecific because the filtrate was very heterogeneous. In 1934, Dr. Florence Seibert working at the Phipps Institute 279

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in Philadelphia developed a technique of extraction of protein from autoclaved tuberculosis bacteria grown on artificial media. Results with this purified protein derivative (PPD) proved much more reproducible and specific (4). After considerable work to standardize this material, a large quantity was carefully prepared by Dr. Siebert in 1939, termed PPD Standard, or PPD-S (5). By international agreement, since that time all tuberculin skin testing material produced must be bioequivalent to this standard lot. North American manufactured tuberculin test material, which is bioequivalent to PPD-S, will be referred to as PPD-T in this review. The final refinement of the tuberculin test, was the addition of Tween, a detergent that minimized the absorption of tuberculin protein by glass or plastic. This allowed prolonged storage and further improved the reproducibility of test results (6–9). Injection of tuberculin material intradermally into a person previously infected with M. tuberculosis will result in infiltration of previously sensitized lymphocytes circulating in peripheral blood. At the site of injection, CD4 and CD8 T lymphocytes will accumulate, as well as monocytes and macrophages. These release inflammatory mediators, which produce edema and erythema. Although there is increased blood flow, the locally increased metabolic activity of these inflammatory cells results in relative hypoxia and acidosis, which may be severe enough to lead to ulceration and necrosis (10). Although tuberculin reactions have often been equated with immune status, it has been well established that tuberculin skin test reactions and immunity are, in fact, independent phenomena (11–13), although both result from exposure and acquisition of infection. New molecular biology techniques (14) could prove useful to better understand these two phenomena and how they affect the tuberculin skin test. It would be of enormous benefit if we could learn how to distinguish tuberculin reactions that indicate immunity from reactions that indicate increased future risk of tuberculosis. II. Technical Aspects A. Administration of the Test

Tuberculin material, manufacturer, and technique of administration may affect tuberculin skin tests results. At the present time, the only accepted material for use in tuberculin testing is PPD. Manufacturers must ensure that each batch of tuberculin material is standardized using experimental animals infected with H-37RV strain against the original batch lot of PPD-S. There are two North American manufacturers: Connaught Laboratories (manufacturing Tubersol) and Parke-Davis (Aplisol). Earlier studies demonstrated that the Connaught product had significantly higher sensitivity when compared to the Parke-Davis product (8,15). Since that time, there have been a number of reports of high rates of apparent false-positive results using the Parke-Davis product (16–18). As a result, the Connaught

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product has been strongly recommended elsewhere (19), although in more recent studies, results with the two products have been closely comparable (20). In Europe, the Serum Statens Institute of Copenhagen, Denmark, developed a tuberculin test material termed RT-23. After considerable effort at standardization (21), this product is now accepted as a standard tuberculin by the World Health Organization (21,22) and is widely used outside of North America. In one comparative study, two tuberculin units (TU) of RT-23 had nearly identical sensitivity as 5 TU of PPD-S, although specificity was lower (23). The results of these two test materials are similar enough that results from studies using 2 TU of RT23 can be considered reasonably comparable to results of studies using 5 TU of PPD-T. Tuberculin test materials are commercially available in strengths ranging from 1 to 250 TU per test dose. Administration of 1 TU is not recommended because this preparation has a sensitivity of only 50% in children (24) and 80% in adults (25) with confirmed active tuberculosis, yet there is no evidence of reduced occurrence of adverse events (26). Higher strength formulations such as 100 or 250 TU are not recommended because virtually all subjects with sensitivity to nontuberculous mycobacteria will be positive (27), these reactions are more likely to revert later (28) and, as shown in Figure 1, there is no relationship of reactions to these higher dose tests and the likelihood of true tuberculosis infection (29).

Figure 1

Reactions to 250 and 5 TU of PPD-S and degree of contact with tuberculosis.

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Commonly used methods of tuberculin skin test administration are the Mantoux method of intradermal injection and multipuncture techniques such as the Tine test. Results of studies comparing the Mantoux with other techniques are summarized in Table 1. In general, multipuncture techniques have lower sensitivity: in young healthy volunteers, false-negative rates of up to 15% have been reported (30). Sensitivity can be improved by lowering the cut-point, but this will reduce specificity (31). Results of dual testing in the same subjects or dual readings of the same test are much less reproducible with multipuncture compared to Mantoux techniques (32,33). In a British study, clinically important differences were noted in 42 of 180 (23%) subjects who had repeat tine tests (32). Problems of the multipuncture devices include uneven coating of the tuberculin material on the tines (34) and difficulty of standardizing the technique of administration (30). Jet injectors have been used, particularly in surveys of young children, but the depth and amount injected is much less reliable so results are more variable (35). Based on this evidence, it can be strongly recommended that for all tuberculin testing a dose bioequivalent to 5 TU of PPD-S be administered using the Mantoux technique of intradermal injection. If by error injections are given subcutaneously, larger, more diffuse reactions will result (36), which are more diffi-

Table 1

Comparison of Mantoux with Other Tuberculin Skin Testing Techniques Population Comparison technique

Author (Ref.)

Year

Age (mean or range)

Badgder (31)

1962

All ages

1001

5 TU

Furcolow (33)

1966

36

5 TU

Fine (165) Wijsmuller (35)

1972 1975

54 Adults

670 100 589 915

5 TU 5 TU

Donaldson (166) Lunn (167)

1976

15–69

135

5 TU

1980

18–21

250

5 TU

Ackerman (168) Hansen (169) Rudd (170) Biggs (171)

1981

14

10 IU

1982 1982 1987

Adults Adults Adults

6239 2574 829 100 105

a

Mantoux taken as gold standard.

No.

Mantoux dose

5 TU 10 IU 10 TU

Type Tine (OT) 3mm 6mm Tine-OT Tine-OT J  T injector—more variable than Mantoux  amount injected  both Tine-OT Tine-PPD Imotest-PPD (Merieux) Tine-PPD Imotest-PPD Tine-OT Imotest-PPD Imotest-PPD 4mm 2mm

Sensitivitya (%)

Specificitya (%)

96 78 98 95 98 73

73 84 92 83 82 —

84 90 67

— — 65

76 75 69 72 33 60

— — 98 94 90 85

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283

cult to read (37). Use of smaller needles will result in less pain, bruising, and bleeding (38) but may result in more leakage and therefore less reliable results (38). Although a wheal should be produced following intradermal injection, the size of this wheal is a poor estimate of the amount injected because it is affected by age and gender (22,39). Failure to inject the correct dose (e.g., from leakage) will result in smaller reactions (37) and so may lead to false-negative results. The site of injection is not important (37), although the inner or volar aspect of the forearm is generally used for convenience. The site of testing should be varied, especially with the two-step protocol, because repeated tests at exactly the same site may result in increased reaction size (40). B. Reading the Test

Timing and method of reading as well as experience of readers may affect results. Reading after 6 hours was suggested as indicative of active disease because 72% of 109 patients with smear-positive active tuberculosis had reactions of 5 mm after 6 hours compared to only 3.5% of 143 healthy volunteers (41). However, in a subsequent study, reactions after 6 hours were equally common in patients with inactive tuberculosis and other respiratory diseases and health-care workers with heavy exposure (42), i.e., this was a nonspecific phenomenon. Readings at 24 hours were compared to readings at 48 hours in another study. Using the 48-hour readings as the gold standard, readings at 24 hours had only 71% sensitivity and 9% false-positive rate (43). In another study of 308 adults with active tuberculosis (mean age 51 years), readings were made every day for 7 days following tuberculin testing. In total, 296 (97%) had positive reactions 48–72 hours following testing. Reading at 96 hours was almost as sensitive, but by day 7, 21% had reverted to negative (25). Among 380 elderly nursing home residents (mean age 75), 23 (19%) of those with positive reactions (10 mm) after 48 hours had reverted to negative after 7 days (44). On the other hand, 20 other residents with negative reactions at 48 hours had positive reactions after 7 days (44). When two-step testing is performed, reading the first tuberculin test after 7 days is suggested because a second test can be administered immediately for those with negative reactions. Although this approach is more practical, the clinical significance of reactions that are positive after one week but negative after 48 hours is unknown because all information regarding risk of tuberculosis is based on tuberculin reactions measured between 48 and 72 hours after testing. In summary, readings should be made 2–3 days following administration given the reduced sensitivity and uncertain interpretation of readings made later (22). Originally induration was defined by palpation. The ballpoint method was introduced by Sokal as a faster, more reliable technique (45). Correlation between these two reading techniques is very high (R  0.94) (46), and differences between readings are small (46–49), irregardless of reader experience (47,49). Over-

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Menzies

all, the ballpoint technique appears to be slightly faster (48), more sensitive (48), and less variable (49). Self-reading by patients has resulted in clinically significant misclassification in 8.5% of Heaf tests (50) and 11% misclassification following Mantoux testing (43). In the latter study, of 525 patients with no tuberculin reaction, only 5 patients believed there was significant induration (specificity 99%). On the other hand, of 212 patients with reactions of 10 mm measured by a trained observer, only 79 believed there was any reaction (sensitivity  37%) (43). Underreading by patients was also reported by a New York hospital where only 1 of 18 patients with a positive tuberculin reaction correctly interpreted their reaction as positive (51). Table 2 summarizes the variability of tuberculin tests using the Mantoux technique. Standard deviation of readings and misclassification errors are considerably less within than between readers, although differences between readers should average less than 2 mm (22). In two studies (52,53) systematic differences between one reader and the others contributed the majority of variance and misclassification

Table 2

Variability of Tuberculin Test Results (Mantoux Test Only) Population

Author (Ref.)

Year

No.

Type

A. Variability of reaction: 2 tests in same subject Furcolow 1966 212 Mental hospital (33) patients Chaparas (172)

1985

1036 46

Reading Age (yr)

Misclassification (Pos. vs. Neg.)

Standard Deviation

36

—

Adults Adults

—

General

16–17

4

1.3–1.9 mm

Mental hospital patients

11–90

2

—

1.2%

20–60

7

—

9%

54 18–25

4 4

— 2.5 mm

770

6

2.3 mm

Adults

2a

—

11%

adults

2

2.7–3.5

12–23%

General TB patients

0–4 mm 5–9 mm 10 mm

92% 7% 1% 4.6% 0

B. Variability of reading: within readers Bearman (53) Furcolow (33)

1964

36

1966

670

C. Variability of readings: between readers Loudon 1963 53 Workers (173) Fine (174) 1972 189 General Erdtmann 1974 121 General (52) Perez Stable 1985 537 Nursing home (175) residents Howard 1988 806 General (43) Pouchot 1997 96 Health workers (176) a

Patient self-reading compared to trained health professional.

12% — 4.3%

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285

errors—a potentially correctable problem through further training and/or elimination of such readers. Another potential cause of reader error is terminal digit preference or rounding. This problem can result in substantial misclassification, particularly if there is conscious or unconscious bias on the part of the reader. This can be eliminated by use of simple measuring calipers, such as are used by mechanics or for sewing, which are available in most hardware stores for less than $2. Biological variation estimated from two simultaneous tuberculin tests is remarkably small given the inherent variability resulting from administration and reading. C. Adverse Reactions

Adverse reactions to tuberculin skin tests are rare. Vaso-vagal reactions can occur as with any injection. Immediate wheal and flare with a local rash was seen in 2.3% of allergy clinic patients (54). These reactions were associated with atopic history but not with positive tuberculin reactions at 48–72 hours. Lymphangitis has been reported following testing using Mantoux or Heaf techniques (55), usually associated with strongly positive tuberculin tests with severe blistering and/or ulceration at the site of injection. Severe anaphylaxis has been reported on one occasion following Mantoux testing. A patient with active tuberculous lymphadenitis developed shock with renal and hepatic dysfunction within hours of receiving a 1-TU dose of PPD-T (26). There have been two cases of anaphylaxis, one of them fatal (56,57), associated with tine testing. In the nonfatal case, serum IgE to PPD was undetectable and the authors believed that the gum used as an adherent to coat the tuberculin material on the tines was responsible (56). Anaphylaxis reactions are not related to true tuberculin reactions. In approximately 1–2% of patients with positive reactions, there may be severe blistering and even ulceration. Hydrocortisone cream is often given but was of no benefit in the only randomized controlled trial to assess its use (58). An undocumented history of a prior positive tuberculin test is not a contraindication to tuberculin testing because patient recall is often inaccurate, and severe reactions are not more frequent (59). There is no evidence whatsoever that tuberculin testing poses any risk in pregnancy (60) or that tuberculin reactions are influenced by pregnancy (61), although the manufacturers’ product monograph mentioned this as a potential precaution in past years (62). III. Simple Cognitive Aspects: False-Negative and FalsePositive Reactions Interpretation of any test in clinical medicine requires understanding of the causes and likelihood of false-negative and false-positive results in the population being tested.

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Menzies A. False-Negative Tests

As summarized in Table 3, tests may give false-negative results because of technical problems in the preparation or storage of material as well as administration or reading of the test. Most of these problems can be avoided by meticulous technique in tuberculin testing and reading. Proper storage is important because test material will deteriorate if exposed to light, heat, or if frozen. However, some misclassification is inevitable because of the variability related to differences in administration, biological response, and reading. Biological cause of false-negative results are more difficult to avoid. Falsenegative tests may occur in patients with active tuberculosis disease: estimates range from 5–8% in cross-sectional studies of patients already on treatment (63) to 17% (7) at the time of diagnosis and up to 30% among elderly patients (64). False-negative tests in TB patients are associated with more advanced forms of tuberculosis (65), malnutrition (66), and elevated serum creatinine levels (67). Malnutrition and associated immunological changes have also been implicated in the temporary anergy seen in refugees from Southeast Asia (68). An important cause of false-negative reactions is HIV infection. The proportion of false-negative reactions in dually infected (HIV and TB) patients ranges Table 3 Causes of False-Negative TST Technical Material

Administration

Reading

• Poor-quality production • Inadequate dose (e.g., 1 TU) • Improper storage (exposure to light/heat) • Material not injected • Too long in syringe • Inexperienced or biased reader • Error in recording • Too early, too late

Biological Viral infection

• HIV • Other infections, measles, mumps, chickenpox • Live virus vaccination

Bacterial or fungal infection Tuberculosis

• Extensive disease

Malignancies Therapy Age Other

• Miliary or pleural forms • Lymphoma, leukemia • Corticosteroids, chemotherapy • Newborn, elderly • Malnutrition, renal failure, sarcoidosis, stress, surgery

Tuberculin Skin Testing

Figure 2

287

Effect of HIV infection on prevalence of TST reactions.

from 15–28% in those with CD4 counts greater than 400–500 up to 100% in patients with CD4 counts less than 200 (69–72). An important observation is that while the proportion of HIV-seropositive patients with a positive TST diminishes, the pattern of reactions in the populations have not changed appreciably (Fig. 2), even as the CD4 count falls progressively (71,73–75) lower (Fig. 3). 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 tuberculin skin test response may be an all-or-nothing phenomenon in HIV-infected individuals and that once immunity falls below a certain threshold the tuberculin response is lost. Another important cause of false-negative tests is older age (76). 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 4, although the number with reactions diminishes with older age, the size of reaction does not change—a finding confirmed elsewhere (77). These cross-sectional findings have been confirmed in longitudinal studies, which have demonstrated reversion of positive tuberculin reactions in elderly nursing home residents (44,78,79). As with HIV-infected patients, it seems that tuberculin reactions in the elderly do not di-

288

Figure 3

Menzies

Effect of HIV infection and CD4 counts on tuberculin reaction.

minish gradually but “turn off,” suggesting that there is some threshold reached during aging. The trigger or threshold for reversion (and presumably conversion) has not been explored. Anergy testing, reviewed extensively elsewhere (80), has been suggested for the assessment of individuals with negative tests (81). Reactions to antigens such as mumps, Candida, diphtheria, or tetanus are seen in almost all healthy adults (82). 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 can be considered true negative if an individual reacts to one or more of these common antigens. As shown in Figure 5, among HIV-infected patients with negative tuberculin tests, the incidence of tuberculosis was significantly higher in those who were anergic compared to those who were not (83–85). In another study, negative tuberculin tests were strongly associated with anergy (69). 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 (72,86,87). Anergy testing may be useful for epidemiological studies in populations with high HIV sero-prevalence but is not useful in populations with low HIV sero-prevalence (88) and is no longer recommended for management of individual patients (89).

Figure 4 dents.

Effect of age on initial tuberculin reactions in Arkansas nursing home resi-

Figure 5 results.

Incidence of active tuberculosis in HIV-infected, by tuberculin and anergy test

289

290

Menzies B. False-Positive Tests: BCG Vaccination

Of the 1.2 million infants born each year worldwide, approximately 88% receive BCG (bacille Calmette-Guérin) vaccination (see Chap. 19). BCG vaccination of tuberculin negative individuals will almost invariably result in tuberculin conversion within 4–8 weeks. The size of reactions following BCG vaccination may be affected by the vaccine manufacturer (90), dose (91), as well as method of administration (91,92). On occasion, individual strains produced by different manufacturers have been associated with significantly fewer tuberculin conversions (11,90). Generally, such strains are discarded because regulatory agencies in most countries require that BCG strains induce tuberculin conversion in over 90% of recipients. This requirement is based on the belief that a positive tuberculin reaction correlates with immunity, a belief based on observations in the preantibiotic era that incidence and mortality from tuberculosis was considerably higher in nursing students who were initially tuberculin negative (93–95). However, this phenomenon was actually the result of the protective effect of prior tuberculosis infection (96). There is convincing evidence from many studies that postvaccinal tuberculin reactions have no relationship to protective efficacy (11,97–99). The continuing insistence on the part of regulatory agencies on demonstration of tuberculin reactivity following BCG vaccination is primarily because there is no alternative practical way to measure immunity. From a tuberculosis-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 2 months of BCG vaccination, these reactions will wane over time. There have been numerous studies of the effect of BCG vaccination on tuberculin reactions, but many of these relied on the presence of BCG scars, which may not form in 20–25% of recipients (100,101). Also, the effect of BCG vaccination on tuberculin reactions will be overestimated in populations with a high prevalence of infection with tuberculosis or nontuberculous mycobacteria (101–104). As summarized in Table 4, virtually all subjects who received BCG vaccination in infancy will have reverted to negative within 5 years. This may reflect the relative immaturity of the immune system in infancy (105), although protective efficacy is, if anything, higher (102,106). Of those vaccinated at an older age, tuberculin reactions are larger and wane more slowly, although after an interval of more than 10 years, further waning does not appear to occur and tuberculin reactions persist in a subgroup of 15–25%. The size of tuberculin reactions in this subgroup is similar to the size of reactions in tuberculosis-infected persons, suggesting that in this group, as well, tuberculin reactions represent an all-or-nothing phenomenon and may be genetically determined (107,108). In the great majority of countries with intermediate or high incidence of tuberculosis, BCG vaccination is given routinely at birth and often repeated in primary school. As shown in Figure 6, among foreign-born schoolchildren and young

Tuberculin Skin Testing Table 4 Author (Ref.) Lifschitz (177) Margus (178) Joncas (179) Karalliede (180) Sepulveda (181) Friedland (182) Menzies (183) Comstock (184) Bahr (102) Horowitz (90) Joncas (179) Menzies (183) Margus (178)

291

Effect of BCG Vaccination on TST in General Population Samples Year of study

Setting

No. of subjects

Age vaccinated (yr)

Age tested (yr)

TST  10mm (% pos.)

1965

Arizona

250

0–1

1–6

0

1965

Israel

758

0–1

1–2

7

1975

Montreal

68

0–1

1

5

1985

Sri Lanka

106

0–1

1

18

1988

Chile

40

0–1

6

10

1990

Southern Africa

85

0–1

1

/2–5

13

1992

Montreal

162

0–1

11–17

1.7a

1971

129

1–18

18–21b

16

1987

Southern United States Lebanon

1200

5

10–14

35

1972

Denmark

955

6

11

60–80

1975

Montreal

165

6

7

1992

Montreal

469

6–8

1965

Israel

241

13

73

15–25

23

14

14

a

No significant differences compared to 1064 nonvaccinated schoolchildren of same age an socioeconomic status. b Minimum interval between BCG and TST was 8 years.

adults in Montreal, history of BCG vaccination appeared to be an important cause of reaction in subjects from low-incidence countries but was less and less important with greater incidence of tuberculosis in their country of origin (109). C. False-Positive Tests: Nontuberculous Mycobacteria

Nontuberculous mycobacteria (NTM) exist in soil and water in the environment, particularly where the climate is warm and moist (110–113). The mechanism of

292

Figure 6

Menzies

Effect of BCG vaccination on initial tuberculin skin test reactions.

acquisition of 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. Although much less pathogenic than M. tuberculosis (114), these NTM are important because they may result in disease in humans, particularly lymphadenitis in young children, pulmonary disease in adults, and disseminated disease in patients with advanced immune suppression (115,116). Antigens purified from the nontuberculous mycobacteria (NTM antigens) have been used for the diagnosis of patients with disease due to these mycobacteria. Sensitivity and specificity vary considerably between studies and NTM antigen cannot, as yet, be recommended for routine clinical use in the differentiation of nontuberculous mycobacterial disease (117–120). The NTM are also important because of the similarity of NTM antigens to tuberculous antigens resulting in cross-reactivity when tuberculin testing. In experimental studies, animals infected with different mycobacteria developed the largest reactions to antigens prepared from that specific mycobacteria (121,122). They also manifested reactions to antigens from other mycobacteria, although these were smaller. As shown in Figure 7, the distribution of reactions to RT-23, PPD-S, or PPD-T in different parts of the world (63) could be reproduced by test-

Tuberculin Skin Testing

293

ing with these antigens in groups of guinea pigs with varying proportions of uninfected, infected with M. tuberculosis, or infected with nontuberculous mycobacteria (122). As shown in Table 6, the relative importance of NTM as a cause of falsepositive tuberculin tests depends upon the frequency of sensitization to nontuberculous mycobacteria, which is determined primarily by climate and geography, and the occurrence of tuberculosis infection, which is low and declining rapidly in many countries. If sensitivity to NTM remains stable and prevalence of tubercu-

Table 5 Prevalence of Positive Reactions to Nontuberculous Mycobacterial Antigens (Non–BCG-Vaccinated Only) Positive reactions (5 mm)

Population Author, year (Ref.) Edwards, 1958–65 (147) Bleiker, 1965–70 1980–85 (185) Jeanes, 1967 (186) Grzy, 1967 (27) Paul, 1975 (187) Karditjo, 1985 (188) Lind, 1986 (189) Menzies, 1987 (109) Ly, 1989 (190) a

Country

Type

Age (yr)

No.

Antigen

No.

(%)

90,935

33

712 2,152 21

5

817 1782

15 7

PPD-Be PPD-Ge PPD-Aviumc

426 538 86 213

11 19 18 62

PPD-Scrof d

30

88

PPD-Bb

United States

Military recruits

17–22

275,558

Netherlands, Delft

Students students

7–14 7–14

13,546 10,312

PPD-Scrof a PPD-Scrof a

Canada

Students

15–17

5,552 24,763

PPD-Be PPD-Ge

Canada, British Columbia Kenya

Students

14–19

Students

6–10 11–17

3,917 2,884 477 344

Indonesia

Healthy adults

21

34

Sweden

Students

8–9

1,368 1,451

RS10a RS15a

442 554

32 38

Canada, Montreal

Students foreign-born

11–17 11–25

3,710 875

PPD-Be PPD-Be

122 57

3 7

Vietnam

Students

7–19

153 155

56 36

37 23

PPD-Aviumd PPD-Scrofd

Serum Statens Institute, Copenhagen — RS10 from M. Avium, RS15 from M. scrofulaceum. U.S. Public Health Service Laboratories — PPD-B, PPD-G. c Prepared in London from organisms isolated from soil/water in Uganda. d Prepared in London from respective organisms. e Connaught Laboratories — PPD-B from M. intracellulare and PPD-G from M. scrofulaceum. b

294

Menzies

Figure 7 Reactions to PPD-S among populations of guinea pigs with varying proportions of mycobacterial infections (top and bottom left), and in schoolchildren in Pakistan (top right), and North Carolina (bottom right). (From Ref. 122.)

losis infection declines, the relative importance of NTM will increase. Reactions to PPD-T in persons infected with NTM are less severe than in persons infected with M. tuberculosis. Therefore, increasing the cut-point for a positive test will improve the specificity. This is the rationale for the recommendation of a 15-mm cut-point in United States (123) where the expected prevalence of NTM sensitivity is high (at least in the southern United States) and true tuberculosis infection low. It should be remembered that the 15-mm cut-point for a positive test is close to the mode of tuberculin reactions in those with true infection (63), so adoption of this cut-point will improve specificity, but the sensitivity of the tuberculin test will be reduced to approximately 50%. In experimental animals infected with NTM, the proportion demonstrating cross-reactivity to tuberculin antigens was reasonably constant (122). One would predict that this should also be true in human populations, although the ratio of NTM reactions to false-positive tuberculin reactions varies considerably (Table 6). However, the age and ethnic origins of populations studied varied consider-

295

3710

875

8–9

11–25

Sweden

Montreal (Can.-born)

Montreal 11–25 (Foreign-born)

1,368 1,451

542

15–19

Quebec

5,552 24,763

No.

15–17

Age

Canada

Setting

Population

PPD-B

PPD-B

RS10 RS95

Battey

PPD-B PPD-G

Antigenb

93

103

442 554

30

817 1782

57

34

140 192

9

N/A N/A

127

80

81 80

9

52 246

 5 mm  10 mm Total (N) (N) N

Reactions to NTMa

54

15

58 61

2

19 128

42%

19%

72% 76%

22%

37% 52%

NTM
PPD-T (N) (%)c

5–9 mm

393

90

11 6

12

93 299

0

9% 21%

16

2

4%

2%

9 82% 6 100%

0

8 64

Total NTM  PPD-T N (N) (%)c

10 mm

Reactions to PPD-T (for MTB)

Effect of Nontuberculous Mycobacteria on Tuberculin Reactions (Non–BCG-Vaccinated Populations)

b

If reaction to NTM was smaller than simultaneous reaction to PPD-T, then it was assumed to represent a cross-reaction and considered negative (0MM). Antigens: PPD-B, prepared from M. intracellulare (Connaught Labs, Toronto, Canada); PPD-G, from M. scrofulaceum (Connaught Labs, Toronto, Canada); RS10, prepared from M. avium (Statens Serum Institute, Coppenhagen, Denmark); RS95, prepared from M. scrofulaceum (Statens Serum Institute, Coppenhagen, Denmark); Battey, prepared from M. intracellulare (Statens Serum Institute, Coppenhagen, Denmark). c Percent of subjects with reactions to PPD-T of 5–9 mm or 10 mm which may have been due to cross-reactivity to NTM antigens because they had larger simultaneous reactions to the NTM antigens.

a

Jeanes, 1967 (186) Frappier, 1975 (191) Lind, 1986 (189) Menzies, 1987 (192) Menzies, 1987 (109)

Author, year (Ref.)

Table 6

296

Menzies

ably, and the nontuberculous mycobacterial antigens used have never been standardized (124). IV. Complicated Cognitive Aspects: Interpreting Tuberculin Tests A. Expected Prevalence of True Positive Tests (Tuberculosis Infection)

As shown in Table 7, the prevalence of positive tuberculin tests in non–BCG-vaccinated populations in North America varies widely. Prevalence is very low in schoolchildren and young adults, although it is substantially higher in certain ethnic minorities (125–127). Particularly high rates of infection are found among the urban poor such as intravenous drug users (IVDU), persons receiving social assistance (128,129), and homeless persons (130,131). 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 tuberculosis in their country of origin and age of immigration (Fig. 8). Another group with high prevalence of infection is contacts of active cases as summarized in Table 8. In these studies risk of infection was consistently higher if the index case was smear positive or if the contact was close. However, absoTable 7 Prevalence of Positive Tuberculin Reactions (Results of Mantoux Testing with PPD5TU or RT23-2TU) Author, year (Ref.)

Country (city)

Population

Ethnic group

Age, mean (SD) or range (yr)

No. tested (N)

TST positive (10 mm) No.

%

A. Native-Born, Non–BCG-Vaccinated General Population Comstock, 1958–69 (125) Reichman, 1973–74 (193) Cross, 1980–86 (194) Menzies, 1987 (192) Barry, 1987 (126) Trump, 1990 (127) Menzies, 1990 (146)

United States

Military recruits

Whites, blacks

17–22 17–22

1,125,193 70,550

42,757 8,749

3.8 12.4

United States (New York)

Workers, Board of Education Military recruits

White, black, Hispanic All

20–68 20–68 20–68 17–22

37,224 10,364 2,744 618,074

3,094 2,384 706 8,962

8.3 23 26 1.5

Canada (Montreal)

Schoolchildren

95% white

11 (1) 16 (2)

1351 628

17 18

1.3 2.9

United States (Boston)

Schoolchildren

United States

Military recruits

Canada (Montreal)

University students

White, black, Hispanic White, black, Hispanic 95% white

16 (2) 17 (2) 17 (2) 17–24 17–24 17–24 21 (2)

661 1235 457 1,588 386 167 837

9 60 29 12 20 9 15

1.4 4.9 6.4 0.8 5.2 5.4 1.8

United States

Tuberculin Skin Testing

297

Table 7 Continued Author, year (Ref.)

Country (city)

Population

Ethnic group

TST positive (10 mm)

Age, mean (SD) or range (yr)

No. tested (N)

No.

%

3,788

853

23

B. Prevalence in Special Populations Reichman, 1973 (129) Several, 1982–89 (44,144,195) Friedman, 1984 (128) Gzrybowski, 1985 (196) Paul, 1993 (131) Zolopa, 1994 (130)

United States (New York)

Methadone clinic

All

N/A

United States Canada Holland United States (New York)

Nursing home residents ETOH/Drug users, welfare Urban poor

All

White, black, Hispanic White males

50–74 75–84 85 36 (9) 36 (9) 36 (9) 15–34 35–54

340 559 643 97 477 311 170 254

155 156 112 17 158 95 28 113

46 28 17 18 33 31 16 44

Canada (Vancouver) United States (New York)

Homeless

All

35 (9)

104

72

69

United States (San Francisco)

Homeless

All

36

843

270

32

United States

Southeast Asia

Refugees

All ages

9328

3300

35

United States

Southeast Asia

Refugees

21

954

424

44

Netherlands

Southeast Asia

Refugees

18

221

86

39

United States

Southeast Asia

Refugees

11–19

77

40

52

Britain

India/ Pakistan

New immigrants

0–14

231

30

13

Pakistan

Afghanistan

Male refugees

8 (1)

1358

187

14

Canada

All countries

Refugees

21

865

329

38

Canada

TB endemic

Schoolchildren, 21 (3) workers

780

288

37

United States

90% from Mexico

Immigrant applicants

All ages

4,840

2039

42

Canada

All countries

Schoolchildren 13 (5)

720

162

23

C. Foreign-Born Populations Nolan, 1980–81 (149) Morse, 1980 (197) Veen, 1981 (68) Fitzpatrick, 1981–85 (198) Omerod, 1983–88 (199) Spinaci, 1985 (200) Godue, 1987 (201) Menzies, 1987–88 (109) Blum, 1988 (202) Yuan, 1992 (203)

Figure 8 Prevalence of positive tuberculin reactions in foreign-born according to age at which immigrated. Immigrants in Montreal grouped into those from regions with intermediate (TB inter) or high (TB endemic) rates of TB.

Table 8 Prevalence of Positive Tuberculin Reactions in Contacts of Active Cases (All Cases Culture-Confirmed Active Pulmonary TB) Contacts Author, year (Ref.)

TST positive

General population TST (%)

Country (population)

Age range

Tested (yr)

(N)

(%)

England (general)

0–14

225

164

73

38

All Ages

3,330

1732

52

13a

0–19 0–19 0–14

2,501 854 115

1209 466 80

48 55 70

21 41 1

0–16

155

37

24


1

A. Smear-Positive Cases Close/Household Contact Zwanenburg, 1949–53 (204) Zaki, 1965–72 (205) Grzybowski, 1966–71 (206) Van Geuns, 1967–69 (207) Karalus, 1980/84 (208)

New York City (general) Canada (white) (aboriginal) Holland (general) New Zealand (general)

Tuberculin Skin Testing

Table 8

299

Continued Contacts

Author, year (Ref.) Casual Contact Grzybowski, 1966–71 (206) Van Geuns, 1967–69 (207) Karalus, 1980–84 (208)

TST positive

General population TST (%)

Country (population)

Age range

Tested (yr)

(N)

(%)

Canada (white) (aboriginal) Holland (general)

0–19 0–19 0–14

5,364 654 1,733

1630 327 519

30 50 30

21 41 1

0–16

898

10

1.1


1

0–14

96

44

46

38

All ages

1096

437

40

13a

0–19 0–19 0–14

1340 527 128

399 237 45

30 45 35

21 41 1

0–16

146

2

1.4


1

0–19 0–19 0–14

2270 413 602

442 161 141

20 39 23

21 41 1

0–16

307

0

0


1

New Zealand (general)

B: Smear-Negative, Culture-Positive Cases Close/Household Contact Zwanenburg, 1949–53 (204) Zaki, 1965–72 (205) Grzybowski, 1966–71 (206) Van Geuns, 1967–69 (207) Karalus, 1980–84 (208) Casual Contact Grzybowski, 1966–71 (206) Van Geuns, 1967–69 (207) Karalus, 1980–84 (208) a

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

General population estimate for this study from Ref. 193.

lute levels of risk have been estimated in relatively few studies that measured the prevalence of infection in noncontacts from the general population. B. Predictive Value of a Positive Initial Tuberculin Test

As shown in Table 9, BCG vaccination and nontuberculous mycobacteria have important effects on the predictive value when the expected prevalence of true in-

None

Age of 6

Age of 6

Southern United States

Western Europe

Southeast Asia (newly arrived)

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

Clinical situationa 2 40  2 10  2 2 40  2 10  2 2 40  2 10  2 50 70 (40  50) 55 (10  50)

True positive 2 2 2 6 6 6 4 4 4 6 6 6

NTM — — — — — — 15 15 15 15 15 15

BCG

False positive

Expected prevalence of reactions (%)b

50 95 86 25 88 67 10 69 39 83 92 85

Predictive value of a positive test (%)

b

Clinical situation: screening means test done in absence of exposure/risk factor; contacts are of smear-positive, culture-positive case of TB. Expected prevalence is prevalence of TB infection in 20-year-olds from general population plus additional prevalence infected depending on clinical situation (see Table 7 for prevalence in population and Table 8 for prevalence according to the clinical situation).

a

None

Northern United States or Canada

History of BCG vaccination

Predictive Value for TB Infection of a Positive Initial TST (10 mm) in a 20-Year-Old Adult

Subject born in

Table 9

300 Menzies

Tuberculin Skin Testing

301

fection is low, such as in screening situations. On the other hand, when the expected prevalence of tuberculous infection is high, such as in close contacts of smear-positive cases or immigrants from tuberculous-endemic areas, then the predictive value of a positive tuberculin test is high even in those with BCG vaccination and possibly sensitized to nontuberculous mycobacteria. In these situations, the effects of BCG vaccination and sensitivity to NTM can be ignored. C. Risk of Tuberculosis for a Given TST

Interpretation of the tuberculin skin test (TST) as true positive is only part of the evaluation. The second step is the assessment of risk of development of disease. As shown in Table 10, the likelihood of developing tuberculosis disease varies by several orders of magnitude in different populations with positive TST. Interestingly, the incidence of tuberculosis was lower among reactors in the Danish study (132,133) than the incidence in some tuberculin-negative groups in other studies (125,134,135). Use of this Danish data would substantially bias cost-benefit or risk-benefit analyses because these results likely represent an underestimate of the likelihood of disease in most tuberculin reactors. D. Serial Tuberculin Testing: Boosting, Conversion, and Reversion

Repeated tuberculin testing can result in larger reaction sizes because of nonspecific variation or as a result of boosting conversion. Nonspecific increases occur because of differences in administration, reading, and minor variation in response. The combined effect of these factors result in standard deviation of results of 2–3 mm (Table 2). Therefore, random variation should result in increased reactions of less than 6 mm (two standard deviations) in 95% of all those tested (136). Increases of 6 mm or more, therefore, should represent a true biological phenomenon but could be conversion or boosting. Both terms refer to a newly positive tuberculin test after an initially negative test. Boosting is defined as recall of immunity in the absence of new infection, whereas conversion is defined as development of new hypersensitivity to mycobacteria following new infection either with tuberculous or nontuberculous mycobacteria, including BCG vaccination. This distinction is not merely academic—boosting is associated with a substantially lower risk of tuberculosis of as little as 0.05% annually, whereas conversion has been associated with annual incidence of tuberculosis of 4% in adolescents (137) or 6% in contacts of smear-positive cases of active TB (138). The boosting phenomenon, first noted among BCG vaccine recipients in 1955 (139), is seen when there has been mycobacterial sensitization many years earlier. It is believed to occur when there are too few sensitized lymphocytes in circulation to produce a significant local response following the initial intradermal injection of tuberculin material. However, this injection results in a rapid increase

302

Menzies

Table 10 Risk of TB According to TST Reactions and Other Factors Risk group author, year (Ref.) HIV-infected Selywn, 1989 (209) Moreno, 1993 (85) Guelar, 1993 (83) Antonucci, 1995 (84) Abnormal chest x-ray Hong Kong Chest Service, 1992 (210) Nolan, 1980 (149) IUAT, 1982 (211)

Population

Country

Group

Follow-up period (yr)

TST (criterion)

Annual incidence of TB (per 100,000)

49 168 108 268

5
5 5
5b

7,900 300 10,400 8,290

87 733

5a
5b

11,100 2,350

197 2,498

5
5b

5,420 2,130

2–5

116

10c

5,400

5

185

10

650

5

6,990 4,701 2,094

6

286 232

12

286,000

6

United States

IVDU

2–5

Spain

IVDU

2–6

Spain

IVDU

1.3 (1)

Italy

IVDU

2

Hong Kong

Elderly men With silicosis

United States

Vietnam refugees

Eastern Europe

Inactive TB Overall Lesions
2cm Lesions 2cm

Horwitz, Denmark 1969 (132) Contacts and abnormal chest x-ray Veening Netherlands (138) Recent conversion Sutherland Britain (137) Normal chest x-ray, no other risk factor Comstock, Alaska 1967 (212) Nolan, United States 1980 (149) Palmer, United States 1968 (134) Comstock, United States 1974 (125)

Young adults Suspicious Calcified

Contacts of S 128 cases First year Next 3 years Adolescence

Inuit

2

5.8

Vietnam refugees

5

Military recruits

4

Military recruits White Black Asian

4

Number

426 710 48

≥5 7,031 2,521 2,170

5 20

2600 4250

570 275

5
5

972 378

3,115 6,028

10
10

133 10

12 1–11 0

377 110 36

10 10 10

79 93 196

1,082,336 62,027 8,238

Tuberculin Skin Testing

303

Table 10 Continued Risk group author, year (Ref.)

Population

Country

Group

Follow-up period (yr)

Ferebee, 1959 (135)

United States

Mental institution patients

Comstock, 1974 (213) Horwitz, 1969 (132)

Puerto Rico

Children

Denmark

Young adults

Number

10

18–20

82,269

12

286,000

TST (criterion) T1  10 T1  5–9 T2  10 T2
5 6d

6e

Annual incidence of TB (per 100,000) 122 82 66 19 90

23

a

Excludes those still on INH therapy. Anergic and nonanergic combined. c 94% had reactions of 10 mm to 1 TU of RT23. d Tested with 1 or 10 Tu RT–20/2 22. e Tested with 10 Tu. b

in the population of sensitized lymphocytes in circulation, so that a second test as little as a week later will produce a much larger reaction. Boosting is maximal if the interval between the first and second test is between 1 and 5 weeks (135,140,141) and is significantly less frequent if the interval is only 48 hours (142) or more than 60 days (141), although it can be seen up to 2 years after a first tuberculin test (139,142,143). As shown in Table 11, the boosting phenomenon has been demonstrated in almost all populations. The prevalence is usually less but is roughly proportional to the prevalence of initial tuberculin reactions in the same populations. In elderly patients, boosting may occur after a third (78) or even a fourth (144) sequential test. This has also been described in a group of malnourished Southeast Asian refugees (68). As shown in Table 12, boosting is strongly associated with BCG vaccination at all ages. As shown in Figure 9, among foreign-born subjects history of BCG vaccination was a more important cause of boosting than country of origin (109). In a study of persons sensitized to NTM antigens, only 1–4% had significant reactions to a first test with 5 TU of PPD-T, compared to 12–13% who demonstrated boosting after a second test with the same antigen (Table 13) (145,146). Based on this, it could be predicted that of young adults in the southern United States, 70% of whom will be sensitive to NTM antigens (147), only 1–3% will have positive initial reactions to PPD-T but 7–9% will demonstrate

304

Menzies

Table 11 Prevalence of Positive Initial and Second TST from Two-Step Testing Author (Ref.)

Population Health-care workers

Nursing home residents

Hospital patients HIV-infected IVDU Foreign-born

No. subjects undergoing T1

Setting

Percent with positive Initial testa

Second testb

Thompson (142)

United States

750

N/A

5.91

Bass (143) Valenti (214) Menzies (146) Gross (215) Richards (145) Slutkin (44)

Alabama Rochester, NY Montreal Maryland Chicago San Francisco

N/A 416 951 2558 267 411

8.2 3.1 2.2 3.8 2.6 35

8.31 01 2.51 0.33 6.61 61

Gordin (78)

San Francisco Washington W. Virginia Tennessee Holland

1726

28

141

510 223

30 29

190 141

Boston Boston United States Uganda United States

323 162 709 345c HIV 900 HIV 95 211 2469 323 524 221

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

61 61 2.72 292 83 122 311 31 161 43 183

Alvarez (216) Van den Brande (144) Barry (217) Burstin (218) Webster (219) Hecker (220) Lifson (221) Morse (222) Cauthen (141) Menzies (109) Morse (197) Veen (68)

New York State United States Montreal New York State Netherlands

Initial test—% based on number undergoing T1, considered positive if 10mm. Second test—% based on number undergoing T2, considered positive if: 0—no definition; 1—▲ 6 10; 2—T1
5, T2  5; —T1
10, T2  10. c Number extrapolated from figures given in paper. a

b 3

Table 12

Effect of BCG Vaccination on the Booster Effect in Two-Step Tuberculin Testing

Author (Ref.)

Year

Sepulveda (181) Friedland (223) Sepulveda (224) Menzies (146)

1988 1990 1990 1994

a

Setting Chile Southeast Africa Chile Montreal

No. of subjects 36 102 73 380 210

Age vaccinated (yr) 0–1 0–5 0–14 0–1 2–8

Definitions of Booster: T1
10mm; T2  10mm and increased by at least 6mm.

Age tested (yr)

% with Boostera

6 1–14 19–22 17–25 17–25

31 16 26 8 15

Tuberculin Skin Testing

Figure 9

305

History of BCG vaccination on reactions to second tuberculin test (boosting).

boosting—remarkably close to observed results in health-care workers in Alabama (143). There has been considerable debate regarding the definition of boosting. This debate seems pointless as there is no evidence that the size of the boosting reaction determines prognosis (except if one is using size to distinguish boosting

Table 13 Effect of Non Tuberculous Mycobacteria on the Booster Phenomenon in 2-Step Tuberculin Testing Author (Ref.) Richards (145) Menzies (146) a

Year

Place

No. tested

1979

Chicago

1994

Montreal

No. response to NTM a

Sensitive to NTM

N

% Boosting

N

% Boostinga

213

110

1

103

13

277

252

1.6

25

12

Initial PPD-T (for MTB)
10mm. Second PPD-T  10mm and increased by at least 6mm.

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from conversion—see below). A simple and practical definition is that the second test is positive if induration is 10 mm or greater. Subjects with such a result should be referred for medical evaluation including a chest x-ray and not undergo further tuberculin testing. If the chest x-ray is normal and there are no associated factors that increase the risk of tuberculosis reactivation, then preventive therapy is probably not warranted. This is because a positive second TST is much less likely to represent true infection (141,146) and because in two longitudinal surveys, the risk of tuberculosis was lower in subjects with a positive second TST compared to subjects with a positive initial TST from the same population (135,148). It must also be remembered that in several large-scale longitudinal surveys, the risk of tuberculosis was very low among those whose initial TST was less than 10 mm (125,149). Boosting is best distinguished from conversion on clinical grounds. One can confidently attribute an increase in reaction size to boosting when the increase in reaction is seen after an interval of 1–5 weeks and there has been no possibility of exposure, such as a health-care worker undergoing preemployment testing. On the other hand, conversion can be confidently stated to have occurred following BCG vaccination in a previously tuberculin-negative individual or in a situation of high risk of exposure, such as in an outbreak investigation or a close contact of a highly contagious index case. One can also be more confident that an increased reaction is due to true conversion if several prior tuberculin tests were negative, particularly if two-step tuberculin testing was performed (143). But in many situations, it is difficult to distinguish conversion from boosting on clinical grounds alone. In these situations, the size of the second reaction and/or the increase in size can be used, although many conflicting size criteria have been recommended, i.e., increases of 10 mm (150,151), 12 mm (152), 15 mm (123), and 18 mm (153). The last three criteria are based on cross-sectional studies in elderly subjects (152) populations with high prevalence of BCG vaccination and/or NTM (153,154). These studies did not fully account for the possibility of boosting, which may have influenced the findings (see Tables 11–13). At the present time it is difficult to recommend any one cut-point to define conversion. The criterion should be lowered for young children or adolescents, close contacts, and immunocompromised hosts, because they have increased risk of disease. The cut-point should also be lowered if there have been two or more negative tuberculin tests in the past—particularly if prior two-step testing has been negative. As with initial tuberculin testing, tuberculin conversions should be interpreted in light of the likelihood of true conversion as opposed to boosting and the likelihood of disease, if truly infected, as well as risks of preventive therapy in a particular patient. Another important issue is the interval between acquisition of infection and tuberculin conversion, which determines the interval between the first and second

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307

test in contact investigations—the so-called window period. Traditionally, this has been considered to be 12 weeks (116), but all available evidence from BCG vaccination and natural infection points to a shorter interval. Following BCG vaccination, all but one of 120 recipients had TST reactions of 11 mm within 6 weeks (155). In a separate group of 163 BCG recipients, all had TST 5 mm in less than 4 weeks (155). In animals experimentally infected with M. tuberculosis, all developed a positive TST within 2–3 weeks if the bacillary load was small (156), as it usually is in natural infection. Following inadvertent vaccination with M. tuberculosis (the Lübeck disaster), tuberculin reactions were positive in all children within 3–7 weeks (157). As shown in Figure 10, the interval from exposure to development of clinical illness accompanied by a positive tuberculin test averaged 37 days and ranged from 19 to 57 days in 127 well-documented cases (158–160). If the interval from infection to conversion is never more than 8 weeks, then the window period for contact investigation could be shortened to 8 weeks. This would mean that new conversions among high-risk contacts would be detected one month sooner. A more important advantage is that this could simplify the contact investigation of low-risk casual contacts and substantially reduce the

Figure 10 Interval from infection to tuberculin conversion in 127 cases with documented time of exposure. (From Refs. 158–160.)

308

Menzies

occurrence of false-positive conversions. As shown in Table 14, when two sequential tuberculin tests are done, boosting is much more likely to account for apparent conversion in casual contacts in populations where BCG or NTM sensitivity are common. This results in unnecessary medical and radiological evaluation as well as potentially unnecessary therapy for these individuals. Also, the resultant overestimate of conversion may result in further extension of contact investigation. In most situations, 4–6 weeks are needed to confirm M. tuberculosis in the index case, evaluate the close or high-risk contacts, and identify lower-risk casual contacts. This means that the first tuberculin test is usually given 6–8 weeks after the contact is broken. Following current recommendations, tuberculin testing is then repeated 12 weeks after the contact was broken. If all tuberculin conversions have occurred by 8 weeks, then a single tuberculin test at 8 weeks would be sufficient to detect all low-risk casual contacts with infection. Performing only one test would avoid the difficulties of distinguishing boosting from conversion in this group. Waiting for 8 weeks to perform a single test would not be appropriate for contacts who are young children and/or are immunocompromised, such as HIV-infected populations, where false-positive results from boosting are of less concern and risks resulting from new infection are much greater. Serial tuberculin testing has also revealed that tuberculin reversion may occur (28). Among 179 sailors treated with INH following tuberculin conversion, the majority later demonstrated reversion (161), although some of the initial tuberculin conversions may have actually resulted from the booster phenomenon in this study. Among South African schoolchildren with reactions of 14 mm who were retested three times over the next 2 years, average reaction size was slightly smaller (perhaps because of regression to the mean), but more than 95% of reactions remained 10 mm on all occasions (162). Of 346 children with TST 10 mm who were treated for primary tuberculosis in Houston between 1953 and 1960 and were retested 3–10 years later, only 29 (8.4%) reverted (163). Reversion is most common for those who react only to 250 TU dose (28), have initial reactions in the 5- to 9-mm range (163) or in the 10- to 14-mm range (28,161,164), or demonstrate the booster phenomenon (79,164). Reversion is also more likely if only a third sequential tuberculin test is positive (164). The phenomenon of reversion emphasizes that once a tuberculin reaction reaches 10 mm or greater, results of further testing become uninterpretable. If the tuberculin reaction reverts to negative and then becomes positive again, no clinical or epidemiological information is available to allow interpretation of such a phenomenon.

None

Age of 6

Age of 6

Southern United States

Western Europe

Southeast Asia (newly arrived)

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

Clinical situationa 1 10  1 2.5  1 1 10  1 2.5  1 1 10  1 2.5  1 15 15  10 15  2.5

True positive 2 2 2 8 8 8 5 20 5 8 8 8

NTM — — — — — — 20 20 20 20 20 20

BCG

False positive

Expected Prevalence of Reactions (%)b

33 85 64 11 58 30 4 33 13 39 54 43

Predictive value of a positive test (%)

b

Clinical situation: screening means test done in absence of exposure/risk factor; contacts are of smear-positive, culture-positive case of TB. Expected prevalence is prevalence in general population plus added prevalence infected from clinical situation (screening—no additional; contacts—from Table 11).

a

None

Northern United States or Canada

Subject born in

History of BCG vaccination

Table 14 Predictive Value of a Positive Second TST in a 20-Year-Old Adult (Second Test Performed 1–3 Months After Initial Negative TST)

Tuberculin Skin Testing 309

310

Menzies V. Conclusions

The following can be concluded about tuberculin skin testing: 1. The tuberculin skin test is a test—not a condition. 2. As with all tests in clinical medicine, the tuberculin test is most useful when used selectively, i.e., when there is a good indication to perform the test. 3. Tuberculin testing can not be recommended for the diagnosis of active disease—specificity is very low and sensitivity is only 70–85%. 4. Although the dictum “once positive always positive” may not be true, the corollary “once documented positive no further utility” is correct. All tuberculin reactions that are 10 mm (or 5 mm in certain situations) should be considered positive. Individuals with positive tests should be referred for medical and radiological evaluation, and tuberculin testing should not be repeated if proper documentation is available. 5. Rather than rely simply on cut-points, more emphasis should be placed on understanding the predictive value of a positive test based on the likelihood of true and false, positive and negative reactions in the population being tested. 6. There is no association between tuberculin reactions and immunity subsequent to BCG vaccination. Therefore the ideal BCG vaccine would stimulate immunity while having no effect on tuberculin reactions. 7. The boosting phenomenon is common and in many populations is almost as frequent as initial tuberculin reactions. However, it is much less specific because it is strongly affected by sensitivity to NTM antigens as well as prior BCG vaccination. Therefore, the likelihood of future development of tuberculosis is lower than for positive initial reactions in the same population. 8. In populations with high prevalence of sensitivity to NTM antigens and/or BCG vaccination who undergo two sequential tuberculin tests, a significant proportion will manifest the boosting phenomenon. 9. Tuberculin skin test conversion occurs within 8 weeks of mycobacterial infection. 10. The best definition of tuberculin conversion remains unclear, because there are few data from cohort studies. Examination of tuberculin reactions from cross-sectional studies in different populations suggests that 10 mm remains a useful criterion and that larger increases will be more specific but will reduce sensitivity substantially. 11. Among casual contacts, even of smear-positive cases, undergoing a second tuberculin test at the end of the “window period,” the majority of new reactions detected will result from the boosting phenomenon

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rather than new infection. Therefore, investigations of casual low-risk contacts should be restricted to a single tuberculin test performed 8 weeks following the end of exposure. 12. Anergy testing, while useful in population studies, is of limited clinical value in the management of individual patients. 13. After close to 100 years of use, there is an enormous amount of clinical and epidemiological information available to assist in interpretation of the tuberculin test, but we still cannot identify with certainty those who will develop the disease. New molecular biology techniques may improve our understanding of the tuberculin reaction and thereby our ability to predict this. Acknowledgments The author acknowledges with thanks additional information, suggestions and comments on an earlier draft of this paper provided by Drs. George Comstock, Cindy Driver, Anne Fanning, the late Stephan Grzybowski, Sonal Munsiff, William Stead, and Jaap Veen. The author also thanks Mme Sylvie Ouimet for, seemingly endless, secretarial support. References 1. Koch R. An address on bacteriological research. Br Med J 1890; 2:380–383. 2. von Pirquet C. Frequency of tuberculosis in childhood. JAMA 1907; 52:675–678. 3. Mantoux MC. La voie intradermique en tubercalinothérapie. Presse Med 1912; 20:146–148. 4. Landi S, Held HR, Gupta KC. The multi-facets of tuberculin standardization. International WHO IABS Symposium on Standardization and Control of Allergens Administered to Man, Geneva, 1974. Dis Biol Stand 1975; 29:393–411. 5. Seibert FB, Glenn JT. Tuberculin purified protein derivative: preparation and analyses of a large quantity for standard. Am Rev Tuberc 1941; 44:49. 6. Landi S, Held HR, Tseng MC. Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Am Rev Respir Dis 1971; 101:385–393. 7. Holden M, Dubin MR, Diamond PH. Frequency of negative intermediate-strength tuberculin sensitivity in patients with active tuberculosis. N Engl J Med 1971; 285:1506–1509. 8. Grzybowski S, Dorken E, Bates C. Disparities of tuberculins. Am Rev Respir Dis 1969; 100:86–87. 9. Guld J, Magnus K, Magnuson M. Instability of the potency of tuberculin dilutions. Am Rev Tuberc 1955; 72:126–128. 10. Swanson Beck J. Skin Changes in the tuberculin test. Am Rev Respir Dis 1979; 120:59–65. 11. Hart P, Sutherland I, Thomas J. The immunity conferred by effective BCG and vole bacillus vaccines, in relation to individual variations induced tuberculin sensitivity and technical variations in the vaccines. Tubercle 1967; 48:201–210.

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107. Schier DJ, Sternick JL, Allen EM, Moore VL. Genetic basis of BCG-induced suppression of delayed hypersensitivity. Nature 1981; 289:405–407. 108. Sepulveda RL, Heiba IM, King A, Gonzalez B, Elston RC, Sorensen RU. Evaluation of tuberculin reactivity in BCG-immunized siblings. Am J Respir Crit Care Med 1994; 149:620–624. 109. Menzies RI, Vissandjee B, Amyot D. Factors associated with tuberculin reactivity among the foreign-born in Montreal. Am Rev Respir Dis 1992; 146:752–756. 110. Kirschner RA, Parker BC, Falkinham JO. Epidemiology of Infection by nontuberculous mycobacteria. Am Rev Respir Dis 1992; 145:271–275. 111. George KL, Parker BC, Gruft H, Falkinham JO. Epidemiology of infection by nontuberculous mycobacteria. II. Growth and survival in natural waters. Am Rev Respir Dis 1980; 122:89–94. 112. Parker BC, Ford MA, Gruft H, Falkinham JO. Epidemiology of infection by nontuberculous mycobacteria. IV. Preferential aerosolization of Mycobacterium intracellulare from natural waters. Am Rev Respir Dis 1983; 128:652–656. 113. Fry KL, Meissner PS, Falkinham JO. Epidemiology of infection by nontuberculous mycobacteria. VI. Identification and use of epidemiologic markers for studies of Mycobacterium avium, M. intracellulare, and M. scrofulaceum. Am Rev Respir Dis 1986; 134:39–43. 114. Robakiewicz M, Grzybowski S. Epidemiologic aspects of nontuberculous mycobacterial disease and of tuberculosis in British Columbia. Am Rev Respir Dis 1974; 109:613–620. 115. Margileth AM. Nontuberculous (atypical) mycobacterial disease. Sem Pediatr Infect Dis 1993; 4:307–315. 116. American Thoracic Society. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 1990; 142:940–953. 117. Huebner RE, Schein MF, Cauthen GM, Geiter LJ, O’Brien RJ. Usefulness of skin testing with mycobacterial antigens in children with cervical lymphadenopathy. Pediatr Infect Dis 1992; 11:450–456. 118. Huebner RE, Schein MF, Cauthen GM, Geiter LJ, Selin MJ, Good RC, et al. Evaluation of the clinical usefulness of mycobacterial skin test antigens in adults with pulmonary mycobacterioses. Am Rev Respir Dis 1992; 145:1160–1166. 119. Fordham von Reyn C, Green PA, McCormick D, Huitt GA, Marsh BJ, Magnusson M, et al. Dual skin testing with mycobacterium avium sensitin and purified protein derivative: an open study of patients with M. avium complex infection or tuberculosis. Clin Infect Dis 1994; 19:15–20. 120. Marks J, Palfreyman JM, Yates MD, Schaefer WB. A differential tuberculin test for mycobacterial infection in children. Tubercle 1977; 58:19–23. 121. Smith DT, Johnston WW. Single and multiple infections with typical and atypical mycobacteria. Am Rev Respir Dis 1964; 90:899–912. 122. Palmer CE, Edwards LB, Hopwood L, Edwards PQ. Experimental and epidemiologic basis for the interpretation of tuberculin sensitivity. J Pediatr 1959; 55:413–428. 123. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990; 142:725–735. 124. Magnusson M. Tuberculins, other mycobacterial sensitins and “new tuberculins.” Eur J Respir Dis 1986; 69:129–134.

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146. Menzies RI, Vissandjee B, Rocher I, St. Germain Y. The booster effect in two-step tuberculin testing among young adults in Montreal. Ann Intern Med 1994; 120:190–198. 147. Edwards L, Acquiviva F, Livesay V, Palmer C. An atlas of sensitivity to tuberculin and PPD-B in the United States. Am Rev Respir Dis 1969; 99:1–132. 148. 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; 23:1483–1487. 149. Nolan CM, Elarth AM. Tuberculosis in a Cohort of Southeast Asian Refugees. Am Rev Respir Dis 1988; 137:805–809. 150. Canadian Thoracic Society. FitzGerald JM, ed. Canadian Tuberculosis Standards. Ottawa: Canadian Lung Association, 1996. 151. American Thoracic Society. The tuberculin skin test. Am Rev Respir Dis 1981; 124:356–363. 152. Stead WW, To T, Harrison RW, Abraham JH. Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons. Ann Intern Med 1987; 107:843–845. 153. March-Ayuela Pd. Choosing an appropriate criterion for true or false conversion in serial tuberculin testing. Am Rev Respir Dis 1990; 141:815–820. 154. Bass JB, Sanders RV, Kirkpatrick MB. Choosing an appropriate cutting point for conversion in annual tuberculin skin testing. Am Rev Respir Dis 1985; 132:379–381. 155. Guld J. Response to BCG Vaccination. In: Edwards LB, Palmer CE, Magnus K., eds. Studies at the WHO Tuberculosis Research Office, World Health Organization: Geneva, 1953, pp. 51–56. 156. Youmans GP. Tuberculosis. Philadelphia: W.B. Saunders Company, 1979. 157. Triep WA. De tuberculinereactie (in Dutch). The Hague, Netherlands: Royal Netherlands Tuberculosis Association (KNCV), 1957. 158. Wasz-Hockert O. On the period of incubation in tuberculosis. Ann Med Fenn 1947; 96:764–772. 159. Wallgren A. The time-table of tuberculosis. Tubercle 1948; 29:245–251. 160. Poulsen A. Some clinical features of tuberculosis. I. Incubation period. Acta Tuberc Scand 1954; 24:311–346. 161. Houk VN, Kent DC, Sorenson K, Baker JH. The eradication of tuberculosis infection by isoniazid chemoprophylaxis. Arch Environ Health 1968; 16:46–50. 162. Felten MK, Van Der Merwe CA. Random variation in tuberculin sensitivity in schoolchildren. Am Rev Respir Dis 1989; 140:1001–1006. 163. Hsu KHK. Tuberculin reaction in children treated with Isoniazid. Am J Dis Child 1983; 137:1090–1092. 164. Gordon FM, Perez-Stable EJ, Reid M, Schecter G, Cosgriff L, Flaherty D, et al. Stability of positive tuberculin tests: Are boosted reactions valid? Am Rev Respir Dis 1991; 144:560–563. 165. Fine MH, Furcolow ML, Chick EW, Bauman DS, Arik M. Tuberculin skin test reactions. Am Rev Respir Dis 1972; 106:752–758. 166. Donaldson JC, Elliot RC. A study of co-positivity of three multipuncture techniques with intradermal PPD tuberculin. Am Rev Respir Dis 1978; 118:843–846. 167. Lunn JA, Johnson AJ, Fry JS. Comparison of multiple puncture liquid tuberculin test with Mantoux test. Lancet 1981; i:695–698.

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168. Ackerman-Liebrich U. (Letter.) Lancet 1982; ii:934. 169. Hansen JP, Falconer JA, Gallis HA, Hamilton JD. Inadequate sensitivity of tuberculin tine test for screening employee populations. J Occup Med 1982; 24:602–604. 170. Rudd RB, Gellert AR, Venning M. Comparison of Mantoux, tine, and ‘Imotest’ tuberculin tests. Lancet 1982; 515–518. 171. Biggs B, Connor H, Dwyer BW, Speed BR. Comparison of a multiple puncture tuberculin test, “Imotest,” and the Mantoux test in an Australian population. Tubercle 1987; 68:285–290. 172. Chaparas SD, Mac Vandiviere H, Melvin I, Koch G, Becker C. Tuberculin test: variability with the Mantoux procedure. Am Rev Respir Dis 1985; 132:175–177. 173. Loudon RG, Lawson JR, Brown J. Variation in tuberculin test reading. Am Rev Respir Dis 1963; 87:852–861. 174. Fine MH, Furculow ML, Chick EW, Bauman DS, Arik M. Tuberculin skin test reactions. Am Rev Respir Dis 1972; 106:752–758. 175. Perez-Stable EJ, Slutkin G. A demonstration of lack of variability among six tuberculin skin test readers. Am J Public Health 1985; 75:1341–1343. 176. Pouchot J, Grasland A, Collet C, Coste J, Esdaile JM, Vinceneux P. Reliability of tuberculin skin test measurement. Ann Intern Med 1997; 126:210–214. 177. Lifschitz M. The value of the tuberculin skin test as a screening test for tuberculosis among BCG-vaccinated children. Pediatrics 1965; 36:624–627. 178. Margus J, Khassis Y. The tuberculin sensitivity in BCG vaccinated infants and children in Israel. Acta Tuberc Pneumonol Scand 1965; 46:113–122. 179. Joncas J, Robitaille R, Gauthier T. Interpretation of the PPD skin test in BCG-vaccinated children. Can Med Assoc J 1975; 113:127–128. 180. Karalliede S, Katugha L, Uragoda C. The tuberculin response of Sri Lankan children after BCG vaccination at birth. Tubercle 1987; 68:33–38. 181. Sepulveda R, Burr C, Ferrer X, Sorensen R. Booster effect of tuberculin testing in health 6-year-old school children vaccinated with Bacillus Calmette-Guerin at birth in Santiago, Chile. Pediatr Infect Dis J 1988; 7:581. 182. American Conference of Governmental Industrial Hygenists. Guidelines for assessment and sampling of saprophytic bioaerosols in the indoor environment. Appl Indus Hyg 1987; 2:R10–R16. 183. Menzies RI, Vissandjee B. Effect of bacille Calmette-Guerin vaccination on tuberculin reactivity. Am Rev Respir Dis 1992; 145:621–625. 184. Comstock GW, Edwards LB, Nabangwang H. Tuberculin sensitivity eight to fifteen years after BCG vaccination. Am Rev Respir Dis 1971; 103:572–575. 185. Bleiker MA, Misljenovic O, Styblo K. Study into the risk of tuberculous infection in schoolchildren in the city of Delft in the period 1966–1985. In: Anonymous Selected Papers. The Hague: Royal Netherlands Tuberculosis Association, 1997:19– 24. 186. Jeanes CWL, Davies JW, McKinnon NE. Sensitivity to “atypical” acid-fast mycobacteria in Canada. CMAJ 1969; 100:1–8. 187. Paul RC, Standord JL, Misljenovic O, Lefering J. Multiple skin testing of Kenyan schoolchildren with a series of new tuberculins. J Hyg Camb 1975; 75:303–313. 188. Kardjito T, Swanson Beck J, Grange JM, Stanford JL. A comparison of the responsiveness to four new tuberculins among Indonesion patients with pulmonary tuberculosis and healthy subjects. Eur J Respir Dis 1986; 69:142–145.

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189. Lind A, Larsson O, Bentzon MW, Magnusson M, Olofson J, Sjogren I, et al. Sensitivity to sensitins and tuberculin in Swedish children. Tubercle 1991; 72:29–36. 190. Ly HM, Trach DD, Long HT, Thuy NK, Tuan NA, Thi Ninh T, et al. Skin test responsiveness to a series of new tuberculins of children living in three Vietnamese cities. Tubercle 1989; 70:27–36. 191. Frappier-Davignon Lise, Fortin Robert, Desy M. Sensitivity to “atypical” mycobacteria in high school children in two community health departments. Can J Public Health 1989; 80:335–338. 192. Menzies RI. The determinants of the prevalence of tuberculous infection among Montreal schoolchildren. M.Sc. thesis Montreal: McGill University, 1989. 193. Reichman LB, O’Day R. Tuberculous infection in a large urban population. Am Rev Respir Dis 1978; 117:705–712. 194. Cross ER, Hyams KC. Tuberculin skin testing in US Navy and Marine Corps personnel and recruits, 1980–1986. Am J Public Health 1990; 80:435–438. 195. Dorken E, Grzybowski S, Allen EA. Significance of the tuberculin skin test in the elderly. Chest 1992; 2:237–240. 196. Grzybowksi S, Allen EA, Black WA, Chao CW, Enarson DA, Isaac-Renton JL, et al. Inner-city survey for tuberculosis: evaluation of diagnostic methods. Am Rev Respir Dis 1987; 135:1311–1315. 197. Morse DL, Hansen RE, Swalbach G, Redmond SR, Grabau JC. High rate of tuberculin conversion in Indochinese refugees. JAMA 1982; 248:2983–2986. 198. Fitzpatrick S, Johnson J, Shragg P, Felice ME. Health care needs of Indochinese refugee teenagers. Pediatrics 1987; 79:118–124. 199. Ormerod LP. Tuberculosis screening and prevention in new immigrants 1983–88. Respir Med 1990; 84:269–271. 200. Spinaci S, De Virgilio G, Bugiani M, Linari D, Bertolaso G. Tuberculin survey among afghan refugee children. Tuberculosis control programme among Afghan refugees in North West frontier province (NWFP) Pakistan. Tubercle 1989; 70:83–92. 201. Godue CB, Goggin P, Gyorkos TW. L’allergie tuberculinique chez les revendicateurs du statut de réfugié nouvellement arrivés au Canada. CMAJ 1988; 139:41–44. 202. Blum RN, Polish LB, Tapy JM, Catlin BJ, Cohn DL. Results of screening for tuberculosis in foreign-born persons applying for adjustment of immigration status. Chest 1993; 103:1670–1674. 203. Yuan L, Richardson E, Kendall PRW. Evaluation of a tuberculosis screening program for high-risk students in Toronto schools. Can Med Assoc J 1995; 153:925–932. 204. van Zwanenberg D. Tuberculous infection in the home. Tubercle 1955; 36:238–244. 205. Zaki MH, Lyons HA, Robins AB, Brown EP. Tuberculin sensitivity. NY State J Med 1976; 2138:2143. 206. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull IUAT 1975; 50:90–106. 207. Van Geuns HA, Meijer J, Styblo K. Results of contact examination in Rotterdam, 1967–1969. Bull Int Union Tuberc 1975; 50:107–121. 208. Karalus NC. Contact screening procedures for tuberculosis in Auckland. NZ Med J 1988; 101:45–49.

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209. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, 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. 210. Hong Kong Chest Service/Tuberculosis Research Centre MM. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992; 145:36–41. 211. 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. 212. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95:935–943. 213. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–137. 214. Valenti WM, Andrews BA, Presley BA, Reifler CB. Absence of the booster phenomenon in serial tuberculin skin testing. Am Rev Respir Dis 1982; 125:323–325. 215. Gross TP, Israel E, Powers P, Cauthen G, Rose J. Low prevalence of the booster phenomenon in nursing-home employees in Maryland. Maryland Med J 1984; 35:107–109. 216. Alvarez S, Karprzyk DR, Freundl M. Two-stage skin testing for tuberculosis in a domiciliarly population. Am Rev Respir Dis 1987; 136:1193–1196. 217. Barry MA, Regan AM, Kunches LM, Harris ME, et al. Two-stage tuberculin testing with control antigens in patients residing in two chronic disease hospitals. JAGS 1987; 35:147–153. 218. Burstin SJ, Muspratt JA, Rossing TH, et al. Studies of the dynamics of reactivity to tuberculin and Candida antigen in institutionalized patients. Am Rev Respir Dis 1986; 134:1072–1074. 219. Webster CT, Gordin FM, Matts JP, Korvick JA, Miller C, et al. Two-stage tuberculin skin testing in individuals with human immunodificiency virus infection. Am J Respir Crit Care Med 1995; 151:805–808. 220. Hecker MT, Johnson JL, Whalen CC, Nyole S, Mugerwa RD, Ellner JJ. Two-step tuberculin skin testing in HIV-infected persons in Uganda. Am J Respir Crit Care Med 1997; 155:81–86. 221. Lifson AR, Grant SM, Lorvick J, Pinto FD, He H, Thompson S, et al. Two-step tuberculin skin testing of injection drug users recruited from community-based settings. In J Tuberc Lung Dis 1997; 1:128–134. 222. Morse DL, Hansen RE, Grabau JC, Cauthen G, Redmond SR, Hyde RW. Tuberculin conversions in Indochinese refugees. Am Rev Respir Dis 1985; 132:516–519. 223. Friedland IR. The booster effect with repeat tuberculin testing in children and its relationship to BCG vaccination. S Afr Med J 1990; 77:387–389. 224. Sepulveda R, Ferrer X, Latrach C, Sorensen R. The influence of Calmette-Guerin bacillus immunization on the booster effect of tuberculin testing in healthy young adults. Am Rev Respir Dis 1990; 142:24–28.

13 Case Finding in High- and Low-Prevalence Countries

HANS L. RIEDER International Union Against Tuberculosis and Lung Disease Paris, France

I. Introduction To ultimately reduce the incidence of tuberculosis in a community, the primary epidemiological aim of tuberculosis control is to reduce the pool of persons with tuberculous infection. Without intervention, future cases of tuberculosis will emerge from this pool. Principally, there are two supplementary lines of action to accomplish this objective. The first is the interruption of transmission from newly occurring infectious cases of tuberculosis with appropriate chemotherapy as swiftly as possible after their occurrence. As shown in Figure 1, what stands between the onset of transmissibility and its arrest is the delay of the patient in seeking medical attention and the delay of health care providers in making the diagnosis and commencing appropriate chemotherapy. These delays are variably attributable to the patient’s attitudes towards symptoms and the health-care provider’s ability to rapidly diagnose tuberculosis. The second line of action is the prevention of tuberculosis cases before they occur with preventive therapy of subclinically infected persons (Fig. 1). The first line of action will reduce the incidence of infection, and the second will reduce the prevalence of infection. 323

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Figure 1

Model of the epidemiology of tuberculosis and points of intervention.

The term “case finding” in its narrowest sense refers to all activities that aim at reducing the interval between the onset of clinically and/or bacteriologically active tuberculosis and the arrest of transmission. Patient’s and doctor’s delay are thus the two major factors that determine the length of uncontrolled transmission of tubercle bacilli in the community and thus the incidence of infection. In its wider sense, “case finding” may also be understood as the identification of population segments infected with tubercle bacilli at high risk of developing tuberculosis who may benefit from preventive intervention. Such preventive treatment will reduce the prevalence of infection. The emphasis here will be placed on case-finding activities in its narrower sense, because it is apparent that failure of preventing uncontrolled transmission from infectious sources has much larger implications for the epidemiological situation than failure to identify subclinically infected persons (1). II. Sources of Transmission and Other Cases It has been recognized for some time and documented in several large studies (2–4) that the major sources of infection in the community are patients with tu-

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berculosis of the respiratory tract who are excreting such large numbers of tubercle bacilli that they can be seen by direct microscopic examination of their sputum. Patients with sputum smear–negative, culture-only–positive tuberculosis are far less efficient transmitters. Epidemiologically, the rapid discovery of infectious cases is of higher priority than that of other cases. However, through reduction of unnecessary morbidity and fatality the identification of the latter group also carries individual and public health benefits. III. Identification of Sources of Transmission A. Active Case-Finding Methods

The term “active case finding” is used here to describe methods for the identification of tuberculosis cases where the first initiative for an individual patient/provider contact is taken by health-care providers. Mass Radiography

Hypothetically, periodic radiographic screening of the entire population could help in identifying tuberculosis patients at a point in time when their disease has not yet progressed to high infectiousness. Mass radiography campaigns became an important component of tuberculosis control activities in the 1940s and 1950s in the United States (5) and in many other industrialized countries (3,6,7). In a series of studies conducted between 1960 and 1973 (3,6,8), it was shown that in places with active case-finding programs between 54 and 66% of sputum smear–positive patients were discovered on account of their symptoms. Only some 20% of new cases were found through indiscriminate mass radiography alone (3). This is explained by the relative speed with which infectious cases develop, which is faster than repeat screening can logistically be accomplished and therefore economically be justified (9). Because of the relatively low yield of cases through indiscriminate mass radiography, the method has generally become recognized as an inefficient tool in tuberculosis control (3,8,10–13). Involvement of Community Leaders

In three studies jointly conducted in Kenya by the Respiratory Diseases Research Centre, Nairobi, and the British Medical Research Council, approaches to improve case finding by involving community leaders have been evaluated (14–16). In the first study the efficiency of case finding by community leaders was investigated in a district in Kenya (14). The reference was a house-to-house investigation with random sampling methods. Suspects were defined as any of the following: cough for more than month, hemoptysis at any time, confined to home on account of illness, or diagnosed previously with tuberculosis. The study showed that almost three quarters of the cases were among those who fit the case definition and that the suspects’ segment made up 6.5% of the 29,508 eligible pop-

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ulation 6 years and older in the district. The authors interpreted the efficiency of community leaders in tuberculosis case finding as disappointing. Nevertheless, among the total eligible population, the utilization of community leaders led to 6 (29.6%) of the expected 20.3 cases by pointing at just 363 (1.2%) suspects among the total population. Most important was the finding that slightly more than 80% of newly diagnosed cases claimed that they had attended a medical facility for treatment of their symptoms but had not been investigated for tuberculosis. In the second study (15) the efficiency of requestioning community leaders about one year later was evaluated. Of the 421 suspected cases, 129 (30.6%) were new among whom three culture-positive (including two smear-positive) cases were identified. Among 189 spontaneously renamed suspected cases, 5 cases were now culture positive and both smear-positive cases among them had become registered. Active follow-up yielded only 0.7 cases per 100 contacts of all cases, but 2.3 contact cases per 100 newly registered cases. Again, the yield was considered to be disappointing. However, reinterrogation yielded several new cases with relatively little work. A third study was undertaken to evaluate the usefulness of requestioning community leaders at shorter intervals. The third study (16) showed that interrogation of household heads on a single occasion produced more than two thirds of all the bacteriologically confirmed cases found in the community by several case-finding methods combined. However, the yield from interrogation of community leaders was almost double per 100 suspected cases. Interrogation of household heads was naturally much more cumbersome than the interrogation of community leaders. Although the yield was increased by requestioning community elders, the yield from repeated questioning was disproportionately lower. A further important finding of the third study was that, among 37 cases who were registered 1 or more years earlier and could be examined, 4 (10.8%) were found to be sputum smear positive. In the three studies, the number of cases per 100 suspected cases identified by community elders was between 1.7 and 2.8. As in previous studies, the most important finding was the confirmation that about 80% of new smear-positive cases claimed to have attended a health-care facility because of their respiratory symptoms but had not been investigated for tuberculosis. B. Identification of Individuals at High Risk of Having or Developing Tuberculosis

Risk Factor: HIV Infection

Among the numerous factors recognized to increase the risk of progression from subclinical (or latent) infection with M. tuberculosis to active tuberculosis, infection with the human immunodeficiency virus (HIV) has been identified as the strongest (17,18). The annual risk of tuberculosis among dually infected persons

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is some 5–10% (18–20). It appears that 30–50% of patients with the acquired immunodeficiency syndrome (AIDS) who are also infected with tubercle bacilli develop tuberculosis at some time, and very commonly before the appearance of other AIDS-defining conditions (21,22). Although screening for disease and subsequent treatment is efficacious and effective, the effectiveness of the therapeutic consequence of screening for infection, i.e., preventive therapy, is much more ambiguous. Preventive therapy in asymptomatic dually infected persons appeared to be quite efficacious in some studies (23), much less so in others (24), and provided no protection in one other study (25). An additional complication is imposed by the difficulty in identifying tuberculous infection among HIV-infected persons (26–29). As is the case for other population groups, failure to make a diagnosis of tuberculosis in this group of patients is not uncommon and may lead to unnecessary morbidity and fatality (30–32). Because HIV-associated tuberculosis often presents with radiologically unusual pictures (33–42) and may be commonly found at any extrapulmonary site (36,43–45), a high index of suspicion is warranted and specimens from numerous sites may be required to establish the diagnosis (46). Although extrapulmonary tuberculosis and sputum smear–negative pulmonary tuberculosis among patients with HIV infection or AIDS is more common than among tuberculosis patients without HIV infection (43,47), large increases in sputum smear–positive tuberculosis have been observed in several populations heavily affected by HIV (48). Such excess infectious cases that are attributable to HIV infection will necessarily lead to a deterioration of the epidemiological situation by increasing the risk of infection in the community. In many population groups, such as large metropolitan areas in the United States (49) and particularly in many sub-Saharan countries, the potential for excess transmission of tubercle bacilli is large. In many areas, the health-care facilities for spontaneously presenting patients have become so overburdened (50) that the remaining room for action does not allow for active case-finding activities. Screening for tuberculosis among patients seeking HIV testing can be rewarding. In Uganda, 2.6% of HIV-positive clients had active tuberculosis (51), and 9.7% of individuals seeking HIV testing at a testing site in the Dominican Republic were found to have tuberculosis (52). The latter study also showed that tuberculosis was not limited to HIV-infected individuals, suggesting that ill persons were especially likely to present for HIV testing, irrespective of their HIV status (52,53). Similar to experiences in low-income countries, screening for both tuberculous infection and tuberculosis proves rewarding in some HIV clinics in industrialized countries (54,55). Risk Factor: Recent Infection

The more recent the tuberculosis infection, the greater will be the risk for progression to tuberculosis (17,56,57). Many hospitals, particularly in the United

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States, where BCG vaccination has never been used routinely, have implemented screening procedures utilizing the tuberculin skin test to identify recent conversion among hospital employees (58), which is not without difficulties in excluding “false conversions” attributable to boosting (59–63). Risk Factor: Fibrotic Lesions

Patients with fibrotic lesions resulting from previous, spontaneously healed tuberculosis without adequate treatment are at high risk of recurrence (64). In a first time prevalence survey of a population group, the prevalence of fibrotic lesions might be severalfold higher than that of bacteriologically active disease (9,65). For this reason, a large proportion of preventable cases might be identified by a single radiographic examination of a high-risk population, such as alcoholics and drug addicts (66), other persons living in socially depressed inner-city areas (65), or immigrants and refugees from high-incidence countries (67,68). Other Risk Factors

Numerous other factors have been identified that increase the risk of progression from subclinical infection to active tuberculosis (17). Accordingly, persons with such factors (diabetes, silicosis, malignancies, hemodialysis, etc.) may be at increased risk of having or developing tuberculosis when receiving treatment for their underlying condition. In industrialized countries, screening for tuberculosis or tuberculous infection is thus often recommended for such patients (27). Passive Case-Finding Methods

The term “passive case finding” is used here to describe methods for the identification of tuberculosis cases where the first initiative for an individual patient/provider contact is taken by the patient. Methods to Reduce Patient Delay

Patients seek medical care when their symptoms are subjectively sufficiently severe to offset the difficulties involved (e.g., costs, interruption of normal activities). It is conceivable that in different societies, among different population segments, and between individuals, different forces are at work that influence a patient’s delay from the first occurrence of symptoms to the seeking of medical attention. In studies that evaluated the role of mass miniature radiography, it has been shown that more than 90% of sputum smear–positive patients have symptoms, predominantly cough (3,6,69). In industrialized countries with a dense network for health-care provision, the distance between residence or workplace and health-care facilities may be an unimportant factor in a patient’s delay in seeking medical attention (70). In con-

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trast, it is conceivable that in resource-poor countries the distance to the next health-care provider may influence the patient’s attitude towards seeking medical attention (71,72). In Japan, the interval between the occurrence of symptoms and the first contact with a health-care provider was 17 days, but this varied remarkably between individual patients (70). Patient delay was also influenced by profession and location of residence. In Hong Kong, an intensive mass media campaign failed to attract significant numbers of tuberculosis patients and failed to attract older subjects more likely to have the disease (73). Methods to Reduce Doctor Delay

In a series of studies in Kenya it became clear that a large proportion of tuberculosis cases found through interrogation of community leaders and heads of households (14–16), a rather cumbersome procedure, had actually attended health-care facilities with complaints but had not been examined bacteriologically or radiographically. Similarly, in Bangalore City in India where both general health institutions and specialized tuberculosis clinics exist, it was observed that patients do not bypass the general city health institutions (74). The problem thus seems to be not so much that patients do not develop symptoms or do not seek medical attention, but when the proper diagnosis is made. In the Japanese study (70), the median patient delay was 17 days and the median doctor delay was 31 days. The authors found that the most influential factor for doctor delay was whether a radiographic examination was done or not done at the first visit. The median delay was only 13 days for patients who had a chest radiograph done at the first visit, but 50 days for those who were not examined. There is little doubt that with decreasing incidence of tuberculosis in most industrialized countries, physicians will think less of tuberculosis as a differential diagnosis. It is appalling that in the United States the diagnosis of tuberculosis is still missed in a large proportion of patients (75). Among all cases reported to the Centers for Disease Control, the proportion of cases that did not receive treatment and in which the diagnosis was made only at death was 5%. The proportion increased with age to 11% among those aged 65 years and older and was 18% among those with meningeal, peritoneal, or miliary tuberculosis. In an additional series of studies jointly conducted by the Respiratory Disease Research Centre, Nairobi, and the British Medical Research Council, approaches to improve case finding by seizing upon opportunities among patients attending health care facilities have been evaluated (72,76–78). In the fourth study (76), similar to the previous three, 90% of suspects without a history of tuberculosis claimed they had attended a health-care facility an average of more than 5 times, yet 65% had neither a chest radiograph nor their sputum examined bacteriologically.

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In the fifth study (72), careful screening for patients with a cough of 1 month’s or more duration in general outpatients attending a district hospital identified 601 (2.9%) suspects among 20,756 new outpatients. Among the suspected cases, 5.6% had bacteriologically or radiographically active tuberculosis. An additional 2.2% were considered to have inactive tuberculosis. The authors found that the method was uniformly effective within a radius of about 9 miles of the hospital but became less effective with increasing distance. The study demonstrated the need for considerable improvement of the infrastructure of the primary health-care system in the periphery. In the sixth study (77) the effectiveness of careful screening of patients attending as general outpatients four different district hospitals for the first time was examined. A suspected case was defined as in the earlier studies (14–16). Among the general outpatient population, 2.6% fit the definition. Among these, 4.7% had culture-positive pulmonary tuberculosis (including 3.6% who were also positive on sputum smear examination). A history of cough for between 1 and 12 months was the most predictive factor for tuberculosis and would have identified 92% of the smear-positive cases by examining 70% of the suspected cases. An important observation was that, similar to the previous study (72), the proportion of cases decreased with increasing distance of their homes from the health-care facility, but the proportion of cases increased with increasing distance of the home from the hospital. In the seventh study (78) the effectiveness of case finding among attendants of maternity and child welfare clinics was examined by questioning them about suspects in their households. The results were disappointing because only 4% of the estimated total annual incidence was undiscovered by this method. The authors concluded from their series of studies in Kenya that a substantial yield of tuberculosis cases can be obtained from the area surrounding district hospitals. The major impediment to finding a larger proportion of cases lay, however, with the complacency of health staff in the periphery. Unless primary healthcare facilities in the periphery were improved, the proportion of identified cases among all actually newly occurring cases would remain disappointing. Furthermore, it might be added, the failure to interrupt transmission by definitively curing the patients was clearly documented in the third study (16), showing that more than 10% of previously treated patients were alive and smear positive. What stands behind the vicious circle of transmission is, first, the failure to undertake appropriate examinations in patients who present themselves with relevant symptoms referable to the respiratory tract in both resource-poor and industrialized countries. Second, in resource-poor countries a strengthening of the primary health care services is imperative. Third, if patients who are being ultimately diagnosed are not cured, but also do not die because of some treatment, the primary objective of curtailing transmission in the community cannot be achieved (79).

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IV. Factors Modifying the Choice of Case-Finding Methods A. Availability of Resources

Where resources are scarce, case-finding methods are limited to those activities that have been shown to offer the highest rewards. In most resource-poor countries, passive case finding for infectious cases while simultaneously raising the awareness of the community and the medical profession coupled with active case finding among contacts has thus become the method of choice (80). In these countries, the emphasis of tuberculosis control lies first with achieving an increase in the proportion of cures (81) and only then in expanding case finding (82). In countries with more resources, targeted screening activities among population groups at high risk for tuberculosis are commonly advocated. B. Prevalence of Disease

For tuberculosis screening to be justified, the prevalence of tuberculosis must be high in the target population and/or the population must have a high prevalence of tuberculous infection and be at high risk of progression to tuberculosis. Population segments that fit one or both of these conditions in industrialized countries are immigrants and refugees from high-prevalence countries (83,84), contacts of newly identified cases (15), inmates of correctional facilities (85), inner-city marginalized populations (65,66), miners (86), professions chosen by high-prevalence groups (87), and many other groups (27). Individuals that meet one or both conditions notably include persons with HIV infection, recent infection, and a multitude of clinical conditions (27). Risk Groups: Contacts of Newly Identified Cases

The effectiveness of active case finding among contacts is undisputed because it is logistically almost always practicable and provides a relatively high yield of new cases (15). Furthermore, active follow-up of contacts of new cases can identify a large proportion of high-risk, asymptomatically infected persons who might benefit from preventive therapy. Risk Groups: Immigrants

Increased international migration from high to low incidence countries influences the distribution of tuberculosis incidence in the host country (88,89), and accordingly policy statements have been elaborated to address the issue as an increasing proportion of cases in industrialized countries is found among foreign-born persons (84,90), and immigrants and refugees from high-prevalence countries are thus often required to submit to an initial radiographic screening (67,84,90,91). Nevertheless, it remains to be seen how cost-effective screening programs among immigrants will prove.

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Tuberculosis outbreaks in correctional facilities, including outbreaks with multidrug-resistant strains, have alerted the public (92–96), and specific guidelines on how to address the problem including screening have been elaborated (97). Recent reports from low-income countries have similarly demonstrated that the prevalence of tuberculosis in correctional facilities is very large and that the problem needs urgent attention (98,99). In industrialized countries where resources are available, active case finding is often expanded to these groups. In resource-poor countries, most active case-finding activities that go beyond contact examination are prohibitively expensive in relation to the yield. V. The Role of Case Finding in Tuberculosis Control Although the logical sequence in tuberculosis control is discovery of cases followed by treatment, it cannot be deduced that the root cause of the documented inefficiency of tuberculosis-control programs in many low-income countries lies primarily with deficiencies in case finding. On the contrary, there is much evidence that the failure to cure those sources of infection that are discovered by one or the other activity is the major problem. The introduction of chemotherapy has tremendously reduced case fatality, but many programs testify that epidemiologically little has been accomplished, because the proportion of cases that remains infectious is largely unchanged, be it with or without chemotherapy (79). It has been clearly recognized that there is an urgent need to increase the proportion of cures if the risk of infection in the community is to be reduced (80,100). The hypothesis has been offered that indeed low cure ratios may even lead to a deterioration of the epidemiological situation, because prolongation of infectiousness may ensue beyond the natural course of untreated disease (79). The experience in New York City (101), where a very small proportion of cases was cured and the number of cases rapidly increased, followed by strengthening of the program with a resulting decline in the incidence (102), provides strong evidence for that hypothesis. Quite clearly, case-finding activities should not be expanded as long as curative treatment of those identified cannot be guaranteed in a large proportion. National tuberculosis programs collaborating with the International Union Against Tuberculosis and Lung Disease have shown that higher cure ratios can be achieved with cost-effective rifampicin-containing chemotherapy (81). The World Health Organization has set the target for a cure ratio of 85% in low-income countries and 95% in affluent countries (82). In numerous studies, notably those in Kenya (14–16), India (74), and Japan (70), it has been demonstrated that the problem of delay between onset of symptoms and initiation of appropriate treatment lies less with the patient than

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with the medical system. This in itself would seem to be sufficient reason to put scarce resources into improving the skills and training of health care providers to pursue appropriate diagnostic action in patients who spontaneously present themselves to health-care facilities rather than into active case-finding methods and screening outside the system. In most low-income, high-incidence countries the primary health-care system is too underdeveloped to appropriately identify and diagnose tuberculosis patients who seek medical attention for symptoms referable to the respiratory tract. In industrialized, low-incidence countries it is not the unavailability of diagnostic services that prevents rapid diagnosis, but commonly the failure to include tuberculosis in the differential diagnosis (30,31,70). If cure cannot be guaranteed for a large majority of patients, expanding case-finding activities does not make sense. This is true not only for low-income countries, but also for high-income countries. In New York City, for example, a study has clearly shown that active case finding among deprived inner-city population segments can be very rewarding (66). Such yield may be, however, of little benefit to the program, because of the high attrition rate before patients complete an adequate course (103). Only once cure of a large proportion of cases can be assured is it appropriate to consider case-finding activities. VI. Conclusions There is little doubt that passive case finding coupled with efficient treatment is the most rewarding activity in tuberculosis control. In both resource-poor and resource-rich countries, the problem of delay in diagnosis does not so much lie with the patient’s failure to seek medical attention as with the failure of the medical system to properly and rapidly diagnose tuberculosis. In resource-poor countries, tremendous efforts need to be made to improve the cure of patients, to expand the primary health care system, and to educate health-care providers to react appropriately to patients who complain about prolonged respiratory tract symptoms. In affluent countries the most important conclusion that can be drawn from available studies is that, although targeted active case finding in high-risk population segments gives a high yield, the emphasis must be placed on continuously educating health-care providers and physicians so that the diagnosis of tuberculosis can easily be made once it is considered. Most important for both low-income and highincome countries is the lesson that all case-finding activities—even successful ones—are in vain if the patient’s compliance cannot be assured. In addition to the failure of improving the epidemiological situation because of inadequate treatment, the threat of losing rather than winning the battle against tuberculosis looms with the emergence of drug resistance (104), to which noncompliance of the medical system may contribute more than is openly admitted.

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14 Diagnosis of Tuberculosis

PHILIP A. LOBUE Centers for Disease Control and Prevention San Diego, California

SHARON PERRY and ANTONINO CATANZARO University of California, San Diego San Diego, California

I. Introduction After many years of steady decline in incidence, the world experienced a resurgence in tuberculosis beginning in the mid-1980s. There were a number of reasons for this, including the HIV epidemic. Because of this resurgence, new interest has focused on the control of tuberculosis. No truly effective vaccination or other means of prevention of infection exists. Therefore, control of tuberculosis relies on identifying and treating cases of active tuberculosis and latent infection in order to interrupt transmission to uninfected hosts and prevent reactivation in infected hosts, respectively. Obviously, accurate and rapid diagnosis of cases of active tuberculosis is a necessity for this strategy to succeed. II. Medical History and Physical Examination A. General Considerations

The goal of the medical history and physical examination is to recognize individuals in whom the diagnosis of tuberculosis should be considered. The information gathered provides the basis for deciding which, if any, diagnostic testing (chest radiograph, sputum sampling, etc.) should be pursued. 341

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Special attention must be given to factors that place a patient at greater risk for contracting or developing tuberculosis. These factors can be divided into three categories: socioeconomic, biological, and contact related. Socioeconomic risk factors include racial/ethnic minority status, country of origin (especially high-tuberculosis-prevalence countries and/or refugee status), low income, and homelessness (1–4). Certain occupations, such as health care workers, are associated with a greater risk of tuberculosis (5–10). Two other high-risk populations are elderly residents of nursing homes and inmates of correctional facilities (11–14). Biological risk factors are basically underlying medical conditions in which cellmediated immunity is depressed, such as HIV infection (the greatest risk factor) (15). Other medical conditions that result in greater risk for contracting tuberculosis include diabetes mellitus, malignancy, organ transplantation, renal failure /dialysis, malnutrition, and silicosis (16,17). B. Pulmonary Disease

The lung is the most common site (80% of cases) of disease due to Mycobacterium tuberculosis. The approach to the diagnosis of pulmonary tuberculosis has, therefore, received the greatest attention. Because tuberculosis is generally insidious in onset, symptoms may be minimal or completely absent until the disease is advanced. In the case of pulmonary tuberculosis, the symptoms include cough, fever, sweats or chills, anorexia, weight loss, and malaise (18,19). Cough, which may be dry or productive, is the most common symptom and the most sensitive indicator of active disease (20). Because tuberculosis is usually slowly progressive, the cough is persistent. The diagnosis of pulmonary tuberculosis should be strongly considered in anyone who is at risk, based on epidemiological factors, and presents with a cough of at least 3 weeks duration (21). Hemoptysis, ranging from minimal to extensive, may occur due to bronchiectasis, erosion of a calcified lymph node into bronchus, a fungus ball superinfecting a cavity, or a Rassmussen’s aneurysm (an exposed dilated blood vessel within a cavity) (22). Dyspnea is more likely to occur from pleural involvement (effusion), but with extensive parenchymal or miliary disease frank respiratory failure may occur (23). Chest pain, usually pleuritic in nature, results from involvement of the pleura or parenchyma directly adjacent to the pleura (22). These symptoms are fairly nonspecific and may be seen with other lung infections or malignancies. They cannot be used to differentiate active tuberculosis from old inactive disease with any certainty, either. For example, a patient may have a chest radiograph with upper lobe fibronodular infiltrates from old, currently quiescent tuberculosis and a productive cough, fever, weight loss, and hemoptysis due to residual bronchiectasis with bacterial superinfection. The physical exam is not particularly helpful in diagnosing pulmonary tuberculosis because physical signs, like symptoms, are both insensitive and non-

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specific. In the early phases of active disease, there are often no abnormal physical findings. As tuberculosis becomes advanced, physical exam may reveal systemic findings such as fever and cachexia and findings of pulmonary involvement (e.g., crackles, wheezes, and bronchial breath sounds). III. Routine Laboratory Tests Routine laboratory tests (complete blood count, serum chemistries) are usually normal except in patients with advanced disease (19). The most common hematological abnormalities are anemia and leukocytosis, which are generally mild (18,24). Hyponatremia, resulting from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been reported in approximately 7–10% of cases of active tuberculosis (25,26). Hypercalcemia is the other electrolyte abnormality that has also been noted to occur in active tuberculosis (27). These findings are clearly all nonspecific and occur in many other pulmonary and systemic disorders. IV. The Tuberculin Skin Test The primary use of the tuberculin skin test (TST) (see Chap. 12) is as an epidemiological tool, and it should not be considered a diagnostic test for active tuberculosis. The vast majority of individuals with a reactive TST do not have active tuberculosis. Conversely, 10–25% of patients with active tuberculosis do not react to tuberculin injection, although there has been significant variability depending on the population studied (28). Certain subpopulations, such as those with suppressed cellular immunity, including patients with severe, widely disseminated active tuberculosis or HIV infection, may have rates of false-negative tuberculin skin tests exceeding 50% (28,29). False-positives also occur with tuberculin skin testing. Causes include errors in administering and interpreting the test, prior vaccination with bacille Calmette-Guérin (BCG), and prior infection with nontuberculous mycobacteria (28). Nevertheless tuberculin skin testing should be performed on all patients with suspected active tuberculosis. A TST, which is indicative of tuberculosis infection, provides additional support for the diagnosis of active disease when other evidence [e.g., compatible clinical syndrome and/or radiographic findings, positive acid-fast bacillus (AFB) smear] points in that direction. This supporting evidence can be critical in evaluating a case of tuberculosis. V. Diagnostic Tests: Pulmonary Disease A. Chest Radiography

The chest radiograph is almost always abnormal in nonimmunocompromised patients with active pulmonary tuberculosis, but may be normal in about 10–15% of HIV-infected patients.

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Primary tuberculosis refers to the initial pulmonary infection occurring in a patient due to inhalation of M. tuberculosis–containing droplets from an infectious source. In most cases of primary tuberculosis infection, the patient is asymptomatic or minimally symptomatic and the chest radiograph is normal. This is particularly the case when the person is young and healthy at the time of infection. However, patients can develop significant illness with marked radiographic abnormalities with progressive primary tuberculosis. There are five major radiographic manifestations of active primary pulmonary tuberculosis: parenchymal consolidation, atelectasis, lymphadenopathy, pleural effusion, and miliary disease (30). Parenchymal consolidation is usually unifocal with multilobar disease occurring in up to 25% of cases (31). It can occur in any lobe, and there is controversy regarding whether there is a predilection for specific lobes (30). It has been reported that lower lobe involvement is more frequent in adults (32). These findings can be indistinguishable from those of bacterial lobar pneumonia. Segmental or lobar atelectasis is most common in children under 2 years old but has also occurred in older children and adults (30). It results from endobronchial obstruction or extrinsic compression from lymphadenopathy, with the most common sites being the anterior segment of the upper lobe or the medial segment of the middle lobe (33). Enlargement of hilar or mediastinal lymph nodes occurs in up to 43% of adults and 96% of children with primary tuberculosis (30). It may be associated with parenchymal disease or may be the only radiographic abnormality. Pleural effusions are present in 6–7% of cases of primary tuberculosis (34). They are usually unilateral and free flowing. While pleural effusion is often the only apparent abnormality in primary disease, computed tomography (CT) may reveal parenchymal disease or adenopathy that is not seen on a plain chest film (35). Miliary or disseminated tuberculosis makes up 1–7% of all forms of tuberculosis and may occur as a manifestation of primary tuberculosis (30,34). The radiographic appearance is that of diffuse 1- to 3-mm nodules, which are usually, but not always, symmetrically distributed. In some cases, the nodules may not be easily detectable by plain film and a high-resolution computed tomography (HRCT) scan, which is more sensitive, may yield the diagnosis (30). Persistent nodular or mass-like opacities, known as tuberculomas, are generally thought to be residua of healed primary disease (36). A review of the literature has revealed that they are found in 7–9% cases of primary tuberculosis, are usually 3 cm or less in size, are found in the upper lobes, are often multiple, may be calcified and generally remain stable in size over time (30).

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Reactivation (Postprimary) Tuberculosis

One radiographic characteristic of reactivation (or postprimary) tuberculosis is its predilection for the upper lobes. The most commonly involved segments are the apical and posterior and the superior segments of the lower lobe (30). While infiltrates in the anterior segment of the upper lobe or basilar segments of the lower lobe are not unusual in combination with disease in the commonly involved areas listed above, it is unusual to have isolated abnormalities in these segments (37). A second abnormality associated with reactivation is cavitation, occurring on average in about 50% of cases (30). Cavities are more frequently multiple than solitary and may be thin walled or thick walled (34,37). Air fluid levels are present as much as 22% of the time (38). In tuberculosis there is generally some surrounding infiltrate so that the appearance of a single cavity without adjacent reaction should lead to consideration of alternative diagnoses (34). Over time the opacities and /or infiltrates in the upper lobe develop into more defined reticular and nodular lesions, or what is often called “fibronodular” or “fibroproliferative” disease (30). As this process continues hilar retraction and volume loss become evident. Unfortunately, this is sometimes read as old, inactive, or healed tuberculosis. Chest radiography, by itself, cannot be used to determine activity of disease, and use of such terminology can lead to misdiagnosis of active cases (37). Even stability of such abnormalities for several months or more does not exclude active tuberculosis (34). Bronchial stenosis and bronchiectasis are two other relatively common manifestations of reactivation tuberculosis. These findings are often easier to see on chest computed tomography (CT) scanning than plain films (30). Pleural involvement may also be seen with postprimary tuberculosis. It is usually manifested by pleural thickening. When this happens in the apex it contributes to the abnormality referred to as “apical capping” (30). Pleural effusions occur but are less common than in primary disease (39). Air fluid levels in the pleural space indicate the presence of a broncho-pleural fistula (40). In immunocompetent hosts hilar and mediastinal lymphadenopathy are rare and have been reported to occur in as little as 5% of cases of postprimary tuberculosis (37). It is usually associated with extensive parenchymal disease. Miliary disease can also occur with reactivation but is thought to be more commonly associated with primary infection (34). HIV-Associated Tuberculosis

The radiographic appearance of pulmonary tuberculosis in HIV-infected patients is often “atypical.” The chest radiograph in HIV-infected patients with active tuberculosis most commonly resembles that of primary disease, i.e., hilar and mediastinal adenopathy with or without noncavitating parenchymal infiltrates

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equally likely to occur in the upper or lower lobes (41). In one study of Haitian patients with tuberculosis, 80% of HIV-seropositive individuals had chest films compatible with primary tuberculosis compared with 30% of HIV-seronegative individuals (42). Another study found that cavities were present in 67% of patients without AIDS, but in no patients with AIDS, whereas adenopathy was noted in 59% of AIDS patients, but only 3% of non-AIDS patients (41). Chest radiographs have been reported to be normal in 12–14% of HIV-infected patients with active pulmonary tuberculosis confirmed by a positive sputum AFB smear or culture (41,43). Pleural effusions are seen in 7–12% of cases of active tuberculosis in HIV-positive patients, which is not significantly different from the rate seen in non-HIV patients (41,42). Findings on chest film consistent with miliary disease have been reported to occur in 6–19% of HIV-infected patients with tuberculosis (41,44). Computed Tomography Scan

Computed tomography scanning of the chest can be helpful in making the diagnosis of tuberculosis in some cases. It has been shown to be more sensitive than plain films for detecting cavities, intrathoracic lymphadenopathy, miliary disease, bronchiectasis, bronchial stenosis, and pleural disease (30,45). HRCT scanning is the preferred technique for detection of miliary disease and bronchiectasis (30). In AIDS patients, one study found that low-density enlarged intrathoracic lymph nodes seen on CT scan were, in particular, associated with tuberculosis (44). It is obviously not necessary or cost effective to perform CT scans on all patients suspected of having tuberculosis. In certain cases where there is significant clinical suspicion and plain film findings are minimal or ambiguous (as often occurs in AIDS patients), CT scanning may provide useful diagnostic information because of its increased sensitivity. At present, magnetic resonance imaging (MRI) of the chest does not appear to have a role in the diagnosis of tuberculosis (45). B. Sputum Sampling

General

If the diagnosis of pulmonary tuberculosis is suspected based on clinical and/or radiographic evaluation, the next step should be examination of the sputum for mycobacteria. For patients with a productive cough, collection of an early morning, freshly expectorated specimen is recommended (20,46). For patients unable to produce sputum, induction of sputum production should be attempted. This is done by having the patient inhale nebulized hypertonic (3%) saline for up to 15 minutes. While this method has been shown to be useful in patients unable to produce sputum on their own, it is not known to have a better diagnostic yield than that of spontaneously expectorated specimens (47). Because the diagnostic yield

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of both AFB smear and culture increase with obtaining multiple samples, it has become standard procedure to obtain at least three specimens, preferably on three consecutive days. An alternative practice is to collect a “spot” sputum at the initial patient visit. The patient is then instructed to collect sputum over the next day and deliver it to the clinic where a second “spot” sputum is collected. If it is not possible to collect a sputum sample, even with induction, lavage of gastric secretions to collect aspirated tuberculosis organisms may be considered. This technique has been used primarily in children (see Sec. VII). Acid-Fast Bacillus Smear

Direct microscopic examination of concentrated sputum continues to play an important role in the diagnosis of tuberculosis because it is inexpensive, rapid, and easy to perform, although it has a less than desirable diagnostic yield (48). Using culture as a gold standard, the sensitivity of the concentrated AFB smear ranges from 22 to 78% (46). These numbers are average values, which include specimens from different anatomical sites and patients at various stages of disease. For the initial diagnosis of pulmonary tuberculosis, the sensitivity of AFB smear compared with culture is felt to be somewhere in the middle of this range (about 50%) (49). Obtaining multiple samples increases the sensitivity of the AFB smear. A review of the literature found that the sensitivity of a single sputum AFB smear was 30–40%, but increased to 65–75% with multiple specimens (50). Another key factor that affects the diagnostic yield of direct microscopy is the extent of disease/organism burden of the patient. For example, one study demonstrated that the presence of cavitary disease resulted in a sensitivity for AFB smear almost twice that (57% vs. 32%) for noncavitary tuberculosis (51). Finally, variability in the test can occur due to differing levels of skill and experience among laboratory workers and the specific method used for specimen preparation. In some developing countries, access to chest radiography may be limited. In such cases it is often the practice to perform direct microscopic sputum examination as the first (and perhaps only) diagnostic test. While this practice may be born of necessity, a significant number of tuberculosis cases may go undiagnosed if the AFB smear is the only diagnostic test utilized due to its relatively poor sensitivity and negative predictive value. Because direct microscopy cannot distinguish between M. tuberculosis and nontuberculous mycobacteria, e.g., M. avium-intracellulare complex (MAC), another concern is specificity. The prevalence of tuberculosis and nontuberculous mycobacteria in the population tested is the major variable, not any property of the test or the testers. The prevalence of nontuberculous mycobacteria in the environment and disease due to nontuberculous mycobacteria varies widely according to geographic location and patient population. Therefore, the specificity of the AFB smear cannot be controlled by the microbiology laboratory. Despite this, most

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published studies show the AFB smear to continue to have excellent specificity (99%) and positive predictive value (91.5–98%) for the diagnosis of tuberculosis (52,53). We have not found the positive predictive value of the AFB smear at our institution to be nearly this good. We attribute this to the high prevalence of nontuberculous mycobacterial infection and colonization, especially among our HIV-infected patients. The utility of the AFB smear has also been examined for HIV-infected patients. The lack of cavitary disease in this population raised the possibility that the sensitivity of AFB smear might be lower for this group. In addition, the high incidence of infection with MAC resulted in concerns about lower specificity in these patients. Both of these issues have been addressed. Studies comparing the sensitivity of the AFB smear in HIV patients (55–66%) and non-HIV patients (55–79%) have demonstrated no significant difference between these two groups (54–56). Similarly, the positive predictive value of the AFB smear from expectorated sputum samples for the diagnosis of tuberculosis in a hospital with a very high incidence of HIV and MAC was found to be comparable (92%) to that found in earlier studies from the pre-AIDS era (54). Mycobacterial Culture

Mycobacterial culture is more sensitive and specific for the diagnosis of tuberculosis than is AFB smear. Determining its true sensitivity and specificity is somewhat difficult. In the United States a diagnosis of active tuberculosis may be reported to the Centers for Disease Control and Prevention (CDC) in the absence of a positive culture. The culture-negative cases represent the final judgment that a physician makes regarding the diagnosis of tuberculosis in an individual patient after reviewing all available data. These include clinical and radiographic evaluation, TST, bacteriological results, and response to antituberculous therapy. This is clearly a subjective determination. Two physicians, even if they are both experts in the field, may disagree on a final diagnosis in any given case. Given these limitations, two studies have reported the sensitivity for sputum culture to be approximately 81% in pulmonary tuberculosis, with a significantly higher sensitivity for 96% for cavitary disease (51,53). This sensitivity of 81% is consistent with more recent national U.S. data. In 1990, for example, only 86.7% of cases of active pulmonary tuberculosis reported to the CDC were culture proven (49). Mainly due to laboratory contamination, false positives also occur with culture. The specificity of culture has been reported to be as high as 98.5% (53). The major limitation of mycobacterial culture is the delay in obtaining results. Using conventional methods in which mycobacteria are inoculated in eggbased (Lowenstein-Jensen, L-J) or agar-based (Middlebrook 7H11) media and incubated, cultures may not grow for 3–8 weeks or more. In the late 1970s new culture methods were developed in order to shorten the delays inherent in culture.

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The most widely used system, BACTEC (Becton Dickinson, Sparks, MD), employs a radiometric method, which detects radiolabeled 14CO2 produced when growing mycobacteria metabolize 14C-labeled palmitic acid incorporated into the media (57). Use of this system can decrease time to detection of positive cultures to 8–14 days (30). In terms of sensitivity, BACTEC is at least as good as conventional culture methods (46). Some authors have recommended using BACTEC in conjunction with conventional media (L-J or M 7H11) as this combination produces the highest yield for detection of mycobacteria (57). Adding to the inherent delay of culture for diagnosis is the condition that once mycobacterial growth is detected, further tests must be performed to identify M. tuberculosis and differentiate it from nontuberculous mycobacteria. Older methods were based on evaluating growth characteristics, biochemical tests, pigment production, and colony morphology. These tests can take weeks to make a definitive identification. Fortunately they have been replaced by newer rapid methods. The NAP ( p-nitro- -acetylamino- -hydroxypropiophenone) test is usually used in conjunction with the BACTEC system. NAP specifically inhibits growth of M. tuberculosis complex species, but not nontuberculous mycobacteria. The NAP test generally takes 5–7 days and has been found to be up to 99% accurate (46,58). The fastest widely available method for identifying mycobacterial species utilizes nucleic acid probes. In this method chemiluminescent DNA probes, designed to hybridize with rRNA sequences unique to the target organism, are used to identify mycobacterial species. Gen-Probe Accuprobe (Gen-Probe, Inc., San Diego, CA) includes probes for M. tuberculosis complex, MAC, M. kansasii, and M. gordonae. This identification system gives same-day results in cultured specimens and is nearly 100% sensitive and specific (46,58). One limitation of both the NAP and Gen-Probe systems is that they cannot differentiate the individual species of the M. tuberculosis complex (e.g., M. tuberculosis vs. M. bovis). This may have clinical significance, especially in areas where species such as M. bovis are prevalent. Because M. bovis is inherently resistant to pyrazinamide and therapy may need to be altered, further identification testing should be performed in such situations. These newer culture and identification techniques have had a major impact on the diagnosis of tuberculosis. This is clearly illustrated in one study that compared the combination of BACTEC and DNA probes for culture and identification with conventional methods (46). When BACTEC and DNA probes were used, the median time from inoculation of cultures to identification was reduced from 73 to 23 days. Despite this significant improvement, even the newer methods can hardly be called rapid when the median time for a positive diagnosis is over 3 weeks. Obtaining a negative result takes even longer, as most labs will not give a final report of no growth until at least 8 weeks have passed. For this reason significant efforts have been made and will continue to be made to develop a truly rapid and accurate test for the diagnosis of tuberculosis (see Sec. VIII).

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In certain instances it may not be possible for a patient to produce a sputum sample, even if the aerosolized induction method is used. In some cases where sputum samples have been obtained and are AFB smear negative, it may not be acceptable to wait for the results of culture or response to empiric therapy, both of which can take 2–3 months. This is particularly true when alternative diagnoses, such as malignancy or other infections (e.g., fungal), are also likely possibilities. Under such circumstances, strong consideration should be given to invasive diagnostic testing such as bronchoscopy. A number of studies have evaluated the usefulness of bronchoscopy in the diagnosis of tuberculosis. In one study of 56 patients suspected of having tuberculosis who either had three negative AFB smears or were unable to produce sputum, fiberoptic bronchoscopy (FOB) provided a diagnosis of mycobacterial infection in 22 (39%) cases (59). Transbronchial biopsy had the highest yield for immediate microscopic diagnosis. Another study showed that of 89 sputum AFB smear–negative patients eventually diagnosed with tuberculosis, 67.4% were diagnosed by FOB, with 39 (44%) having a rapid diagnosis made by positive AFB smear from bronchial brushings or by histology from transbronchial biopsy (60). Bronchoalveolar lavage (BAL) has also been found to be sensitive for the diagnosis of tuberculosis. In one investigation of patients diagnosed with tuberculosis, sputum was smear positive in 16 of 47 (34%) and culture positive in 24 of 47 (51%), while BAL was smear positive in 34 of 50 (68%) and culture positive in 46 of 50 (92%) (61). FOB has also been evaluated for the diagnosis of tuberculosis in HIV-infected patients. The diagnostic yield was found to be similar to that for non–HIV-infected patients, with transbronchial biopsy providing additional yield, especially for immediate diagnosis (62,63). Based on these studies and others, FOB clearly has a role in the diagnosis of tuberculosis, especially in patients with negative sputum smears. It will yield the diagnosis, often rapidly, in some cases, which would have otherwise been missed by sputum sampling. With FOB one also has the ability to make other diagnoses such as malignancy. The major problem with bronchoscopy is the need for specialized equipment and trained personnel, making it costly. Another concern is the infection control risk posed by the generation of infectious aerosols that occurs with FOB. Transthoracic fine needle aspiration (FNA) has primarily been used for the diagnosis of malignancy, but also has been used to make the diagnosis of tuberculosis (64). Compared with FOB, little has been written about the efficacy of this procedure for diagnosing tuberculosis. In one study 10 patients ultimately diagnosed with tuberculosis who had negative AFB smears from sputum or bronchoscopic brushings underwent ultrasound guided transthoracic FNA (with a Tru-cut needle biopsy if initial AFB smear from aspiration was negative) (65). FNA/

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biopsy yielded the diagnosis of tuberculosis in 9 of 10, with an immediate diagnosis by AFB smear or histology in 8 of 10. Because the numbers are small and the patients represent a select population, it is difficult to draw a firm conclusion regarding the sensitivity of FNA. Nevertheless, it may have some utility in diagnosing patients who are AFB smear negative by sputum and/or bronchoscopy. Rarely is a surgical procedure necessary for diagnosis in a patient suspected of having active tuberculosis. The most frequent way in which tuberculosis is diagnosed surgically is when a patient undergoing thoracotomy or thoracoscopy for removal of a lung nodule suspected of being a malignancy is subsequently found to have a tuberculoma (66). As tuberculosis, especially in AIDS patients, can present as isolated mediastinal and /or hilar adenopathy, mediastinoscopy may be useful in certain cases (66). Open lung biopsy by thoracotomy or thoracoscopy has been shown to be useful for the diagnosis of diffuse parenchymal lung diseases (67). Therefore, open lung biopsy should be considered in cases where miliary pulmonary tuberculosis is considered a possibility and other procedures, such as transbronchial biopsy, have failed to provide a diagnosis. D. Culture-Negative Pulmonary Tuberculosis: Diagnosis Based on Response to Empiric Therapy

A diagnosis of active tuberculosis can be made in the absence of a positive culture. The combination of a reactive TST and a chest radiograph consistent with tuberculosis with or without symptoms often leads a physician to begin antituberculous therapy even in the absence of a positive AFB smear. A subsequent clinical and /or radiographic response to multidrug therapy over an appropriate time course (1–3 months) is considered sufficient to make a diagnosis of tuberculosis in the face of negative cultures (22,49,68). In fact, in 1990 14.3% of cases of active tuberculosis reported to the CDC were culture negative and 9.4% were smear and culture negative. VI. Extrapulmonary Tuberculosis A. General Considerations

Extrapulmonary tuberculosis is seen in only about 15% of cases in nonimmunocompromised individuals, but it occurs with greater frequency in those infected with HIV (69). Extrapulmonary tuberculosis is found in up to 70% of patients with a preexisting diagnosis of AIDS or a diagnosis of AIDS occurring shortly after being diagnosed with tuberculosis (70–72). The occurrence of “atypical” presentations of tuberculosis in HIV-seropositive patients appears to be related to the degree of immunosuppression. This is illustrated by the finding that the frequency of extrapulmonary disease, mycobacteremia, and “atypical” radiographic findings increases with low CD4 counts (73,74).

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The most common sites of extrapulmonary tuberculosis are peripheral lymph nodes, the pleura, the bones and joints, the genitourinary system, the abdomen (peritoneum and gastrointestinal tract), and the central nervous system (CNS) (69). Widely disseminated or miliary disease occurs in about 8% of cases of extrapulmonary tuberculosis, although this number is substantially higher in HIV-associated disease. In fact, tuberculous bacteremia is relatively common in HIV-associated tuberculosis, and blood cultures can be a useful diagnostic tool in these cases (71). In the presence of concurrent documented active pulmonary tuberculosis, a compatible clinical and/or radiographic presentation are 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 AIDS patient with pulmonary tuberculosis and CNS toxoplasmosis). In these cases, if there is deterioration or failure to respond to tuberculosis therapy at the extrapulmonary site, additional diagnostic evaluation should be performed. In cases where the disease is isolated to an extrapulmonary site, a biopsy for histology, AFB smear, and culture is usually necessary. B. Pleural Tuberculosis

Pleural effusions are the second most common manifestation of extrapulmonary tuberculosis. Tuberculous effusions are usually unilateral with bilateral effusions being present in less than 10% of cases (39,75). They generally occupy less than one half of a hemithorax but rarely can fill the entire hemithorax (75). Associated pulmonary infiltrates may be seen in up to 50% of patients (76). Pleural fluid analysis generally reveals an exudate with a lymphocytosis (39,76). AFB smears of pleural fluid are rarely positive (39,77). Although cultures have a better yield, the sensitivity is still not much better than 50% (39,70,76,77). Several relatively new tests may also be useful for the analysis of suspected tuberculous effusions. Adenosine deaminase (ADA) is an enzyme that is particularly abundant in activated T lymphocytes. High pleural fluid ADA activity has been associated with tuberculous pleuritis. In one study of 221 patients with pleural or peritoneal effusions, it was discovered that all subjects with an ADA level of 70 or higher had tuberculosis and none of the tuberculosis patients had an ADA level below 40 (78). Using a cut-off of 47 U/L for ADA activity, another investigation had similar results, reporting a sensitivity of 100% and a specificity of 95% (79). Despite the high sensitivity and specificity of ADA activity for the diagnosis of pleural effusion found in these studies and others, this test is not commonly used in the United States. There may some reservations about its use because the studies cited were done in Spain, where tuberculous pleurisy is much more common and therefore the positive predictive value of this test may be lower in the United States.

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High pleural fluid levels of interferon-gamma (IFN-), another lymphocyte product, are also seen in tuberculosis pleuritis. One study of 80 patients with pleural effusions found that the mean IFN- level was 90 in individuals with tuberculous pleuritis compared to a mean of
2 for pleural effusions of all other causes (80). Another study, using a IFN- level of 140 as a cut-off, revealed that this test had a sensitivity of 94.2% and a specificity of 91.8% (79). As with ADA, this test is not frequently used in the United States. The most useful diagnostic test is closed needle biopsy. The combination of histology and culture from this procedure has a diagnostic yield of greater than 90% (75–77,81). If closed needle biopsy is not diagnostic, thoracoscopy should be considered (67,82). C. Tuberculous Lymphadenitis

The most common site of extrapulmonary tuberculosis is the lymphatic system. Intrathoracic adenopathy is usually seen in children or adults as a manifestation of primary disease or in HIV-seropositive patients and has already been discussed. The cervical lymph nodes are the most common site of extrathoracic tuberculous lymphadenitis and are involved in about 70% of cases (83,84). The next most frequently involved lymph node groups are the inguinal and axillary (83). For diagnosis of peripheral lymph node disease excisional lymph node biopsy has the best yield (83,84). Some authors believe percutaneous fine needle aspiration should be considered because the test is less invasive (83–85). D. Tuberculosis of the Central Nervous System

Central nervous system tuberculosis may be manifested by meningitis or parenchymal brain or spinal cord lesions (tuberculomas). Patients with meningeal tuberculosis are almost always symptomatic, with the most common complaints being fever, headache, mental status alteration, and nausea /vomiting (86,87). Meningeal signs are present on physical examination in about 70% of cases, with cranial nerve palsy and or other focal neurological findings seen in about 25% and 16–18% of individuals, respectively (86–88). CT scan and MRI usually show basal enhancement and hydrocephalus with meningitis (89,90). The lumbar puncture often shows a lymphocytic pleocytosis with elevated protein and a low glucose (86,88). The cerebrospinal fluid (CSF) AFB smear is usually negative (86–88). CSF cultures are more sensitive, but still are negative in up to 50% of cases (87,91). Often the diagnosis must be based on detecting M. tuberculosis at another site or response to an empiric trial of therapy when other causes of meningitis have been excluded. Parenchymal tuberculomas have a characteristic appearance on CT and MRI. They are round or ovoid lesions, which have a rim of enhancement with contrast (89,90). If characteristic brain lesions are seen on CT or MRI in a patient sus-

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pected of having tuberculosis, some advocate an empiric trial of therapy, reserving biopsy for those patients who do not respond (92). However, as the radiographic findings are nonspecific and may be seen with other infections or tumors, others would favor a brain biopsy at the outset (93). E. Bone and Joint Tuberculosis

The most frequent site of tuberculous bony involvement is the spine (known as Pott’s disease), which accounts for 50–60% of cases (94). Within the spine the lower thoracic and thoraco-lumbar regions are the most commonly involved, comprising 48–67% of spinal lesions. Tuberculosis typically infects the vertebra (osteomyelitis) and the adjacent joint space (arthritis), resulting in inflammation and destruction (95). With time the infection may spread to the adjacent soft tissue, resulting in the formation of a paravertebral abscess. On occasion, the paravertebral collection of pus may track along the sheath of the psoas muscle and present clinically as a fluctuant mass in the groin. Localized pain at the site of involvement is the most frequent presenting complaint, occurring in over 90% of patients (96,97). Systemic symptoms such as fever and weight loss are less common, but are reported to be present in up to 24–58% of cases (96,97). With very advanced disease, weakness and even paralysis may occur. Plain bone films may be negative in early disease and cannot differentiate between tuberculosis and other forms of osteomyelitis (98). Radionuclide bone scanning is also not particularly sensitive and is not at all specific (99). MRI is the most sensitive and specific radiological test (98,100). If therapeutic surgery is necessary, tissue for histology and culture can be obtained during the operation. If surgery is not required, percutaneous fine needle aspiration biopsy is useful for diagnosis. Tuberculous arthritis excluding the spine usually occurs in weight-bearing joints (101). For patients with suspected tuberculous arthritis with a joint effusion, arthrocentesis should be performed. The effusion is usually characterized by a high-protein, low-glucose, and WBC count of 10,000–20,000 with a neutrophil predominance (101). Synovial fluid cultures are significantly more sensitive than AFB smears. Synovial biopsy including smear, culture, and pathology is the most sensitive test for diagnosing tuberculous arthritis (101). In children, bone and joint disease usually presents at the epiphiseal areas of growing long bones. F. Genitourinary Tuberculosis

Tuberculosis can affect essentially all organs of the genitourinary system including the kidney, bladder, prostate, seminal vesicles, epididymus, fallopian tubes, ovaries, and endometrium. Most patients with renal tuberculosis are symptomatic. The most common complaints are dysuria, hematuria, and flank pain (102). Constitutional symptoms, such as fever and weight loss, are less frequent. The finding

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of sterile pyuria should alert the clinician to the possibility of urological tuberculosis. For urological tuberculosis, urine AFB smears and cultures are usually the first test of choice. Urine cultures have a sensitivity of 80–90% (102,103). Ultrasound guided biopsy of renal lesions also appears to have a good yield (104). For disease of the genital organs, biopsy is usually required for diagnosis. G. Abdominal Tuberculosis

Abdominal tuberculosis refers to disease of the peritoneum, gastrointestinal tract, liver, biliary tract, and pancreas. The peritoneum, small bowel, and colon are the most frequent sites of infection. Involvement of the biliary tract and pancreas are quite rare. When hepatic disease occurs, it is usually associated (about 95% of the time) with miliary disease (95). Clinically, peritoneal tuberculosis is manifested by abdominal distention or swelling, abdominal pain, fever, anorexia, and weight loss (105–107). Ascites is detectable on physical exam in 75–100% of cases (106,107). Analysis of the ascitic fluid generally reveals a high protein content and an elevated white blood cell (WBC) count with a lymphocytic predominance (105,107). AFB smears are almost always negative (105,107,108). Cultures are positive in 70% of cases or less (105,107,108). For this reason further diagnostic testing is often necessary. The procedure of choice is laparoscopy with biopsy. The diagnostic yield of this procedure is on the order of 80–100% (109–111). Although tuberculosis can affect any portion of the gastrointestinal tract from the mouth to the anus, the most commonly involved sites are the ileo-cecum, colon, and the small bowel ( jejunum and ileum). These three sites comprise 52–80% of enteric tuberculosis (108,112–114). The most frequent presenting signs and symptoms are weight loss, acute or chronic abdominal pain, anorexia, nausea and vomiting, diarrhea, and fever (108,112,113). Rectal bleeding, melena, and constipation have also been reported to occur. An abdominal mass may be palpated (usually in the right lower quadrant) (113). Enteric tuberculosis may present as a small bowel obstruction or (rarely) as a perforation (113). Radiological studies (barium enema and CT scan) often show bowel wall abnormalities, but the findings are nonspecific and may be confused with other entities such as Crohn’s disease (95,115). Stool AFB smears and cultures may be helpful in some cases, but their diagnostic yield is probably low (113). Endoscopy with biopsy and/or needle aspiration is usually required for diagnosis (116–118). H. Pericardial Tuberculosis

Pericardial tuberculosis is uncommon. It generally presents as a pericardial effusion, often with tamponade, or constrictive pericarditis (119,120). Chest radiograph, EKG, and echocardiogram findings are not specific (119–121). Pericardial fluid is most often serosanguinous and characterized by an elevated WBC count

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with mostly lymphocytes (95,119). AFB smears are very rarely positive (95,120). Pericardial fluid culture has a better yield, but pericardial biopsy is definitely the most sensitive test (119–121). I. Miliary Tuberculosis

Miliary tuberculosis is disseminated tuberculosis spread hematogenously from a previously infected focus. In cases of miliary disease, peripheral lymph node biopsy, bronchoscopy with transbronchial biopsy, bone marrow biopsy, or liver biopsy should be considered if the diagnosis cannot be made noninvasively (e.g., sputum smear and culture) (122–125). VII. Pediatric Tuberculosis The diagnosis of tuberculosis in infants and children is particularly challenging. Even in pulmonary disease, bacteriological confirmation of the diagnosis is established in the minority of cases (126). Because of this, the diagnosis can be made in the absence of a positive culture if the following criteria are present: close contact to a source case, a positive tuberculin skin test, and a compatible chest radiograph (127). In suspected pulmonary tuberculosis, if cultures are necessary, the best method for obtaining specimens in infants and children is aspiration of gastric contents (127–129). For suspected extrapulmonary tuberculosis, the diagnostic evalution for a given site is generally based on the same approach used in adults. VIII. Developments in Rapid Diagnosis: Nucleic Acid Amplification Tests Timely diagnosis of active tuberculosis remains a vexing problem for clinicians. Even with the use of genetic probes and radiometric detection systems, culture results may be delayed for 2–5 weeks (130), and in most developing countries routine confirmation by culture is not feasible. In the interim, critical decisions regarding treatment, isolation, and contact tracing must be made. For more than a century, the most important criteria for accomplishing a presumptive diagnosis have been the AFB smear and empiric evidence, which may be based on radiographic signs, sentinel symptoms, or these factors in combination with the smear. Detection by smear requires a relatively large (104) organism burden, and the test does not distinguish mycobacteria of the M. tuberculosis complex from other pathogenic and nonpathogenic mycobacteria. Thus, in patients with early-stage or extrapulmonary disease, in children, and in many immunocompromised patients, the smear is a much less reliable indication of disease (48,68,131). Worldwide, it

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is estimated that only 35% of active disease is detected with the AFB smear (132). Use of empirical criteria may greatly improve the likelihood of detecting disease; however, the predictive value of this approach is typically quite low, because the signs and symptoms of active disease are nonspecific (133–135). For the U.S. public health system, which evaluates more than 100,000 patients annually, Brown has estimated that three suspected cases are placed on treatment for every case of confirmed disease (136). The development of new diagnostic approaches is a critical component of the worldwide tuberculosis control effort (137–139). Recent advancements in molecular biology have greatly accelerated the development of more accurate rapid tests. At the present time, this research is proceeding along two basic lines. Nucleic acid amplification tests (NAAs) combine probe and genetic amplification technology in an assay system which can be performed rapidly in clinical specimen and is specific for M. tuberculosis complex. A new generation of antibody tests, using more highly purified antigen derivatives and enzyme-linked immunosorbent assay (ELISA), is also in development. This chapter discusses developments with respect to the NAAs. Developments in the field of serology are considered in Chapter 8. Nucleic acid amplification tests combine a genetic probe assay (which has heretofore required culture of the target organism) with amplification technology (140). Enzymatically driven amplification systems are used to replicate the amount of target genetic product present in a clinical specimen several millionfold, thus providing sensitivities for probe to within 1–100 organisms (141,142). Once the genetic target has been sufficiently amplified, it can be detected using a complex-specific nucleic acid probe similar to the method described previously for detection in culture. Results are described qualitatively, using a spectrophotometric cut-off. The complete assay, including amplification, hybridization, and probe detection, can be completed within a matter of hours and is theoretically available for use in any type of clinical specimen. The basic format is also adaptable to multiplex designs enabling simultaneous testing of several mycobacterial species. More experimental procedures such as multiplex strand displacement amplification (143,144) and spoligotyping (148) are increasingly encountered in the laboratory literature. NAAs require sophisticated laboratory infrastructure, including specialized equipment, staff, and reagent supplies. Operating costs vary substantially, are volume dependent, and likely to be higher for smaller clinical laboratories (130). Several different amplification-detection systems have been described. Polymerase chain reaction (PCR)–based amplification using the M. tuberculosis IS6110 insertion sequence (146,147), a target present in 8–20 copy numbers in most but not all M. tuberculosis strains, was the first rapid diagnostic test format to be widely reported (148–150) and remains the most popular basis for so-called “home-brew” preparations. Commercial kits, using standardized controls and offering integrated amplicon/oligonucleotide detection systems, have also been de-

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veloped. Among the more extensively tested at the present time are the Mycobacterium Tuberculosis Direct Test (MTD, Gen-Probe, Inc., San Diego, CA) (151–161), which uses transcription-mediated amplification of ribosomal RNA in conjunction with the manufacturer’s Accu-Probe test for culture (151,157, 162–165), and the Amplicor (Roche Molecular Systems, Branchburg, NJ), a polymerase chain reaction system targeting DNA of genes encoding rRNA (155,166–175). The LCx MTB assay (Abbott Laboratories, Chicago, IL), which utilizes a semi-automated ligase chain reaction system to target Antigen b, a constituent of the species-specific 38 kDa protein, is currently undergoing demonstration trials (176–178). A Q-beta replicase system (Gene-Trak, Framingham, MA), targeting the 23S subunit of ribosomal RNA, has also been described (179–181). Several of the aforementioned reports are comparison studies. There is no evidence that different amplification procedures, when performed by trained personnel, differ significantly in reliability, but blind proficiency studies have cautioned that other laboratory procedures required to support these systems, including quality control and specimen-preparation procedures, can affect test performance intra- as well as interlaboratory (182,183). A. Laboratory Performance

Most studies have been carried out in respiratory specimens and primarily in U.S. and European settings, but also in some developing countries (169,184,185). Respiratory Specimens

The largest studies have been conducted in the United States under U.S. Food and Drug Administration protocols for review of two commercial applications, the Gen-Probe MTD and the Roche Amplicor. These multicenter studies have collectively examined performance in over 20,000 patient specimens. Based on these trials, sensitivity against culture has ranged from 70 to 100%, with a sensitivity of 80% considered typical. Overall specificity has generally been 95% or better. Versus culture, positive predictive value of the NAAs has averaged about 78%, and the negative predictive value has been over 90%. Falsenegative results have been attributed to low volume of target in specimen (153,186,187) or the presence of amplification inhibitors. False-positive results have been associated with amplification of contaminants (183) or, in specimens from patients recently treated for tuberculosis, with amplification of inactive tuberculous target (158,165,188). The best sensitivity has been achieved in smearpositive samples where the tests have detected 95–100% of culture-positive specimens. Depending on the proportion of specimens containing nontuberculous mycobacteria (NTM), perhaps 50–75% of false-positive smears have also been identified when the test is examined in a smear-positive group. This has produced estimated positive predictive values (versus culture) approaching 100%. Sensitiv-

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ity in smear-negative samples has been more variable, ranging from 40 to 75%, although specificity in these samples is similar to that achieved overall, or about 95%. As a result estimated positive predictive values have been lower, around 50–60%, although negative predictive values have approached 100%. The MTD and the Amplicor are currently approved in the United States for use in smear-positive respiratory specimens of a patient who has not received antituberculous medication for 7 or more days within the previous 12 months (140). Under its revised case surveillance definition, CDC will accept a positive NAA as confirmation of disease in patients tested under FDA criteria (189). Other Specimens

Although less systematically studied at the present time, the sensitivity of amplification systems in extrapulmonary specimens (156,187,190–192) and for detection of disease in children (193–196) warrants continued investigation. With the exception of pleural effusions, for which results have been inconclusive (160,197), performance in cerebrospinal fluid (159,198–202), blood, urine (203–205), bone marrow and liver biopsy specimen (206), and gastric aspirate (194) has been encouraging when compared to current alternatives. Two recent studies from Africa and Brazil, where tuberculosis bacteremia in association with HIV infection is relatively common, have reported promising results in blood specimen (201,202). In a controlled design, Sechi et al. reported consistent sensitivities across a range of body fluids in a group of AIDS patients with tuberculosis (204). A few studies in children, using an IS6110-targeted in-house PCR assay, have been described. A single PCR assay in gastric aspirate identified 25% of 22 clinically defined primary cases versus 0% by culture and smear, and sensitivity was increased to 100% when multiple specimens were examined (193). In 68 children referred for suspicion of disease, Delacourt compared performance in BAL and gastric aspirate specimens, reporting a sensitivity of 83% for active disease and of 39% for tuberculous infection (specificity 100%) when compared to culture (194). Using clinical case definitions, Fauville-Dufaux et al. (195) and Smith et al. (196), in a small case series and a larger controlled study, respectively, have reported similar sensitivities for active disease (40 or 45%) versus a sensitivity of 22 or 37% by culture. B. Clinical Utility

Few studies to date have examined the tests against clinical detection systems, and no controlled clinical trials have been completed. In a retrospective analysis, and when compared against the classification system of the American Thoracic Society, Bradley et al. (158) reported that the Gen-Probe MTD yielded the “correct” diagnosis 100% of the time when both the smear and MTD were positive and 96.2% of the time when both tests were negative. In approximately 6% of cases,

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discordant results occurred, which were resolved in conjunction with other clinical information and repeat testing (158). Compared with a clinical case definition, which included response to therapy as well as bacteriological evidence, Chin et al. reported equivalent sensitivities for the culture (56%) and the Roche Amplicor (58%) versus a sensitivity of the AFB smear of only 22% (207). Cohen et al. compared three NAA assays as a tool for screening within the first 24 hours of hospital admission. When at least one of two specimens was positive, sensitivities against culture ranged from 74 to 85%, versus 48% by smear, and from 53 to 73% in smear-negative patients (208). There remains a pressing need for well-conducted clinical trials using clinical reference standards of diagnosis and comparing alternative testing strategies under appropriately randomized and blinded conditions. Among the many questions that need to be addressed in these trials are the role of physician assessment in setting test and treatment thresholds, how differences in the clinical spectrum of disease or immediate objective of testing affect the utility of alternative rapid tests, and cost-effectiveness. Because the predictive value of testing is strongly influenced by the physicians’ prior suspicion of disease, the American Thoracic Society has stressed the importance of evaluating the NAAs at different levels of physician suspicion (209). Although the U.S. FDA trials have included a broad cross section of patients likely to be evaluated for pulmonary tuberculosis in the United States, more systematic case-control designs are needed in order to develop guidelines for special groups, such as children, the elderly, and HIV-positive patients. Additional studies are also needed to characterize utility for different management objectives. Because the NAAs can detect less as well as more contagious stages of disease, optimal uses for public health and clinical purposes may differ. The current regulatory situation in the United States, limiting use of commercial products to smear-positive respiratory specimen, tends to blend these agendas. Cost and operational requirements of the NAAs are also important aspects of clinical utility. Because the technology is new, laboratory costs per patient determination are unlikely to be fully recognized by payment authorities. These costs are also highly volume dependent and may be difficult for smaller clinical laboratories to support (30). Another important area of inquiry is outcomes research. The potential impact of the NAAs on resource utilization has been simulated in theoretical models. One preliminary study modeling costs for a U.S. inpatient setting, illustrated overall savings for a scenario in which the enhanced specificity of rapid diagnosis led to reduction of unnecessary isolation and treatment (210). This result is plausible for the U.S. system, where incidence is low and as much as 60% of clinical program resources may be expended in management of patients found ultimately not to have tuberculosis (136). Although the NAAs have been considered less relevant for developing countries (211), the need for more sensitive tests is also greatest in these areas. Using program management re-

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ports for Kenya’s outpatient system and U.S.-based laboratory costs, Roos et al. characterized threshold conditions that would make the NAAs cost-effective in that system (212). These models have also been useful in illustrating important differences in the diagnostic needs, economic constraints, and planning horizons that apply to different health systems. Further theoretical research is needed to develop models of diagnostic technology assessment that are more relevant to developing countries. The contribution of delayed diagnosis to tuberculosis epidemics over time has not been studied; however, more recent epidemic models have suggested that current treatment and prophylaxis benchmarks will not alone achieve WHO targets for control of the disease (213). C. Recommendations for Clinical Use

Based on experience at the authors’ facility, we have proposed the following tentative recommendations for clinical use of the NAAs (214). These guidelines assume a high level of proficient laboratory resources and would not necessarily apply in less developed health systems. Smear-Positive Patients

As recommended by the CDC, a positive NAA in a smear-positive patient may confirm disease (140). Conversely, a negative NAA in these patients is suggestive of NTM when it is confirmed by a second test on a second specimen. This information is of particular value in evaluating immunocompromised individuals who are at elevated risk of pathogenic as well as nonpathogenic NTMs and for whom some antituberculosis drugs may be contraindicated (215). Although in the FDA trials less than 10% of patients evaluated would have been candidates for this use, the relative false-positive rate of the AFB smear (i.e., false positives as a proportion of all test positive results) can exceed 20% in some regions of the United States (216–219). We suggest that it is most effective in geographic areas or populations where the rate of NTM isolation is expected to exceed 5% in patients evaluated. Smear-Negative Patients

Although the positive predictive value of the test in smear-negative patients is considered too low to support confirmation of disease, in laboratory trials, the NAA has still represented a 50% improvement in yield for this subgroup and therefore is of great value to a skilled clinician. In selected circumstances, such as high-risk patients, where paucibacillary or atypical disease is strongly suspected, or where more invasive procedures would otherwise be considered, positive predictive values are likely to exceed those reported in laboratory trials. In combination with other clinical evidence, a positive NAA, particularly when it is repeated

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on a second specimen, even in a smear-negative patient may signal an indication for presumptive treatment or a need for further work-up. The very diversity of this group counsels against generalization and reflects the need to further define this spectrum in clinical trials. Use of NAAs for Initial Testing

Because the overall accuracy of the NAAs is superior to that of the AFB smear, initial testing with the NAA may be plausible when the prior risk of disease is elevated (Fig. 1). The patient population that has been screened by clinician and thought likely to have active tuberculosis may have a prior risk of disease in the range of 30–60% depending on the skill of the clinician. The probability of disease when an initial NAA is positive may be between 80 and 90% given that the test has a specificity of 95%. In these circumstances, a positive test should be followed up with an AFB smear to quantitate mycobacterial load and culture to recover organism for drug susceptibility testing. If both tests are positive, the patient should be considered to have confirmed diseased and appropriate treatment and isolation steps should be taken. If the AFB smear is negative, there still remains a heightened possibility of disease, and the patient should be treated presumptively. If the initial NAA is negative, disease is less likely; however, the test should be repeated to rule out laboratory artefact. If the repeat test is positive, steps outlined for follow-up with AFB series should be followed, and if the repeat test is nega-

Figure 1

Proposed algorithm for use of the NAA in patients for initial testing.

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tive, the diagnostic plan should be reformulated on the basis of other medical evidence and clinical judgment. X. Summary Tuberculosis remains a leading cause of morbidity and mortality throughout the world. Current control strategies are based on identifying and treating cases of active tuberculosis and latent infection in order to break the chain of transmission. The accuracy and timeliness of diagnosis therefore is a cornerstone of the strategy to control and eventually eradicate the disease. Despite several improvements in laboratory instrumentation over the years, timely diagnosis of the disease must rely on the clinical case definition. In addition to the medical history, chest radiograph, bacteriological reports, and physical examination, this assessment requires attention to the patient’s socioeconomic background and exposures that would place him or her at greater risk for contracting disease. Because the vast majority of cases of tuberculosis (80%) involve the lung, this approach to diagnosis has received the greatest attention. With the changing epidemiology of tuberculosis, including such factors as the HIV epidemic and the higher incidence among individuals migrating from endemic regions, major gaps in the armamentarium in the cases of extrapulmonary disease, diagnosis in children, and smear-negative or paucibacillary disease have been exacerbated. Nucleic acid amplification tests, more sensitive than AFB smear and faster than culture, represent the first major breakthrough in diagnosis since the work of Koch nearly a century ago. These tests require highly sophisticated infrastructure, and applications in the clinical setting have been hampered by the lack of appropriate research designs for evaluating clinical utility and cost-effectiveness. Randomized designs using clinically relevant diagnostic standards need to be established for assessment of the NAAs and other emerging diagnostics. Given the complexity of the disease and its sentinel role in many other conditions, no single test can substitute for sound clinical judgment. The clinician must remain constantly alert to the fact that, in the final analysis, tuberculosis is a clinical diagnosis. References 1. Cantwell MF, Snider DE, Jr., Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992 [see comments]. JAMA 1994; 272:535–539. 2. 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. 3. Concato J, Rom WN. Endemic tuberculosis among homeless men in New York City. Arch Intern med 1994; 154:2069–2073.

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62. Kennedy DJ, Lewis WP, Barnes PF. Yield of bronchoscopy for the diagnosis of tuberculosis in patients with human immunodeficiency virus infection. Chest 1992; 102:1040–1044. 63. Salzman SH, Schindel ML, Aranda CP, Smith RL, Lewis ML. The role of bronchoscopy in the diagnosis of pulmonary tuberculosis in patients at risk for HIV infection. Chest 1992; 102:143–146. 64. Das DK, Pant CS, Pant JN, Sodhani P. Transthoracic (percutaneous) fine needle aspiration cytology diagnosis of pulmonary tuberculosis. Tuberc Lung Dis 1995; 76:84–89. 65. Yuan A, Yang PC, Chang DB, et al. Ultrasound guided aspiration biopsy for pulmonary tuberculosis with unusual radiographic appearances. Thorax 1993; 48:167– 170. 66. Langdale LA, Meissner M, Nolan C, Ashbaugh DG. Tuberculosis and the surgeon. Am J Surg 1992; 163:505–509. 67. Mathur PN, Loddenkemper R. Medical thoracoscopy. Role in pleural and lung diseases. Clin Chest Med 1995; 16:487–496. 68. Gordin FM, Slutkin G, Schecter G, Goodman PC, Hopewell PC. Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings [see comments]. Am Rev Respir Dis 1989; 139:1090–1093. 69. 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; pp. 173–184. 70. Braun MM, Byers RH, Heyward WL, et al. Acquired immunodeficiency syndrome and extrapulmonary tuberculosis in the United States. Arch Intern Med 1990; 150:1913–1916. 71. Barnes PF, Bloch AB, Davidson PT, Snider DE, Jr. Tuberculosis in patients with human immunodeficiency virus infection [see comments]. N Engl J Med 1991; 324:1644–1650. 72. Barnes PF, Le HQ, Davidson PT. Tuberculosis in patients with HIV infection. Med Clin North Am 1993; 77:1369–1390. 73. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection [see comments]. Am Rev Respir Dis 1993; 148:1292–1297. 74. Post FA, Wood R, Pillay GP. Pulmonary tuberculosis in HIV infection: radiographic appearance is related to CD4 T-lymphocyte count. Tuberc Lung Dis 1995; 76:518–521. 75. Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973; 63:88–92. 76. Seibert AF, Haynes J, Jr., Middleton R, Bass JB, Jr. Tuberculous pleural effusion. Twenty-year experience. Chest 1991; 99:883–886. 77. Chan CH, Arnold M, Chan CY, Mak TW, Hoheisel GB. Clinical and pathological features of tuberculous pleural effusion and its long-term consequences. Respiration 1991; 58:171–175. 78. Ocaña I, Martinez-Vazquez JM, Segura RM, Fernandez-De-Sevilla T, Capdevila JA. Adenosine deaminase in pleural fluids. Test for diagnosis of tuberculous pleural effusion. Chest 1983; 84:51–53.

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15 Contact Follow-Up in High- and Low-Prevalence Countries

SUE C. ETKIND

JAAP VEEN

Massachusetts Department of Public Health Boston, Massachusetts

Royal Netherlands Tuberculosis Association (KNCV) The Hague, The Netherlands

I. Introduction The Centers for Disease Control and Prevention (CDC) estimates that an average investigation of a case of tuberculosis (TB) in the United States results in approximately 9 contacts identified for each case. Of these, 21% are expected to be infected and another 1% will have already progressed to active disease (1,2). In other parts of the world, even higher rates of infection and disease have been found. Because of the risk for progression to TB disease, infected contacts have been designated a high-risk group and, as such, are candidates for TB preventive therapy under current recommendations (3). The examination of contacts or persons exposed to a case of tuberculosis is, therefore, one of the most important methods of case finding for either tuberculosis disease or infection (4). Its utility and importance has been demonstrated in many different types of settings: the workplace (5), among the foreign-born (6), for children under 15 years of age (7–12), and for follow-up of multidrug–resistant cases (13,14). It has also been shown that adherence to preventive therapy may be highest among contacts (15). Given that these individuals are among the highest risk for progression to disease, ensuring completion of therapy is the ultimate objective. The actual risk of transmission to contacts is related to the characteristics of the source case, the 377

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characteristics of the organism, the nature of the contact, and the environments that they share (16–18). Contact tracing is an integral part of any tuberculosis program. This activity encompasses all aspects of tuberculosis control, including surveillance, case containment, and prevention. In many respects, contact tracing corresponds to basic epidemiological methodology, particularly as it relates to surveillance and outbreak control. However, contact tracing is in fact much more. Successful contact tracing requires skills in patient assessment, interviewing, counseling, and evaluation. The quality of contact tracing has been shown to markedly affect the ability to identify potentially infected persons and allow for their integration into the clinical care system (19,20). Therefore, the ability to perform this investigative process is key to tuberculosis-elimination efforts. As cases of tuberculosis have retreated into defined pockets of the population (e.g., geographic and risk-behavior groups), it has become necessary to modify traditional contact-tracing methods in order to address the specific needs of these individuals. Although the basics of epidemiology and follow-up are unchanged, the cultural and/or linguistic barriers, the influence of socioeconomic factors (affecting the homeless population or the injection drug user, for example), the institutional setting, the ramifications of co-infection with HIV, etc., are all factors that will affect the type and content of the contact tracing investigation. This chapter will discuss the purposes of contact tracing as an epidemiological tool and the step-by-step methodology needed to address today’s multifaceted tuberculosis problem for both high- and low-prevalence countries. It will also introduce newer technologies and discuss their additive value to contact-tracing procedures. Finally, it will review identified obstacles to conducting contact investigations, proposed strategies where applicable, and remaining research questions. II. Definitions In discussing contact tracing, a distinction must be made between cases, suspects, and contacts. For the purposes of this chapter, the following definitions will apply: Presenting case—a person with or suspected of having tuberculosis. Index case—the infectious individual who is believed to have transmitted infection to another person(s) (may also be referred to as the source case). Secondary case—TB disease in a contact as a result of transmission from an identified index case. Contact investigation—the process of conducting an epidemiological investigation into a case (or suspected case) of tuberculosis in order to

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identify contacts, screen them for infection and TB disease, and give therapy as indicated. TB contacts—those persons who may have a risk of acquiring TB because they have shared air with the presenting case. The degree of risk is dependent on the duration and frequency (times) of exposure and is influenced by the degree of infectiousness of the patient. The risk is also influenced by characteristics of the environment, the organism, and the new host’s (contact) susceptibility to tuberculosis infection or disease. Close contacts—individuals who have shared air with the presenting case for a prolonged period of time (from hours to months depending on the circumstances). Other-than-close contacts—individuals with less frequent or less intense exposure to the presenting case than close contacts. Concentric circle (stone-in-the-pond principle)—a method of screening contacts in order of risk. Contacts with the highest designated risk are screened first.

III. Need for Contact Tracing There are several reasons for conducting a contact tracing. They include the following: To identify persons who have been exposed to the presenting case and who, therefore, are at greater risk of developing tuberculosis infection and disease than the general population. To identify persons who are infected with the TB bacillus through appropriate screening of these individuals. To ensure access to medical evaluation and preventive therapy as appropriate for these infected individuals in order to prevent disease from occurring. To identify, when possible, the source of TB disease transmission for the presenting case under investigation. This is particularly important for children with active tuberculosis. When tuberculosis occurs in children, given their age, there is reason to suspect recent transmission. To identify, when possible, environmental factors that may be contributing to the transmission of tuberculosis. To ensure medical evaluation, treatment, and follow-up of any additional cases of active tuberculosis that are identified in the course of the contact tracing. A contact investigation may also identify a TB outbreak when more newly infected persons or more tuberculosis cases are discovered during the investigation

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than were anticipated based on the previous epidemiological data. In this situation, the contact tracing may then lead to expanded outbreak investigation activities. IV. Contact Tracing in Low-Prevalence Countries A. Methods for Contact Tracing

Initiation

A contact investigation is begun once a case/suspect of tuberculosis comes to the attention of the person responsible for infectious disease follow-up (health department, infection control nurse, etc.). Prioritizing which tuberculosis cases require contact tracing can be difficult. In some areas, investigations are restricted to contacts of smear-positive pulmonary or laryngeal cases, whereas in other jurisdictions a broader definition may apply. In addition, as children are rarely infectious, a contact investigation may be replaced by a source case investigation in order to identify the person who transmitted disease to the child initially. Because of the possibility of the existence of other infectious TB cases related to the reported case, the investigation should begin as soon as possible—ideally, within 3 working days. Data Collection

Once a case or suspect of tuberculosis has been reported, the investigator should begin the epidemiological process by collecting all currently available information about the presenting case in a systematic fashion. A case/client record should be opened and relevant data should be obtained from the medical record review (hospital, clinic, or other health care records), conversations with the health care provider or other reporting source, and laboratory report reviews. Information obtained should include the TB disease site, dates/sources and bacteriological results for acid-fast bacillus (AFB) and cultures, chest x-ray results including the extent of disease (cavitary/noncavitary), purified protein derivative (PPD) skin test result(s) in millimeters, clinical signs and symptoms (presence of cough—productive/nonproductive, duration?), and anti-TB drug regimen including dosages and date initiated. Armed with this background information, the investigator can then complete the preliminary data-collection process by interviewing the presenting case. This patient interview may be conducted in the hospital, at the patient’s home, or wherever is convenient and conducive to establishing trust and rapport between both parties. The ability to conduct an interview in order to obtain client and contact information will determine the success or failure of the epidemiological investigation. Good interviewing skills can elicit important information that otherwise might not be forthcoming.

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The presenting case interview has many purposes. These include providing opportunities to: 1. Establish rapport and trust with the client (face-to-face contact facilitates building a relationship between the client and the health care provider). 2. Obtain information relative to the presenting case’s potential level of infectiousness or other needed clinical data (e.g., how long has the case been symptomatic?). 3. Obtain place and time information in order to establish duration and location of potential exposures. 4. Identify potentially exposed contacts. 5. Obtain locating/demographic/risk factor and environmental information (living quarters/work/school or leisure activities) for the identified contacts. Environmental factors may include such things as the ventilation, air volume, etc., at the potential exposure sites; for example, were there complaints about air quality? Was this a “tight” building? Were air-quality assessments done in the recent past? 6. Provide TB education on diagnosis, transmission, treatment, and treatment for latent TB infection. 7. Assess compliance elements as they may relate to the presenting case (i.e., are there any factors in the case’s lifestyle, or daily routines, which could interfere with his or her ability to complete TB therapy, or is there a previous history of noncompliance with therapy?). Many factors can interfere with both the case interview and the subsequent contact interviews. These can be attitudinal (on the part of the interviewer or interviewee), social, or cultural differences, mistrust of the government or health care system, fear or stigmatization due to TB, TB/human immunodeficiency virus (HIV), etc. Understanding these potential problems can sensitize the interviewer during the interview process. Furthermore, good communication skills that promote client understanding will enhance the effectiveness of the interview and may potentially result in increasing the number of contacts identified. B. TB Transmission Risk Assessment

The need to set limits and establish priorities for the contact investigation has been well established (16,21). Without a systematic approach to the process, the investigative efforts will be diluted and limited resources are likely to be spent on delivering services to persons who are not at demonstrated risk of TB infection or disease. In order to focus the contact tracing on those who are most at risk, an assessment of the risk of TB transmission to the identified contacts can be done prior

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to the actual field investigation. Transmission risk assessment is best accomplished by organizing the background information into the basic epidemiological categories of person, time, and place. For this chapter, these categories will be defined as (1) person factors—the infectiousness of the presenting case—(2) time factors—the duration and frequency of exposure—and (3) place factors—the characteristics of the environment. Upon completion of all three aspects of this risk assessment, the investigator will be able to establish the contact tracing priorities. Person Factors

Because one of the purposes of contact tracing is to identify infected individuals who have been exposed to the presenting case, an assessment of the potential level of infectiousness of the presenting case must be done. The two most significant factors are disease site and sputum smear positivity. For example, if the presenting case has been shown to have only extrapulmonary disease and no respiratory symptoms, the likelihood of TB transmission is very low. If however, the presenting case is shown to have cavitary disease, hemoptysis, and heavily positive smears, the likelihood of disease transmission is much greater and the need for rapid contact tracing is clear. Table 1 lists suggested factors to be used in this assessment. The susceptibility of the host (or contact) to tuberculosis will also affect the likelihood of TB transmission. Even if all presenting case factors listed above suggest a high probability of TB disease transmission, an immunocompetent contact who has been previously infected with tuberculosis is rarely reinfected with the organism. However, HIV-infected immunosuppressed individuals may be reinfected, and although immunocompetent persons with recently

Table 1

Person-Assessment Factors Likelihood of disease transmission

Clinical data TB disease location

High

Smear status Smear source

Laryngeal Pulmonary Positive Spontaneous specimen

Chest x-ray Symptoms Anti-TB drug

Cavitary Cough No

Low Extrapulmonary alone Negative Induced or clinical (bronchoscopy, etc.) Noncavitary No cough Yes (2 weeks or more)

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acquired tuberculosis infection are at high risk of developing active tuberculosis within 2 years of primary infection (22), research suggests that the risk is increased dramatically for persons infected with HIV (23–25). Given the higher disease attack rates, shorter incubation periods, and high mortality that has been demonstrated for these individuals, contact tracing assumes a much greater urgency. Time Factors

After the investigator has made an assessment of the potential infectiousness of the presenting case, a determination of the duration and intensity of exposure must be made (i.e., how long the identified contacts were potentially exposed to the case while he or she was infectious). Because tuberculosis is an airborne infection, this is normally done by determining the date of the onset of symptoms (particularly coughing) for the presenting case. This date can provide the approximate time frame (or period of infectiousness) upon which to focus the investigation. For example, if it is determined during the case interview that the presenting case has had a productive cough for one month prior to diagnosis and the initiation of treatment, then all identified contacts during that month may be at increased risk of TB transmission. When the contact is unable to remember reliably when his or her symptoms began, some jurisdictions elect to define the period of infectiousness as beginning at least 3 months before treatment started. The period of infectiousness ends when all of the following criteria are met: symptoms have improved, the patient has been receiving adequate treatment for at least 2 weeks, and the patient has had at least three consecutive negative sputum smears from sputum collected on different days. Place Factors

Knowing the level of potential infectiousness of the presenting case and the time frame during which possible exposures may have occurred, the next step in the contact-tracing process is to establish the place (or places) where contacts may have been exposed. In other words, where did the presenting case associate with others during the established time frame? Keeping in mind that the likelihood of transmission is greatest for contacts who have spent the most time with the presenting case, the closest contacts are usually those persons exposed in the home. However, given the changing risk groups for tuberculosis, the investigation may include other types of domicile such as homeless shelters, correctional facilities, nursing homes, HIV hospices, etc. Transmission has been documented in many diverse locations such as institutions (14), doctors’ offices (26), airplanes (27), crackhouses (28), HIV respite facilities (29), drug rehabilitation centers (30), navy ships (31), and renal transplant units (32). It is also important to keep in mind that sociological knowledge of the local culture and its

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definition of “family” may be required to adequately define the limits of the initial investigation (33). In addition to establishing the exact locations of potential exposures, additional information relative to place assessment is needed in order to complete the picture. As can be seen in Table 2, environmental factors such as direction of air flow, volume of ventilation, UV light, crowding, volume of air space, etc. may affect the extent to which TB transmission occurs at any given identified site. For example, the risk of TB transmission is higher when the presenting case is in a small, enclosed space that is very crowded for a prolonged period of time, such as a long bus ride, a crowded factory or office space area, etc. If that area also lacks proper ventilation (no fresh air or inadequate mechanical ventilation) and no sunlight, the risk of transmission is further increased. During the interview process, the investigator may discover that the presenting case spent most nights during the previous 3 months sleeping on the floor in a very crowded lobby of the largest shelter in the city, leaving with the rest of the guests at 6 a.m. and spending the remainder of the day (with the exception of meals at the local soup kitchen) on the street. This information suggests that the contacts who are at greatest risk of transmission are those at the largest shelter and the soup kitchens. Identified “street” contacts are assumed to have the least likelihood of transmission, given the dilution of the outside air. Obtaining and understanding technical environmental information may be a difficult task during the site visit. At best, the investigator may only be able to obtain information from the presenting case and the contacts and to make a visual assessment of the surrounding area in order to further narrow the limits of the investigation. In summary, the risk-assessment step in contact tracing involves analyzing person, time, and place factors for the presenting case in order to determine the case’s level of infectiousness, host susceptibility, the duration and place or places of exposure and environmental factors that affect the subsequent risk to identified contacts. Table 2

Place-Assessment Factors Likelihood of disease transmission

Factor Volume of air common to the case/contacts Adequacy of ventilation Recircularized air Upper room UV light *CFM, cubic feet per minute.

High

Low

Low Poor
10 CFM*/person Yes Not present

High Good 20 CFM/person No Present

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Once the TB transmission risk assessment has been completed and potential close and other-than-close contacts have been identified, the field investigation may begin. C. The Contact Field Investigation

The contact field investigation is a mandatory component of the contact-tracing process. A personal visit to the identified contacts, whether in the home, a shelter, an institution, etc., will assist in establishing rapport and trust between these individuals and the health-care provider. The same principles that were suggested for the presenting case interview apply to the contact interview. Because prevention of both further disease transmission and further progression from infection to active disease are among the purposes of contact tracing, the timeliness in which the field investigation is conducted is paramount. Current recommendations suggest that high-risk contacts be evaluated within 7 days of the presenting case interview and the medical evaluation of these individuals be completed within one month. The field visit serves many purposes. It allows the investigator to (1) interview and skin test the identified contacts, (2) observe the contacts for any signs or symptoms suggestive of tuberculosis, (3) collect sputum samples from any contact who is symptomatic, (4) identify sources of health care and make appropriate referrals, (5) identify additional potential contacts who may also need follow-up, (6) educate the contacts about the purpose of the investigation and the basics of TB pathogenesis and transmission, (7) observe the contact’s environment for potential transmission factors (crowding, ventilation, etc.), (8) assess the contact’s psycho-social needs and other risk factors that may influence future compliance with medical evaluation recommendations, and (9) reinforce confidentiality. The actual skin testing (see Chap. 12) of identified contacts must be done in a logical order and must be prioritized according to those contacts who are at highest risk for progression to disease. As we have noted, these include (1) contacts who have been identified as being at highest risk of transmission based on the transmission risk assessment and (2) high-risk susceptible hosts. Both categories of contacts are highlighted in Table 3. Even with the risk-assessment and prioritization guidelines as outlined thus far, the investigator may still not be able to precisely define the limits of the contact investigation. Although mathematical models exist to analyze potential transmission of tuberculosis (34), the factors affecting both transmission and the acquisition of disease are variable and difficult to calculate. The best measure of actual TB transmission is the identified number of persons who are determined to have been infected by the presenting case. The methodology for determining this is described as the concentric circle approach. The concentric circle approach [or the stone-in-the-pond principle (35)] (Fig. 1) begins with skin testing the closest contacts to the presenting case (as

386 Table 3

Etkind and Veen Contacts at Highest Risk for Progression to Disease

Contacts most likely to be infected

Contacts at high risk of developing TB disease once infected

Contacts exposed to the patient during the period of infectiousness Contacts exposed to the patient in: small rooms poorly ventilated or dark areas areas without HEPA filters or ultraviolet lights Contacts who: routinely spend a lot of time with the patient have been physically close to the patient have never had TB infection

Contacts with any of these conditions: HIV infection injection of illicit drugs diabetes mellitus silicosis prolonged corticosteroid therapy immunosuppressive therapy certain types of cancer severe kidney disease certain intestinal conditions low body weight (10% or more below ideal) Contacts who are young children

Figure 1 The concentric circle or stone-in-the-pond approach to contact tracing. See text for detailed description.

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identified by the risk-assessment and prioritization process). Those persons who are most likely to have been infected by the presenting case or who are otherwise at greater risk of progression to disease make up the inner circle. If close contact skin testing reveals that the infection level in this group (calculated by dividing the new positive skin tests by the total number of contacts with no documentation of previous positive skin test results) exceeds that expected for the population, the investigation proceeds to the next circle of contacts (“other than close”)—those who frequently share air with the presenting case, but not as often as the close contacts. Examples might be frequent household visitors, close relatives, close friends, etc. When infection is found in this group as well, the investigation is expanded to the third circle of contacts and then beyond as necessary using the same formula. The investigation should stop when a circle of contacts is found to have no more infection than is expected for the general community. If the inner-circle close contact skin testing reveals that all or most of the contacts have negative skin tests (
5 mm induration), it is usually not necessary to expand the investigation to the next circle of contacts. Exceptions to this might be when the contacts at the next level are determined to potentially pose a greater risk to others (teachers, hospital nursery workers, HIV health-care providers, etc.) or are persons who are at greater risk themselves (persons with immunosuppression, etc.). Inner-circle contacts should receive the highest priority during the investigation and follow-up process. Two groups in particular should be looked upon with a sense of urgency. These include persons infected with HIV (as described earlier) and children under 4 years of age (some countries use 6 years of age as the cut-off). Newly infected young children also have a higher disease attack rate and can develop miliary spread, with or without meningitis, within weeks unless given TB preventive therapy (36). These two high-risk groups should receive a medical evaluation as soon as possible, regardless of their skin test results. The advantages of the concentric circle approach are that when it is used prospectively, groups of contacts can be examined in sequence, beginning with those established to be at greatest risk. This systematizes the investigation by avoiding spending time on low-risk areas initially and allowing for continued contact tracing in areas yielding the greatest TB infection rates. Retrospectively, this approach documents the degree of infectivity and evaluates the effectiveness of the investigational procedure. In some settings such as schools, institutions, or worksites, there may be difficulties in orchestrating the concentric circle approach. Problems encountered include difficulties in narrowing down just who is a part of the inner circle, a reluctance to identify individuals in certain settings, the desire on the part of the employees or administration to overtest individuals in order to ameliorate the hysteria often associated with knowledge of a tuberculosis case, and pressure exerted by various organizations or groups to protect their members through case isolation and/or universal testing. The best method for approaching such situations is to

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identify and understand the sources of concern. Once this is known, an educational effort can be mounted to alleviate the problem. Although the concentric circle approach allows the investigation to proceed in an orderly fashion, any exposed individual who presents for examination should be tested regardless of the level of risk. D. Medical Evaluation of Contacts

Wherever the contact investigation and resultant skin testing is performed (field visit, TB clinic referral, etc.), arrangements must be made to ensure that the skin test is read within 48–72 hours and that chest x-rays (and sputums as indicated) are obtained for all contacts who need a medical evaluation. Adequate medical histories for the contacts must be obtained in order to evaluate the possibility of previous exposure to tuberculosis, the existence of TB infection or disease, whether treatment was prescribed and, if taken, previous skin test results, current risk factors for developing TB disease, and current symptoms if any. Skin testing of identified contacts should also proceed in an organized fashion: 1.

For those persons with prior positive skin test results—Contacts who have a documented prior positive PPD who are not known or likely to be immunosuppressed or have other medical risk factors need no further evaluation unless they have symptoms suggestive of active TB. Contacts who have a history of a prior positive tuberculin skin test but who are currently known or likely to be immunosuppressed or who are less than 4 years of age are at greater risk and require a medical evaluation. In some countries, close contacts who have been intensely exposed would have a chest x-ray examination regardless of the presence of symptoms. 2. For those persons who are skin test positive at the first screening— Other contacts who have tuberculin skin test reactions 5 mm at the first screening and who have no history of positive reaction in the past are considered to be at risk of having newly identified tuberculosis and should be medically evaluated for active TB and the possibility of preventive therapy. 3. For those persons who were skin test negative initially—All other contacts who are skin test negative initially should be retested in approximately 8–12 weeks in order to allow time for skin test reactivity to occur (unless at the time of the initial skin test 12 weeks had already elapsed since the last contact with the presenting case). This period of time between the initial skin test and the date that is 10–12 weeks postexposure is referred to as the “window period.” Persons found to be

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skin test positive at the second testing are considered to be newly infected and require further medical evaluation. The total contact tracing process should be completed within 3 months unless concentric circle testing results require further expansion of the testing. Contact tracing may need to be reinitiated if a tuberculosis patient becomes a treatment failure or relapses and the sputum remains smear positive or becomes positive again. In this situation, newly identified contacts must be examined, and exposed, previously uninfected contacts not on preventive therapy who have continued to be exposed should be reexamined. Given the risk of progression to active disease without interventions, all contacts who are placed on preventive therapy should be carefully monitored (with supervised or directly observed therapy if resources allow) by the healthcare provider for the duration of their treatment. E. The Contact Investigation Report

The contact-tracing investigation should be well documented and the results analyzed. These findings serve as the basis for decisions regarding future follow-up. The report should include a summary of the presenting case evaluation including relative infectivity, the environmental investigation, and the collective results of the contact study. Contact study results should include the following: the point when contact with the presenting case was broken for various contacts; the identification, number, and percentage of newly positive, previously positive, documented conversions, and negative skin test responses; the identification, number, and percentage of contacts with abnormal chest x-rays; suspects or new cases; the identification, number, and percentage of contacts placed on preventive therapy or anti-TB drugs; the outcome of preventive therapy (treatment completion, interruptions for side effects, default, etc.); and recommendations for further contact management or follow-up as needed. V. Contact Tracing in High-Prevalence Countries Not much research on contact tracing has been done in resource-poor high-prevalence countries. The general approach is not to start active case finding until a full course of adequate treatment can be assured for all patients detected. In Europe and the United States and in temperate climates in general, tuberculosis in the past was seen, at least to some extent, as a household infection. In low-income countries, housing conditions can generally be described as overcrowded, usually poorly lighted and ill-ventilated. It is therefore likely that tuberculosis is transmitted in the home. In warm climates where social events take place in the open air, the dilution of bacilli will be sufficiently large to preclude transmission taking place.

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Studies have differing conclusions about the importance of contact investigations under these circumstances. One analysis based on data collected in eight different territories in sub-Saharan Africa concluded that, although a statistically significant occurence of infection does occur in certain households, its extent is so moderate that it gives some grounds for scepticism with regard to the usefulness of contact examinations (37). An investigation of household contacts of infectious cases in Kenya, published shortly thereafter (38), showed that household contact investigation produced an additional 15% of sputum smear–positive cases and high tuberculin reactor rates compared to the general population. Children aged 0–5, 6–9, and 10–19 years had 10, 5, and 2 times higher reactor rates, respectively, than the same age groups in the general population. An interesting finding was that the gender of the index case made a difference in transmission. Among 56 contacts of a male index case, 32% of the children reacted, while 53% of 114 contacts of female index cases showed a positive skin test. Another study emphasized that in developing countries with limited financial and organizational resources, long-term follow-up of contacts has little or no place in a service program (39). A recent study from Malawi (40) showed, however, that 64% of 282 children who lived in the household with at least one smear sputum–positive adult showed signs of tuberculosis, with half of them fulfilling all the criteria for active tuberculosis. This indicates that even in resource-poor countries, examination of household contacts followed by adequate treatment or preventive chemotherapy is a cost-effective intervention. In view of the increasing HIV epidemic, especially in countries with a high prevalence of tuberculosis, there has been concern that HIV-infected sputum smear–positive adults could be more infectious than HIV-negative sputum smear–positive patients. Reports from Zaire and Malawi (10) showed no difference in transmission among household contacts, the latter being high, regardless of the sero-status of the index case. An often neglected line of thinking is that a child with tuberculosis must have been infected recently, and chances are high that the source of infection will be found among the parents or grandparents. Thus, one need not only undertake centrifugal contact examination in the household, but also centripetal source tracing. The proper procedure is not different from contact examination in high-income countries, but tuberculin for skin testing is often not available, and in many circumstances chest x-rays are also not available. History of contact and medical history regarding symptoms must then guide decisions. If tuberculin is available, children under 6 years of age are eligible for testing. Positive tests need to be interpreted with care. Most children were BCG vaccinated at birth, while older persons have been exposed to the relative high risk of infection in the population at large. For that reason a cut-off point of 15 mm for a positive test has been used (10). False-negative tests are relatively frequent due to

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malnourishment and concomitant disease, like childhood infections or HIV infection. Chest x-rays are expensive, and their use depends on the affluence of the program. All family contacts 6 years of age and older are eligible, but such investigation can also be restricted to persons with symptoms suggestive of tuberculosis. As soon as a case of tuberculosis has been detected in the family, all family members should be investigated by the methods described earlier. Where the person examined is over 6 years of age, judgment as to further action is based on the results of a possible chest x-ray and/or the presence of symptoms. In resourcepoor countries, if no abnormalities are found no further action is taken. Children under the age of 6 years with symptoms suggestive of tuberculosis should be treated as tuberculosis cases with a full course of antituberculosis drugs. Children under the age of 6 years with a skin test of 15 mm or more, irrespective of symptoms, should be given a full course of anti-tuberculosis drugs. All other children under 6 years of age who were household contacts should be given preventive chemotherapy with isoniazid in a dose of 5 mg/kg body weight. VI. New Technology: The Role of Restriction Fragment Length Polymorphism Testing Knowledge about the relationship between the source of infection and subsequent infections and satellite cases is the result of contact information and microbiological methods. Phage typing has been used to study the transmission of a particular Mycobacterium tuberculosis strain (40), but the method has a low specificity and is laborious and time-consuming. A particular resistance pattern may be suggestive for the pathway of transmission but is not conclusive. Restriction fragment length polymorphism (RFLP) (see Chap. 11) enables us to compare patterns of the genomic DNA of the mycobacteria. Since the method yields a kind of “fingerprint,” this genetic barcode helps in mapping the transmission of identical strains, which can be used as an epidemiological tool. Analysis of the chain of transmission theoretically may lead to earlier intervention. Fingerprinting has also produced new insights in the development of tuberculosis. New infections generally result in active tuberculosis in only 5–10% of the infected population. In HIV-infected populations however, the progression to disease is more rapid and more frequent, as was demonstrated in a nosocomial outbreak where DNA fingerprinting showed that the clustering of patients in place and time was due to recent transmission (29). This has implications for the organization of contact investigation. Small (41) recognized three current trends contributing to the increase of tuberculosis: geographic disparity in tuberculosis case rates, the emergence of multidrug resistance, and population mobility. He stated that the knowledge of M. tu-

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berculosis genotypes characteristic of specific geographic areas would significantly facilitate the international tracking of tuberculosis. The following examples show that the combination of conventional and molecular epidemiology in outbreak investigations contributes to the understanding of the dynamics of long-distance transmission: 1.

Conventional contact investigation following the stone-in-the-pond principle led to the identification of an extensive microepidemic in Harlingen, a harbor town in The Netherlands. DNA fingerprinting showed similarity of the strains isolated in patients detected. Comparison with strains from the national DNA library showed that in other parts of the country similar strains had been identified. Mapping the transmission led to the identification of the source case 5 months later in Great Britain. More than 6000 persons were screened, 276 infections were detected, and 49 cases of active tuberculosis identified (42). Without DNA fingerprinting, the relationship between all these cases would never have been discovered. 2. Another example of individual traffic contributing to the spread of tuberculosis was reported by Casper et al., but in this case transmission was limited (43). A strain of M. tuberculosis widely prevalent in New York was found in only one of 755 patients in San Francisco, who was a traveling salesman. As the authors reassuringly conclude, transmission to other geographic areas may not be as likely as expected, especially if the disease is limited to populations that do not migrate. 3. Conventional contact investigation failed to identify epidemiological links, whereas RFLP typing led to the detection of a community outbreak among HIV-infected persons (44). The common place of transmission turned out to be a local bar, which could not have been identified without this new tool. The authors suggested a number of preventive measures as a consequence of their findings. 4. In another study conventional contact investigation was thought to be so successful that the authors claim that their inability to identify many epidemiological links among cases with the same RFLP pattern may reflect the fact that most contacts are effectively identified and prophylaxed before they develop the disease (45).

New cases of tuberculosis [30% in San Francisco (41) and 40% in The Netherlands (46)] are due to recent infection. The difference is caused by the difference in sample size. In San Francisco conventional contact tracing produced epidemiological links in only 10% of the clustered patients. In The Netherlands, of 1170 clustered cases countrywide, in 31% epidemiological linkage was certain and in an additional 10% probable before the RFLP results became available (47). It is known, however, that in the city of Amsterdam

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the results are similar to San Francisco. It has therefore been suggested that current tuberculosis-control strategies have important limitations in contemporary urban environments (41). For example, an investigation in Los Angeles showed that the locations at which the homeless population congregate are important sites of tuberculosis transmission for homeless and nonhomeless persons (48). Measures that reduce tuberculosis transmission should then be based on these locations rather than on personal contacts. RFLP typing could guide the evaluation of these specific interventions. Another contribution to prevention is by identifying unexpected transmission caused by lapsed compliance with procedures. Examples are laboratory-acquired tuberculosis (49) and nosocomial transmission (32). There are also legal and ethical issues involved in contact tracing. While contact tracing seems justified to prevent the occurrence of tuberculosis in the individual and source tracing is justified to prevent further spread of the disease, DNA fingerprinting may give conclusive evidence of the transmission from one individual to another, which could lead to damage claims or cause embarrassment by linking persons who might experience this as a breach of their individual privacy. One of the drawbacks of RFLP typing is the relatively long duration before the results become known. Typing is done on cultured mycobacteria, which, depending on the size of the inoculum, may take 3–8 weeks to grow. The typing itself takes another week. When large numbers of mycobacterial strains must be compared for epidemiological purposes, computer-assisted analysis is needed. It is because of this long duration that fingerprinting has been primarily used as an evaluation tool for traditional contact investigation in microepidemics and for evaluation of preventive measures. New developments with spoligotyping directly from the clinical material may substantially shorten the time for the fingerprints to become known. In a recent report linkage was shown between two patients over an interval of 8 years, while from the first patient only a sputum smear was available (50). It remains to be seen if earlier results will contribute to an earlier interruption of the chain of transmission. For the moment, one has to conclude that new techniques like DNA fingerprinting are useful for the evaluation of interventions. Epidemiological linking will explain the chain of transmission and thereby contribute to redirected interventions. Conventional contact investigation, however, still has an important role to play: first, because the new techniques are still too slow in producing results, and second, because these new techniques are based on the isolation of mycobacteria and therefore are unable to detect infections before disease occurs. Early detection of infection and ensuing preventive chemotherapy still remain very important and powerful tools of tuberculosis control.

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Etkind and Veen VII. Challenges and Unanswered Questions

There are numerous examples in the literature of both highly productive and less-than-adequate contact tracings (12,25,27,49,51–55). Even the most skilled investigator will find numerous challenges during the contact-investigation process. Some of these are patient related, but most are more likely to be system related. Some of the patient-related challenges include a reluctance to name contacts initially, misconceptions about the receipt and presumed protectiveness of BCG, cultural health beliefs (e.g., the use of home remedies), competing lifestyle priorities (drug use or the need for food and shelter), and fears related to immigration issues. System-related challenges may be such things as poor training of staff, failure to prioritize contact activities programmatically and individually, a lack of education for physicians (particularly those in the private sector) about concentric circles and the need for contact investigation as well as the importance of preventive therapy, presumed effectiveness of BCG, lack of after-business hours clinic time, public health infrastructure problems (e.g., lack of funding, downsizing, staff turnover, and inexperience), the influence of managed care and other aspects of the changing health-care–delivery system that affect access to care and follow-up, political pressures, difficulties in the evaluation process, difficulties in identifying HIV risk factors, problems associated with having the contact return for second testing, data upkeep, continued problems with defining level of infectiousness, and avoiding unnecessary screenings. In an effort to meet these challenges, some jurisdictions, such as New York City, have established comprehensive contact programs in order to ensure that contacts are identified, provided access to adequate and appropriate care, and followed until completion of therapy (56). These include the following: establishment of a priority system at the clinics for identified contacts; outreach worker assignments to contacts and follow-up home visits; directly observed preventive therapy (DOPT) for select categories of contacts such as those of a multiple-drug resistant case; use of culturally and linguistically appropriate interviewers; the provision of education and training on interviewing skills, medical management of contacts, etc.; computerized contact registry systems to ensure the collection of data, identify contacts who need further follow-up, and continually evaluate the contact process; and the inclusion and discussion of contact information and follow-up during routine case conferences. The transmission risk-assessment process is based on a number of assumptions that may need scientific clarification. Some of these questions follow: 1.

Differences in the Infecting Organism: How does the virulence of the organism affect transmission? Can it be defined in such a way as to help prioritize contact efforts (57,58)?

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Presenting Infectious Case: Is smear status a useful indicator for contact investigation purposes (59,60)? Do we miss potential high-risk contacts by basing our efforts on smear-positive patients (4,61)? How can we factor in the adequacy and quality of the originating specimen source and laboratory variability in interpreting smears?

What is the best balance of conventional epidemiology and molecular epidemiology in intervention and control efforts (29,42–47)? When is a presenting infectious patient a “superspreader”? Are these markers that would be useful in defining level of infectiousness? Are there levels of infectiousness that could be defined for children? Could this be useful in evaluating school settings? 3.

Host Assessment: Can HIV risk assessment (particularly for those who are skin test negative) be done with confidence in the context of contact investigations (25,62)? If not, should the concentric circle be modified to reflect this?

Do we need to modify our definitions of contacts? Should we use the social network approach (63) or some other sociological model to enhance our contact identification efforts? How do we define “excess positivity” for those who have received BCG? Is there a priority methodology based on exposure that could be used for BCG-vaccinated persons (64)? 4.

The Environment: Is there a better way to identify and quantify environmental factors related to transmission? How much does the type of setting affect transmission? What are the benefits of engineering controls?

VIII. Summary If tuberculosis-elimination efforts are to be successful, prevention activities must be targeted to the groups at highest risk for progression from tuberculosis infection to disease. This chapter has illustrated that contacts of infectious cases of tuberculosis are such a high-risk group and should be priorities for tuberculosis-control programs. Although the focus of contact tracing is prevention, other potential benefits of the investigation may include the identification of additional cases of tuberculosis and the opportunity for education about TB disease, the risk of transmission, the TB/HIV connection, etc. The actual contact-tracing procedure should be done in a systematic, logical fashion. This chapter has outlined the step-by-step progression of such an investigation beginning with the notification of a case or suspect case of tuberculosis. It

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has described the collection of needed epidemiological data for planning purposes, the establishment of investigational priorities based on this data, the methodology for contact tracing in the field setting, the utilization of the concentric circle approach in order to set the limits of the investigation, and the documentation of the procedures and results of the investigation. In addition, this chapter has discussed the differences in contact tracing between high- and lowprevalence countries and the epidemiological role of RFLP testing. Because every case of tuberculosis began as a contact, the ability to rapidly identify tuberculosis cases and to effectively conduct the subsequent contact tracing is one of the cornerstones of tuberculosis-control public health efforts. Without this capacity, transmission of tuberculosis will persist, the TB case rate will continue to escalate, and tuberculosis elimination will be impossible to achieve. References 1. Farer LS. Tuberculosis: What the Physician Should Know. Atlanta, Georgia: Centers for Disease Control, 1986. 2. Moodie AS, Riley RL. Infectivity of patients with pulmonary tuberculosis in inner city homes. Am Rev Respir Dis 1974; 110:810–812. 3. American Thoracic Society/Centers for Disease Control. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359–1374. 4. Capewell S, Leitch AG. The value of contact procedures for tuberculosis in Edinburgh. Br J Dis Chest 1984; 78:317–329. 5. MacIntyre CR, Plant AJ, Hulls J, Streeton JA, Graham NMH, Rouch GJ. High rate of transmission of tuberculosis in an office: impact of delayed diagnosis. Clin Infect Dis 1995; 21:1170–1174. 6. Wells CD, Zuber PLF, Nolan CM, Binkin NJ, Goldberg SV. Tuberculosis prevention among foreign-born persons in Seattle—King County, Washington. Am J Respir Crit Care Med 1997; 156:573–577. 7. Casanova MC, Gonzalez MC, Perez MM, Piqueras AR, Estelles DC, Morera LM. The investigation of contacts of the tuberculous pediatric patient. Med Clin 1991; 97(13):486–490. 8. Goldman JM, Teale C, Cundall DB, Pearson SB. Childhood tuberculosis in Leeds, 1982–90: social and ethnic factors and the role of the contact clinic in diagnosis. Thorax 1994; 49(2):184–185. 9. Fernandez RA, Arazo GP, Aguirre EJM, Arribas LJL. The study of contacts of tuberculosis patients. An Med Interna 1994; 11(2):62–66. 10. Topley JM, Maher D, Mbewe LN. Transmission of tuberculosis to contacts of sputum positive adults in Malawi. Arch Dis Child 1996; 74(2):140–143. 11. Rubilar M, Brochwicz-Lewinski MJ, Anderson M, Leitch AG. The outcome of contact procedures for tuberculosis in Edinburgh, Scotland 1982–1991. Respir Med 1995; 89(2):113–120.

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12. Mehta JB, Bentley S. Prevention of tuberculosis in children: missed opportunities. Am J Prev Med 1992; 8(5):283–286. 13. Snider DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection and disease among contacts of tuberculosis cases with drug resistant and drug susceptible bacilli. Am Rev Respir Dis 1985; 132:125–132. 14. Centers for Disease Control. Multi-drug resistant tuberculosis—North Carolina. MMWR 1987; 35(51–52):785–787. 15. Menzies R, Rocher I, Vissandjee B. Factors associated with compliance in treatment of tuberculosis. Tuber Lung Dis 1993; 74(1):32–37. 16. Rose DE, Zerbe GO, Lantz SO, Bailey WC. Establishing priority during investigation of tuberculosis contacts. Am Rev Respir Dis 1979; 119:603–609. 17. Nardell EA. Tuberculosis in homeless, residential care facilities, prisons, nursing homes, and other close communities. Semin Respir Infect 1989; 4(3):206–215. 18. Sepkowitz KA. How contagious is tuberculosis? Clin Infect Dis 1996; 23:954–962. 19. Swallow J, Sbarbaro JA. Analysis of tuberculosis case-finding in Denver, Colorado 1965–1970. Health Services Rep 1972; 87:135. 20. Hsu KH. Contact investigation: a practical approach to tuberculosis eradication. Am J Public Health 1963; 53:1761. 21. Citron KM. Control and prevention of tuberculosis in Britain. Br Med Bull 1988; 44:704–716. 22. Styblo K. Epidemiology of tuberculosis. In: Selected Papers, Royal Netherlands Tuberculosis Association. Vol. 24. The Hague: Broekmans, 1991. 23. DiPerri G, Danzi MC, DeChecchi G, Pizzighella S, Solbiati M, Cruciani M, Luzzati R, Malena M, Mazzi R, Concia E, Bassetti D. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 1989; 23(30):1502– 1504. 24. Centers for Disease Control. Tuberculosis outbreak among persons in a residential facility for HIV-infected persons. MMWR 1991; 40:649–652. 25. Barnes PF, Bloch AB, Davidson PT, Snider DE. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644–1650. 26. Askew Gl, Finelli L, Hutton M, Laraque F, Porterfield D, Shilkret K, Valway SE, Onorato I, Spitalny K. Mycobacterium tuberculosis transmission from a pediatrician to patients. Pediatrics 1997; 100(1):19–23. 27. Kenyon TA, Valway SE, Ihle WW, Onorato IM, Castro KG. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 1996; 334:933–938. 28. Centers for Disease Control. Crack cocaine use among persons with tuberculosis— Contra Costa county, California, 1987–1990. MMWR 1991; 40(29):485–489. 29. Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR, Hopewell PC. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 1992; 326:231–235. 30. Centers for Disease Control. Tuberculosis in a drug rehabilitation center—Colorado. MMWR 1980; 29(45):543–544. 31. DiStasio AJ, Trump DH. The investigation of a tuberculosis outbreak in the closed environment of a U.S. navy ship, 1987. Mil Med 1990; 155(8):347–351.

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32. Jereb JA, Burwen DR, Dooley SW, Haas WH, Crawford JT, Geiter LJ, Edmond MB, Dowling JN, Shapiro R, Pasculle AW. Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates. J Infect Dis 1993; 168(5):1219–1224. 33. Pust RE. Family tuberculosis contacts: resource-contingent management. Fam Pract 1985; 2(1):30–34. 34. Nardell E, Keegan J, Cheney S, Etkind S. Airborne infection: theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991; 144:302–306. 35. Veen J. Microepidemics of tuberculosis: the stone-in-the-pond principle. Tuber Lung Dis 1992; 73(2):73–76. 36. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 37. Andersen S, Geser A. The distribution of tuberculosis infection among households in African communities. Bull WHO 1960; 22:39–60. 38. WHO Tuberculosis Chemotherapy Centre, Nairobi. An investigation of household contacts of open cases of pulmonary tuberculosis amongst the Kikuyu in Kiambu, Kenya. Bull WHO 1961; 25:831–850. 39. Devadatta S, Dawson JJY, Fox W, Janardhanam B, Radhakrishna S, Ramakrishnan CV, Velu S. Attack rate of tuberculosis in a 5-year period among close family contacts of tuberculous patients under domiciliary treatment with isoniazid plus PAS or isoniazid alone. Bull WHO 1970; 42:337–351. 40. Gruft H, Johnson R, Claflin R, Loder A. Phage-typing and drug resistance patterns as tools in mycobacterial epidemiology. Am Rev Respir Dis 1994; 130:96–97. 41. Small PM. Editorial: Towards the understanding of a global migration of M. tuberculosis. J Infect Dis 1995; 171:1593–1594. 42. Kiers A, Drost AP, Soolingen D van, Veen J. Use of DNA fingerprinting in international source case finding during a large outbreak in The Netherlands. Int J Tuberc Lung Dis 1997; 1:239–245. 43. Casper C, Singh SP, Rane S, Daley CL, Schecter GS, Riley LW et al. The transcontinental transmission of tuberculosis: a molecular epidemiological assessment. Am J Public Health 1996; 86:551–553. 44. Tabet SR, Goldbaum GM, Hooton TM, Eisenach KD, Cave MD, Nolan CM. Restriction fragment length polymorphism analysis detecting a community-based outbreak among persons infected with human immunodeficiency virus. J Infect Dis 1994; 169:189–192. 45. Bishai WR, Harrington S, Hooper N, Pope D, Coggin W, Sheely L, et al. Tuberculosis in Baltimore: high rates of molecular clustering despite a low incidence rate. Abstract ALA/ATS Int Conference, 1997. 46. Soolingen D van, Haas PEW de, Kremer K, Borgdorff M, Veen J, Dessens M, Embden JDA van. Molecular epidemiology of tuberculosis in a low incidence country: A nationwide study on transmission of tuberculosis between immigrants and native population in The Netherlands. Thesis, University of Utrecht, 1996. 47. Sebek MMGG. Transmission of M. tuberculosis in The Netherlands, results December 1994-December 1996. The surveillance project of DNA fingerprinting. Int J Tuberc Lung Dis 1997; (suppl S57)1:5.

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48. Barnes PF, Yang Z, Preston-Martin S, Pogoda JM, Jones BE, Otaya M, Eisenach KD, Knowles L, Harvey S, Cave MD. Patterns of tuberculosis transmission in central Los Angeles. JAMA 1997; 278(14):1159–1163. 49. Peerbooms PGH, Doornum GJJ van, Deutekom H van, Coutinho RA, Soolingen D van. Laboratory-acquired tuberculosis. Lancet 1995; 345:1311–1312. 50. Dooveren RFC, Keizer ST, Kremer K, Soolingen D van. Verband tussen 2 tuberculose-explosies na 8 jaar bewezen door DNA-‘fingerprinting’ van de oorzakelijke mycobacterien. Ned T Geneesk 1998; 142:189–192. 51. Hussain SF, Watura R, Cashman B, Campbell IA, Evans MR. Audit of a tuberculosis contact tracing clinic. BMJ 1992; 304(6836):1213–1215. 52. Hedemark LL. Contact investigation of a neighborhood bar patron. Investigation of Contacts to Tuberculosis Cases: New York City, June 7–8, 1996 Symposium Summary. New York: New York City Department of Health, 1996. 53. Holcombe JM. Contact investigation in a rural setting: a state perspective. Investigation of Contacts to Tuberculosis Cases: New York City, June 7–8, 1996 Symposium Summary. New York: New York City Department of Health, 1996. 54. Sasaki Y, Yamagishi F, Suzuki K. The present condition of patient’s, doctor’s and total delays in tuberculosis case finding and countermeasures in the future. Kekkaku 1995; 70(1):49–55. 55. Allos BM, Gensheimer KF, Bloch AB, Parrotte D, Horan JM, Lewis V, Schaffner W. Management of an outbreak of tuberculosis in a small community. Ann Intern Med 1996; 125:114–117. 56. Glaser T, Simmons C. Contact investigation in New York City. Investigation of Contacts to Tuberculosis Cases: New York City, June 7–8, 1996 Symposium Summary. New York: New York City Department of Health, 1996. 57. Soolingen D van, Lambregts-van Weezenbeek CSB, Haas PEW de, Veen J, Embden JDA van. Transmission of sensitive and resistant strains of Mycobacterium tuberculosis in The Netherlands, 1993–1995. Ned Tijdschr Geneeskd 1996; 140:2286–2289. 58. Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992; 358:591–593. 59. Rodriguez EM, Steinbart S, Shaulis G, Bur S, Dwyer DM. Pulmonary tuberculosis in a high school student and a broad contact investigation: lessons relearned. Md Med J 1996; 45(12):1019–1022. 60. Liippo KK, Kulmala K, Eero OJT. Focusing tuberculosis contact tracing by smear grading of index cases. Am Rev Respir Dis 1993; 148:235–236. 61. Menzies D. Issues in the management of contacts of patients with active tuberculosis. Can J Public Health 1997; 88(3):197–201. 62. Barnes PF, Silva C, Otaya M. Testing for human immunodeficiency virus infection in patients with tuberculosis. Am J Respir Crit Care Med 1996; 153:1488–1450. 63. Rothenburg RB. Social network approach in contact tracing. Investigation of Contacts to Tuberculosis Cases: New York City, June 7–8, 1996 Symposium Summary. New York: New York City Department of Health, 1996. 64. Menzies, R. Interpreting contact investigation results: the effect of BCG vaccination. Investigation of Contacts to Tuberculosis Cases: New York City, June 7–8, 1996 Symposium Summary. New York: New York City Department of Health, 1996.

16 Treatment of Tuberculosis

PAULA I. FUJIWARA

PATRICIA M. SIMONE

New York City Department of Health New York, New York, and Centers for Disease Control and Prevention Atlanta, Georgia

Centers for Disease Control and Prevention Atlanta, Georgia

SONAL S. MUNSIFF New York City Department of Health New York, New York

I. Introduction Research in tuberculosis treatment has served as an important and inspirational model of how well-designed clinical trials could address important practical problems facing medical practitioners and public health officials: the efficacy of drugs in general rather than old-fashioned cures such as bedrest, the prevention of drug resistance, the use of standardized regimens to enable comparison of results between investigations, the importance of specific drugs in improving cure rates and shortening treatment duration, the efficacy of intermittent versus daily treatment, and the importance of directly observed therapy. In addition, many of the concepts that inform clinical practice today were developed using international collaborations, the most notable of which were developed by the British Medical Research Council and colleagues in East Africa, India, Hong Kong, and Singapore (1–3). Although treatment for tuberculosis has been standardized and is relatively inexpensive (4), differences in clinical practice exist between countries with high tuberculosis prevalence (which tend to be resource-poor) and low tuberculosis prevalence (which tend to be resource-rich). The differences mainly involve the use of technology, the priority of addressing multidrug-resistant tuberculosis in 401

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the tuberculosis control program, and the luxury most resource-rich countries have to focus on the specific, often costly, needs of individual patients. This chapter will address issues that are useful and practical in both settings. The theoretical basis for tuberculosis treatment, including mechanisms of drug resistance and the role of intermittent regimens, will be discussed. The drugs available for the treatment of tuberculosis, including mechanisms of action, doses, side effects, and clinical and laboratory parameters to be monitored when specific drugs are used, will be presented. The currently recommended regimens for the United States will be contrasted to the regimens recommended in high-prevalence countries. Some clinical issues relevant mainly to resource-rich countries will be addressed, such as the impact of antiretroviral drugs on treatment of persons dually infected with the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis, the treatment of persons with and exposed to multidrug-resistant tuberculosis, and the role of surgery. The chapter will end with a discussion of adherence to treatment and the important role of directly observed therapy in the control of tuberculosis. II. History of Tuberculosis Treatment in the Chemotherapeutic Era The chemotherapy era for tuberculosis began with the introduction of streptomycin in 1944. Used alone, streptomycin was found to be highly effective at producing a clinical and bacteriological response. However, this was followed quickly by clinical deterioration and the emergence of drug resistance (5,6). After the introduction of para-aminosalicylic acid (PAS) and isoniazid, it was discovered that the emergence of resistance could be prevented by using two or more drugs in combination (7). Standard regimens of 18–24 months of combinations of isoniazid, PAS, and streptomycin proved to be highly effective in treating cavitary tuberculosis and preventing drug resistance (8,9). With the introduction of rifampin in 1968, short-course therapy of tuberculosis became possible. A. Theoretical Basis for Antituberculosis Treatment

Mitchison has described antituberculosis drugs in terms of their activity in three areas: prevention of drug resistance, early bactericidal activity, and sterilizing activity (see Table 1) (10). Drugs that are highly active in the prevention of drug resistance suppress the growth of the entire bacterial population to prevent the emergence of mutants resistant to another drug. This activity is measured by how well the drug prevents treatment failure due to the emergence of drug resistance during therapy. Early bactericidal activity is the ability of a drug to reduce the number of bacilli during the initial part of therapy (11). Sterilizing activity is the ability of a drug to kill semidormant bacteria and is measured by the speed with

Treatment of Tuberculosis Table 1

Relative Activities of Antituberculosis Medications Preventing drug resistance

Sterilizing activity

INH

INH RIF

RIF PZA

EMB RIF

SM

INH

EMB THA

SM EMB

PZA

THA

Early bactericidal activity In vitro INH RIF SM EMB PZA

THA PAS

403

In vivo

SM PZA THA PAS

Activity High

Low

INH  isoniazid; RIF  rifampin; PZA  pyrazinamide; EMB  ethambutol; THA  ethionamide.

which the last few viable bacteria are killed (12). Drugs with potent sterilizing activity have enabled regimens as short as 6 months in duration to be used. Isoniazid and rifampin have the highest activity in preventing the emergence of drug resistance, followed by streptomycin and ethambutol. The activity of pyrazinamide in this area is poor. Isoniazid is the most potent bactericidal agent, and rifampin and pyrazinamide are the most potent sterilizing agents. Drug-resistant organisms result from random mutations, which occur spontaneously in wild-type strains of M. tuberculosis (13). These mutations occur at different rates for the antituberculosis medications. For example, mutations producing isoniazid-resistant bacilli occur at a rate of 2.56  108 per bacterium per generation. The mutation rates for ethambutol and streptomycin are similar to that for isoniazid, whereas the rate for rifampin is lower (2.25  1010). Mutants with resistance to two drugs occur even more rarely, at a rate determined by multiplying the rates for the individual drugs. For instance, mutations producing isoniazidand rifampin-resistant bacilli occur at a rate of approximately 5.76  1018. Based on these rates, in a population of tubercle bacilli, the expected ratio of resistant to susceptible bacilli would be about 1:106 for isoniazid, 1:108 for rifampin, and 1:1014 for both isoniazid and rifampin. Cavities in pulmonary tuberculosis contain about 107–109 organisms and thus are likely to include a few mutants resistant to one antituberculosis drug but no doubly resistant mutants (14). These naturally occurring resistant mutants are selected during inadequate or inappropriate therapy. If tuberculosis is treated with a single drug, all the organisms in the population will be killed except for the few mutants resistant to that drug. These organisms will multiply and over time will become the dominant

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strain. In a large population of resistant mutants, further mutations can occur, producing doubly resistant organisms. Drug resistance in tuberculosis may be classified as either primary or secondary (acquired) resistance. Primary resistance occurs when a patient is initially infected with a resistant organism. Acquired resistance occurs when a patient is nonadherent to treatment or an inadequate regimen is prescribed. Conceptually, effective treatment regimens are divided into two phases. The initial, intensive phase contains bactericidal agents used in combination to kill large, rapidly multiplying populations of M. tuberculosis and to prevent the emergence of drug resistance. This is followed by a consolidating, continuation phase containing sterilizing agents to kill the less active, intermittently dividing populations. A 9-month regimen of isoniazid and rifampin, with ethambutol or streptomycin in the first 2 months, provides excellent bactericidal and sterilizing activity (15). Furthermore, the potent sterilizing activity of rifampin and pyrazinamide reduces the duration of treatment from 9 to 6 months, while maintaining the ability to retain low relapse rates (16–19). Even when pyrazinamide is added for only the first 2 months of treatment, highly successful regimens of only 6 months are possible (17). Ethambutol or streptomycin are added initially before susceptibility results are available to prevent the emergence of rifampin resistance if there is unrecognized initial isoniazid resistance. B. Intermittent Treatment

Despite the effectiveness of the early antituberculosis treatment regimens, their full potential was not being realized due to the problem of nonadherence to therapy. Nonadherence has been recognized as the major cause of treatment failure, relapse, and the emergence of drug resistance (20–22). Researchers began to study the feasibility of two methods to enhance adherence: supervised treatment and intermittent treatment (23,24). Supervised therapy (watching the patient swallow each dose of medication) was discovered to be an effective way to address nonadherence. To improve the cost-effectiveness of treatment, the possibility of intermittent (two or three times a week) rather than daily therapy had great appeal. In a series of experiments, guinea pigs were infected with tubercle bacilli and treated with drugs given daily or every 2, 4, or 8 days over a 6-week period, with each group receiving the same total dosage of medication (25). At the end of the treatment period, the amount of viable organisms in the spleen was measured. The efficacy of isoniazid changed little as the interval of dosing was increased from daily to every 4 days, although loss of activity was significant with the 8-day interval. Ethambutol and rifampin were found to be actually more effective when given intermittently. Intermittent regimens have proved to be effective and no more toxic than daily regimens (26–28). In another study, a fully intermittent regimen of four drugs given three times weekly for the full course of treatment has

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also been found to be effective, even in the presence of initial resistance to isoniazid or streptomycin (29). III. Antituberculosis Medications A. First-Line Medications (Tables 2, 3)

Isoniazid

Isoniazid is the antituberculosis medication most commonly used throughout the world. It is highly active against M. tuberculosis, especially against actively dividing bacilli, through inhibition of mycolic acid synthesis. It is usually given by the oral route, although parenteral preparations are available. The usual daily dose is 5 mg/kg for adults and 10 mg/kg for children (maximum 300 mg daily). The most significant adverse reactions associated with isoniazid administration are hepatoxicity and neurotoxicity. Isoniazid may produce asymptomatic elevation of serum transaminases, overt hepatitis requiring discontinuation of therapy, severe hepatitis resulting in liver transplantation (31), or even fatal hepatitis (32). The risk of hepatitis is increased in older age groups and in those who consume alcohol daily (33). Baseline measurement of hepatic enzymes is recommended for adults starting therapy with isoniazid. Measurements should be repeated in patients whose baseline results are abnormal, who have risk factors for hepatitis, or who develop symptoms of hepatitis. All patients taking isoniazid should be monitored clinically for adverse reactions at least monthly. Isoniazid may interfere with pyridoxine metabolism and produce peripheral neuropathy. This occurs most commonly in persons who are mildly pyridoxine deficient, such as pregnant women, alcoholics, and malnourished patients. As little as 6 mg of pyridoxine daily can prevent peripheral neuropathy (34). Other adverse reactions associated with isoniazid include hypersensitivity reactions, monoamine oxidase inhibitor–like effects with the ingestion of such foods as red wine or cheese (35), and the development of antinuclear antibodies or rarely overt systemic lupus erythematosus (36). Isoniazid may interfere with the metabolism of some anticonvulsants and may reduce serum ketoconazole levels (see Appendix). Rifampin

Rifampin is the cornerstone of antituberculosis treatment. It is a potent agent against actively dividing intracellular and extracellular organisms, but also has activity against semidormant bacilli. It works primarily by inhibiting DNA-dependent RNA polymerase, blocking RNA transcription. It is usually given in a daily dosage of 10 mg/kg (maximum 600 mg daily) by the oral route.

406

Oral

Oral

Oral

Oral

IM or IV

Oral

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

Streptomycin

Thioacetazone

N/A

20–30 (1 g)

15–25

15–30 (2 g)

10–20 (600 mg)

10 (300 mg)

Child

N/A

15 (1 g)

15–25

15–30 (2 g)

10 (600 mg)

5 (300 mg)

Adult

N/A

25–30 (1.5 g)

50

50–70 (4 g)

10–20 (600 mg)

20–40 (900 mg)

Child

N/A

25–30 (1.5 g)

50

50–70 (4 g)

10 (600 mg)

15 (900 mg)

Adult

2 times/weeka

Children
12 years old. Adjust weight-based dosages as weight changes. a All regimens administered 2 or 3 times a week should be used with DOT. b WHO does not usually recommend twice weekly regimens. c IUATLD states 3.0 mg/kg. Source: Adapted from Refs. 30, 45, 62.

Route

Drug

Daily Child

N/A

25–30 (1.5 g)

25–30

50–70 (3 g)

10–20 (600 mg)

N/A

25–30 (1.5 g)

25–30

50–70 (3 g)

10 (600 mg)

15 (900 mg)

Adult

3 times/weeka

20–40 (900 mg)

Dose in mg/kg (United States) (maximum dose)

Table 2 First-Line Antituberculosis Drugs: Dosages

15 (12–18) —

2.5c

45 (40–50)

50 (40–60)

10 (8–12)

15 (13–17)

2 times/weekb

15 (12–18)

15 (15–20)

25 (20–30)

10 (8–12)

5 (4–6)

Daily

—

15 (12–18)

30 (25–35)

35 (30–40)

10 (8–12)

10 (8–12)

3 times/week

Dose in mg/kg (WHO and IUATLD) (range mg/kg)

Treatment of Tuberculosis Table 3 Drug Isoniazid

407

First-Line Antituberculosis Drugs: Adverse Reactions and Monitoring Adverse reactions Hepatic enzyme elevation Hepatitis Peripheral neuropathy Mild effects on central nervous system Drug interactions

Rifampin

GI upset Drug interactions Hepatitis Bleeding problems Flu-like symptoms Rash

Pyrazinamide

Hepatitis Rash GI upset Joint aches Hyperuricemia Gout (rare)

Ethambutol

Optic neuritis

Streptomycin

Ototoxicity (hearing loss or vestibular dysfunction) Renal toxicity

Thioacetazone Severe dermatological reactions: Stevens-Johnson syndrome toxic epidermal necrolysis exfoliative dermatitis

Monitoring

Comments

Baseline measurements of hepatic enzymes for adults Repeat measurements: if baseline results are abnormal if patient is at high risk for adverse reactions if patient has symptoms of adverse reactions Baseline measurements for adults: CBC and platelets hepatic enzymes Repeat measurements: if baseline results are abnormal if patient has symptoms of adverse reactions Baseline measurements for adults: uric acid hepatic enzymes Repeat measurements: if baseline results are abnormal if patient has symptoms of adverse reactions Baseline and monthly tests: visual acuity color vision

Hepatitis risk increases with age and alcohol consumption

Baseline and repeat monthly: hearing kidney function Skin exam

Pyridoxine can prevent peripheral neuropathy

Significant interactions with: methadone birth control pills many other drugs Colors body fluids orange May permanently discolor soft contact lenses

Treat hyperuricemia only if patient has symptoms

Not recommended for children too young to be monitored for changes in vision unless TB is drug resistant Avoid or reduce dose in adults 60 years

Do not use if HIV or clinical symptoms of AIDS

Source: Adapted from Refs. 30 and 69.

Rifampin produces relatively few adverse reactions (37). Patients started on rifampin therapy should be warned that rifampin causes a harmless red or orange discoloration of the urine, tears, and other body fluids. Rifampin may cause gastrointestinal upset. Hepatotoxicity occurs less frequently than with isoniazid administration. Some adverse reactions, such as hypersensitivity reactions, throm-

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bocytopenia, and renal failure, occur only rarely but appear to occur more frequently with intermittent rather than daily administration. Rifampin is a potent inducer of hepatic cytochrome P450 oxidative enzymes, accelerating the metabolism of many other drugs, thereby reducing their effects (see Appendix) (38). Patients who are using oral contraceptives or long-acting injectable progestin agents should be counseled about using other forms of birth control while on rifampin. Rifampin also interacts significantly with protease inhibitors and non-nucleoside reverse transcriptase inhibitors, two classes of potent antiretroviral agents used in combination with other agents for treatment of HIV infection (see Table 4 and Appendix) (39). Pyrazinamide

Pyrazinamide is a potent sterilizing agent that plays a key role in effective shortcourse chemotherapy regimens (40). It is most active in acid environments, espeTable 4 Rifamycins, Protease Inhibitors (PI), and Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Rifabutin

HIV drug Saquinavir (Invirase) Saquinavir soft gel capsules (Fortovase) Ritonavir Indinavir Nelfinavir Amprenavir Nevirapine Delavirdine Efavirenz

Rifampin

Effect of Effect of PI or Effect of rifabutin on AUC NNRTI on AUC rifampin on AUC of PI or NNRTIa of rifabutina of PI or NNRTIa

Effect of PI or NNRTI on AUC of rifampinb

↓ 40%

NR

↓ 80%

NR

↓ 47%

↑ 44%

↓ 70%

NR

NR ↓ 24% ↓ 32% ↓ 14% Unchanged ↓ 75% Unchanged

↑ 4c ↑ 270% ↑ 207% ↑ 204% NR (↓) ↑ 150% ↓ 38%e

↓ 35% ↓ 90% ↓ 82% ↓ 81% ↓ 58% ↓ 90% ↓ 26%

Unchangedd NR NR NR Unchanged Unchanged Unchanged

NR  not reported; AUC  area under the curve. a Information in parentheses is predicted value. b No significant changes are predicted in AUC of rifampin. c 25-O-desacetyl rifabutin (active metabolite) increased 35. d Data from only 2 subjects. e 25-O-desacetyl rifabutin (active metabolite) decreased 74%. Note: Effects are expressed as a percentage change in area under the curve of the concomitant treatment relative to that of the drug alone. Data are for daily administration of standard recommended dosages of both drugs except that rifabutin was given at half dose (150 mg daily) with ritonavir 500 mg twice daily. Source: Refs. 89–98.

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cially in the intracellular environment of macrophages. The precise mechanism of action of pyrazinamide on tubercle bacilli is not known. The daily dose of pyrazinamide is 15–30 mg/kg given by the oral route. Hypersensitivity reactions and gastrointestinal upset may occur with pyrazinamide administration. Hepatotoxicity occurs infrequently with current recommended dosages. Pyrazinamide often produces elevated uric acid serum levels, although arthralgias occur infrequently and acute gout is rare. Ethambutol

Ethambutol inhibits the transfer of mycolic acids into the cell wall. It is active against both intracellular and extracellular organisms. Because it can deter the selection of resistant mutants by other antituberculosis drugs, ethambutol plays an important role as part of the initial regimen for cases for which isoniazid resistance is possible. Ethambutol is administered by the oral route at a daily dosage of 15–25 mg/kg. The higher dosage is usually reserved for retreatment cases and is reduced to 15 mg/kg after 2 months to help reduce the occurrence of ethambutol’s most significant side effect, optic neuritis. The symptoms of optic neuritis include blurred vision and color blindness, which are reversible if they are detected early and the medication is stopped promptly. Patients taking ethambutol should have their visual acuity and color vision checked at least monthly. Ethambutol generally is not given to children who are too young for visual acuity or color vision monitoring, although a recent review suggests that it is safe for use in children (41). Ethambutol is excreted via the kidneys, and the dosage should be reduced in renal failure (42). Streptomycin

Streptomycin was the first drug discovered for the treatment of tuberculosis. It is an aminoglycoside antibiotic that interferes with bacterial protein synthesis. It must be given by injection, usually intramuscularly at a daily dosage of 15 mg/kg, 5 days a week until cultures convert to negative, and then reduced to two to three times a week. Ototoxicity and nephrotoxicity are associated with streptomycin administration and occur more frequently in the elderly. Vestibular dysfunction is more common than auditory damage. Renal toxicity occurs less frequently than with capreomycin or kanamycin. Hearing and renal function should be monitored in patients getting streptomycin. Thioacetazone

Thioacetazone is a semicarbazone that is not available in the United States. It is inexpensive and has been used commonly throughout the world as a first-line agent with isoniazid in the continuation phase of therapy to prevent failure and relapse in patients with initially isoniazid-resistant strains. It is usually given at a dosage of 150 mg daily, commonly in a combination tablet with 300–400 mg of

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isoniazid. Gastrointestinal upset is common, but the most significant side effects are cutaneous reactions. These reactions may be severe, including exfoliative dermatitis, toxic epidermal necrolysis, or Stevens-Johnson syndrome, and occur commonly in persons with HIV infection, limiting its usefulness in some parts of the world. Fixed-Dose Combinations of First-Line Antituberculosis Medications

The use of fixed dose combinations is recommended for patients taking self-administered therapy to prevent monotherapy and the emergence of drug resistance (43,44). Combinations of isoniazid and rifampin (Rifamate) and isoniazid, rifampin, and pyrazinamide (Rifater) are available in the United States. Combination tablets of isoniazid and thioacetazone and isoniazid and ethambutol are available in other countries (44–46). Two tablets of Rifamate provide conventional daily doses of both isoniazid (300 mg) and rifampin (600 mg). Each Rifater tablet available in the United States contains 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide. Several other Rifater preparations of different dosage combinations are available. Five tablets a day is recommended for patients weighing less than 55 kg, and six tablets a day is recommended for those weighing 55 kg or more. Because of the lower bioavailability of rifampin in this formulation, these dosages actually contain more rifampin than the recommended dosage of rifampin given in the single drug preparation. Fixed-dose combinations of antituberculous drugs have the advantage of ensuring that patients always take more than one type of medication. Other advantages include the decreased possibility of making medication errors and the simplification of procurement, storage, and distribution of drugs. The disadvantages of fixed-dose combination therapy include higher cost, the need for the patient to continue to take many pills, the possibility of underdosing if the patient takes fewer tablets than prescribed, and the incorrect prescriptions written and filled because of the similarity of trade names (Rifadin for rifampin alone; Rifinah and Rifamate for isoniazid and rifampin, and Rifater for isoniazid, rifampin, and pyrazinamide). Fixed-dose combinations are unnecessary when treatment is administered by directly observed therapy. All fixed dose combinations used for TB must be of demonstrated bioavailability because improper bioavailability may lead to inadvertent monotherapy and, thus, resistance (44). B. Second-Line Medications

The second-line medications (Table 5) for the treatment of tuberculosis are less potent and more toxic than the first-line medications and are reserved for cases of drug resistance or drug intolerance.

411

15–20 mg/kg po in divided doses {1 g} (250–500 mg BID)

15–20 mg/kg po in divided doses {1 g} (250–500 mg BID)

150 mg/kg po in divided doses {16 g} (4 g TID)

15–30 mg/kg IM or IV qd {1 g}

Cycloserine

Ethionamide

para-Aminosalicylic acid (PAS)

Capreomycin

Drug

United States daily dosea {maximum dose} (usual dose)

20 mg/kg qd {1 g}

150 mg/kg po in divided doses (5–6 g BID)

15–20 mg/kg po in divided doses {1 g} (250–500 mg BID)

15–20 mg/kg po in divided doses (500–750 mg po in divided doses)

WHO daily dose {maximum dose} (usual dose)

Table 5 Second-Line Antituberculosis Drugs

Toxicity: auditory vestibular renal Hypokalemia Hypomagnesemia

Psychosis Convulsions Depression Headaches Rash Drug interactions GI upset Hepatotoxicity Hypersensitivity Metallic taste Bloating GI upset Hypersensitivity Hepatotoxicity

Adverse reactions

Assess: vestibular function hearing function Measure: blood urea nitrogen creatinine potassium, magnesium

Measure hepatic enzymes Assess volume status

Measure hepatic enzymes

Assess mental status Measure serum drug levels

Monitoring

continues

Start with low dosage and increase as tolerated May cause hypothyroid condition, especially if used with PAS Start with low dosage and increase as tolerated Monitor cardiac patients May cause hypothyroid condition, especially if used with ethionamide After bacteriologic conversion, dosage may be reduced to 2–3 times per week

Start with low dosage and increase as tolerated Pyridoxine may decrease CNS effects

Comments

412

600–800 mg/day po (400 mg BID; 800 qd)

500 mg/day 200 mg/day

Ofloxacin

Levofloxacin Sparfloxacin

— —

600–800 mg/day po in single or divided doses

1000–1500 mg/day in single or divided doses

15 mg/kg IM qd {750 mg–1 g}

WHO daily dose {maximum dose} (usual dose)

Photosensitivity may occur with sparfloxacin

GI upset Dizziness Hypersensitivity Drug interactions Headaches Restlessness

Toxicity: auditory vestibular renal

Adverse reactions Monitoring Assess: vestibular function hearing function Measure: blood urea nitrogen creatinine

Doses for children same as adults. Use these drugs only in consultation with a clinician experienced in the management of drug-resistant TB. PO  by mouth; IM  intramuscular; IV  intravenous; qd  once a day; BID  twice a day; TID  three times a day. a Adjust weight-based dosages as weight changes. b Not approved by FDA for TB treatment. Not recommended for use in children. c Avoid coadministration within 2 hours of taking antacids, iron, zinc, and sucralfate.

750–1500 mg/day po (750 mg BID)

Ciprofloxacin

15–30 mg/kg IM or IV qd {1 g}

United States daily dosea {maximum dose} (usual dose)

Continued

Fluoroquinolonesb,c

Kanamycin/ Amikacin

Drug

Table 5

After bacteriological conversion, dosage may be reduced to 2–3 times per week

Comments

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Cycloserine

Cycloserine interferes with mycobacterial cell wall synthesis. The usual dosage is 15–20 mg/kg daily up to 1000 mg/day in divided doses by the oral route. Cycloserine not infrequently causes dose-related neurological or psychiatric disturbances, including headache, drowsiness, confusion, seizures, or psychosis. These effects can be exacerbated by renal insufficiency but are usually reversible with discontinuation of the medication. Serum level monitoring and concomitant use of pyridoxine can minimize adverse reactions. Renal impairment decreases excretion of the drug and can exacerbate adverse reactions. Ethionamide

Ethionamide is a derivative of isonicotinic acid that appears to interfere with peptide synthesis. The usual daily dosage is 15–20 mg/kg up to 1000 mg/day by mouth in divided doses. Ethionamide frequently causes gastrointestinal side effects, such as abdominal pain, nausea, vomiting, and anorexia. Bedtime dosing, taking the medication with food, or gradually increasing to the full dose may improve tolerance. Rarely, ethionamide may cause hepatitis. It can cause hypothyroidism, particularly if it is used with para-aminosalicylic acid. PAS

In the early chemotherapy era, PAS was used in combination with isoniazid and streptomycin to produce the first regimen that could effectively cure cavitary disease and prevent the emergence of drug resistance. PAS produces significant side effects, however, and was replaced as a first-line drug with other more effective, less toxic medications as they became available. PAS appears to interfere with folic acid metabolism. The usual dose is 4 g by mouth three times a day. It is currently available in the United States in a granular preparation (47), which, unlike older formulations, has the advantage of not containing large amounts of sodium. The most common adverse reactions associated with PAS are gastrointestinal disturbances. Hypersensitivity reactions, hepatitis, and thyroid dysfunction may occur; the last is more common when PAS is used concomitantly with ethionamide. Capreomycin

Capreomycin is an injectable polypeptide antibiotic for which the mechanism of action is unknown. It is administered intramuscularly in a dosage of 15–30 mg/kg/day with the usual maximum daily dosage of 1 g. It is usually given 5 days a week until cultures convert to negative, and then reduced to two or three times a week. Nephrotoxicity occurs not infrequently with capreomycin administration, resulting in reduced creatinine clearance and electrolyte disturbances. Renal function should be monitored closely, especially in elderly patients. Capreomycin may

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also cause hearing loss, and baseline and monthly audiograms are recommended for patients while on therapy. Kanamycin and Amikacin

Kanamycin and amikacin are aminoglycoside antibiotics with activity against M. tuberculosis. They may be administered intramuscularly or intravenously at a daily dosage of 15–30 mg/kg. They have complete cross-resistance, and cross-resistance may also occur with capreomycin. Like capreomycin, these drugs are usually administered 5 days a week until culture conversion, and then reduced to two or three times a week. Renal toxicity occurs with similar frequency as with capreomycin, whereas auditory toxicity may be more common. Regular monitoring of hearing and renal function is recommended. Fluoroquinolones

Fluoroquinolones are broad-spectrum antibiotics that are widely available in the United States and internationally and have a favorable toxicity profile. They inhibit bacterial DNA gyrase. They are less effective than other first-line agents in treating tuberculosis (48,49) and are mainly used in the treatment of drug-resistant tuberculosis (50,51). When given singly, resistance predictably emerges (52,53). Four fluoroquinolones that are useful in the treatment of tuberculosis are currently available in the United States: ciprofloxacin, ofloxacin, sparfloxacin, and levofloxacin. Ciprofloxacin and ofloxacin have similar potency. Ciprofloxacin is given orally at a dosage of 500–750 mg twice a day, and the daily dosage of ofloxacin is 600–800 mg/day. Levofloxacin is the L-isomer of ofloxacin and has approximately twice the potency. The maximum recommended dose is 500 mg daily, although 750–1000 mg/day has been used by some clinicians for the treatment of tuberculosis. Sparfloxacin has even greater potency than levofloxacin; however, photosensitivity reactions may occur, and patients must be instructed to avoid sunlight. The recommended dosage is 200 mg/day, although higher dosages have been suggested for the initial phase of treatment of multidrug-resistant tuberculosis until sputum conversion. In general, the fluoroquinolones are well tolerated (54). Animal studies have reported arthropathies in juvenile animals, suggesting that fluoroquinolones should not be used in children. However, a review of findings in children suggests that concern may not be warranted (55). Clofazimine

Clofazimine is a riminophenazine dye that binds to DNA, although its mechanism of action against mycobacteria is not known. It is usually given at a daily dosage of 100 mg for adults. It has activity against Mycobacterium avium-intracellulare complex (MAC) and Mycobacterium leprae and is primarily used for treating

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these organisms. It is occasionally used in the treatment of multidrug-resistant tuberculosis, although its usefulness has not been clearly demonstrated. Clofazimine causes an orange-bronze discoloration of the skin and may also cause gastrointestinal side effects, such as nausea and abdominal pain. Rifabutin and Rifapentine

Rifabutin is a rifamycin antibiotic with properties similar to rifampin. In vitro, it is more active against mycobacteria than rifampin; however, it has lower achievable serum levels. The usual daily dose is 300 mg by mouth. It has been used most often for the treatment or prophylaxis of MAC infections. Rifabutin appears to be effective in the treatment of tuberculosis (56). There is cross-resistance with rifampin, and its usefulness in the treatment of rifampin-resistant tuberculosis has not been clearly demonstrated. However, because it is a less potent inducer of cytochrome P450 metabolism, it has a role in tuberculosis therapy in cases where drug interactions may occur, as with the concomitant use of protease inhibitors in HIV-infected patients (see Table 4). Rifapentine is a long-acting rifamycin that is currently being studied in a clinical trial comparing once-weekly isoniazid and rifapentine with standard twice-weekly isoniazid and rifampin in the 16-week continuation phase of therapy. A preliminary analysis showed an unexpected finding of relapse with rifampin-monoresistant tuberculosis in a disproportionate number of HIV-infected patients who were treated with once-weekly isoniazid and rifapentine (57). Enrollment of HIV-infected patients was stopped and further analysis is underway, although this may be related to the increasing prevalence of experience with rifampin monoresistance in HIV-infected TB patients (57a). IV. Standard Antituberculosis Treatment Regimens in the United States In 1993, in the face of recent increases in drug resistance, new recommendations were issued for the initial therapy of tuberculosis in the United States: drug susceptibility tests should be performed on all initial isolates of M. tuberculosis, all tuberculosis patients should be started on a four-drug initial regimen (except in areas with low levels of drug resistance), and directly observed therapy should be considered for all patients (58). A joint statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) outlines the standard regimens recommended in the United States (59). There are three options for the initial treatment of tuberculosis in adults and children (Table 6). In all three options, the initial, intensive phase of the recommended regimen contains four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. The first option is

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Pulmonary and extrapulmonary TB in adults and children

Pulmonary and extrapulmonary TB in adults and children Smear and culture-negative pulmonary TB in adults

2

3

4

Pulmonary and extrapulmonary TB in adults and children

Indication

1

Option

16

24

24

24

Total duration (weeks)

Daily for 2 weeks and then 3 times/weeka for 6 monthsb

Follow option 1, 2, or 3 for 8 weeks

HRZ (E or S)c

HRZ (E or S)c

HRZ (E or S)c

2 times/ weeka for 6 weeks

Daily for 8 weeks

Interval and duration

HRZ (E or S)c

Drugs

Intensive phase

4

3

2

1

Option

Comments

Daily or 2 or 3 times/weeka for 8 weeks

Continue all four drugs for 4 months. If drug resistance is unlikely (primary isoniazid resistance
4% and patient has no individual risk factors for drug resistance), ethambutol or steptomycin may not be necessary and pyrazinamide may be discontinued after 2 months.

Daily or 2 or 3 Ethambutol or steptomycin should be times/weeka continued until susceptibility to for 16 weeksb isoniazid and rifampin is demonstrated. In areas where primary isoniazid resistance
4%, ethambutol or streptomycin may not be necessary for patients with no individual risk factors for drug resistance. 2 times/weeka After the initial phase, continue for 16 weeksb ethambutol or streptomycin until susceptibility to isoniazid and rifampin is demonstrated, unless drug resistance is unlikely. — Continue all four drugs for 6 months.d This regimen has been shown to be effective for isoniazid-resistant TB.

Interval and duration

Continuation phase

HRZ (E or S)c

—

HR

HR

Drugs

Table 6 Regimen Options for Treatment of Tuberculosis in the United States

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Pulmonary and extrapulmonary TB in adults and children when pyrazinamide is contraindicated

36

HR (E or S)c Daily for 4–8 weeks

HR

5

Daily or 2 or 3 times/weeka for 28–32 weeksb

Ethambutol or streptomycin should be continued until susceptibility to isoniazid and rifampin is demonstrated. In areas where primary isoniazid resistance
4%, ethambutol or streptomycin may not be necessary for patients with no individual risk factors for drug resistance.

Note: For all patients, if susceptibility results show resistance to any of the first-line drugs or if the patient remains symptomatic or smear- or culture-positive after 3 months, consult a TB medical expert. H  isoniazid; R  rifampin; Z  pyrazinamide; E  ethambutol; S  streptomycin. a DOT should be used with all regimens administered two or three times weekly. b For infants and children with miliary TB, bone and joint TB, or TB meningitis, treatment should last at least 12 months. For adults with these forms of extrapulmonary TB, response to therapy should be monitored closely. If response is slow or suboptimal, treatment may be prolonged as judged on a case-by-case basis. c Avoid streptomycin for pregnant women because of the risk of ototoxicity to the fetus. d There is some evidence that streptomycin may be discontinued after 4 months if the isolate is susceptible to all drugs. Source: Adapted from Ref. 30.

5

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based on the U.S. Public Health Service Tuberculosis Short-Course Chemotherapy Trial 21 (60). In this study, patients were randomized to two different self-administered regimens: isoniazid and rifampin for 9 months or isoniazid and rifampin for 6 months, with the addition of pyrazinamide for the first 2 months. The study found similar effectiveness, toxicity, and acceptability in both regimens. For the first regimen it is recommended that a fourth drug, either ethambutol or streptomycin, be added initially until susceptibility to both isoniazid and rifampin is documented to protect against the emergence of rifampin resistance in the case of unsuspected primary isoniazid resistance. In addition, intermittent therapy (two or three times a week) may be used after the first 2 months (if given under direct observation). The second regimen is based on a trial from Denver in which patients were given a 24-week regimen, with all doses given under direct observation: isoniazid, rifampin, pyrazinamide, and streptomycin daily for 2 weeks, then twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 18 weeks (61). This regimen was found to be well tolerated and effective as well as cost-effective. For this second regimen ethambutol may be substituted for streptomycin. A third regimen is based on a Hong Kong Chest Service/British Medical Research Council trial of four three-times-weekly regimens given under direct observation (29). Four drugs (isoniazid, rifampin, and various combinations of pyrazinamide, ethambutol, and streptomycin) were given three times a week for the entire 6 months of therapy. These regimens were also found to be well tolerated and effective, even in the presence of isoniazid resistance. V. Antituberculosis Treatment Regimens in ResourcePoor Countries In resource-poor countries, not all cases of tuberculosis are given the same priority for treatment. Both the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) have developed empiric treatment regimens based on case definitions, which are determined by several criteria (45,62). First, those with acid-fast bacillus (AFB) smear-positive pulmonary tuberculosis are the most potent sources of infection and are given high priority for treatment. Second, persons with certain severe forms of disease that may cause a threat to life (tuberculous meningitis, pericarditis, or miliary disease) or significant handicap (disease of the spine or kidney) are also given high priority. Finally, those who have had previous treatment are at increased risk for drug resistance and need a prolonged, more costly retreatment regimen. Both WHO and IUATLD divide cases into four treatment categories (see Fig. 1):

Figure 1

Tuberculosis suspect categories.

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Fujiwara et al. Category I Never previously treated: (a) sputum smear-positive and (b) severe forms of pulmonary sputum smear-negative and extrapulmonary TB. Category II Sputum smear-positive: (a) relapses, (b) treatment failures, and (c) treatment after interruption (TAI). Category III Never previously treated, less severe forms of sputum smearnegative and extrapulmonary TB. Category IV Chronic cases who remain sputum smear-positive despite a supervised course on a retreatment regimen.

Treatment regimens are assigned according to these categories (see Table 7). Both WHO and IUATLD follow the principle of using the most potent medications in the intensive phase, and both organizations use the same medications in the retreatment regimen (Category II). For individuals who are HIV negative or do not have clinical evidence of acquired immunodeficiency syndrome (AIDS), one important difference is the IUATLD’s recommendation to use isoniazid and thioacetazone throughout the treatment of previously untreated AFB smear-negative tuberculosis and in the continuation phase for previously untreated patients with AFB smear-positive tuberculosis. Thioacetazone’s chief advantage is its low cost, but severe, potentially fatal, drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (63–65), have caused debate over whether it should be used (66). Some have argued that not using thioacetazone would lead to many individuals not being treated at all (67) and cite evidence that with improved patient management and close monitoring, the rate of occurrence of severe skin reactions can be decreased greatly (68). Recently, however, the IUATLD, having acknowledged that persons dually infected with tuberculosis and HIV are at greater risk for these adverse reactions, issued an official statement recommending that thioacetazone should not be used in HIV-positive individuals or in those with evidence of AIDS (69). Both the IUATLD and WHO give lower priority to chronic cases of tuberculosis because of limited resources and the general unavailability of diagnostic procedures and second-line medications. VI. Methods Used to Diagnose Tuberculosis and Monitor Treatment A. Resource-Rich Countries

In countries with adequate resources, the initial evaluation should include the patient’s medical and social history, a physical examination, and a chest x-ray. While it is recommended that three sputum smears for AFB be obtained to determine infectiousness and need for rapid isolation and contact investigation, the gold standard for diagnosis of tuberculosis is a positive culture for M. tuberculo-

421

Never previously treated: Sputum smear () Sputum smear () with extensive parenchymal involvementb Severe forms of extrapulmonary TBb Sputum smear (): Relapse Treatment failure Treatment after interruption New smear () [other than Category I]b New less severe forms of extrapulmonary TB Chronic case (still sputum smear-positive after supervised retreatment)

Patients

6 HE, or 4 HR, or 4 H3R3 Referral to specialized treatment center (see text)

5 H3R3E3, or 5 HRE

2 HRZES/1HRZE

2 HRZ

6HE or 4HRa, or 4H3R3

Continuation

2 HRZE (HRZS)

Intensive (daily or thrice weekly)

Not applicable

12 HTc

5 HRE

10 HTc

2 HTc (S or E)

2 HRZES/1 HRZE

6 HTc

Continuation

2 HRZE

Intensive

phase

phase

H  isoniazid; R  rifampin; Z  pyrazinamide; S  streptomycin; E  ethambutol; T  thiacetazone. a Some authorities recommend extending the continuation phase to 7 months for TB meningitis, miliary TB, and spinal TB with neurological signs. b In the IUATLD model, all cases of TB other than those who are smear positive are placed on a Treatment Category III regimen, unless they are seriously ill, in which case the decision to use HRZE in the intensive phase rests with the medical officer (62). c Substitute ethambutol for thiacetazone in HIV positive or with clinical evidence of AIDS. The number preceding the drugs equals the number of months of administration; subscripts following individual drugs indicate that the drugs are given intermittently [twice (2) or thrice (3) weekly], instead of daily. Source: Adapted from Refs. 45 and 62.

IV

III

II

I

Treatment category (see text for explanation)

IUATLD

World Health Organization

Table 7 World Health Organization and International Union Against Tuberculosis and Lung Disease Recommended Treatment Regimens

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sis; drug susceptibility testing is performed to tailor the treatment regimen. Rapid diagnostic tests, using DNA- and RNA-based technology, may be considered for previously untreated persons with positive AFB smears from a pulmonary source (70). A complete blood cell count and a chemistry panel (especially liver and renal function tests; serum uric acid if pyrazinamide is used) should be obtained at baseline. If ethambutol is included in the initial regimen, tests for visual acuity and red-green color perception should be performed (59). During treatment, patients should be evaluated at least monthly for symptoms and signs of tuberculosis, adherence to treatment, and adverse reactions to the medications. Monthly sputum specimens for AFB smear and culture should be obtained; susceptibility testing should be repeated if cultures remain positive after 2–4 months of treatment (59,71). Monthly liver function tests should be performed if the patient has abnormal initial liver function tests; has a history of, or physical findings consistent with, liver disease; has a risk factor for liver disease; or is taking hepatotoxic medications for medical conditions other than tuberculosis (59,71). The performance of other laboratory tests should be tailored to the medication and any observed side effects. Chest x-rays need only be performed at the end of treatment to set a new baseline. However, if the patient has negative cultures for tuberculosis, a chest x-ray should be obtained after 3 months of treatment. Improvement in the chest x-ray and/or signs and symptoms of tuberculosis allows the clinician to classify the individual as a culture-negative or clinical case of tuberculosis (72). Posttreatment evaluation of persons with drug-susceptible strains of tuberculosis is not needed (59). They should, however, be advised to return for evaluation if they develop symptoms consistent with tuberculosis. Persons who should be considered for periodic posttreatment evaluation include: (1) those with multidrug-resistant tuberculosis; (2) those who did not have a rifamycin in the regimen; (3) persons on self-administered treatment where there was doubt as to adherence; and (4) individuals treated empirically for culture-negative tuberculosis, whose chest x-ray may also be consistent with another pulmonary process, and who refuse to be referred to a general chest clinic. Follow-up evaluations should be individualized. B. Resource-Poor Countries

In countries where tuberculosis treatment is based on AFB sputum smear results and empiric regimens, the most important parameter to monitor is the conversion of the smear from positive to negative. Patients’ sputum smears should be checked at the end of the intensive phase, during the continuation phase, and at the end of treatment to document cure. For those with AFB smear-negative pulmonary tuberculosis or extrapulmonary tuberculosis, clinicians should monitor increase in weight and overall improvement. The routine use of blood chemistries, chest xrays, and sputum culture and susceptibility testing is not recommended (45,62).

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VII. Special Clinical Situations A. Treatment Failure

Treatment failure ensues when a person continues to have a culture positive for M. tuberculosis despite 4–6 months of a treatment regimen to which the organism is known to be susceptible. When cultures are unavailable or pending, treatment failure should also be considered when the patient manifests clinical deterioration and/or the chest x-ray worsens. The evaluation of an individual who is failing treatment includes: (1) ensuring that the patient is treated under a program of directly observed therapy; (2) repeating specimens for smear, culture, and susceptibility; and (3) continuing the current regimen until susceptibility results are available, unless the patient is clinically deteriorating. If the patient is clinically deteriorating, he or she should be given at least two antituberculosis medications to which the organism is likely to be susceptible, and the regimen should be adjusted once susceptibility results are available (59,71). In countries that monitor sputum smears for response to treatment, treatment failure is defined as a case of tuberculosis that, during treatment, remains sputum smear positive or reverts to having a positive smear 5 or more months after initiating treatment. Patients are then begun on a standardized retreatment (Category II) regimen (see Table 7) (45,62). In the WHO model, chronic cases of tuberculosis (Category IV) are those who fail the standardized retreatment regimen given under the direct observation of a health worker. WHO states that treatment of chronic cases should be done by a specialized unit, which has access to a laboratory capable of performing culture and reliable susceptibility testing and a reliable supply of second-line drugs, since chronic cases are more likely to excrete drug-resistant bacilli. If drug susceptibility results are pending or unavailable, WHO recommends an empiric regimen of at least 3 months of an aminoglycoside, ethionamide, pyrazinamide, and ofloxacin, followed by 18 months of ethionamide and ofloxacin. If the strain is resistant to isoniazid (streptomycin or thioacetazone), rifampin, an aminoglycoside, pyrazinamide, and ethambutol are used for 2–3 months, followed by 6 months of rifampin and ethambutol. If the strain is resistant to isoniazid and ethambutol (streptomycin), 3 months of rifampin, an aminoglycoside, pyrazinamide, and ethambutol are followed by 6 months of rifampin and ethionamide. If the strain is resistant to at least isoniazid and rifampin, a five-drug regimen of an aminoglycoside, ethionamide, pyrazinamide, ofloxacin, and another bacteristatic drug for 3 months followed by ethionamide, ofloxacin, and another bacteristatic drug for 18 months is recommended (73). B. Tuberculosis Treatment After Relapse

A person who relapses with tuberculosis is one who develops tuberculosis again after having completed an adequate antituberculosis treatment regimen

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(59). If the original organism was fully susceptible and the individual completed an isoniazid and rifampin-containing regimen, the original regimen can be used, as the organism usually remains susceptible (74). For those who did not have isoniazid and rifampin in the initial regimen, drug resistance to the previously used agents should be presumed until proven otherwise. In all situations, drug susceptibility tests should be performed and treatment regimens modified according to the results. In resource-poor countries, where cultures are not routinely available, a relapsed case is one that becomes AFB-smear positive after having been cured (45,62). These cases are given the standard retreatment regimen. Recently tailored retreatment regimens based on drug susceptibility testing has been recommended (see Chap. 17). C. Extrapulmonary Tuberculosis

Treatment regimens for extrapulmonary forms of tuberculosis are generally the same as for pulmonary tuberculosis, with the main difference being the recommendation to extend the continuation phase for certain forms (see Table 6). Children with miliary tuberculosis, bone or joint tuberculosis, or tuberculous meningitis should be treated for at least 12 months (59). Compared with pulmonary tuberculosis, cases of extrapulmonary tuberculosis may require surgery more often to confirm the diagnosis or treat complications. Corticosteroids may be needed for tuberculous pericarditis and meningitis; some experts also recommend their use in miliary tuberculosis (71). In the WHO model, persons with severe forms of sputum smear–negative (extensive parenchymal involvement) and extrapulmonary tuberculosis (meningeal, miliary, pericardial, peritoneal, spinal, intestinal, genitourinary, and bilateral or extensive pleural effusions) are given the same priority for treatment as those with AFB smear–positive, pulmonary tuberculosis. In the IUATLD model, all cases of tuberculosis other than those who are smear positive are placed on the IUATLD Treatment Category III regimen, unless they are seriously ill, in which case the decision to use isoniazid, rifampin, pyrazinamide, and ethambutol in the intensive phase rests with the medical officer (see Table 7). D. Culture-Negative Tuberculosis

Shorter treatment regimens are effective for pulmonary tuberculosis that is both smear and culture negative. A 4-month regimen of isoniazid and rifampin, preferably with pyrazinamide for the first 2 months, has been shown to be effective (75). In Hong Kong, patients given 4 months of thrice-weekly isoniazid, rifampin, pyrazinamide, and streptomycin had a relapse rate of 4% within 5 years (76). Ethambutol should be included unless drug resistance is unlikely.

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E. Tuberculosis Treatment in Chronic Renal Failure

In chronic renal failure, some of the antituberculosis medications should be given at decreased dose or prolonged intervals, including the injectables, ethambutol, pyrazinamide, cycloserine, and fluoroquinolones. Isoniazid, rifampin, and ethionamide can be given in normal doses in renal failure. Antituberculosis drugs are cleared to a variable degree by hemodialysis; therefore, on days dialysis is performed, medications should usually be given after dialysis. WHO states that pyrazinamide at normal doses can be used in renal failure and recommends 2 months of isoniazid, rifampin, and pyrazinamide followed by 6 months of isoniazid and rifampin as the safest alternative. Since thioacetazone is partially excreted in the urine and the margin of safety between therapeutic and toxic doses is small, it is recommended that the drug not be given to patients in renal failure (45). F. Tuberculosis Treatment in Liver Disease

Patients with hepatic abnormalities who will be placed on tuberculosis therapy should be evaluated for hepatic tuberculosis. There may be greater potential for liver toxicity from antituberculosis drugs in patients who have underlying liver disease. The doses of most antituberculosis drugs do not need to be reduced in these patients, but closer monitoring of liver function and signs and symptoms of toxicity is indicated. In the United States, pyrazinamide use continues to be advised in established liver disease patients, but closer monitoring is recommended (59). In acute hepatic failure, a regimen including nonhepatotoxic drugs that are not hepatically cleared (e.g., aminoglycosides, capreomycin, ethambutol, cycloserine, and the fluoroquinolones) should be used until the liver function improves. Serum drug concentrations may be beneficial in the management of patients with tuberculosis and chronic hepatic failure. WHO recommends that patients with established chronic liver disease not receive pyrazinamide. The recommended regimens are (1) 2 months of isoniazid and rifampin with streptomycin and ethambutol followed by 6 months of isoniazid and rifampin or (2) two months of isoniazid, streptomycin, and ethambutol followed by 10 months of isoniazid and ethambutol (45). If tuberculosis treatment must be given during the acute phase of viral or other hepatitis, a regimen of drugs with low potential for liver toxicity such as ethambutol and streptomycin can be used for up to 3 months, followed by isoniazid and rifampin for another 6 months (45). G. Tuberculosis Treatment and Pregnancy

Treatment for suspected or confirmed tuberculosis should not be delayed during pregnancy. Ensuring effective therapy for tuberculosis is the best way to prevent

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infection to the fetus and the newborn. WHO and IUATLD recommend that the standard short-course regimens containing pyrazinamide be used during pregnancy (45,62). In the United States, pyrazinamide is not recommended during pregnancy because of inadequate data on teratogenicity (59). Streptomycin should not be used during pregnancy because of its known teratogenic effects. Therefore, the initial regimen consists of isoniazid, rifampin, and ethambutol for 2 months followed by isoniazid and rifampin for 7 months if the organism is fully susceptible. Pyridoxine supplementation should be given to prevent peripheral neuropathy from isoniazid in all pregnant women. If the suspicion for multidrug resistance is high, pyrazinamide should be used from the beginning if treatment is started after the first trimester; it may be started in the first trimester if the woman is HIV-infected (71). If the pregnancy is identified after the woman has already been on pyrazinamide for 2 months, the standard duration of treatment can be given. Because many of the medications used to treat MDRTB either are known to cause fetal abnormalities or have not been studied adequately, women of childbearing age with MDRTB should be counseled to use birth control. Pregnant women with MDRTB should be counseled about the potential effects of the medications on the fetus; abortion counseling should be offered. The small concentrations of antituberculosis drugs in the breast milk are not toxic to the newborn. Therefore breast feeding should not be discouraged in HIV-seronegative women. In the United States, breast feeding is not recommended for HIV-infected women (77). In resource-poor countries, breast feeding is recommended regardless of HIV status when adequate formula products are not available (78). However, the low concentration of drugs in breast milk should not be considered effective treatment for a diseased or infected nursing infant. H. Tuberculosis and HIV Infection

Length of Treatment

Concurrent infection with HIV requires several considerations related to treatment (see Chap. 20). In a prospective study from Haiti, use of a 6-month regimen of isoniazid, rifampin, and pyrazinamide (with or without ethambutol) for 2 months in the intensive phase, followed by isoniazid and rifampin in the continuation phase, has been shown to be effective for the treatment of tuberculosis in persons with HIV infection (79). However, these patients had higher median CD4 counts at time of diagnosis of tuberculosis than HIV-infected patients with tuberculosis in the United States (80,81). One prospective study from the United States showed similar low rates of relapse for a group that received a standard 6-month regimen compared to a group that received a 9-month regimen (3 extra months of isoniazid and rifampin). However, the study had a small number of patients in each arm (82). The

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length of treatment for tuberculosis in patients infected with HIV has been debated (83,84). The United States recommendations for the treatment of HIV-related tuberculosis were modified in 1994 to state that individuals with tuberculosis with or without HIV infection could be treated for 6 months (the previous recommendation had been that persons with HIV and tuberculosis be treated for 9 months) (85). However, the recommendations strongly advise prolonging the continuation phase if the clinical and bacteriological response is slow or suboptimal (59). Antiretroviral Drugs

Since 1995, the U.S. Food and Drug Administration (FDA) has approved two new types of drugs for the treatment of HIV infection: protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). While these medications have reduced morbidity and mortality from HIV and are now recommended as part of multidrug regimens in all patients with AIDS (86,87), they have an important impact on the treatment of tuberculosis because of their drug interactions with the rifamycins, especially rifampin, and, to a lesser extent, rifabutin. Given that the rifamycins are the most important medications for the treatment of tuberculosis (88), the use of PIs and NNRTIs thus complicates the clinical management of HIV-infected persons who also have tuberculosis disease. The protease inhibitors and rifamycins are both metabolized by the liver’s cytochrome P450 system, but have opposing effects. Rifamycins induce the cytochrome P450 system, causing increased metabolism and thus decreased levels of the protease inhibitors, while the protease inhibitors inhibit the P450 system, causing increased, potentially toxic levels of the rifamycins (89–93a). Likewise, because of similar interactions with rifampin, the NNRTIs nevirapine and delavirdine should not be used with rifampin. Efavirenz levels are decreased when used with rifampin, but the clinical significance of this is unclear (94). Although rifabutin has been reported to decrease NNRTI levels less than rifampin, the level of interaction between delavirdine and the rifamycins is such that their use together is contraindicated (95,96). Nevirapine can be used with rifabutin without any dose adjustment (97). Efavirenz decreases rifabutin levels, and the dose of rifabutin has to be increased (98) (see Tables 4 and 5). Of the four first protease inhibitors approved for use in the United States (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir), indinavir, nelfinavir, and amprenavir have the least amount of interaction with the rifamycins. Of the rifamycins, rifabutin has fewer interactions than rifampin and should be substituted for rifampin if the person will be treated simultaneously with an appropriate protease inhibitor (see Tables 4 and 5). Several tuberculosis treatment options are possible, depending on whether an individual is or is not already taking a protease inhibitor or an NNRTI (see Fig. 2). The CDC most recently published recommendations in 1998 (39). Some key principles to consider are:

Figure 2 New York City Department of Health–recommended treatment regimens for HIV-infected persons with drug-susceptible tuberculosis.

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1. Can the use of the PI or NNRTI be delayed? If delay is possible, the ATS/CDC recommendations for the treatment of tuberculosis described above should be followed. Alternatively, for the continuation phase, the rifamycins can be discontinued, and any PI or NNRTI can be used. If delay is not possible, the ATS/CDC recommendations should be considered at least until the end of the intensive phase; in the continuation phase, rifampin should be switched to rifabutin and an appropriate PI or NNRTI can be used. 2.

If the use of a PI or NNRTI cannot be delayed until the end of the intensive phase of treatment for tuberculosis, non–rifampin-containing regimens can be used from the beginning. If the individual is taking a PI or NNRTI at the time of diagnosis of tuberculosis, two parameters can be considered. The PI or NNRTI can be switched to one that can be administered with rifabutin, and can be substituted for rifampin, or any PI or NNRTI can be used with a non–rifamycincontaining regimen.

I. Multidrug-Resistant Tuberculosis

Although drug resistance occurs in nature, it is exacerbated by human error, caused by either patients not taking medications properly or health-care providers prescribing treatment incorrectly. The presence of high rates of drug resistance in a community usually reflects the presence of a poorly managed tuberculosis control program. Multidrug-resistant tuberculosis (MDRTB) is difficult to cure and costly to treat; its prevention is the better course to follow (99). In resource-rich countries, the optimal treatment of drug-resistant tuberculosis depends upon the clinician knowing susceptibility results and having available the antituberculosis medications to which the strain of M. tuberculosis is susceptible. This course has been termed DOTS-Plus (see Chap. 18). If the strain is resistant to isoniazid only, a 6-month regimen of rifampin, ethambutol, and pyrazinamide is recommended (59). For other drug-resistance patterns, it is difficult to develop standardized treatment regimens because good efficacy data are not available and because the side effects of the second-line medications can be so intolerable as to preclude their use for the recommended period of time. The most difficult type of tuberculosis to cure is a strain that is resistant to both isoniazid and rifampin, two of the most potent medications in the antituberculosis treatment armamentarium. In 2000, most references to MDRTB imply resistance to at least these two medications. The MDRTB treatment principles described below are relevant primarily to resource-rich countries. For resource-poor countries, most forms of MDRTB are often considered untreatable, given that countries are unable to purchase the more

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expensive drugs and do not have ready access to the more sophisticated laboratory procedures needed to monitor the patient. However, WHO has published guidelines for the treatment of MDRTB, for use only when treatment can be provided in a specialized unit and a laboratory exists that is able to perform cultures and reliable susceptibility testing (see Sec. VII. A) (73). WHO has also endorsed DOTSPlus (see Chap. 18). MDRTB Treatment Principles

All persons with MDRTB should be treated using directly observed therapy. As this is the patient’s last opportunity for cure, every effort should be made to ensure that the medications are being ingested. MDRTB should always be treated in consultation with a clinician who has experience in treating the disease. Since treatment with only one medication quickly leads to the strain’s resistance to it, patients should be treated with at least two, and preferably three to four, medications to which the strain is known or likely to be susceptible. An aminoglycoside or capreomycin should be one of the medications because of evidence that the duration of treatment with this family of drugs is the strongest predictor of culture conversion and survival; it should be used for at least 4–6 months after M. tuberculosis cultures convert to negative (100). Most experts recommend that treatment should be given for at least 18 months after M. tuberculosis cultures have converted to negative; in persons with HIV infection or cavitary disease, treatment is often extended to 24 months after culture conversion (101). Intermittent regimens for MDRTB have not been studied and thus should not be used. Monitoring of Treatment for MDRTB

If a patient’s M. tuberculosis culture remains positive after 4–5 months of treatment, the most recent positive specimen should be sent to the laboratory for susceptibility testing to first- and second-line antituberculosis drugs. While awaiting drug susceptibility results, the patient may remain on the most recent regimen if clinically stable. Alternatively, if the patient is acutely ill, at least two new drugs should be added while continuing the original medications. A single antituberculosis medication should never be added to a regimen that is failing. Adding a single drug to a failing regimen has the same effect as monotherapy. At least two medications to which the strain is likely to be susceptible should be added. If the patient is clinically stable, it is preferable to wait until updated susceptibility results are available.

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If a regimen is not failing but the patient develops an adverse drug reaction, the offending drug can be removed and the rest of the regimen continued. Alternatively, a new medication can be substituted. However, physicians should make every attempt to ascertain that a medication is indeed the cause of the reaction. J. Treatment of Persons Exposed to MDRTB

In 1992, CDC published recommendations regarding the management of persons exposed to cases of tuberculosis resistant to isoniazid and rifampin (102). In making decisions about preventive therapy in persons exposed to MDRTB, three factors should be considered: (1) the likelihood that the individual is newly infected with M. tuberculosis (an individual with a history of a prior positive tuberculin skin test is considered less likely to be infected with an MDRTB strain; a baby of a woman with MDRTB is considered more likely); (2) the likelihood that the infected individual would develop tuberculosis (those with AIDS, HIV, or other immunocompromising conditions, infection within the previous 2 years and age 5 years or 60 years are considered to be at highest risk); and (3) the likelihood that the person is infected with MDRTB. To help clinicians determine the likelihood of the third condition, three parameters should be considered: (1) the infectiousness of the source MDRTB patient (AFB smear-positive pulmonary tuberculosis versus extrapulmonary tuberculosis); (2) the closeness and intensity of the exposure (living in poorly ventilated quarters for weeks to months versus one-time contact lasting a few minutes); and (3) the contact’s risk of being exposed to persons with drug-susceptible tuberculosis (a nurse working on a hospital tuberculosis ward versus a tuberculin skin test–positive child of a mother with MDRTB). For those with intermediate to high likelihood of infection with MDRTB, preventive treatment with two drugs to which the organism is susceptible is recommended. Decisions regarding who should be treated have evolved since the CDC recommendations were developed. Experience has shown that many people do not tolerate the medications and stop before completing a full course of treatment (103,104) In New York City’s tuberculosis-control program, which has had considerable experience in this area, persons who are immunosuppressed or children under 5 years of age are offered 12 months of two drugs to which the infecting strain of M. tuberculosis is susceptible. Persons not immunosuppressed or 5 years of age or older are given no treatment but are followed with chest radiographs at 4, 8, 12, 18, and 24 months (71). K. Surgery for Tuberculosis

In the preantibiotic era, various surgical procedures were utilized to decrease the volume of the thorax and thereby collapse tuberculous cavities. The collapse was

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thought to decrease the amount of oxygen available for the survival of M. tuberculosis, thus decreasing or eliminating tubercle bacilli from the sputum (105). However, after long-term studies showed that chemotherapy alone was able to cause complete sterilization of tuberculous lesions, surgery in the treatment of tuberculosis was abandoned (106). Surgery for tuberculosis was used to correct the consequences of severe disease, such as major bronchial obstruction, a bronchopleural fistula, or severe hemoptysis (107). Recently, with the resurgence of multidrug-resistant tuberculosis, surgery has been used to debulk areas of the lung with extensive disease to improve the likelihood that a patient will be cured with an antituberculous drug regimen. In New York City, surgery is considered when the following four criteria have been satisfied: (1) an adequate chemotherapeutic regimen, including those including both first- and second-line anti-TB medications, has failed to cure or cause M. tuberculosis culture conversion to negative within 4–6 months; (2) the extent of disease is limited enough to necessitate only a lobectomy or pneumonectomy; (3) the remaining lung tissue is relatively devoid of tuberculosis; and (4) the patient has enough pulmonary reserve to tolerate the procedure and has an acceptable surgical risk (71). The National Jewish Medical and Research Center has had an additional criterion of there being “sufficient drug activity to diminish the mycobacterial burden enough to facilitate probable healing of the bronchial stump” (107,108). In its series of 130 patients who underwent surgery for MDRTB, patients who received pre- and postoperative antituberculous therapy had a cure rate of over 90%, compared to an overall success rate of 65% in a similar group of historical controls (107,109). VIII. Adherence to Treatment A. Predicting and Improving Adherence

The difficulty of patients’ adhering to treatment was recognized even before the advent of chemotherapy, with a quarter of patients discharging themselves from U.S. sanitoria (2). Shortly after the initiation of the chemotherapeutic era for tuberculosis, Wallace Fox, one of the architects of the widely influential British Medical Research Trials on tuberculosis treatment, reported the difficulty of getting patients to comply with treatment (20,23). In general, adherence to medical treatment depends on the characteristics of the treatment, the characteristics of the health-care delivery system, and the patient/health-care worker bond. The characteristics of tuberculosis treatment that can cause a decrease in adherence include its length, the need to take several medications, and the cost of treatment. In order to maximize the chance that patients with tuberculosis complete treatment, programs of directly observed therapy (DOT) have been developed. These programs

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usually include the use of a trained health-care worker to observe a patient take every dose of medication, the offering of incentives such as cash, transportation tokens, food, and shelter, and practices that actively attempt to reduce barriers to completion. Such practices include limiting patient waiting times, using appointment reminders, having all services provided in one setting, expanding the availability of services to evenings and weekends, not charging for medications, and providing access to social services such as housing and alcohol and drug counseling. The relationship between the patient and all members of the tuberculosis-control program team is enhanced by having bilingual and bicultural staff if the patient population speaks languages other than the dominant one. Another important practice is to have staff treat patients as if they are the most important persons to the program, without regard to economic or legal status, race or ethnicity, or personal beliefs. Although there may be a prejudice among health professionals and the public to judge certain patients as more likely to be nonadherent, studies have shown that nonadherence is difficult to predict. One’s age, sex, race or ethnicity, socioeconomic status, level of education, occupation, income, marital status, or religious beliefs have not been shown to be predictive of adherence (110,111). B. Role of Directly Observed Therapy in the Treatment of Tuberculosis

The direct observation of treatment has been discussed as a needed strategy since the early days of the chemotherapeutic era. Antituberculosis treatment trials conducted during the early 1960s showed the feasibility of supervision, and the efficacious outcomes from intermittent treatment also meant that fewer doses needed to be supervised (23,24,112). Despite this early evidence, U.S. physicians and public health officials from the 1960s through the early 1990s rejected the option of universal direct supervision of tuberculosis treatment; the selective use of DOT, if it was used at all, was the preferred strategy (113). However, in 1992, based on increasing evidence that patients were not completing an adequate course of treatment (114) as well as nosocomial outbreaks of multidrug-resistant tuberculosis (115), the ATS and CDC updated its statement on the control of tuberculosis to recommend that DOT, using intermittent treatment regimens, be considered for all patients (116). Recent studies have reinforced the efficacy of supervised treatment on program outcomes (117–120). The adoption by one community in Texas of almost universal DOT, whereby patients ingest medications under the direct observation of a trained health worker, led to reductions in the levels of primary and acquired drug resistance and relapse (117). In New York City, with the increased use of DOT beginning in 1992, treatment completion improved from less than 50% to over 90%, the incidence of tuberculosis dropped 55% between 1992 and 1997, and new cases of MDRTB declined 88% in the same time period (118,121). Chaulk and colleagues showed that the implementation of DOT

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in 1981 in Baltimore led to a decline of tuberculosis, despite the fact that the community had risk factors, such as HIV, poverty, unemployment, and immigration from high-prevalence countries, which were conducive to the presence of the disease. This result was in contrast to the increased number of cases seen in the five major U.S. cities having the highest incidence of tuberculosis but that did not use DOT widely or at all (119). In Beijing, China, a large-scale community tuberculosis control program quickly implemented between 1991 and 1994, using DOT, had a cure rate of 90% for over 55,000 patients with AFB smear-positive tuberculosis (120). Finally, in a report that compared studies of various types of DOT programs to unsupervised tuberculosis treatment programs, programs that used DOT with incentives and enablers had the highest percentage of patients who completed treatment (91.0%), followed by those that used DOT without incentives and enablers (86.3%), and those that used modified DOT (78.6%); in nine programs where treatment was not supervised, an average of only 61.4% completed treatment (122). C. DOT Versus DOTS

In 1991, based on the global magnitude of the tuberculosis problem, evidence of rising rates of drug resistance, and the ability of HIV to fuel the tuberculosis epidemic, WHO adopted the successful strategy of the International Union Against Tuberculosis and Lung Disease’s tuberculosis mutual assistance program to develop a new tuberculosis control and research strategy. The new strategy was named directly observed therapy, short-course (DOTS). It comprises government commitment to the control of tuberculosis; finding cases through the use of sputum smear microscopy, which implies a functioning laboratory network; the use of standardized, short-course regimens; trained health workers to observe patients take each dose of medication (DOT); a consistent supply of essential antituberculosis medications; and an information system that allows the program to monitor and evaluate treatment outcomes (45). Thus, DOT is one component of the DOTS strategy. However, despite there being a clear definition of DOT, the term has been misused in various ways, such as the patient being known to, and under the “observation” of, the local tuberculosiscontrol program, or the patient being observed to take medications once a week, with the other doses to be taken at home. D. Other Alternatives to Improve Adherence

Although the gold standard for the treatment of tuberculosis is the direct observation of every dose of medication, in some tuberculosis-control programs this goal has not been reached, due to, for example, lack of resources and program infrastructure, lack of acceptance by staff, and the need to travel long distances.

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Several alternatives exist for those who truly cannot be observed to take their medications. One option is to use fixed-dose combinations, which at least ensures that a patient is ingesting at least two medications, and thus may avoid drug resistance. Medication monitors, which indicate when pill bottles are being opened, can serve as a proxy for the intent to take medications. However, in at least one study, approximately one third of supposedly reliable patients had poor adherence to treatment (123). Monitoring may also be achieved by unannounced pill counts or urine checks for metabolites of antituberculous medications. A final alternative would be not to use a rifampin-containing treatment regimen when ingestion of medications cannot be observed (62). While this means that patients will not receive optimal treatment and must take medications for a longer period of time, it avoids the possibility of acquiring resistance to the most potent drug in the tuberculosis treatment armamentarium. It should be noted that the use of these alternatives is suboptimal to the direct observation of treatment and does not guarantee that the medicines are actually being ingested. IX. The Future of Treatment Although effective treatment regimens are available for tuberculosis, tuberculosis continues to cause significant morbidity and mortality worldwide. A better understanding of the biology of M. tuberculosis will hopefully address such issues as developing medications or modulators that can kill the organism in the actively and intermittently metabolizing, as well as dormant phases, developing medications that will both shorten treatment and allow it to be given intermittently, as was the case with rifampin, activating dormant organisms so that drugs can work against them, and determining how to better prevent drug resistance. To improve adherence and be able to move away from the labor-intensiveness of DOT, implantable, sustained-release forms of existing and new drugs would be useful. Primary prevention, in the form of an effective vaccine, should be given high priority on the research agenda, for what respiratorily transmitted disease has been controlled without one? New effective measures to prevent the pool of already infected individuals from breaking down with disease also need to be developed; the issues relevant to treatment of disease apply as well to treatment of latent TB infection. In the final analysis, however, political commitment, in the form of economic support for tuberculosis-control programs and funding for basic and applied research, plus a willingness to be open to innovation will be the most important factors in controlling tuberculosis in the future. Acknowledgments The authors acknowledge Lisa Fine Sherman, Janette Yarwood, and Audrey M. Henry for assistance in the preparation of the chapter.

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84. Perriens JH, St. Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portaels F, Willame JC, Mandala JK, Kaboto M, Ryder RW, Roscigno G, Piot P. Pulmonary tuberculosis in HIV-infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995; 332:779–784. 85. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 1986; 134:355–363. 86. Carpenter CCJ, Fischl MA, Hammer SM, Hirsch MS, Jacobson DM, Katzenstein DA, Montaner JGS, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA panel. JAMA 1997; 277:1962–1969. 87. U.S. Department of Health and Human Services and the Henry J. Kaiser Foundation Panel on Clinical Practices for Treatment of HIV Infections. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, May 5, 1999; 1–49 (URL “http.//www.hivatis.org”). 88. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of tuberculosis. Am Rev Respir Dis 1986; 133:423–430. 89. McCrea JB. Indinavir (MK 639) drug interaction studies. Int Conf AIDS 1996; Abstract Mo.B.174. 90. Sun E, Heath-Chiozzi M, Cameron DW, Hsu A, Granneman RG, Mauratu CJ, Leonard JM. Concurrent ritonavir and rifabutin increase the risk of rifabutin associated adverse events. Int Conf AIDS. 1996; Abstract Mo. B. 171. 91. Sadler B, Gillotin C, Chittick GE, et al. Pharmokinetic drug interactions with amprenavir [Poster]. Geneva: 12th World AIDS Conference, 1998:12389. 92. Agouron Pharmaceuticals. Viracept® package insert. La Jolla, CA: Agouron Pharmaceuticals, October 29, 1997. 93. Roche Pharmaceuticals. Invirase® package insert. Nutley, NJ: Roche Laboratories Inc., January 1998. 93a. Jorga K, Buss NE. Pharmacokinetic (PK) drug interactions with saquinavir soft gelatin capsule. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy [abstract]. 1999; 339. 94. Dupont Pharmaceuticals. Sustiva™ package insert. Wilmington, DE: Dupont Pharmaceuticals. September, 1998. 95. Borin MT, Chambers JH, Carel BJ, Gagnon S, Freimuth WW. Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate. Clin Pharmacol Ther 1997; 61:544–553. 96. Cox SR, Herman BD, Batts DH, Carel BJ, Carberry PA. Delavirdine and rifabutin: pharmacokinetic evaluation in HIV-1 patients with concentration targeting of delavirdine (abstract). Chicago, IL: 5th Conference on Retroviruses and Opportunistic Infections, 1998:344. 97. Maldonado S, Lamson M, Gigliotti M, Pav JW, Robinson P. Pharmacokinetic (PK) interaction between nevirapine (NVP) and rifabutin (RFB). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy [abstract].1999; 341. 98. Benedek IH, Fiske WD, White SJ, Stevenson D, Joseph JL, Kornhauser DM. Pharmacokinetic interactions between multiple doses of efavirenz and rifabutin. Denver, CO: 36th Annual Meeting of the Infectious Disease Society of America [abstract]. 1998; 461. 99. Fujiwara PI, Sherman LF. Multidrug-resistant tuberculosis: many paths, same truth. Int J Tuberc Lung Dis 1997; 1:297–298. 100. Frieden TR, Sherman LF, Maw KL, Fujiwara PI, Crawford JT, Nivin B, Sharp C, Hewlett D, Brudney K, Alland D, Kreiswirth B. A multi-institutional outbreak of

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Appendix

Drug Interactions with Antituberculosis Medications

Antituberculosis medication Isoniazid

Drug or drug type Acetaminophen Antacids Anticoagulants (oral) Benzodiazepines Carbamazepine Cycloserine Disulfiram Enflurane Haloperidol Ketoconazole Phenytoin Theophylline Valproate

Rifampin and rifabutin

Aminosalicylic acid Amprenavir Anticoagulants (oral) Antidepressants

-Adrenergic blockers (most) Benzodiazepines

Interaction ↑ toxic metabolites ↓ isoniazid absorption ↑ anticoagulant effect ↑ benzodiazepine toxicity ↑ toxicity of both drugs ↑ central nervous system effect of cycloserine Severe psychotic episodes (avoid concurrent use) ↑ nephrotoxicity (avoid concurrent use) ↑ haloperidol toxicity ↓ ketoconazole effect ↑ phenytoin toxicity ↑ theophylline toxicity ↑ hepatic and central nervous system toxicity ↓ rifampin absorption Possible ↑ rifabutin toxicity, marked ↓ amprenavir effect ↓ anticoagulant effect ↓ antidepressant effect (tricyclic, barbiturates, benzodiazepines) ↓ beta blockade ↓ benzodiazepine effect continues

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Appendix Continued Antituberculosis medication

Drug or drug type Chloramphenicol Clofazimine Clofibrate Contraceptives (oral) Corticosteroids Cyclosporine Dapsone Delavirdine Digitoxin Digoxin Diltiazem Disopyramide Efavirenz Estrogens Fluconazole Haloperidol Indinavir Itraconazole Ketoconazole Mephenytoin Methadone Metoprolol Mexiletine Nelfinavir Nevirapine Nifedipine Nisoldipine Phenytoin Probenecid Progestin Propafenone Quinidine Ritonavir

Interaction ↓ chloramphenicol effect Possible ↓ rifampin effect ↓ clofibrate effect ↓ contraceptive effect Marked ↓ corticosteroid effect ↓ cyclosporine effect Possible ↓ dapsone effect Marked ↓ delavirdine effect, ↑ rifabutin effect ↓ digitoxin effect ↓ digoxin effect ↓ diltiazem effect ↓ disopyramide effect ↓ efavirenz effect, ↓rifabutin effect ↓ estrogen effect ↓ fluconazole effect ↓ haloperidol effect Possible ↑ rifabutin toxicity, marked ↓ indinavir effect ↓ itraconazole effect ↓ ketoconazole and rifampin effect ↓ mephenytoin effect ↓ methadone effect with rifampin Possible ↑ beta blockade ↓ antiarrhythmic effect Possible ↑ rifabutin toxicity, marked ↓ nelfinavir effect Probable ↓ rifabutin effect ↓ antihypertensive effect ↓ antihypertensive effect ↓ phenytoin effect Possible ↑ rifampin effect ↓ progestin effect ↓ propafenone effect ↓ quinidine effect ↑ rifabutin toxicity, ↓ ritonavir effect (rifampin), unknown ritonavir effect (rifabutin)

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Continued

Antituberculosis medication

Drug or drug type Saquinavir

Aminoglycosides

Sulfonylurea Tetracyclines Theophyllines Tocainide Trimethoprimsulfamethoxazole Verapamil Amphotericin Bumetanide Capreomycin Cephalosporins Cisplatin Cyclosporine Enflurane Ethacrynic acid Furosemide Gallium Methotrexate Neuromuscular blocking agents Vancomycin

Pyrazinamide

Allopurinol

Pyridoxine

Barbiturates Levodopa Phenytoin Alcohol Ethionamide

Cycloserine

Isoniazid Fluoroquinolones

Antacids with metal cations (Ca, Mg, Al, Fe) Sucralfate

Interaction Marked ↓ saquinavir effect (rifampin), ↓ saquinavir effect (rifabutin), ↑ rifabutin toxicity (gel form) ↓ sulfonylurea effect ↓ tetracycline effect ↓ theophylline effect Possible ↑ tocainide effect Possible rifampin toxicity ↓ verapamil effect ↑ Nephrotoxicity (synergistic) ↑ ototoxicity ↑ oto- and nephrotoxicity (additive) ↑ nephrotoxicity ↑ nephrotoxicity ↑ nephrotoxicity Possible ↑ nephrotoxicity ↑ ototoxicity ↑ oto- and nephrotoxicity ↑ nephrotoxicity Possible ↑ methotrexate toxicity with kanamycin ↑ neuromuscular blockade ↑ oto- and nephrotoxicity (additive) Failure of allopurinol to ↓ serum uric acid level ↓ barbiturate effect ↓ levodopa effect ↓ phenytoin effect ↑ alcohol effect and seizures ↑ central nervous system effect of cycloserine ↑ central nervous system effect of cycloserine ↓ absorption of fluoroquinolones ↓ absorption of fluoroquinolones continues

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Appendix Continued Antituberculosis medication

Drug or drug type Drugs metabolized by cytochrome P450 (cyclosporine, theophylline, warfarin, phenytoin, sulfonylurea) Nonsteroidal anti-inflammatory agents Probenecid

Sparfloxacin

para-Aminosalicylic acid Ethionamide

Anti-arrhythmics such as disopyramide and amiodarone; other drugs such as terfenadine, astemizole, clarithromycin, azithromycin, erythromycin, ketoconazole, itraconazole, cisapride, or phenothiazines Digoxin Cycloserine

Source: Adapted from Ref. 71.

Interaction ↑ effect of additional drug

↑ central nervous system stimulation and possible convulsions ↑ serum level of fluoroquinolones torsades de pointes secondary to prolongation of QTc interval

Possible ↓ digoxin effect ↑ central nervous system effect of cycloserine

17 Responding to Outbreaks of Multidrug-Resistant Tuberculosis Introducing DOTS-Plus

PAUL E. FARMER, JIM YONG KIM, and CAROLE D. MITNICK Program in Infectious Disease and Social Change Harvard Medical School Boston, Massachusetts

RALPH TIMPERI Massachusetts State Laboratory Institute Massachusetts Department of Public Health Boston, Massachusetts

I. Introduction: Strengths and Limitations of DOTS Even before Robert Koch identified the tubercle bacillus in 1882, many in the scientific and medical communities were convinced that tuberculosis (TB) was an airborne infectious disease and that only isolation of those with active pulmonary disease would decrease transmission of the disease to others. Although the sanatorium movement corresponded to secular trends of decreasing TB incidence in North America and Western Europe, the degree to which isolation practices contributed to the decline of TB in industrialized countries is still debated (1–4). It is clear, however, that the identification and isolation of all those with active disease was a burdensome and costly strategy of TB control; its impact on families was often devastating.* *Bates (4) offers myriad examples of patients troubled by families’ want for income or food as a result of caring for sick relatives. She cited Mabel Jacques, of the Visiting Nurse Society of Philadelphia, who described the effects of institutionalization on families: “What effect does the sending of a tuberculous patient to an institution have on the family . . . In nine cases out of ten it means eventually the breaking up of the family.” Children, wrote Jacques, “become unruly, probably live on the streets and are generally neglected; the father loses heart and interest and either places them in an institution or allows them to go utterly to the bad.”

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The era of modern TB control began with the development, at mid-century, of effective chemotherapy. As ambulatory chemotherapy was shown to be more effective and less costly than inpatient treatment, the understanding that treatment is prevention became a cornerstone of modern TB control. As Sir John Crofton has observed (5), treating effectively a single case of active pulmonary TB is in essence as much a public-health intervention as a clinical one: “If all patients could be treated, and their sputum converted to negative, new infections would cease. For a time new cases would continue to rise from previous infections, but this source should gradually decrease.” As is clear from other chapters in this book, the promise of mid-century— eradication of TB shortly after the advent of highly effective antituberculous agents—was never realized: TB remains the leading single infectious cause of adult deaths in the world today (6). Since the introduction of highly effective therapy has yet to have a major impact on global burden of disease, disagreement about the causes of this failure was to be expected. Elsewhere, we have discussed this debate, including the contribution to treatment failure of patient noncompliance (7–9). But the rigorous application of directly observed therapy (DOT) virtually removes the onus of adherence from the patient. The development of DOTS-based treatment strategies, discussed elsewhere in this book (see Chap. 16), has thus been a major breakthrough in TB control. Although the acronym DOTS has been ascribed several meanings, for most it means directly observed therapy, short-course. This chapter discusses situations in which short-course chemotherapy (SCC)—even if directly observed—is likely to be ineffective due to high rates of drug resistance; we will consider alternative and complementary control strategies appropriate to these settings. A. The Problem of Resistance to Antituberculous Agents

What happens when TB is treated ineffectively? One of the risks of haphazard and unmonitored therapy, and even of monitored empiric therapy, is the acquisition by Mycobacterium tuberculosis of resistance to anti-TB medications. This was recognized rapidly in the 1940s, when patients who had initially responded to monotherapy with streptomycin—at the time, the only available medication— later relapsed with disease that was clearly resistant to the new agent (10–13). In a study published in 1948, researchers noted that of 41 patients receiving 2 g of streptomycin daily, 35 acquired resistance to the drug, most within 2 months of beginning daily streptomycin treatment. By 1950, even the drug’s manufacturer, Merck, admitted that, when streptomycin was administered alone, “in most cases highly drug sensitive strains become highly resistant in 2–4 months of therapy” (14). By 1958 investigators had discovered that once strains acquired resistance, they did not revert to a sensitive phenotype, even after the drug was no longer given. Unless new antituberculous drugs were administered or localized disease

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could be resected, the patient was not cured and the disease took its course—leading, often enough, to early death. It was soon recognized that administration of streptomycin in combination with para-aminosalicylic acid might prevent or postpone the emergence of drug resistance. Thus, drug resistance was the primary reason that TB treatment regimens came to consist of long courses of more than one drug. During the past few decades, a number of regimens have been deployed, often in haphazard fashion. Table 1 lists commonly used first-line drugs and their approximate times of introduction. In recent years, many DOTS-based regimens have comprised rifampin, isoniazid, ethambutol, and pyrazinamide; some have contained thiacetazone instead of rifampin or ethambutol. These drugs, along with streptomycin, are often termed the “first-line” anti-TB drugs. From a public-health standpoint, ineffective therapy may cause more harm than no therapy. Patients with acquired resistance, if not treated, are of course infectious and capable of transmitting resistant strains to others. Thus does the legacy of improper TB control include primary multidrug-resistant tuberculosis (MDRTB) infections that may subsequently give rise to cases of active disease untreatable through conventional therapy. Patients with MDRTB are sick with strains resistant to at least H and R, the two most powerful agents, and the basis of the short-course chemotherapy regimens used in DOTS programs. B. Standardized Retreatment Regimens

What can be done for patients who fail TB therapy? First, it is important to note that failure can take several forms. Some patients fail to respond at all, others respond but quickly relapse, and still others relapse long after the completion of therapy. Some patients fail directly observed regimens; at this writing, however, most fail unsupervised regimens. The clinical implications of these various routes to failure are often profound. Compare, for example, two different cases of treatment failure. One is a 25-year-old Haitian man who presents with left-upper-lobe cavitary disease; other family members, he reports, have died of TB. The patient was prescribed a regimen consisting of 3 months of HST (see Table 1 for abbreTable 1

Commonly Used Antituberculous Drugs and Their Time of Introduction

Drug Streptomycin Isoniazid para-Aminosalicylic acid Thiacetazone Pyrazinamide Ethambutol Rifampin (rifampicin)

Abbreviation

Date of introduction

S H PAS T Z E R

1944 1952 1948 1946 (discovery date) 1955 1961 1966

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viations) followed by 15 months of HT (3HST/15HT). Therapy was not directly observed, but the patient became smear-negative by 2 months and was symptomfree shortly thereafter; he also gained weight. The clinical record, which was scant, made no comment on adherence to therapy, and no clinical exchanges were documented during most months. The patient was discharged from the program after 18 months only to return, just over a year after discontinuing therapy, with recurrent symptoms; again, he was found to be smear positive. The second patient is a 28-year-old Peruvian woman, also with TB contacts and a family history of death due to TB. She received a fully supervised course of 2 months of RHEZ followed by 4 months of twice-weekly RH (2RHEZ/4R2H2), but was smear-negative only in her third month of therapy. After 6 months of treatment, she became smear-positive and symptomatic. What is the likely cause of treatment failure in these two cases? How would these patients, both with smear-positive relapsed pulmonary TB, best be managed? First, it is highly unlikely that the first patient has MDRTB; he certainly does not have acquired MDRTB, since he never received R. In fact, laboratory testing revealed that the young Haitian man relapsed with pan-susceptible disease. Although irregular ingestion of medications is an excellent means of inducing resistance, this patient was fortunate in one sense: he had not acquired resistance to any first-line agents. The Peruvian woman is in a very different situation. She has failed DOTS based on top-of-the-line initial empiric therapy and administered in the context of an excellent national TB program (NTP). Culture and susceptibility testing subsequently revealed resistance to all four first-line drugs that she had received. Screening of her family suggested that she had been infected with a strain resistant to R and H and that she had acquired resistance to E and Z in the course of her initial therapy. In contrast to the Haitian patient, the young woman’s resistance appears to have been amplified by short-course chemotherapy. Current WHO recommendations would have all patients who fail primary empiric therapy receive a retreatment regimen based on RHEZ, but with the addition of a brief short course of S (15). The Haitian man would of course likely be cured by this or any other RH-based, directly-observed retreatment regimen; following a national protocol, he was in fact cured by a retreatment regimen consisting of SHREZ. But although a WHO-endorsed retreatment regimen was effective in the first case, it would fail to cure the second patient. Failure of DOTS, we believe, is often tantamount to a positive diagnostic test for MDRTB (16). That is, since patients who fail DOTS are often resistant to RH, RH-based retreatment regimens are unlikely to cure them (16a–19). In summary, the current WHO-recommended retreatment regimen is not adequate in settings in which MDRTB is already entrenched or for many patients who have failed strictly supervised short-course, RH-based chemotherapy.

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C. DOTS and MDRTB: Managerial Success, Clinical Failure

If RH-based regimens are unlikely to cure patients resistant to these medications, what are their likely effects? Unfortunately, it is not possible to claim, as have many, that such regimens do no harm.* Use of a regimen slated to fail is of course a waste of resources; it is also a means of acquiring resistance to E, Z, and S. We have termed this the “amplifier effect of short-course chemotherapy” and documented its contribution to a large outbreak of MDRTB in urban Peru (16a). Figure 1 shows the effect of empiric short-course regimens that are administered to a patient with drug-resistant disease. YM, 23 years old, was infected with a strain resistant to three drugs; when she was examined in 1996, her infecting isolate demonstrated resistance to six antituberculous drugs. The arrow represents time and shows how a patient with primary MDRTB can be exposed to inadvertent monotherapy by receiving sequential courses of empiric therapy and empiric retreatment regimens. Adding a single agent to a failing regimen is well known to lead to acquired resistance (20–22); consecutive empiric short-course regimens in patients with MDRTB result in treatment failure through the same mechanisms—inadvertent

Figure 1 Sequential short-course chemotherapy amplifying drug resistance in a 23-yearold female with primary MDRTB.

*In the TB Treatment Observer (19a) it was reported by Klaudt that “DOTS stops MDRTB. DOTS makes it virtually impossible to cause a patient to develop the incurable forms of TB that are becoming more common.”

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monotherapy. Treating patients after they have experienced the amplifier effect is far more difficult—and far more costly—than treating patients with strains of M. tuberculosis with primary resistance to H and R alone. And to these costs might reasonably be added the cost of each sequential round of therapy doomed to fail. In the end, then, we are left with the following dilemma: an effective TB management system (DOTS) has been developed, but its exclusive reliance on SCC and standardized regimens may make it inappropriate for those settings in which MDRTB is already established. The global epidemiology of drug-resistant TB, now coming into focus thanks to the drug-resistance survey conducted by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease, suggests that a single strategy will never suffice to stem all TB epidemics; such surveillance efforts can help us to detect settings in which cure rates with DOTS will be unacceptably low. In parts of the former Soviet Union, for example, there is widespread resistance to RHS. In Ivanovo Oblast, Russia, 5% of strains isolated from patients never before treated demonstrated multidrug resistance (23), 100% of patients previously treated demonstrated resistance to at least one first-line drug (23a). This suggests that the amplifier effect of SCC will likely have an even larger effect in the region, and four- or five-drug resistance can be expected to become the rule in settings in which DOTS is introduced. Precisely this situation has already been documented in settings in Siberia (see Chap. 24). In the Mariinsk TB prison colony in Siberia, 22.6% of 164 patients receiving five-drug therapy (SHREZ) had strains resistant to H, R, and S; another 37.2% had isolates resistant to H and S; and more than 14% had strains resistant to one of the three. In this cohort, only 25% of prisoners had strains sensitive to all four drugs. Even though the regimen for new patients was “reinforced” with S, cure rates with DOTS in this prison were low: among 210 smear-positive patients who received five-drug therapy from June 1996 through March 1997, only 46% could be declared cured; 39% failed treatment or died. There were no defaulters. The authors conclude that “inadequate treatment regimens are likely to lead to amplification of resistance . . . creation of additional resistance is also likely with Category 2 [SHREZ] therapy” (24). Whether resistance was primary or acquired, cases of active TB due to these infecting strains are not likely to be cured by either recommended first-line or retreatment regimens. Instead, the amplifier effect of SCC will iatrogenically render these patients the unwilling incubators of highly resistant strains of M. tuberculosis. Novel strategies, such as DOTS-Plus, are now required in these and other MDRTB “hot spots.”

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II. What Is DOTS-Plus? The history of DOTS-Plus is brief. The concept arose in response to two questions: What is the impact of DOTS on MDRTB? What is the impact of MDRTB on DOTS? As noted above, SCC cannot cure MDRTB; managerial successes do not compensate for clinical failures. In 1997, groups working in TB control in Peru and Haiti joined forces with the WHO Global Tuberculosis Programme, the Pan-American Health Organization (PAHO), the Centers for Disease Control and Prevention (CDC), and the International Union Against Tuberculosis and Lung Disease (IUATLD) to make common cause in an effort to expand DOTS in a manner that would take into account MDRTB. In April 1998, representatives of these bodies came together in Cambridge, Massachusetts, in order to evaluate the existing data and to propose strategies. The Cambridge meeting was soon followed by an informal consultation at WHO headquarters, where treatment protocols were proposed (25). Although careful comparative research and cost-efficacy evaluations were planned and will eventually be initiated, the gravity of the problem in Russia and the former Soviet Union has led to greater pressure for prompt and effective action. By the close of 1998, the WHO began to constitute “DOTS-Plus teams,” which were to form part of a broader “Stop-TB Initiative.” In early 1999, the WHO formally announced the establishment of a working group to plan the implementation of pilot DOTS-Plus interventions. A. Models of DOTS-Plus

Two basic approaches to DOTS-Plus have been proposed: individualized treatment regimens (ITRs) and standardized regimens incorporating secondand third-line drugs. The strengths and weaknesses of each of these approaches are compared in Table 2. The first approach—in which ITRs are designed according to the resistance pattern of the strain infecting each patient—has already been piloted in Peru and is discussed in the following section. Its advantages are that ITRs are unlikely to fail because of unappreciated resistance to medications in the treatment regimen, since only drugs to which a patient’s Table 2

Attributes of DOTS-Plus Models

Attribute Maximum Cost Risk of amplification Toxicity Technical capacity required

ITRs

Standardized

Very high High Very low Moderate High

Moderate–high Moderate–high Low–moderate Moderate Moderate

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strain is susceptible are incorporated into the definitive treatment regimen. Amplification of drug resistance is thus a less likely sequela of ITRs since clinicians are aware of each patient’s drug-susceptibility pattern and inadvertent monotherapy is unlikely to occur. Indeed, there is every reason to believe that if all doses are supervised, ITRs will yield higher rates of treatment success than will standardized regimens. ITRs do have drawbacks, however. They require labor-intensive laboratory testing, multiple adjustments of each patient’s treatment regimen, and nonstandardized dosing. These features of ITRs render them more expensive and less straightforward than fully standardized regimens. Two standardized approaches to MDRTB may be envisioned. One would be “uniform” across settings throughout the world: if patients failing DOTS are presumed to have MDRTB, then a preestablished empiric retreatment regimen that does not rely on first-line drugs may be used to treat such failures. Standardized MDRTB regimens may also be adapted to local epidemiology by relying on population surveillance data. In this case, regimens would be designed and administered according to common resistance patterns identified in a given population. In both cases, individual patients with strains susceptible to powerful first-line drugs may be inadvertently deprived of them. In either case, advantages include lower cost, since laboratory work is not required for each patient, and greater ease of administration and management, since all patients receive standardized doses of the same drugs. Thus the demand for technical expertise is less when using standardized retreatment regimens. The Peruvian National TB Programme is currently piloting a standardized MDRTB treatment regimen in urban Lima. Definitive results of this 18-month treatment protocol have not yet been published. Toxicity of second-line drugs is considerable, although our own experience in Peru suggests that serious adverse effects are much less common than was previously believed (26). In terms of toxicity, there would be little difference between ITRs and standard DOTS-Plus regimens, since similar formularies are required. B. Controversies About DOTS-Plus

There have been three chief objections to the treatment of MDRTB: that it is expensive, drawing resources away from the treatment of pan-susceptible disease; that it is technically difficult and yields low cure rates; and that treatment of drugresistant strains, when improperly monitored, gives rise to even more resistant organisms. Other claims include those about decreased virulence and transmissibility of MDRTB strains. Each of these claims is open to critique. Although the treatment cost of a known MDRTB case is greater than that of a known pan-susceptible case, this observation is incorrectly applied to the treatment and, by extension, to the prevention costs of tuberculosis cases in general. If the drug-resistance pattern is un-

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known, the cost is not predictable. Available cost-effectiveness data do not address this specific question, and empiric data suggest that ineffective treatment of MDRTB may increase the costs of tuberculosis treatment and prevention in the longer run (22). In fact, many involved in advocacy for DOTS-Plus programs have argued that new resources must be brought to TB control in general and that the threat of MDRTB can serve as a means of bringing previously untapped public and private resources to TB control (16a). This proved true, certainly, of the outbreak of MDRTB in New York City (28). Moreover, the specter of amplified resistance and of a growing proportion of drug-resistant TB exhorts us to act now before the costs of treating MDRTB increase even more dramatically. Figure 2 illustrates the cost of treating two-, four-, and five-drug resistant TB at 1998 prices. Other means by which costs may be decreased are discussed below. III. Making DOTS-Plus Work: A Case Study Although DOTS-Plus may take more than one form, participants in the consultations mentioned above agreed that such initiatives should ideally be implemented

Figure 2 Cost for 18-month regimen for the treatment of 2-, 4-, and 5-drug–resistant TB (6 months for the injectable).

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as part of a DOTS-based national TB program. Accordingly, a collaboration among the Harvard Medical School, Partners In Health (a U.S.-based, TB-focused nongovernmental organization) and the Peruvian National Tuberculosis Program has played a central role in the elaboration of strategies to respond to the rising tide of resistance to antituberculous drugs.

A. Epidemiology of Drug Resistance in Northern Lima, Peru

The epidemiology of TB in Peru, and of resistance to antituberculous drugs there, is well characterized. In 1984, Hopewell and colleagues estimated the overall rate of success in treating 2510 Peruvian patients diagnosed in 1980 at only 47%, due largely to the fact that 41% of patients failed to complete more than 10 months of treatment. But even among those who completed more than 10 months of fully supervised therapy, greater than 21% experienced treatment failure, relapse, or death. The authors concluded that these unfavorable outcomes among the treated were the result of “many years of poor chemotherapy resulting in a high prevalence of patients with drug-resistant organisms” (29). In 1985, the same team evaluated outcomes in 2669 TB cases diagnosed in 1981. Again, success rates were low: only 70% of those receiving an 8-month and 53% of those receiving a 12month regimen were presumed to be cured by bacteriological or clinical criteria. Since rates of cure were higher in Lima, where the 8-month regimen was more commonly used, the study also compared outcomes within the city and found that, “in patients who did not abandon treatment, the major determinant of outcome was whether or not there had been prior treatment rather than the current treatment regimen employed” (30). Although much of the resistance was presumed to be acquired, the report also cited a study of tubercle bacilli isolated from 83 consecutive previously untreated young patients from Lima; 25% of them were found to have primary drug resistance (31). Both studies led the authors to conclude that the degree of resistance in Peru was significant and should figure in decisions regarding national TB policy. Peru still has high rates of TB, with incidence estimated at 161.5 cases per 100,000 population in 1996 (32), but a great deal has happened in the decade since Hopewell and colleagues presented their overview of the Peruvian experience. Following WHO guidelines, in 1991 the government of Peru reorganized its NTP. In subsequent years, the program can point to significantly increased rates of therapy completion, in large part because of the adoption of DOTS. Furthermore, the NTP has recently increased access to TB services in previously underserved regions of the country. But what happened to the “treatment failures” described by Hopewell and colleagues in 1985? Many have no doubt died. But many others, it is clear,

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became persistent sources of infection with drug-resistant bacilli: approximately 50% of the patients who abandoned treatment were defined as having positive sputum at the time of abandonment. In our experience in three of the poorer districts of northern Lima, cases of suspected drug-resistant disease (patients persistently smear-positive throughout DOTS) have been reported from almost all area health centers. Of 160 DOTS “treatment failures” referred to our laboratory, 93.8% of patients (150) were documented to have strains of M. tuberculosis resistant to at least HR (16). Furthermore, most of these patients had long had culture-confirmed MDRTB, even though none was receiving effective therapy. In fact, many continued to receive first-line drugs to which their isolates had demonstrated resistance; several had been prescribed “INH for life.” Nosocomial spread likely continues apace: 10% of our patients are former health-care workers. Culture and susceptibility testing of specimens from these patients have confirmed resistance, most often to all four first-line drugs, and has also revealed resistance, in certain patients, to ethionamide, kanamycin, the fluoroquinolones, and even capreomycin (34). Even with passive case finding, we have discovered that prevalence of active MDRTB is at least 30 cases per 100,000 population in the district. As prevalence of TB is estimated at about 300 per 100,000 for the district, cases of active MDRTB accounted for about 10% of all TB cases in 1995. Finally, the amplifier effect of SCC would seem to be having significant adverse impact: while resistance to H and R is the predominant pattern in the group of previously treated patients in a 1995 national sample, the most common resistance pattern found in isolates in a group of northern Lima patients who had been identified as DOTS failures was resistance to RHEZ—precisely those medications used in Peru’s DOTS program (16). The northern Lima epidemic has been felt beyond Peruvian borders as well: cases of TB resistant to all first-line drugs, all acquired in Lima’s northern cone, have recently been reported in Boston, suburban New York, and Puerto Rico. MDRTB appears to be a problem in other poor areas of Lima. Gilman and coworkers recently reported that, of the isolates obtained from 109 hospitalized patients with TB at one hospital in central Lima, 29% demonstrated resistance to at least two drugs, with 13% resistant to H and R (35). Other sampling methods confirm the impression of significant rates of drug-resistant TB in Peru. In a WHO study of 10 Latin American countries, the highest levels of drug resistance were from a cluster in Peru: fully 54.5% of samples from Callao, Lima’s port, exhibited resistance to at least one drug (36). The Peruvian NTP recently reported that, among a sample of 1500 patients who had never been treated for TB, 15.4% had isolates demonstrating primary resistance to at least one first-line drug, while 2.4% had isolates demonstrating resistance to both H and R. Among 458 patients previously treated for TB, 36.0% had isolates resistant to at least one antituberculous drug, and 15.7% had isolates resistant to both H and R (37).

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The DOTS-Plus initiative in Lima was the result of a collaboration between the NTP and other MOH offices in northern Lima, the Massachusetts State Laboratory Institute, and the Harvard/Partners team (see Fig. 3). Although the project was initially slated to serve one neighborhood of northern Lima, it has since expanded to serve three districts with a total population estimated at 757,000 inhabitants (38). The Lima DOTS-Plus effort is community-based, which has meant that it relies most heavily on community health workers who deliver treatment in patients’ homes (39). This not only reduces costs, but also helps to prevent nosocomial transmission, which often occurs when TB patients are hospitalized. The treatment strategy used in the Lima project includes ITRs for all patients. Since MDRTB treatment failure has usually been attributed to using too few drugs for too short a time at too low doses, the Lima patients receive aggressive, multidrug therapy for 18–24 months. Dosing, with a minimum of five drugs, is generally at the high end of recommended ranges. Each regimen includes a parenteral antimycobacterial agent, which is administered until at least 6 consecutive months of smear- and culture-negativity are documented. Patients undergo regular bacteriologic, radiographic, and clinical monitoring. All doses of medication are directly observed—in the home while the patients remain smear-positive and in health centers after conversion.

Figure 3

Schematic of an effective DOTS-Plus initiative.

Introducing DOTS-Plus 1%

459 7%

7%

1%

84% cured or culture-negative failed died

culture-positive abandoned

Figure 4 Preliminary results of community-based ITRs in MDRTB patients receiving 4 months or more of ITR between August 1996 and September 1999.

At the outset of treatment, empiric regimens are designed by a consulting international TB clinician-specialist, based on suspected resistance patterns, and adjusted to reflect confirmed results of susceptibility testing. Drugs to which the strain demonstrates in vitro resistance are discontinued; first-line drugs that have not been included in the empiric ITR but to which the strain demonstrates in vitro susceptibility are added to the ITR. Thus, all drugs used in the definitive regimen are those to which the individual’s infecting strain has demonstrated susceptibility. Table 3 lists the drugs used in MDRTB treatment, recommended dosing, and commonly encountered toxicities. Collaboration with a supranational reference laboratory was essential to ensure complete drug-susceptibility testing of all M. tuberculosis isolates of those patients referred for evaluation. At this writing, a first cohort of 50 patients with resistance to a mean of five drugs, longstanding disease, and significant parenchymal damage has already received directly observed, individualized therapy with drugs to which their isolates had demonstrated susceptibility. The mean age of the patients is 34 years; 50.8% were male and 49.2% female. Although side effects are universal, most patients tolerate high doses and long durations of even the more toxic second-line drugs. Preliminary outcomes among 74 patients who have received at least 4 months of therapy are heartening. All patients who received appropriate treatment for at least 2 months smear-converted; the average length of time for smear-positive patients to convert is 1.6 months. Only five patients abandoned therapy, and nearly 85% remain smear- and culture-negative as they reach the end of protracted courses of therapy (see Fig. 4) (40). We conclude that community-based MDRTB treatment is feasible and less costly than hospital-based therapy; it is also a means by which nosocomial transmission may be reduced. During the first 24 months of the Lima DOTS-Plus initiative, 643 person-months of smear- and culture-negativity were achieved among patients who initiated treatment with smear- and culture-positive MDRTB. If, as Styblo has suggested (41), a patient with active pul-

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Nicotinic acid hydrazide. Bactericidal. Inhibits mycolic acid synthesis most effectively in dividing cells. Hepatically metabolized.

Aminoglycoside. Bactericidal.

Aminoglycoside. Bactericidal. Inhibits protein synthesis through disruption of ribosomal function. Less effective in acid, intracellular environment. Renally excreted.

Bacteriostatic. Hepatic acetylation, renally excreted.

Likely bactericidal. DNA-gyrase inhibitor. Levofloxacin appears to be active moiety, and may well be the drug of choice. Not FDA-approved for use during pregnancy—associated with arthropathies in studies with immature animals. Renally excreted. Crossresistance among fluoroquinolones thought to be near complete.

Amikacin

Kanamycin

para-Aminosalicylic acid

Fluoroquinolones: Ciprofloxacin Sparfloxacin Ofloxacin Levofloxacin

Description

Ciprofloxacin: 750 mg PO BID Sparfloxacin: 200 mg PO BID Ofloxacin: 400 mg PO BID Levofloxacin: 500 mg PO QD Adjust doses for creatinine clearance
50 mL/min.

4 g PO TID Delayed-release granules should be administered with acidic food or drink.

1 g IM QD

15 mg/kg IM or IV QD Adjust for renal insufficiency

High dose: 15 mg/kg PO 2/wk (in patients with demonstrated in vitro susceptibility to INH at 5.0  cg) Administer with pyridoxine 150 mg QD.

Administration

Chemotherapeutic Agents Used in the Treatment of Multidrug-Resistant Tuberculosis

Isoniazid (high dose)

Drug name

Table 3

Well tolerated, well absorbed. Occasionally, GI upset, dizziness, hypersensitivity. Has been associated with seizures in MDRTB patients receiving multiple drugs with CNS side effects. Prolong half-life of theophylline. Antacids with Al, Mg, CaSO4 or FeSO4 may inhibit GI absorption of quinolones. Sparfloxacin may cause a photosensitivy reaction in up to 8%; also should not be used in persons receiving any drug that prolongs the Q-T interval. Ofloxacin may cause a mild transaminitis.

Adverse effects in 10%. GI upset (nausea, vomiting, diarrhea), hypersensitivity in 5–10% of patients; rarely, hepatitis.

Ototoxicity and nephrotoxicity dose-related (both cumulative and peak concentrations), increased risk with renal insufficiency. Pain at injection site.

Ototoxicity and nephrotoxicity dose-related (both cumulative and peak concentrations), increased risk with renal insufficiency. Pain at injection site.

Adverse reactions 5.4%. Most commonly, rash (2%), fever (1.2%), jaundice (0.6%), peripheral neuritis (0.2%). Anemia, agranulocytosis, thrombocytopenia, eosinophilia, optic neuritis, positive ANA, vasculitis, and hypersensitivity have all been reported. Interacts with phenytoin.

Side effects

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Rifabutin/Rifapentine

Clofazimine

Clarithromycin

Amoxicillin-clavulanate

Ethionamide Prothionamide

Cycloserine

Capreomycin

Rifamycin spiropiperidyl derivative. Cross-

Substituted iminophenazine bright-red dye. Bacteriostatic. Transcription inhibition by binding guanine residues of mycobacterial DNA.

Semisynthetic erythromycin derivative. Efficacy shown against M. avium complex. In vitro killing of susceptible strains of M. tuberculosis.

Beta-lactam antibiotic with a betalactamase inhibitor.

Derivative of isonicotinic acid. Bacteriostatic. Cross-resistance with thiacetazone occurs. Hepatically metabolized, renally excreted.

Alanine analogue. Bacteriostatic. Interferes with cell-wall proteoglycan synthesis. Renally excreted.

Polypeptide isolated from Streptomyces capreolus. Renally excreted. Varying degrees of cross-resistance reported between KM and CM; no crossresistance reported between SM and CM. Frequent cross-resistance between viomycin and CM.

GI upset (nausea, vomiting, abdominal pain, loss of appetite) and metallic taste in mouth common. May cause hypothyroidism when taken with PAS. Rarely, hepatitis, arthralgias, impotence, gynecomastia, photosensitive dermatitis. GI upset. Administer with food. Hypersensitivity reactions. Well tolerated. GI side effects (abdominal pain, diarrhea, abnormal taste) less common than with erythromycin. Ototoxicity extremely rare. May cause metallic taste. Discoloration of skin, GI upset, and crystal deposition causing discoloration of the eye. Less commonly, phototoxicity reactions, malabsorption, and severe abdominal distress.

750–1000 mg PO QD Increase gradually to maximum dose.

500 mg PO TID

500 mg PO BID

200–300 mg PO QD Initiate dose at 300 mg; may lower to 200 mg when skin begins to bronze.

Considered to be of comparable or lesser toxicity as R. Hepatotoxicity, GI upset, hypersensitivity.

Neurological and psychiatric disturbances, including psychosis, convulsions, peripheral neuropathy, especially when taken with isoniazid. These adverse reactions may be lessened by pyridoxine coadministration. Interacts with phenytoin. Effects may be potentiated by alcohol.

750–1000 mg PO QD Administer with pyridoxine 150–300 mg QD.

150–300 mg PO QD

Ototoxicity and nephrotoxicity dose related (both cumulative and peak concentrations). Increased risk with renal insufficiency. Pain at injection site. Rarely, electrolyte abnormalities, eosinophilia, hypersensitivity, neuromuscular blockade.

1 g IM QD Adjust for renal insufficiency.

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monary TB infects on average 11 patients per person-year of infectiousness, then 590 new infections with MDRTB were averted during the first 24 months of the project’s operations. The Lima DOTS-Plus initiative has also resulted in enhanced community capacity to respond to threats to the community’s health (42). One of the hidden benefits of DOTS-Plus has been a process of community-capacity building. Training previously unemployed community members to respond to this epidemic has had “surplus value” in many other arenas—from education to primary health care—and has helped to promote cooperation between NGOs, community-based organizations, and public health authorities. Previously unemployed young people have found jobs as community-health workers and received extensive training in tuberculosis prevention, detection, and management—in skills ranging from administering parenteral drugs to identifying symptoms of disease, understanding drug-susceptibility reports, to advocating for and counseling patients. These developments stand all participants—and, ultimately, all community residents—in good stead to defend against future assaults on health and well-being. IV. Pitfalls in the Planning and Execution of DOTS-Plus Programs Any pilot project has strengths and limitations, and those of the Lima DOTS-Plus effort have yet to be fully assessed. Some of the issues meriting careful analysis are noted in Table 4. Although some have argued that DOTS-Plus efforts should not rely on resources from abroad, we believe that the concentration of TB-control resources in precisely those regions with low levels of TB argues for transnational collaboration of the sort that made the Lima DOTS-Plus initiative possible (43). Table 4

Strengths and Limitations of Lima DOTS-Plus Pilot Project

Strengths High efficacy Uses local resources Public–private initiative Builds community capacity Population-based Detailed documentation Under the aegis of the National Tuberculosis Programme

Limitations High cost Requires international laboratory and drug-supply effort Demands elaborate coordination and power sharing Most appropriate for small outbreaks National coverage and treatment in rural populations pose greater logistical problems Documentation requires significant technical training Any NTP weaknesses could impact DOTS-Plus initiative

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A. Clinical Pitfalls

When patients with MDRTB fail to respond to appropriate treatment, the reason is usually failure to treat in a timely fashion. In our cohort, more than half of previous failures occurred in patients with evidence of the amplifier effect: failures were also most likely to occur in patients with longstanding disease and significant parenchymal destruction. These conditions seemed to be more predictive of poor outcomes than was the number of drugs to which a patient’s isolate was resistant. Other causes of treatment failure include failure of DOT, failure to manage side effects, and failure to provide social and psychological support. Numerous socioeconomic factors also shape a patient’s likelihood of continuing, and responding to, therapy. In the Lima effort, community health workers were responsible for ensuring full adherence with therapy and also for responding to social and other problems. Interventions include: • Subsidy of transportation costs • Scheduling of appointments and tests at hours appropriate to patients’ work and family commitments • Availability of free medical consultations, laboratory and radiology services • Provision of supplies such as syringes, needles, and drugs to control side effects under the supervision of clinical staff • Nutritional assistance B. Laboratory Pitfalls

The difficulty of susceptibility testing has been much commented upon (38,44,45). We have argued that, given the low prevalence of TB in precisely those settings with the best TB labs, transnational TB collaboration is warranted (43) (see Chaps. 4 and 7). Given the difficulties in drug-susceptibility testing, collaboration with a supranational reference laboratory helps to ensure that the most reliable data are made available to the DOTS-Plus team. For example, sample-tosample discrepancies in susceptibility testing are a source of frustration for patients and providers alike and should be anticipated (16). Cross-contamination in the laboratory during the inoculation of patient specimens is problematic even in laboratories with sophisticated biological safety cabinets and air-handling systems. The existence of high positivity rates of specimens and of individual specimens with high concentrations of viable organisms is associated with occasional cross-contamination, which can occur more frequently in labs without technologically advanced air-flow systems. Also problematic is the slow turnaround time inherent in drug-susceptibility testing. The development of rapid screening tests for rifampin resistance will make more rapid triage of MDRTB cases possible, thereby averting another significant pitfall: the slow pace at which clinically significant information becomes available.

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Farmer et al. C. Financing Pitfalls

As noted above, one of the chief arguments against MDRTB treatment is that it is too expensive. Indeed, costs of treatment are often high and in hospital settings in the United States have exceeded $100,000 per patient (46,47). But we have found several ways of substantially reducing cost. As noted, community-based treatment is often orders of magnitude less expensive than hospital-based treatment. Second, the cost of medication is the major expense, and the cost of second-line drugs varies widely, as Figures 5 and 6 suggest. For illustrative purposes, let’s consider the case of capreomycin, a cornerstone of our treatment program in Peru because of the extent of first-line resistance in that community. A 6-month supply of capreomycin, off-patent for several years, can be purchased from Eli Lilly and Company for as much as $4,140 or for as little as $1,518. This variability, it seems, has little to do with the actual cost of the drug, but much to do with the negotiating strategies and leverage of groups working in different locations to obtain medicines from the manufacturers. Moreover, the true demand for MDRTB drugs is not felt by the pharmaceutical industry, in large part because those ill with the disease are generally not able to pay for the drugs at current prices. A global, coordinated approach, one in which a central

Figure 5

Drug cost comparison—second-line antituberculous drugs.

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Figure 6

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Cost comparison—capreomycin (1 g/day).

MDRTB authority would help supply NTPs with second-line drugs, would lead to the emergence of economies of scale that could lower drug prices dramatically.* D. Epidemiological Pitfalls

Among the epidemiological pitfalls mentioned, unopposed transmission of highly resistant strains would seem to be the greatest: in the Lima cohort our outbreak investigation shows that many families have been “saturated” with MDR strains due to delays in instituting effective treatment. Furthermore, the amplifier effect of short-course chemotherapy has proven a major blow to all efforts to treat patients with MDRTB: repeated courses of empiric treatment have not only wasted resources that might have been best used elsewhere, but have allowed increasingly resistant strains to destroy more and more lung parenchyma in individual patients and, for these patients to infect many others.

*Previous efforts to lower the prices of second-line drugs—by the IUATLD, for example— were disappointing. For an overview of the pitfalls facing those who would finance such efforts, see Ref. 48.

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Farmer et al. V. Conclusions: DOTS-Plus, We Can’t Afford Not to Try It

The best way to work towards elimination of TB is to treat effectively all cases of active disease. If DOTS had been introduced at mid-century before the advent of MDRTB, surely it would have sufficed as the single strategy necessary to stop TB through universal treatment of all patients with active disease. In fact, a 1993 editorial in the New England Journal of Medicine, “Directly observed treatment of tuberculosis—we can’t afford not to try it,” sounded the alarm on the risk, even at that late date, of not implementing directly observed therapy (47). If this strategy had been implemented sooner, transmission would have been brought to a halt and the TB situation at the end of this century would have been markedly different. Instead, we live in a time in which a series of MDRTB epidemics are progressing, unchallenged as yet by any coherent strategy. Only DOTS-Plus can respond to complex epidemics in which both drug-susceptible and drug-resistant disease account for disease and new infections; only DOTS-Plus incorporates the managerial advances of DOTS while at the same time affording new strategies that can stop MDRTB transmission. That is, DOTS-Plus should incorporate strict DOT, standardized case finding and reporting, and many of the financing and supply advantages of DOTS. DOTS-Plus builds on all the strengths of DOTS, incorporating its basic components except one: it does not rely solely on fixed-dose, short-course chemotherapy. In conclusion, we argue that where MDRTB causes significant morbidity and mortality, DOTS-Plus strategies can be incorporated into NTPs already committed to DOTS. Both strategies require political commitment at the highest national level and, at times, at supranational levels. DOTSPlus projects are likely to rely on transnational collaboration, in some settings for clinical and laboratory support and in others for financing and drug supply. There is no doubt that such projects are difficult and costly. But effective DOTS-Plus programs will require a consistent supply of high-quality second- and third-line antituberculous drugs. Aggressive advocacy for all patients sick with TB—regardless of drug-susceptibility patterns—is tantamount to striking a blow for equity and universal treatment as the primary goal of modern public health. References 1. McKeown T, Record RG. Reasons for the decline of mortality in England and Wales during the nineteenth century. Popul Stud 1962; xvi:94–122. 2. Dubos R, Dubos J. The White Plague: Tuberculosis, Man, and Society. New Brunswick, NJ: Rutgers University Press, 1992. 3. Farmer P, Nardell N. Editorial: nihilism and pragmatism in tuberculosis control. Am J Public Health 1998; 88(7):1014–1015.

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4. Bates B. Bargaining for Life: A Social History of Tuberculosis, 1876–1938. Philadelphia: University of Pennsylvania Press, 1992. 5. Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Against Tuberc 1962; 2(2):643. 6. Murray C, Lopez A. The Global Burden of Disease. Cambridge, MA: Harvard School of Public Health, 1996. 7. Farmer PE. Social scientists and the new tuberculosis. Soc Sci Med 1997; 44(3):347–358. 8. Farmer PE, Robin S, Ramilus SL, Kim JY. Tuberculosis, poverty, and “compliance”: lessons from rural Haiti. Sem Respir Infect 1991; 6(4):254–260. 9. Farmer PE. Infections and Inequalities: The Modern Plagues. Berkeley: University of California Press, 1998. 10. Steenken W Jr. Streptomycin and the tubercle bacillus. In: Riggins and Hinshaw, eds. Streptomycin and Dihydrostreptomycin in Pulmonary Tuberculosis. New York: National Tuberculosis Association, 1949. 11. Florey ME. The Clinical Application of Antibiotics. Vol II. Streptomycin and Other Antibiotics Active Against Tuberculosis. London: Oxford University Press, 1961. 12. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council Investigation. Br Med J 1948; 2:769–782. 13. Long ER. The Chemotherapy of Tuberculosis. Baltimore, MD: Williams & Wilkins Co, 1958. 14. Merck & Co. Chemotherapy of Tuberculosis. 1950. 15. Crofton J, Chaulet P, Maher D. Guidelines for the Management of Drug-Resistant Tuberculosis. Geneva: World Health Organization, 1997. 16. Becerra MC, Freeman J, Bayona J, Shin SS, Furin OJ, Kim JY, Werner B, Timperi R, Sloutsky A, Wilson ME, Pagano M, Farmer PE. Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 1999b. In press. 16a. Farmer P, Bayona J, Becerra M et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 1998; 2(11):869–878. 17. Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing “DOTS-Plus.” BMJ 1998; 317:671–674. 18. Manalo F, Tan F, Sbarbaro JA, Iseman MD. Community-based short-course treatment of pulmonary tuberculosis in a developing nation: initial report of an eightmonth, largely intermittent regimen in a population with a high prevalence of drug resistance. Am Rev Respir Dis 1990; 142:1301–1305. 19. Shimao T. Drug resistance in tuberculosis control. Tubercle 1987; 68(suppl):5–15. 19a. Klaudt K. Use DOTS more widely. TB Treatment/Observer, March 24, 1997; 4(2):2. 20. Schluger NW, Harkin TJ, Rom WN. Principles in therapy of tuberculosis in the modern era. In: Rom WN, Garay SM, eds. Tuberculosis. New York: Little, Brown and Company, 1996:751–762. 21. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329:784–791. 22. Heifets LB. Antimycobacterial drugs. Semi Respir Infect 1994; 9(2):84–103. 23. Centers for Disease Control and Prevention. Primary multidrug resistant tuberculosis—Ivanovo Oblast, Russia, 1999. MMWR 1999; 48(30):661–664.

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23a. WHO/IUATLD. Anti-tuberculosis Drug Resistance in the World. Geneva: WHO, 1997. 24. Kimerling ME, Kluge H, Vezhnina N, et al. Inadequacy of the current WHO re-treatment regimen in Russia: MDRTB in a central Siberian prison. Int J Tuberc Lung Dis 1999; 3(5):451–453. 25. Espinal M, ed. Report on Multidrug Resistant Tuberculosis: Basis for the Development of an Evidence-Based Case-Management Strategy for MDR TB within the WHO’s DOTS Strategy. Proceedings of 1998 Meetings and Protocol Recommendations. Geneva: World Health Organization, 1999. 26. Furin J, Becerra MC, Shin SS, Kim JY, Bayona J, Farmer PE. Amplifying resistance? The effect of short-course, empiric regimens in individuals infected with drug-resistant strains of Mycobacterium tuberculosis: a case report. Working Paper No. 6, Boston, MA: Program in Infectious Disease and Social Change, 1999. 27. Brewer TF, Heymann SJ, Ettling M. An effectiveness and cost-analysis of presumptive treatment for Mycobacterium tuberculosis. Am J Infect Control 1998; 26(3):232–238. 28. Frieden TR, Fujiwara P, Washko R, Hamburg M. Tuberculosis in New York City— turning the tide. N Engl J Med 1995; 333(4):229–233. 29. Hopewell PC, Sanchez-Hernandez M, Baron RB, Ganter B. Operational evaluation of treatment for tuberculosis. Results of a “standard” 12-month regimen in Peru. Am Rev Respir Dis 1984; 29(3):439–443. 30. Hopewell PC, Ganter B, Baron RB, Sanchez-Hernandez M. Operational evaluation of treatment for tuberculosis. Results of 8- and 12-month regimens in Peru. Am Rev Respir Dis 1985; 132(4):737–741. 31. Black W, Ganter B, Grzybowski S, Sanchez-Hernandez M, Hopewell P. Prevalence of initial bacillary resistance to antituberculous drugs in Peruvian patients with newly-discovered tuberculosis [abst]. Am Rev Respir Dis 1985; 131(suppl): A225. 32. Ministerio de Salud. Programa Nacional de Control de la Tuberculosis. Tuberculosis en el Perú Informe 1996. Lima, Perú: Ministerio de Salud, 1997. 34. Farmer PE, Bayona J, Becerra M, et al. The emergence of MDRTB in urban Peru: A population-based study using conventional, molecular, and ethnographic methods. Int J Tuberc Lung Dis 1997; 1(Suppl 1):S44. 35. Gilman RH. Lecture delivered at IX National Congress of Internal Medicine, Lima, Peru, 1996. 36. Laszlo A, de Kantor IN. A random sample survey of initial drug resistance among tuberculosis cases in Latin America. Bull WHO 1994; 72(4):603–610. 37. Ministerio de Salud, Programa Nacional de Control de Enfermedades Transmisibles—Control de la Tuberculosis. Vigilancia de la resistencia a los medicamentos antituberculosos en el Perú, 1995–1996. Lima, Perú: Ministerio de Salud, 1996. 38. Webb R, Fernandez-Baca G. Peru en Numeros 1997: Anuario Estadistico. Lima, Peru: Cuanto S.A, 1997. 39. Farmer PE, Bayona J, Becerra M, et al. Poverty, Inequality, and Drug Resistance: Meeting Community Needs. Proceedings of the International Union Against Tuberculosis and Lung Disease North American Region Conference 1997, Feb 27-Mar 2, pp. 88–102.

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18 Treatment of Latent Tuberculosis Infection

DAVID L. COHN

WAFAA M. EL-SADR

University of Colorado Health Sciences Center and Denver Public Health Denver, Colorado

Columbia University College of Physicians and Surgeons and Harlem Hospital Center New York, New York

I. Introduction In the context of tuberculosis (TB) control, the term preventive therapy is a misnomer in that in most circumstances, preventive therapy should be considered as “early treatment” or “secondary prevention.” Preventive therapy refers to the treatment of patients who are known or likely to be infected with Mycobacterium tuberculosis, but without active disease, with a simple regimen (usually isoniazid), with the intention of preventing TB in the future. Hence, the terminology “treatment of latent tuberculosis infection” has recently been adopted rather than “preventive therapy” to better and more specifically describe this strategy. Both terms will be used in the text that follows. On a global scale, treatment of latent tuberculosis infection (LTBI) is a relatively uncommon TB-control strategy, being implemented much less frequently than treatment of disease (see Chap. 16) or the use of BCG vaccination (see Chap. 19). In developing countries with limited resources, the highest priority of control programs is case detection (see Chap. 13) and treatment of active cases, both to decrease morbidity and mortality and to prevent secondary transmission to others (1). However, in industrialized countries, especially in the United States and Canada, preventive therapy is an important and effective component of TB-con471

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trol programs and is usually offered to recent contacts of active cases, recent tuberculin skin test converters, patients with abnormal chest x-rays and inactive disease, and selected patient populations considered at high risk for TB (2). The global HIV pandemic and its effect on the incidence of TB in most countries of the world has rekindled interest in treatment of LTBI as a potential TB-control strategy in developing countries (3,4). Several recently conducted controlled trials have demonstrated the efficacy of different convenient regimens in preventing TB, and other ongoing studies are evaluating feasibility and cost-effectiveness of such strategies. The first section of this chapter includes a review of older studies of preventive therapy that were largely conducted in immunocompetent populations. In subsequent sections, more recent studies in HIV-infected persons as well as preventive therapy in other populations are discussed. Current recommendations for the treatment of LTBI in these groups are also presented. Finally, we conclude with a discussion of future directions for the treatment of LTBI. II. Treatment of Latent Tuberculosis Infection in Immunocompetent Hosts A. Review of Studies: Efficacy

In the 1960s preventive therapy with isoniazid became an accepted component of medical practice and of TB-control programs in the United States. This was based on multiple studies conducted in the United States and worldwide, which provided the evidence for efficacy of isoniazid in preventive therapy in diverse populations. Several studies were conducted among individuals with presumed recent acquisition of infection, including contacts of TB cases and residents of communities with high rates of TB. Other studies included individuals with remote or longstanding infections, including residents of mental institutions and individuals with chest radiographic evidence of inactive lesions. Thus, the studies assessed the efficacy of isoniazid preventive therapy (IPT) in the prevention of disease among those with both recent and long-standing infection. Studies Among Contacts of TB Cases

Several studies in the late 1950s and early 1960s were conducted among contacts of active cases of TB in recognition of this group’s high risk of infection and for the development of disease (Table 1). In the largest of these studies, the U.S. Public Health Service (USPHS) sponsored a trial in the United States, Puerto Rico, and Mexico, which enrolled over 25,000 contacts of new TB cases (irrespective of skin test reactivity) (5). The participants were randomized to isoniazid (5 mg/kg/day) versus placebo for one year duration of therapy. The study demonstrated a 60% reduction in the rates of development of TB. In addition, the study

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showed that untreated contacts were at highest risk during the year after the diagnosis of the source case and that the efficacy of isoniazid was not affected by age of the participants. Other studies were conducted among contacts of TB cases in Japan, Kenya, the Philippines, and the Netherlands (6–9). With the exception of the study conducted in Japan, all of these studies demonstrated a protective effect associated with IPT (range 40–92%). Some have speculated that rapid acetylator status among the participants in the study conducted in Japan may have explained why no benefit was demonstrated. However, another study conducted among Japanese railway workers demonstrated a significant benefit with the use of IPT, showing a 62% reduction (10). Community Studies

Another target group for preventive therapy were residents of communities with high rates of TB. Three such studies were conducted in Alaska, Greenland, and Tunisia in settings where the high rates of TB defined almost all community members at risk due to the high likelihood of contact with an active case. The study populations in Alaska and Greenland were similar in that the communities were remote and isolated for a significant proportion of the year. The rate of TB in Greenland was, however, significantly higher than that in Alaska. In the Bethel region of Alaska, 6275 participants from 30 communities were enrolled in a study of IPT (11). The study demonstrated a 59% reduction in rates of TB among the participants who received isoniazid. In long-term follow-up, the greatest benefit was seen in participants who took more than 70% of the oneyear course of therapy (12). Also, the protection conferred by IPT appeared to be lifelong. In Greenland, a study was initiated in 1956 in which 8081 adults without evidence of active disease were enrolled from various villages (13,14). In contrast to other community studies, this study evaluated a 52-day intermittent regimen given twice-weekly in two 13-week periods. There was a 31% reduction in rates of TB in association with the use of IPT given in this manner. In 1958, a study was initiated in Djebel Lahmar, a poor urban section of Tunis City, an area of high incidence of TB (15). The goal of the study was to enroll all 25,000 community residents without evidence of TB. The study enrolled 15,910 participants who were randomized by household blocks to daily isoniazid or placebo. In this study, isoniazid assays on random urine samples obtained by surprise night visits were conducted and demonstrated erratic pill taking. The study failed to demonstrate a benefit of isoniazid in preventing the development of culture-confirmed TB. However, there was a favorable effect in preventing the development of abnormal chest radiographic findings consistent with TB in the group that received IPT.

474

Contacts of new cases (25,033)

Contacts of cases (2,238)

Contacts of cases (775)

Household contacts (327)

Ferebee (5) United States, Puerto Rico, Mexico 1957–1959/1962

Bush (6) Japan 1957/1968

Egsmose (7) Kenya 1959–1963/1965

Del Castillo (8) Philippines 1961–1965

Study subjects (n)

Endpoints: chest x-ray abnormality

Endpoints: pulmonary lesions

Individual

Family

Drug regimen(s)

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Close Contacts of TB Cases

Unit of randomization/ endpoints

41

100

56

54

30

1.0% 0.7% Nonreactors 10.8% 5.0% Reactors 4.8% 2.1% Pulmonary lesions 9.1 0 2-year follow-up 13.9% 8.2%

60

60

% Reduction

10-year rate per 1000 15.4 6.2 Reactors 26.9 11.1

TB rates

Outcomes

Prospective Randomized Clinical Trials of Preventive Therapy of Tuberculosis in Largely Immunocompetent Populations

Author (Ref.) Location Years of study/ publication

Table 1

Comments

475

Adults without TB (8,081)

Entire suburb Persons without TB (15,910)

Nyboe (15) Tunisia 1958/1963

30 communities (6,275)

Groth-Peterson (13) Greenland 1956/1960 Horowitz (14) 1966

Comstock (11,12) Alaska 1957–1963/1967, 1979

Individual

Railway workers (548)

Chiba (10) Japan 1951–1962/1963

Household

Housing blocks

Village

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

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

Placebo INH for 1 year

Community Trials or Institutions

Individual

Contacts of cases (261)

Veening (9) Netherlands 1960–1964/1968

59

31

26

6-year rate per 1000 82.7 57

Rate per 1000 3.1 2.3

62

92

6-year rate per 1000 46.1 19.0

1.03% 0.39%

7-year follow-up 9.4% 0.8%

(continued)

Random urine checks; poor compliance

476

Study subjects (n)

Mental institutions, reactors and nonreactors (27,924)

Tuberculin skin test positive and fibrotic lung disease, consistent with TB and

Author (Ref.) Location Years of study/ publication

Ferebee (20) United States 1957–1960/1963

IUAT (16) Czechoslovakia, Finland, German Democratic Republic,

Table 1 Continued

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Placebo INH for 1 year

Drug regimen(s)

Individual Placebo INH for 12 wks INH for 24 wks

TB rates

Overall 9.6 3.6 10 mm 12.2 3.9 5–9 mm 8.2 4.7 Abnormal chest x-ray 36.0 18.4 Normal chest x-ray 6.9 2.1

5-year rate per 1000 All assigned participants: 14.3 11.3 5.0

— 21 65

70

49

47

68

62

% Reduction

Outcomes

10-year rate per 1000

Patients with Inactive Lesions on Chest X-Ray

Ward or building

Unit of randomization/ endpoints

Pill calendars given; symptoms of hepatitis monitored; urine test for INH q3 months

Comments

477

stable for prior year (27,830)

Inactive lesions 2/3 prior active TB 1/3 inactive (4,575)

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

Hungary, Poland, Romania, Yugoslavia 1969–1977/1982

Ferebee (17) United States 1960–1964/1970

Katz (18,19) United States 1958–1964/1965 Ward

Individual

Placebo INH for 2 years Placebo INH for 2 years

Placebo INH for 1 year

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

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

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

INH for 52 wks

93.0 76.0 245.0 132.0

6-year rate per 1000

2-year rate per 1000 19.0 7.0

3.6 “Completers-compliers” 15.0 — 10.4 4.7 1.1 Small lesion
2 cm2 11.6 9.2 4.0 4.2 Large lesions 2 cm2 21.3 16.2 7.0 2.4

46

18

63

— 24 67 89

— 20 66 64

31 69 93

75

478

Cohn and El-Sadr Studies in Patients with Inactive Pulmonary Lesions

Patients with prior evidence of pulmonary TB, as reflected by fibrotic lung lesions noted on chest radiographs, also represented an important target population for preventive therapy studies. These individuals were thought to have longstanding TB infection in contrast to those with recently acquired infection as described above. The largest preventive study conducted to date was sponsored by the International Union Against Tuberculosis (IUAT), which evaluated the efficacy of IPT among individuals who were tuberculin skin test positive and had inactive fibrotic lung lesions (16). This study enrolled 27,830 participants from Czechoslovakia, Finland, the German Democratic Republic, Hungary, Poland, Romania, and Yugoslavia. This placebo-controlled trial had several unique characteristics including the evaluation of different durations of preventive therapy, i.e., 12, 24, and 52 weeks of daily IPT, and stratification based on chest x-ray findings. In addition, participants were provided with reminder calendars and their urine was tested for isoniazid every 3 months. The IUAT study demonstrated that IPT given for 52 weeks resulted in a 75% reduction of confirmed TB and a 65% reduction with 24 weeks, but only a 21% reduction with 12 weeks of IPT, compared with placebo. Of note, in patients who were designated as “completer-compliers” (at least 80% compliance during each month of the regimen), reduction of TB was 93% in those who received 52 weeks, 69% for 24 weeks, and 31% for 12 weeks, compared with placebo. In the subgroup of patients with fibrotic lesions greater than 2 cm, 52 weeks of therapy (88% reduction) was superior to 26 weeks (67% reduction). However, in patients with small lesions on chest radiography, therapy for 52 weeks (64% reduction) and for 26 weeks (66% reduction) was similar. The study also demonstrated that two thirds of cases of hepatitis occurred during the first 24 weeks of therapy. This finding suggested that one third of cases of hepatitis may be avoided by prescribing 24 weeks rather than 52 weeks of IPT. In another study among 4575 patients with inactive pulmonary lesions conducted in the United States, IPT for one year was associated with a 63% reduction in TB rates over 5 years (17). If patients took at least 80% of their medications for 10–12 months, there was a 68% reduction in TB, compared to a 23% reduction in those who took 7–9 months. Finally, in a smaller study conducted at the Hudson River Hospital, which evaluated IPT given for 2 years among 513 patients with mental illness and fibrotic lung disease, there was only an 18% reduction in rates of TB over 6 years of follow-up (18,19). However, IPT was more effective in the group of patients known to have previously had active disease, demonstrating a 46% reduction. Studies Among Patients with Likely Remote Infection

The efficacy of IPT in the prevention of TB among individuals with remote infection was investigated as well. In the late 1950s, a study was initiated among

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27,924 residents of 37 mental hospitals in the United States (20). These individuals were most likely infected in the remote past, to be at low risk of exposure to new active cases, and to be an ideal population for long-term follow-up. Both tuberculin reactors and nonreactors were enrolled. The study demonstrated that IPT among all participants was associated with 62% reduction in the risk of TB. The most significant effect noted with IPT was among patients with tuberculin skin reactions  10 mm in size (68% reduction), with less significant findings among the participants with tuberculin skin tests between 5 and 9 mm in diameter (47% reduction). No protective effect was noted in patients who converted their skin tests during the conduct of the study. The investigators hypothesized that the observed conversions in skin tests may have reflected boosting rather than recent acquisition of infection. Of note, among 90% of the study participants who were tuberculin reactors and had normal chest x-rays at baseline, IPT was associated with a 70% reduction in event rate. Studies in Children with Primary Disease

In 1955, the USPHS initiated a study of the efficacy of IPT among children with primary TB (21,22). The study enrolled 2750 asymptomatic children from the United States, Canada, and Mexico. To fulfill eligibility criteria, children less than 3 years of age were required to have a tuberculin reaction of at least 5 mm, while those 3 years or older were required to also have evidence of primary TB on chest radiographs. Isoniazid was given at a dose of 4–6 mg/kg daily for 12 months or matching placebo. Ten years after the initial detection of primary TB in these children, the complication rate was decreased from 30.2 to 3.6 per 1000 children in the placebo and isoniazid groups, respectively, with no cases of tuberculous meningitis or miliary disease in the latter group. The beneficial effect of isoniazid was observed irrespective of the initial chest x-ray findings, although the largest decrease in event rate was noted in those with hilar/paratracheal lymphadenopathy or parenchymal disease. B. Adverse Events and Risk–Benefit Analyses

The relative risks and benefits of IPT have been debated for over three decades. Although isoniazid is generally considered a well-tolerated medication, concern has been expressed regarding the development of isoniazid-associated hepatitis. During the initial studies conducted in the 1950s and 1960s, it has been claimed that patients were deliberately not asked about adverse events in the belief that this may discourage adherence with medication (17). This may have contributed to delay in appreciation of the risk of hepatitis associated with isoniazid use. However, the issue received particular attention when 19 of 2321 participants in a study of preventive therapy developed liver disease and two died from this complication (23). This report and others resulted in the initiation of a USPHS study to assess the risk of isoniazid-associated hepatitis (24). Participants were specifically asked

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about signs and symptoms of hepatitis on a regular basis. Among 13,838 participants from 21 cities, the rate of probable isoniazid-associated hepatitis was 10.2 per 1000 person years. The study noted an association between increased risk of hepatitis and increasing age, alcohol consumption, and among Asian men. Eight deaths were reported in this study (0.8%), seven from one city. The results of the latter study had a significant impact on clinical practice. The Centers for Disease Control (CDC) subsequently recommended that patients be evaluated on a monthly basis during preventive therapy and prophylaxis be restricted to those at high risk of TB and older than 35 years (25). Of note, it was recognized at that time that asymptomatic elevations in transaminase levels occurred in 10–20% of patients initiating IPT and that this was not associated with increased risk of hepatitis (26). In 1975, Israel raised concern about the recommendations that supported the use of IPT in light of reports of hepatitis and associated mortality (27). In an analysis of the risk versus benefit of IPT, Comstock and Edwards suggested that the data supported offering IPT to individuals at low risk of TB who are younger than 45 years (28). However, a study reported by Taylor et al. did not support the ATS recommendations or the results of the analysis by Comstock and Edwards (29). The preventive therapy recommendations were further modified in 1983, when the American Thoracic Society (ATS) published guidelines which recommended regular monitoring of liver function tests among those older than 35 years of age and discontinuation of therapy if there is a three- to fivefold rise in their levels (30). The controversy continued with conflicting results reported by Rose et al., which supported the use of IPT among low-risk tuberculin-positive individuals of all age groups (31). 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. Rose et al. used life expectancy and lifetime likelihood of fatal illness as the outcome measures rather than lifetime risk of illness or death. Tsevat et al. conducted another decision analysis and arrived at the opposite conclusions by assuming lower risk of TB and higher rates of isoniazid-associated hepatitis and mortality than did Rose and colleagues (32). While age has been the major variable studied in these decision analyses, Jordan et al. examined the impact of gender and ethnicity (33). In that study, the results supported prescribing IPT except among black women, irrespective of the magnitude of their risk of TB. To further evaluate the association between the use of isoniazid and the development of hepatitis and the risk of death, Snider et al. initiated a study of all known cases of death associated with IPT in the United States (34). Of 177 cases they identified, an increased risk of death was noted among older persons, women, and those in the postpartum period. However, it is important to note that this study involved a retrospective review of medical records with its usual limitations, and therefore it was difficult to definitively attribute the deaths to isoniazid.

Treatment of Latent Tuberculosis Infection

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Another retrospective study of the risk of death following the institution of the aforementioned monitoring guidelines identified two deaths among 202,497 persons who initiated IPT (0.001%) with no deaths noted among postpartum women (35). The author stated that this rate was 10 times lower than the rate prior to routine monitoring of patients. Finally, in a recent prospective study of over 11,000 consecutive patients in Seattle who received IPT 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 (36). While the studies described above focused on the assessment of risk–benefit, Fitzgerald et al. performed a cost-effectiveness analysis (37). This study suggested that the costs incurred per case of TB prevented were reasonable from a societal perspective. Finally, Salpeter et al. conducted both risk-benefit and cost-effectiveness analyses of IPT among low-risk tuberculin reactors older than 35 years and concluded that preventive therapy with monitoring was associated with reductions in mortality rates and health care costs (38). Thus, they supported expanding the current IPT recommendations to include all individuals with positive tuberculin skin tests irrespective of age. The issue of the benefits versus risks associated with IPT remains controversial. The risk to the individual associated with the development of TB are compounded by the societal risk due to potential transmission to others. On the other hand, the lifelong remote risk of disease needs to be also weighed against the risk of hepatitis in the short term during therapy and remote risk of death due to toxicity from isoniazid. In addition, the societal costs are also governed by the rates of tuberculin reactivity in the population. Thus, most experts support the use of IPT among specific groups of tuberculin reactors who are at high risk of development of disease as described below. Indeed, an expert committee convened by the ATS and CDC recently recommended that targeted skin testing be offered only to groups at risk of TB infection and that treatment be offered to all persons found to be tuberculin positive, irrespective of age (39). III. New Regimens for Treatment of Latent Tuberculosis Infection A. Short-Course Preventive Therapy

While most of the early studies of IPT utilized a daily regimen for 12 months, this is associated with considerable costs to the health-care system and inconvenience to the patients. In addition, the lengthy duration of treatment jeopardizes the ability of patients to adhere with and complete therapy. Finally, as more programs implemented 6-month regimens as standard courses of treatment of disease and fewer resources were available in many TB control programs, it became more dif-

482

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ficult to complete 12-month regimens in those without evidence of disease. Thus, interest in shorter durations of preventive therapy influenced Snider et al. to conduct a cost-effectiveness analysis of various durations of preventive therapy used in the IUAT study (40). Based on this analysis, the data supported a 24-week course of treatment in persons with positive tuberculin tests and normal chest radiographs. Several lines of evidence suggest that rifampin-containing regimens used for short periods may be as effective or more effective than isoniazid for treatment of LTBI. Rifampin has greater sterilizing activity in vitro and in animal models than isoniazid. In a murine model of chronic TB, Lecoeur et al. showed that rifampin for 3 months and rifampin plus pyrazinamide for 2 months were more effective than isoniazid for 6 months (41). In tuberculin-positive patients with silicosis in Hong Kong, rifampin for 3 months, isoniazid and rifampin for 3 months, and isoniazid for 6 months resulted in 63, 41, and 48% protection, respectively, compared to placebo (42). These preliminary data led to a series of comparative trials using short-course rifampin-containing regimens in HIV-infected patients, as discussed below. B. Intermittent Regimens

The recognition of the importance of supervision of doses of antituberculosis medications during the treatment of tuberculosis (see Chap. 16) has sparked interest in the use of directly observed preventive therapy (DOPT) regimens, primarily due to efforts at improving rates of completion of preventive therapy. While there are no studies that have specifically compared intermittent IPT with daily therapy among individuals on preventive therapy, TB-control programs have utilized twice-weekly high-dose IPT. This strategy has been used in settings such as methadone maintenance treatment programs, shelters for homeless persons, clinics in high schools, and in programs for released jail inmates (43–47). In the study of released jail inmates, completion rates of DOPT were 60% compared to 29% in those who chose self-administered therapy, but given the difficulties and expense of locating and retaining inmates, the program was not considered cost-effective (47). In contrast, DOPT in a methadone maintenance program was thought to be a cost-effective intervention for injection drug users in treatment (44). IV. Treatment of Latent Tuberculosis Infection in HIV-Infected Persons A. Interaction of Tuberculosis and HIV Infection

The strong association of TB and HIV/AIDS (see Chap. 20) has been noted throughout the AIDS epidemic and has been confirmed by numerous studies (48,49). Compared to HIV-negative persons, HIV-infected patients have a higher incidence and prevalence of TB, are more likely to progress to active TB with

Treatment of Latent Tuberculosis Infection

483

LTBI, and are more likely to develop progressive primary disease and dissemination after exposure. Indeed, underlying HIV infection is considered the greatest single risk factor for the development of TB, with severalfold greater risk than previously recognized risk factors, i.e., silicosis, hemodialysis, diabetes mellitus, immunosupressive conditions or therapies, and fibrotic chest x-ray lesions (50). Rates of TB among HIV-infected patients are 50–100 times greater than in the general population in the United States (51). The annual risk of developing TB in HIV-infected persons is shown in Table 2, which summarizes previous retrospective and prospective epidemiologi-

Table 2 Annual Risk of Developing Tuberculosis in HIV-Infected Persons Risk per 100 patient-years (no. patients studied) Author (Ref.) Location Years of study Selwyn (52) USA/IDUb 1985–1987 Selwyn (53) USA/IDUc 1988–1990 Markowitz (51) USA/23% IDUd 1988–1994 Moreno (54) Spain/80% IDUc 1985–1990 Guelar (55) Spain/60% IDUc 1988–1992 Antonucci (56) Italy/72% IDU 1990–1993 Braun (57) Zaire/women 1987–1989 Allen (58) Rwanda/women 1988–1992

PPDa Anergic

PPD not tested for anergy

PPD not anergic

Total

7.9 (49)b

—

0.3 (166)

—

2.1 (215)

9.7 (25)

6.6 (68)

—

—

7.7 (93)

3.5 (66)

0.7 (603)

—

0.2 (429)

0.7 (1107)

10.4 (84)

12.4 (112)

—

5.4 (151)

9.1 (374)

16.2 (26)

2.6 (235)

—

0 (87)

3.0 (1649)

—

0.45 (849)

2.2 (2695)

—

—

3.1 (249)

—

2.4 (401)

PPDa

5.4 (197)

—

—

5.5 (73)

—

2.1 (221)

PPD  purified protein derivative; PPD  5 mm; PPD 
5 mm; IDU  injection drug user. 73% did not receive isoniazid preventive therapy (IPT). Did not receive or complete IPT. d 55% did not receive IPT. Source: Adapted and updated from Ref. 65. a

b c

—

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cal studies (51–58), and in Table 3, showing rates of TB in placebo recipients in clinical trials (59–64). The risk of TB varied by tuberculin status, population studied, geographic region, and timing of the study. In general, HIV-infected persons with positive-tuberculin tests (5 mm) had the greatest risk of developing TB, with rates of 1.2–16.2 per 100 person-years (65). Tuberculin-negative persons who were anergic appear to be at intermediate risk with an estimated risk of 0–12.4 per 100 person-years, whereas HIV-infected persons who were tuberculinnegative and not anergic were at lower risk, with an estimated risk of 0–5.4 per 100 person-years. This is in contrast to the estimated 10% lifetime risk in tuberculin-positive persons who are not HIV infected (66). HIV-infected patients with tuberculin skin tests 20 mm have twice the risk of developing TB than those whose induration is 5–19 mm (51). Patients with CD4 cell counts
200/mm3 have two to five times the risk of developing TB than those with CD4 cell counts of 200/mm3 (51,56). In addition, recent data suggest that active TB disease may alter the natural history of HIV infection. In a retrospective case-control study from four centers in the United States, HIV-infected patients with TB compared to matched controls without TB had a higher rate of other opportunistic infections and increased risk for death, suggesting that TB may act as a cofactor to accelerate the clinical course of HIV infection (67). Viral load has been shown to increase during active TB, and in vitro, M. tuberculosis increases viral replication in peripheral blood mononuclear cells from tuberculin-positive donors, probably as a result of antigen-specific stimulation of T cells (68). A prospective cohort study from Uganda showed an increased relative risk of death in HIV-infected persons with TB compared to those without TB, when controlling for other predictors of survival, including previous opportunistic infections, CD4 cell counts, and antiretroviral therapy (69). Hence the rationale for the prevention of TB in HIV-infected persons is considerable, with the intent of decreasing morbidity and mortality directly related to TB, secondary transmission to others, and possibly HIV progression unrelated to TB. Isoniazid preventive therapy (IPT) has been recommended in the United States for all HIV-infected persons as a TB-control strategy since 1989 (70) and in developing countries for the HIV-infected individual since 1993 (71). As a result of the completion of several prospective randomized clinical trials, regimens other than isoniazid have been shown to be effective, and preventive therapy in HIV-infected persons is being considered by national TB-control programs for more widespread implementation in low- and middle-income countries. B. Review of Studies: Efficacy and Safety

Early in the AIDS epidemic, there were few data supporting the efficacy of IPT in HIV-infected patients. However, two retrospective noncontrolled studies suggested that TB was less commonly noted in patients who received IPT than those

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who did not. Among HIV-infected injection drug users in New York City known to be tuberculin positive, 4 of 25 patients (16%) who declined IPT or had a relative contraindication developed TB compared with none of 27 patients who completed 12 months of IPT (rate difference 9.7/100 person-years) (53). Similarly, in a retrospective analysis of tuberculin-positive HIV-infected patients in Madrid (90% injection drug users), 29 of 94 patients (31%) who did not receive IPT developed tuberculosis compared with only one of 27 (4%) of those who did (54). Long-term follow-up of these groups revealed an incidence of TB of 9.4 per 100 person-years among patients with no IPT compared with a rate of 1.6 per 100 person-years among patients who received IPT (72). There was also a mortality difference, in that 54% of patients without IPT died, compared to 24% of isoniazid recipients. Summary results of prospective, randomized clinical trials are shown in Table 3. In a relatively small prospective trial in Haiti, 60 HIV-infected patients were randomized to vitamin B6 alone and 58 patients to isoniazid plus B6; 42% of the B6 recipients and 66% of the isoniazid recipients were tuberculin-positive, respectively (59). The incidence of TB was significantly higher in the B6 recipients than in those who received isoniazid (7.5 versus 2.2 per 100 person-years); this difference was greater in those who were tuberculin-positive (10.0 versus 1.7 per 100 person-years) (Table 4). In addition, 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 in Africa compared daily IPT with placebo for 6 months duration. In a prospective single-blind study in Zambia, 23 of 246 (9%) vitamin B6 recipients (11.3 per 100 person-years) (60) developed TB compared with 7 of 298 (2%) IPT recipients (2.6 per 100 person-years). Subsequently, Hawken et al. performed a double-blind study in Kenya (63). Unlike prior studies, there was no overall benefit of isoniazid (4.29 per 100 person-years) compared to placebo (3.86 per 100 person-years). However, only 23% of persons were tuberculin positive; in that group there appeared to be some evidence of protection by IPT (although this was not statistically significant), whereas there was none noted in tuberculin-negative patients. A larger sample size of tuberculin-positive subjects may have shown a significant benefit from IPT. Other studies have evaluated regimens other than isoniazid and have used twice-weekly dosing with partial supervision. In Haiti, isoniazid twice weekly for 6 months was compared to rifampin and pyrazinamide twice weekly for 2 months in tuberculin-positive subjects (73). After the first 10 months, there was a greater incidence of TB in the group randomized to rifampin and 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 ri-

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Table 3 Prospective, Randomized Clinical Trials of Preventive Therapy of Tuberculosis in HIV Infection Author (Ref.) Location Years of study

Study subjects PPD status (n)

CD4 cell counts or percent

Drug regimen (months)

Pape59 Haiti 1986–1992

PPD (25)a PPD (38) PPD (35)a PPD (20)

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

Wadhawan60 Zambia 1988–1992

NTa (246) NTa (298)

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

Halsey73 Haiti 1990–1994

PPD (370) PPD (380)

Whalen61 Uganda 1993–1997

PPD (464) PPD (536) PPD (556) PPD (462)

22.5% 22.2%

INH, 600–800 mg biwb (6) RIFb 450–600 mg/PZAb 1500–2500 mg biw (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) INH 300 mg, qD (6)

Anergic (323) Anergic (395) Mwinga62 Zambia 1992–1996

PPD/ (350)c PPD/ (352)c PPD/ (351)c

Hawken63 Kenya 1992–1996

PPD/ (342) PPD/ (342) PPD (67) PPD (69) PPD (235) PPD (224)

346/mm3 321/mm3

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

Gordin64 United States 1991–1996

Anergic (257) Anergic (260)

247/mm3 233/mm3

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

Gordin74 United States, Mexico, Haiti, Brazil 1991–1997

PPD (792) PPD (791)

427/mm3 454/mm3

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

Placebo (INH), biw (6) INH 900 mg, biw (6) RIF 600 mg/PZA 3500 mg biw (3)

PPD  purified protein derivative; PPD  PPD ≥5 mm; PPD  PPD
5 mm; NT  not tested. INH  isoniazid; RIF  rifampin; PZA  pyrazinamide; qD  daily; biw  twice-weekly. c Percent tuberculin-positive: 27% in placebo, 23% in INH, 22% in RIF/PZA. a

b

Treatment of Latent Tuberculosis Infection

No. TB cases (%) 6 (24) 2 (5) 5 (14) 2 (10)

TB rate/ 100 p-years

Relative risk of TB (95% CI)

No. deaths (%)

487

Death rate/ 100 p-years

7 (28) 3 (8) 6 (17) 2 (10)

Relative risk of death (95% CI)

10.0 1.7 5.7 3.2

1 0.17 (0.03–0.83) 1 0.56 (0.11–2.5)

3.6 (1.0–12.4) 1

23 (9) 7 (2)

11.3 2.6

1 0.4 (0.20–0.82)

14 (4) 19 (5)

1.7 1.8

1 1.1

72 71

21 (5) 7 (1) 9 (2) 10 (2)

3.41 1.08 1.32 1.73

1 0.32 (0.14–0.76) 0.41 (0.19–0.89) 0.42 (0.20–0.92)

64 (14) 58 (11) 57 (10) 58 (13)

10.2 8.9 8.3 9.8

1 0.9 (0.6–1.2) 0.8 (0.5–1.2) 0.9 (0.7–1.4)

10 (3) 9 (2)

3.06 2.53

1 0.75 (0.30–1.89)

76 (23) 86 (22)

22.3 23.5

1 1.05 (0.77–1.42)

44 (13) 27 (8) 25 (7)

8.06 4.94 4.65

1 0.62 (0.38–0.99) 0.58 (0.35–0.95)

58 (17) 59 (17) 68 (19)

9.62 10.02 11.76

1 1.05 (0.73–1.50) 1.24 (0.87–1.76)

23 (7) 25 (7)

3.86 4.29 8.03 5.59 2.73 3.28

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

57 (17) 62 (18)

9.58 10.64

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

6 (2) 3 (1)

0.9 0.4

1 0.48 (0.12–1.91)

126 (49) 129 (50)

17.8 17.7

1 0.96 (0.75–1.23)

29 (4) 28 (4)

1.2 1.2

1 0.95 (0.56–1.16)

159 (20) 139 (18)

6.5 5.7

1 0.87 (0.69–1.11)

1 0.64 (0.39–1.03) 9.1

488 Table 4

Cohn and El-Sadr Criteria for Tuberculin Positivity, by Risk Group

5 mm induration HIV positive Recent contact of TB case Fibrotic changes on chest X-ray consistent with old TB Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of 15 mg/day of prednisone)a

10 mm induration

15 mm induration

Recent arrival (
5 years) from high-prevalence country Injection drug user Residents and employees of high-risk congregate settings: prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health-care facilities, residential facilities for AIDS patients, and homeless shelters Mycobacteriology lab personnel Persons with high-risk medical conditions other than HIV infectionb Children
4 years of age or infants, children, and adolescents exposed to adults in high-risk categories

Persons with no risk factors for TB

a

Risk of TB in patients with corticosteroids increases with higher dose and longer duration. Includes silicosis, insulin-dependent diabetes mellitus, some hematological disorders (e.g., leukemias and lymphomas), other specific malignancies (e.g., carcinoma of the head and neck), chronic renal failure, weight loss 10% of ideal body weight, gastrectomy, jejunoileal bypass. Source: Adapted from Refs. 2, 39. b

fampin 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 rifampin and pyrazinamide than on isoniazid for all comparable cut-off points (i.e., 50, 80, and 100% of study regimens taken). A large, placebo-controlled trial in Zambia by Mwinga and colleagues compared twice-weekly isoniazid for 6 months and rifampin and pyrazinamide twice weekly for 3 months (62). Both tuberculin-positive and tuberculin-negative patients were enrolled, and similar to the aforementioned study in Kenya 24% of patients were tuberculin-positive. Both isoniazid (4.94 per 100 person-years) and rifampin and pyrazinamide (4.5 per 100 person years) were more effective than placebo (8.06 per 100 person-years), with each showing about 40% protection. There were no differences in survival among the three regimens. Of note, the effect of preventive therapy was greater in those with positive tuberculin tests, hemoglobin 10 g/dL, and absolute lymphocyte counts 2  109/L. The largest clinical trial in HIV-infected persons was conducted by Whalen et al. in Uganda (61). In tuberculin-positive patients, isoniazid daily for 6 months (1.08 per 100 person-years), isoniazid and rifampin daily for 3 months (1.32 per 100 person-years), and isoniazid, rifampin, and pyrazinamide daily for 3 months

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(1.73 per 100 person-years) were all 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. Isoniazid and isoniazid plus rifampin 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 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%. In another large international study performed in the United States, Mexico, Haiti, and Brazil in tuberculin-positive patients, rifampin and pyrazinamide given daily for 2 months (1.2 per 100 person-years) was found to be as effective as 12 months of isoniazid (1.2 per 100 person-years), the standard regimen used in the United States (74). Once again, no differences in survival were noted. There was a higher rate of treatment discontinuation in the rifampin and pyrazinamide group (9%) than in the isoniazid group (6%). Nausea and vomiting were more common with rifampin and pyrazinamide (2%) than with isoniazid (0.1%), whereas elevated liver function tests were more common with isoniazid (3%) than with rifampin and pyrazinamide (1%). Of note, as in the Haiti study of twice-weekly regimens of 2 months versus 6 months, adherence to the 2-month regimen (defined as taking drugs for 60 days) was greater—80%—than with the 12-month regimen (i.e., 6 months continuous treatment)—68%. Efficacy of preventive therapy in anergic patients has been evaluated in two studies. In the Uganda study, patients were randomized to receive 6 months of daily isoniazid or placebo; there were no apparent differences in efficacy or survival, although confidence intervals were wide (61). Not surprisingly, the death rate was higher in the anergic cohort (22%) than in the PPD-positive groups (8–10%). Similarly, in a study by Gordin et al. in the United States in anergic patients at high risk of TB, 6 months of isoniazid showed a slight protective effect compared to placebo, but this difference was not statistically significant (64). There was no impact demonstrated on survival. Hence the study results in anergic patients were very similar in a high-incidence country (Uganda, TB rate 2.5–3.1% per year) and a low-incidence country (United States, TB rate 0.4–0.9% per year). In summary, a great deal of information has been learned as a result of the completion of several large controlled trials in HIV-infected patients in the past decade. In tuberculin-positive, HIV-infected patients, IPT given for 6–12 months is effective in preventing TB. Also rifampin and pyrazinamide given for 2 or 3 months and isoniazid and rifampin for 3 months appear to be as effective as isoniazid, and regimens may be given daily or twice weekly. In contrast, in anergic, HIV-infected patients, IPT for 6 months does not appear to be effective. Medications are generally well tolerated, and adherence is better with regimens of 2–3

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months than 6–12 months. Treatment of LTBI, given for this duration, has limited or no effect on mortality in HIV-infected persons, and effects on HIV progression have not been clearly determined. C. Feasibility of Treatment of Latent Tuberculosis Infection

Although efficacy in HIV-infected patients has been firmly established in clinical trials, the true effectiveness in other settings may be different. This is of special concern in developing countries, where resources are limited and the relative impact of preventive therapy may be small. In a study from Uganda, Aisu and colleagues recruited HIV-infected clients from a counseling and testing site for IPT, included tuberculin skin testing, and noted significant attrition at each step of the process (75). Of the 23% of clients who tested HIV positive, 24% returned for test results and had tuberculin testing, and of those, 39% initiated IPT; 62% completed at least 80% of a 6-month regimen. Overall, of 5594 HIV-infected clients who returned for HIV test results, 322 (6%) completed IPT. In a more recent study in Uganda, of patients already receiving HIV care and who did not undergo tuberculin testing, a larger percentage initiated IPT and 60–70% completed a 6-month regimen (T. Aisu, personal communication). In contrast, in a hospital-based study in Thailand, of 412 HIV-infected patients, 89% initiated IPT and 79% completed a 9-month regimen (76). D. Cost-Effectiveness and Cost-Benefit of Treatment of Latent Tuberculosis Infection

There have been few studies investigating the cost-effectiveness and cost-benefit of treatment of LTBI in HIV-infected patients. In the aforementioned feasibility study in Uganda, the incremental cost of a preventive therapy program was about $18.00 per patient, assuming counseling and testing services were already in place; a formal cost-effectiveness analysis was not performed (75). A modeling of costbenefits of preventive therapy in Zambia showed that if the treatment prevented two additional cases of TB, costs would exceed benefits (benefit/cost ratio  0.86), whereas if five new cases were prevented, benefits would exceed the costs (benefit/cost ratio  1.71) (77). Other scenarios suggested that it would be cost-effective if targeted programs could access significant populations of risk, such as in selected occupational settings. Data from feasibility studies suggest that about 15–70 clients need to be screened to prevent one case of TB; whether this is cost-effective is contingent on marginal costs incurred to establish and run the preventive therapy program within the infrastructure present within a region or country (78). Using decision analysis, Nguyen and colleagues from CDC evaluated the cost-effectiveness of several strategies of preventive therapy in HIV-infected patients, including self-administered (daily) and directly observed (twice-weekly), and 2-month (rifampin and pyrazinamide) and 12-month (isoniazid) regimens (79).

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All strategies prevented cases and saved money. Compared to self-administered 12-month IPT, the 2-month regimens were cost-effective, and DOPT (12 months) also prevented cases but at an additional cost. Another decision analysis by Bell et al. showed that preventive therpy with isoniazid for 6 months, isoniazid and rifampin for 3 months, and rifampin and pyrazinamide for 2 months used in HIV-infected patients in sub-Saharan Africa would result in monetary savings (80). V. Treatment of Latent Tuberculosis Infection in Special Populations A. Pregnant and Breastfeeding Women

Among pregnant women eligible for IPT, many experts would postpone IPT until after delivery. Additionally, some experts prefer delay in initiation of IPT until 2–3 months after delivery. This is based on the results of a study in which the risk of death appeared to be increased among women receiving IPT during the immediate postpartum period (34). However, among certain groups of pregnant women at substantial risk of TB, IPT has been recommended during pregnancy. These include pregnant women who are HIV infected, those with recent skin test conversion, and women with a history of a close contact with a case of TB (81). Because of the safety and efficacy of isoniazid during pregnancy, as well as significant morbidity to infants who may become infected in the postpartum period, the most recent recommendations are to offer preventive therapy to most pregnant women who are found (or known) to be tuberculin positive (39,82). There are limited data on the safety of breastfeeding for infants of mothers on IPT. While measurable amounts of isoniazid have been detected in breast milk, only a small proportion of the dose is secreted in breast milk (83). Based on these data, most experts support breastfeeding by women receiving IPT after appropriate counseling regarding risks and benefits. B. Children

Children who are recently infected and infants are at significant risk for development of TB (see Chap. 21). In addition, when TB occurs, disseminated disease and TB meningitis are more common than in adults. As noted previously, several studies have demonstrated the efficacy of IPT in children with primary infection or who are contacts of cases (5,21,22). Hepatotoxicity from isoniazid in infants and children is rare (84,85). There are no controlled trials on the use of rifampin or rifampin and pyrazinamide for treatment of LTBI in children. C. Contacts of INH-Resistant Tuberculosis

There is no consensus on the choice of a preventive therapy regimen in a contact with history of exposure to a patient with probable or confirmed isoniazid-resis-

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tant TB. A decision analysis and Delphi methodology were used to recommend either rifampin alone or in combination with isoniazid or ethambutol in this setting (86). These results were supported by ATS recommendations in 1983 (30) and by an expert panel of the American College of Chest Physicians in 1985 (87). In an outbreak of homeless persons with TB resistant to isoniazid and streptomycin, of exposed skin test converters who received no preventive therapy, 6 of 71 (9%) developed TB, compared to 3 of 38 (8%) who received isoniazid, and 0 of 98 who received rifampin or isoniazid and rifampin (88). Similarly, of 157 high school students who took rifampin after being exposed to an infectious case of isoniazid-resistant TB, none had developed TB after 2 years (89). However, one episode of rifampin prophylaxis failure was reported among contacts of an isoniazid-resistant case of TB in a community outbreak (90). D. Contacts of Multidrug-Resistant Tuberculosis

The occurrence of outbreaks of multidrug-resistant tuberculosis (MDR-TB) and the rise in resistance rates worldwide have focused attention on options for preventive therapy for individuals exposed to such cases (91). This is particularly important when there is exposure to a TB case with organisms resistant to both isoniazid and rifampin. This issue has not been evaluated in prospective studies. However, in 1992 CDC published recommendations for such situations including the use of pyrazinamide and ethambutol or pyrazinamide and a quinolone for 6–12 months (92). A Delphi technique among 31 experts failed to achieve consensus on a definite course of action, although pyrazinamide and a quinolone for 4 months was the most favored (93). VI. Development of Disease Due to Resistant Organisms The risk of development of TB that is resistant to the agent(s) used for preventive therapy has been an issue of concern. In studies conducted among immunocompetent patients who utilized isoniazid, the data were reassuring with a low risk of development of isoniazid-resistant TB (17). However, a small proportion of isolates was available for susceptibility testing, and some were obtained after initiation of therapy for active disease rather than at time of diagnosis. More recently concern has been expressed in relation to the potential for development of resistant TB with more widespread use of rifampin-containing preventive therapy regimens. In the international study by Gordin et al. of the 19 culture-confirmed cases of TB that developed among patients assigned to rifampin and pyrazinamide, three patients had isolates resistant to rifampin (74). However, all these isolates were also resistant to other antituberculosis medications, suggesting prior infection with drug-resistant TB. Among the 26 cases of TB that occurred in those assigned to the isoniazid, one was due to an isolate resistant to iso-

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niazid, rifampin, and streptomycin. In the Haiti study by Halsey et al., susceptibility testing of the available isolates of M. tuberculosis did not appear to show an increase in resistance over those from other patients with TB in the same population who had not received preventive therapy (73). Thus, the available information is reassuring, although more extensive data are needed to assess the risk of development of rifampin-resistant isolates (61,73,74). VII. Recommendations for Treatment of Latent Tuberculosis Infection Persons at risk and criteria for initiation of preventive therapy in industrialized countries are shown in Table 4 (2,39). Any tuberculin-positive person with an identified risk factor should be offered preventive therapy regardless of age. Significant risk factors include HIV infection, recent contact with infectious cases or skin test conversion, an abnormal chest x-ray consistent with old healed TB, injection drug use, and several other medical conditions. These conditions, most of which are associated with decreases in cellular immunity and/or local host defenses in the lung, include silicosis, diabetes mellitus, corticosteroid and other immunosuppresive therapy, hematological malignancies, end-stage renal disease, and other diseases associated with rapid weight loss. For most of these risk factors, a PPD induration of 10 mm is considered a positive skin test reaction; for HIV-infected and other immunosupressed persons, recent contacts of TB, and persons with radiographic evidence of old TB, 5 mm is considered positive. In the past, for persons without the above risk factors and a positive tuberculin skin test, preventive therapy was recommended for individuals
35 years of age, but not for those 35 years. This recommendation was based on the risk-benefit analyses discussed earlier, whereby hepatotoxicity of IPT increases with age. Owing to the controversy and the different decision analyses, some experts suggested a lower age cut-off than 35 years (e.g., 20 years of age) and others recommend a higher age cut-off than 35 years of age (e.g., 45 years of age) or no age cut-off at all (28,31,32,38). Since the new recommendations focus on targeting testing of high-risk groups only, any person at risk who is tuberculin-positive should be offered treatment of LTBI, irrespective of age (Table 4). The main exception to this is in elderly individuals (e.g., 70 years old), who would gain less cumulative benefit by having fewer years to live independent of TB, with greater potential for hepatotoxicity. For persons in high-incidence groups (i.e., foreign-born, medically underserved populations, and residents of long-term care facilities) 10 mm induration is considered positive, and for all others considered to be in low-incidence groups, 15 mm induration. Different cut-off points may be considered in geographical areas, depending on the prevalence of M. tuberculosis infection in a population and cross-reactivity to nontuberculous mycobacteria (Table 4).

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Recommended regimens for the treatment of LTBI are shown in Table 5 (39,82). These recommendations utilize the recently developed USPHS rating system, which provides the strength of the recommendation and the quality of the supporting evidence. In most settings, isoniazid is the standard drug, given 300 mg daily for 9 months or, where directly observed preventive therapy is indicated or preferred, 900 mg twice weekly for 9 months (12,16,17). In selected situations, depending on priorities and available resources, programs may choose to administer therapy for 6 months, which has also been shown to be effective. In HIV-infected patients both 6 months and 12 months have been shown to be effective in randomized trials but have not been compared to each other. Previously, 12 months of therapy was recommended because of the high risk of TB with HIV infection (greater than with fibrotic lung lesions) and because in some of the aforementioned studies, the protective effect on IPT appeared to wane over time (62,73). In order to achieve consistency and simplicity in recommendations, a 9-month regimen is now recommended (39,82). Because of the equivalent efficacy of rifampin and pyrazinamide daily for 2 months compared with isoniazid for 12 months (74), this regimen can also be used (Table 5). Although studies demonstrating efficacy have only been done in HIVinfected patients, it is likely that rifampin and pyrazinamide would be effective in immunocompetent persons. In situations where adherence may be a problem and/or shorter regimens are desirable (e.g., short-term incarceration in jails or prisons), rifampin and pyrazinamide for 2 months is particularly attractive. Since rifampin and pyrazinamide given twice weekly may not be as effective as daily (62,73), the regimen is not recommended, but it may be administered in selected situations. In HIV-infected persons receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors, rifampin is contraindicated owing to bidirectional drug interactions (see Chap. 20). Rifabutin may be substituted for rifampin, or isoniazid should be used. For pregnant women who are tuberculin-positive, isoniazid daily or twice weekly for 9 months is recommended. Similarly, children should be treated with isoniazid given daily or twice weekly for 9 months (39,81,82). For persons intolerant to isoniazid or who are likely to be infected with isoniazid-resistant organisms, rifampin and pyrazinamide for 2 months are recommended, and if intolerant to pyrazinamide, rifampin for 4 months is recommended (39). For persons who are contacts of cases of MDR-TB, pyazinamide and ethambutol or pyrazinamide and a quinolone (e.g., ofloxacin) for 6–12 months are recommended (92). Immunocompetent contacts may be observed or treated for 6 months, and immunocompromised contacts (e.g., HIV-infected persons) may be treated for 12 months. There are no data demonstrating the efficacy of these regimens, which have been associated with gastrointestinal side effects and liver function abnormalities (94).

495

Twice weekly for 9 monthsb,c

Daily for 6 monthsed

Twice-weekly for 6 monthsc

Daily for 2 months

Twice-weekly for 2–3 months

Daily for 4 months

Daily for 6–12 months

INH 900 mg (15 mg/kg)

INH 300 mg (5 mg/kg)

INH 900 mg (15 mg/kg)

RIF 600 mg PZA 1500–2000 mg (15–20 mg/kg)

RIF 600 mg PZA 2000–3000 mg

RIF 600 mg

PZA (25–30 mg/kg) EMB (15–25 mg/kg) PZA (25–30 mg/kg) OFLX (400 mg bid) or LEVO (500 mg daily)

For persons who cannot tolerate PZA. For persons who are contacts of patients with INH-resistant, RIF-susceptible TB, and cannot tolerate PZA. For persons who are contacts of patients with MDR-TB (resistant to INH and RIF).

May also be offered to persons who are contacts of patients with INHresistant, RIF-susceptible TB. In HIV-infected patients, protease inhibitors or NNRTIs should not be administered concurrently with RIF; an alternative is the use of rifabutin for patients treated with indinavir, nelfinavir, soft-gel saquinavir, amprenavir, nevirapine, or efavirenz.e DOT must be used with twice-weekly dosing.

Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children. DOT must be used with twice-weekly dosing.

In HIV-infected patients, INH may be administered concurrently with NRTIs, protease inhibitors, or NNRTIs. DOT must be used with twice-weekly dosing.

Comments

CIII

CIII

BII

CII

BII

BII

BI

BII

AII

HIV

CIII

CIII

BIII

CI

AI

CI

CI

BII

AII

HIV

Ratingf

a INH  isoniazid; RIF  rifampin; PZA  pyrazinamide; EMB  ethambutol; OFLX  ofloxacin; LEVO  levofloxacin; bid  twice daily; DOT  directly observed therapy; NRTIs  b Recommended regimen for children
18 years of age. nucleoside reverse transcriptase inhibitors; NNRTIs  non-nucleoside reverse transcriptase inhibitors. c Recommended regimens for pregnant women. Some experts would use rifampin and pyrazinamide for 2 months as an alternative regimen in HIV-infected pregnant women. d In developing countries, INH should be given daily (self-administered) for 6 months. e Dose of rifabutin 150 mg daily or 300 mg twice-weekly. Rifabutin should not be used with ritonavir, hard-gel saquinavir, or delaviridine. f Strength of the recommendations: A  preferred, should generally be offered; B  alternative, acceptable to offer; C  offer when preferred or alternative regimens cannot be given. Quality of evidence: I  at least one randomized trial with clinical endpoints; II  clinical trials that either are not randomized or were conducted in other populations; ID  expert opinion. Source: Adapted from Refs. 39, 82.

Daily for 6–12 months

Daily for 9 monthsbc

INH 300 mg (5 mg/kg)

Interval and duration

Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection

Drug regimena

Table 5

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In developing countries, treatment of LTBI is not routinely recommended. However, recognizing the risk of TB in HIV-infected persons as well as the demonstrated efficacy of preventive therapy, in 1993 the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommended IPT for 6–12 months in tuberculin-positive (5 mm) individuals with HIV infection (71). This recommendation did not obligate national TB programs to offer preventive therapy in settings where greater emphasis and resources toward detection and treatment of disease are paramount. In 1998, WHO and the United Nations AIDS Program broadened this recommendation so that preventive therapy could be offered as part of a package for persons living with HIV, including access through voluntary counseling and testing sites (78). The recommendation, however, indicates that treatment of LTBI should only be used in settings where it is possible to exclude active TB disease and in which monitoring can be ensured. Isoniazid daily for 6 months (self-administered) is the recommended regimen for developing countries. VIII. Conclusions and Future Directions Numerous clinical trials over the past four decades have clearly demonstrated that treatment of LTBI with different regimens is effective in preventing TB in persons with latent infection with M. tuberculosis. In industrialized countries, preventive therapy is an important component of control programs, whereby screening of high-risk populations will identify candidates for the treatment of LTBI and resources can be devoted to completion of therapy. In low- or middle-income countries with much higher caseloads of TB, case detection and treatment of active cases is the highest priority. In areas where programs have achieved some success in achieving WHO-recommended targets for TB control (i.e., case detection of 70% and cure of 85% of smear-positive cases), treatment of LTBI programs for selected individuals or targeted populations should be considered, i.e., household contacts of active cases and persons with HIV infection. This strategy is not likely to have a large impact on the control of TB, but it will certainly result in some decrease in morbidity and secondary transmission. Continued research on the treatment of LTBI should be pursued in several directions. Additional studies of feasibility, cost-effectiveness, and cost-benefit are necessary, especially in developing countries and in HIV-infected populations. Further studies of directly observed intermittent regimens of preventive therapy should be done with both isoniazid and the new rifampin-pyrazinamide regimens to obtain additional information on effectiveness, tolerability, safety, and ease of implementation. In HIV-infected patients, longer duration of therapy, i.e., 12month regimens, or life-long therapy should be evaluated, especially in areas where antiretroviral therapy may not be readily available. Finally, new regimens

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with novel agents, such as rifapentine, perhaps once weekly or even less often, or other drugs to be developed should be evaluated in an attempt to continue improving the effectiveness and outcomes of the treatment of LTBI. Acknowledgments We thank Ms. Michelle Puplava for assistance in preparation of the manuscript and Dr. Victor Kuteyi for literature retrieval. References 1. 2.

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19 BCG Vaccines and Vaccination

PAUL E. M. FINE London School of Hygiene and Tropical Medicine London, England

I. Introduction BCG vaccines are both the most widely used (more people alive today have received BCG than have received any other vaccine) and most controversial of today’s vaccines. In order to understand this situation, we first retrace its history. Against this background, we describe the current uses of BCG, the controversies surrounding its use, and the efforts being made to develop and evaluate improved vaccines against tuberculosis.

II. Historical Background BCG (literally the bacillus of Calmette and Guérin) was derived at the Institut Pasteur in Lille, by serial passage (231 times, from 1906 to 1919, in a medium containing ox bile) of an isolate of Mycobacterium bovis. The strain was found to lose virulence to calves over this period and, following Pasteur’s tradition of the development of attenuated vaccines, was first given to a human (per os) in 1921. The vaccine was used increasingly in Europe during the 1920s, until a serious accident occurred in Lübeck, Germany, in 1929, when a laboratory error led to 72 deaths 503

504

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among 251 children given virulent Mycobacterium tuberculosis instead of BCG vaccine. At about the same time, the early evidence supporting BCG’s utility was strongly criticized in the medical press (1), and the combined effect of these problems led to a decline in the use of BCG. Despite these difficulties, however, other workers, in particular Heimbeck in Norway (2), accumulated evidence for the effectiveness of BCG in prevention of tuberculosis, and the first formal trials of BCG were organized in the 1930s. By the late 1940s, several studies had appeared providing evidence for the utility of BCG in protection against tuberculosis. Tuberculosis had emerged as a major concern in the aftermath of World War II, and BCG use was encouraged, stimulated in particular by UNICEF, by the fledgling World Health Organization (WHO), and by Scandinavian Red Cross Societies. The campaigns spread to the developing countries over the next decade. Also in the 1950s, major trials were set up by the Medical Research Council in the United Kingdom and by the Public Health Service in the United States. It was soon evident that the procedure employed in the United Kingdom (a Copenhagen strain BCG, given to tuberculinnegative 13-year-olds) was providing high efficacy against tuberculosis (3), whereas that in the United States (Tice strain, given to tuberculin negatives of various ages) provided little or no protection (4). On the basis of these results, the respective public health agencies did the logical thing—BCG was recommended as a routine for tuberculin-negative adolescents in the United Kingdom, whereas BCG was not recommended for routine use in the United States but restricted to certain high-risk populations. The majority of the world followed the lead of Europe and the WHO and introduced routine BCG vaccination according to various schedules (e.g., at birth, school entry, school leaving), whereas the Netherlands and the United States decided against routine BCG use and based their tuberculosis control strategy upon contact tracing and the use of tuberculin to identify individuals for preventive therapy. Two hypotheses emerged early as explanations for the disparate results observed between different evaluations of BCG. One attributed the differences to variation between strains of BCG. In fact, BCG had never been cloned and had been passaged under different conditions, by different laboratories, ever since its original derivation in the 1920s (5). It was recognized that strains produced by different manufacturers differed in microbiological properties (6), and hence it was not unreasonable to suggest that these might be reflected in differences in immunogenicity (7). An alternative hypothesis grew up around the USPHS trials, which noted that the poor results were observed in Alabama, Georgia, and Puerto Rico, in populations known to be exposed to many different “environmental” mycobacteria. It was thus proposed, originally by Palmer and colleagues, that exposure to various environmental mycobacteria could itself provide some protection against tuberculosis and affect the immune system in various ways and that BCG could not improve greatly upon that background (8).

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In an effort to decide between these views, a large trial was organized in the Chingleput area of South India, starting in 1968, with assistance of the Indian Council of Medical Research, the WHO, and the U.S. Public Health Service. The plan was to compare two different BCG strains (Paris/Pasteur versus Danish), each in two doses, in an area known to have a very high prevalence of environmental mycobacterial exposure. A companion trial was to have been set up in an area in northern India with little exposure to environmental mycobacteria, but unfortunately, due in part to political unrest, this was never initiated. The results of the Chingleput trial were made public in 1979, and they revealed that neither vaccine imparted any protection against pulmonary tuberculosis (9). The detailed results of this trial are strange in several ways. The risk of disease among individuals considered tuberculin “negative” at the start was far lower than predicted at the outset, and it appeared that there were actually more cases among the vaccinees than among the controls in the interval shortly after vaccination (though the statistical significance of this observation is questionable). Though two WHO-organized workshops reviewed the trial and concluded that the results could not be attributed to methodological error (10), a fully detailed presentation of the results of this massive trial has never appeared, and without detailed data we are unable to understand exactly what happened. The surprising results of the Chingleput trial led to a series of observational studies aimed at evaluating BCG use in different populations of the world (11,12). These are summarized in Figure 1. Although most studies showed some degree of protection, the overall impression is one of great variation, for which there is as yet no universally agreed-upon explanation. III. BCG Vaccines There are several BCG vaccines in use today. The major producers for the international market are Pasteur-Merieux-Connaught, the Danish Statens Serum institut, Evans Medeva (which has taken over the old Glaxo vaccine), and the Japan BCG Laboratory in Tokyo. Each of these BCG vaccines is produced in a different manner, and they are recognized to differ in various qualities, such as the proportion of viable cells per dose (6). BCG strains derived from the original Paris strain after 1925 (e.g., the current Pasteur, Copenhagen, Glaxo-Evans strains) lack a region of the genome known as the RD-2, which is still present in strains derived earlier than that date [represented by the current Brazilian (Moreau), Japanese and Russian strains] (13). The implications of these differences for protection against tuberculosis are unknown. IV. Current BCG Policies Approximately 100 million children receive BCG annually throughout the world today. Most countries now follow the policy of the Expanded Programme on Im-

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munization (EPI)/Global Programme on Vaccines of the WHO, which recommends only a single dose of BCG, given at birth or at earliest contact with a health service (14). Several countries follow their own special policies, either by targeting only select high-risk groups or by giving BCG more than once, with repeat doses either at school entry or leaving, and/or to individuals who either lack a scar or are still considered to be tuberculin “negative” by some criterion. These variations follow the views of local experts and have been determined by a combination of history, by the particular pattern of tuberculosis in the country, and by the capabilities and policies of the health service. Unfortunately, there have been almost no evaluations of the relative effectiveness of these different BCG policies. A particular example of region-specific policies has been the use of repeated doses of BCG in countries of the ex-Soviet bloc (e.g., up to five doses in Azerbaijan, Bulgaria, Poland). In the absence of evidence for the utility of such schedules, WHO has recently issued a statement discouraging the use of BCG booster doses unless and until evidence of their utility becomes available (14). There is a trend towards discontinuation of routine BCG use in northern Europe, as its benefit /cost ratio decreases in the face of continued declines in tuberculosis incidence in the community (15,16). Thus, Sweden gave up routine BCG in 1976 and restricts its use to defined high-risk groups (in particular contacts and recent immigrant populations) (7). Several health authorities in England have followed a similar path. Sweden has noted an increase in tuberculous meningitis and mycobacterial lymphadenopathies in children since discontinuing routine use of BCG (17). While these data confirm the utility of BCG against these conditions (the precise efficacy is difficult to estimate, they have not been considered important enough to reintroduce routine BCG vaccination for all children. A. Contraindications

In general, the world’s wealthier countries have more strict guidelines on contraindications to all vaccines than do the poorer countries, reflecting the different abilities of the health services to ascertain relevant information and to provide alternative preventive services to individuals in particular categories. As an example, BCG is contraindicated in the United Kingdom to individuals with impaired immunity (specifically on corticosteroid or other immunosuppressive therapy or under-

Figure 1 Efficacy of different BCG vaccines against different forms of tuberculosis [childhood tuberculous meningitis (TBM), miliary disease (MilTB), and pulmonary disease], and against leprosy, as measured in controlled trials (CT), case-control studies (CC), cohort studies (COH), and household contact studies (HH). These studies illustrate the variation reported within and between the various outcomes and study designs.

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going general radiation therapy) or with malignant conditions such as lymphoma, leukemia, Hodgkin’s disease or other tumor of the reticuloendothelial system, or who have impaired immunological mechanisms such as hypogammaglobulinemia as well as to anyone who is HIV positive, pregnant, tuberculin positive, febrile, or with a generalized septic skin condition (18). This contrasts with the current WHO guidelines for BCG use within the EPI, which mentions only clinical AIDS as a contraindication for BCG. Importantly, HIV positivity in the absence of clinical signs of impaired immunity is not considered a contraindication by the EPI (19). B. Administration

Most BCG vaccines now come in freeze-dried form, and all are extremely sensitive to sunlight. They have historically been given per os in some countries, but this procedure has now been discontinued everywhere, in part because it was reported to produce cervical lymphadenopathy in an unacceptably high proportion of vaccinees. By far the most common method of administration is by intradermal injection, employing a 25 or 26 gauge needle. A 0.1 mL dose is injected into the dermis, generally on the upper arm. Many manufacturers recommend a half dose for infants below the age of 1 year. Some countries (e.g., South Africa) have recommended BCG administration by the percutaneous route, with multiple puncture devices. V. The Protective Efficacy of BCG The protective efficacy of a vaccine is defined as the percentage reduction in risk among vaccinees as compared to a comparably exposed nonvaccinated group. As evident in Figure 1, this quantity is difficult to measure, let alone to summarize for BCG. All our evidence indicates that protection varies between vaccines and/or populations for reasons not yet known or not yet agreed upon. It is important to emphasize that this variability refers in particular to protection against pulmonary disease. For reasons that are not well understood, the protection imparted by BCG vaccination appears to be more consistently high against systemic forms of tuberculosis, in particular childhood tuberculous meningitis and miliary disease, than against (adult) pulmonary forms of the disease. Despite the observed differences in protection, we should note that the vast majority of evaluations of BCG vaccines show some degree of protection against pulmonary tuberculosis. This fact, along with their consistent protection against the severe systemic forms of tuberculosis, in addition to protection against leprosy, has supported their continued use in countries with high prevalence of these diseases. The great variation in BCG’s effectiveness should be obvious, but it still needs to be emphasized. A recent review of the subject failed to point out this heterogeneity and calculated a weighted average of published efficacy estimates, concluding “on average, BCG vaccine significantly reduces the risk of TB by 50% (20). Such a conclusion is improper statistically and is misleading for the im-

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munological and public health communities, as it implies that the variability observed is attributable to chance variations in study results. The implied logic is comparable to calculating the mean of the per capita incomes of Burkina Faso and of Switzerland and concluding that the world is, on average, middle class. There are real differences, and it is our task to understand them if we are to use BCG optimally, let alone to develop an improved tuberculosis vaccine. There is a large literature exploring various hypotheses for the variable behavior of BCG vaccines (21–23). The major themes are summarized briefly here. A. Methodological “Flaws”

Though undoubtedly some of the observed variation can be attributed to differences in study designs and implementation between the various studies, and even to some errors, there is a general acceptance that this cannot explain all the variation (24). The differences reflect important biological factors as well. B. Differences Between M. tuberculosis Strains

This idea was first proposed to explain the failure of BCG in the Chingleput trial, when it was noted that many strains of M. tuberculosis from that area were of relatively low virulence for guinea pigs (25). It was suggested that the “South India strain” bacilli were such as rarely to cause primary disease, against which BCG should be most protective, and that they were causing disease mainly through reinfection or reactivation, long after an initial infection. This idea was consistent with the observed low incidence of tuberculosis among individuals who were initially tuberculin negative, but it was not supported by subsequent animal experiments (26) and has been labeled a “red herring” by Mitchison himself (personal communication, 1997), who was first to note the low virulence of the South Indian strains. The idea has arisen again, recently, in the context of molecular epidemiological evidence for regional differences between M. tuberculosis “strains” on the basis of IS6110 fingerprints (27), but there is as yet no evidence that any of these differences are relevant for immunogenicity of BCG. C. Nutritional Differences Between Human Populations

That nutritional differences between populations might be relevant has repeatedly been suggested and may appear consistent with the tendency for the vaccines to provide less protection in poorer than in wealthier populations. Animal experiments show that extreme nutritional deficiencies affect susceptibility to tuberculosis, but there is little direct evidence that nutrition has affected BCG’s efficacy. The only study to employ a measure of nutritional status showed no association between protection and skinfold thickness (4), and it seems unlikely to attribute the similarly high protection in British schoolchildren and North American Indi-

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ans to good nutrition. Furthermore, the fact that the vaccines protect better against leprosy than against tuberculosis, in the same population, suggests that the failures against tuberculosis do not reflect just nutritional impairment of the immune response. D. Genetic Differences Between Host Populations

This idea keeps haunting the literature, though with very little direct support. Protection was observed to be slightly greater among whites than blacks in the U.S. Public Health Service trials, but this was based on small numbers and was not statistically significant (4). Case-control studies carried out in the United Kingdom indicate that BCG vaccines protect Asians in that environment better than in Chingleput (28,29). Of course this can be argued away, in that the Asians in the United Kingdom are for the most part not South Indian Dravidians, but the evidence is at least not in favor of a genetic influence. There is increasing evidence for genetic influences in tuberculosis, based upon linkage and association studies looking at genetic loci associated with cellular immune functions (30,31), but none of these studies has provided evidence directly relevant to the BCG story. For example, no one has yet compared genetic markers between cases with and without a history of BCG or between populations where BCG appears to work to different degrees. E. Strain Differences in BCG

The microbiological differences between BCG strains have made this an obvious explanation for the observed differences in protection. It is a particularly attractive hypothesis in that a demonstration of its validity would point to a very simple resolution to the BCG controversy—just use strain X, which is of demonstrable high efficacy, and identify the particular antigenic composition of that strain, which must be the key to protection. Two studies have provided evidence that different vaccines provided different protection in the same population. Comstock reanalyzed data from case-control studies in Indonesia and Colombia and found evidence that the effectiveness of BCG had declined after the programs shifting from Japan or Glaxo to Paris or Copenhagen vaccines (32). More convincing evidence is provided by a trial carried out in Hong Kong, where 300,000 infants were effectively randomized to receive either Paris or Glaxo BCG, either percutaneously or intradermally, over the years 1978 to 1982. Follow-up until 1986 revealed that those who had received the Paris vaccine experienced 40% less tuberculosis (p
0.05) (2). However, it is interesting to note that the specific strain implications noted in Hong Kong are the opposite of those suggested by Comstock’s analysis! Despite the evidence that the Paris strain might provide greater protection than the Glaxo product, Hong Kong concluded that both vaccines were highly effective and decided to discontinue the Paris vaccine because it was responsible for more adverse reactions than was the Glaxo strain.

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Evidence for a correlation between reactogenicity and efficacy has been suggested more recently by Behr and Small (33), who noted that the efficacy of several strains of BCG appeared to decline with serial subculture. They interpreted this as evidence that manufacturers were selecting vaccines on the basis of their ability to induce tuberculin sensitivity (a routine potency assay, though with no evidence of validity) and were consciously selecting against strains that induced lymphadenopathy. This is an interesting suggestion, but the result is confounded by the fact that later trials, which were carried out with higher passage number vaccines, generally took place at lower latitudes than did the earlier lowpassage vaccine trials, and it is known that latitude itself correlates with efficacy (34). In addition, the argument is countered by the fact that very different vaccines have been observed to behave similarly in the same population. The best example of this was provided by the British MRC trial, in which a strain of M. microti was observed to provide protection identical to that of the (Copenhagen) BCG. More importantly, there is good evidence that the same Glaxo freeze-dried vaccine that provides protection against tuberculosis in the United Kingdom fails to do so in some other populations, for example, in Malawi (35). Such evidence indicates that strain differences between BCG cannot explain all of the observed differences. F. Geographic Differences in Environmental Mycobacteria

The suggestion that interference or masking by environmental mycobacterial exposure can reduce the apparent efficacy of BCG is supported by several lines of evidence. Animal experiments show that exposure of guinea pigs or mice to various environmental mycobacterial species can induce significant protection against subsequent challenge with M. tuberculosis, and this protection varies depending upon the environmental species (8,36). Experiments have shown that the apparent protection imparted by BCG, when given “on top of” exposure to the environmental mycobacteria, is reduced, as the combination of prior exposures gives no more protection than does BCG alone. Such an observation makes sense and is consistent with two observations in humans. First is the finding that individuals with low levels of tuberculin sensitivity, such as are induced by environmental mycobacterial exposure, and individuals who respond more strongly to skin tests with PPD-B (M. intracellulare) than to M. tuberculosis, are at reduced risk of tuberculosis, implying that the environmental exposures provided some protection (37). The second observation is the evidence that BCG vaccines have in general been more effective in northern latitudes (34), far from the equator, than at warmer, wetter latitudes. Given that environmental mycobacteria are in general more prevalent in the warmer, wetter climates, this hypothesis provides an explanation for the crude latitude trend observed in BCG’s effectiveness. It is interesting to note that many of the low estimates of BCG efficacy have come from rural populations (9,35,38), and it has repeatedly been shown that individuals from ru-

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ral areas are more likely to have skin test evidence of prior mycobacterial exposure than do individuals from urban environments (39–41). VI. Protection Against Diseases Other Than Tuberculosis Though BCG is known primarily as a vaccine against tuberculosis, there is much evidence that BCG vaccines can (at least certain conditions) protect against other mycobacterial infections. Their effectiveness against leprosy has been evaluated repeatedly, and statistically significant protection has been shown in all studies. Though protection against leprosy appears to vary between populations (perhaps for reasons analogous to the tuberculosis situation), protection has been observed consistently against lepromatous as well as tuberculoid forms of the disease, and the three studies that have compared protection by BCG against leprosy and against tuberculosis in the same population have all observed higher protection against leprosy than against (pulmonary) tuberculosis (35,38,42). There is also evidence that BCG vaccination can impart some degree of protection against other mycobacterial diseases such as Buruli ulcer (M. ulcerans) (43) and lymphadenopathies associated with environmental mycobacteria such as M. avium. Evidence for the latter is based on increases in these conditions in children subsequent to discontinuation of routine BCG vaccination in Sweden and Czechoslovakia (44,45). There have been claims that BCG vaccination might prevent some cancers, in particular leukemias. Despite several reports, there is no convincing evidence for such effects. BCG vaccination has also been used in treatment of some malignancies, in particular breast and bladder cancers. There is no evidence that such treatment is effective in breast cancer patients (46), but several controlled trials have supported the use of BCG vaccines as an adjunct to surgery in the treatment of bladder cancer. VII. Adverse Reactions A local ulcer typically forms at the site of a BCG vaccination a few days after it is given. This persists for several weeks, rarely months, and generally leaves a moreor-less characteristic round, depressed scar. These scars have often been used in vaccine uptake surveys and as indicators of prior vaccination in case-control studies. It should be emphasized that though some BCG vaccination scars are distinctive, this is by no means true of all of them, and there is evidence that vaccination in infancy is less likely to leave a permanent scar than is vaccination in childhood or adolescence (47). This may be due in part to the convention of giving only half a dose (0.05 mL) to young infants, but may also reflect the nature of the immune

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response in young infants. There is no evidence as to whether or not the formation of a scar is a correlate of protection, but one study of scar size failed to show evidence of any association with protection against either tuberculosis or leprosy (48). Regional lymphadenopathy is reported in a small minority of vaccinees (generally less than 5%) and may occur more frequently with some vaccine strains (e.g., Pasteur) than others (e.g., Glaxo-Evans). Systemic BCGosis is a very rare complication that occurs in individuals with immune deficiencies. The advent of HIV has raised concerns about increased BCGosis, and several case reports and cohort studies have now been published (49). Some of the original cases arose as a consequence of the inappropriate use of BCG to treat AIDS (50). The importance of this issue led to a series of studies in Africa comparing local and systemic reactions to BCG among infants born to mothers with HIV infection to those in infants whose mothers did not have HIV (49). These studies found no evidence for significantly increased reactogenicity in the HIV-exposed and infected groups and hence support the WHO recommendation to give BCG to all infants except those with illness attributable to immunosuppression (51).

VIII. The Impact of BCG Vaccination Programs Despite the massive use of BCG vaccines for many years, it is difficult to measure their effect on tuberculosis morbidity in national or population statistics. BCG differs in this regard from all of the other widely used vaccines (diphtheria, tetanus, pertussis, polio, measles, rubella, mumps, and Haemophilus). There are four reasons for the difficulty in demonstrating BCG’s overall impact. First, BCG vaccines were introduced in developed countries against a background of already falling tuberculosis incidence and coincided with other improvements in tuberculosis case finding and treatment, which has made it difficult to demonstrate a specific BCG effect. Second is the fact that the main burden of tuberculosis is pulmonary disease in adults, in particular older adults, whereas BCG has been administered mainly to children. This means a delay of many years before vaccinated cohorts enter those age bands at highest risk of tuberculosis. It is not clear whether protection from the vaccination lasts sufficiently long to have an impact decades after administration [there are very few data on protection for more than 15 years (52)], and this lag exacerbates the problem of identifying BCG-attributable effects from declines attributable to other tuberculosis-control measures. Third, the advent of HIV in recent years has led to increases in tuberculosis in many populations, which obscure potential vaccine-attributable effects. And fourth, the fact that transmission of M. tuberculosis is mainly from adult pulmonary cases in endemic communities has meant that introduction of BCG has had little impact upon infection incidence (53).

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Despite the difficulty in identifying an obvious impact of BCG on global disease statistics, there are examples of population data that show clear effects of BCG. Analysis of age-specific trends of tuberculosis in the United Kingdom and Scandinavia showed a rapid decline in tuberculosis among young adults subsequent to introduction of the vaccine, and this was consistent with what was predicted in those cohorts as a consequence of vaccination (54). In addition, the discontinuation of BCG in Sweden and in Czechoslovakia has been associated with demonstrable increases in tuberculous meningitis and in glandular disease associated with atypical mycobacteria (17,44,45). Finally, the rapid declines in leprosy observed in many African countries have coincided with the introduction of wide-scale use of BCG on that continent and are consistent with the repeated observation of appreciable protection against leprosy by BCG vaccination on that continent.

IX. Improving Upon BCG Given the global import of tuberculosis, there is an obvious need for an improved vaccine against this disease. This is no simple task. The major obstacles against this development are twofold. First, we are asking a great deal of a vaccine to protect against a disease for which there is no evidence of solid “sterile” immunity in the first place. Though individuals and animals with a history of prior infection may have an enhanced resistance to subsequent challenge, there is much evidence both for reactivation disease in individuals who have been infected for many years and also for reinfection-attributable disease in individuals with prior history of infection. The majority of the tuberculosis burden in the world is in adults and is thought to reflect so-called endogenous reactivation or exogenous reinfection in individuals who have already met tubercle bacilli, and who thus have already had an opportunity to develop a homologous immune response to the antigens of M. tuberculosis. Tuberculosis differs from most of the other vaccine-preventable diseases in this respect (with the possible exception of varicella-zoster and hepatitis B, both of which are associated with chronic infections). In vaccinating against tuberculosis, we are thus trying to improve upon nature. The second obstacle against an improved tuberculosis vaccine is our ignorance of the immunological mechanism of protection against tuberculosis (see Chap. 8), which is in turn manifested in the absence of any known correlate of protective immunity. It was thought for many years that tuberculin sensitivity (see Chap. 12) provided a measure of protective immunity (55), but it is now recognized that this is not so, or at least that tuberculin sensitivity is a more complicated response than had been appreciated (32,56). Many studies have shown that strong tuberculin sensitivity is associated with high risks of disease. Such reactivity may be interpreted as reflecting ongoing aggressive immunological activity in the host, and the stronger the reactivity, the less likely it is to end in victory for the host. In-

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terestingly, several studies have suggested that a low degree of tuberculin sensitivity is more protective than a high degree (57), though it is unknown whether such sensitivity reflects prior exposure to tubercle bacilli or some cross-reacting antigens common to the tuberculin reagent and to other mycobacteria or even other related bacteria. Thus, despite the fact that some authors have described tuberculin delayed type hypersensitivity (DTH) as the “sine qua non” of protective immunity (55), others have argued that an effective vaccine should avoid inducing delayedtype hypersensitivity at all (58)! Such confusion, on top of the recognized difficulties associated with the standardization, batch variation, administration and reading of tuberculin reactions, has meant that tuberculin reactivity has provided a poor guide for the development of an effective tuberculosis vaccine. There is much hope that recent advances in our understanding of cell-mediated immunity, in particular the identification of various antigen-specific (and nonspecific) responses measurable in terms of cytokine release by particular cell types, may ultimately provide a clear correlate of a protective response against mycobacterial infection and hence provide a guide for the development of improved vaccine products. Despite these theoretical difficulties, several laboratories are actively pursuing the development of new tuberculosis vaccines. Three broadly different approaches are attracting attention. One is based on the identification and evaluation of subunit antigens of the tubercle bacillus. There is particular interest in secretory antigens, in particular ESAT-6 and antigens of the antigen 85 complex, which are thought to be released by tubercle bacilli early in the infection process (59). It is thus thought that an immune response to these antigens might affect tubercle bacilli early in the course of an infection. A second approach is based upon the development of mutant or auxotrophic strains of various mycobacteria, which might set up time-limited infections in the host but still induce protective immune responses (60). Yet a third approach involves the delivery of DNA encoding various specific mycobacterial antigens within plasmid carriers (61). This DNA is taken up by host muscle cells, where it is translated into foreign proteins, which then induce specific antibody and T-cell responses. There is now an active international collaborative program for the evaluation of new vaccine reagents in animal (mainly guinea pigs and mouse) models. Several reagents appear to provide as much protection as does BCG in these models, but none has yet done better. The animal models themselves raise profound questions, insofar as tuberculosis is an unnatural infection in all of them, and hence their relevance for the human situation is unclear. Furthermore, the observation that at least some BCG vaccines behave differently in different human populations raises questions about the interpretability of any single animal model. There is increasing recognition of the problems inherent in these experimental systems and interest in the development of models that mimic the human disease process. Thus, there is increased interest in models based upon low-dose challenge and which are associated with long latency (62).

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The ultimate evaluation of any new vaccine product in humans poses formidable difficulties. The experience gained in past BCG vaccine trials will be highly relevant to such evaluation but shows us that the evaluation of new vaccines is likely to be costly, time consuming, and difficult to interpret. A particular problem is raised by the fact that the most important ultimate target for a new tuberculosis vaccine is adult pulmonary disease, especially as it occurs in developing countries. It is on account of this form of the disease that tuberculosis was declared a global emergency by the WHO in 1993. What is more, BCG is likely to continue to be given in most highly endemic countries for the foreseeable future, and these vaccines appear to be providing reasonable protection against the childhood forms of tuberculosis, in particular meningitis. In addition, more than 90% of the world’s tuberculosis is in developing countries, and developed countries are moving away from BCG vaccines, even where they appear to be effective, given their low benefit-to-cost ratios under conditions of low incidence. The challenge is thus to provide a vaccine to protect against adult pulmonary disease in populations where BCG has already been widely used, where there is a high prevalence of nonspecific tuberculin sensitivity both from BCG and from environmental mycobacteria, and where a high proportion of adults has already met the tubercle bacillus. This is no easy task. In theory the best approach would be to develop a vaccine that was effective in individuals who have already been exposed to a variety of mycobacteria, BCG, environmental species, and perhaps M. tuberculosis itself and which could provide an appropriate boost to the immune response in such individuals. Whether such an approach is immunologically feasible is by no means clear. Research employing animal models is currently exploring the feasibility of various approaches to booster vaccination; if any are successful, this may open a window onto a new approach to immunoprophylaxis against tuberculosis. X. Immediate Prospects for Vaccination Against Tuberculosis Given the formidable challenges in the development and evaluation of a new and improved tuberculosis vaccine, it is likely that BCG vaccines will remain our only vaccines against tuberculosis for the foreseeable future. Given the imperfections of these vaccines, the medical, scientific, and public health communities would do well to at least try to maximize the benefits in their continued use. This should include the following actions. 1. Future evaluations of the effectiveness of BCG vaccines should not attempt simply to provide another point estimate of efficacy in another population, but should be designed to explain this estimate, in so far as

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is possible, in terms of the various current hypotheses relating to BCG’s variable behavior. Thus, it is now possible to explore whether any of the human genetic determinants newly recognized to be associated with tuberculosis, or any of the genetic variants in the tubercle bacillus that will be revealed in the mycobacterial genome projects, can explain the observed variation in BCG’s behavior. There needs to be a concerted effort to identify measurable immunological correlates of BCG’s behavior in different populations where the effectiveness of the vaccine is known. These data may point towards a measurable correlate of protection, which can be used both to guide policy, by revealing populations in which BCG works better or worse, and to guide the research community towards those immune responses that should be induced by an improved vaccine. Vaccine program managers should consider the important implications of changing vaccines. Changing vaccines often implies a change in reactogenicity, and this needs to be recognized in order to avoid excessive local reactions such as have occurred in several populations in recent years. Insofar as is possible, it would be helpful to set up additional comparisons between different vaccines, such as was carried out in Hong Kong. Such comparisons could be organized in some countries relatively easily and would ultimately provide valuable data on the relative efficacy of different vaccines. There is a need for additional data on the implications of repeated BCG vaccination. Booster vaccination has been policy in many countries but has been evaluated only once—in the recent trial in Malawi. A trial is currently underway in Brazil to evaluate a second BCG given to secondary school students. Similar evaluations should be carried out in other countries. There is a need for continued monitoring of the implications of BCG in high-HIV-prevalence populations.

An active program of research on these issues will enhance our understanding of BCG vaccines and allow us to use these vaccines to best effect. In addition, such research will provide an essential background for the development and ultimate evaluation of any new tuberculosis vaccine. Acknowledgment The author is grateful to Dr. Ilona Carneiro for assistance in preparation of the figure.

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4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

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21. Bloom BR, Fine PEM. The BCG experience: implications for future vaccines against tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection and Control. Washington, DC: American Society of Microbiology, 1994:531–557. 22. ten Dam HG. Research on BCG vaccination. Adv Tuberc Res 1984; 21:79–106. 23. ten Dam HG, Pio A. Pathogenesis of tuberculosis and effectiveness of BCG vaccination. Tubercle 1982; 63:225–233. 24. Clemens JD, Jackie JH, Chuong JH, Feinstein AR. THe BCG controversy: a methodological and statistical reappraisal. JAMA 1983; 249:23623–2369. 25. Mitchison DA. The virulence of tubercle bacilli from patients with pulmonary tuberculosis in India and other coutries. Bull Int Un Against Tuberc 1964; 35:287. 26. Hank JA, Chan JK, Edwards ML, Muller D, Smith DW. Influence of the virulence of Mycobacterium tuberculosis on protection induced by Bacille Calmette-Guerin in guinea pigs. J Infect Dis 1981; 143:734–738. 27. Hermans PWM, Messadi F, Guebrexabher H, et al. Analysis of the population structure of mycobacterium tuberculosis in Ethiopia, Tunisia and the Netherlands: Usefulness of DNA typing for global tuberculosis epidemiology. J Infect Dis 1995; 171:1504–1513. 28. Rodrigues LC, Gill N, Smith PG. BCG vaccination in the first year of life protects children of Indian subcontinent ethnic origin against tuberculosis in England. J Epidemiol Community Health 1991; 45:78–80. 29. Packe GE, Innes JA. Protective effect of BCG vaccination in infant Asians: a casecontrol study. Arch Dis Child 1988; 63:277–281. 30. Bellamy R, Ruwende C, Corrah T, McAdam K, Whittle H, Hill A. Variations in the NRAMPI gene and susceptibility to tuberculosis in West Africans. N Eng J Med 1998; 338:640–644. 31. Blackwell JM. Genetics of host resistance and susceptibility to intramacrophage pathogens: a study of multucase families of tuberculosis, leprosy and leishmaniasis in north-eastern Brasil. Int J Parasitol 1998; 28:21–28. 32. Comstock GW. Identification of an effective vaccine against tuberculosis. Am Rev Respir Dis 1988; 138:479–480. 33. Behr MA, Small PM. Has BCG attenuated to impotence? Nature 1997; 389:133–134. 34. Fine PEM. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995; 346:1339–1345. 35. Ponnighaus JM, Fine PEM, Sterne JAC, et al. Efficacy of BCG against leprosy and tuberculosis in Northern Malawi. Lancet 1992; 339:636–639. 36. Orme IM, Collins FM. Efficacy of Mycobacterium bovis BCG vaccination in mice undergoing prior pulmonary infection with atypical mycobacteria. Infect Immun 1984; 44(1):28–32. 37. Edwards LB, Acquaviva FA, Livesay VT. Identification of tuberculous infected: dual tests and density of reaction. Am Rev Respir Dis 1973; 108:1334–39. 38. Orege PA, Fine PEM, Lucas SB, Obura M, Okelo C, Okuku P. Case control study of BCG vaccination as a risk factor for leprosy and tuberculosis in Western Kenya. Int J Lepr 1993; 61(4):542–549. 39. Paramasivan CN, Govindan D, Prabhakar R, Somasundaram PR, Subbammal S, Tripathy SP. Species level identification of non-tuberculous mycobacteria from south Indian BCG trial area during 1981. Tubercle 1985; 66:9–15.

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40. Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Am Rev Respir Dis 1969; 99:1–132. 41. Comstock GW, Livesay VT, Woolpert SF. Evaluation of BCG vaccination among Puerto Rican children. AJPH 1974; 64(3):283–291. 42. Tripathy SP. Fifteen-year follow-up of the Indian BCG prevention trial. Bull Int Union Tuberc Lung Dis 1987; 62:69–72. 43. Smith PG, Revill WDL, Lukwago E, Rykushin YP. The protective effect of BCG against Mycobacterium ulcerans disease: a controlled trial in an endemic area of Uganda. Trans R Soc Trop Med Hyg 1976; 70:449–457. 44. Trnka L, Pankova D, Svandova E. Six years’ experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against Mycobacterium avium-intracellulare complex. Tuberc Lung Dis 1994; 75:348–352. 45. Romanus V, Hollander HO, Wahlen P, Olinder-Nielsen AM, Magnusson PHW, Juhlin I. Atypical mycobacteria in extrapulmonary disease among children. Incidence in Sweden from 1969 to 1990, related to changing BCG coverage. Tuberc Lung Dis 1995; 76:300–310. 46. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992; 339:1–15. 47. Fine PEM, Ponnighaus JM, Maine N. The distribution and implications of BCG scars, with particular reference to a population in northern Malawi. Bull WHO 1989; 67(1):35–42. 48. Sterne JAC, Fine PEM, Ponnighaus JM, Sibanda F, Munthali M, Glynn JR. The implications of BCG scar size for protection against tuberculosis and leprosy. Tuberc Lung Dis 1996; 77:117–123. 49. O’Brien KL, Ruff AJ, Louis MA, et al. Bacillus Calmette-Guerin complications in children born to HIV-1-infected women with a review of the literature. Pediatrics 1995; 95:414–418. 50. Disseminated Mycobacterum bovis infection from BCG vaccination of a patient with acquired immunodeficiency syndrome. MMWR 1985; 34:227–228. 51. BCG immunization and paediatric HIV infection. WHO Wkly Epidemiol Rec 1992; 67:129–132. 52. Sterne JAC, Rodrigues LC, Guedes IN. Does the efficacy of BCG decline with time since vaccination? Int J Tuberc Lung Dis 1998; 2:200–207. 53. Styblo K, Meijer J. Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem. Tubercle 1976; 57:17–43. 54. Bjartveit K, Waaler H. Some evidence of the efficacy of mass BCG vaccination. Bull WHO 1965; 33:289–319. 55. Mackaness GB. Delayed hypersensitivity and its significance. In: Fogarty International Proceedings No. 14: Status of Immunization in Tuberculosis in 1971. Washington, DC: U.S. DHEW, 1991:69–89. 56. Hart PD’A, Sutherland I, Thomas J. The immunity conferred by effective BCG and vole bacillus vaccines, in relation to individual variations in tuberculin sensitivity and to technical variations in the vaccines. Tubercle 1967; 48:201–210.

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57. Fine PEM. Immunities in and to tuberculosis: implications for pathogenesis and vaccination. In: Porter JDH, McAdam KPWJ, eds. Tuberculosis: Back to the Future. Chichester: J Wiley, 1993:53–74. 58. Dannenberg AM. Immune mechanisms in the pathogenesis of pulmonary tuberculosis. Rev Infect Dis 1989; 11 (suppl 2):S369–S378. 59. Andersen P. Host responses and antigens involved in protective immunity to mycobacterium tuberculosis. Scand J Immunol 1997; 45:115–131. 60. Guleria I, Teitelbaum R, McAdam RA, Kalpana G, Jacobs WR, Bloom BR. Auxotrophic vaccines for tuberculosis. Nature Med 1996; 2:334–337. 61. Lowrie DB, Silva CL, Colston MJ, Ragno S, Tascon RE. Protection against tuberculosis by a plasmid DNA vaccine. Vaccine 1997; 15:834–838. 62. Brown DH, Miles BA, Zwilling BS. Growth of Mycobacterium tuberculosis in BCGresistant and susceptible mice: establishment of latency and reactivation. Infect Immun 1995; 63:2243–2247. 63. Medical Research Council. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early life. Bull WHO 1972; 46:371–385. 64. Stein SC, Aronson JD. The occurrence of pulmonary lesions in BCG-vaccinated and unvaccinated persons. Am Rev Tuberc Pulm Dis 1953; 68:695–712. 65. Miceli I, de Kantor IN, Colaiacovo D, et al. Evaluation of the effectiveness of BCG vaccination using the case-control method in Buenos Aires, Argentina. Int J Epidemiol 1988; 17(3):629–634. 66. Wunsch Filho V, de Castilho EA, Rodrigues LC, Huttly SRA. Effectiveness of BCG vaccination against tuberculous meningitis: a case-control study in Sao Paulo, Brazil. Bull WHO 1990; 68(1):69–74. 67. Camargos PAM, Guimaraes MDC, Antunes CMF. Risk assessment for acquiring meningitis tuberculosis among children not vaccinated with BCG: a case-control study. Int J Epidemiol 1988; 17(1):193–197. 68. Putrali J, Sutrisna B, Rahayoe N. A case-control study of the effectiveness of BCG vaccination in children in Jakarta, Indonesia. Proceeding I of the Eastern, Regional Tuberculosis Conference of IUAT, 1983, Jakarta, Indonesia, pp. 194–200. 69. Murtagh K. Efficacy of BCG [letter]. Lancet 1980; 1:423. 70. Rosenthal SR, Loewinsohn E, Graham ML, et al. BCG vaccination against tuberculosis in Chicago. A twenty year study statistically analyzed. Pediatrics 1961; 28:622–41. 71. Fine PEM. Implications of different study designs for the evaluation of acellular pertussis vaccines. In: Brown F, Greco D, Mastrantonio P, Salmaso S, Wassilak S, eds. Pertussis Vaccine Trials. Basel: Karger, 1997:123–133. 72. Frimodt-Moller J, Acharyulu GS, Kesava Pillai K. Observations on the protective effect of BCG vaccination in a south Indian rural population. Bull Int Union Tuberc Lung Dis 1973; 48:40–52. 73. Comstock GW, Woolpert SF, Livesay VT. Tuberculosis studies in Muscogee County, Georgia: Twenty-year evaluation of a community trial of BCG vaccination. Pub Health Rep 1976; 91(3):276–280. 74. Comstock GW, Webster RG. Tuberculosis studies in Muscogee County, Georgia: VII—A twenty year evaluation of BCG vaccination in a school population. Am Rev Respir Dis 1969; 100:839–845.

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Fine Bettag OL, Kaluzny AA, Morse D, Radner DB. BCG Study at a state school for mentally retarded. Dis Chest 1964; 45(5):503–507. Blin P, Delolme HG, Heyraud JD, Charpak Y, Sentilhes L. Evaluation of the protective effect of BCG vaccination by a case-control study in Yaounde, Cameroon. Tubercle 1986; 67:283–288. Shapiro C, Cook N, Evans D, et al. A case-control study of BCG and childhood tuberculosis in Cali, Columbia. Int J Epidemiol 1985; 14:441–446. Jin BW, Hong YP, Kim SJ. A contact study to evaluate the BCG vaccination in Seoul. Tubercle 1989; 70:241–248. Tidjani O, Amedome A, ten Dam HG. The protective effect of BCG vaccination of the newborn against childhood tuberculosis in an African community. Tubercle 1986; 67:269–281. Padungchan S, Konjanart S, Kasiratta S, Daramas S, ten Dam HG. The effectiveness of BCG vaccination of the newborn against childhood tuberculosis in Bangkok. Bull WHO 1986; 64:247–258. Stanley SJ, Howland C, Stone MM, Sutherland I. BCG vaccination of children against leprosy in Uganda: final results. J Hyg (Camb) 1981; 87:235–248. Bagshawe A, Scott GC, Russell DA, Wigley SC, Merianos A, Berry G. BCG vaccination in leprosy: final results of the trial in Karimui, Papua New Guinea. Bull WHO 1989; 67:389–399. Tripathy SP. The case for BCG. Ann Natl Acad Med Sci 1983; 19:11–21. Lwin K, Sundaresan T, Gyi MM, et al. BCG vaccination of children against leprosy: fourteen-year findings of the trial in Burma. Bull WHO 1985; 63:1069–1078. Rodrigues MLO, Silva SA, Neto JCA, de Andrade ALSS, Martelli CMT, Zicker F. Protective effect of intradermal BCG against leprosy: a case-control study in central Brazil. Int J Lepr Other Mycobact Dis 1992; 60:335–339. Boelens JJ, Kroes R, van Beers S, Lever P. Protective effect of BCG against leprosy in South Sulawesi, Indonesia. Int J Lepr 1995; 63:456–457. Bertolli J, Pangi C, Frerichs R, Halloran ME. A case-control study of the effectiveness of BCG vaccine for preventing leprosy in Yangon, Myanmar. Int J Epidemiol 1997; 26:888–895. Baker DM, Nguyen-Van-Tham JS, Smith SJ. Protective efficacy of BCG vaccine against leprosy in southern Malawi. Epidemiol Infect 1993; 111:21–25. Convit J, Smith PG, Zuniga M, et al. BCG vaccination protects against leprosy in Venezuela: a case control study. Int J Lepr Other Mycobact Dis 1993; 61:185–191. Abel L, Cua VV, Oberti J, et al. Leprosy and BCG in southern Vietnam. Lancet 1990; 1:1536. Muliyil J, Nelson KE, Diamond EL. Effect of BCG on the risk of leprosy in an endemic area: a case control study. Int J Lepr Other Mycobact Dis 1991; 59:229–236.

Part Four SPECIAL PROBLEMS

20 Tuberculosis and Human Immunodeficiency Virus Infection

PHILIP C. HOPEWELL

RICHARD E. CHAISSON

University of California, San Francisco and San Francisco General Hospital San Francisco, California

Johns Hopkins University Baltimore, Maryland

Throughout the industrialized and developing world, tuberculosis and HIV disease are closely linked in mutually disadvantageous synergy: HIV infection promotes progression of tuberculous infection to disease, and tuberculosis accelerates the course of HIV disease (1,2). HIV infection greatly increases the likelihood that infection with Mycobacterium tuberculosis, either recent or latent, will progress to active tuberculosis. In fact, HIV infection may be the most potent risk factor for tuberculosis yet identified. Conversely, tuberculosis is the most common cause of death in persons with HIV infection throughout the world (Fig. 1). The extraordinary, deadly interactions of HIV and M. tuberculosis have been amplified by the rapid spread of HIV in populations with a high prevalence of tuberculous infection. Increasingly, therefore, the control of tuberculosis requires dealing with HIV infection, and vice versa. This chapter will review the interactions of HIV and M. tuberculosis and the special issues that are raised by coinfection with these two pathogens. I. Risk of Tuberculosis in Persons with HIV Infection A number of studies have described the incidence of tuberculosis in persons with HIV infection. In an early report, Selwyn and coworkers (3) followed a group of 525

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Figure 1.

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Causes of death among persons with HIV infection.

HIV-seropositive and -seronegative intravenous drug users in New York City. Of 49 HIV-seropositive subjects, seven who had positive (5 mm induration) tuberculin skin test reactions and one tuberculin-negative subject developed tuberculosis in a 2-year period (7.9 cases per 100 person-years of observation). These findings suggest that seven and perhaps all eight patients who developed tuberculosis had had preexisting tuberculous infection, indicating that endogenous reactivation was the dominant mechanism by which tuberculosis developed. Of additional concern was the observation that 11% and 13% of the seropositive and seronegative subjects, respectively, developed positive tuberculin skin tests during the study. If this observation is truly indicative of new infections, it suggests that there was a large number of infectious cases within the population. Selwyn and coworkers (4) reported subsequently that in the same cohort the incidence of tuberculosis was 6.6 cases per 100 in HIV-infected subjects who were anergic compared with 9.7 cases per 100 among those who were tuberculin positive. It could be assumed that in a population having a high prevalence of tuberculous infection, a negative tuberculin skin test in an HIV-infected person would likely be a false negative and that failure to react to the other antigens was a marker for severe immune compromise. Thus, such persons would be expected to have a high rate of tuberculosis. It would not be expected that this high risk of tuberculosis would apply to anergic persons from groups in which the prevalence of tuberculous infection is low. Allen and colleagues (5) prospectively followed a cohort of women of childbearing age in Kigali, Rwanda, and found that the incidence of tuberculosis was approximately 2.5% per year. In comparison with HIV-negative women the risk ratio (RR) for tuberculosis among the HIV-infected women was 22.9. Among the HIV-positive women, having had a positive tuberculin skin test was associated with a significantly increased risk of tuberculosis but the risk ratio was only 3, and 9 of 17 patients with tuberculosis had negative tuberculin tests, perhaps as a result of anergy.

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In a prospective study conducted in 23 hospital infectious disease units in Italy, Antonucci and coworkers (6) reported that the 12-month rate of tuberculosis among 2760 HIV-infected subjects was 2.2%. Among subjects with positive (5 mm) tuberculin tests, the 12-month incidence was 4.5%, whereas among persons who were anergic (failed to respond to seven intradermal antigens), the incidence was 2.9%. The cohort from which these data were derived consisted largely (72%) of injecting drug users. Graham and associates (7) have also prospectively determined the rate of tuberculosis in HIV-infected injecting drug users in a cohort from Baltimore. These investigators reported an overall annual rate of tuberculosis of 0.22%, substantially lower than the rates reported from other areas and perhaps reflecting less transmission of new infection in the community. In Europe there is a north-to-south gradient in the percentage of AIDS patients with tuberculosis (8). In the northern region 5.6% of AIDS patients are reported to have tuberculosis, in central Europe, 11.8%, and in the south 25%. In the study describing the north-south gradient in Europe, the factor that was most associated with the incidence of tuberculosis in multivariate analyses was the geographic area of residence. This was assumed to be a proxy for the community prevalence of tuberculosis, which is highest in the south, lower in the central, and least in the north. As noted below, the relationship to the local prevalence of tuberculosis has also been observed in the United States. In perhaps the most intensive study reported to date, Markowitz and associates (1) followed a cohort of HIV-infected persons in six cities in the United States (New York, Newark, Detroit, Chicago, Los Angeles, San Francisco) for approximately 4.5 years. The group included mainly homosexual men and injection drug users. Subjects with a broad range of immunosuppression were included. The overall rate of tuberculosis was 0.7 per 100 person-years. In multivariate analyses the factors most associated with increased incidence were place of residence (RR for Eastern sites  3.3 compared with midwest and western sites together). Rates were also higher among subjects with a positive tuberculin test (4.5 per 100 person-years) and for those who developed a new positive tuberculin test (5.4 per 100 person-years). From all the data summarized above it is evident that there is no single figure that conveys the risk of tuberculosis in persons with HIV infection. There are at least four factors that are associated with the variations in reported rates. The first of these factors is the prevalence of latent infection with M. tuberculosis in the population represented by the cohort. Second is the likelihood of exposure to infectious tuberculosis, a function of the prevalence of tuberculosis in the population the cohort represents. The third factor is the degree of immunosuppression among cohort members. Finally, the use of preventive therapy (treatment of latent infection) by cohort members will have an important effect in reducing the incidence of tuberculosis.

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Beginning in 1988, a systematic sampling of the prevalence of HIV infection in newly reported tuberculosis cases in the United States was undertaken by the Centers for Disease Control and Prevention (CDC) in 14 urban tuberculosis clinics (9). The median seropositivity rate in 4301 persons with or suspected of having tuberculosis in these clinics was 3.4%. The rates varied widely, ranging from 0 to 46%. The highest rate was reported from New York City (46%), followed by Newark (34%), Boston (27%), Miami (24%), and Baltimore (13%). In 1990, the survey was expanded to 24 clinics in 16 cities and the median HIV seropositivity rate was 7.5% (10). In 1991, 33 clinics in 20 cities reported a median seropositivity rate of 9.5%. Trend data are available for 13 large urban areas that conducted surveys each year. The overall seroprevalence rate in these areas in 1989 was 13%, in 1990 18%, and in 1991 21%. During the 1989–1991 interval, HIV seroprevalence among males increased from 15 to 28% among Hispanics, 24 to 40% among African Americans, and 12 to 20% among whites. Among Asians, the HIV seroprevalence was less than 1% throughout the period. Extrapolating from these data and from tuberculosis case rates, it was estimated that approximately 2000 tuberculosis patients between 15 and 54 years of age were infected with HIV in the 13 areas participating in the study. Although data are incomplete, among persons aged 25–44 in the United States with tuberculosis reported in 1995, the percentage who were HIV infected ranged from 0% (Vermont with only one case) to 60.6% (New York City) (11). However, there is evidence that the impact of HIV may be decreasing. In San Francisco, for example, the proportion of tuberculosis cases with HIV infection decreased from a high of 20% in 1994 to 16% in 1996, an observation consistent with both a decreasing prevalence of HIV infection and a decreasing incidence of tuberculosis (Fig. 2) (12). Data from developing countries indicate a substantial rate of HIV infection among patients with tuberculosis (13–18). In 1992, Raviglione and associates (15) from the World Health Organization (WHO) estimated that worldwide there were approximately 4 million persons who are infected with both M. tuberculosis and HIV, nearly 80% of these being in Africa. As summarized by DeCock and coworkers (19), various studies have reported the prevalence of HIV infection among tuberculosis patients in sub-Saharan African countries to range from 20 to 67%. In 1998, however, the WHO and the United Nations AIDS Program (UNAIDS) estimated that of a global total of over 30 million people living with HIV infection, 15 million were coinfected with M. tuberculosis, mostly in sub-Saharan Africa. Although this estimate is quite rough, it reflects the devastating impact that HIV is having on developing countries. The growth of the HIV epidemic in Africa is unparalleled in recent history. UNAIDS now estimates that more than 10% of the entire populations of some

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Figure 2. Tuberculosis cases and cases with HIV infection, San Francisco, 1980–1996. (From the Division of Tuberculosis Control, Department of Public Health, City and County of San Francisco, California.)

countries in sub-Saharan Africa are HIV-infected. The effect of this in tuberculosis rates has been monumental. In a survey of national tuberculosis programs in sub-Saharan Africa, Cantwell and Binkin (20) found increases in tuberculosis incidence in virtually all countries. The increases were largest in countries with the highest HIV prevalences and with the poorest quality National Tuberculosis Programs. Nonetheless, in countries with very good tuberculosis control programs but a high HIV prevalence, tuberculosis case rates have risen substantially. In Botswana, for example, which has had a model tuberculosis control program using directly observed therapy for more than 15 years, the incidence of disease has increased by more than 25% since 1995. The effect of HIV on tuberculosis rates is also apparent elsewhere. In Chiang Rai, Thailand, tuberculosis incidence doubled in a period of several years in the early 1990s as the HIV epidemic emerged (21). Similar increases are being seen elsewhere in Thailand in India and in Latin America. HIV infection therefore contributes to the risk of tuberculosis at both the individual level and the community level. The WHO estimates that by the year 2000, at least 12% of the global tuberculosis burden will be associated with HIV infection, up from 4% in 1995 (18). III. Influence of HIV Infection on the Pathogenesis of Tuberculosis Tuberculosis develops by either direct progression from recently acquired infection or reactivation of latent infection. In areas of low prevalence of tuberculosis,

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it is generally thought that most cases arise from latent infections, because few new infections are occurring (22). HIV impairs the host response to both new and latent infections. However, the risk of rapid progression of new infection is much greater among persons with HIV infection, thus, an increasing number of cases may be occurring via this sequence. In areas where the number of new cases (providing more sources of infection) is increasing, there will be more transmission of infection and, thus, more opportunity for direct progression to occur. Under these circumstances, the epidemiology of tuberculosis in some parts of low-incidence countries may evolve to resemble that of developing countries in which there is a high prevalence of the disease. Cell-mediated immunity is the predominant mechanism by which a contained tuberculous infection is kept quiescent (23). Because of the effect HIV infection has on cell-mediated immunity, the likelihood of reactivation of latent tuberculous infection leading to clinical tuberculosis is greatly increased. For this reason persons with latent tuberculous infection are at greatly increased risk of developing tuberculosis after being infected with HIV. In the healthy host, once the cell-mediated immune response to infection with M. tuberculosis develops, there is a low likelihood that new exogenous infection will be acquired. However, reinfection has been documented in persons without evident immune compromise (24). Because of the immune defect induced by HIV, someone who has been previously infected with M. tuberculosis may still be vulnerable to new infection. Reinfection with drug-resistant organisms has been demonstrated by RFLP analysis among HIV-infected persons being treated for drug-susceptible tuberculosis (25). Data from San Francisco using DNA fingerprinting of M. tuberculosis strains suggest that at the community level (even a community in which during the study period approximately 23% of the patients with tuberculosis had HIV infection) reinfection is rare (26). Only one of 44 patients with positive cultures for M. tuberculosis 90 days apart appeared to have been infected with a second strain. Reinfection may, however, be more common in areas such as sub-Saharan Africa, where both the prevalence of infectious tuberculosis and of HIV infection are high. It has been speculated that HIV-infected patients are more likely to acquire tuberculous infection when exposed to M. tuberculosis (27). Although this concept is unsubstantiated, it has been clearly demonstrated that once an HIV-infected person becomes infected with M. tuberculosis, the infection can progress very rapidly to cause clinical disease (27,28). In situations where groups of HIVinfected persons are exposed to a patient with infectious tuberculosis, explosive outbreaks of tuberculosis may occur. For example, in a residential care facility for HIV-infected persons in San Francisco, 11 of 31 (35%) residents exposed to a person with infectious tuberculosis developed active tuberculosis within 120 days (27). By the use of DNA fingerprinting it was confirmed that tuberculosis was

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caused by the same strain of M. tuberculosis in all 11 of the culture-positive patients. Population-based application of DNA fingerprinting over a 5-year period in San Francisco has demonstrated that, although clustering (more than one case caused by the same strain of M. tuberculosis) occurs in both HIV-infected and uninfected persons, large clusters are more likely to involve persons with HIV infection (R. Jasmer, personal communication). This sort of clustering could be the result of social circumstances, the HIV-induced immune compromise, or both. In fact, a combination of social and biological factors would appear to be the most plausible explanation. Because M. tuberculosis is a potential virulent pathogen even in the normal host, tuberculosis tends to occur relatively early in the course of HIV infection. This is supported by the findings of several groups that HIV-seropositive patients with tuberculosis tend to have higher CD4 lymphocyte counts than patients with other “opportunistic” infections such as Pneumocystis carinii pneumonia (29,30). For example, in a group of 17 patients, reported by Theuer and associates (29), tuberculosis was the initial manifestation of HIV infection in all but two patients, and the median CD4 lymphocyte count was 354/L. Tuberculosis can occur later in the course of HIV infection, however, and the clinical manifestations tend to vary with the level of HIV-induced immunosuppression. Patients with lower CD4 counts tend to have more dissemination of their disease, including mycobacteremia (30). IV. Diagnosis of Tuberculous Infection and Tuberculosis The approach to diagnosing tuberculous infection and tuberculosis in the setting of HIV infection is essentially the same as is used in persons without HIV infection (see Chap. 14). The sensitivity of tuberculin skin testing is substantially reduced in HIV-infected people. A. Tuberculin Skin Testing and Anergy Testing

The tuberculin skin test (see Chap. 12) may show little or no reaction in persons with advanced HIV infection, particularly in populations with a low prevalence of tuberculous infection. However, in earlier stages of the infection, reactivity may be maintained. The ability to respond to tuberculin is an indicator of the status of cell-mediated immunity that in turn is an indicator of the stage of HIV infection. Nonetheless, even in advanced HIV disease, up to 50% of patients with confirmed tuberculosis have a reactive tuberculin test (31). In a study reported by Markowitz and coworkers (32), the prevalence of positive (5 mm induration) tuberculin skin tests decreased progressively as the CD4 cell count decreased. The relationship between CD4 cell count and the preva-

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Figure 3. Tuberculin skin test reactions in persons with HIV infection and differing CD4 lymphocyte counts compared with an HIV-uninfected control group. (From Ref. 32.)

lence of tuberculin reactions is shown in Figure 3. In addition, the rate of reactivity to mumps and candida skin test antigens was related to the CD4 count. Stated conversely, the prevalence of anergy increased with decreasing CD4 counts, as shown in Figure 4. It should be noted, however, that the prevalence of anergy was 42% among non–HIV-infected injecting drug users and 12% among homosexual/bisexual men.

Figure 4. Proportion of HIV-infected subjects with anergy defined as failure to react to tuberculosis, mumps, and candida antigen. (From Ref. 32.)

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Chin and associates (33) described the results of serial skin testing using candida and mumps antigen as well as tuberculin in a cohort of HIV-infected subjects. Of the subjects who had no reaction to any of the three antigens, 30% reacted to mumps or candida antigen when tested a year later, thus reverting from being anergic to being reactive, counter to what would be expected as HIV infection progressed. These same investigators also examined the results of mumps antigen tests in 50 subjects who had a false-negative tuberculin test after a previous positive test. The mumps antigen test was reactive in 39% of the subjects when the tuberculin test was falsely negative. Given the unreliability of anergy testing, the authors concluded that anergy tests should not be used to make individual patient decisions concerning the validity of a negative tuberculin skin test result. In a study of Johnson and coworkers in Haiti (34), although HIV-infected adults were more likely to have no reaction to tuberculin, 65% had reactions 5 mm, similar to the 70% of HIV seronegative adults who had 10 mm reaction. In sum, these studies illustrate that tuberculin skin testing retains clinical value in the presence of HIV infection. Because of the frequency of blunted skin test responses, or anergy, it is recommended by the American Thoracic Society and the CDC that a reaction of 5 mm induration to 5 tuberculin units of purified protein derivative be regarded as indicative of tuberculous infection in HIV-infected persons (35). The validity of a 5 mm cutoff is suggested by the finding that the risk of tuberculosis is substantially increased in persons with reaction sizes 5 mm compared with the risk in persons with 1–5 mm reaction. As reported by Markowitz and coworkers (1), the rate of tuberculosis in a cohort of HIV-infected subjects who had 0 mm reaction was 0.5 cases per 100, with reactions of 1–4 mm the rate was 0, with 5–9 and 10–19 mm the rates were 2.4 and 2.5, respectively, and for reactions 20 mm the rate was 5.4. B. Clinical Features of Tuberculosis

The clinical manifestations of tuberculosis in patients with HIV infection depend, at least in part, on the severity of the immunosuppression (29,30,36). As noted previously, presumably because of the virulence of M. tuberculosis, tuberculosis may occur relatively early in the course of HIV infection. In the series reported by Markowitz and coworkers (1) in which HIV-infected subjects were followed prospectively, the median CD4 lymphocyte count within 6 months before the diagnosis of tuberculosis was 144/L, with a range of from 2 to 543/L. Thus, the immunodeficiency was relatively severe but not as severe as was noted in subjects who developed infections such as P. carinii pneumonia or disseminated M. avium complex disease. It has been shown that the earlier tuberculosis develops, the more “usual” is its clinical presentation, whereas the later it occurs, the more atypical are its fea-

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tures (30). Clinical reports have emphasized that tuberculosis in advanced HIV infection is frequently disseminated, has unusual radiographic manifestations, and produces nonreactive tuberculin skin tests. Lymph node involvement, including intrathoracic adenopathy, has been described frequently. Jones and coworkers (30), in a retrospective analysis, correlated the manifestations of tuberculosis with CD4 lymphocyte counts in patients with HIV infection. These investigators reported a clear association between low CD4 cell counts and an increased frequency of extrapulmonary tuberculosis, positive blood cultures for M. tuberculosis, and intrathoracic adenopathy on chest radiograms. Conversely, pleural effusions were more frequent in persons with CD4 cell counts 200/L. Of the 31 patients reported by Markowitz and associates (1), 16 (52%) had only pulmonary involvement, 7 (23%) had only extrapulmonary disease, and 8 (26%) had extrapulmonary and pulmonary sites of disease. Given that this cohort was followed prospectively, the distribution of sites of involvement is probably more representative of the HIV-infected population as a whole. A variety of unusual manifestations of tuberculosis have been noted in HIVinfected patients. These include central nervous system involvement with brain abscesses, tuberculomas and meningitis, bone (including vertebral) disease, pericarditis, gastric tuberculosis, tuberculous peritonitis, and scrotal tuberculosis. In addition, M. tuberculosis has been cultured from the blood as well as bone marrow. However, despite the increased frequency of unusual forms of tuberculosis in persons with HIV infection, standard pulmonary disease tends to predominate in most series (1,29–31). C. Radiographic Findings

The unusual findings on chest radiographs of HIV-infected patients who have tuberculosis have received considerable emphasis. In retrospective studies, features that are not regarded as “typical” for pulmonary tuberculosis have been the norm (37,38). Lower lung zone or diffuse infiltrations have been commonly observed rather than the usual upper lobe involvement. Cavitation has been less frequent and intrathoracic adenopathy has been relatively frequent, as noted in a report by Jones and associates (30). Small and associates (39) followed the radiographic course of treated pulmonary tuberculosis in persons with HIV infection and noted that, in general, there was rapid improvement with little residual scarring after completion of therapy. Of note was the fact that all eight patients who had radiographic worsening had new superimposed diseases other than tuberculosis. D. Bacteriological Examinations

The proportion of positive sputum smears and cultures in patients with pulmonary tuberculosis is approximately the same in HIV-infected and noninfected persons,

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although this finding has not been universal (14,29,40). In some instances, sputum induction or bronchoscopic procedures have been necessary to diagnose pulmonary tuberculosis, although the diagnostic yield of bronchoscopy is no greater in HIV-infected than in uninfected patients (41). The general lack of cavitation in patients with HIV-related tuberculosis probably accounts for a lower number of bacilli in expectorated sputum. Because of the high frequency of extrapulmonary involvement, specimens from any site of abnormality in patients with or suspected of having HIV infection should be examined for mycobacteria by smear and culture. Potential high-yield sources include lymph nodes, bone marrow, urine, and blood (42). The value of nucleic acid amplification assays for diagnosis HIV-related tuberculosis is no greater than for other patient populations (43). V. Treatment There is substantial information from both retrospective and prospective studies indicating that treatment regimens that include isoniazid and rifampin for 6 months supplemented by pyrazinamide and ethambutol (or streptomycin) are effective in treating HIV-infected patients with tuberculosis (see Chap. 16), although this has been questioned (44–48). A summary of the results of prospective trials is given in Table 1. In a study in Zaire by Perriens and associates (45), it was shown that prolongation of isoniazid and rifampin administration for an additional 6 months resulted in a lower relapse rate compared with the results in a group given placebo. Unfortunately, rates of survival were no different in the group given extended therapy. Of note was the fact that the HIV-uninfected control group had the same relapse rate as the HIV-infected group treated for 6 months.

Table 1 Treatment Outcomes for HIV-Related Tuberculosis Results from Prospective Studies Author

Setting

Perriens

Zaire

Kassim

Cote D’lvoire

Chaisson

Haiti

El-Sadr

United States

Patients (N) HIV (119) HIV (121) HIV (180) HIV1 (106) HIV2 (86) HIV1/2 (138) HIV (198) HIV (129) HIV (212) HIV (51) HIV (50)

Regimen

Relapses (%)

2IRZE/4IR 2IRZE/7IR 2IRZE/4IR 6IR/2ZE 6IR/2ZE 6IR/2ZE 6IR/2ZE 2 I3R3Z3E3/4 I3R3 2 I3R3Z3E3/4 I3R3 2IRZELevo/4 IR 2IRZELevo/7 IR

8 1 5 3 4 7 3 5 3 4 2

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In spite of the differences in relapse rates, whatever the cause, the investigators did not feel that their findings justified prolongation of chemotherapy as a routine in developing country circumstances. Chaisson and colleagues (46) conducted a prospective study that compared the outcome of therapy in HIV-infected and noninfected patients in Haiti. The treatment regimen consisted of isoniazid, rifampin, pyrazinamide, and ethambutol given three times weekly for 2 months, followed by isoniazid and rifampin three times weekly for 4 months. Although the death rate from nontuberculosis causes was greater among the HIV-infected group, rates of treatment failure and relapse were not different for HIV-seropositive patients and those who were not infected. El-Sadr and associates (47) have recently reported the results of a trial in which patients with HIV-related tuberculosis were randomly assigned to receive either a 4- or 7-month continuation phase of isoniazid and rifampin after a 2month induction phase of four or five drugs. Of 102 patients enrolled, only one patient in the 9-month treatment arm relapsed versus two in the 6-month arm. One of the two relapses in the latter arm was confirmed by DNA fingerprinting to be a new infection. Current recommendations state that for adult patients with HIV infection, treatment for tuberculosis should include isoniazid 300 mg/day, rifampin 600 mg/day (450 mg/day for persons weighing less than 50 kg), pyrazinamide 20–30 mg/kg/day, and ethambutol 15 mg/kg/day during the first 2 months of therapy; isoniazid and rifampin should be continued for at least another 4 months, making the total duration of therapy at least 6 months (49). Directly observed therapy (DOT) is considered to be the standard of care by many in the field (48–52). Regimens using DOT have been advocated by the WHO as the key to controlling tuberculosis in developing countries (53). DOT can be facilitated by twice-weekly drug administration after an initial phase of daily treatment or even, as demonstrated in Haiti, a thrice-weekly regimen throughout the course of treatment. A study in Baltimore demonstrated that mortality was lower for HIV-infected tuberculosis patients who received DOT rather than self-administered therapy (31). For patients with pulmonary tuberculosis, response to therapy should be determined by bacteriological examination of sputum as well as by clinical and radiographic examinations. In patients with less accessible sites of disease, generally only clinical and radiographic evaluations can be used to determine the response. It should be kept in mind that worsening clinical and radiographic findings may be caused by other HIV-related diseases. There is probably less of a margin for error (i.e., missed doses) in patients with HIV infection, thus, the threshold for prolonging therapy should be low. If there is a period of noncompliance or if the disease responds more slowly than would be expected, treatment should be prolonged. Overall, however, it is probably more important to supervise closely a regimen of 6 months than to give a longer regimen with a lesser degree of super-

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vision. Patients who cannot take isoniazid and rifampin together should be treated for a minimum of 18 months, usually with isoniazid or rifampin and ethambutol plus pyrazinamide in the initial phase. This recommendation also applies to patients with tuberculosis caused by organisms that are resistant to isoniazid or rifampin. There are several areas in which therapy for tuberculosis in persons with HIV infection differs from that for HIV-negative persons. Although rates of relapse do not seem to be increased, some data suggest at least an ecological association between HIV infection and acquired drug resistance, especially resistance to rifampin alone (54). The data indicated that having HIV infection, having gastrointestinal symptoms, and being noncompliant were the main factors associated with acquired rifampin resistance. The mechanism by which rifampin resistance develops is unclear, but alteration in drug absorption or other kinetics is suggested by the association with HIV infection and with gastrointestinal symptoms. Patel and associates (55) reported two patients with HIV infection who relapsed: one with rifampin-resistant M. tuberculosis and one with isoniazid- and rifampin-resistant organisms. In both patients suboptimal serum levels of isoniazid, rifampin, and ethambutol were found. A recent report by Benator and colleagues (56) found that HIV-infected tuberculosis patients treated with rifapentine, a new rifamycin with a long serum half-life, had an unusually high rate of relapse (10%) with acquired rifampin resistance. Factors associated with acquired rifampin resistance included low CD4 cell count, diarrhea, and azole use. In view of these observations, measurement of serum drug concentrations should be considered in patients who are not responding to treatment (given as DOT) and who have susceptible organisms (57). Consideration could also be given to routine measurement of drug levels in patients who have risk factors for having subtherapeutic concentrations. Another potential cause for rifampin resistance is the use of rifabutin as prophylaxis for M. avium complex disease in a person who is not recognized as having tuberculosis or who acquires a new tuberculous infection (58). For this reason tuberculosis should be carefully excluded before beginning rifabutin prophylaxis. A second special concern in treating tuberculosis in patients with HIV infection is the potential interaction of the antituberculosis agents with other drugs. Of particular concern is an interaction between rifamycin derivatives and the protease inhibitor class of antiretroviral agents (59). Similar problems are expected with nonnucleoside reverse transcriptase inhibitors. The interaction is bidirectional with rifamycins, inducing hepatic P450 cytochrome oxidases, which accelerates the metabolism of the protease inhibitors and may result in subtherapeutic concentrations; conversely, protease inhibitors may decrease rifamycin metabolism, thus increasing its serum concentration resulting in increased drug toxicity. Rifabutin is a less potent inducer of the cytochrome P450 system and is

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preferred when antiretroviral drug interactions are of concern. Guidelines for using rifamycins and antiretroviral agents are emerging. The CDC has presented four options, summarized in Table 2 (59). Of these, the most practical for many patients is the concurrent use of indinavir or nelfinavir and rifabutin, with careful clinical monitoring. The antifungal agents ketoconazole and fluconazole both have interactions with isoniazid and rifampin resulting in reduction in serum concentrations of the antifungal agents (60,61). In addition, ketoconazole interferes with the absorption of rifampin. A third issue in the treatment of HIV-related tuberculosis is the occurrence of paradoxical worsening of signs and symptoms in patients receiving combination antiretroviral therapy. These so-called reversal or paradoxical reactions are similar to the Type 1 reactions of lepromatious forms of leprosy and represent reconstitution of the immune response to mycobacteria. Typical presentations involve the new onset of fever, lymphadenopathy, new or worsening infiltrates, effusions, and, less often, abscesses. Narita and coworkers (62) found that 36% of patients with HIV infection being treated with combination antiretroviral therapy had paradoxical reactions, compared to only 7% of patients not receiving antiretroviral drugs. Symptoms and signs generally begin about 3–6 weeks after antiretroviral therapy is initiated. Patients who have paradoxical reactions typically have initially very low CD4 levels, which rise modestly with therapy. Treatment is supportive (e.g., antipyretics, drainage of effusions or abscesses), although corticosteriods may be required for severe cases. It is impor-

Table 2 Options for Avoiding Interactions Between Rifamycins and Protease Inhibitors 1. Management of HIV/TB patients who are not on protease inhibitor therapy: For HIV-infected patients with TB for whom protease inhibitor therapy is being considered but has not yet been initiated: administer a complete regimen containing rifampin before initiating PI therapy. 2. Management options for HIV/TB patients who are on protease inhibitor therapy: Option I. Discontinue the administration of the PI and administer a complete regimen containing rifampin. When complete (usually in 6 months), restart PI therapy: Option II. Discontinue the administration of the PI and administer a four-drug TB treatment regimen containing rifampin for a minimum of 2 months, then substitute rifabutin 150 mg/day. Option III. Continue the PI therapy with indinavir or nelfinavir and administer a daily four-drug, 9-month TB treatment containing rifabutin (150 mg/day) in place of rifampin. Source: Ref. 59.

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tant to rule out treatment failure due to drug resistance or noncompliance, as well as other opportunistic diseases.

VI. Tuberculosis Caused by Multidrug-Resistant Organisms Outbreaks of tuberculosis caused by multidrug-resistant (MDR) M. tuberculosis resistant to at least both isoniazid and rifampin have been described as taking place in hospitals and clinics and have, predominantly, involved HIV-infected patients (63). Patients and health-care workers, both HIV seropositive and negative, were infected. Substantial epidemiological and laboratory (RFLP analysis) data indicated that transmission of the resistant M. tuberculosis took place in healthcare facilities (25,63–65). These outbreaks were characterized by very high case fatality rates, ranging from 72 to 89% in median times ranging from 4 to 16 weeks. Also noteworthy were the relatively high rates of tuberculin skin test conversions among health-care workers exposed to these patients. In New York City a very worrisome strain resistant to at least the four first-line drugs and often resistant to seven drugs was prevalent throughout the city and mainly occurred in patients with HIV infection (65,66). At least three factors led to these outbreaks. The first was a relatively high prevalence of multiple drug resistance in the communities in which they occurred, particularly in the groups that are most likely to be HIV infected (67). The high prevalence of drug resistance, a predictable outcome of the lack of attention and resources devoted to tuberculosis during the 1970s and 1980s, provided a reservoir of MDR organisms. Second is the effect of HIV on the host response to tuberculous infection. As noted earlier, recently acquired infection with M. tuberculosis in an HIV-infected person may progress very rapidly to cause clinical disease, which in turn is capable of being transmitted (27,28). If the organism causing disease in the source patient is MDR, all of the secondary infections will be caused by MDR organisms. The third factor is that tuberculosis in HIV-infected persons may not be easily recognizable. For this reason the disease may go undiagnosed, perhaps in a hospital or clinic environment, for a relatively prolonged period of time (67). During this time, unless adequate infection control measures are applied presumptively, the patient will be capable of transmitting the infection. Moreover, even if the disease is diagnosed, it may not be appreciated for several weeks that the organisms are MDR because of the time required for standard techniques to identify drug resistance. An additional important factor that contributed to the spread of MDR organisms was the lack of effective controls for airborne infections in many health-care facilities (67). Because of the possible delays in determination of drug resistance, in areas where there is a high prevalence of tuberculosis caused by resistant organisms, em-

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piric therapy based on prevailing resistance patterns may be necessary. Once the drug susceptibility results are known, regimens can be appropriately tailored. At least two agents to which the organisms are thought to be susceptible should be used. In some instances, this may entail use of agents such as the fluorquinolones and amikacin, which are not yet approved as antituberculosis drugs. Table 3 lists possible regimens that may be used for MDR tuberculosis (68). Treatment regi-

Table 3 Potential Regimens for Patients with Tuberculosis with Various Patterns of Drug Resistance Resistance Isoniazid, streptomycin, and pyrazinamide

Isoniazid and ethambutol ( streptomycin)

Isoniazid and rifampin ( streptomycin)

Isoniazid, rifampin, and pyrazinamide ( streptomycin)

Isoniazid, rifampin, and pyrazinamide ( streptomycin)

Isoniazid, rifampin, pyrazinamide, and ethambutol, ( streptomycin)

Suggested regimen Rifampin Pyrazinamide Ethambutol Amikacina Rifampin Pyrazinamide Ofloxacin or ciprofloxacin Amikacina Pyrazinamide Ethambutol Ofloxacin or ciprofloxacin Amikacina Pyrazinamide Ofloxacin or ciprofloxacin Amikacina Plus 2b Ethambutol Ofloxacin or ciprofloxacin Amikacina Plusb Ofloxacin or ciprofloxacin Amikacina Plus 3b

Duration of therapy

Comments

6–9 months

Anticipate 100% response rate and less than 5% relapse

6–12 months

Efficacy should be comparable to above regimen

18–24 months

Consider surgery

24 months after conversion

Consider surgery

24 months after conversion

Consider surgery

24 months after conversion

Surgery, if possible

a If there is resistance to amikacin, kanamycin, and streptomycin, capreomycin is a good alternative. Injectable agents are usually continued for 4–6 months if toxicity does not intervene. All the injectable drugs are given daily (or twice or thrice weekly) and may be administered intravenously or intramuscularly. b Potential agents from which to choose: ethionamide, cycloserine, or aminosalicylic acid. Others that are potentially useful but of unproved utility include clofazimine and amoxicillinclavulanate. Clarithromycin, azithromycin, and rifabutin are unlikely to be active (see text). Source: Ref. 68.

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Figure 5. Kaplan Meier survival plot in persons with multidrug-resistant tuberculosis by HIV status. (From Ref. 71.)

mens for patients with MDR tuberculosis have not been well studied and, because of the large number of potential combinations, probably will never be subjected to prospective trials. Experience from the National Jewish Center reported by Goble and associates (69) has shown that the overall rate of cure among selected patients with MDR tuberculosis who were not immune compromised was 56%. Telzak and associates (70) reported better results in a smaller group of HIVuninfected patients with MDR tuberculosis in New York City. Of 24 patients, 23 responded to tailored therapy. At the time of the report, 16 had successfully completed therapy and 7 were “in remission”—still being treated. One patient died. The median duration of follow-up was 91 weeks. An analysis of the results of therapy in a mixed group of HIV-infected and uninfected patients with MDR tuberculosis by Park and coworkers (71) also showed better results than described in earlier reports. Figure 5 shows survival curves for the HIV-positive, HIV-negative, and unknown HIV status groups demonstrating the markedly worse survival of the HIV-positive group. Nevertheless, survival was better than noted in early reports. It should be noted that the major factor predictive of better survival was institution of appropriate therapy, as illustrated in Figure 6. VII. Prevention The effectiveness of isoniazid preventive therapy (see Chap. 18) in persons infected with both HIV and M. tuberculosis has been substantiated in two con-

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Figure 6. Kaplan Meier survival plot in persons with HIV infection and multidrug-resistant tuberculosis. Survival was considerably improved by appropriate therapy. (From Ref. 71.)

trolled trials. In a study conducted in Haiti, Pape and coworkers (72) reported that administration of isoniazid 300 mg/day and pyridoxine 50 mg/day for 12 months significantly decreased the incidence of tuberculosis compared with pyridoxine alone. Among HIV-infected persons who were without symptoms, rates of tuberculosis were 2.2 per 100 for those given isoniazid compared with 7.5 per 100 in subjects given placebo. This benefit was confined to subjects who had positive (5 mm) tuberculin skin test reactions. Subjects with positive tuberculin tests who were given placebo had an incidence of tuberculosis of 10 per 100 compared with 1.7 per 100 in those given isoniazid. The rates in tuberculinnegative subjects (including those who were anergic) were 5.7 and 3.2 per 100 for the placebo and isoniazid-treated groups, respectively, a difference that was not statistically significant. In addition to the benefit in preventing tuberculosis, it was observed that the group treated with isoniazid had a slower rate of progression to AIDS and also a lower risk of death. Again, this benefit was found only in the tuberculin-positive group. In a more recent report data from a prospective controlled trial in Uganda also showed substantial protection from isoniazid (73) given for 6 months as well as for 3 months of rifampin and isoniazid and 3 months of rifampin, isoniazid, and pyrazinamide. Among tuberculin-positive subjects the rates (per 100 persons observed) of tuberculosis were as follows: placebo, 3.41; isoniazid, 1.08; rifampin plus isoniazid, 1.32; rifampin, isoniazid, and pyrazinamide, 1.73. None of the reg-

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imens was protective in anergic subjects. All regimens were well tolerated, although the rate of adverse effects increased with an increasing number of drugs. Two recent trials have demonstrated the efficacy of 2 months of rifampin and pyrazinamide for preventing tuberculosis in HIV-infected tuberculin-positive people. Halsey and colleagues (74) studied 750 dually infected Haitian adults, randomizing them to receive twice-weekly rifampin and pyrazinamide for 2 months or isoniazid for 6 months. Annual rates of tuberculosis were 1.6% for both regimens, and there was no difference in survival. Gordin and associates (75) compared 2 months of daily rifampin and pyrazinamide to 12 months of daily isoniazid: rates of confirmed tuberculosis were 0.8 and 1.1 per 100, respectively. Narcotic withdrawal syndromes were reported by 12 of 792 patients assigned to rifampin and pyrazinamide versus no patients assigned to isoniazid. Thus, a 2month regimen of rifampin and pyrazainmide is as efficacious as 6–12 months of isoniazid for preventing tuberculosis in people with HIV infection and offers considerable programmatic advantages (see Chap. 18). Preventive therapy for anergic patients has not been shown efficacious. Gordin and colleagues (76) randomized patients with HIV infection and anergy to receive 6 months of isoniazid daily or a placebo, with a mean follow-up of about 3 years. Rates of tuberculosis were 0.9 per 100 for placebo versus 0.4 per 100 for isoniazid, a nonsignificant difference. The authors concluded that giving isoniazid preventive therapy to anergic, HIV-infected adults was not warranted. In view of these data, tuberculin testing should be performed as a routine part of management for patients with HIV infection (Table 4). Patients with reacTable 4

Prevention of Tuberculosis in HIV-Infected Persons

1. All HIV-infected individuals should have a baseline tuberculin skin test. 2. Annual testing should be considered in those patients at risk of exposure to infectious tuberculosis. 3. Anergy testing is of no value and should not be included as part of tuberculosis screening. 4. A positive tuberculin skin test is defined as 5 mm induration. 5. Preventive therapy should be given to the following patients, after active tuberculosis has been ruled out: Tuberculin-positive (5 mm) History of tuberculin positivity without prior prophylaxis Exposure to infectious tuberculosis, regardless of tuberculin test results 6. Preventive therapy regimens: Isoniazid 300 mg daily  12 months Isoniazid 15 mg/kg twice weekly  12 months Rifampin 600 mg/pyrazinamide 20 mg/kg daily  2 months Rifampin 600 mg/pyrazinamide 50 mg/kg twice weekly  2 months Isoniazid 300 mg/rifampin 600 mg daily  3 months

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tions of 5 mm to 5 tuberculin units of purified protein derivative should be considered as having tuberculous infection and be offered preventive therapy. Treatment with isoniazid for 12 months is recommended in the presence of HIV infection (77). There are no data that suggest that treatment for more than 12 months confers additional protection unless there are repeated exposures. Rifampin and pyrazinamide for 2 months is an alternative that is equally appropriate. It is not known if rifabutin can be substituted for rifampin, though many authorities would endorse this strategy. Rifampin or rifabutin should be used as preventive therapy in persons exposed to and presumably infected with isoniazid-resistant organisms, although there are no data to support this recommendation. Recommendations for preventive therapy in persons thought to be infected with organisms resistant to isoniazid and rifampin are difficult to formulate. The use of experimental regimens such as pyrazinamide and a fluoroquinolone may be the only option. In HIV-infected persons exposed to a person with infectious tuberculosis, preventive therapy should be given regardless of the results of tuberculin skin testing. For this reason it is important to know the HIV status of close contacts of newly discovered cases. Moreover, as opposed to the recommendations that apply in non–HIV-infected close contacts, repeated courses of preventive therapy should be given if there are subsequent exposures. VIII. Infection Control Tuberculosis is the only common HIV-associated infection that can be transmitted from person to person, including persons who are not HIV infected. For this reason, it is extremely important that tuberculosis be taken into account in applying infection-control measures in persons with HIV infection. In patients who are being evaluated because of respiratory symptoms and/or findings, respiratory precautions should be applied until tuberculosis is excluded. Sputum induction and bronchoscopy should be performed in areas with adequate ventilation or ultraviolet air sterilization with the exhausted air not being recirculated to other parts of the building. Similar considerations should apply to areas in which other potentially cough-inducing procedures are performed. Transmission of tuberculous infection has occurred in a poorly ventilated clinic where aerosol pentamidine prophylaxis for P. carinii pneumonia was being administered to two patients whose sputum contained M. tuberculosis (78). Guidelines for the prevention of nosocomial transmission of M. tuberculosis have been developed by the CDC (79,80). Implementation of these guidelines has been shown to be effective in decreasing transmission in hospitals (81) (see Chap. 23). Because of the potentially severe consequences of new tuberculous infections in immunocompromised patients, it is prudent to be cautious in patients with tuberculosis who will be in contact with HIV-infected persons. In most patients

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who are being treated effectively, because of the decrease in the number of bacilli present in sputum and a decrease in the frequency of coughing, infectivity is reduced by more than 99% within 2 weeks of beginning treatment (82). Even with a reduction of this magnitude, sputum smears may still show acid-fast bacilli. To be even more confident that infectiousness is extremely low, precautions may continue to be applied until sputum smears are negative. In most instances, however, 2 weeks of therapy is sufficient, assuming the organisms are susceptible to the agents given. IX. Influence of Tuberculosis on the Course of HIV Infection There is substantial evidence that tuberculosis accelerates the course of HIV disease. In a case-control study Whalen and colleagues (2) demonstrated that the incidence rate of new opportunistic infections among HIV-infected patients with tuberculosis was 4.0 per 100 compared with 2.8 for matched control subjects who did not have tuberculosis. Those with tuberculosis also had a shorter survival time. At one year after diagnosis 83% of the patients with pulmonary tuberculosis and 49% of patients with extrapulmonary disease were living compared with 90% of the control subjects. In addition to these observations, Pape and associates (72) reported that preventive therapy with isoniazid in tuberculin-positive Haitian adults seemed to delay the onset of HIV-associated opportunistic infections. Moreover, survival seemed to be prolonged. This latter finding has not been consistent, however (73). The mechanism by which tuberculosis accelerates the course of HIV disease is thought to be via immune activation by M. tuberculosis leading to increased viral replication (83–85). Tuberculosis leads to activation of mononuclear cells, resulting in increased levels of cytokines. Recently, the effect of tuberculosis on the circulating viral load was quantified by Goletti and associates (86). Of particular note was the fact that with treatment of the tuberculosis, the amount of circulating virus decreased to predisease levels. This finding has not been confirmed by others, however. These data suggest that the measures designed to prevent tuberculosis in persons with HIV infection will have a beneficial effect on the course of HIV disease as well as decreasing the incidence of tuberculosis. X. Necessary Changes in Approaches to Tuberculosis Control Infection with HIV has caused a dramatic change in the natural history of tuberculosis. No longer can it be assumed that only approximately one third of close

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contacts of new cases will be infected as has been generally true in the United States. As noted previously, there is inferential evidence that HIV-infected persons are more likely to acquire infection with M. tuberculosis than is the general population. Perhaps of greater importance, it is quite clear that an HIV-infected person who acquires a new infection with M. tuberculosis is much more likely to progress rapidly to have clinical tuberculosis. As a consequence of the rapid progression, case fatality rates for tuberculosis are much higher than in nonimmunocompromised patients, with the majority of fatalities occurring before treatment is started or in the first month of therapy. Contributing to the higher case fatality rates is the occurrence of tuberculosis caused by MDR organisms. Superimposed on these changes in the nature of the disease is the fact that the HIV-infected patients in whom tuberculosis is of greater likelihood may also be more difficult to maintain on a regular treatment regimen, thus, making directly observed therapy even more important. It is clear from the major points covered in this chapter that basic tuberculosis control measures must be applied more quickly and with greater intensity in order to be effective. Specific applications of the principles discussed can be summarized as follows: 1. In hospitals and clinics providing care for HIV-infected persons, rapid tests for detecting and speciating mycobacteria should be used and DNA probes or other rapid techniques should be used (see Chap. 14). If such technology is not available in a given institution, strong consideration should be given to using another laboratory in which they are available. 2. Sensitivity testing of organisms isolated should be performed on all initial isolates as quickly as possible. 3. Screening investigations of persons in contact with a new case of tuberculosis should be initiated immediately upon identification of a presumed (positive smear) or confirmed case (see Chap. 15). All contacts identified should be evaluated promptly. If it is thought that either the case or contacts are at risk of HIV infection, the contact should be asked his or her HIV status and counseling and testing should be performed. If the contact is known or thought to be at risk of being HIV infected, decisions about preventive therapy should not be based on skin test results; rather, preventive therapy should be given to contacts regardless of the skin test results after active tuberculosis has been excluded. Preventive therapy for persons suspected of having been infected with drug-resistant organisms should be based on prevailing sensitivity patterns. If it is suspected or known that the contact is HIV infected, careful questioning regarding possible symptoms of tuberculosis should be under-

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taken and the patient should have a thorough physical examination and chest film to exclude current tuberculosis. 4. HIV-infected patients with tuberculosis should be treated initially with isoniazid, rifampin, pyrazinamide, and ethambutol. The last two drugs can be discontinued after 2 months. The duration of therapy generally should be 6 months. Because compliance is the most important determinant of outcome, directly observed therapy is the preferable treatment scheme. If there are problems with compliance or if the response to therapy, judged clinically, radiographically, or bacteriologically, is suboptimal, serum drug concentrations should be measured and therapy should be prolonged. It should be kept in mind, however, that apparent treatment failure or relapse may be caused by paradoxical reactions or by another HIV-related disease, not necessarily tuberculosis. As noted previously, if drug resistance is known or proven, appropriate regimens that are based on prevailing community susceptibility patterns or measured sensitivities should be used. In these situations, more prolonged therapy is necessary. 5. Management of persons with HIV infection should include tuberculin testing, preferably before the CD4 cell count has declined markedly. All persons with HIV infection and positive tuberculin skin tests should be treated with preventive therapy after active tuberculosis has been excluded. 6. Appropriate infection-control measures must be rigorously applied. This includes accurate assessment of the adequacy of ventilation and, in some instances, utilization of ultraviolet light and ambient air filtration. References 1. Markowitz N, Hansen N, Hopewell PC, et al. Incidence of tuberculosis in the United States among HIV-infected patients. Ann Intern Med 1997; 126:123–132. 2. Whalen C, Horsburgh CR, Hom D, Hahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995; 151:129–135. 3. 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. 4. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIV infected drug users with cutaneous anergy. JAMA 1992; 268:504–509.

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5. Allen S, Batungwanayo J, Kerlikowski K, et al. Prevalence of tuberculosis in HIV infected urban Rwandan women. Am Rev Respir Dis 1992; 146:1439–1444. 6. Antonucci G, Girardi E, Raviglione MC, Ippolito G, GISTA. Risk factors for tuberculosis in HIV infected persons: a prospective cohort study. JAMA 1995; 274:143–148. 7. Graham NMH, Nelson KE, Solomon L, et al. Prevalence of tuberculin positivity and skin test energy in HIV-1–seropositive and –seronegative intravenous drug users. JAMA 1992; 267:369–373. 8. Sudre P, Hirschel BJ, Gatell JM, et al. Tuberculosis among European patients with the acquired immuned deficiency syndrome. Tuberc Lung Dis 1996; 77:322–328. 9. Onorato IM, McCray E, Field Services Branch. Prevalence of human immunodeficiency virus infection among patients attending tuberculosis clinics in the United States. J Infect Dis 1992; 165:87–92. 10. Onorato I, McCombs S, Morgan WM, McCray E. HIV infection in patients attending tuberculosis (TB) clinics, United States, 1988–1991. Ninth International Conference on AIDS, Berlin, 1993. (abstract no. WS-C18-6, p. 99). 11. Reported Tuberculosis in the United States, 1995. Atlanta: Centers for Disease Control and Prevention, August 1996. 12. Tuberculosis in San Francisco, 1996. Tuberculosis Control Division, City and County of San Francisco, March 1997. 13. Gilks CF, Brindle RJ, Otieno LS. Extrapulmonary and disseminated tuberculosis in HIV seropositive patients presenting to the acute medical services in Nairobi. AIDS 1990; 4:981–985. 14. Nunn P, Gicheka R, Hages S, et al. Cross-sectional survey of HIV infection among patients with tuberculosis in Nairobi, Keyna. Tuberc Lung Dis 1992; 73:45–51. 15. Raviglione MC, Narain JP, Kochi A. HIV-associated tuberculosis in developing countries: clinical features, diagnosis, and treatment. Bull WHO 1992; 70:515–526. 16. Long R, Scalcini M, Manfreda J, et al. Impact of human immunodeficiency virus type 1 on tuberculosis in rural Haiti. Am Rev Respir Dis 1991; 143:69–73. 17. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Org 1994; 72:213–220. 18. Raviglione MC, Snider DE Jr., Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 1995; 273:220–226. 19. DeCock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa. JAMA 1992; 268:1581–1587. 20. Cantwell MF and Binkin NJ. Impact of HIV on tuberculosis in sub-Saharan Africa: a regional perspective. Int J Tuberc Lung Dis 1997; 1:205–214. 21. Yinai H, Uthaivoravit W, Panich V, et al. Rapid increase in HIV-related tuberculosis, Ching Rai, Thailand, 1990–1994. AIDS 1996; 10:527–531. 22. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis 1982; 125:8–15. 23. Daniel TM, Ellner JJ. Immunology of tuberculosis. In: Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, Inc., 1993:75–101. 24. Nardell E, McInnis B, Thomas B, Weidhaus S. Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 1986; 315:1570–1575.

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25. Small PM, Shafer RW, Hopewell PC et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993; 328:1137–1144. 26. Daley CL, Small PM, Ponce de León A et al. Tuberculosis recurrences in San Francisco: relapse or reinfection. Am J Respir Crit Care Med 1996; 153 (part 2):A410. 27. Daley CL, Small PM, Schecter GF et al. An outbreak of tuberculosis with accelerated progression among persons infected with human immunodeficiency virus: an analysis using restriction-fragment-length polymorphisms. N Engl J Med 1992; 326:231–235. 28. DiPerri G, Cruciani M, Danzi MC, et al. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 1989; 2:1502–1504. 29. Theuer CP, Hopewell PC, Elias D, Schecter GF, Rutherford GW, Chaisson RE. Human immunodeficiency virus infection in tuberculosis patients. J Infect Dis 1990; 162:8–12. 30. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292–1297. 31. Alwood K, Keruly JC, Moore-Rice K, Stanton DL, Chaulk P, Chaisson RE. Effectiveness of supervised, intermittent therapy for tuberculosis in HIV-infected patients. AIDS 1994; 8:1103–1108. 32. Markowitz N, Hansen NI, Wilcosky TC, et al. Tuberculin and anergy testing in HIVseropositive and HIV-seronegative persons. Ann Intern Med 1993; 119:185–193. 33. Chin DP, Osmond D, Page-Shafer K, et al. Reliability of energy skin testing in persons with HIV infection. Am J Respir Crit Care Med 1996; 153:1982–1984. 34. Johnson MP, Coberly JS, Clermont HC, Chaisson RE, et al. Tuberculin skin test reactivity among adults infected with human immunodeficiency virus. J Infect Dis 1992; 166:194–198. 35. American Thoracic Society. Control of tuberculosis in the United States. Am Rev Respir Dis 1992; 146:1623–1633. 36. Batungwanayo J, Taelman H, Dhote R, Bogaerts J, Allen S, Van De Perre P. Pulmonary tuberculosis in Kigali, Rwanda: impact of human immunodeficiency virus infection on clinical and radiographic presentation. Am Rev Respir Dis 1992; 146:53–56. 37. Chaisson RE, Schecter GF, Theuer CP, Rutherford SW, Echenberg DF, Hopewell PC. Tuberculosis in patients with the acquired immunodeficiency syndrome. Am Rev Respir Dis 1987; 136:570–574. 38. Pitchenik AE, Rubinson HA. The radiographic appearance of tuberculosis in patients with the acquired immunodeficiency syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis 1985; 131:393–396. 39. Small PM, Hopewell PC, Schecter GF, Chaisson RE, Goodman PC. Evolution of chest radiographs in treated patients with pulmonary tuberculosis and HIV infection. J Thoracic Imaging 1995; 9:74. 40. Cauthen GM, Dooley SW, Onorato IM et al. Transmission of Mycobacterium tuberculosis from tuberculosis patients with HIV or AIDS. Am J Epidemiol 1996; 144:69–77.

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41. Kennedy DJ, Lewis WP, Barnes PF. Yield of bronchoscopy for the diagnosis of tuberculosis in patients with human immunodeficiency virus infection. Chest 1992; 102:1040. 42. Glassroth J. Diagnosis of tuberculosis. In: Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, Inc., 1993:149–165. 43. American Thoracic Society. Rapid diagnostic tests for tuberculosis. What is the appropriate use? Am J Respir Crit Care Med 1997; 155:1804–1814. 44. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991; 324:289–294. 45. Perriens JH, St. Louis ME, Mukadi YB et al. Pulmonary tuberculosis in HIV infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995; 332:779–784. 46. Chaisson RE, Clermont HC, Holt EA, et al. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996; 154:1034–1038. 47. El-Sadr WM, Perlman DC, Matts JP, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Clin Infect Dis 1998; 26:1148–1158. 48. Iseman MD. Is standard chemotherapy adequate in tuberculosis patients infected with the HIV? Am Rev Respir Dis 1987; 136:1326. 49. American Thoracic Society/Centers for Disease Control. Treatment and prevention of tuberculosis in adults and children. Am J Respir Crit Care Med 1994; 149:1359–1374. 50. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995; 274:945–951. 51. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998; 279:943–948. 52. Weiss SE, Slocum PC, Blair 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. 53. World Health Organization, Global Tuberculosis Program. WHO Report on the Tuberculosis Epidemic, Geneva, 1997. 54. Bradford WZ, Martin JN, Reingold AL, Schecter GF, Hopewell PC, Small PM. The changing epidemiology of acquired drug resistant tuberculosis in San Francisco, USA. Lancet 1996; 348:928–931. 55. Patel KB, Belmonte R, Crowe HM. Drug malabsorption and resistant tuberculosis in HIV infected patients. N Engl J Med 1995; 332:336–337. 56. Benator D, Burman W, Chaisson RE, et al. Acquired rifampin mono-resistant tuberculosis in HIV-infected patients treated with once-weekly isoniazid and rifapentine (abstract 735). 5th Conf Retrovir Opport Infect, Chicago, February 1–5, 1998. 57. Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets LB, ed. Drug Susceptibility in the Chemotherapy of Mycobacterial Infection. Boca Raton, FL: CRC Press, 1991:59–88.

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75. Gordin F, Chaisson RE, Matts J, et al. A randomized trial of 2 months of rifampin and pyrazinamide versus 12 months of isoniazid for the prevention of tuberculosis in HIV-positive, PPD patients (abstracts 5LB). 5th Conf Retrovir Opport Infect Chicago, February 1–5, 1998. 76. Gordin FM, Matts JP, Miller C, et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. N Engl J Med 1997; 337:315–320. 77. USPHS/IDSA. Prevention of opportunistic infection working group. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: disease-specific recommendations. Clin Infect Dis 1995; 21 (suppl 1):S32–S43. 78. Centers for Disease Control. Mycobacterium tuberculosis transmission in a health clinic—Florida. MMWR 1989; 38:256. 79. Dooley SW Jr., Castro KG, Hutton MD, Mullon RJ, Polder JA, Snider DE Jr. Guidelines for preventing transmission of tuberculosis in health care settings with special focus on HIV-related issues. MMWR 1990; 39 (RR-17):1–29. 80. Centers for Disease Control. Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, 1995. MMWR 1994; 43 (RR-1 3):1–132. 81. Blumberg HM, Watkins DL, Berschling JD, et al. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122:658–663. 82. Hopewell PC. Factors influencing transmission and infectivity of Mycobacterium tuberculosis: implications for clinical and public health management. In: Sande MA, Hudson LD and Root RK, eds. Respiratory Infections. New York: Churchill Livingstone, 1986:191–216. 83. Wallis RS, Vjecha M, Amer Tahmosseb 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; 167:43–48. 84. Lederman MM, Georges DL, Kusner DJ, Mudido P, Gaim CZ, Toossi Z. Mycobacterium tuberculosis and its purified protein derivative activate expression of the human immunodeficiency virus. J AIDS 1994; 7:727–733. 85. Zhang Y, Doerfier M, Lel TC, Guillemia B, Rom WM. Mechanisms of stimulation of interleukin 1 and tumor necrosis factor by Mycobacterium tuberculosis components. J Clin Invest 1993; 91:2076–2083. 86. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication: role of immune activation. J Immunol 1996; 157:1271–1278.

21 Tuberculosis in Children

˜ FLOR M. MUNOZ and JEFFREY R. STARKE Baylor College of Medicine Houston, Texas

I. Introduction A. General Information

Tuberculosis continues to be a significant cause of morbidity and mortality for children throughout the world. After a steady decline in the number of cases for decades, there was a resurgence of pediatric tuberculosis in the United States and other industrialized countries from 1984 to 1994 (1,2). Tuberculosis infection and disease among children are much more prevalent in developing countries, where resources for tuberculosis control are scarce (3,4). Since most children with tuberculosis infection and disease acquire the organism from adults in their environment, the epidemiology of childhood tuberculosis follows that in adults. The most important reasons for this recent worldwide resurgence of pediatric tuberculosis include (1) increased population migration, (2) the human immunodeficiency virus (HIV) epidemic, (3) the emergence of drug resistance (5,6), (4) continued poverty and poor access to medical care, and (5) inadequate public health infrastructure required to prevent tuberculosis in children. The World Health Organization (WHO) has estimated that in the 1990s, about 15 million new cases and 5 million deaths due to tuberculosis will occur among children under 15 years of age (7). 553

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Although tuberculosis can have profound consequences for the affected children and their families, childhood tuberculosis has a limited influence on the immediate epidemiology of the disease within a community because children are rarely the source of infection to contacts (8). However, the occurrence of tuberculosis in children is a marker for recent and ongoing transmission of infection in a society. Infected children also represent a large proportion of the pool from which future tuberculosis cases arise. Programs that target children for treatment of tuberculosis infection and disease have little short-term influence on disease rates but are critical to effect long-term control of the disease. B. Terminology

The pathophysiology and the clinical presentation of tuberculosis disease are different in infants, children, and adolescents from what they are in adults. Most adult pulmonary tuberculosis is caused by reactivation of dormant organisms that become lodged in the apices of the lung lobes during lymphohematogenous dissemination at the time of initial infection. Pediatric tuberculosis disease usually occurs as a direct consequence of the initial infection with M. tuberculosis, which in children can progress to disease in a shorter period of time than in adults, particularly among infants. Although not always easily distinguished, three different stages of pediatric tuberculosis are recognized: exposure, infection, and disease. Exposure means that a child has had significant contact with an adult with infectious pulmonary tuberculosis, but the tuberculin skin test (see Chap. 12) is negative, the chest radiograph is normal, and the child has not developed signs or symptoms of disease. In this stage, the child may be infected, but not enough time has passed for the tuberculin skin test to become reactive. The contact investigation (see Chap. 15)—examining persons close to a suspected case of pulmonary tuberculosis—is the activity that identifies exposed children (8). The most frequent setting for exposure of a child is the household, but it can occur in a school, day care center, or other closed settings (9,10). In many developed countries, owing to the short incubation period (several weeks to several months) of tuberculosis in infants and young children, children less than 5 years old in the exposure stage are treated with a single drug—usually isoniazid—to prevent the rapid development of disseminated or meningeal tuberculosis (11–13). Tuberculosis infection in children is diagnosed by a reactive skin test. In this stage the child has no signs or symptoms of disease, and the chest radiograph is normal or reveals only granuloma or calcifications in the lung parenchyma or lymph nodes. In developed countries, virtually all children with tuberculosis infection should receive treatment (see Chap. 18), usually with isoniazid, to prevent the development of disease. Tuberculosis disease occurs when the child with tuberculosis infection becomes symptomatic or radiographic manifestations caused by M. tuberculosis be-

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come apparent. The risk of a child acquiring tuberculosis infection is directly related to the probability of exposure to infectious adults or adolescents in his environment; the progression to disease is determined by the host’s immune status and genetic predisposition. Studies performed in the early twentieth century showed that immunocompetent infants with untreated tuberculosis infection had a 40% risk of developing disease—often serious, life-threatening forms—within 1–2 years. The majority of milder cases of tuberculosis disease in children in most developing countries are not diagnosed because of the lack of appropriate resources (14). Even in countries with modern clinical and laboratory facilities, the diagnosis of tuberculosis in a child can be confirmed by culture in fewer than 40% of cases (15,16). The low rate of culture confirmation makes investigations of new diagnostic techniques in children difficult to design and interpret. The term “primary tuberculosis” has been used to describe pediatric pulmonary tuberculosis that arises as a complication of the initial infection. Unfortunately, this term also has been used to describe the initial infection, even in the absence of radiographic or clinical manifestations. In adults, infection and the onset of disease are usually distinct events because they are separated by time, often years. In children, disease complicates the initial infection so the two stages are a continuum with often indistinct clinical borders. The consensus is to consider disease present if adenopathy or other chest radiograph manifestations of infection by M. tuberculosis can be seen. II. Epidemiology A. Worldwide Infection and Disease

It is difficult to assess the worldwide extent of childhood morbidity due to tuberculosis because of scarce and incomplete data and because of the difficulty of diagnosing childhood tuberculosis with certainty in many countries. Reported disease rates are grossly underestimated, and the prevalence of infection without disease is completely unknown in most areas of the world. The WHO estimated that during the 1990s 90 million new cases of tuberculosis would occur worldwide, accompanied by 30 million related deaths (4,17). Children younger than 15 years of age would represent about 15 million of these new cases, and 5 million of the deaths (7). In many developing countries, the annual risk of tuberculosis infection in children is 2–5% (18), with 8–20% of the deaths caused by tuberculosis occurring in children. There is no indication that tuberculosis rates among children in developing nations are declining. Trends in mortality of pediatric tuberculosis in industrialized nations are well illustrated by data from Europe. The annual mortality from tuberculosis fell from 600 per 100,000 children in 1860 to 50 per 100,000 in the late 1930s and below 0.08 per 100,000 in 1977, (14). The mortality rates for children from newborn

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to 4 years of age have been and are still about twice that for children ages 5–15 years, mostly because of the higher incidence of tuberculous meningitis and disseminated disease in the younger population. Some European countries have experienced an increase in pediatric tuberculosis cases over the past 10 years due mostly to immigration of high-risk families (see Chap. 25). B. Disease in the United States

The most complete recent epidemiological data for pediatric tuberculosis comes from the United States (2,19). Reported tuberculosis cases in children younger than 15 years of age declined from 6036 in 1962 to 1261 in 1985, an average annual decline of about 6%. Case rates declined in a similar fashion from 10 per 100,000 children in 1962 to 2.4 per 100,000 in 1985. However, beginning in 1988, the number of cases began to increase. After a low of 1177 cases in 1987, annual cases in children increased and peaked in 1992 when the number of pediatric tuberculosis cases had risen by 40% since 1985 (2). Case numbers remained elevated until 1995, when a discrete 2.4% decline to 1558 cases was observed. This increasing and persistently elevated incidence means that transmission of infection in the United States is ongoing, and a new generation of infected individuals will serve as reservoir of the disease in the future, unless they are appropriately treated. The most important factors that caused these increases in children include (1) the epidemic of HIV infection, (2) increasing rates of tuberculosis in foreignborn children immigrating to the United States who had undetected tuberculosis disease at arrival or developed disease after arrival, or were infected after arrival and progressed to disease and (3) a decline in the tuberculosis public health infrastructure in some regions and cities causing slow identification and examination of infectious cases and their close contacts (1,20,21). Both age and gender are important variables for tuberculosis among children. There is no evidence that the likelihood of infection with M. tuberculosis is influenced by either; however, both influence the risk of an infected child developing active disease. From 1990 to 1995, 59% of pediatric tuberculosis cases in children in the United States occurred in children younger than 5 years of age, the group traditionally at highest risk for the disease. The interval between ages 5 and 14 years is often called “the favored age,” since children in this group consistently have a lower rate of tuberculosis disease than any other segment of the population. Age also affects the anatomical site of involvement with tuberculosis. Younger children are more likely to develop meningeal, miliary, or lymphatic tuberculosis, whereas adolescents more frequently present with pleural, peritoneal, or genitourinary disease (Table 1). Although tuberculosis in adults occurs for the most part among men, historical evidence implies that during the latter part of childhood and during adolescence, girls have a higher incidence of and mortality from tuberculosis than do boys. Among infants and young children there is no difference in incidence by gender.

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

Site Pulmonary Lymphatic Pleural Meningeal Bone/Joint Other Miliary Genitourinary Peritoneal Not stated

77.5 13.3 3.1 1.9 1.2 1 0.9 0.8 0.3 0.1

Median age (yr) 6 5 16 2 8 12 1 16 13 —

At every age in the United States, tuberculosis case rates are strikingly higher in ethnic and racial minority groups than in whites. The difference is most likely a result of environmental factors, such as socioeconomic status, housing conditions, and exposure to high-risk adults. Approximately 80–87% of childhood tuberculosis cases in the United States occur among African Americans, Hispanics, Asian Americans, and Native Americans, with a relatively higher number of cases in the Hispanic population in more recent years (2). Although most children with tuberculosis were born in the United States, the proportion of foreign-born children with tuberculosis increased steadily between 1986 and 1991, rising from 19.1 to 27.2% for children younger than 15 years of age, modestly decreasing to 22.8% in 1995 (1,2). Childhood tuberculosis has been reported from 23% of counties in the United States but is concentrated in cities with populations greater than 250,000 residents. C. Transmission

Transmission of tuberculosis is from person to person, usually by droplets of mucus that become airborne when the individual coughs, sneezes, laughs, or sings. Studies performed in orphanages and children’s hospitals showed that children with primary tuberculosis rarely, if ever, infect other children or adults (22). In these children, tubercle bacilli are sparse in endobronchial secretions, and cough may not be present. When young children do cough, they rarely produce sputum, and they lack the tussive force of adults. When transmission of M. tuberculosis has been documented in a children’s hospital, it almost invariably has come from an adult staff member, parent, or visitor with undiagnosed pulmonary tuberculosis

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Table 2

Adults at High Risk for Tuberculosis in the United States

Foreign-born persons from high-prevalence countries Persons with HIV co-infection Residents of correctional institutions Residents of nursing homes Homeless persons Users of intravenous or other street drugs Poor and medically indigent city dwellers Persons with certain medical risk factors (e.g. diabetes, silicosis) Persons receiving immunosupressive therapies

(23–25). Adolescents or younger children with reactivation forms of pulmonary tuberculosis, such as cavities or extensive infiltrates with productive cough, may be highly infectious to others (26). The Centers for Disease Control and Prevention (CDC) guidelines for hospitals state that children with typical pediatric tuberculosis do not need respiratory isolation unless they have an uncontrolled productive cough, a cavity, or an acid-fast bacillus-positive sputum smear (27). Children are usually infected with M. tuberculosis by an adult in the same household. The increasing tuberculosis case rates among children in the United States were related to the increasing rates among young adults, especially in urban centers. Among adults, tuberculosis has retreated into pockets of high-risk individuals (Table 2). Children cared for or exposed to adults in these groups are most likely to become infected. Casual extrafamilial contact is less frequently the source of infection, but school janitors and teachers, bus drivers, nurses, day care workers, and candy store keepers have been implicated as sources of infection in individual cases and epidemics (28–30). In the northern hemisphere, childhood tuberculosis is more common from January to June, perhaps because of increased close indoor contact during winter months and more frequent coughing in adults produced by winter and spring respiratory infections. D. Human Immunodeficiency Virus–Related Tuberculosis in Children

The ongoing epidemic of infection with HIV has had a profound effect on the epidemiology of tuberculosis. Beside population migration, infection with HIV is the most important factor contributing to the recent resurgence of tuberculosis (see Chap. 20). In 1990, 4.2% of tuberculosis cases in the world were attributed to HIV infection, and this proportion is expected to rise to 13.8% by the year 2000 (4). Adults with HIV infection are more likely to develop tuberculosis from latent infections, and those who encounter M. tuberculosis after HIV-related immune suppression has progressed have a more rapid progression to disease (31,32). The

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HIV epidemic can increase the incidence of tuberculosis in children by two major mechanisms (33,34): (1) HIV-infected adults with tuberculosis may transmit M. tuberculosis to children, a portion of whom will develop tuberculosis disease, and (2) children with HIV infection may be at increased risk of developing tuberculosis disease after infection has occurred. Generally, children acquire tuberculosis from adults with active, usually smear-positive, pulmonary disease. Pulmonary involvement is common among HIV-seropositive adults with tuberculosis, especially when the tuberculosis precedes other opportunistic infections (35). The impact of the HIV epidemic on pediatric tuberculosis has been reported in several studies. A retrospective population study in Florida implied that an observed increase in pediatric tuberculosis cases was linked with an increase in cases in HIV-infected adults (36). In Abidjan, Cote d’Ivoire, and in Lusaka, Zambia, a higher rate of pediatric tuberculosis is more commonly observed among HIV-infected children (37,38). In Zambia, Brazil, and Haiti, HIV-infected pediatric cohorts have a higher risk of developing tuberculosis (39). The difficulty encountered in many reports is that the diagnosis of tuberculosis in children is established usually by only clinical scores, especially in the youngest children in whom the highest rates of HIV infection are found. Tuberculosis is probably underdiagnosed in HIV-infected children because of the similarity of its clinical presentation to other opportunistic infections and the difficulty of confirming tuberculosis in children with positive culture (40). When HIV-infected children develop tuberculosis, the clinical features are similar to those of immunocompetent children, but with a greater degree of severity, a more rapid progression of the disease, and a higher mortality rate (41–43). There may be an increased tendency for extrapulmonary or disseminated disease, but data are limited. Unusual presentations such as chronic fever, tachypnea, or lobar infiltrates may be found in HIV-infected children, making more difficult the diagnosis of tuberculosis (41,44). Children who acquire HIV infection by vertical transmission may have a rapid progression of tuberculosis from infection to disease (45). E. Tuberculosis Infection

Although there are estimates that up to one third of the world’s population is infected with M. tuberculosis (7), it is impossible to determine how many children actually have asymptomatic tuberculosis infection. Since all but two countries have used BCG vaccine extensively, population surveys for tuberculosis infection using the tuberculin skin test are rarely performed and would be difficult to interpret. Even in the United States, the incidence of tuberculosis infection is unknown, since a positive tuberculin skin test is a reported condition in only three states, and national surveys were discontinued in 1971. At that time, the incidence of tuberculosis infection among 5- and 6-year-olds was about 0.2%.

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The most efficient method of finding children infected with M. tuberculosis is through contact investigations of adults with infectious pulmonary tuberculosis. On average, 30–50% of household contacts have a reactive tuberculin skin test. Even in countries where BCG vaccine is used extensively, a positive tuberculin skin test in a child who has close contact with an adult with infectious tuberculosis probably represents infection with M. tuberculosis, and treatment of this latent infection should be considered, especially if the child is under 5 years of age. In developing countries, tuberculosis infection rates among the young population average 20–50%. Among most children in the United States, the prevalence of tuberculosis infection is less than 1%. However, in some urban populations, the rates are much higher. Several surveys conducted in the late 1980s in Boston, Los Angeles, and Houston demonstrated positive tuberculin skin tests among 2–9% of school-age children and adolescents (46–48). In these and other surveys, the majority of children with positive tuberculin skin tests were foreignborn (49,50). The increased numbers of pediatric tuberculosis cases, the high rates of tuberculosis infection and disease among immigrants, and the results of these urban skin test surveys imply that the pool of children with latent tuberculosis infection in the United States is growing. III. Pathogenesis A. Primary Tuberculosis in Children

The primary complex of tuberculosis consists of local disease at the portal of entry and the regional lymph nodes that drain the area of the primary focus. In more than 95% of cases the portal of entry is the lung. Tubercle bacilli within particles larger than 10 m usually are caught by the mucociliary mechanisms of the bronchial tree and are expelled. Small particles are inhaled beyond these clearance mechanisms. However, primary infection may occur anywhere in the body. The number of tubercle bacilli required to establish infection in children is unknown, but only a few to several organisms are probably necessary. The incubation period in children between the time the tubercle bacilli enter the body and the development of cutaneous hypersensitivity is usually 2–12 weeks, most often 4–8 weeks. The onset of hypersensitivity may be accompanied by a febrile reaction that lasts from 1 to 3 weeks. During this phase of intensified tissue reaction, the primary complex may become visible on chest radiograph. The primary focus grows larger but does not yet become encapsulated. As hypersensitivity develops, the inflammatory response becomes more intense and the regional lymph nodes often enlarge. The parenchymal portion of the primary complex often heals completely by fibrosis or calcification after undergoing caseous necrosis and encapsulation. Occasionally, the parenchymal lesion may continue to en-

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large, resulting in focal pneumonitis and thickening of the overlying pleura. If caseation is intense, the center of the lesion liquefies, empties into the associated bronchus, and leaves a residual primary tuberculous cavity. During the development of the parenchymal lesion and the accelerated caseation brought on by the development of hypersensitivity, tubercle bacilli from the primary complex spread via the bloodstream and lymphatics to many parts of the body. The areas most commonly seeded are the apices of the lungs, liver, spleen, meninges, peritoneum, lymph nodes, and bone. This dissemination can involve either large numbers of bacilli, which leads to disseminated disease, or small numbers of bacilli that leave microscopic tuberculous foci scattered in various tissues. Initially, these metastatic foci are clinically inapparent, but they are the origin of both extrapulmonary tuberculosis and reactivation pulmonary tuberculosis in some children. The tubercle foci in the regional lymph nodes develop some fibrosis and encapsulation, but healing is usually less complete than in the parenchymal lesions. Viable M. tuberculosis may persist for decades after calcification of the node. In most cases of primary tuberculosis infection, the lymph nodes remain normal in size. However, because of their location, hilar and paratracheal lymph nodes that become enlarged by the host inflammatory reaction may encroach upon the regional bronchus. Partial obstruction caused by external compression may lead at first to hyperinflation in the distal lung segment. Such compression occasionally causes complete obstruction of the bronchus, resulting in atelectasis of the lung segment (51,52). More often, inflamed caseous nodes attach to the bronchial wall and erode through it, leading to endobronchial tuberculosis or a fistulous tract (53,54). The extrusion of infected caseous material into the bronchus can transmit infection to the lung parenchyma and cause bronchial obstruction and atelectasis (55). The resultant lesion is a combination of pneumonia and atelectasis. The radiographic findings of this process have been called epituberculosis, collapseconsolidation, and segmental tuberculosis. B. Timetable of Childhood Tuberculosis

There is a fairly predictable timetable of events related to the primary tuberculosis infection and its complications (56). This timetable is very useful for the clinician, permitting a realistic prognosis, an understanding of what complications to look for and when, and a useful approach to finding the source case for infection. When symptomatic lymphohematogenous spread occurs, it does so no later than 3–6 months after the initial infection, leading to miliary disease and tuberculous meningitis. Endobronchial tuberculosis, often accompanied by segmental pulmonary changes, usually develops between 4 and 9 months after infection. Clinically significant lesions of bones or joints do not appear until at least 1 year after infection (57), whereas renal lesions develop 5–25 years later. The interval

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between the initial infection and reactivation of pulmonary tuberculosis is extremely variable, depending on the age of the child at initial infection; in adolescents, the interval is often months to several years, whereas in infants it is much longer. The age of the child at acquisition of tuberculosis infection has a great effect on the occurrence of both primary and reactivation tuberculosis. Hilar lymphadenopathy and subsequent segmental disease complicating the primary infection occur most often in younger children (58). Approximately 40% of untreated children less than 1 year of age develop radiographically significant lymphadenopathy or segmental lesions, compared with 24% of children 1–10 years of age and 16% of children 11–15 years of age. However, if young children do not suffer early complications, their risk of developing reactivation tuberculosis later in life appears to be low. Conversely, older children and adolescents rarely experience complications of the primary infection but have a much higher risk of developing reactivation pulmonary tuberculosis as an adolescent or adult. C. Pregnancy and the Newborn

True congenital tuberculosis is very rare, with less than 300 cases reported in the medical literature (59). The Beitzke criteria for the diagnosis of true congenital tuberculosis are no longer used as they were based on autopsy findings (6). Hageman and others (61,62) have redefined congenital tuberculosis, identifying two major routes for true congenital infection. The first is transplacental passage of M. tuberculosis via the umbilical vein from a mother with lymphohematogenous spread during pregnancy. The infected infant’s mother commonly has tuberculous pleural effusion, meningitis, or miliary disease during pregnancy or soon after (61–63). However, in many cases, the diagnosis of tuberculosis in the newborn has led to the discovery of the mother’s disease. Hematogenous dissemination may also lead to infection of the placenta, with transmission to the fetus (64), although even massive involvement of the placenta does not always give rise to congenital tuberculosis. In either event, bacilli first reach the fetus’s liver, where a primary focus involving the periportal lymph nodes develops, producing hepatomegaly or even widespread miliary disease. The organisms can also pass through the liver into the main circulation, leading to a primary focus in the fetal lung. The tubercle bacilli in the lung may remain dormant until after birth, when oxygenation and circulation increase significantly (65). A second mechanism for congenital tuberculosis infection is through aspiration or ingestion of infected amniotic fluid in utero. Amniotic fluid can be infected from tuberculous endometritis or the presence of ruptured caseous lesions in the placenta. Inhalation of amniotic fluid is the most likely cause of congenital tuberculosis if multiple primary foci are present in the lung or gut and middle ear (66).

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Postnatal acquisition of tuberculosis by inhalation of tubercle bacilli from the mother is the most common route of infection for the neonate (67,68). It is often impossible to differentiate postnatal infection from true congenital tuberculosis on clinical grounds (59). The distinction is not of major importance for the baby, as the treatment regimens are the same. However, determining the true source of infection is vital for proper evaluation and treatment of the mother and other adults in the baby’s environment. IV. Clinical Forms of Tuberculosis In the developing world, the only way children with tuberculosis disease are discovered is when they present with a profound illness that is consistent with tuberculosis. Having an ill, adult contact is an obvious clue to the correct diagnosis. The only available laboratory test may be an acid-fast smear of sputum, which the child rarely produces. In many regions, chest radiography is not available. To aid in diagnosis, a variety of scoring systems have been devised that are based on available tests, clinical signs and symptoms, and known exposures (69). However, the sensitivity and specificity of these systems can be very low, leading to both over- and underdiagnosis of tuberculosis (70). In industrialized countries, children with tuberculosis usually are discovered in one of two ways (70–73). One way is consideration of tuberculosis as the cause of symptomatic pulmonary or extrapulmonary illness. Discovering an adult contact with infectious tuberculosis is an invaluable aid to diagnosis; the yield from a contact investigation usually is higher than from cultures from the child. The second way is discovery of a child with pulmonary tuberculosis during the contact investigation of an adult with tuberculosis. Typically, the affected child has few or no symptoms, but investigation reveals a positive tuberculin skin test result and an abnormal chest radiograph. In some areas of the United States, up to 50% of children with pulmonary tuberculosis are discovered in this manner before significant symptoms have begun (74). It is rare to find tuberculosis disease in a child as the result of a community- or school-based tuberculin skin testing program (75). A. Intrathoracic Disease

Pulmonary Disease

A primary pulmonary complex includes the parenchymal focus and regional lymphadenitis. Almost 70% of primary foci are subpleural, and localized pleurisy is a common part of the primary complex. Infection begins with the deposition of infected droplets into lung alveoli. All lobar segments are at equal risk of being seeded, and in 25% of cases there are multiple primary lung foci (74). The initial parenchymal inflammation usually is not visible on chest radiograph, but a local-

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ized, nonspecific infiltrate may be seen. The infection spreads within days to regional lymph nodes. When tuberculin hypersensitivity develops, within 3–10 weeks after infection, the inflammatory reaction in the lung parenchyma and lymph nodes intensifies. The hallmark of primary tuberculosis in the lung is the relatively large size and importance of the hilar, mediastinal, or subcarinal adenitis compared with the relatively small size of the initial parenchymal focus. Because of the patterns of lymphatic drainage, a left-sided parenchymal lesion often leads to bilateral adenopathy, whereas a right-sided focus is associated with rightsided adenopathy only. Hilar or mediastinal lymphadenopathy is invariably present with primary tuberculosis but may not be distinct (from the atelectasis and infiltrate) or may be too small to be clearly visible on a plain radiograph. Computed tomography (CT) may reveal small lymph nodes when the chest radiograph appears normal, but this finding appears to have no clinical implications (76). It can, however, create a dilemma in deciding on a treatment regimen and reinforces the idea that, in children, infection and disease are on a continuum with often indistinct borders (70).

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

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

In most children, the parenchymal infiltrate and adenitis resolve early. In some children, especially infants, the lymph nodes continue to enlarge (Figs. 1 and 2). Bronchial obstruction begins as the nodes impinge on the neighboring regional bronchus, compressing it and causing diffuse inflammation of its wall (54). The inflammation may intensify, and the lymph nodes erode through the bronchial wall, leading to perforation and formation of thick caseum in the lumen, with partial or complete obstruction of the bronchus (51,53). The common radiographic sequence is hilar adenopathy, followed by localized hyperaeration and, eventually, atelectasis (55). These findings are similar to those caused by aspiration of a foreign body; in tuberculosis, the lymph node acts as the foreign body.

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(b) Figure 2.

Continued

Obstructive hyperaeration of a lobar segment may accompany bronchial obstruction. This unusual complication occurs most often in children younger than 2 years of age and may be accompanied by wheezing. The obstruction will usually resolve spontaneously, but this may take months. Surgical removal of the lymph nodes may hasten clinical improvement but is rarely necessary. The most common complication of the bronchial obstruction is the fanshaped segmental lesion (Fig. 1), which results from a combination of the primary pulmonary focus, the caseous material from an eroded bronchus, the host inflammatory response, and the subsequent atelectasis. Up to 43% of children younger

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than 1 year of age who are infected with M. tuberculosis develop a segmental lesion, compared with 25% for children ages 1–10 years, and 15% for children ages 11–15 years (58). Segmental lesions and obstructive hyperaeration can occur together. Physical signs and symptoms caused by hilar adenopathy and segmental lesions are surprisingly uncommon but are more frequently seen in infants (Table 3). Occasionally, the initiation of the primary infection is marked by fever and cough. As the primary complex progresses, nonspecific symptoms such as fever, cough, night sweats, and weight loss occur. Pulmonary signs are usually absent. Some children have localized wheezing or diminished breath sounds, which are rarely accompanied by tachypnea or respiratory distress. Nonspecific symptoms and pulmonary signs are sometimes alleviated by antibiotics, suggesting that bacterial superinfection distal to the bronchial obstruction may be present. Involvement of other groups of intrathoracic lymph nodes cause various clinical manifestations. Enlarged subcarinal nodes, which cause splaying of the large bronchi, may impinge on the esophagus and cause difficulty swallowing or a bronchoesophageal fistula. Infected enlarged nodes may compress the subclavian vein, producing edema of the hand or arm. Nodes may rupture into the mediastinum and point in the right or left supraclavicular fossa. Most cases of tuberculous bronchial obstruction in children resolve fully with or without antituberculosis chemotherapy. However, up to 60% of untreated children have residual anatomical sequelae not apparent on radiographs. Chemotheraphy is given to prevent local progression of disease, dissemination of

Table 3

Symptoms and Signs of Pediatric Pulmonary Tuberculosis Occurrence in Infants and young children

Symptom: Fever Night sweats Cough Productive cough Hemoptysis Dyspnea Sign: Rales Wheezing Dullness Diminished breath sounds

Older children and adolescents

Common Rare Common Rare Never Common

Uncommon Uncommon Common Common Rare Rare

Common Common Rare Common

Uncommon Uncommon Uncommon Uncommon

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disease, and future chronic pulmonary tuberculosis. Without early therapy, calcification of the caseous lesions is common. Occasionally, healing of the pulmonary segment is complicated by scarring or contraction that may be associated with cylindrical bronchiectasis and bronchial stenosis. These complications are usually clinically silent when they occur in the upper lobes, and they are quite rare in children who have successfully completed chemotherapy. Progressive Pulmonary Disease

A rare but serious complication of primary tuberculosis occurs when the primary focus enlarges steadily and develops a large caseous center. The radiograph shows bronchopneumonia or lobar pneumonia. Liquefaction results in the formation of a

Figure 3. A chronic pulmonary tuberculosis lesion in the left upper lobe of a child who had respiratory symptoms for 8 months before diagnosis.

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thin-walled primary cavity associated with large numbers of tubercle bacilli (77). A tension cavity develops rarely as a result of a valve-like mechanism, allowing air to enter into an adjacent bronchus, leading to further intrapulmonary dissemination. Rupture into the pleural space can lead to bronchopleural fistula or pyopneumothorax. Unlike segmental lesions, significant symptoms and signs usually accompany locally progressive disease. High fever, night sweats, weight loss, and severe cough with sputum production are common. Physical signs include diminished breath sounds, rales, dullness, and egophony over the cavity. The clinical picture is similar to that of pyogenic pneumonia caused by Staphyloccoccus aureus or Klebsiella pneumoniae. Before the introduction of antituberculosis chemotherapy, prognosis was poor with a fatality rate of 30–50%. However, with current therapy the prognosis for complete recovery is excellent. Chronic Pulmonary Disease

Chronic pulmonary tuberculosis (“adult” or “reactivation” type) represents endogenous reactivation of a site of tuberculosis infection established previously. Even before the discovery of antituberculosis drugs, chronic pulmonary tuberculosis occurred in only 6–7% of pediatric patients (78). Children with a healed primary tuberculosis infection acquired before 2 years of age rarely develop chronic pulmonary disease; it is more common among those who acquire the initial infection after age 7, particularly if they become infected close to the onset of puberty (79). The most common pulmonary sites are the original parenchymal focus, the regional lymph nodes, or the apical seedings (Simon’s foci) (Fig. 3). This form of disease is identical to pulmonary disease in adults and usually remains localized to the lungs because the presensitization of the tissues to mycobacterial antigens evokes an immune response that prevents further lymphohematogenous spread. Pleural Effusion

Tuberculous pleural effusions originate in the discharge of bacilli into the pleural space from a subpleural primary pulmonary focus or from subpleural caseous lymph nodes (80). The discharge may be small and the pleuritis localized and asymptomatic, or a larger discharge may cause a generalized effusion, usually 3–6 months after infection. The effusion is usually unilateral but can be bilateral (81). Clinically significant pleurisy with effusion occurs in 5–30% of tuberculosis cases in young adults but is infrequent in children younger than 6 years of age and almost nonexistent in those below age 2 years. It is virtually never associated with a segmental pulmonary lesion and occurs rarely with military tuberculosis. The onset of symptoms and signs is usually abrupt, with fever, chest pain, shortness of breath, dullness to percussion, and diminished breath sounds. Fever can be high and last for several weeks, even when antituberculosis chemotherapy is given. Al-

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though corticosteroids may reduce or shorten the duration of associated symptoms, they have little effect on the ultimate outcome (80). Diagnosis can be difficult because the acid-fast stain of the pleural fluid is usually negative and the culture is positive in only 30–50% of cases. A pleural biopsy is more likely to establish the diagnosis by finding typical tubercles on histopathology and/or by recovering the organism (82,83). The prognosis of pleural effusion in children is excellent, but resolution of radiographic abnormalities may take months. Scoliosis occasionally complicates recovery of a longstanding effusion. Pericardial Disease

The most common form of cardiac tuberculosis is pericarditis. It is relatively rare, occurring in between 0.4 and 4% of tuberculosis cases in children (84). Tuberculous pericarditis usually arises from direct invasion of lymphatic drainage from subcarinal lymph nodes. Early in the course, the pericardial fluid is serofibrinous or hemorrhagic. Continued fibrosis leads to obliteration of the pericardial sac, with development of constrictive pericarditis over months to years. The presenting symptoms are nonspecific, including low-grade fever, malaise, and weight loss. Chest pain is unusual in children with tuberculous pericarditis. As the infection progresses, a pericardial friction rub or distant heart sounds with pulsus paradoxicus develop. Congestive heart failure is rare. An acid fast smear of the pericardial fluid rarely reveals the organism, but cultures are positive in 30–70% of cases. Pericardial biopsy may be necessary to confirm the diagnosis. Partial or complete pericardiectomy may be required when constrictive pericarditis is present. B. Lymphohematogenous Dissemination

It is suspected that tubercle bacilli are disseminated to distant sites from the primary complex in all cases of tuberculosis infection. The clinical picture produced by the lymphohematogenous dissemination depends on the quantity of organisms released and the host immune response. The occult dissemination usually produces no symptoms, but it is the event that causes extrapulmonary foci that can become the site of disease months to years after the initial infection. Rarely, children experience a protracted hematogenous infection caused by the intermittent release of tubercle bacilli when a caseous focus erodes through the wall of a blood vessel. The clinical onset may be acute, with high spiking fevers, but more often, the course is indolent and prolonged. Multiple organ involvement is frequent; the most common findings are hepatosplenomegaly, deep and superficial adenitis, and crops of papulonecrotic tuberculids. Pulmonary findings are common early on, but meningitis is a late complication. Paradoxically, culture confirmation may be difficult and often requires a biopsy of deep tissue such as bone marrow or liver.

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Miliary tuberculosis arises when massive numbers of tubercle bacilli are released into the bloodstream, resulting in simultaneous disease in two or more organs. This usually is an early complication of the primary infection, occurring within 3–6 months after formation of the primary complex. The disease is most common in infants and young children (85,86). The clinical manifestations of miliary tuberculosis are protean and depend on the numbers of disseminated organisms and the involved organs. Occasionally, the onset is explosive, the child becoming gravely ill in a matter of days. More often, the onset is insidious with weight loss, anorexia, malaise, and low-grade fever developing over weeks. Within several weeks, hepatosplenomegaly and generalized lymphadenopathy develop in 50–70% of children. Initially, the chest radiograph may be normal or show evidence of only the primary complex. Within 3–4 weeks, the lung fields become filled with tubercles in 90% of cases. The child may develop respiratory distress and diffuse rales or wheezing. Meningitis occurs in only 20–30% of cases. Cutaneous lesions are often absent, but the appearance of crops of papulonecrotic tuberculids or nodules may be an important diagnostic clue. Choroid tubercles may appear several weeks after onset with variable frequency. The diagnosis can be difficult to establish, requiring a high index of suspicion by the clinician. The key is often establishing an epidemiological link to a recently diagnosed case of pulmonary tuberculosis in an adult. Up to 30% of children with miliary tuberculosis have a negative tuberculin skin test, especially late in the course. A biopsy of liver or bone marrow may facilitate a more rapid diagnosis. The diagnosis can be confirmed by culture in about 33% of cases (86). With proper chemotherapy, the prognosis of miliary tuberculosis in children is excellent. However, resolution may be slow, with fever declining in 2–3 weeks and chest radiograph abnormalities persisting for months. C. Central Nervous System

Involvement of the central nervous system is the most serious complication of tuberculosis in children. Before the development of chemotherapy, tuberculous meningitis was uniformly fatal. The pathogenesis of central nervous system tuberculosis results from formation of a metastatic caseous lesion in the cerebral cortex or meninges during the occult lymphohematogenous dissemination of the primary infection (87). This lesion, the so-called Rich focus, may increase in size and discharge tubercle bacilli into the subarachnoid space. A thick, gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. The brain stem usually is the site of greatest involvement, which accounts for the frequent dysfunction of cranial nerves III, VI, and VII. Eventually, the basilar cisterns may become obstructed, leading to a communicating hydrocephalus.

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Tuberculous meningitis complicates about 1 of every 300 untreated primary infections (88). This disease is almost unheard of in children younger than 4 months of age because it takes that long for the causative pathological sequence to develop. It is most common in children younger than 4 years of age and usually occurs within 3–6 months of the initial infection. The clinical onset of tuberculous meningitis in children usually is gradual, but may be abrupt (89–91). The more rapid progression of disease tends to occur in young infants, who may experience symptoms for only several days before the onset of acute hydrocephalus, brain infarct, or seizures (92,93). The usual clinical course can be divided into three stages. The first stage, which often lasts 1–2 weeks, is characterized by nonspecific symptoms such as fever, irritability, headache, sleepiness, and malaise. There are no focal neurological signs, but infants and young children may experience a loss or stagnation of developmental milestones. The second stage often begins abruptly, with lethargy, convulsions, nuchal rigidity, hyperreflexia, hypertonia, vomiting, and cranial nerve palsies. The onset of this stage usually correlates with the development of hydrocephalus, increased intracranial pressure, and meningeal irritation. Some children lack signs of meningeal irritation, but show signs of encephalitis, such as disorientation, abnormal movements, and speech abnormalities (94). The third stage is marked by coma, irregular pulse or respiration, hemiplegia or paraplegia and, eventually, death. The prognosis is directly related to the clinical stage at diagnosis (95,96). The occurrence of the syndrome of inapproriate antidiuretic hormone secretion is common and is also linked to a poor prognosis (97). The most important clue to the diagnosis of tuberculous meningitis in a child is the history of a recent contact with an adult with pulmonary tuberculosis. However, a recent study showed that the initial contact history is often negative, as the adult with infectious pulmonary tuberculosis has often not been correctly diagnosed at the time the child with meningitis becomes symptomatic (90). The tuberculin skin test result is negative in up to 40% of cases, and the chest radiograph is normal in up to 50% of cases (98). The cerebrospinal fluid (CSF) leukocyte cell count ranges from 10 to 500/mm3; polymorphonuclear cells may be preponderant early, but a lymphocyte preponderance is more typical. The CSF glucose level is typically between 20 and 40 mg/dL, whereas the CSF protein concentration is elevated and may be markedly high (400 mg/dL). The success of microscopic examination of stained CSF and mycobacterial culture is related to the amount of CSF sampled. Computed tomography may help establish the diagnosis of tuberculous meningitis and can aid in evaluating the success of therapy. Tuberculoma is manifested clinically as a brain tumor. As many as 30% of brain tumors in a population of children may be tuberculomata, depending on the incidence of tuberculosis in the region. Tuberculomata are most common in children younger than 10 years of age. Whereas most tuberculomata in adults are supratentorial, many in children are infratentorial, most often located at the base

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of the brain near the cerebellum. Headache, convulsions, fever, and other signs and symptoms of an intracranial space-occupying lesion are common. The widespread use of improved cranial imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), has shown that tuberculomata are more common than previously realized. The distinction in children between tuberculous meningitis and tuberculoma is not as clear as was once thought. A recently recognized phenomenon is the paradoxical development of intracranial tuberculomata appearing de novo or enlarging during the treatment of meningeal, disseminated, and even pulmonary tuberculosis (90–101). This phenomenon is similar to the well-described worsening of intrathoracic adenopathy that occurs in many children during the first few months of ultimately successful antituberculosis chemotherapy. The tuberculomas and surrounding edema usually respond to corticosteroid therapy, and a change in antituberculosis therapy is not required. D. Other Extrapulmonary Sites

In general, extrapulmonary tuberculosis is more common in children than adults (102). Up to 30% of children with tuberculosis will have extrapulmonary manifestations (16). A complete review of various types is beyond the scope of this chapter, but a few salient points can be emphasized. The most common form of extrathoracic tuberculosis in children is infection of the superficial lymph nodes, sometimes called scrofula (103). The nodes most commonly involved are in the tonsillar and submandibular regions. Early, the nodes are firm, nontender, and discrete, most often unilateral, but they can be bilateral. Other than low-grade fever, systemic signs and symptoms are usually absent (104). Although the nodes generally enlarge slowly, there may be rapid enlargement associated with high fever, tenderness, and fluctuance. If untreated, necrosis of the node usually occurs, accompanied by thinning and erythema of the skin and, eventually, rupture through the skin with formation of a sinus tract. Skeletal tuberculosis in children is rare in technically advanced countries but is still common in developing nations. It most commonly affects the vertebrae, resulting in a paravertebral abscess and spondylitis, but also can affect in order of incidence, the knee, hip, elbow, and smaller joints. Tuberculous peritonitis occurs most often in adolescents and is similar clinically to disease in adults (105). Extrapulmonary tuberculosis in children affecting the eye, middle ear, kidneys, and skin may occur but is fairly rare. E. Adolescents

Tuberculosis in adolescents falls into two major categories: tuberculosis acquired as an initial infection during adolescence and tuberculosis acquired in early childhood that is exacerbated during adolescence (106). Most commonly, recently infected adolescents develop a classic primary complex, with relatively few signs or

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symptoms (107). Occasionally, the primary complex may progress rapidly to chronic pulmonary tuberculosis while the hilar lymph node involvement characteristic of primary tuberculosis is still present. A primary tuberculosis infection in infancy rarely leads to chronic tuberculosis in adolescence. A primary infection acquired between ages 7 and 10 years is more likely to result in reactivation during adolescence. When primary tuberculosis is acquired during adolescence, chronic pulmonary tuberculosis often develops within 1–3 years, a phenomenon that is two to six times more common in girls than in boys. In both sexes, the adolescent growth spurt is the time of greatest risk. Because of this propensity to progress fairly rapidly to contagious pulmonary tuberculosis, high-risk adolescents are an important target group for tuberculin screening with treatment of latent infection and case finding. F. Neonatal Disease

The clinical manifestations of tuberculosis in the fetus and newborn vary according to the site and size of the caseous lesions (59,108). Clinical symptoms usually become apparent in the second or third week of life (61,62) in the form of respiratory distress syndrome, fever, hepatic or splenic enlargement, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, ear discharge, and skin lesions. The clinical presentation can be similar to that caused by bacterial sepsis and other congenital infections, such as syphilis and cytomegalovirus. Diagnosis is often difficult, with 50% of cases discovered at autopsy. The tuberculin skin test is essentially always negative. The chest radiograph may be normal initially and become abnormal as the disease progresses, but most neonates have an abnormal chest radiograph, 50% with a miliary pattern. Fewer than 50% of infected newborns develop meningitis and the rate of isolation of mycobacteria from the spinal fluid is low. The diagnosis is usually established by finding acid-fast bacilli in gastric aspirates, urine, middle ear fluid, bone marrow aspirate, or liver biopsy. The major clue to diagnosis, however, is finding tuberculosis in the mother (61). Infants born to a mother with tuberculosis can be protected from postnatal infection by giving isoniazid to the newborn (109–112) or isolating the infant from the infectious adult while initiating treatment on the adult and administering BCG vaccine to the newborn (113). Breastfeeding is probably safe while the mother is on antituberculosis therapy since only small amounts of the drugs and no organisms are present in the milk (114). III. Diagnosis of Tuberculosis in Children A. General Principles

Throughout the world, the most highly predictive method for diagnosing tuberculosis in children consists of finding the triad of a positive tuberculin skin test, an

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abnormal chest radiograph, and history of exposure to an adult with probable or proven tuberculosis. Although the only definitive way to diagnose active tuberculosis is by demonstration of the tubercle bacilli in tissues or secretions, in children, particularly those under 10 years of age, the isolation of M. tuberculosis is difficult and uncommon. B. Tuberculin Skin Test

The tuberculin skin test has been reviewed extensively in Chapter 12. The placement of the Mantoux intradermal skin test, although fairly simple in a cooperative adult, can be a challenge in a squirming, scared child. A special technique for children often helps. The skin tester anchors his or her hand along the longitudinal axis of the child’s arm, which enhances stability and allows the last two fingers to form a fulcrum to guide inoculation of the solution. The tuberculin is injected laterally across the arm. A wheal of 6–10 mm should be raised after injection. The test is interpreted at 48–72 hours after placement. Although recent formal studies are lacking, most experts believe the time course of the reaction and the amount of induration produced is similar in children and adults. Infants may yield slightly less induration, on average, when infected. The interpretation of the Mantoux skin test should be similar in children and adults (Table 4). However, most of the “risk factors” for children are actually the risk factors of the adults in their environment—the likelihood that the child has had significant contact with an adult with contagious pulmonary tuberculosis.

Table 4 Interpretation of a Positive Mantoux Tuberculin Reaction According to Risk Factors 5 mm


10 mm

15 mm

Persons in contact with infectious persons Persons with an abnormal chest radiograph HIV-infected and other immunosupressed patients

Infants Children in contact with adults at high risk Foreign-born persons from highprevalence countries Residents from prisons, nursing homes, institutions Persons who inject drugs Persons with other medical risk factors Some health-care workers Locally identified populations at high risk

No risk factors

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Correctly classifying a child’s reaction supposes that the risk factors of the adults around the child have been considered (115–117). The American Academy of Pediatrics (AAP) has suggested that 10 mm be the cutpoint for all children less than 4 years of age. This recommendation is not based on diminished ability to make an induration reaction in children; it was made to minimize false-negative reactions in small children who are at increased risk for developing life-threatening forms of tuberculosis once infected. The same factors that influence the accuracy of tuberculin skin testing in adults also affect children. About 10–20% of children with tuberculosis disease initially have a negative reaction to tuberculin (74,118). The lack of reactivity may be global or may occur only for tuberculin, so “control” skin tests may be of limited usefulness in children. In most cases (other than those with HIV infection or other ongoing immunosuppression), the reaction becomes positive as the child recovers on chemotherapy. Incubating or manifest viral infections are a frequent cause of false-negative results in children. Previous inoculation with a bacille Calmette-Guérin (BCG) vaccination can pose problems with interpretation of a subsequent tuberculin skin test (see Chap. 19). Although many infants who receive a BCG vaccine never develop a skin test reaction to tuberculin, about 50% do (119). The reactivity fades over time but can be boosted in children with repeated skin testing (120). Most experts agree that skin test interpretation in children who received a BCG vaccine more than 3 years previously should be the same as if they had never received vaccine (121). When skin testing is performed sooner after vaccination, interpretation is difficult. The clinician should have a clear understanding of why the test was performed and realize that a positive reaction most likely represents infection with M. tuberculosis if the child had a specific exposure to an infectious adult or adolescent (122). In children with tuberculosis infection, the skin test reactivity persists long after treatment is completed (123,124). Unfortunately, many studies have demonstrated that parents are unable to accurately interpret tuberculin skin tests on their child (123). A disturbing recent study showed that pediatricians consistantly underread the amount of induration caused by a tuberculin skin test (124). C. Diagnostic Mycobacteriology

Direct smears and acid-fast stains from clinical specimens, particularly sputum, are the easiest, least expensive, and most rapid procedure for obtaining preliminary information and establishing a presumptive diagnosis of tuberculosis. However, smears may not detect the relatively small number of mycobacteria that are characteristically present in children with tuberculosis, and sputum is rarely produced by children under 10 years of age. Acid-fast stains of gastric washings obtained in lieu of sputum in children have a sensitivity below 25% (125). Obtain-

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ing three consecutive early morning gastric aspirates for culture increases this sensitivity to 30–50% in children with pulmonary tuberculosis, and in infants the yield can be as high as 70% (126). If gastric aspirates are obtained correctly, they are more likely to yield the organism than are bronchial washings (127–129). Gastric aspiration should be performed early in the morning as the child awakens before the stomach empties itself of overnight accumulation of secretions swallowed from the respiratory tract (130). First, the stomach contents should be aspirated. If no fluid is obtained, 50–75 mL of sterile distilled water should be injected, then aspirated. The gastric acidity in the sample should be neutralized immediately. Most studies have shown that hospitalization is required for optional sample collection, but one recent survey suggested that the yield from early morning outpatient gastric samples was the same as from those obtained in the hospital (131). Acid-fast stains and cultures of other body fluids and tissue specimens have lower yields than from samples from children with pulmonary disease but should be attempted when extrapulmonary tuberculosis is suspected. In practice, the difficulty of isolating M. tuberculosis from a child with tuberculosis disease does not greatly influence the approach to therapy. If the epidemiological, tuberculin skin test, clinical and radiographic information are compatible with the diagnosis, the child should be treated for tuberculosis even if the cultures are negative. If the adult source case culture and susceptibility results from his isolate are available, they can be used to guide antituberculosis chemotherapy in the child. However, it is important to attempt to isolate M. tuberculosis from the child if the diagnosis is in question, no source case confirmation is available, the source case has drug-resistant M. tuberculosis infection, or if the child has suspected extrathoracic tuberculosis. D. Serology and Nucleic Acid Amplification

After years of investigation, the serological diagnosis of tuberculosis in children has found little place in the current clinical practice (see Chap. 8). Available methods include enzyme-linked immunosorbent assays (ELISA) to detect antibodies to various purified or complex antigens of M. tuberculosis, particularly antibodies against antigen A60, but both the sensitivity and specificity of these tests are low and variable in children (132,133) and therefore inadequate to use under various clinical conditions. The use of nucleic acid amplification (NAA) (see Chap. 14), specifically the polymerase chain reaction (PCR) technique, for the diagnosis of tuberculosis in children is limited. Compared with a clinical diagnosis of pulmonary tuberculosis in children, sensitivity of PCR has varied from 25 to 83%, and specificity has varied from 80 to 100% (134–136). In the United States, FDA has approved NAA tests only for acid-fast smear-positive specimens, which are rare from children. However, PCR may have a special role in the diagnosis of extrapulmonary and

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pulmonary tuberculosis in young children and immunocompromised patients, especially those with HIV infection, when the diagnosis is not established readily by clinical or epidemiological data and when the yield of positive acid-fast smears of sputum, gastric aspirates, or other clinical specimens is low. A negative PCR result, however, does not eliminate tuberculosis as a diagnostic possibility, and a positive result does not necessarily confirm it. VI. Treatment A. General Principles

During the past decade dramatic changes in the therapeutic approach to childhood tuberculosis have occurred as a result of large numbers of treatment trials for children and increased concern about the development of resistance to antituberculosis drugs. Newer regimens are often called “short-course” chemotherapy because treatment durations as short as 6 months are successful. The key to this approach, however, is not the short duration, but the intensive initial therapy with three or more antituberculosis drugs. There are several special considerations to keep in mind when treating children with tuberculosis. First, children usually develop tuberculosis disease as an immediate consequence of the primary infection, and they typically have closed caseous lesions with relatively fewer mycobacteria than those found in adults. Since the likelihood of developing resistance to any antimycobacterial drug depends primarily upon the size of the bacillary population, resistance that emerges during therapy, secondary drug resistance, is rare in children. Most resistance encountered in children is primary (i.e., infection was by an already resistant organism). Second, children have a higher propensity than adults to develop extrapulmonary forms of tuberculosis, particularly disseminated disease and meningitis. It is important that antituberculosis drugs used in children penetrate a variety of tissues and fluids, especially the meninges. Third, the pharmacokinetics of antituberculosis drugs differ between children and adults. In general, children tolerate larger doses per kilogram of body weight and have fewer adverse reactions than adults (137–139). Although higher serum concentrations of the antituberculosis drugs are achieved in children, it is unclear whether they provide a therapeutic advantage (140). In general, children with more severe forms of tuberculosis, or those with malnutrition, experience more significant hepatotoxic effects than less severely ill children treated with the same doses per kilogram of isoniazid and rifampin, especially if the dose of isoniazid exceeds 10 mg/kg per day (141,142). Finally, most available dosage forms for antituberculosis drugs are designed for use in adults, and giving these preparations to children often involves crushing pills or making up suspensions that may be inadequately absorbed (147). Problems or difficulties taking the several medications required should be anticipated

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and resolved, especially at the beginning of therapy, to avoid delays and interruptions of treatment. B. Antituberculosis Drugs for Children

The first-line drugs are all bactericidal except ethambutol, which is bacteriostatic in vitro at 15 mg/kg but bactericidal at 25 mg/kg (Table 5). Infants and children tolerate antituberculosis drugs very well, and adverse reactions are rare. Isoniazid (INH) is the mainstray of treatment of tuberculosis in children because it is effective and familiar to most pediatricians. Although it is metabolized by acetylation in the liver, there is no correlation in children between acetylation rate and either efficacy or adverse reactions (144). The doses of INH in regular use are high enough that drug concentrations are sufficient even in children who acetylate the drug very Table 5

Antituberculosis Drugs in Children

Drugs First-line drugs Isoniazida

Rifampina

Pyrazinamide Streptomycin (IM) Ethambutol

Second-line drugs Ethionamide Kanamycin (IM) Cycloserine para-Amino salicylic acid a

Dosage forms

Twice-weekly Daily dose dose (mg/kg) (mg/kg/dose)

Maximum dose

Scored tablets: 100 mg 300 mg Syrup: 10 mg/mLb Capsules: 150 mg 300 mg Syrup: formulated from capsulesc Scored tablets: 500 mg Vials: 1 g, 4 g Scored tablets: 100 mg 400 mg

10–15

20–40

Daily: 300 mg Twice-weekly: 900 mg

10–20

10–20

600 mg

20–40

50–70

2g

20–40 15–25

20–40 50

1g 2.5 g

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

10–20 15 10–20 200–300

15–25

1g 1g 1g 10 g

Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules provide the usual adult (more than 50 kg) daily dose of each drug. b Many experts recommend not using isoniazid syrup, as it is unstable and is associated with frequent gastrointestinal complaints, especially diarrhea. c Marion Merrell Dow issues directions for preparation of this “extemporaneous” syrup.

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rapidly. The two major toxic effects of INH seen in adults, pyridoxine deficiency associated peripheral neuritis and hepatotoxicity, are rare in children (139,145). Only certain children—teenagers with inadequate diets, children from ethnic groups with low milk or meat intake, and breastfeeding babies—require pyridoxine supplementation (146,147). Of children taking INH, 3–10% have transiently elevated liver transaminase levels, but clinically significant hepatitis is exceedingly rare (139). Adolescents are more likely than younger children to experience hepatotoxicity (148). 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 (especially anticonvulsants), or has disseminated tuberculosis or meningitis. It is common to observe elevations in serum liver enzymes to two to four times normal, but discontinuation of the drugs is unnecessary if all other clinical findings are normal. Rifampin (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 these 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, rifampin is safe, effective, and routinely used in children. Pyrazinamide (PZA) plays a major role in intensive, short-course treatment regimens, exerting its maximum effect during the first 2 months of therapy (149,150). Formal pharmacokinetic studies of PZA in children have not been reported. The adult dose of 30–40 mg/kg daily is well tolerated by children, results in adequate CSF levels, rarely produces toxicity, and appears to be effective (151). 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 1–3 months if clinical improvement is documented. Ethambutol can cause dose-related reversible optic neuritis or alterations in red/green color discrimination. It is not routinely recommended for young children in whom visual field and color discrimination tests are difficult or inaccurate, but the incidence of opthalmic toxicity in infants and children is exceedingly low (152). It can be used safely in children with life-threatening forms of tuberculosis or when there is concern about the presence of drug-resistant tuberculosis. The second-line drugs (Table 5) are less commonly used and are indicated only in cases of drug-resistant tuberculosis or when patients do not tolerate firstline drugs. Ethionamide is well tolerated by children, who experience much less grastrointestinal distress than adults, but it can cause significant hepatitis. Other antituberculosis drugs used in children include the aminoglycosides kanamycin, amikacin, and capreomycin, with specific activity against different mycobacterial strains; cycloserine, which can cause significant mood changes and other neurological complaints; clofazimine and rifabutin, used most often in children with

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AIDS and M. avium-intracellulare infections (153); and the fluoroquinolones (ciprofloxacin and levofloxacin), which can be used in multidrug-resistant tuberculosis after weighing the potential risks (damage to growing cartilage noted only in animal models) and benefits in children (154). C. Specific Regimens

Exposure

In the United States, it is recommended to start treatment with INH (RIF if the adult case has INH-resistant tuberculosis) alone in children under 5 years of age, or children with other risk factors such as immunosuppression, 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. At a minimum of 3 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 treatment is continued for a total duration of 9 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 if they become infected. Frequently they are also anergic and therefore should be treated as if they have tuberculosis infection. Infection Without Disease

The treatment of children with asymptomatic latent tuberculosis infection to prevent the development of tuberculosis disease is an established practice. In infected children, the effectiveness of isoniazid therapy has approached 100%, and the protective effect has lasted for at least 30 years (155). The younger the infected child, the greater the benefit (156). Tuberculin-positive children with known contact to an infectious adult case are at the highest risk of developing disease and always should be given treatment. Tuberculin-positive children without known contact also should receive therapy, especially those under 5 years of age and adolescents. The American Academy of Pediatrics and CDC currently recommend a duration of 9 months of therapy with INH in children. Rifampin can be used in children with asymptomatic infection 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. If the infecting strain is resistant to both INH and RIF, most experts recommend giving the child two other drugs to which the isolate is susceptible for 12 months. Short course (2-month) regimens with rifampin and pyrazinamide have been recommended for adults and will likely become popular in children (see Chap. 18). 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

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and on improving adherence to treatment. Abernathy et al. (157) reported in 1983 successful treatment of 50 children with tuberculosis using INH and RIF daily for 1 month, then twice weekly for 8 months, a total duration of 9 months. Several studies of 6-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 (158–164). The most commonly used regimen is 6 months of INH and RIF supplemented during the first 2 months with PZA. This 6-month, three-drug regimen is currently the standard therapy for presumed or confirmed drug-susceptible intrathoracic tuberculosis (pulmonary and/or hilar adenopathy) (147,165). 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 2 weeks to two months is preferable, followed by twice-weekly administration under directly observed therapy (DOT) for the duration (161,164). Although 9-month regimens of INH and RIF are effective in areas where rates of drug resistance 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 prior treatment, HIV co-infection, or residence in an area or country with high rates of drug resistance) or if the community where the child lives has a rate of resistance greater than 4%, a fourth antituberculous drug should be considered (166). However, the risk of the additional volume of medicine should be weighed against the risk of drug resistance. The usual choice is ethambutol, which offers the advantage of oral administration, particularly in countries where using parenteral preparations is difficult or risks HIV transmission. Streptomycin is a second alternative, but since it has to be administered by intramuscular injections, it is not the preferred choice for children. Extrapulmonary Tuberculosis

Controlled clinical trials comparing treatment regimens for various forms of extrapulmonary tuberculosis have been few. In general, the 6-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 (147). Bone and joint tuberculosis may require a treatment duration of 9–12 months, especially if surgical intervention has not been performed (167). For meningitis and disseminated tuberculosis, most children are treated initially with four drugs (INH, RIF, PZA, and ethambutol or streptomycin) for the first 2 months, followed by INH and RIF for a total duration of no less than 6 months, usually 9–12 months (147).

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Drug-Resistant Tuberculosis

The rates of antituberculosis drug resistance are greater than 20% and as high as 80% in some countries of the world (168). In the United States approximately 10% of M. tuberculosis isolates are resistant to at least one drug (169). Patterns of drug resistance among children with tuberculosis tend to reflect those found among adults in the same population (170,171). Certain epidemiological factors such as residence in a country or area with high rates of drug resistance, homelessness, previous antituberculosis therapy, and HIV infection, in the child or the adult source case, are clues to predicting drug resistance in childhood tuberculosis. The treatment of drug-resistant tuberculosis in children must be guided by the drug susceptibility pattern of the isolate (172). Treatment regimens must include at least two bactericidal drugs to which the organism is susceptible to prevent the development of more secondary resistance (173–175). Duration of therapy is usually 9–12 months if either INH or RIF can be used and 18–24 months if resistance to both drugs is present (176). Rifampin-resistant disease in children is more difficult to treat than isoniazid-resistant disease. The treatment regimens for multidrug resistance may include four to seven drugs administered daily under DOT and should be managed by experts in tuberculosis. Human Immunodeficiency Virus–Related Tuberculosis

The optimal treatment of tuberculosis in children with HIV infection has not been established. 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 9 months. Tuberculosis disease in these and patients with other with immunocompromising conditions should be treated with at least three drugs initially (INH, RIF, and PZA) for 2 months, followed by INH and RIF to complete a total duration of 6–12 months (177). 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 always should 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 (178). 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 (128,179). A frequently used regimen includes prednisone (1–2 mg/kg/day) for

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4–6 weeks with gradual taper over 1–2 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 from medications, 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 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 (180). 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, directly observed therapy (DOT) is considered the optimal method of drug administration by the CDC, AAP, and WHO for all children with tuberculosis disease, particularly for those with drugresistant 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 take the medications at a time and place convenient for the patients and, at present, only few communities in the world have identified the resources to provide DOT for children with tuberculosis. Public Health and Pediatric Tuberculosis

It is hoped that it has become obvious that the control of tuberculosis—for a community and for individuals—depends on close cooperation between the clinician and the local health department. It is critically important that clinicians report cases of tuberculosis to the health department as soon as possible. Public health law in all states requires that the suspicion of tuberculosis disease in an adult or child be reported immediately to the health department. The clinician should not wait for microbiological confirmation of the diagnosis, because it is this reporting that leads to the initiation of the contact investigation that may find infected children and allow them to be treated before disease occurs. If the clinician waits for confirmatory results, the child may progress from infection to disease before intervention can occur. It is estimated that about 1 million children in the United States are infected by M. tuberculosis. The major purpose of finding and treating these children is to prevent future cases of tuberculosis. Frequent or periodic skin testing of children,

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however, prevents few cases of pediatric tuberculosis, especially if the screening is centered on school-age children (who rarely develop primary disease). The major purpose of testing children is to prevent future cases of tuberculosis in adults. Even among high-risk groups in the United States, the infection rates are low among young children. The incubation period for pediatric tuberculosis is weeks to months, so even annual testing will not prevent many cases. The best way to prevent pediatric tuberculosis is via prompt contact investigation centered on adults with suspected contagious tuberculosis. This investigation has a high yield—on average, 30–50% of childhood household contacts are infected—but also finds the most important individuals, those most recently infected who are in the period of their lives when they are most likely to develop tuberculosis disease. If perfect contact investigations were performed and foreign-born children coming to the United States underwent tuberculin skin tests, there would be virtually no reason to skin-test any other children because all infected children would be found. Obviously, these two activities do not occur in a perfect fashion, and testing of certain selected individuals is appropriate. The CDC and AAP have changed their recommendations for tuberculin skin testing of children several times since the 1980s. The AAP continues to emphasize that routine tuberculin skin testing of all children, including school-based programs that include populations at low risk, has a low yield of positive results or a large number of false-positive results, representing an inefficient use of limited health care resources. Children without specific risk factors who reside in areas with a low prevalence of tuberculosis, therefore, should not undergo routine tuberculin skin testing. A child should be considered at increased risk in the following cases: The child was born or has resided in a country with high tuberculosis rates (Central and South America, Africa, Asia, Eastern Europe). There is a family history of tuberculosis, an adult with HIV infection or AIDS has spent time in the household or with the child, or an adult who has been in jail or prison has spent time in the household or with the child. The child is a member of a group identified locally to be at increased risk for tuberculosis infection (e.g., migrant worker families, the homeless, certain census tracts or neighborhoods). The focus for tuberculin skin-testing programs should be placed on identifying risk factors for a child being in a group with a high prevalence of infection. Local health departments must identify risk factors that are germane to their area. Clinicians and their organizations must work closely with local health departments to establish which children should be tested and which should not. Obviously, social and political problems can occur when selective testing is suggested. What is correct from a public health point of view may not be easy to translate into a workable and generally acceptable policy. Local clinicians can be extremely helpful to

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health departments in advancing prudent and reasonable tuberculosis control policies, particularly when other government or public agencies are involved. References 1. 2.

3. 4. 5. 6.

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36. Braun MM, Cauthen G. Relationship of the human immunodeficiency virus epidemic to pediatric tuberculosis and bacillus Calmette Guerin immunization. Pediatr Infect Dis J 1992; 11:220–227. 37. Chintu C, Bhat G, Luo C. Seroprevalence of human immunodeficiency virus type 1. Infection in Zambian children with tuberculosis. Pediatr Infect Dis J 1993; 12:499–504. 38. Sassan-Morokro M, De lock KM, Ackah A. Tuberculosis and HIV infection in children in Abidjan, Cote d’Ivoire. Trans R Soc Trop Med Hyg 1994; 88:178–181. 39. Coovadia HM, Jeena P, Wilkinson D. Childhood human immunodeficiency virus and tuberculosis co-infections: reconciling conflicting data. Int J Tuberc Lung Dis 1998; 2:844–851. 40. Schaaf HS, Geldenduys A, Gre RP, Cotton MF. Culture-Positive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998; 17:599–604. 41. Chan SP, Binbaum J, Rao M. Clinical manifestations and outcome of tuberculosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1996; 15:443–447. 42. Khouri Y, Mastrucci M, Hutto C. Mycobacterium tuberculosis in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1992; 11:950–955. 43. Mukadi YD, Wiktor SZ, Caulibaly 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; 11:1151–1158. 44. Garay JE. Clinical presentation of pulmonary tuberculosis in under 10s and differences in AIDS related cases: a cohort study of 115 patients. Tropical Doctor 1997; 27:139–142. 45. Gutman LT, Moye J, Zimmer B, Jion C. Tuberculosis in HIV-exposed or infected United States children. Pediatr Infect Dis J 1994; 13:963–968. 46. Barry MA, Shirley L, Grady MT, Etkind SW, Almeida C, Bernardo J, Lamb GA. Tuberculosis infection in urban adolescents: results of a school-based testing program. Am J Public Health 1990; 80:439–441. 47. 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. 48. Starke JR, Taylor KT, Martindill CA, Pyle ND, Herrin CM. Extremely high rates of tuberculin reactivity among young school children in Houston (abstr). Am Rev Respir Dis 1988; 137:22. 49. Pong AL, Anders BJ, Moser KS, Starkey M, Gassmann A, Besser RE. Tuberculosis screening at 2 San Diego high schools with high-risk populations. Arch Pediatr Adolesc Med 1998; 152:646–650. 50. Mohle-Boetani JC, Miller B, Halpern M. School-based screening for tuberculosis infection: a cost-benefit analysis. JAMA 1995; 273:613–619. 51. Lincoln EM, Harris LC, Bovornkitti S, Carretero R. The course and prognosis of endobronchial tuberculosis in children. Am Rev Tuberc 1956; 74:246–256. 52. Lorriman G, Bentley FJ. The incidence of segmental lesions in primary tuberculosis in childhood. Am Rev Tuberc 1959; 79:756–763.

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53. Morrison JB. Natural history of segmental lesions in primary pulmonary tuberculosis. Arch Dis Child 1973; 48:90–98. 54. Daly JF, Brown DS, Lincoln EM, et al. Endobronchial tuberculosis in children. Dis Chest 1952; 22:380–398. 55. Stansberry SD. Tuberculosis in infants and children. J Thorac Imaging 1990; 5:17–27. 56. Wallgren A. The time table of tuberculosis. Tubercle 1948; 29:245–256. 57. Zahraad J, Johnson D, Lim-Dunham JE, Herold BC. Unusual features of osteoorticular tuberculosis in children. J Pediatr 1996; 129:597–602. 58. Miller FJW, Seale RME, Taylor MD. Tuberculosis in Children. Boston: Little Brown & Co., 1963. 59. Cantwell M, Shehab Z, Costello A. Brief Report: Congenital tuberculosis. N Engl J Med 1994; 330:1051–1054. 60. Beitzke H. Ueber die angeborene tuberkoloese infektion. Ergeb Gesamten Tuberkuloseforsch 1935; 7:1–20. 61. Hageman J, Shulman S, Schreiben M, Luck S and Yogev R. Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 1980; 66:980–985. 62. Nemir RL, O’Hare D. Congenital tuberculosis: review and diagnostic guidelines. Am J Dis Child 1985; 139:284–287. 63. Grenville-Mathers R, Harris WC, Trenchard HJ. Tuberculous primary infection in pregnancy and its relation to congenital tuberculosis. Tubercle 1960; 41:81–87. 64. Kaplan C, Benirschke K, Tarzy B. Placental tuberculosis in early and late pregnancy. Am J Obstet Gynecol 1980; 137:858–861. 65. Hallum JL, Thomas HE. Full term pregnancy after proved endometrial tuberculosis. J Obstet Gynaecol Br Emp 1955; 62:548–551. 66. Hughesdon MR. Congenital tuberculosis. Arch Dis Child 1946; 21:121–126. 67. Jacobs RF, Abernathy RS. Management of tuberculosis in pregnancy and the newborn. Clin Perinatol 1988; 15:305–319. 68. Vallejo JG, Starke JR. Tuberculosis and pregnancy. Clin Med 1992; 13:693–707. 69. Migliori GB, Borghesi A, Rossaniyo P. Proposal of an improved score method for the diagnosis of pulmonary tuberculosis in childhood in developing countries. Tuberc Lung Dis 1992; 73:145–149. 70. Khan EA, Starke JR. Diagnosis of tuberculosis in children: increased need for improved methods. Emerg Infect Dis 1995; 1:115–122. 71. Driver C, Luallen J, Good W. Tuberculosis in children younger than five years old: New York City. Pediatr Infect Dis J 1995; 14:117–121. 72. Kimerling ME, Vaughn ES, Dunlap NE. Childhood tuberculosis in Alabama: epidemiology of disease and indicators of program effectiveness, 1983 to 1993. Pediatr Infect Dis J 1995; 14:678–684. 73. Schaaf HS, Beyers N, Gre RP. Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations. Pediatr Infect Dis J 1995; 14:189–194. 74. Starke JR, Taylor-Watts KT. Tuberculosis in the pediatric population of Houston, Texas. Pediatrics 1989; 84:28–35.

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75. Driver CR, Valway SE, Cantwell ME, Onorato IM. Tuberculosis skin test screening of school children in the United States. Pediatrics 1996; 98:97–102. 76. Delacourt C, Mani TM, Bonnerot VI. Computed tomography with normal chest radiograph in tuberculosis infection. Arch Dis Child 1993; 69:430–432. 77. Teeratkulpisarn J, Lumbigagnon P, Pairojkul S. Cavitary tuberculosis in a young infant. Pediatr Infect Dis J 1994; 13:545–546. 78. Lincoln EM, Gilbert L, Morales SM: Chronic pulmonary tuberculosis in individuals with known previous primary tuberculosis. Dis Chest 1960; 38:473–482. 79. Holm S. Om der Friske Tuberculose Infection den Klink, Prognose og Behandlung. Copenhagen: Rosenkilde, 1947. 80. Smith MHD, Matsaniotis N. Treatment of tuberculosis pleural effusions with particular reference to adrenal corticosteroids. Pediatrics 1958; 22:1074–1987. 81. Lincoln EM, Davies PA, Bovornkitti S. Tuberculous pleurisy with effusion in children. Am Rev Tuberc 1958; 77:271–289. 82. Levine H, Metzger W, Lacera S. Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 1970; 126:269–271. 83. Loddenkemper R. Prospective individual comparison of blind needle biopsy and of thoracoscopy in the diagnosis and differential diagnosis of tuberculous pleurisy. Scand J Respir Dis 1978; 102(suppl):196–198. 84. Hugo-Hammon CT, Scher H, DeMoor MMA. Tuberculous pericarditis in children: a review of 44 cases. Pediatr Infect Dis J 1994; 13:13–18. 85. Hussey G, Chisolm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991; 10:832–836. 86. Schuitt KE. Miliary tuberculosis in children. Clinical and laboratory manifestations in 19 patients. Am J Dis Child 1979; 133:538–585. 87. Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933; 52:5–35. 88. Jaffe IP. Tuberculous meningitis in childhood. Lancet 1982; 1:738. 89. Waecker NJ Jr, Connors JD. Central nervous system tuberculosis in children: a review of 30 cases. Pediatr Infect Dis J 1990; 9:539–543. 90. Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculosis meningitis. J Pediatr 1995; 127:27–33. 91. Yaramis A, Gurkan F, Eleveli M, Soker M, Haspolat K, Kirbas G, Tas, MA. Central nervous system tuberculosis in children: a review of 214 cases. Pediatrics 1998; 102:e49. 92. Idriss ZH, Sinno A, Kronfol NM. Tuberculous meningitis in childhood: forty-three cases. Am J Dis Child 1976; 130:364–367. 93. Sumaya CV, Simek M, Smith MHD. Tuberculous meningitis in children during the isoniazid era. J Pediatr 1975; 87:43–49. 94. Udani PM, Parekn UC, Dastur DK. Neurologic and related syndromes in CNS tuberculosis: clinical features and pathogenesis. J Neurol Sci 1971; 14:341–357. 95. Ramachandran P, Duraipandian M, Nagarajan M, Probhakar R, Ramakrishan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986; 67:17–29.

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96. Schoeman JF, Vanzyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997; 99:226–231. 97. Cotton MF, Donald PR, Schoeman JF, Aalbers C, VanZyl LE, Lombard C: Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in tuberculous meningitis. Pediatr Infect Dis 1991; 10:837–842. 98. Zarabi M, Sane S, Girdany BR. Chest roentgenogram in the early diagnosis of tuberculous meningitis in children. Am J Dis Child 1971; 121:389–392. 99. Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994; 9:1092–1094. 100. Shepard WE, Field ML, James DH. Transient appearance of intracranial tuberculomas during treatment of tuberculous meningitis. Pediatr Infect Dis J 1986; 5:599–601. 101. Teoh R, Humphries MJ, O’Mahoney, Sister Gabriel. Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: report of 10 patients and review of the literature. QJ Med 1987; 63:449–460. 102. Reider HL, Snider DE Jr, Cauthen GM. Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 1990; 141:347–351. 103. Margileth AM, Chandra R, Altman RP. Chronic lymphadenopathy due to mycobacterial infection. Clinical features, diagnosis, histopathology and management. Am J Dis Child 1984; 138:917–922. 104. Appling D, Miller RH. Mycobacterial cervical lymphadenopathy. 1981 update. Laryngoscope 1981; 91:1259–1266. 105. Chavalittamvong B, Talalak P. Tuberculous peritonitis in children. Prog Pediatr Surg 1982; 15:161–167. 106. Smith MHD. Tuberculosis in adolescents: Characteristics, recognition, management. Clin Pediatr 1967; 6:9–15. 107. Nemir RL. Perspectives in adolescent tuberculosis: three decades of experience. Pediatrics 1986; 78:399–405. 108. Siegel M. Pathologic findings and pathogenesis of congenital tuberculosis. Am Rev Tuberc 1934; 29:297–310. 109. Kendig EL, Rodgers WL. Tuberculosis in the neonatal period. Am Rev Tuberc 1958; 77:418–424. 110. Dormer BA, Swarit JA, Harrison I. Prophylactic isoniazid protection of infants in a tuberculosis hospital. Lancet 1959; 2:902–904. 111. Kendig EL Jr: Prognosis of infants born to tuberculous mothers. Pediatrics 1960; 26:97–100. 112. Light J, Saidleman M, Sutherland JM. Management of newborns after nursery exposure to tuberculosis. Am Rev Respir Dis 1974; 109:415–418. 113. Kendig EL Jr. The place of BCG vaccine in the management of infants born of tuberculous mothers. N Engl J Med 1969; 250:1969–1972. 114. Snider DE Jr., Powell KE. Should women taking antituberculous drugs breastfeed? Arch Intern Med 1984; 144:589–590.

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115. Heubner RE, Schein MF, Boss JB. The tuberculin skin test. Clin Infect Dis 1993; 17:968–975. 116. American Academy of Pediatrics, Committee on Infectious Diseases. Screening for tuberculosis in infants and children. Pediatrics 1994; 93:131–134. 117. American Academy of Pediatrics, Committee on Infectious Diseases. Update on tuberculosis skin testing of children. Pediatrics 1996; 97:282–284. 118. Steiner P, Rao M, Victoria MS, Jabbar H, Steiner M. Persistently negative tuberculin reactions: their presence among children culture positive for Mycobacterium tuberculosis. Am J Dis Child 1980; 134:747–750. 119. Hardy JB. Persistence of hypersensitivity to old tuberculin following primary tuberculosis in childhood: a long term study. Am J Public Health 1946; 36:1417–1426. 120. Sepulveda RL, Burr C, Ferrer X, Sorensen RU. Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with bacille Calmette-Guerin at birth in Santiago, Chile. Pediatr Infect Dis 1988; 7:578–581. 121. Nemir RL, Teichner A. Management of tuberculin reactions in children and adolescents previously vaccinated with BCG. Pediatr Infect Dis 1983; 2:446–451. 122. Johnson H, Lee B, Dohert E, et al. Tuberculin sensitivity and the BCG scan in tb contacts. Tuberc Lung Dis 1995; 76:122–125. 123. Asnes RS, Maqbool S. Parent reading and reporting of children’s tuberculin skin test results. Chest 1975; 68:459–462. 124. Kendig EL Jr, Kirkpatrick BV, Carter WH, Hill FA, Caldwell K, Entwistle M. Underreading of the tuberculin skin test reaction. Chest 1998; 113:1175–1177. 125. Klotz SA, Penn RL. Acid-fast staining of urine and gastric contents is an excellent indicator of mycobacterial disease. Am Rev Respir Dis 1987; 136:1197–1198. 126. Vallejo J, Ong L, Starke J. Clinical features, diagnosed and treatment of tuberculosis in infants. Pediatrics 1994; 94:1–7. 127. de Blic J, Azevedo I, Burren CP, Le Burgeois M, Lallemand D, Scheinmann P. The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Chest 1991; 100:688–692. 128. Toppet M, Malfroot A, Derde MP, Toppet V, Spehl M, Dab I. Corticosteroids in primary tuberculosis with bronchial obstruction. Arch Dis Child 1990; 65:1222–1226. 129. Laff HI, Goldberg M, Russell WF Jr. Bronchoscopy in primary tuberculosis of childhood. Am Rev Tuberc 1956; 74:267–289. 130. Pomputius WF, Rost J, Dennehy PH, Carter EJ. Standardization of gastric aspirate technique improves yield in the diagnosis of tuberculosis in children. Pediatr Infect Dis J 1997; 16:222–226. 131. Lobato MN, Loeffler AM, Furst K, Cole B, Hopewell PC. Detection of Mycobacterium tuberculosis in gastric aspirate collected from children: hospitalization is not necessary. Pediatrics 1998; 102:e40(1–4). 132. Delacourt C, Gobin J, Gaillard JL. Value of ELISA using antigen 60 for the diagnosis of tuberculosis in children. Chest 1993; 104:393–398. 133. Turneer M, Van Nerom E, Nyabenda J, et al. Determination of tumoral immunoglobulin 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; 150:1508–1512.

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134. Pierre C, Olivier C, Lessier D. Diagnosis of primary tuberculosis in children by amplification and detection of mycobacterial DNA. Am Rev Respir Dis 1993; 147:420–424. 135. Smith KC, Starke JR, Eisenach K, Ong LT. Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 1996; 97:155–160. 136. Delacourt C, Poveda JD, Churean C. Use of polymerase chain reaction for improved diagnosis of tuberculosis in children. J Pediatr 1995; 126:703–709. 137. Beaudry PH, Brickman HF, Wise MB, Macdougall D. Liver enzyme disturbances during isoniazid chemoprophylaxis in children. Am Rev Respir Dis 1974; 110:581–584. 138. Stein MT, Liang D. Clinical hepatotoxicity of isoniazid in children. Pediatrics 1979; 64:499–505. 139. O’Brien RJ, Long MW, Cross FS, Lyle MA, Snider DE Jr. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983; 72:491–499. 140. Olson WA, Pruitt AW, Dayton PG. Plasma concentrations of isoniazid in children with tuberculous infections. Pediatrics 1981; 67:876–878. 141. Tsagarpoulou-Stinga H, Mataki-Emmanouilidou T, Karida-Kavalioti S, Manios S. Hepatotoxic reactions in children with severe tuberculosis treated with isoniazid-rifampin. Pediatr Infect Dis 1985; 4:270–273. 142. Donald PR, Schoeman JF, O’Kennedy A. Hepatic toxicity during chemotherapy for severe tuberculosis meningitis. Am J Dis Child 1987; 141:741–743. 143. Notterman DA, Nardi M, Saslow JG: Effect of dose formulation on isoniazid adsorption in two young children. Pediatrics 1986; 77:850–852. 144. Martinez-Roig A, Roig A, Cami J, Llorens-Terol J, de la Torre R, Perich F. Acetylation phenotype and hepatotoxicity in the treatment of tuberculosis in children. Pediatrics 1986; 77:912–915. 145. Pellock JM, Howell J, Kendig EL Jr, Baker H. Pyridoxine deficiency in children treated with isoniazid. Chest 1985; 87:658–661. 146. McKenzie SA, Macnab AJ, Katz G. Neonatal pyridoxine responsive convulsions due to isoniazid therapy. Arch Dis Child 1976; 51:567–569. 147. American Academy of Pediatrics Committee on Infectious Disease. Chemotherapy for tuberculosis in infants and children. Pediatrics 1992; 89:161–165. 148. Litt IF, Cohen MI, McNamara H. Isoniazid hepatitis in adolescents. J Pediatr 1976; 89:133–135. 149. Girling DJ. Role of PZA in primary chemotherapy for pulmonary tuberculosis. Tubercle 1984; 65:1–4. 150. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J 1990; 9:785–793. 151. Donald PR, Seifart H. Cerebrospinal fluid pyrazinamide concentrations in children with tuberculosis meningitis. Pediatr Infect Dis J 1988; 7:469–471. 152. Trebucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. Int J Tuberc Lung Dis 1997; 1:12–15. 153. Jagannoth C, Reddy MV, Kailasam S, et al. Chemotherapeutic activity of clofazemine and its analogues against Mycobacterium tuberculosis. Am J Respir Crit Care Med 1995; 151:1083–1986.

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154. Hussey G, Kibel M, Porker N. Ciprofloxacin treatment of multiple drug-resistant extrapulmonary tuberculosis in a child. Pediatr Infect Dis J 1992; 11:408–409. 155. Hsu KHK. Thirty years after isoniazid: its impact on tuberculosis in children and adolescents. JAMA 1984; 251:1283–1285. 156. Comstock GW, Livesay VT, Woopart SF. Prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 157. Abernathy RS, Dutt AK, Stead WM and Doers DL. Short course chemotherapy for tuberculosis in children. Pediatrics 1983; 72:801–806. 158. Biddulph J. Short-course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9:794–801. 159. Ibanez S, Ross G. Quimioterapia abreviada de 6 meses en tuberculosis pulmonar infantil. Rev Chil Pediatr 1980; 51:249–252. 160. Khubchandani RP, Kumta NB, Bharucha NB, Ramakantan R. Short-course chemotherapy in childhood pulmonary tuberculosis (abstr). Am Rev Respir Dis 1990; 141:A338. 161. Kumar L, Dhand R, Singhi PD, Rao KLN, Katariya S. A randomized trial of fully intermittent and daily followed by intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9:802–806. 162. Pelosi F, Budani H, Rubenstein C, Velez HD, Bonavena B, Beltran OP, GonzalezMontaner J. Isoniazid, rifampin and pyrazinamide in the treatment of childhood tuberculosis with duration adjusted to the clinical status (abstr). Am Rev Respir Dis 1985; 131:A229. 163. Tsakalidis D, Pratsidou P, Hitogbu-Metedov A. Intensive short course chemotherapy for treatment of Greek children with tuberculosis. Pediatr Infec Dis J 1992; 11:1036–1042. 164. Varudkar BL. Short-course chemotherapy for tuberculosis in children. Indian J Pediatr 1985; 52:593–597. 165. Starke JR, Correa AG. Management of mycobacterial infection and disease in children. Pediatr Infect Dis J 1995; 14:455–470. 166. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. MMWR 1993; 42:1–8. 167. Dutt AK, Moers D, Stead WW. Short course chemotherapy for extrapulmonary tuberculosis. Ann Intern Med 1986; 107:7–12. 168. Nunn P, Felten M, Surveillance of resistance to antituberculosis drugs in developing countries. Tubercl Lung Dis 1994; 75:163–167. 169. Bloch AB, Cauthen GM, Onorato IM. Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 1994; 271:665–671. 170. Steiner P, Rao M, Victoria MS, Hunt J, Steiner M. A continuing study of primary drug-resistant tuberculosis among children observed at the Kings County Hospital Medical Center between the years 1961–1980. Am Rev Respir Dis 1983; 128:425–428. 171. Steiner P, Rao M, Mitchell M. Primary drug-resistant tuberculosis in children: correlation of drug susceptibility patterns of matched patient and source case strains of Mycobacterium tuberculosis. Am J Dis Child 1985; 139:780–782. 172. Swanson DS, Starke JR. Drug-resistant tuberculosis in pediatrics. Pediatr Clin North Am 1995; 42:553–581.

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22 Case Management The Key to a Successful Tuberculosis-Control Program

BONITA T. MANGURA

KAREN E. GALANOWSKY

New Jersey Medical School National Tuberculosis Center and International Center for Public Health UMDNJ–New Jersey Medical School Newark, New Jersey

New Jersey Department of Health and Senior Services Trenton, New Jersey

I. Introduction The well-known U-shaped curve (1) reflected the fall and resurgence of tuberculosis (TB) in the United States before and after 1985. Ironically, in the calm before the surge, plans were designed to eliminate tuberculosis by the year 2010 (2). The 1989 Centers for Disease Control and Prevention (CDC) national strategic plan to eliminate tuberculosis in the United States recommended the containment of continuous spread through the assignment of a specific health department employee to each tuberculosis case. Each employee was to be responsible for ensuring not only prescription of adequate treatment but assuring ingestion of the medicine by the patient (2). These mandates provided the basis for the concept of a manager for the patient and directly observed therapy (DOT) for assuring proper combination of drugs and completion of treatment of the patient. How this mandate was applied and implemented varied in different TBcontrol programs. This chapter will describe the application of this concept in many cities while focusing on the specific organization of one of the more successful programs in the United States. Between 1985 and 1992, a total of almost 70,000 excess TB cases rang the alarm (3). Service decentralization occurred while the human immunodeficiency virus (HIV) added to the increasing numbers of TB cases. Simultaneously, cate597

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gorical services and funding were cut back for public services. Aptly speaking, the prophetic “U-shaped” curve of concern (1) paralleled the fall and rise pattern of U.S. TB cases. An unfortunate series of nosocomial outbreaks in 11 U.S. hospitals (4,5) with transmission to health care workers were soon reported. In some, the transmission involved multidrug-resistant TB. In 1990, the United States fell short of an International Union Against Tuberculosis and Lung Disease (IUATLD) definition of low-prevalence country (5) when national tuberculosis case rates were 10 per 100,000 population (3). In New York City alone, incidence doubled while it more than doubled in other cities. Disappearance of TB expertise among physicians servicing multiple health services compounded the problem. Old tuberculosis concepts of physical isolation by sanatorium care were no longer practical. Ambulatory care was apparently insufficient, and innovative approaches had to be designed and promoted anew. II. Directly Observed Therapy Many major TB programs reverted to sentinel strategies such as supervised therapy or DOT to combat the resurgence. The basis for the 1989 CDC mandate is not unique. Supervised therapy, the mode of successful treatment in the sanatoria, was transposed to the ambulatory setting for recalcitrant patients. Ambulatory supervised therapy in the 1970s was first suggested in Denver (7) and applied in the New Jersey Medical School’s Lattimore Clinic (8) in a selected group of patients. The city of Baltimore (9), a decade before New York City “turned the tide” of tuberculosis (10), used community workers to deliver DOT. Subsequently, the Tarrant County TB Program in Texas reduced its multidrug-resistance rates applying the same principle (11). Although the earliest reports on DOT were from Fox (12) and Moodie (13) based on their experiences in the 1960s (British Medical Research Council: Madras and Hong Kong), DOT was not popular in the United States because of intrusion or perceived infringement of civil rights (14). In 1992, CDC guidelines recommended DOT (15), but its application as standard of therapy even in areas with poor TB drug adherence was delayed. III. Clinical Care and Public Health Until early 1994, many U.S. TB clinics operated with some form of “parallel activities model.” This refers to a system in which clinical services were directed and provided separately from outreach (governmental) TB-control activities. Self-administered therapy was the major mode of treatment, and DOT was the exception based on patient failure to pick up medications, multidrug resistance, or multiple missed monthly clinic visits. Overall the response to failure of therapy was reac-

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tive. There was very little synchronization between the clinical follow-up and TBcontrol activities, thus accountability for a patient treatment outcome was addressed separately from case investigation or compliance issues (16). Factors that impact on adherence such as social and behavioral issues were discussed apart from clinical issues so that each unit had a fragmented picture of the total patient. One common scenario of fragmentation that occurs in the parallel activity model is as follows: An outreach worker from the TB-control program would be assigned to locate, pick up, and often unexpectedly deliver the delinquent patient to the TB clinic. When repeated multiple times in a day or a week, this type of (mistiming) would often adversely impact on the clinic schedule, patient flow, and personnel resources. Nursing and physician interactions with the patient become strained as a result. This asynchrony results in conflicts between nursing and TB control staff particularly in achieving their respective disciplines’ timetables and objectives. Deficiencies, conflicts, and gaps in the system overwhelmed the few successes that specialized units for nonadherence produced. Many cities eventually narrowed the gaps, corrected the deficiencies of existing models, and utilized these models to apply DOT with major success as shown in Baltimore and New York City (17,18). Naturally, commitment from legislators and sustained funding were necessary to carry out these changes. IV. The Newark Experience Newark’s unique patient population is the largest of any city in New Jersey (estimated 258,751 in 1997), of which 84% are classified as minority black and Hispanic. In addition, there are significant enclaves of undocumented foreign-born individuals, who comprise a major medically undeserved population. Newark has several other significant societal problems that impact on the incidence of TB, such as unemployment, poverty (26% below poverty level, 22% on public assistance), high crime rate, low education rates, and poor housing. Serious medical problems resulting from injection drug use, HIV, and AIDS are prevalent. Newark ranked third highest in tuberculosis cases among 20 U.S. cities with a population of more than 250,000 in 1985. During the period of U.S. national resurgence (1985–1992) (9), only about half of the total cases in Newark completed therapy within 12 months. This city had suffered a profound decline in TB control as a result of budget cuts and personnel downsizing at the time. In order to achieve a reduction in TB cases, incremental change from selfadministered and selective DOT in 1993 to “universal” DOT in 1994 was instituted. However, transition to selective DOT and subsequently universal DOT only showed minimal improvement (19) in contrast to the other successful reports (17,18).

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Because of the difficulties described above, the Nurse Case-Management Model was implemented. The infrastructure, objectives, and function of this model addressed the deficiencies of the “parallel activities model” and matched the needs (20) of the demographic characteristic of the population. As part of the Nurse Case-Management Model, we implemented a merger of the parallel disciplines: patient care and public health. Nursing activity and TB control activity were analyzed and placed into a coordinated and integrated system of case management with common goals. The organizational tree and management system were totally redesigned according to a Nurse Case-Management model at the service delivery level. The concept of case management has existed since 1920s. It was originally utilized in the fields of psychiatry and social work for long-term illnesses managed in community-based settings. Visiting nurses used some case-management models in the 1930s (21), while public health nurses utilized the process for community-based patient care (22). As a care-delivery system, however, it is relatively new in acute care settings and in the treatment of patients with specific disease entities such as tuberculosis. Similar management models had been adopted in the medical world from the business sector. Businesses addressed optimization of efficiency and outcomes from tasks and responsibilities in the 1970s (23) by setting up managers and management for establishments. Integration of patient care delivery using the patient management model in medical practice was one of the earliest changes in health-care delivery. This model identifies specific patients with specific medical problems and handles patient care with specialized medical teams to achieve optimal outcomes. In nursing, the practice model of case management (24) included establishment of appropriate plans of care based on assessment of the patient, the patient’s family or “significant other” persons, and coordination of available resources for the patient’s benefit. The role of case manager is adaptable to many professionals, such as nurses, social workers, health advisors, and others. For our particular model, the nurse was chosen to take on the role of case manager to provide services and improve the overall medical outcome. Case management is a practice model that provides assessment, implementation, planning, coordination, monitoring, referral, collaboration, and evaluation of patient care to ensure optimal outcomes (25). The process of case management allows the effective delivery of health-care services to a cohort of patients according to internal organizational policies and external standards of practice. This approach is patient oriented, utilizing a multidisciplinary team. The team works collaboratively to provide services and ensure that the patient experiences care along a continuum as opposed to fragmentation of care, which is often found when various separate disciplines are involved.

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The objectives of our case-management model are (1) to identify actual or potential health and non–health-related problems that would impact TB care and treatment of the individual patient, (2) to achieve positive patient outcomes, (3) to improve treatment-completion rates within acceptable time frames, and (4) to place all of newly diagnosed patients with active TB on DOT at the beginning and throughout treatment and achieve a DOT adherence rate of at least 80% each month. A series of interventions were instituted to shift the management system through several phases between 1993 and 1994: preparation, transition, and ultimately the application of case management. The first intervention was service delivery change: case management that involved clinical record review and redefinition of tasks and responsibilities by structuring of roles and functions of all the staff. During the succeeding periods of time, incremental changes were implemented such as interventions of DOT and case management, which were applied singly and in combination. Treatment regimens had been modified from totally self-administered to selective DOT to universal DOT; they were then incorporated into the case-management model.

VI. Tuberculosis Therapy by Directly Observed Therapy DOT became our standard of care in 1994, and self-administered therapy became a rare exception. All patients diagnosed or suspected of tuberculosis were prescribed an ATS/CDC recommended four-drug regimen of anti-TB medication (26) for 6 months. Definitions of DOT (27) in the United States differ considerably from program to program. The New Jersey Medical School National TB Center specifically defines it as delivery of the anti-TB medication to the patient by an outreach worker or nurse and observation of the patient ingesting each dose of his or her medication. DOT was given daily except weekends when patients took self-administered fixed-dose combination treatment. In the transition phase, incremental modifications of role definitions, introduction of a team concept, skill-enhancing sessions, mentoring, discharge planning, and archiving of inactive charts occupied some of the staff activities. Review of adequacy of treatment, identification of barriers to adherence, and establishment of comprehensive proactive care plans were also carried out. The transition phase covered the shift from self-administered with selective DOT to Universal DOT. In 1993, the year of self-administered therapy with selective DOT, only obviously very difficult to manage, confirmed cases were given DOT with an average adherence rate of 62% each month. Addition of outreach workers to deliver universal DOT surprisingly did not improve the adherence rate (63%) in 1994.

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Review of the New Jersey Medical School National TB Center’s patient cohort showed increasing adherence over the transition and case-management phases. The final phase of multidisciplinary team approach was implemented in 1995 with the subdivision of Newark into four geographical areas by postal zones. Casemanagement teams were created and assigned to each postal zone. The teams were responsible for 35–60 patients with active TB as well as their contacts and associates as indicated. By patient’s choice, DOT was delivered to 75% of the patient population in their homes or preferred locations, 25% in the clinic setting. Each team led by a nurse case manager consisted of field workers, licensed practical nurse, shared HIV counselor, social worker, pediatric nurse, and physician. As much as possible, teams were made up of personnel ethnically matched to their patients. The case-management process (Fig. 1) includes admission of the patient, assignment to nurse case manager, baseline assessment including TB-control service interview and contact investigation, physician visit, nurse postcounseling, HIV counseling and testing, social assessment and intervention, field work investigations, and individualized care plan. The plan is then evaluated on an ongoing basis. The specially trained nurse assigned as case manager met with the team to direct and conduct the work reviews including opening and closing of investigations. The clinic physician as well as private sector physicians [including pediatricians (28)] worked with the nurse case manager on a continuing basis. The patient’s overall treatment was overseen by the nurse case manager throughout the TB treatment course. Accountability for TB care and control for the patient cohort from the defined postal zones was thus assigned to the nurse case managers who supervised team members for specific patient outcomes. The most positive outcome was the completion of tuberculosis therapy in the least amount of time and optimal treatment of infection for contacts; the most negative outcome was loss to follow-up or treatment failure. In 1995, after adoption of the nurse case-management model, adherence rate per month rapidly rose to 90%. Case management continued to enhance the effect of DOT, increasing the adherence rate 95% in 1997. This result was even more remarkable because it utilized the same personnel employed in 1994. In addition, this improvement occurred despite an increase in numbers of TB cases seen in the facility during those years. Another way to look at adherence is the length of time for completion of therapy or how many months it takes to get a patient to ingest 6 months of a shortcourse ATS/CDC treatment regimen (26). The baseline length of time for completion of treatment was 11.6 months, and over the 3-year period the time to completion improved from an average length of 10.5 months to 7.8 months in 1996.

Case Management

Correctional Facility

Figure 1.

Community Health Care Organization

603

Drug Treatment Center

Hospital

The case-management process.

Managed Care Organization

Nursing Home

Private MD

Shelter

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From 1996 to 1998, the total TB cases declined in Newark, reflecting the reported national trend (29). VIII. The Interaction: Patient and Health-Care Provider Goals such as active involvement and participation in the treatment plan were encouraged for each patient. To achieve specified outcomes, knowledge intervention and reinforcement were given to the patients throughout the interaction with the nurse case managers and their teams. The case-management team members were able to have an overview of the patient in his social and clinical milieu as a whole and thus saw the progress as a continuum. Fractured views from the parallel system were no longer possible. Specific problem patients and patients’ problems— clinical, social, personal, and public health related—were subsequently addressed as they arose. During the first 2 months of the medication-initiation phase, patientoutreach relationship was optimized to promote bonding, building, and strengthening of the unique relationship. DOT was carried out at the patient’s home, at the clinic, or in a mutually agreed-upon location (e.g., railroad station, “crack den,” “shooting gallery,”) (30). A proactive approach required each team to formulate plans of action before a potential decline in adherence (default of 2 days or
80% adherence) were documented. At the start of treatment, patients were made aware that if they missed any DOT dose, the outreach worker or DOT nurse will make a phone call or if necessary revisit their residence. Incentives and enablers tailored to the patient’s needs were used liberally for all patients. Incentives included Sustacal (31), food vouchers, and sandwiches. As enablers, patients received bus passes and travel assistance. The incentives were tied to adherence based on 100% adherence rates or occasionally as a behavior-modification tool. IX. Impact on TB Control Measures of successful treatment and program performance such as prompt diagnosis, sputum conversion, optimum lengths of treatment, and good adherence as shown by high completion rates are benchmarks of a successful TB control program (6). One of the greatest obstacles any program might address is the demographic characteristics of the population being served. Occurrence of multidrug-resistant TB invariably reflects a TB program’s failure to address if not alleviate the multiple human problems of a once-treatable infectious case. Innovative strategies and practical variation of existing models, applicable to each location and population, need to be designed. Commitment and the will to accomplish a vision at all levels is crucial. Community participation is essential for continued success. More importantly, DOT can only work when there is accountability for the outcome at the most basic level—service delivery. Therefore, management policies should in-

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clude one person accountable for each patient’s treatment outcome as in our nurse case-management model. For Newark, the measures of program performance indicate that for this type of demographic population, DOT enhanced by nurse case management achieved a very successful outcome in an extremely difficult to treat inner city population. The refinement of the nurse case-management system to meet the needs of hardto-reach patients with tuberculosis is achievable and replicable in areas with appropriate resources, creativity in application, and political will. The evaluation of outcomes including variance analysis must continue to be measured to improve service delivery and impact TB control efforts in the twenty-first century. References 1. 2. 3. 4. 5.

6.

7. 8. 9. 10. 11.

12. 13. 14.

Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991; 144:741–742. Centers for Disease Control and Prevention. A strategic plan for the elimination of tuberculosis in the United States. MMWR 1989; 38(S3):1–25. Cantwell MF, Snider DE, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994; 272:535–539. Kantor HS, Poblete R, Pusateri SL. Nosocomial transmission of tuberculosis from unsuspected disease. Am J Med 1988; 84:833–838. CDC. Nosocomial transmission of multi-drug resistant tuberculosis to health care workers and HIV infected patients in an urban hospital-Florida. MMWR 1990; 89:718–722. Broekmans JF. Evaluation of applied strategies in low-prevalence countries. In Reichman LB Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, 1993:641–667. Sbarbaro JA, Johnson S. Tuberculosis chemotherapy for recalcitrant outpatients administered directly twice weekly. Am Rev Respir Dis 1968; 99:895–903. McDonald RJ, Memon AM, Reichman LB. Successful supervised ambulatory management of tuberculosis treatment. Ann Intern Med 1982; 96:297–302. Chaulk PC, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995; 274:945–951. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333:229–233. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330:1179–1184. Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis. Tubercle 1958; 89:269–274. Moodie AS. Mass ambulatory chemotherapy in the treatment of tuberculosis in a predominantly urban community. Am Rev Respir Dis 1967; 95:384–397. Annas GJ. Control of tuberculosis—the law and the public’s health. N Engl J Med 1993; 828:585.

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15. ATS, CDC American Academy of Pediatrics, Infectious Disease Society of America. Control of Tuberculosis in the United States. Am Rev Respir Dis 1992; 146: 1623–1633. 16. Brudney K, Dobkin J. A tale of two cities: Tuberculosis control in Nicaragua and New York City. Sem Respir Infect 1991; 6:261–272. 17. Schluger N, Ciotoli C, Cohen D, Johnson H, Rom WN. Comprehensive tuberculosis control for patients at high risk for noncompliance. Am J Respir Crit Care Med 1995; 151:1486–1490. 18. Fujiwara P, Larkin C, Frieden TR. Directly observed therapy in NYC: history implementation, results and challenges. Clin Chest Med 1997; 18(1):135–148. 19. Galanowsky K, Napolitano E, Wolman M, Timmer G, McDonald RJ, Mangura BT, Reichman LB. Directly observed therapy (DOT) is not the entire answer. Am J Respir Crit Care Med 1996; 153(4):A491. 20. Sumartojo E. When TB treatment fails: a social behavioral account of patient adherence. Am Rev Respir Dis 1993; 147:1311–1320. 21. Cesta TG, Tahan HA, Fink LF. The Case Manager’s Survival Guide: Winning Strategies for Clinical Practice. St. Louis: Mosby Year Book Inc., 1998. 22. Knollmueller RW. Case management: What’s in a name? Nursing Manage 1984; 20(10):38–42. 23. Drucker PF. Management: Tasks, Responsibilities, Practices. New York: Harper and Row, Publishers, Inc., 1974. 24. Priebe P. Just what does case management mean these days? Med Group Manage 1995; 42(1):12. 25. Commission for Case Manager Certification: CCM Certification Guide. Rolling Meadows, IL: 1996. 26. American Thoracic Society and the Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359–1374. 27. Lardizabal A, Mangura BT, Reichman LB. Directly observed therapy (DOT): variations in local application. Am J Respir Crit Care 1998; 157(3):A188. 28. Pirog L, Galanowsky K, Aguila H, Mangura BT, Reichman LB. Pediatric case management in developing adherence to TB control. Am J Respir Crit Care Med 1996; 153(4):A490. 29. CDC. Tuberculosis morbidity—United States, 1997. JAMA 1998; 279(19):1515– 1516. 30. Voelker R. ‘Shoe leather therapy’ is gaining on TB. JAMA 1996; 275(10):743–744. 31. Mangura BT, Passannante MR, Reichman LB. An incentive in tuberculosis preventive therapy for an inner city population. Int J Tuberc Lung Dis 1997; 1(6):576–578.

Part Five UNIQUE ASPECTS OF TUBERCULOSIS CONTROL

23 Tuberculosis Infection Control

HENRY M. BLUMBERG Emory University School of Medicine and Grady Memorial Hospital Atlanta, Georgia

I. Introduction and Historical Overview Tuberculosis (TB) has been recognized by the medical community as a potential occupational hazard for several decades. The risk for transmission of Mycobacterium tuberculosis from hospitalized patients to other patients and health-care workers was established by the 1950s (1) when, as noted by Myers et al., “rapid decline of tuberculosis in the general population [made] the disease among physicians more conspicuous” (2). While concern about the threat of tuberculosis to health-care workers is longstanding, during the first half of the twentieth century there was a vigorous debate over whether such a risk existed (3). Heimbeck (4) was one of the first investigators to document the increased risk of occupational infection and development of tuberculosis disease among health-care workers. In 1928 he reported that 210 (95%) of 220 student nurses in Oslo with a negative tuberculin skin test converted their skin test by graduation, and 22% developed clinical tuberculosis. Subsequent reports from large hospitals in the United States (in Philadelphia, Boston, and New York) in the 1930s and early 1940s demonstrated that most nurses working in these institutions converted their tuberculin skin test and were in addition at increased risk of developing tuberculosis disease compared to non–health-care workers (1,5–7). 609

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Myers in 1930 made a series of recommendations for the control of tuberculosis transmission in hospitals, and some of his recommendations are still applicable (4,8): 1. Perform tuberculin skin testing and chest radiographs on all new employees. 2. Do follow-up skin testing every 6–12 months. 3. Exclude tuberculosis in all new patients admitted to the hospital, including initiating routine admission chest radiography. 4. Establish a tuberculosis service in all hospitals. 5. Practice aseptic technique as was routine for other infections such as diphtheria and scarlet fever. Gradually hospitals implemented these or other control measures as their benefits were demonstrated (1). However, after the introduction of highly effective chemotherapy in the 1950s to treat those with active disease, the use of treatment of infection among those with tuberculosis infection, and the progressive decline in the incidence of tuberculosis in the United States and other developed countries, the risk of occupational infection and clinical tuberculosis declined among health-care workers. There were only scattered reports of hospital outbreaks in the 1960s, 1970s, and early 1980s (9–12). As the incidence of tuberculosis declined in the United States and risk of occupational exposure and infection continued to decline, less and less attention was paid to infection-control practices in hospitals (13). Thus, few institutions were prepared for the changing epidemiology of the disease (14) and the resurgence of tuberculosis in the United States that occurred beginning in the mid-1980s. This resurgence especially impacted urban areas, where the majority of cases in the United States occur, and thus urban hospitals (15). The recent outbreaks of disease reported from the United States (16–22) and around the world (23–34) have highlighted the risk of nosocomial transmission of tuberculosis and occupational acquisition as well as the importance of effective infection-control measures. These outbreaks usually occurred because of a failure to identify and appropriately isolate those with active tuberculosis. A number of these outbreaks have involved transmission of multidrugresistant (MDR) strains of TB and were associated with a high morbidity and mortality, most often involving HIV-infected individuals. Effective infection-control strategies are needed to have a safe workplace in the health-care arena and to protect the health and safety of patients and health-care providers. II. Trends in Nosocomial Transmission of Tuberculosis A. The United States

Nosocomial tuberculosis is driven by the occurrence of disease in the community served by the hospital or health-care system (35). The resurgence of tuberculosis

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in the United States—a 20% increase in the number of cases between 1985 and 1992—was due in large part to decay of the public health infrastructure (due to underfunding) and the HIV epidemic (36,37). Other factors included immigration from areas where tuberculosis is endemic, increasing poverty, homelessness, substance abuse, and nonadherence to therapy. This changing epidemiology has been termed “the new tuberculosis” (14). In the late 1980s and early 1990s, many health departments, which have the primary role in ensuring tuberculosis control, did not have sufficient infrastructure nor funding to deal with the changing epidemiology of disease and ensure that patients who were diagnosed with tuberculosis took appropriate medications in the appropriate fashion and were cured. The resurgence of disease in the community was thus a major factor in the resurgence of nosocomial transmission of tuberculosis as hospital policies that had been developed to prevent nosocomial transmission fell into neglect (38,39) during periods of decreasing incidence of disease. Increasing incidence of tuberculosis also fueled institutional transmission of tuberculosis in settings outside of hospitals, such as residential centers for AIDS patients, prisons, and homeless shelters (40,41). The most common site of nosocomial transmission of tuberculosis over the past decade has been the inner city, where the majority of cases of tuberculosis occur in the United States. The major burden of tuberculosis care today is usually provided by inner-city health-care facilities, especially public hospitals, which care for the indigent and working poor who have no other access to health care (15,35). Few if any hospitals or other institutional facilities in the late 1980s were prepared to deal with “the new tuberculosis” and the changing epidemiology of disease. Thus, in retrospect it is not surprising that there have been multiple reports of outbreaks of disease in the late 1980s and early 1990s. Most outbreaks have involved patientto-patient or patient–to–health-care worker transmission, although one report documents health-care worker–to–health-care worker transmission (22). Health-care worker–to–patient transmission has rarely been recognized or reported. Factors that have facilitated nosocomial transmission of tuberculosis are listed in Table 1. In outbreaks investigated by the Centers for Disease Control and Prevention (CDC), a major factor responsible for nosocomial transmission of disease was the lack of adequate procedures to identify patients with possible tuberculosis and the failure to isolate such patients immediately once tuberculosis was suspected (35,42). In many urban settings co-infection with HIV and M. tuberculosis is common and up to one half of patients with tuberculosis may be co-infected with HIV (43). HIV-infected patients with tuberculosis, especially those with low CD4 counts, may have a clinical presentation much different from that of the classic patient with an upper lobe infiltrate. Failure to consider the diagnosis and missed or delayed diagnosis of tuberculosis due in part to the “atypical” or “nonclassic” presentation of tuberculosis among those with HIV infection (e.g., higher incidence of primary disease among those HIV-infected patients with low CD4 counts and high degree of immunosuppression) has contributed to nosocomial

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Table 1

Factors Facilitating Nosocomial Transmission of Tuberculosis

1. Inefficient infection-control procedures A. Delayed suspicion and diagnosis • Clustering of patients with unsuspected TB with susceptible immunocompromised patients on AIDS wards of large urban hospitals • Delayed recognition of TB in HIV-infected patients because of “atypical” presentation or low clinical suspicion leading to misdiagnosis • Failure to isolate patients with active pulmonary disease B. Failure to recognize ongoing infectiousness of patients 2. Laboratory delays in identification and susceptibility testing of M. tuberculosis isolates 3. Inadequate respiratory isolation facilities and engineering controls Lack of respiratory isolation rooms Recirculation of air from isolation rooms to other parts of the hospital 4. Delayed initiation of effective antituberculosis therapy

spread of tuberculosis in a number of outbreaks. Other factors have included commingling of undiagnosed patients with tuberculosis and those (e.g., with AIDS) who were highly susceptible and likely to rapidly progress to active disease after infection with M. tuberculosis; inadequate laboratory facilities and/or delayed laboratory identification of drug-resistant strains; and delayed institution of effective antituberculosis therapy. The delay in instituting effective therapy also contributed to prolonged infectiousness and increased risk of transmission of MDR strains (42). Additional factors that have contributed to nosocomial transmission of tuberculosis include inadequate engineering controls (e.g., lack of negative pressure, recirculation of air from respiratory isolation rooms to other parts of the hospital), failure to isolate hospitalized patients until they were no longer infectious, allowing patients in respiratory isolation to leave their rooms without wearing a mask or for nonmedical reasons (e.g., go to bathroom, group meetings, watch television, walk the halls, attend social events), and leaving respiratory isolation room doors open (35,42). Inadequate precautions during aerosol-generating procedures such as sputum induction or aerosolization of pentamidine have also contributed to nosocomial spread of M. tuberculosis at some institutions (19). Nosocomial Transmission of Multidrug-Resistant Tuberculosis

The devastating effects of MDR-TB among HIV-infected TB patients have been demonstrated in outbreaks of MDR-TB at a number of U.S. hospitals and subsequently worldwide. Between 1988 and 1992, CDC investigated outbreaks of MDR-TB at eight hospitals in Florida, New Jersey, and New York as well as in the New York State prison system (Table 2) (17,41,42). Most of the outbreaks in-

16

13 37 42

1990–1991 1990–1991

1990–1991

4 New York City 5 New York State

6 New York City

7 New Jersey 1990–1992 8 New York 1991–1992 9 New York Prisons 1990–1992

100 96 98

82

91 14

93 100 95

4 NA NA

4

4 4

7 16 4

85 93 79

82

83 43

72 89 77

Mortality rate (%) INH, RIF (EMB, ETA) INH, SM (RIF, EMB) INH, RIF, SM (EMB, ETA, KM, RBT) INH, RIF (EMB, ETA) INH, RIF, SM (EMB, ETA, KM, RBT) INH, RIF, SM (EMB, ETA, KM, RBT) INH, RIF (EMB) INH, RIF INH, RIF

No. HCW Resistance pattern

5/10 (50) Unknown NA

Unknown

6/12 (50) 46/696 (6.6)

13/39 (33) 11/60 (18) 88/352 (25)

TST conversions (%)

122 123 41

121

119 120

18, 19 20 118

Ref.

NA  Not applicable or not stated in report; INH  isoniazid; RIF  rifampin; EMB  ethambutol; ETA  ethionamide; SM  streptomycin; KM  kanamycin; RBT  rifabutin. Source: Adapted from Ref. 42.

29 7

65 35 70

1988–1991 1989–1991 1989–1992

1 Miami 2 New York City 3 New York City

Patients

Outbreak period

Hospital location

Patients with HIV infection (%)

Median interval from TB isolation to death (weeks)

Table 2 Characteristics of Nosocomial MDR-TB Outbreaks Investigated by CDC, 1988–1992

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volved HIV-infected patients and mortality was striking. At most of the institutions investigated, the mortality rate was 70–90% among HIV-infected patients with MDR-TB with a median time from diagnosis to death of 4 weeks; often in these outbreaks patients were dead before the susceptibility results were available. Factors responsible for the outbreaks have been discussed above and are listed in Table 1. In each outbreak, epidemiological investigations documented nosocomial transmission and were supported by molecular typing studies, which showed identical IS-6110 restriction fragment length polymorphism (RFLP) patterns among outbreak cases; outbreak strains differed from RFLP patterns from susceptible cases. Patients with MDR-TB were more likely to have had a previous admission to the respective hospital and, while hospitalized, a significantly greater likelihood of exposure to a patient with infectious MDR-TB than did control patients (HIV-infected patients with drug-susceptible tuberculosis) (42). A significant proportion of MDR-TB cases in the United States in the early 1990s were related to nosocomial transmission of a single strain of M. tuberculosis (strain W, which is resistant to six or seven antituberculosis drugs including isoniazid, rifampin, and other first-line drugs) at several New York City hospitals. Frieden et al. describe a multi-institutional outbreak of M. tuberculosis strain W over a 43-month period between 1990 and 1993 (44). Most of those affected were HIV infected (86%). The 357 cases described accounted for more than one third of the MDR-TB cases in New York and nearly one fourth of the MDR-TB cases in the United States over the same time period. Epidemiological linkages were identified for 70% of patients, of whom 96% likely had nosocomially acquired disease at 11 hospitals. Most cases occurred at four New York City hospitals. The number of strain W MDR-TB cases in New York City peaked in 1992 with 122 cases reported and by 1995 decreased to 19 cases presumably due to improved infection-control activities in New York City hospitals and an improved public health infrastructure and community control including implementation of directly observed therapy (DOT) (44,45). The consequences of the numerous MDR-TB outbreaks have been significant for health-care workers in addition to patients. In these MDR-TB outbreaks, 6.6–50% of exposed health-care workers had documented tuberculin skin test conversions (Table 2). Well over 100 tuberculin skin test conversions have been documented among health-care workers during these outbreaks of MDR-TB. At least 20 health-care workers have developed active MDR-TB, and at least 9 of these have died due to MDR-TB (nearly all who died were HIV infected) (46). Risk of Tuberculosis Infection Among Health-Care Workers

While nosocomial outbreaks of tuberculosis in the United States in the late 1980s and early 1990s highlighted the risk of occupational infection with M. tuberculosis, the exact risk of occupational infection for health-care workers, especially in the

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nonoutbreak setting, has been incompletely defined. The reported incidence of tuberculin skin test conversion among U.S. health-care workers varies widely, ranging from 0.1 to 10% (13,47). Several national surveys of U.S. hospitals with tuberculin skin testing programs have reported rates that range from 0.33 to 5.5% per year (48–51). Several reports have noted that if the number of patients admitted to an institution is low, the risk of exposure is low. Hospitals with
10 TB patients per year or less than one TB patient per 100 workers have reported low rates of tuberculin skin test conversion (
0.5%) (13,52). Fridkin et al. (48) reported the results of a 1992 SHEA-CDC national survey of hospitals, which indicated that institutions with 6 TB patients per year had a higher rate of health-care worker tuberculin skin test conversion than other institutions (1.2% vs. 0.6%). Reports on risk of tuberculin skin test conversion among health-care workers have often been limited because they are questionnaire/self-report type studies or reports from individual institutions and suffer from the fact that health-care worker participation rates were variable or often not specified, which may have resulted in a substantial selection bias (13). In addition, two-step skin testing was not performed in many of the studies. Several recent reports of tuberculin skin test conversion rates among medical students, house staff, and non-physician health care workers working in a high-incidence area where mandatory tuberculin skin testing of all health-care workers was required every 6 months (i.e., Grady Memorial Hospital in Atlanta, which cares for about 200 TB patients annually) noted a conversion rate of less than 1 per 100 person-years worked among U.S.-born individuals following implementation of expanded infection-control measures (53,53a,54). It is usually assumed that all tuberculin skin test conversions among healthcare workers represent occupational exposure. However, recent reports indicate that community acquisition is a risk as well, and for some employees the risk of community exposure is greater than the risk of occupational exposure. Bailey et al. looked at rates and risk factors for tuberculin skin test conversion among employees of Barnes Hospital in St. Louis in 1994 (55). Twenty-nine of 3106 employees who had at least two tests had skin test conversions, and more than half of the conversions (15 or 52% of conversions) occurred among employees who had no direct contact with patients. Only the percentage of low-income persons within the employee’s residential postal zip code area was independently associated with conversion in their study. Thus, health-care worker tuberculin skin testing results reflect a combination of occupational exposure, community exposure, and probably false-positive tests due to cross-reaction with nontuberculous mycobacteria or prior BCG vaccination. The proportion of conversions due to occupational versus community exposure likely varies from region to region and from institution to institution. Efficacy of infection-control measures also influences conversion rates. Despite the limitations of the tuberculin skin test (see Chap. 12), it remains an important component of an infection-control program in the United States and in assessing the efficacy of the infection-control program.

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Nosocomial transmission of tuberculosis has also been reported from a variety of areas around the world over the past decade including Europe—Spain (32), Italy (27,56), France (25,30), Netherlands (29), England (16)—South America—Argentina (23,31)—Africa—South Africa (33), Malawi (28)—Asia—Japan (34)— and Australia (57). Undoubtedly, nosocomial transmission of tuberculosis is occurring in developing countries around the world as well but has not been reported or likely remains undetected because of inadequate surveillance systems and/or lack of resources, including laboratory facilities. In developing countries, hospital admissions of persons with TB are more frequent, HIV infection is more prevalent, and infection-control activities are less common than in developed countries (58). It has also been noted that there is a reluctance to deal with nosocomial transmission in developing countries because of the methodological difficulty of studying it in high-incidence areas and the fear of adverse effects on staff motivation and program function if documented. Further investigations of nosocomial transmission of tuberculosis in developing countries is clearly needed, and preventing such transmission, if documented, would be an important public health intervention in controlling tuberculosis in these areas. A number of the reports of nosocomial transmission of tuberculosis outside of the United States over the last several years have involved MDR strains of M. tuberculosis (16,23,25,31,32,56,59); one report from Madrid involved nosocomial transmission of MDR M. bovis (24). The events described in these reports have been similar to that reported from nosocomial MDR-TB outbreaks in the United States including a very high proportion of affected patients who were coinfected with HIV, outbreaks often occurring on a HIV-dedicated ward, an extremely high mortality rate (often approaching 100%) for these patients, mycobacteria laboratory surveillance in recognizing similar resistance patterns, and confirmation through IS-6110 RFLP molecular typing. These outbreaks occurred among hospitalized patients in institutions unprepared for nosocomial airborne infections (60) similar to that which occurred in the U.S. outbreaks. The largest MDR-TB outbreaks outside of the United States have been reported from Spain (32,59) and Argentina (31). The MDR-TB outbreak reported from Madrid involved 47 HIV-infected patients and 1 HIV-infected health-care worker on an HIV-dedicated ward. Ritacco et al. (31) reported the largest MDR-TB outbreak described outside of the United States. This occurred at an urban hospital in Buenos Aires, which was a referral center for infectious diseases (including tuberculosis and HIV) and involved 100 patients with HIV co-infection hospitalized in 1994 and 1995. RFLP analysis of MDR-TB strains from the outbreak revealed two closely related patterns, suggesting they had a clonal origin and recent transmission. At the time the article was written, the infection-control measures

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taken by the hospital to contain the outbreak were inadequate and the number of MDR-TB cases approached 300 (60). The morbidity and mortality associated with MDR-TB outbreaks emphasizes the importance of infection-control measures to prevent nosocomial transmission of tuberculosis. These are discussed below. III. Institutional Controls in the United States and Other Developed Countries An effective tuberculosis infection-control program requires early identification, isolation, and effective treatment of persons who have active disease (61). The importance of an effective tuberculosis infection-control plan is emphasized by the outbreaks of tuberculosis at health-care facilities throughout the world and the prevention of nosocomial transmission of tuberculosis following implementation of effective control measures. Policies and procedures should be developed by each institution to reflect their risk and the patient population served. CDC and other groups have published guidelines for preventing the transmission of M. tuberculosis in health-care facilities (1,61–63), and practical recommendations for developing and implementing an effective infection-control program have recently been published (64). Major goals in the control and prevention of nosocomial tubercuTable 3 Major Current Goals in the Control and Prevention of Nosocomial Tuberculosis 1. Respiratory isolation of patients as soon as tuberculosis is suspected, whether during emergency care or on admission to the institution. 2. Start empirical antituberculous therapy as soon as tuberculosis is suspected with an appropriate regimen including at least two drugs to which the organism is likely to be susceptible. (Generally, a four-drug regimen will be employed.) 3. Comply with isolation procedures during the patient’s hospitalization until laboratory and clinical evidence eliminates the possibility of tuberculosis or the risk of transmission. 4. Conduct laboratory studies as soon as possible to confirm or exclude the presence of tuberculosis and to identify multidrug-resistant strains of M. tuberculosis. 5. Enhance occupational health services to monitor for infection and disease in healthcare workers. 6. Discharge tuberculosis patients from acute care only when they are no longer infectious or when arrangements have been made for appropriate isolation from contact with susceptible individuals (e.g., in a stable home or another stable location with no new persons exposed). 7. Cooperate closely with public health and other community agencies to provide resources that ensure the completion of therapy (e.g., direct observation). 8. TB-related health-care worker education to support the above goals. Source: Adapted from Ref. 35.

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losis are outlined in Table 3. In addition, the Occupational Safety and Health Administration (OSHA) has mandatory requirements for health-care facilities in the United States (65). In late 1997, OSHA published in draft form a proposed TB Standard, which might be finalized following a comment period and likely revision, by 2000 (66). The basic elements of an effective tuberculosis-control program are outlined in Table 4 and discussed below. A. Assignment of Responsibility—Assemble a Task Force

The first step in establishing an infection-control program is for an institution to assign a specific person or group of persons the responsibility for developing a tuberculosis-control program and the authority to implement the plan and carry it out. The designated person or group should have expertise (or access to such) in infection control, hospital epidemiology, employee health issues, and engineering (e.g., air handling and ventilation) (64). At smaller institutions this could be carried out by the Infection Control Committee, while at larger institutions a TB Task Force or subcommittee of the Infection Control Committee may be convened. These groups should develop a written infection-control plan based on a TB risk assessment of the institution and outline a time line and mechanism for implementing the plan as well as methodology that will be used to assess the efficacy of the program. At institutions that care for large number of patients, it has been very useful to designate an individual to serve as a coordinator of tuberculosis infection-control activities. This frequently is a member of the infection control or hospital epidemiology staff. B. Risk Assessment

It has been emphasized that a “one-size-fits-all” approach to tuberculosis infection control is not appropriate and makes little sense since not all hospitals have the same risk for tuberculosis transmission (1,35). The steps that need to be taken at an inner-city public hospital, which may care for a large number of patients with tuberculosis each year, is very different from those at a community hospital in an area that may never or only rarely encounter a patient with active disease (nearly half the counties in the United States report no cases of tuberculosis). Therefore, CDC guidelines suggest that each institution conduct a risk assessment, which can be used in helping formulate what measures should be implemented and the frequency of review of the program as part of that health-care institution’s tuberculosis infection-control plan (61). Elements of tuberculosis risk assessment are shown in Table 4. The first step is to review the community profile for tuberculosis (e.g., incidence and prevalence of tuberculosis in the community, drug-susceptibility patterns) and review the number of patients with tuberculosis disease cared for by the institution over the past year. If there are tuberculosis patients cared for by the institution or in the community, then an assessment of the number of patients with active disease admitted to each area or ward of the hospital,

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Table 4 Basic Elements of an Effective Tuberculosis Infection-Control Program I. Assignment of responsibility A. Assign responsibility for the TB infection-control program to qualified people. B. Ensure that people with expertise in infection control, occupational health, administration, engineering are identified and included. II. Elements of tuberculosis risk assessment A. Review community TB profile (incidence and prevalence of TB and drug-susceptibility patterns). B. Review facility’s TB profile (number of TB patients admitted to facility in past year). C. If TB found in community or facility 1. Analyze the number of infectious TB patients admitted to each area or ward during past year. 2. Analyze health-care worker PPD skin-test results by area or occupational group to determine if clusters of PPD conversions or person-to-person transmission may have occurred. D. Evaluate TB infection control practices by reviewing medical records of TB patients and by observing practice. E. Evaluate whether engineering controls are maintained. III. Identification, evaluation, and treatment of TB patients A. Screen patients for signs and symptoms of active TB 1. On initial encounter in emergency department or ambulatory care setting. 2. Before or at the time of admission. B. Perform radiological and bacteriological evaluation of patients who have signs and symptoms suggestive of TB. C. Promptly initiate treatment. D. Periodically reevaluate response to therapy; modify regimen if no improvement. IV. Managing outpatients who have possible infectious TB A. Promptly initiate TB precautions. B. Place patients in separate waiting areas or TB isolation rooms. C. Give patients a surgical mask or box of tissues and instructions regarding the use of these items. D. Instruct patients to cover their mouth and nose with tissue when coughing or sneezing. V. Managing inpatients who have possible infectious TB A. Promptly isolate patients who have suspected or known infectious TB. B. Monitor the response to treatment. C. Follow appropriate criteria for discontinuing isolation. VI. Engineering recommendations A. Design local exhaust and general ventilation in collaboration with people who have expertise in ventilation engineering. B. Use a single-pass air system or air recirculation after HEPA filtration in areas where infectious TB patients receive care. C. Use additional measures, if needed, in areas where TB patients may receive care.

Table 4

VII.

VIII.

IX.

X.

XI. XII.

Continued

D. Design TB isolation rooms in health-care facilities to achieve at least 6 air changes per hour for existing facilities and at least 12 air changes per hour for new or renovated facilities. E. Regularly monitor and maintain engineering controls. F. TB isolation rooms that are being used should be monitored daily to ensure they maintain negative pressure relative to the hallway and all surrounding areas. G. Exhaust TB isolation room air to outside or, if not possible, recirculate only after HEPA filtration. Respiratory protection A. Respiratory protection should be used by people entering rooms in which patients with known or suspected infectious TB are being isolated, by HCWs when performing cough-induced or aerosol-generating procedures on such patients, and by people in other settings where administrative and engineering controls are not likely to protect them from inhaling infectious airborne droplet nuclei. B. U.S. federal regulations require respiratory protective devices should meet certain performance criteria (e.g., N-95 respirator mask). C. A respiratory protection program is required by OSHA for facilities in which respiratory protection is used to protect health-care workers. Cough-inducing procedures A. Do not perform such procedures on TB patients unless absolutely necessary. B. Perform such procedures in areas that have local exhaust ventilation devices (e.g., booths or special enclosures) or in a room that meets ventilation requirements for TB isolation. C. After completion of procedures, TB patients should remain in the booth or special enclosure until their coughing subsides. HCW TB training and education A. All HCWs should receive periodic TB education appropriate for their work responsibilities and duties. B. Training should include the epidemiology of TB in the facility and community served by the facility. C. TB education should emphasize concepts of the pathogenesis of and occupational risk for TB. D. Training should describe work practices that reduce the likelihood of transmitting M. tuberculosis. HCW counseling and screening A. Counsel all HCWs regarding TB and TB infection. B. Counsel all HCWs about the increased risk to immunocompromised people for development of active TB. C. Perform PPD skin tests on HCWs at the beginning of their employment, and repeat PPD tests at periodic intervals. D. Evaluate symptomatic HCWs for active TB. Evaluate HCW PPD test conversions and possible nosocomial transmission of M. tuberculosis Coordinate efforts with public health department

PPD  Purified protein derivatives; HCW  health-care worker; HEPA  high-efficiency particulate air. Source: Adapted from Refs. 47, 61, 64.

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analysis of tuberculin skin testing results by area or occupational group to detect any clustering, and an evaluation of current tuberculosis infection-control practices (e.g., review of medical records, observation of practices) is indicated. CDC (61) classifies the risk as: Minimal: no cases of tuberculosis in the community or at the facility within the past year Very low: patients with active tuberculosis are not admitted to the facility but may receive initial assessment or diagnostic evaluation in an outpatient clinic or emergency room Low: areas or occupational groups in which the tuberculin skin test conversion rates are not greater among those who care for TB patients compared to those who do not; no clustering of skin test conversions by area or occupational group; no person-to-person transmission has been detected; and
6 patients with active tuberculosis are cared for each year Intermediate: similar to low, but 6 patients with active disease are cared for each year High: areas or occupational groups in which skin test conversion rates are significantly higher than for areas or groups that have little occupational exposure or conversion rates are higher than previous conversion rates; a cluster of skin test conversions has occurred in an area or among an occupational group and epidemiological evaluation suggests nosocomial transmission; or possible person-to-person transmission of M. tuberculosis has been detected Recommendations for the minimal and very-low-risk facilities have been published (61,64), and subsequent discussion will focus on institutions that care for patients with active tuberculosis. C. Hierarchy of Controls

A hierarchy of infection-control measures, in order of importance, has been recommended to prevent nosocomial transmission of tuberculosis (Table 5) (61,64). Table 5

Hierarchy of Tuberculosis Infection-Control Measures

1. Administrative controls (most essential component) Careful screening of patients, isolation, early diagnosis, and treatment Health-care worker–directed measures Comprehensive tuberculin skin testing program Health-care worker education 2. Engineering controls Negative pressure respiratory isolation rooms 3. Personal respiratory protection equipment (i.e., masks)

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These include administrative controls, engineering controls, and personal respiratory protective equipment (i.e., masks). Administrative Controls Surveillance, Detection, and Early Isolation

Administrative controls are the most important component of an infection-control program (67) and should be the first priority of an infection-control program, especially at institutions where resources are limited. Administrative controls include measures to reduce the risk of exposure to persons with infectious tuberculosis. Effective administrative controls include measures to ensure that patients are screened carefully and appropriately for tuberculosis, those at risk are isolated on admission, a diagnosis is made promptly, and appropriate antituberculosis therapy is initiated (68). This includes careful screening and early identification of patients with or at risk for tuberculosis. A high index of suspicion is critical; patients with or at risk for tuberculosis should be isolated upon admission. The protocol for early identification and isolation of patients should be based on the prevalence and demographic profile of the tuberculosis patients in the community and served by the institution. Because HIV-infected patients with tuberculosis disease (especially those with low CD4 counts and recent infection) can present with “atypical” signs and symptoms compared to the classic HIV-seronegative patient with upper lobe reactivation disease (69), facilities that care for significant numbers of HIVinfected patients with tuberculosis have included in their protocols that all HIVinfected patients who have clinical symptoms that could be consistent with tuberculosis (e.g., fever and cough or an abnormal chest radiograph) be isolated. Other patients who should be isolated upon admission include those admitted with tuberculosis in the differential diagnosis, patients for whom respiratory specimens for AFB smear and culture have been ordered, and patients with known active pulmonary tuberculosis. Patients admitted to respiratory isolation should remain in isolation while hospitalized unless tuberculosis (or at least a high likelihood of infectiousness) has been “ruled out” by three consecutive acid-fast bacillus (AFB) smear-negative respiratory specimens. Respiratory isolation rooms need to be used in an efficient and effective manner since they may be limited in number. This can be accomplished in part by having a respiratory therapist induce sputum in patients who have not been able to produce a specimen in the first 24 hours of hospitalization. CDC guidelines recommend obtaining a sputum every 24 hours (61). However, a number of institutions collect specimens on a more frequent basis (e.g., every 8–12 hours) because of the need to “turn over” or use the rooms more efficiently and move patients who have been “ruled out” for tuberculosis so that other patients needing respiratory isolation will have rooms available when admitted. The optimal time interval between collections of sputum samples is not known.

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Health-Care Worker Issues: Tuberculin Skin Testing and Education

A compressive and mandatory periodic tuberculin skin testing program (see also Chap. 12) for all health-care workers to evaluate transmission is important and is indicated in the United States and other areas where BCG vaccination is not routinely used. Testing should be done at baseline (when the health-care worker initiates their duties at a facility) and at least annually for those health-care workers who are not documented to be previously tuberculin skin test positive. Testing may be carried out more frequently (e.g., every 6 months) in high-incidence areas or if there is evidence of ongoing nosocomial transmission (i.e., high risk as defined by CDC). Surveillance for health-care worker conversions is essential in order to evaluate whether nosocomial transmission is occurring in an institution and at what level and to assess the efficacy of an institution’s infection control efforts. In addition, it is important for the individual health-care worker who has a positive tuberculin skin test so that preventive therapy can be offered if indicated (e.g., for a recent tuberculin skin test conversion or those at high risk for active TB). Analysis of tuberculin skin testing results should also be carried out by occupational group or area because overall facility rates can mask potential focal problems (61). The Mantoux method is recommended for tuberculin skin testing of health-care workers (70). Multiple panctula tests should never be used. In addition, when initiating a tuberculin skin testing program and for new health care workers joining a facility, two-step testing [a second test performed 1–3 weeks after the initial tuberculin skin test (61)] is recommended for all health-care workers who have not had a documented tuberculin skin test in the preceding year. Two-step testing is used to reduce the likelihood that a boosted reaction will be misinterpreted as a recent conversion that could lead to a falsely high conversion rate. At one U.S. hospital in New York City that has a relatively high proportion of health-care workers born outside of the United States, nearly 10% of new employees became positive on two-step testing (71). Health-care workers who were male, foreign-born, or had received BCG vaccination were more likely to have had a booster reaction in that study. Older age has also been shown in previous studies to increase the risk of boosting. It has also been shown that the booster effect may be seen among young adults if they have received BCG vaccination (72). Health-care worker education is of course an important and crucial component of an effective tuberculosis infection-control program. Health-care workers must appreciate the risk of occupational exposure to patients with tuberculosis as well as the measures and policies adopted by health-care facilities to prevent nosocomial transmission of tuberculosis, and they must be able to effectively implement these policies and procedures in order to safeguard their own health, that of coworkers and of patients. Tuberculosis education should be included in the ori-

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entation of health-care workers to a facility, especially at facilities that care for significant numbers of patients with tuberculosis. Basic information is necessary for all employees, and more targeted efforts for specific groups that may provide more care to patients with or at risk for tuberculosis is indicated. OSHA now requires that U.S. health-care workers receive annual tuberculosis-related training, and a number of institutions have incorporated tuberculosis related training into other OSHA-mandated training sessions such as that for bloodborne pathogens. Laboratory Diagnosis

Enhanced diagnostic laboratory procedures, which include rapid turnaround on processing specimens as well as effective communication between the laboratory and infection-control practitioners, are another component of administrative controls. Laboratory diagnostic studies are important in confirming or excluding the diagnosis of tuberculosis and in identifying multidrug-resistant strains. Delays in laboratory diagnostic tests were a contributing factor in a number of hospital outbreaks of tuberculosis including those involving MDR strains (46). Broth culture techniques (e.g., BACTEC system) have been demonstrated to significantly reduce (by 10–14 days) the time to detection of positive AFB cultures including M. tuberculosis (73). In addition, CDC recommends that AFB smear-positive results be reported within 24 hours of collection (61). Thus, not only the management of individual patients but also implementation of hospital infection-control policies and public health depend on speedy detection of patients with tuberculosis (35). The recent introduction of nucleic acid amplification techniques into the clinical microbiology laboratory (see Chap. 14) (74) has the potential to increase the efficiency of isolation room use and to provide cost savings by allowing AFB smearpositive patients (e.g., HIV-infected patients with M. avium complex infection or colonization) who do not have tuberculosis to have isolation discontinued. Further studies are needed to validate this potential. Antituberculosis Chemotherapy

Prompt initiation of effective antituberculosis chemotherapy is another important control measure. While the exact time that it takes to render a patient noninfectious is unclear (75), effective therapy to patients with drug-susceptible tuberculosis can rapidly decrease the degree of infectiousness of these patients. Therefore, beginning effective therapy in patients in whom tuberculosis is suspected is a major step in decreasing the potential for spread (76,77). This is also the case since it generally takes several weeks until the case can by confirmed by culture. In the United States and most parts of the world, the recommended initial therapy for patients with tuberculosis consists of a four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) (78,79) (see also Chap. 16).

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Engineering Controls

The second level of controls consists of engineering controls that reduce or eliminate TB droplet nuclei in the air. These include (164): 1. 2.

3.

4. 5.

Direct source control using local exhaust ventilation (e.g., isolation room, sputum induction booths, etc.) Controlling the direction of air flow to prevent contamination of adjacent areas (i.e., negative pressure isolation rooms so air flows from the hall or adjacent areas into the respiratory isolation room) Dilution and removal of contaminated air by general ventilation (a minimum of 6 air exchanges per hour is recommended by CDC for isolation rooms and 12 air exchanges per hour for new construction or renovations) Air filtration with high-efficiency particulate air (HEPA) filters Air disinfection with ultraviolet germicidal irradiation.

Isolation rooms allow potentially infectious patients to be separated from other patients and health-care workers, focus engineering controls, which can help reduce the concentration of infectious droplet nuclei, and prevent infectious droplet nuclei from escaping to other areas in the health-care facility. If air from an isolation room cannot be exhausted directly to the outside, it should be exhausted through a HEPA filter before being recirculated (61). The recommended number of air changes per hour is somewhat arbitrary and is based on comfort and odor-control considerations rather than scientific data from the clinical setting. A mathematical model can be used to predict the time required for removal of airborne contaminants for various removal efficiencies (e.g., 90%, 99%, 99.9%) depending on the number of air changes per hour (61). Construction of respiratory isolation rooms or retrofitting of existing rooms can be very expensive (80,81). These costs can be reduced by the use of a nonportable HEPA filtration unit (82) or portable HEPA filtration units (83). These devices can be connected to the isolation room exhaust duct and effectively clear bacterial aerosols before air is recirculated and maintain negative pressure of the isolation room. It is recommended by CDC that the negative pressure should be monitored daily while infectious patients are in an isolation room. This can be done through smoke tube testing (61) or by continuous electronic monitoring, which is useful and cost effective at institutions that frequently use these rooms. The use of ultraviolet germicidal irradiation (UVGI) in controlling institutional transmission of M. tuberculosis has been somewhat controversial. CDC and the American Thoracic Society have recommend UVGI as a supplementary measure for tuberculosis control and not as a substitute for other engineering controls, and some have questioned the safety of UVGI (1,61,84,85). Other investigators disagree with these recommendations and concerns and have strongly advocated

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the use of UVGI, citing advantages of efficacy, ease of application, and relatively low cost, especially compared to other types of engineering controls (81,84). It has been suggested that a 30 W ultraviolet fixture provides the equivalent of 20 air exchanges an hour depending on the air-mixing and flow pattern (86). However, high humidity (60%) may limit their efficacy. Germicidal lamps are low-pressure, mercury vapor lamps that produce ultraviolet radiation predominantly in the region of 254 nm, look much like fluorescent lamps, and can be used in shielded or unshielded fixtures (84). Unshielded germicidal lamps inside ventilation system ducts can be used as an adjunctive measure to disinfect air before it is recirculated, but this is not recommended as a substitute for HEPA filtration of recirculated air. Shielded lamps used for upper-room air irradiation are attached to ceilings or wall mounted and are used to reduce the concentration of airborne mycobacteria. The most useful areas to consider using UVGI include areas that are difficult to ventilate such as waiting rooms, emergency rooms, corridors, and other central areas of an institution where undiagnosed tuberculosis patients may contaminate the air with droplet nuclei. Recommendations for use of UVGI have been published (61,84,86). When UVGI is used it is important that these systems be monitored appropriately, as would be expected with other types of engineering controls, that responsible individuals maintain them, and that health-care workers receive appropriate education about UVGI safety-related issues. Respiratory Protection

Personal respiratory protection (i.e., use of respiratory masks) is the last step in the hierarchy of controls and has been the most controversial area because of U.S. federal regulations that mandate which type of mask should be used when caring for TB patients and lack of data on the efficacy of different respirators. Personal respiratory protective devices or masks should be worn in areas where the risk of exposure to M. tuberculosis droplet nuclei is higher than normal (e.g., respiratory isolation rooms and areas where cough-inducing or aerosol-producing procedures are performed such as bronchoscopy suites). Until late 1995, Occupational Safety and Health Administration (OSHA) had mandated the use of a HEPA-filtered respirator masks in health-care facilities. HEPA respirators are expensive (about $5 each, more than five times that of the dust-mist or N-95 respirator) and no data exist to support their use over other types of respirators (e.g., when caring for a patient in isolation). Two cost-effectiveness analyses performed at the University of Virginia and involving VA hospitals have suggested that HEPA respirators would offer negligible additional efficacy at a great cost (e.g., $7 million per case of TB prevented) (87,88). The mandate for HEPA respirators has been modified. The minimum level of respiratory protection mandated by OSHA is the National Institute for Occupational Safety and Health (NIOSH)–certified N-95 respirator, which has the ability to filter 95% of 0.3 m particles (89). A respiratory pro-

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tection program that includes medical evaluation, training, and individual fit testing of health-care workers is required by OSHA. Developing a respiratory protection program including fit testing can be time-consuming, expensive, and logistically difficult; published data suggest that the impact of formal fit testing on proper mask use is small (64,90). It is important to note that those with beards cannot be certified for fit testing under the current OSHA regulations because of faceseal leakage. OSHA regulations require bearded health-care workers to use a positive airway pressure respirator (PAPR), although there are no data to indicate that health-care workers with beards are at increased risk for occupational infection with M. tuberculosis compared to other health-care workers. D. Efficacy of Control Measures

Data on the efficacy of tuberculosis infection control measures come from reports from several hospitals that had outbreaks of nosocomial transmission of M. tuberculosis (Table 6) (67,91–93). This includes three hospitals with MDR-TB transmission (two in New York and one in Miami) and one hospital (in Atlanta) with nosocomial transmission of drug-susceptible tuberculosis. At these institutions implementation of control measures was successful in terminating outbreaks and preventing nosocomial transmission of M. tuberculosis, thereby reducing health-care worker tuberculin skin test conversions. In addition, termination of outbreaks of tuberculosis and reduction of tuberculin skin test conversion rates at these institutions took place before introduction of NIOSH-approved masks and OSHA-mandated fit testing (35,67,91–93).

Table 6 Reports on the Control of Outbreaks of Nosocomial Tuberculosis at Acute Health-Care Facilities Control measure(s) used Administrative measures

Engineering measures

Miami, Jackson Memorial New York, Cabrini

Extensive Extensive

Extensive Exhaust fansa

New York, Roosevelt Atlanta, Grady Memorial

Extensive Extensive

Laterb Exhaust fansa

Location, hospital

PPE masks Submicron Molded Surgical Mask Surgical Mask Submicron

Ref. 92 93 91 67

PPE  Personal protective equipment. a Exhaust fans were placed in windows to produce negative pressure in isolation rooms. b Engineering controls were implemented later (after administrative controls) and consisted of wall mounted ultraviolet light and retrofitting rooms with exhaust fans which created negative pressure respiratory isolation rooms. Source: Adapted from Ref. 35.

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At Cabrini Hospital in New York, Maloney et al. reported that the proportion of patients with MDR-TB decreased, the proportion of MDR-TB patients with same ward exposures decreased, and tuberculin skin test conversion rates of health care workers assigned to the outbreak ward were lower in the follow-up period subsequent to infection-control interventions (93). Wenger et al. reported that after implementation of control measures at Jackson Memorial Hospital in Miami, no episodes of MDR-TB could be traced to contact with infectious patients on an HIV ward, and there was a marked and significant reduction in health-care worker tuberculin skin test conversion rates (92). At Roosevelt Hospital in New York, Stroud et al. reported that transmission of MDR-TB among AIDS patients decreased markedly (from 8.8% to 2.6%) after implementation of administrative control measures and the outbreak was terminated (91); engineering controls were implemented later. The risk of health-care worker tuberculin skin test conversion could not be adequately evaluated by Stroud et al. due to lack of data on a sufficient number on workers. At Grady Memorial Hospital in Atlanta following implementation of expanded infection-control measures, which consisted chiefly of administrative controls, there was a marked reduction in tuberculosis exposure episodes and healthcare worker tuberculin skin test conversion rates. Early identification and isolation of patients was facilitated by the development of an expanded respiratory isolation policy based on the prevalence and demographic profile of the tuberculosis patients in the community and served by the institution. Following implementation of the protocol in March 1992, the number of tuberculosis exposures (patients with AFB smear-positive pulmonary tuberculosis who were not admitted into respiratory isolation upon admission to the hospital) was reduced significantly from 4.4 to 0.6 exposures per month) and the number of days infectious patients were not appropriately isolated was reduced from 35.4 to 3.3 days per month (67). Concomitant with the decrease in the number of tuberculosis exposure episodes, there was a marked and significant decrease in the number of tuberculin skin test conversions from 3.3% to 0.4% among the hospital’s health-care workers during 6month testing periods. Other institutions have also reported decreases in tuberculin skin test conversions among health-care workers after implementation of tuberculin infectioncontrol measures (94–96). In all of these reports, multiple control measures (i.e., administrative, engineering, and personal respiratory protection) were implemented at about the same time, making it more difficult to identify the most crucial aspect of the program. No actual field trials assessing the independent importance of any of the tuberculosis infection-control measures have been performed (97). However, extensive administrative controls were implemented at all of the hospitals and appear to be the most crucial component of an infection-control program as described above (Table 6). The importance of administrative controls is also emphasized by outbreak at an institution that had a respiratory fit testing pro-

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gram; failure of implementation of administrative and engineering controls at that hospital was associated with nosocomial transmission of MDR-TB (98). Preventing nosocomial transmission of tuberculosis by enhancing tuberculosis infection-control measures has been a critical component along with enhanced community-control measures such as expansion of directly observed therapy programs in helping reduce the incidence of tuberculosis in the United States beginning in 1993 following the resurgence of cases between 1985 and 1992 (99). Improved infection-control measures are thought in large part to be responsible for the dramatic decrease in MDR-TB cases in New York City beginning in 1993 (45). Thus, while nosocomial transmission of tuberculosis helped further fuel the resurgence of disease in the United States, infection-control measures to prevent institutional transmission have helped turn the tide (68). Further definition of a number of infection-control issues await better definition including improving the efficiency of infection control measures and determining the most cost-effective strategies. For example, while tuberculosis infection-control measures have been demonstrated to be very effective in preventing nosocomial transmission of M. tuberculosis, they may not be highly efficient, and respiratory isolation policies have clearly resulted in overisolation of patients. A high sensitivity for detecting previously undiagnosed patients is critical because there is essentially no room for error because a single patient with unsuspected tuberculosis can lead to transmission to multiple patients or health-care workers (68,100). Reports indicate that 1 in 8 patients isolated in Atlanta had confirmed tuberculosis, 1 in 7 in New York City, and between 1 in 10 and 1 in 28 in Buffalo, New York (depending on the incidence of TB in the community) (35,101,102). In a less endemic area (Iowa), if strict isolation guidelines were followed only 1 in 92 would have had confirmed TB (103). In a multivariate analysis of clinical data and other risk factors available at the time of admission, Bock et al. (101) identified a number of clinical predictors for tuberculosis among patients at Grady Memorial Hospital in Atlanta (e.g., chest radiograph with upper lobe infiltrate or cavity, prior positive tuberculin skin test), and a hypothetical policy was developed. This model would have reduced the degree of overisolation by about 50% (to 1 in 4) but would have resulted in a significant decrease in the sensitivity of the policy (from 96% to 81%). The decreased sensitivity of the hypothetical policy made it unacceptable. Further work is needed to determine if it is possible to identify clinical predictors available at the time of admission that would decrease the overuse of isolation while maintaining an extremely high level of sensitivity for detecting patients with tuberculosis (68). E. Other Measures: BCG Vaccination

The efficacy of bacille Calmette-Guérin (BCG) vaccination for the prevention of tuberculosis disease has been somewhat controversial (see Chap. 19). BCG vac-

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cination has long been proposed by some for use in health-care workers for preventing tuberculosis disease (104,105). Several studies done a half century ago when rates of tuberculosis in the United States were much higher than they are today (and prior to implementation of tuberculosis infection-control measures) suggest that BCG may reduce the risk of developing active disease in vaccinated health care workers compared to that among nonvaccinated health care workers (106–112). Protection was not absolute in these studies, and cases occurred among vaccinated health-care workers. These studies had too many methodological flaws (e.g., nonrandomization, follow-up procedures and case definitions not specified) to be combined in a quantitative meta-analysis (104). In addition, BCG may be poorly tolerated by adults, who may have severe reactions to BCG vaccination. In one study carried out in the United States, all 20 previously healthy PPD-negative and HIV-seronegative adults who received BCG vaccination developed erythema, induration, and tenderness at the site of administration, and local ulceration with drainage was documented in 14 cases (113). BCG is not recommended for health-care workers in the United States except in situations where there may be high rates of MDR-TB and infection-control measures cannot be implemented (61). Use of BCG interferes with interpretation of tuberculin skin testing, and in the United States a strategy of routine testing of health-care workers is recommended with preventive therapy for those with tuberculin skin test conversions. In addition, BCG is thought not to reduce the risk of infection with M. tuberculosis but to reduce the risk of progressing from latent infection to active disease (114). Several reports have noted higher skin test conversions among foreign-born health-care workers (who were documented or presumed to have been BCG vaccinated in their home country) at U.S. health-care facilities (53,53a,54,115), which may result from a combination of boosting or late boosting due to BCG. IV. Hospital Discharge Planning and Standards In order to improve control of TB, there needs to be close cooperation and coordination of activities among the wide variety of organizations involved in TB patient care, education, management, and TB control. Directly observed therapy has been shown to improve outcomes (116) and there must be a smooth transition from the in-patient to the out-patient setting and close collaboration between hospitals and public health agencies. A written policy or critical pathway management of tuberculosis patient discharges that provides guidance as to what constitutes an appropriate discharge is important (35). Patients with tuberculosis should (1) be discharged on an appropriate antituberculosis regimen (e.g., four-drug regimen), (2) have arrangements to ensure close follow-up after discharge (for example, at Grady Memorial Hospital all TB patients have their discharge endorsed

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in the chart by the hospital’s TB social worker and the local county health department liaison), and (3) meet appropriate criteria for discharge (e.g., be medically ready for discharge and have a stable home or other stable location if potentially infectious). The close coordination between the hospital and local county health departments and contact with the patient by local county health department liaison prior to hospital discharge has greatly enhanced efforts in improving patients follow-up after discharge at a number of institutions. V. OSHA Requirements for a Tuberculosis-Control Program OSHA has developed enforcement policies specifying measures to reduce occupational exposure to tuberculosis. OSHA has regulatory and enforcement authority, and noncompliance with OSHA requirements can result in fines of up to $70,000 for each violation (64). Currently, OSHA’s authority to conduct inspections for occupational exposure to tuberculosis comes from the general duty clause of the Occupational Safety and Health Act of 1970, which requires that a hazard be present (e.g., a case of tuberculosis) in the work site for OSHA to conduct an inspection and to cite an employer for not having a TB-control program. OSHA requirements (Table 7) have been based in part upon the CDC 1994 guidelines (61). OSHA is developing a specific TB Standard and in late 1997 published this in draft form (66). The proposed OSHA TB Standard would apply to health-care facilities, correctional facilities, homeless shelters, and drug-treatment centers. It is anticipated that the final standard will be issued in 2000. The proposed requirements of the standard are outlined in Table 8. The final standard is being revised by OSHA based on extensive comments received and may differ from the proposed standard especially with regard to tuberculin skin testing requirements and frequency. VI. Institutional Controls in Developing Countries and Areas with Very Limited Resources It is highly likely that nosocomial transmission of tuberculosis is occurring in developing countries, although the extent of this has not been fully evaluated (58). In most of the developing world infection-control or tuberculosis infection-control measures are minimal or nonexistent (47). The extent of control measures recommended or mandated for the United States and other developed countries may not be possible or appropriate for developing countries due to lack of resources. However, this does not mean that simple measures that would likely reduce the risk of nosocomial transmission such as those that are administrative in nature cannot be implemented. This would include expansion of administrative controls, separation of infectious TB patients from other patients such as those with HIV or

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Table 7 Occupational Safety and Health Administration’s Requirements for Tuberculosis-Control Programs Criteria for Inspection: A Suspect or Confirmed Case of TB in the Past 6 Months Protocol for early identification of patients with active TB, including training staff to identify patients with active TB Medical surveillance of health-care workers Offer TB skin testing at no cost to all potentially exposed workers and all new workers before they begin work Base frequency of repeat TB skin testing on risk assessment Evaluate workers who have had unprotected TB exposure Evaluate workers who developed symptoms of TB Case management of infected workers Have protocol for follow-up of recent PPD converters When first hired, and annually, employees should be given training on modes of transmission, signs and symptoms, medical surveillance, site-specific protocols for TB control, and protocols for exposure incidents Use of engineering controls Place patients with possible or confirmed TB in isolation rooms with negative pressure and air that is exhausted directly outside or through a HEPA filter if recirculation is unavoidable Use special booths, hoods, or isolation rooms that meet above isolation criteria for hazardous procedures (e.g., aerosolized medication treatment, autopsies) Monitor negative pressure in isolation rooms with smoke tubes or other indicators Use respirators when entering isolation rooms if hazardous procedures are performed without local source control or local exhaust (i.e., booth, hood, tent) until air is purged of droplet nuclei Have a complete respiratory protection program in place Use NIOSH-approved respirators (e.g., N-95) for TB control Develop protocol for reuse of disposable respirators (by the same worker) and circumstances when the respirator must be discarded (e.g., loss of structural integrity, damaged filter media, or contamination) Keep records of employee exposures to TB, results of TB skin tests, and all medical evaluations and treatment Use signs or tags outside TB isolation or treatment rooms that describe the necessary precautions (e.g., respirators must be donned before entering) Record on the OSHA 200 log all TB skin-test conversions and active cases of TB among workers. Assume all TB skin-test conversions are occupationally acquired, unless clear documentation exists for nonoccupational exposure Abbreviations: TB, tuberculosis; PPD, purified protein derivative; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration. Source: Adapted from Refs. 64, 65.

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633

Summary of the Proposed OSHA TB Standard

I. Scope Standard applies to all workers with occupational exposure to TB in: Hospitals Long-term care facilities for the elderly Correctional facilities Hospices Shelters for the homeless Drug abuse–treatment facilities Facilities where highly hazardous procedures are performed Laboratories handling, processing, or maintaining of M. tuberculosis specimens or cultures Standard applies to any worker in the above settings that may be reasonably anticipated to contain aerosolized TB or to have been exposed to a suspect or confirmed case of TB, including those providing social work, teaching, law enforcement, legal services, emergency medical service, home health care, home hospice care, and repair or maintenance of air systems or equipment. II. Exemptions Exemptions for certain portions of the standard for employers with workers at minimal risk of occupational exposure to TB. These include those sites that: Do not admit or provide medical services to individuals with suspected or confirmed infectious TB Have no cases of confirmed TB in past 12 months Are located in a county that in the past 2 years has had: No cases of TB in one year Fewer than 6 cases in the other year Minimal program for these worksites include: Exposure control plan Baseline skin testing and medical history Medical management and follow-up after exposures Employee training and record keeping III. Exposure Control Exposure determination of workers with “occupational exposure” Written exposure control plan For all employers: procedures for providing information on potential TB exposures and reporting exposure incidents For employers who transfer patients: procedures for prompt identification, isolation and/or transfer of suspect or confirmed cases of TB For employers who admit or provide medical services: procedures for prompt identification, isolating and managing care, list of high hazard procedures, and schedule for inspection and maintenance of engineering controls

634 Table 8

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IV. Work Practices Identify and isolate TB patients in isolation rooms/areas called “AFB isolation” Conduct high hazard procedures in AFB isolation rooms/areas Maintain negative pressure in AFB isolation and monitor daily Ventilate AFB isolation rooms after tuberculosis patient vacates room Exhaust air directly outside or use HEPA filtration before recirculation Inform ventilation contractors about potential exposures Follow NIH/CDC recommendations for “Biosafety in Microbiologic and Biomedical Laboratories” V. Respiratory Protection Wear respirators when entering AFB isolation, during procedures on TB patients, when transporting TB patient in enclosed vehicle, when repairing or maintaining air systems or equipment containing TB aerosols, when working in residences of individuals with TB, when working in research lab when TB is not contained safely, when transporting an unmasked TB patient Minimum respiratory protection is the N-95 respirator capable of being “fit checked” by worker Initial fit testing required for all; annual fit testing not required Inspect and discard disposable respirators when unsuitable for use VI. Medical Evaluations Conduct medical evaluations, including medical history, baseline tuberculin skin test, and physical exam, if indicated, prior to initial assignment to job with occupational exposure and at least annually Conduct medical evaluations including follow-up after exposure incidents and skin test conversions Tuberculin Skin Testing Baseline skin testing Required for all workers with potential for occupational exposure using Mantoux skin test. Two-step baseline testing is required unless worker has documented negative test in last year. Follow-up skin testing every 6 months for workers Entering isolation rooms/areas Present during high hazard procedures Transporting TB patients in enclosed vehicles In “intake areas” (e.g., emergency department) where identification of TB cases is done and there are 6 or more confirmed TB cases per year Follow-up skin testing every 12 months for all other employees Follow-up skin testing also required After an exposure incident Within 30 days of termination of employment

Tuberculosis Infection Control Table 8

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Continued

Medical Management and Follow-Up Medical management and follow-up to be provided after exposure incidents and skin test conversions. Drug susceptibility of source case should be determined if possible. Medical removal protection, including all earnings, job status, and seniority, shall be maintained for all workers removed from duty as a result of occupationally acquired TB. VII. Communication of Hazards and Training Hazard labeling is required of ventilation systems, lab waste, and isolation rooms/areas. A “stop” sign is required for labeling of AFB isolation rooms. Initial training and annual retraining unless employer can demonstrate that worker has specific knowledge and skills. Record Keeping Records must be kept for all medical evaluations, exposure incidents, training, and engineering control maintenance. Source: Ref. 124.

other immunocompromising conditions, respiratory protection for health-care providers, and excluding immunocompromised health-care workers from caring for patients with tuberculosis. Engineering controls found in developed countries may be the most difficult to implement given the resources required, but simple measures such as opening windows or installing window fans to exhaust air to the outside and create negative pressure may be possible. Further investigations into the efficacy of tuberculosis infection-control measures in developing countries is needed. WHO/IUATLD issued in 1993 brief guidelines for the control of tuberculosis transmission in health-care settings (117). Currently, efforts are ongoing to develop revised recommendations. The current WHO/IUATLD guidelines recommend: Early identification of infectious tuberculosis patients (e.g., screen patients with respiratory signs and symptoms suggestive of tuberculosis including those with a cough for more than 3 weeks’ duration by sputum smear microscopy for AFB). Initiation of effective therapy as soon as the diagnosis is established. Ambulatory treatment reduces the risk of institutional transmission; therapy should be observed, and some patients will require in-patient care. Isolation of patients admitted with suspected TB from other patients with known TB and other patients; HIV-infected patients suspected of having TB should not be admitted to a TB ward unless the diagnosis is confirmed (e.g., by smear microscopy).

636

Blumberg Smear-positive patients should remain in isolation while hospitalized until they are smear negative. Environmental controls include good ventilation, keeping doors to tuberculosis wards closed and windows open to the outside; exhaust fans are useful for moving air from wards and isolation rooms to the outside. UV lights are a consideration as an adjunct but require proper maintenance to be effective and can be harmful if not installed properly. Sunlight is an inexpensive source of UV light, so ideally patient rooms should have large windows. Protection of health-care workers includes education about tuberculosis, excluding HIV-infected health-care workers from caring for tuberculosis patients, and masking of patients with cough who are transported out of their room to another part of the hospital (e.g., radiology). References

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47. Jarvis. WR. Tuberculosis. In: Bennet JV, Brachman PS, eds. Hospital Infections. 4th ed. Philadelphia: Lipincott-Raven, 1998:515–536. 48. Fridkin SK, Manangan L, Bolyard E, Jarvis WR. SHEA-CDC TB survey, Part II: efficacy of TB infection control programs at member hospitals, 1992. Infect Control Hosp Epidemiol 1995; 16:135–140. 49. Fridkin SK, Manangan L, Bolyard E, Jarvis WR. SHEA-CDC TB survey, Part I: status of TB infection control programs at member hospitals, 1989–1992. Infect Control Hosp Epidemiol 1995; 16:129–134. 50. Sinkowitz RL, Fridkin SK, Manangan L, Wenger PN, Jarvis WR. Status of tuberculosis infection control programs at United States hospitals, 1989 to 1992. Am J Infect Control 1996; 24:226–234. 51. Malasky C, Jordan T, Potulski F, Reichman LB. Occupational tuberculous infections among pulmonary physicians in training. Am Rev Respir Dis 1990; 142:505– 507. 52. Woeltje KF, L’Ecuyer PB, Seiler S, Fraser VJ. Varied approaches to tuberculosis control in a multihospital system. Infect Control Hosp Epidemiol 1997; 18:548–553. 53. Blumberg HM, Welsh MA, Sotir MJ, Wyndham J, Shulman JA. Risk of tuberculin skin test conversion among medical students training at an inner-city hospital in a high incidence area. In: The Eighth Annual Meeting of the Society of Hospital Epidemiology of America. Orlando: Society of Hospital Epidemiology of America, 1998. 53a. Larsen N, Larson CE, Sotir MJ, White N, Bock NN, Blumberg HM. Risk of tuberculin skin test conversion among employees at a public inner-city hospital in a high incidence area. In: The Ninth Annual Meeting of the Society for Healthcare Epidemiology of America. San Francisco: Society for Healthcare Epidemiology of America, 1999. 54. Blumberg HM, Sotir M, Erwin M, Bachman R, Shulman JA. Risk of housestaff tuberculin skin test conversion in a high incidence area. Clin Infect Dis 1998; 27:826–833. 55. Bailey TC, Fraser VJ, Spitznagel EL, Dunagan WC. Risk factors for a positive tuberculin skin test among employees of an urban, Midwestern teaching hospital. Ann Intern Med 1995; 122:580–585. 56. Monno L, Angarano G, Carbonara S, Coppola S, Costa D, Quarto M, Pastore G. Emergence of drug-resistant Mycobacterium tuberculosis in HIV-infected patients. Lancet 1991; 337:852. 57. Couldwell DL, Dore GJ, Harkness JL, Marriott DJ, Cooper DA, Edwards R, Li Y, Kaldor JM. Nosocomial outbreak of tuberculosis in an outpatient HIV treatment room. AIDS 1996; 10(5):521–525. 58. De Cock KM, Binkin NJ, Zuber PL, Tappero JW, Castro KG. Research issues involving HIV-associated tuberculosis in resource-poor countries. JAMA 1996; 276(18):1502–1510. 59. Centers for Disease Control and Prevention. Multidrug-resistant tuberculosis outbreak on an HIV ward—Madrid, Spain, 1991–1995. MMWR 1996; 45(16):330– 333. 60. Nolan CM. Editorial: nosocomial multidrug-resistant tuberculosis—global spread of third epidemic. J Infect Dis 1997; 176:748–751.

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61. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 1994. MMWR 1994; 43(RR-13):1–132. 62. American Hospital Association Technical Panel on Infections. Tuberculosis Control in the Hospital—A Special Briefing. Chicago, IL: American Hospital Association, 1994. 63. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 1994. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1994; 49:1193–1200. 64. Pugliese G, Tapper M. Tuberculosis control in health care. Infect Control Hosp Epidemiol 1996; 17:819–827. 65. Occupational Safety and Health Administration. Enforcement Procedures and Scheduling for Occupational Exposure to Tuberculosis. OSHA Instruction (CPL 2.106), February 9, 1996. 66. Occupational Safety and Health Administration. Occupational exposure to tuberculosis. Proposed Rule. (29 Code of Federal Regulations Part 1910). Fed Reg 1997; 62:54160–54308. 67. Blumberg HM, Watkins DL, Berschling JD, Antle A, Moore P, White N, Hunter M, Green B, Ray SM, McGowan JE Jr. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122:658–663. 68. Blumberg, HM. Tuberculosis and infection control: What now? Infect Control Hosp Epidemiol 1997; 18:538–541. 69. Perlman DC, el-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N, Chirgwin K, Hafner R. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. Clin Infect Dis 1997; 25:242–246. 70. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993; 17:968–975. 71. Sepkowitz KA, Feldman J, Louther J, Rivera P, Villa N, DeHovitz J. Benefit of twostep PPD testing of new employees at a New York City hospital. Am J Infect Control 1997; 25:283–286. 72. Menzies R, Vissandjee B, Rocher I, St Germain Y. The booster effect in two-step tuberculin testing among young adults in Montreal. Ann Intern Med 1994; 120:190– 198. 73. Anargyros P, Astill DS, Lim IS. Comparison of improved BACTEC and Lowenstein-Jensen media for culture of mycobacteria from clinical specimens. J Clin Microbiol 1990; 28:1288–1291. 74. American Thoracic Society. Rapid diagnostic tests for tuberculosis: What is appropriate use? Am J Respir Crit Care Med 1997; 155:1804–1814. 75. Menzies D. Effect of treatment on contagiousness of patients with active pulmonary tuberculosis. Infect Control Hosp Epidemiol 1997; 18:582–586. 76. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329:784–791. 77. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuberc Lung Dis 1995; 76:95–99.

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78. Bass JB Jr, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, Snider DE Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. Am J Respir Crit Care Med 1994; 149:1359–1374. 79. Enarson DA, Rieder HL, Arnadottir, Trebucq A. Tuberculosis Guide for Low Income Countries. 4th ed. Paris: International Union Against Tuberculosis and Lung Disease, 1998. 80. Fella P, Rivera P, Hale M, Siegal M, Dehovitz J, Sepkowitz K. Implementation of OSHA guidelines for protection of employees against TB at a NYC hospital [abstract no L1]. Am J Infect Control 1994; 22:100. 81. Nardell EA. Fans, filters, or rays? Pros and cons of the current environmental tuberculosis control technologies. Infect Control Hosp Epidemiol 1993; 14:681–5. 82. Marrier RL, Nelson T. A ventilation-filtration unit for respiratory isolation. Infect Control Hosp Epidemiol 1993; 14:700–705. 83. Rutala WA, Jones SM, Worthington JM, Reist PC, Weber DJ. Efficacy of portable filtration units in reducing aerosolized particles in the size range of Mycobacterium tuberculosis. Infect Control Hosp Epidemiol 1995; 16:391–398. 84. Macher JM. The use of germicidal lamps to control tuberculosis in healthcare facilities. Infect Control Hosp Epidemiol 1993; 14:723–729. 85. Murray WE. Ultraviolet radiation in a mycobacteriology laboratory. Health Physics 1990; 58:507–510. 86. Nardell EA. Interrupting transmission from patients with unsuspected tuberculosis: a unique role for upper-room ultraviolet air disinfection. Am J Infect Control 1995; 23:156–164. 87. Adal KA, Anglim AM, Palumbo CL, Titus MG, Coyner BJ, Farr BM. The use of high-efficiency particulate air-filter respirators to protect hospital workers from tuberculosis. A cost-effectiveness analysis. N Engl J Med 1994; 331:169–173. 88. Nettleman MD, Fredrickson M, Good NL, Hunter SA. Tuberculosis control strategies: the cost of particulate respirators. Ann Intern Med 1994; 121:37–40. 89. U.S. Department of Health and Human Services. 42 CFR Part 84. Respiratory protective devices; proposed rule. Fed Reg 1994; 59:26849–26889. 90. Hannum D, Cycan K, Jones L, Stewart M, Morris S, Markowitz SM, Wong ES. The effect of respirator training on the ability of healthcare workers to pass a qualitative fit test. Infect Control Hosp Epidemiol 1996; 17:636–640. 91. Stroud LA, Tokars JI, Grieco MH, Crawford JT, Culver DH, Edlin BR, Sordillo EM, Woodley CL, Gilligan ME, Schneider N. Evaluation of infection control measures in preventing the nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in a New York City hospital. Infect Control Hosp Epidemiol 1995; 16: 141–147. 92. Wenger PN, Otten J, Breeden A, Orfas D, Beck-Sague CM, Jarvis WR. Control of nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis among healthcare workers and HIV-infected patients. Lancet 1995; 345:235–240. 93. Maloney SA, Pearson ML, Gordon MT, del Castillo R, Boyle JF, Jarvis WR. Efficacy of control measures in preventing nosocomial transmission of multidrug-resistant tuberculosis to patients and health care workers. Ann Intern Med 1995; 122(2): 90–95.

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24 Tuberculosis in Correctional Facilities

NAOMI N. BOCK Centers for Disease Control and Prevention Atlanta, Georgia

I. Introduction A 1947 article in the Swiss medical journal Schweizerische Medizinische Wochenschrift described tuberculosis among former concentration camp inmates in Eastern Europe (1). A makeshift hospital was established behind the Allied line in the spring of 1945, and 296 evacuated prisoners underwent medical evaluation there. Among them, 151 had tuberculosis: 124 (42%) with active disease and 27 (9%) inactive disease. Only 145 (49%) were disease-free. The authors compared this prevalence of tuberculosis to that detected during a radiological survey of 362,043 citizens of Stuttgart in 1941. The prevalence of active tuberculosis among the justreleased prisoners was 200 times that of the general population of Stuttgart. The prevalence of inactive disease was 14 times greater in the former inmates. The authors were concerned with controlling tuberculosis in Europe in the immediate postwar period, with the population malnourished and unsettled. Among the former prisoners, two thirds of the active cases appeared to be postprimary tuberculosis and one third primary tuberculosis. The postprimary cases might have been due to either endogenous reactivation or exogenous reinfection, but the authors postulated that most cases were due to reinfection based on 1) a high rate of pleural disease and other clinical similarities to primary disease 645

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among the postprimary cases, 2) a high rate of transmission in the camps, as evidenced by the amount of primary disease, 3) a high rate of inactive disease that had not reactivated despite the extreme conditions, and 4) a low rate of postprimary disease among a comparison group of former prisoners who were equally malnourished but who worked in the fields and thus had less contact with inmates with tuberculosis. The authors concluded that elimination of sources of infection could prevent a tuberculosis epidemic in the famished postwar European countries and that reactivation of latent infection was of less concern. Although one may question some of the criteria used by the authors or the strength of their conclusions based on the data, this article is nonetheless prescient in its delineation of the key issues concerning tuberculosis in correctional facilities 50 years later. The prevalence and incidence of tuberculosis among the incarcerated remains much higher than in the general population. Correctional institutions are environments of transmission because they are often overcrowded and poorly ventilated. Inmates, compared with the general population, have more risk factors for progression to active disease once infected with M. tuberculosis, though human immunodeficiency virus (HIV) infection now plays more of a role than malnutrition. And tuberculosis incubated in jails and prisons is not confined there, but becomes a source of infection for the general population. Only drug resistance, now increasingly reported in correctional institutions, was not a problem in 1947.

II. Epidemiology of Tuberculosis in Correctional Facilities Recent studies have consistently shown the incidence and prevalence of tuberculosis to be higher among inmates in prisons and jails than in the nonincarcerated population. This finding persists across high-, low-, and increasing-prevalence (Eastern Europe and the former Soviet Union) (2) countries (see Appendix). In the Bouak’O prison, Ivory Coast, an average annual incidence of 3,600 per 100,000 was reported for 1990–1992 (3). Eighty percent of the cases were acid-fast bacilli smear-positive pulmonary cases. The case fatality rate was 24%. The authors note that the tuberculosis problem in the prison population of the Ivory Coast was first highlighted in 1990, when an incidence of 7,000 per 100,000 was reported from the country’s largest prison, Maison d’Arret et de Correction d’Abidjan (4). An active case-finding survey in Zomba Central Prison, Malawi, conducted in 1996, found that 47 (5%) of 914 inmates screened had pulmonary tuberculosis (5). Based on interviews with the patients about their symptoms, particularly cough, the authors concluded that 46 of the 47 prisoners with pulmonary tuberculosis probably developed their illness while in prison. In Madagascar from June 1990 to December 1993, 454 cases of tuberculosis were reported from among 19,214 admissions to the prison in Antananarivo (6). This prevalence of 2.4% was

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eight times that of the general population of Madagscar during the same time period. The International Committee of the Red Cross, working in prisons in Azerbaijan, reported an incidence of tuberculosis among prisoners of 4,667 per 100,000, 47 times the incidence for the general population (7). The case fatality rate was also high—24% in 1994. Drobniewski reported incidence rates in Siberian prisons in 1993 ranging from 824 to 6,500 per 100,000 (8). A case study of the tuberculosis epidemic in Siberian correctional institutions in the late 1990s is presented in Appendix A, at the end of this chapter. In one of the few reports available on tuberculosis infection in correctional facilities, a cross-sectional survey of new transfers from another correctional institution to a Barcelona jail over a 9-month period in 1989–1990 found that 404 (56%) of 719 inmates undergoing Mantoux testing had tuberculosis infection (9). The authors note that this prevalence is higher than that found in a marginal neighborhood of Barcelona inhabited primarily by gypsies (20–36%) or that found in a population of drug addicts undergoing detoxification treatment (37%). Nineteen cases of pulmonary tuberculosis were diagnosed in this Barcelona jail, a prevalence of 2,700 per 100,000. The authors note that this prevalence was almost 50 times greater than that in the city of Barcelona. In the prison system in Madrid in 1993–1994, the incidence of tuberculosis was 2,283 per 100,000 (10). In the United States, increasing rates of tuberculosis in correctional facilities have been noted for almost a decade (11), although rates vary among states and among institutions within states. In the New York State correctional system in 1990–1991 there were 156 cases per 100,000 inmate years, compared with 24 per 100,000 for the state population (12). In California in 1991, one state prison facility had an incident rate of 184 per 100,000, more than 10 times greater than the state general population rate (13). In Georgia, however, the case incident rate in the prison system from 1991 to 1995 was only 2.6 times greater than the average annual general population rate of 12 per 100,000 (14). Many state prison systems in the United States conduct active case finding among new inmates. This is a useful tool for tuberculosis control (see below), but care must be taken with epidemiological interpretation, as these cases are reported (notified) from the correctional system, and then may be interpreted as being incident cases within the system (14). They are indeed incident cases in the state, but in the prison system are prevalent cases found at the time of admission medical evaluation, not incident cases occurring in a cohort of inmates followed over time. In a survey of reported tuberculosis cases from 29 states in the United States in 1984–1985, 1.8% of cases between 15 and 64 years old were inmates of correctional institutions at the time of diagnosis (15). This incredibly high proportion of cases reported from correctional institutions reflects a combination of incident cases in the incarcerated population and active case finding among a high-risk group with little access to health-care services (16). In the studies described above, the authors have taken pains to distinguish between

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cases in cohorts followed over time and those detected during case-finding programs. III. Transmission of Tuberculosis in Correctional Facilities The physical structures of most correctional facilities create potent environments for M. tuberculosis transmission. As discussed in Chapter 10, droplet nuclei from an infectious source case can survive indoors for hours. Undiluted contaminated air, due to recirculating air systems and a dearth of windows, facilitates transmission. The overcrowding of inmates within prisons and jails further enhances transmission (17). Additionally, the rotation of prisoners from one facility to another, a common practice in some correctional systems, fosters transmission from one physical setting to another (9,12). Some of the high case rates in the correctional systems described above were attributed in part to transmission of M. tuberculosis within the institutions. In the Madrid prison system, restriction fragment length polymorphism (RFLP) analysis, clinical and epidemiological data were interpreted to indicate that the majority of incident cases over an 18-month period were due to transmission of tuberculosis within the prison system (10). In Zomba Central Prison, Malawi, RFLP analysis was not available, but using clinical histories and epidemiological data the authors postulate active transmission within the prison (5). In the New York State prison system, 31 inmates with multidrug-resistant (MDR) tuberculosis were linked in a transmission chain by epidemiological data and drug resistance and RFLP patterns (12). In Antananarivo prison, the authors propose that the decrease in rates over time following the initiation of effective standard, internationally recognized treatment regimens may have been due to decreased transmission within the prison (6). Two decades ago Stead documented previous incarceration as an independent risk factor for tuberculosis infection among new inmates in the Arkansas State prison (18). More recently Bellin et al. demonstrated an association between jail time or jail admissions and the development of active tuberculosis among inmates in the New York City jail system (19). IV. Risk Factors for Tuberculosis Among Inmates in Correctional Facilities HIV infection (see Chap. 20) is the strongest known risk factor for the development of tuberculosis disease among persons with latent tuberculosis infection (20). Among tuberculin skin test–positive, HIV-infected intravenous drug users, 8% a year progressed to active tuberculosis. In one reported outbreak, 37% of HIV-infected persons exposed to an infectious tuberculosis case developed active tuberculosis within 6 months (21).

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Persons with HIV infection are overrepresented in correctional institutions. Although data are sparse, in 1997 the United Nations Joint Program on HIV/AIDS reported to the media that HIV infection rates in European prisons and jails were extremely high (22). They cited figures of possibly up to 20% infected in Spanish and Irish jails, 6.6% infected in Danish prisons, and 1.9% in France. In the United States, following widespread implementation of mandatory sentencing for drug users beginning in the early 1990s, an increased proportion of inmates are drug offenders, many with HIV infection (23). In California, 2.5% of male inmates in the state prison system are HIV infected; in Georgia, 3% of all inmates are HIV infected (14,24). In industrialized countries HIV infection rates among inmates are correlated with rates of HIV infection among injection drug users in the community (25). In sub-Saharan Africa HIV infection among inmates reflects the prevalence of HIV among young, urban adults, and few if any prisoners are intravenous drug users. One seroprevalence survey of male inmates in Mexican prisons found 3.7% to be HIV infected; sex with other males was the predominant risk factor, and intravenous drug use less frequent (26). Prisons in Brazil and Thailand show HIV infection both among injection drug users and non–drug users (25). Persons who inject drugs may be at increased risk for tuberculosis even if not infected with HIV (27). High rates of tuberculosis in correctional institutions in industrialized countries are increasingly reported to be associated with HIV infection. Braun et al. reported a sevenfold increase in tuberculosis among inmates of the New York State prison system between 1976 and 1986 (11). During that period the proportion of tuberculosis cases in inmates with HIV infection increased from zero to 56%. In the Georgia State prison system, 41% of 142 tuberculosis cases were HIV infected, although the prevalence of HIV infection among the inmate population during this time was 3% (14). Matching of AIDS and tuberculosis registries from 1982 through 1994 in Georgia indicated that residence in the state prison was the strongest predictor of HIV infection among tuberculosis cases (28). In the prison hospital in Madrid 88% of 343 tuberculosis cases treated from 1991 through 1994 were HIV infected (29). Fewer data are available for nonindustrialized countries, but in Central Zomba Prison, Malawi, 73% of the tuberculosis cases tested for HIV were seropositive (5).

V. Correctional Facility Tuberculosis and the Community at Large Tuberculosis in correctional institutions is not confined to the incarcerated but affects the general community in several ways. First, as discussed above, correctional facilities are environments of transmission, and many inmates become infected while incarcerated. Once released back to the community they may develop

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and transmit tuberculosis. Second, inmates receiving antituberculosis treatment may be released before completing therapy, and many are then lost to follow-up, especially in the absence of prospective follow-up programs. Third, employees of prisons and jails can become infected in the workplace, then develop and transmit tuberculosis to their families and contacts in the community. Fourth, active case finding among new admissions is undertaken by some prison systems. The detected cases are managed by prison health services, which are usually separate from the local tuberculosis-control program. Communication between the two programs is often poor, and cases detected at entry to the prison often do not have contact investigations conducted in the communities or jails, where they may have transmitted tuberculosis prior to transfer to the prison. Data on numbers of persons imprisoned and released worldwide are sparse. In the United States, more than a half million inmates are discharged each year from federal and state correctional institutions (30) and almost 10 million from jails (31). A 25-site national survey of tuberculosis infection and use of treatment for latent infection among inmates in correctional facilities found that 24.6% of the inmates being discharged annually may have had tuberculosis infection (32). Many of these released inmates are injection drug users or have or are at risk for HIV infection. They are thus at increased risk for developing active tuberculosis and transmitting it to others, including children (15). Tuberculosis transmission from prison or jail to the community was demonstrated in two reports from the United States. In 1978 Stead described an outbreak of tuberculosis in a state prison system and traced the transmission from there into the surrounding population (18). Within a year of being released 5 of 122 former inmates who were infected during the outbreak developed active tuberculosis. At least one case was documented to have infected his wife and two children; one of the children died of presumed tuberculous meningitis. A second report, a population based study in Nassau County, New York, between 1988 and 1990 found that 49 (24%) of 205 cases occurred in jail inmates, former inmates, jail employees, or their community contacts (33). Eight (8%) of the county cases over the 2-year period were in community contacts of former inmates. In the state of Georgia over the 5-year period 1991–1995, 38% of inmates under treatment for tuberculosis in the state prison system were lost to follow-up after being released to the community (14). Similar problems with failure to complete treatment have been described in former inmates in Siberia (34). Forty percent of inmates started on isoniazid preventive therapy in Seattle, Washington, were never located after release from jail despite an aggressive outreach program (35). A New York State prison employee developed MDR tuberculosis and subsequently died after exposure during an outbreak in the prison system in 1990–1991 (12). Employees of jails and prisons have been noted to have high rates of tuberculosis infection (36,37), and periodic surveillance for infection

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among employees has been recommended by the Centers for Disease and Control and Prevention (CDC) (38). Two thirds of the tuberculosis cases treated in the Georgia State prison system from 1991 to 1995 were detected during active case finding upon admission to the prison. Most of these cases had been living in the community or in a county jail just prior to admission to prison, but in 75% of the cases no contact investigation was conducted, although evaluation of contacts for disease or infection is the standard of care in the United States (14). VI. Controlling Tuberculosis in Correctional Facilities “Tuberculosis problems tend to be worse in prisons than in national tuberculosis programmes [which] will have to take into account and address the problems in prisons before they become unmanageable and will compromise future control programs, not only in the prison, but countrywide” concludes a report from the International Committee of the Red Cross (39; see Appendix B for The Baku Declaration). Inadequate tuberculosis-control efforts may be interpreted as deliberate indifference to the medical needs of prisoners (38). A correctional system tuberculosis-control program requires 1) early identification, isolation, and effective treatment of persons who have active tuberculosis, 2) ongoing surveillance to detect an outbreak or unusual cluster of events, 3) a response plan should an outbreak be detected, and 4) an effective collaboration with the national or local tuberculosis-control program. Program specifics will depend on the prevalence of tuberculosis in the population, the resources available (although the two are often inversely related), and whether inmates stay for shorter or longer durations of incarceration. A. Case Detection, Isolation, and Treatment

Although most national tuberculosis-control programs are based on passive case finding, where the first initiative for any individual medical evaluation is taken by the patient, an argument can be made for active case finding within correctional facilities. As noted above, populations entering jail or prison have a high prevalence of infection and disease, and the environment they are entering facilitates transmission of M. tuberculosis. Screening for disease should be done upon admission prior to transfer from one facility to another and, if the incidence rate is high, prior to release to the community. Routine periodic screening among longterm inmates can detect incident cases; prompt medical evaluation and a high index of suspicion for tuberculosis among inmates with medical complaints can also increase early detection of new cases. CDC guidelines for tuberculosis control in correctional facilities distinguish between short-term and long-term facilities (38). Short-term facilities are jails, de-

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tention centers, and holding pens that house inmates who remain in custody for less than 14 days. Long-term facilities are state and federal prisons, juvenile facilities, and jails that house predominately inmates who remain in custody for 14 days or longer. The main difference in recommended protocols for the two types of facilities is that tuberculin testing for detection of infection is discouraged for short-term facilities. For resource-poor countries tuberculin testing has not been a routine part of tuberculosis control. For both short-term and long-term facilities, a symptom screen should be done as soon as possible for new inmates. Any inmate with symptoms of tuberculosis disease should be placed in a respiratory isolation room and further evaluation, with chest radiography or sputum smear microscopy, conducted. Facilities without adequate respiratory isolation should have a plan for transfer of tuberculosis suspects to a facility equipped to isolate, evaluate, and treat them. For symptom screen the CDC guidelines recommend determining whether the person has experienced productive, prolonged cough; hemoptysis; chest pain; weight loss; anorexia; fever; night sweats; or chills. There have been no reports on the efficacy of this symptom screen. Nyangulu et al. used a symptom screen for active case finding in Zomba Central Prison, Malawi, where only passive case finding had been routine (5). Nine hundred prisoners not known to have tuberculosis were interviewed about the presence of cough; those with a cough of more than one week’s duration were investigated with three sputum samples, examined on the day of collection with smear microscopy for AFB with the Ziehl-Neelsen stain. Two hundred and twenty-two inmates had a cough and gave sputum samples; 18 or 8% of those with cough and 2% of the population screened were sputum smear positive! An additional 15 cases of smear-negative tuberculosis were detected in the second stage of their protocol. The inmates with cough but smear-negative sputums were treated with a broad-spectrum antibiotic and reinterviewed after 3 weeks. Those with no improvement in cough with antibiotic treatment, cough for 3 weeks, and weight loss were evaluated with chest radiography and the smearnegative cases diagnosed. These screening methods, the first reported in a correctional institution setting, appear promising, and further evaluation of their efficacy will be useful. Two studies on the use of radiographic screening for tuberculosis in urban jails in the United States report an increased case-detection rate for this method compared with symptom screen and tuberculin testing without routine radiography of all admissions (40,41). The cost is high, however, and it is unlikely that this screening method will come into widespread use. Of additional interest, in one of the studies, done over an 11-week period in a New York City jail where 32 cases were detected among 4172 inmate admissions (767 cases per 100,000 persons), 7 cases were previously undiagnosed and found with symptom, tuberculin test, and radiographic screen. However, most cases were detected by checking new jail admissions against the computerized New York City Tuberculosis Registry. Twenty-five (78%) of the

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cases in the jail during this period were previously diagnosed but incompletely treated (41). This registry match for new admissions may be a useful method of case detection and emphasizes the need for collaboration between local tuberculosis-control programs and correctional health services (see below). Once detected, tuberculosis cases need to be in respiratory isolation until no longer infectious. Respiratory isolation is not synonymous with solitary confinement since, depending on the air flow in the facility, droplet nuclei produced in those cells may be recirculated throughout the facility. Also, having infectious tuberculosis is not a punishable offense mandating solitary confinement, although respiratory isolation is necessary to protect the rest of the correctional population. Effective treatment of cases is essential. Components of effective treatment include (1) appropriate standard drug regimens, (2) direct observation of treatment, (3) no financial cost to the patient, and (4) a plan for recognizing and managing drug-resistant cases. The International Committee of the Red Cross documented too few antibiotics used for too short a duration in the Baku prison, probably contributing to transmission and drug resistance within the prison population (39). Tuberculosis case rates declined after appropriate treatment regimens were introduced in the prison in Madagascar (6). Inmates or their families were required to pay for medical services in the prison camp of Bouak’O, Ivory Coast—an impediment to case detection and treatment (3). Directly observed therapy is the international standard of care and needs to be implemented within jails and prisons. Treatment of drugresistant tuberculosis is generally beyond the resources of most national tuberculosis programs outside of the industrialized countries. The World Health Organization (WHO) has recently recommended treatment of drug-resistant cases in prisons, reflecting their potential for transmission in and out of the institution and their ultimate impact on the national tuberculosis program (42). B. Surveillance

Tuberculosis cases within correctional institutions should be monitored by prison health services and reported to the local or national tuberculosis-control program. Surveillance often can reveal weaknesses in institutional control programs or outbreaks where special interventions are necessary. In countries where resources are available, routine periodic tuberculin testing of long-term inmates and employees can reveal unsuspected transmission within the institution and identify persons for preventive therapy. C. Treatment of Latent Tuberculosis Infection

Where resources are available, treatment of latent tuberculosis infection (preventive therapy) (see Chap. 18) should be considered for long-term inmates with tuberculosis infection. As noted above, inmates are at increased risk of progression to tuberculosis once infected because of the high prevalence of HIV infection and intra-

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venous drug use in the population. Few inmates have access to preventive health services outside of the correctional system (16). Although the priority for prison tuberculosis control is to decrease transmission by detection, isolation, and treatment of cases, effective treatment of latent infection for infected inmates is another component that can contribute to tuberculosis control in the prison and the community. In a 25-site survey in the United States, 94% of inmates treated with isoniazid completed treatment (32). Once the inmate is released, however, completion of treatment for latent infection in the community is much less successful (43). Preliminary data on the use of primary isoniazid prophylaxis for HIV-infected inmates regardless of their tuberculin test results indicate that this may be useful in environments where transmission is inevitable (43). D. Collaboration Between Correctional Health Services and Tuberculosis-Control Programs

Upon incarceration a prisoner’s health care becomes the legal responsibility of the correctional system. However, the impact of tuberculosis within jails and prisons on the general community and vice versa makes collaboration essential. As noted, in the New York City jail system access to the computerized tuberculosis registry aided detection of 78% of cases entering the jail over the study period and identified many of them as delinquent cases (41). Cases released from prison prior to completing treatment are at increased risk of being lost to follow-up (14,34). For cases detected on admission to correctional facilities, contacts from the community need to be evaluated. National and state tuberculosis-control programs should offer their expertise in screening, containment, and assessment to correctional system administrations. References 1. Zuppinger A, Labhart A. Gestalt und Frühverlauf der Tuberkulose bei Patienten aus Konzentrationslagern. Schweiz Med Wochenschr 1947; 77:144–146. 2. Raviglione MC, Reider HL, Styblo K, Khomenko AG, Esteves K, Kochi A. Tuberculosis trends in Eastern Europe and the former USSR. Tubercl Lung Dis 1994; 75:400–16. 3. Koffi N, Ngom AK, Aka-Danguy E, S’Oka A, Akoto A, Fadiga D. Smear positive pulmonary tuberculosis in a prison setting: experience in the penal camp of Bouak’O, Ivory Coast. Int J Tuberc Lung Dis 1997; 3:250–253. 4. Coulibaly IM. Rapport d’Activit de la Lutte antituberculeuse en Côte d’Ivoire. Centre Antituberculeux d’Adjam, 1990. 5. Nyangulu DS, Harries AD, Kang’ombe C, Yadidi AE, Chokani K, Cullinan T, Maher D, Nunn P, Salaniponi FM. Tuberculosis in a prison population in Malawi. Lancet 1997; 350:1284–1287. 6. Auregan G, Rakotomanana F, Ratsitorahina M, Rakotoniaina N, Rabemananjara O, Raharimanana R, Boisier P. La tuberculose en milieu carceral a Antananarivo de 1990 a 1993. Arch Inst Pasteur Madagascar 1995; 62:18–23.

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7. Coninx R, Eshaya-Chauvin B, Reyes H. Tuberculosis in prisons (letter). Lancet 1995; 346:1238–1239. 8. Drobniewski F. Tuberculosis in prisons—forgotten plague. Lancet 1995; 346: 948– 949. 9. Martin V, Gonzalex P, Cayla JA, Mirabent J, Ca’Oellas J, Pina JM, Miret P. Casefinding of pulmonary tuberculosis on admission to a penitentiary centre. Tuberc Lung Dis 1994; 74:49–53. 10. Chaves F, Dronda F, Cave MD, Alonso-Sanz M, Gonzales-L’Opez A, Eisenach KD, Ortega A, López-Cubero L, Fernandez-Mart’On I, Catalan S, Bates JH. A longitudinal study of transmission of tuberculosis in a large prison population. Am J Respir Crit Care Med 1997; 155:719–725. 11. Braun MM, Truman BI, Maguire B, DiFerdinando GT, Wormser G, Broaddus R, Morse DL. Increasing incidence of tuberculosis in a prison inmate population—association with HIV infection. JAMA 1989; 261:393–397. 12. Valway SE, Greifinger RB, Papania M, Kilburn JO, Woodley C, DiFerdinando GT, Dooley SW. Multidrug-resistant tuberculosis in the New York State prison system, 1990–1991. J Infect Dis 1994; 170:151–156. 13. Centers for Disease Control. Tuberculosis transmission in a state correctional institution—California, 1990–1991. MMWR 1992; 41:927–929. 14. Bock NN, Reeves M, LaMarre M, DeVoe B. Tuberculosis case detection in a state prison system. Public Health Rep 1998; 113:359–364. 15. 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. 16. Bock NN, McGowan JE, Jr, Blumberg HM. Few opportunities for tuberculosis prevention among the urban poor. Int J Tuberc Lung Dis 1998; 2:124–129. 17. Kuemmerer JM, Comstock GW. Sociologic concomitants of tuberculin sensitivity. Am Rev Respir Dis 1967; 96:885. 18. Stead W. Undetected tuberculosis in prison. JAMA 1978; 240:2544–2547. 19. Bellin EY, Fletcher DD, Sayfer SM. Association of tuberculosis infection with increased time in or admission to the New York City jail system. JAMA 1993; 269: 2228–2231. 20. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, Walker AT, Friedland GH. 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. 21. Daley CL, Small PM, Schecter FG, Schoolnik GK, McAdam RA, Jacobs WR, Jr, Hopewell PC. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 1992; 326:231–235. 22. UN alarmed by high HIV rates in Europe’s prisons. Reuters Health Information Services, December 12, 1997. 23. Glaser JB, Greifinger, RB. Correctional health care: a public health opportunity. Ann Intern Med 1993; 118:139–145. 24. HIV rate in CA prisons higher than in community. AIDS Alert 1996; 11:23. 25. WHO, Global Programme on AIDS. HIV/AIDS and Prisons: A Survey Covering 55 Prison Systems in 31 Countries. Geneva: University Institute of Legal Medicine, 1992.

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26. Magis C, Del Rio A, Gonzalez G, Garcia ML, Valdespino JL, Sepulveda J. HIV infection in prison in Mexico (abstr). Yokohama: Int Conf AIDS/STD 1994:44. 27. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 1992; 268:504–509. 28. Khan AD, Vernon A, Stetler H, Page R, Askew T, DeVoe B. HIV-related tuberculosis (HIV-TB) in Georgia (abstr). Am Rev Respir Crit Care 1996;153:A132. 29. Chaves F, Alonso-Sanz M, Dronda F, Fernandez-Mart’On I, López-Cubero L, Catalan S. High prevalence of tuberculosis (TB) and Mycobacterium tuberculosis (Mtb) bacteremia in Spanish HIV-infected inmates: a 3-year study (abstr). Program Abstr Intersci Conf Antimicrob Agents Chemother 1994:107. 30. American Correctional Association. Juvenile and adult correctional departments, institutions, agencies and paroling authorities. Laurel, MD: American Correctional Association, 1992:XXII. 31. Correctional Populations in the United States, 1991. Washington, DC: Bureau of Justice Statistics, August 1993. U.S. Department of Justice document No. NCJ-142729. 32. Centers for Disease Control. Tuberculosis prevention in drug-treatment centers and correctional facilities—selected U.S. sites, 1990–1991. MMWR 1993; 42:210–213. 33. Pelletier AR, DiFerdinando GT, Greenberg AJ, Sosin DM, Jones WD, Bloch AB, Woodley CL. Tuberculosis in a correctional facility. Arch Intern Med 1993; 153:2692–2695. 34. Drobniewski F, Tayler E, Ignatenko N, Paul J, Connolly M, Nyye P, Lyagoshina T, Besse C. Tuberculosis in Siberia: 1. An epidemiological and microbiological assessment. Tuberc Lung Dis 1996; 77:199–206. 35. Nolan CM, Roll L, Goldberg SV, Elarth AM. Directly observed isoniazid preventive therapy for released jail inmates. Am J Respir Crit Care Med 1997; 155:583–586. 36. Bock NN, Toomey KE, DeVoe B, Tapia JR, Blumberg HM. High prevalence of tuberculosis infection among employees of an urban jail (abstr). Am Rev Respir Crit Care 1996; 153:A135. 37. Tannenbaum TN, Jochem K, Menzies D. Tuberculin screening among prison staff (abstr). Am Rev Respir Crit Care 1996; 153:A136. 38. CDC. Controlling TB in Correctional Facilities. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1995. 39. Coninx R, Pfyffer GE, Mathieu C, Savina D, Debacker M, Jafarov F, Jabrailov I, Ismailov A, Mirzoev F, de Haller R, Portaels F. Drug resistant tuberculosis in prisons in Azerbaijan: case study. BMJ 1998; 316:1423–1425. 40. Puisis M, Feinglass J, Lidow E, Mansour M. Radiographic screening for tuberculosis in a large urban county jail. Public Health Rep 1996; 111:330–334. 41. Layton MC, Henning KJ, Alexander TA, Gooding AL, Reid C, Heyman BM, Leung J, Gilmore DM, Frieden TR. Universal radiographic screening for tuberculosis among inmates upon admission to jail. Am J Public Health 1997; 87:1335–1337. 42. Barker A. UN urges steps to limit HIV, TB in Europe’s jails. Reuters Health Information Services, December 16, 1997. 43. Ijaz K, Stead WW. INH prophylaxis in HIV positive persons before exposure to tuberculosis (abstr). National TB Controllers Workshop, Atlanta, 1996.

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Appendix A Case Study of Tuberculosis in the Russian Correctional System* Background

Tuberculosis case rates and mortality rates in Russia have been steadily increasing since 1989 (Fig. 1). Whether the increases are due to changes in surveillance and reporting or to failure of the tuberculosis-control infrastructure amidst the social disorganization that accompanied perestroika is unknown. A lot is known, however, about the crisis of tuberculosis control within the correctional system,

Figure 1

Tuberculosis cases in Russia, 1960–1997.

*This case study was prepared by Sasha Chapkovsky and Naomi Bock.

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thanks to the active involvement of several international nongovernmental organizations working in close collaboration with the prison medical services and administration, particularly in western Siberia. In 1997 the incidence rate of new tuberculosis cases was 74 per 100,000 persons according to the Central Tuberculosis Research Institute in Moscow. Among the incarcerated population, which in 1997 comprised about 1,000,000 persons in this country of approximately 147,000,000, the tuberculosis incidence rate was 4,065 per 100,000 inmates. The Russian civilian tuberculosis mortality rate reported by the Institute was 17 per 100,000 and that in the prison population was 484 per 100,000, or 0.5%. According to the Central Office of the Penal System, in mid-1998 there were 92,000 prevalent tuberculosis cases among inmates, i.e., close to 10% of the inmate population had active tuberculosis. Transmission of Tuberculosis in the Russian Penal System

There are three levels of penal facilities within the Russian correctional system, and each level has its own method of managing tuberculosis among inmates. Entry into the correctional system takes place at the IVS, a detainment center within the local police stations. Newly arrested persons are held there and inmates who have been transferred to the next level, the pretrial detention centers, return there up to 10 times during their pretrial incarceration for investigative procedures. Both groups of inmates are held in the IVS for up to 30 days. No medical evaluation, treatment, or isolation of tuberculosis cases is available in these centers. Upon initial transfer to the detention center, inmates undergo fluorography for tuberculosis case detection and testing for HIV. Inmates diagnosed with active tuberculosis are usually isolated within a tuberculosis cell and treated with isoniazid and rifampin. The duration of incarceration in the detention centers ranges from 18 months to 5 years. Inmates undergo fluorography every 6–12 months to detect incident cases of tuberculosis. As noted above, inmates in the detention centers are repeatedly transported back to the IVS for investigative procedures. During their 10- to 14-day stay at the IVS, they receive no antituberculosis medication and are not isolated from the rest of the inmate population. After sentencing, inmates are transferred from the detention center to one of the regional prison colonies to serve their sentence. Inmates from the detention center known to have active tuberculosis are transferred to a specialized tuberculosis prison colony, where they are treated with four- or five-drug treatment regimens. The transfer to the specialized tuberculosis colony can take 6–8 weeks. During this time, inmates are either on the road or housed in detention centers along the route. They receive no medication and are not isolated from the general population at the transit detention centers. The prison population in the general nontuberculosis penal colonies undergo fluorography every 6–12 months, and any newly detected tuberculosis cases are then sent to the specialized tuberculosis colony, via the transit system, if beds are available. Currently the specialized

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tuberculosis colonies are filled, and newly diagnosed cases in the general penal colonies are neither isolated from the rest of the population nor given standardized treatment or in many cases no treatment while awaiting transfer. More worrisome is the fact that many receive mono-therapy with whatever inexpensive drugs the colony medical staff can obtain or whatever antibiotics the inmate’s family can purchase and send. The time to transfer can be months, and some inmates are treated with serial mono-therapy, first one antituberculosis antibiotic and then another, while awaiting transfer. Treatment of Tuberculosis

Treatment protocols in the specialized tuberculosis colonies are the same as those in the civil society, as issued by the Ministry of Health. However, the antibiotic supply within the prison system is severely depleted, and even if protocols call for multidrug therapy, such drugs are often not available. Thus, the Central Office of the Penal System reported that by international standards in mid-1998, two thirds of inmates were receiving inadequate therapy. An additional problem with treatment regimens is that even in areas where there are drugs available for appropriate four- or five-drug standard regimens, many inmates are failing treatment despite directly observed therapy. Adequate drug supplies are available in the Tomsk oblast specialized tuberculosis colony, where the British human rights organization MERLIN has been working for several years. However, preliminary drug susceptibility results from early 1998 indicated that among 54 “new” cases to the colony, only 43% had isolates susceptible to all first-line drugs, 26% had MDR-TB, while another 31% were resistant to one or two drugs but not both isoniazid and rifampin. Among 64 retreatment cases in this cohort, only 23% were pansusceptible, and 45% had MDR-TB. Medicins sans Frontiers is assisting in the specialized tuberculosis colony in Kemerovo oblast, Colony 33. Despite implementing a model directly observed therapy program with a standard five-drug initial treatment regimen (WHO category II), 40% of all smear-positive cases and 60% of all cases failed initial therapy. Preliminary susceptibility testing on isolates from inmates in Colony 33 showed 20% MDR-TB among new admissions to the colony. Risks Factors for Tuberculosis

The current increases in tuberculosis incidence and mortality in Russian civil and prison populations has not been associated with a documented increase in HIV infections. Malnutrition has been documented among inmates, where annual per capita expenditures are $26 and food rations are limited. All three levels of correctional facilities are overcrowded and poorly ventilated, but the IVS is the worst.

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Bock The Impact of Inmate Tuberculosis on the Civil Community

The average duration of incarceration in the penal colonies is 4 years. Once their sentence is served, inmates are released to the community without specific plans to continue any tuberculosis treatment or follow-up. No reliable data on the rate of loss to follow-up are available, although various authorities have estimated that between 50 and 80% of cases do not complete treatment once released. Among the factors that contribute to the poor follow-up rates is the stigma associated with tuberculosis, which can prevent persons with tuberculosis from finding work or housing. Also, many tuberculosis cases in civil society are hospitalized for months, which may not be appealing to persons just released from prison and trying to reestablish themselves in society. The impact of tuberculosis from penal institutions on the civil community is not limited to cases released prior to completing treatment and then lost to followup. Many inmates become infected with tuberculosis while incarcerated and only develop disease once released. In Kemerovo oblast, the civilian tuberculosis program reported that one third of their new 1997–1998 cases were among former inmates. As described above, many of these former inmates were exposed to inadequately treated tuberculosis cases in the IVS and detention centers, and there is concern that many of these new civilian cases will have drug-resistance patterns similar to the inmate population. Appendix B The Baku Declaration We the participants at the Baku TB in Prisons Meeting recognized that TB has become a major health threat to prisoners, and observing that often-incurable, drug resistant forms of TB are increasing in prisons, and further observing that the spread of HIV within prisons increases the risk of death from TB, and noting that TB in prisons easily spreads into the community from infectious prisoners and infectious prison staff, and acknowledging that adequately funded and staffed prison health services are essential to address the problem of TB in prisons call upon governments, through ministries of Justice and Interior and State and Health to work together toward providing prisoners with adequate health care, and the means to cure TB, and prison health services to implement DOTS and ministries of health to strengthen national TB programmes through application of DOTS strategy and warn that if there is no response to our call for action incurable TB will increase death among prisoners and their families and prison staff and the community (39). Baku, 9 July 1997

25 Tuberculosis Among Immigrants

MONA SARAIYA and NANCY J. BINKIN Centers for Disease Control and Prevention Atlanta, Georgia

I. Introduction Although most industrialized countries have relatively low prevalence rates of tuberculosis (TB), an increasing proportion of cases in many of these countries occur among foreign-born persons. This chapter will describe the epidemiology of TB among persons migrating from high-prevalence countries to those with lower prevalence and will highlight some approaches the low-prevalence countries have proposed and used to decrease TB among their foreign-born populations.

II. History of Migration of TB Historically, the incidence of TB began to increase in Western Europe in the early 1600s. With European migration to the Americas, Eastern Europe, sub-Saharan Africa, and Asia, the spread of TB to these areas began (1). TB was almost unknown within the interior of sub-Saharan Africa as late as 1908 (2), and it was not identified in New Guinea until 1920 (3). Today, countries where TB was once rare now account for the vast majority of the world’s TB cases, while countries that once had a high prevalence of TB now have low prevalence. Furthermore, the 661

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same factors of overcrowding and urbanization that contributed to the spread of TB in Europe continue to play an important role in the spread of TB in the developing world (1).

III. Definitions For purposes of this chapter, “low-prevalence country” will refer to the industrialized nations or the “established market economies” as defined by the World Bank, (4), including the United States, Canada, Western Europe, Israel, Australia, New Zealand, and Japan. Many, but not all, low-prevalence countries collect at least partial information on the geographic origin of their TB patients, although the definitions used are not consistent. Unless otherwise specified, the term “foreign-born” will be used to refer to persons born outside their country of residence. This definition is used in TB case reporting in the United States, Canada, Scandinavia, Australia, and Japan (Table 1). However, some European countries report by country of citizenship (i.e., nationality), and Great Britain collects data only on ethnicity, which is used as a proxy for country of birth. Other low-prevalence countries, including nearly half of the 41 countries participating in the European TB surveillance network (5), do not report on the origin of their TB patients, in some cases because its collection is illegal (6). Because of differences in the definition, caution is therefore needed in making comparisons between the statistics in various countries; the impact of foreign birth may be masked in countries that define geographic origin based on citizenship, while ethnicity may not always be an adequate surrogate for country of birth. For example, in the United States, where data on both ethnicity and country of birth are collected, there were substantial differences between foreign-born Asians and native-born Asians that might not have been noted if analysis was based on ethnicity alone (7). Foreign-born persons may include immigrants (legal or undocumented), refugees, asylum seekers, migrant workers, students, and other visitors. For the purposes of this chapter, the definitions employed by Rieder et al. (6) will be used; in this classification system, an “immigrant” is defined as a foreign-born person legally admitted and expected to settle in a host country. A “refugee” is defined as a person who meets the refugee definition of the 1951 Convention related to the Status of Refugees and its 1967 Protocol or other relevant regional instruments. An “asylum seeker” is defined as a person wishing to be admitted to a country as a refugee and awaiting decision on his or her application for refugee status under relevant international instruments. A “migrant worker” is defined as a person who is to be, is, or has been engaged in a remunerative activity in a state of which he or she is not a national. The term “indigenous” will generally refer to the native-born population of the country. However, some countries such as Canada and Australia further clas-

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Table 1 Tuberculosis Cases Among the Foreign-Born (FB) and Native-Born (NB) for Selected Countries

Country (year of data) North America United States (1996)b Canada (1995)c Western Europed Austria (1995) Belgium (1995) Denmark (1995) Finland (1995) France (1995) Germany (1995) Iceland (1995) Italy (1995) Luxembourg (1995) Netherlands (1996)e Norway (1995) Sweden (1995) Switzerland (1995) United Kingdom (1988)f Israel (1993)g Asia/Pacific Australia (1995)h Japan (1987–1992)i New Zealand (1985–1990)j a

How is FB defined?

% of TB cases among FB

COB COB

37 53

COC COC COB COB COC COC COB COC COB COC COB COB COC Ethnicity COB

24 33 55 30 28 29 1 10 50 52 41 56 53 39 93

COB COB Ethnicity

75 1.2 42

Crude rate ratio FB:NB

Incidence rate—FBa

Incidence rate—NBa

31.3 20.4

8.1 1.9

3.9 10.7

43.7

10.7

4.3

95.1 60.0 66.8

13.0 10.2 13.5

7.3 5.9 4.9

120 57.2 40.5 35.2 25.9–34.6

5.5 4.2 3.6 9.2 4.7

22 13.5 11.3 3.8 5.5–28.6

17.3 76 19.6–29.7

1.7 39 1.9

10.4 1.9 10.3–15.6

Rates are per 100,000 population. From Ref. 11. c Courtesy of Dr. Njoo, Health Canada. NB population is noted to be nonaboriginal native-born. d Percentage foreign-born for all Western European countries (except the Netherlands, United Kingdom, and Israel) (5). Case rates and rate ratios in Western Europe (except for Netherlands, United Kingdom, and Israel) are from 1992 report (6). e Dutch patients born abroad to foreign mother are included in the category of “foreign citizens” (15). f Foreign-born were defined as those of nonwhite ethnic origin. Incidence rates varied from 134.6 for those of Indian origin, 100.5 for those of Pakistani and Bangladeshi origin, 29.2 for those of West Indian origin, and 25.9 for those of other ethnic origin (39). g Percentage is based on 384 TB cases occurring among Jewish populations of which 93% were non–Israeli born. No data on country of origin was available for 35 cases which occured in the non-Jewish population (21). h Courtesy of Dr. Aileen Plant, University of Western Australia. Native-born includes aboriginal population. i From Ref. 24. j NB population was non-Maorian persons of European ethnicity (26% of whom were foreign-born). Foreign-born population was separated by Asian ethnicity—annual incidence of 29.7 (97% of whom were foreign-born) and Pacific Islander ethnicity—annual incidence of 19.6 (87% of whom were foreign-born) (93). b

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sify the native-born population into aboriginal and nonaboriginal populations since the TB experience of the two may be quite heterogeneous. “Extrapulmonary” TB refers to other than pulmonary TB, while “nonrespiratory,” often used in the British literature, refers to other than one or any combination of pulmonary TB, mediastinal lymphadenopathy, or pleural effusion. IV. Epidemiology of TB Among Foreign-Born Persons The reasons for the recent resurgence of TB in both developed and developing countries are complex and can be attributed to a wide variety of factors, including demographic shifts in the population, immigration, HIV, poverty, program decline, and drug resistance (8). While TB among foreign-born persons in lowprevalence countries has been a public health concern since the 1960s in Great Britain (9), it did not receive widespread attention in most countries until the TB resurgence in the past decade. In the United States, for example, data were not routinely collected on country of birth of TB patients until 1986, and it was not until TB rates began to increase in the early 1990s that the increasingly important role of foreign-born TB cases was fully recognized (7). Increased migration from high-prevalence countries to low-prevalence countries has contributed substantially to the stagnation and, in some cases, the increased TB rates seen in many low-prevalence countries. Available data on the percentage of TB cases among foreign-born persons and the TB incidence among foreign-born and indigenous populations of selected low-prevalence countries are shown in Table 1. At present, foreign-born cases account for a substantial fraction of total cases in many industrialized countries, ranging from less than 10% in Iceland and Japan to more than 50% in Canada, the Netherlands, Israel, and Australia. In all countries for which data are available, TB rates among foreign-born persons are approximately 2–30 times higher than those of the native-born population. Both the absolute number and the percentage of total cases among foreignborn persons are increasing in many low-prevalence countries. In some of these countries, the rates among foreign-born persons have increased as well. Figure 1a shows trends in the number of foreign-born and native-born TB cases for the United States, the Netherlands, Australia, and Canada, four countries in which a large proportion of TB cases are foreign-born and where consistent data are available on number and trends of foreign-born cases. Figure 1b shows the percentage of foreign-born cases in the four countries, and Figure 2 illustrates trends in total rates as well as the rates among the foreign-born and indigenous populations in three of these countries. The four countries share many common elements: a decline in TB cases in the early 1980s that was followed by no change or an increase that was at least in

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(a)

(b) Figure 1 Trends in (a) number and (b) percentage of TB cases among foreign-born persons for selected countries (foreign-born defined by country of birth except for Netherlands, where defined by country of citizenship). (Australia data courtesy of Dr. Aileen Plant, University of Western Australia. Canada data courtesy of Dr. Howard Njoo, Health Canada. U.S. data from Ref. 11. Netherlands data from Ref. 15.)

part attributable to immigration, and an increasing percentage of cases among the foreign-born population in the face of declining incidence rates in the indigenous population. In the United States, after decades of decline the incidence of TB began to level off in 1985 and in 1989 began to increase. Immigration was one of the major factors contributing to the increase in the late 1980s and was estimated to be responsible for at least 60% of the total increase in the number of U.S. cases from 1986 through 1992 (10). From 1993 to 1996, the incidence declined an esti-

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Figure 2 Tuberculosis case rates by origin for selected countries. (Foreign-born defined by country of birth except for Netherlands, where defined by country of citizenship. Case rates are not age-adjusted.) (Australia data from Ref. 16. U.S. data from Ref. 11. Netherlands data from Ref. 15.)

mated 6–7% annually (11). However, the recent decline has been limited to U.S.born persons, and until 1998 the number of foreign-born cases actually continued to increase. By 1998, there were 7591 foreign-born cases, representing 42% of the national total, compared to 4925 cases (22% of the total) in 1986 (12–14). In addition, during 1992–1998, while cases among U.S.-born persons decreased 38%, the number of foreign-born TB cases increased 4% (14a). Studies in the United States have shown that among foreign-born persons the incidence rate of TB was almost four times the rate for native residents of the United States (30.6 vs. 8.1 per 100,000 person-years) (7). TB trends in recent years in the Netherlands are similar to those of the United States, with a decrease in cases until the mid-1980s followed by an increase that appears to have reversed in 1994. Much of the increase appears to be among foreign-born persons; between 1984 and 1994, the number of Dutch cases actually decreased almost 20%, from 1052 to 845, while the number of non-Dutch cases increased more than threefold, from 309 cases in 1984 to 966 in 1994 (15). The decline noted between 1994 and 1996 has occurred in both groups, although it actually has been more substantial in the foreign-born than the Dutch population. By 1996, 52% of all TB cases were among non-Dutch persons, and the TB

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667

rate in this group was 120/100,000, 22 times higher than the rate of 5.5/100,000 in the Dutch population. In Australia, the number of TB cases and the incidence rate have been relatively stable since the mid-1980s. While the case rate among persons born in Australia has exhibited a steady decline from 2.8 cases per 100,000 in 1986 to 1.7 per 100,000 in 1995, the case rate among foreign-born persons has fluctuated and in recent years appears to have actually increased (16). In 1995, foreign-born persons accounted for 75% of all TB cases, a substantial increase over the 61% reported in 1986, and the rate among foreign-born persons is more than 10 times that of the Australian-born population. In Canada, both the number and percentage of TB cases among foreign-born persons have increased in the past decade, from 859 cases (40% of total cases) in 1985 to 1116 (58%) in 1995. Although annual incidence data for foreign-born persons are not readily available, the 1995 rate is more than 10 times that of the native-born Canadians. In Israel (Fig. 3), the number of TB cases and the case rate declined substantially in the 1970s and was stable until 1985, at which time a large wave of Ethiopian immigrants entered the country. In subsequent years, case rates decreased to a low of 3.5 per 100,000 in 1989 but rose to 10.2 in 1991 with the arrival of an additional 14,200 Ethiopians in 1991. The rate declined again in 1992 but has continued to increase in recent years as a result of continued migration from Ethiopia as well as a large migration from the former Soviet Union and has never returned to the levels achieved in the late 1980s. In 1993, the most recent

Figure 3 Incidence rate of active tuberculosis in Israel, 1960–1996, and the relation to the size of immigration waves. (Data from 1960 to 1986 from Ref. 17. Data from 1987 to 1996 courtesy of D. Chemtob, Israel Ministry of Health.)

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year for which a detailed breakdown of country of birth is available, the vast majority of cases were among foreign-born persons (D. Chemtob, personal communication). The reasons behind the differences between low-prevalence countries in the percentage of cases among foreign-born persons, the rates between the foreign-born and indigenous populations, and the trends are complex. As described below, they involve the overall percentage of the population in the low-prevalence country that is foreign-born, the country of origin of the immigrants, their current age as well as their age at immigration, the amount of time they have been in the new country, whether the immigrants return home periodically to their country of origin where exposure to TB is more likely, and whether active preimmigration or postimmigration screening is conducted in the host country. The TB epidemiology and decreasing trends of the indigenous population also influence the increasing proportion of TB seen among foreign-born persons.

A. Effect of Immigration Trends

The relationship between levels of recent immigration and TB can perhaps most clearly be seen in Israel, which has experienced a large influx of immigrants in recent years. The arrival of large numbers of Ethiopian immigrants in late 1984 and early 1985 increased the number of TB cases in 1985 by 40% compared with the previous year, and a second large wave in 1991 resulted in a doubling of the number of TB cases reported that year (17). In other countries, the effect is more subtle, but the increase in TB seen in the United States between 1986 and 1992 parallels an increase in immigration (Fig. 4) (7). The total percentage of the population that is foreign-born rather than recent immigration trends would appear to be more closely correlated with the contribution of foreign-born TB cases to total TB levels. Countries with large foreign-born populations, particularly those whose foreign-born populations were born in countries with a high prevalence, tend to have higher percentages of foreign-born TB cases. In Canada, Australia, and Israel, all of which report having more than half of their cases among foreign-born persons, a substantial proportion of the population is also foreign-born: 16% in Canada (18), 23% in Australia (A. Plant, personal communication), and more than 38% in Israel (O. Meir, personal communication). By contrast, however, 56% of all TB cases in the Netherlands were among the non-Dutch, who represent approximately 5% of the population (K. Lambregts, personal communication). In the United States, where the percentage of the population that was foreign-born increased from 7.9% in 1990 to 9.3% in 1996 (19), the percentage of cases among foreign-born persons increased during the same period from 25 to 37%.

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Figure 4 Number of legal immigrants according to year of admission (bars) and tuberculosis cases rates for U.S.-born (broken lines) and foreign-born (solid-line) persons. The black portions of the bars represent the number of illegal residents who were granted legal residence status under the provisions of the Immigration Reform and Control Act of 1986. (Adapted from Ref. 7. TB case rates (not age-adjusted) from Ref. 11. Number of legal immigrants from Ref. 26.)

B. Country of Origin

The countries of origin of the foreign-born population differ for each low-prevalence country and thus appear to influence the number and percentage of TB cases that are foreign-born. Where individuals choose to migrate is dependent on several factors: proximity, their countries’ previous colonial ties, family, work, and ease of immigration. Interestingly, some countries have a greater diversity of immigrants than others, which increases the complexity and amount of resources required for conducting timely identification of persons with TB infection and disease. Rates in foreign-born populations in industrialized countries tend to parallel rates among their compatriots that reside in their country of origin (20). In the United States, for example, immigrants from Mexico, the Philippines, Vietnam, the Republic of Korea, China, Haiti, and India accounted for approximately two thirds of all foreign-born cases in 1990–1996 (Fig. 5) (7). The age-adjusted rates of TB in immigrants from these countries range from 43.6 per 100,000 among persons from Mexico to 92 among immigrants from the Philippines and 176.8 among those from Vietnam (12,14), paralleling the rates observed in the countries themselves.

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Figure 5 Reported tuberculosis cases by country of origin, United States, 1990–1996 (2143 cases with unknown country of origin excluded). **Includes at least 132 countries. (From National TB Surveillance System, United States.)

In Israel, for example, recent immigrants have primarily come from Ethiopia, where TB rates are high, and from the former Soviet Union, where TB rates are moderate. Although the number of immigrants from the former Soviet Union was more than 13 times higher than the number of Ethiopians, Ethiopians accounted for 41% of TB cases between 1989 and 1993 compared with 15% for persons from the former Soviet Union (D. Chemtob, personal communication; 21). Country of origin of foreign-born populations may also influence the magnitude of the difference observed in Table 1 between TB case rates in the indigenous and foreign-born populations; countries such as Australia (16) and Canada (22), where the majority of immigrants are from countries in Asia with TB rates several times higher than those of industrialized countries, have greater disparity between the two rates than do countries such as Switzerland and Germany, where proportionately more immigrants may be from other European countries and the Middle East (23). This is also observed in Japan, whose immigrant population is from countries with rates more similar to its own (24). C. Chronological Age and Age at Immigration

In most low-prevalence countries, foreign-born cases tend to be younger than cases in their native-born population (5,25). In countries such as the United States,

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671

this partially reflects the age structure of the immigrant population (26). Additionally, it may reflect the characteristic distribution of TB in such countries, where the highest incidence is usually in adults between the ages of 15 and 59 years (27). Although the number of cases in younger immigrants tends to be higher, younger immigrants nonetheless tend to have lower TB case rates than older immigrants. This may be due to the declining trends in TB rates in many areas of the world (i.e., cohort effect), or it may reflect changes in the sociodemographic characteristics of migrant populations over time (14). Age at immigration also plays a role in the risk of TB among the foreignborn population; persons who migrated to a low-prevalence country at a young age tend to have rates more comparable to those of their new country than persons of the same age who migrated later in life (14). The longer lifetime experience overseas in countries where the annual risk of infection is high may result in a greater likelihood that persons will be infected and thus be at risk of developing TB at some point during their lives. D. Time in the Host Country

Multiple studies have shown that the risk of TB tends to decline with the number of years after immigration (9,20,28,29), although in most cases the rates remain higher than those for the indigenous population. Historically, British studies had determined that an increased incidence among foreign-born persons was limited to persons who had arrived less than 5 years previously. However, even though the incidence rates fall steadily with increased duration of residence in a lowprevalence country, TB rates often exceed that of the native population even 20 years after immigration (28,30). In the United States and elsewhere, TB rates among foreign-born persons are highest in the first year after arrival. These initially high rates may in part be an artefact of the various screening strategies for new immigrants or to increased access to health care in the new country, both of which detect prevalent cases (14,17), or they might also be due to war or refugee conditions in the country of origin. The overall decline over time is most likely related to lack of ongoing exposure to TB after immigration (14); the risk of developing active TB is greatest in the first 2 years after exposure, with a gradual decrease in risk after the initial infection (31). Overall, in the United States (7), Australia (32), and Canada (33), approximately 10–30% of the foreign-born cases were diagnosed in the first year of residence in the country, and a total of 51–60% were diagnosed within 5 years of arrival. These findings have major implications for strategies for TB control since efforts will be needed to provide adequate diagnostic and treatment strategies not only for new arrivals but also for long-term foreign-born residents.

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The relationship between birthplace, age, and time elapsed since immigration is complex. Fig. 6 shows 1986–1994 TB case rates in the United States by age and length of residence for persons born in the Philippines, Mexico, and Former Socialist Economies of Europe (FSE). In all three populations, TB incidence rates decreased with longer duration of residence and increased with older age. However, persons from the Philippines had rates of TB higher than 50 per 100,000 person-years in the first 5 years after their arrival regardless of their age, while for the FSE, only persons 75 years experienced such rates in the first 5 years of arrival (14). E. Ongoing Contact with the Country of Origin

Although the role of ongoing contact with the country of origin has not been well documented, a study in the 1980s suggested that 20% of Asian immigrants who developed TB in a 5-year period in the West Ham region of England did so as a result of a recent visit to Asia (33). In addition, studies in the United States, the Netherlands, and Australia have suggested that some of the increase in TB cases and infection among native-born children are attributable to infection acquired from visits to and from the country of origin (35–37). F. Clinical Patterns of Disease

Immigrants are more likely to have extrapulmonary TB than the indigenous populations. British studies have consistently reported over the past three decades a higher rate of nonrespiratory TB among persons of Indian subcontinent (ISC) ethnicity (those of Indian, Pakistani, and Bangladeshi origin) than among those of white ethnicity (9,29,38). Surveillance data have demonstrated that in Great Britain, where TB reporting is by ethnicity rather than race, persons of ISC ethnicity had rates of nonrespiratory TB 50 times higher than persons of white ethnicity (81 per 100,000 vs. 1.6) (39). Findings in the United States and Australia are similar. In the United States between 1993 and 1996, 21% of the foreign-born cases were extrapulmonary compared with 16% for the U.S.-born population. In Australia, the corresponding values were 41% and 23%. In Japan, by contrast, the proportions of extrapulmonary cases were virtually identical for the two groups (6% for foreign-born vs. 7% for Japanese-born) (24). Among the immigrant population, the percentage and type of extrapulmonary TB varied by country of origin. In the United States from 1993 to 1996, the percentage of all foreign-born cases that were extrapulmonary ranged from 17% among foreign-born TB cases from China to 42% among foreign-born cases from India; the most common form of extrapulmonary TB in the foreign-born populations was lymphatic TB. In British Columbia, Canada, the proportion of extrapulmonary cases varied greatly among Asian immigrants, from 20% among those from Japan to 54% among those from the Philippines. Additionally, the pre-

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A

B

C

D Figure 6 Rates of reported tuberculosis by place of birth, age, and length of residence in the United States, 1986–1994. (From Ref. 14.)

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dominant types of extrapulmonary TB differed as well; TB lymphadenitis accounted for 44% of TB cases among persons born in the Philippines but just 10% of cases among Japanese immigrants (and 6% among the indigenous population) (22). In Great Britain, all forms of extrapulmonary TB (lymphatic TB being the most common) besides genitourinary TB were more common in the ISC ethnic groups than in the white ethnic groups (38). In the United States, pulmonary TB among foreign-born cases is more likely to be smear- and culture-negative and to be defined on clinical rather than laboratory grounds (40,41). This pattern may reflect a greater likelihood on the part of clinicians to diagnose a patient coming from a high-prevalence country with pulmonary symptoms and an abnormal radiograph as having TB in the absence of laboratory verification. Among newly arrived immigrants that have been screened for TB abroad and may have sought treatment prior to their overseas examination, lack of bacteriological proof may result from partially treated TB. G. Access to Care Issues and Treatment Outcomes in ForeignBorn Persons

Many immigrants are faced with obstacles to seeking care and completing treatment that may predispose them to a higher risk of poor outcomes. Newly arrived immigrants often live in crowded and poor conditions, and some believe that the stress associated with migration may advance disease presentation (42–45). In addition, decreased access to care as a result of cultural, linguistic, and socioeconomic barriers, anti-immigrant sentiments and legislation (47,48), and fear of deportation (49) could potentially delay diagnosis and treatment. Indeed, delays of up to 8 months have been reported for undocumented aliens in California (46). A recent study of foreign-born Hispanic patients along the U.S.-Mexican border demonstrated a median delay of four months after symptom onset in seeking care (50). In the Netherlands, the diagnostic delay is actually shorter in foreign cases compared to Dutch cases, probably indicating that physicians are aware of an increased TB risk in patients from high-prevalence countries (51). Despite delays, the mortality rates were lower among foreign-born TB patients in the Netherlands, in part reflecting the younger age of the foreign-born population with TB (15). Furthermore, in the United States, overall completion rates were the same among U.S.-born (65.8%) and foreign-born TB (69%) cases (50) and for some immigrant groups were higher than among U.S.-born cases (A. Bloch, personal communication). In the United States, particularly in California, diagnosis and treatment of TB among foreign-born persons might become problematic; recent legislation (Proposition 187) requires publicly funded health-care providers to deny nonemergency care to undocumented immigrants and to report them to government officials (53). Such legislation and its associated media attention might actually lead

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to increased TB morbidity and mortality if persons with active TB delay seeking timely treatment and spread the disease to others. H. Contribution of HIV to TB Among Foreign-Born Persons

Few data exist on the relationship between HIV and TB among foreign-born residents of low-prevalence countries. In Israel, 15 (1%) of all patients tested between 1990 and 1993 were recorded as HIV positive; 13 of the 15 (87%) were from African countries. In the United States, the overall impact that HIV infection has had on TB among foreign-born persons has been minimal. U.S. TB and AIDS registry matching (conducted by the 50 states, New York City, and Puerto Rico) found that 14% of TB cases (reported from 1993 through 1994) were also co-infected with HIV. Only 15% of TB-AIDS cases were foreign-born in contrast to 33% of TB/non-AIDS cases (54). In a nationwide serosurvey of more than 19,000 TB patients conducted in major metropolitan areas in four regions of the United States between 1989 and 1996, 6% of 9400 foreign-born persons and 19% of 9995 U.S.-born persons tested were found to HIV seropositive (55). In one study in south Florida, however, the majority (75%) of the 54% of Haitian immigrants with TB who had been tested for HIV were positive (56). HIV is an excludable medical condition for entry into the United States, however, some HIV-positive immigrants have been allowed in the United States with a waiver. Due to limited data, we are unable to measure the impact that HIV as an excludable condition will have on TB among the foreign-born in the United States. HIV’s impact on TB is highly dependent on the prevalence of TB infection in segments of the population most susceptible to HIV infection (57), and in many high-prevalence countries the TB infection rates are increasing. Given the rising HIV rates in Africa and Asia and continued immigration from these areas, lowprevalence countries may be likely to see more of an impact of HIV infection on TB rates among foreign-born persons in the future. V. Drug Resistance The emergence of drug resistance to TB is not a new problem, but it has recently received more attention because of the numerous multidrug-resistant outbreaks noted in low-prevalence countries (58,59). Drug resistance is generally more common in the foreign-born populations than in the indigenous populations of lowprevalence countries, most likely reflecting inadequate treatment programs and sporadic drug availability in high-prevalence countries (60). In the United States, data from 1993 to 1996 demonstrated that levels of primary drug resistance to any TB drug (defined as resistance to a first-line drug: INH, rifampin, pyrazinamide, ethambutol, or streptomycin) was higher among foreign-born than among U.S.-born TB patients (17.6% vs. 10.1%) (Table 2) (61).

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Findings were similar in the Netherlands, where the overall rate of resistance was 9% in the foreign-born versus 18% in the Dutch patients (62). In Japan, by contrast, levels were similar in both the foreign-born and the Japanese TB patients (63). Levels of drug resistance among foreign-born persons in the United States and the Netherlands also differed by country of origin (Table 2). In the United Table 2 Percentage of TB Patients with Drug-Resistant Isolates by Country of Birth and Duration of Residence for Selected Countries Country (year of data) United States (1993–1996) a Overall native-born Overall foreign-born Mexico  1 year  1 year Unknown time Philippines  1 year  1 year Unknown time Vietnam  1 year  1 year Unknown time Netherlands (1993–1994)b Overall native-born Overall foreign-born Somalia Turkey Morocco Japan (1992)c Overall native-born Overall foreign-born a

% of new TB patients with drug resistance 10.1 17.6 16.1 18.9 16.3 14.5 18.4 20.4 18.4 16.3 27.4 29.7 27.2 24.9 9.0 18.0 26.0 20.0 13.0 5.6 4.8

From Ref. 61. In. Ref. 61, resistance is defined as resistance to one or more drugs (isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide). b From Ref. 62. In Ref. 62, resistance is defined as resistance to one or more drugs (isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide). c From Ref. 63. In Ref. 63, resistance is defined as resistance to any drug (isoniazid, rifampin, streptomycin, ethambutol, kanamycin). For new culture-positive cases, 21 foreign-born cases were tested.

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States, a higher proportion of resistance was seen among immigrants from the Philippines and Vietnam than among those from Mexico (61), while in the Netherlands, a higher proportion of resistance was seen among immigrants from Somalia, Turkey, and Morocco (64). Furthermore, in the United States, rates of drug resistance also varied by the amount of time in the country; persons who had been in the United States longer had lower levels of drug resistance than those who arrived more recently (Table 2). This pattern, also seen in the Netherlands (not shown), probably reflects resistance of TB acquired in the country of origin prior to immigration (64). VI. Contribution of Immigration to Transmission of TB in Low-Prevalence Countries A frequently raised concern about immigrants with TB is the risk they pose to the population of the host country. The risk is in part dependent on the amount of interaction between the foreign-born and indigenous populations. In many communities, first-generation immigrants live primarily in communities consisting of individuals from the same country, and contact with the native-born population is minimal, while in others there may be greater integration. Although the number of studies in this area is limited, most evidence suggests that the risk to the local population is low. Zuber et al. (30), in their study of TB among foreign-born persons in Hawaii, observed that the TB rate in the native-born population was 4.6 per 100,000, while that in the foreign-born population was nearly 30 times higher among Vietnamese persons and 60 times higher among Filipinos, suggesting that the risk posed by the foreign-born TB cases was minimal. Similar observations in which there is considerable disparity between the rates of TB among the indigenous and foreign-born populations have been made in Australia (16) and Israel (21). A recent study in Canada in which a cross-sectional tuberculin skin test survey of schoolchildren, health-care profession students, and young adults employed in various sectors was performed also failed to demonstrate a relationship between tuberculin positivity and contact with the foreign-born population as determined by various indices (65). DNA fingerprinting techniques using restriction fragment length polymorphism (RFLP) have proven useful in examining transmission between the foreign-born and indigenous populations. Studies have shown that among TB cases, U.S.-born cases were more likely the result of recent infection, while in the foreign-born population disease is more likely the result of activation of remotely acquired infection (66–68). By contrast, in the Netherlands, where foreign-born persons might be more closely integrated with the Dutch population, a study has shown that over a 2-year period, among Dutch patients with TB, 17% of cases were attributed to recent transmission from a non-Dutch source (69,70). One recent study in the San Francisco area identified transmission between the U.S.-born

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and the foreign-born population, but eight out of the nine clusters that involved both populations identified a U.S.-born person as the index case (71). The role of transmission within foreign-born communities after arrival in the United States is not clear. A considerably higher percentage of positive tuberculin skin tests among close contacts of foreign-born TB cases than among U.S.-born TB cases was documented in Seattle (50% vs. 18%), but it was unclear the extent to which this represented recent infection rather than infection acquired prior to immigration or possibly BCG cross-reactivity (72). The Dutch RFLP study identified some transmission of TB disease within the foreign-born community (69), as did a recent RFLP study in Montreal, Canada, which identified transmission within its Haitian community (K. Schwartzman, personal communication; 73). In addition, as mentioned in the section on ongoing contact with the country of origin, transmission from household contacts to U.S.-born children of immigrants has been demonstrated to contribute to increasing rates of pediatric TB in the United States (35). VII. Approaches to TB in the Foreign-Born The European Task Force has recommended a broad strategy for use in European countries that consists of five major elements: the use of surveillance system data to identify high-risk groups within the population; possible screening of high-risk foreign-born entrants for TB disease and for TB infection amenable to preventive intervention; utilization of existing governmental and nongovernmental organizations to provide services that are culturally and socially appropriate; provision of comprehensive curative and preventive services for TB treatment; and ongoing evaluation of the efficiency and efficacy of screening activities (6). A similar series of recommendations for use by state and local health departments has recently been developed in the United States (74). In this section, we will emphasize the strategies currently being used by low-prevalence countries for screening for TB disease and infection, present the available data on the yield of such screening, and finally identify some of the obstacles encountered in the provision of curative and preventive services in foreign-born persons. A. Screening

In low-prevalence countries, three broad screening strategies appear to be employed, either alone or in combination. These strategies include prearrival screening, postarrival screening (including at the port of entry), and screening of foreignborn populations that is done for other purposes but that potentially identifies foreign-born persons with infection or disease (e.g., school-based or preemployment screening). Foreign-born persons who are applying for immigration or who have recently arrived are the principal focus of active case-finding activities in many countries. As documented elsewhere in this chapter, TB rates are highest among

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recent arrivals. Furthermore, the process of applying for immigration or long-term residence provides a unique opportunity for such screening and may represent one of the few reliable points of contact with new arrivals. Most low-prevalence countries therefore conduct some form of pre- and/or postarrival screening of foreignborn persons, although the populations screened and the methods used vary considerably (Table 3). Most countries limit their screening to persons intending to Table 3 Tuberculosis Screening Programs for Immigrants and Refugees for Selected Countries

Country North America United Statesa

Screening system*

Screening method**

Target group

Time of screening

A

CXR TST

Immigrants

Prearrival Postarrival

A

CXR

Immigrants Long-term visitors (6 mos)

Prearrival Postarrival

A

CXR, TST

Foreign workers (asylum seekers)

At entrance

Belgium

A

CXR

At entrance

Denmark

P

CXR

Finland

A

CXR

France

A

CXR

Germany

A

Iceland

A

Ireland

P

Italy

A

CXR TST in children CXR TST CXR TST CXR

Asylum seekers Foreign workers All entering foreigners Asylum seekers Foreign workers All entering foreigners Asylum seekers Foreign workers

Luxembourg

A

Netherlands

A

Norway

A

Portugal

A

Spain

A

Canadab

Western Europec Austria

CXR TST CXR (TST) CXR TST CXR TST CXR TST

Utilization of preventive chemotherapy

Mandatory notification system

Contacts Children Adults Contacts Children Adults

Physicians Laboratories

Contacts Children Adults Fibrotic lesions Not used

Physicians

At entrance

Children

At entrance

Children

Physicians Laboratories Physicians

At entrance Before residence

(Children) (Adults)

Physicians Laboratories

All entering foreigners All entering foreigners Foreign workers

At entrance Before residence Variable

Physicians Laboratories Physicians

All entering foreigners Asylum seekers Foreign workers All entering foreigners Asylum seekers Foreign workers

At entrance Before residence At entrance Before residence At entrance Before residence At entrance Before residence

Children Adults Children Adults Children Adults Contacts Children Contacts Children No policy

At entrance

Contacts Children Contacts Children Adults

Physicians Laboratories

Physicians Physicians

Physicians Physicians Laboratories Mandatory (no details) Physicians Laboratories Physicians

continues

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Table 3

Continued

Screening system*

Country

A

Sweden

Screening method** TST CXR

Switzerland

A

CXR (TST)

United Kingdom

A

CXR

Israeld

A

CXR TXT

Asia/Pacific Australiae

A

CXR

Target group Asylum seekers Some foreign workers All entering foreigners outside EU and EFTA, North America, New Zealand, and Australia All entering foreigners Some immigrants

All immigrants from high risk countries Students 3 mos

Time of screening At entrance

At entrance Before residence

At entrance Before residence After entrance

Prearrival Postarrival

Utilization of preventive chemotherapy

Mandatory notification system

Contacts Children Adults

Physician Laboratories (voluntary)

Contacts Children Adults

Physicians Laboratories

Children Adults Contacts Children Adults No policy

Physicians (laboratories) Physicians

Physicians Laboratories

* In all countries, some refugees might be screened before entrance if the medical procedures are organized through the International Organization for Migration. ** Most countries use history and physicals as part of evaluation process. P  passive; A  active; CXR  chest x-ray or radiograph; TST  tuberculin skin test. a Source: From Ref. 75 b Source: N. Heywood, personal communication, 1997. c Source: From Ref. 6, except for Israel. d Source: S. Wartski, personal communication, 1997. e Source: A. Plant, personal communication, 1997.

become long-term residents, although others, such as Canada, screen all persons intending to stay more than 6 months, and still others, such as the Netherlands, screen all asylum seekers and foreign workers who intend to stay for more than 3 months. In the United States, the decision has been made to concentrate only on those who intend to reside permanently in the United States. This is in part due to the practical consideration of the impossibility of screening the large number of persons who enter the United States each year; in 1996, for example, more than 22 million visitors and 427,000 students entered the country (26). Prearrival Screening Methods

Some countries, including the United States, Canada, and Australia, conduct prearrival screening in which applicants must undergo a medical history, physical ex-

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amination, and a chest radiograph prior to being allowed to enter the country. Criteria for admission among those found to have an abnormal test differ between countries. In the United States, all radiographs consistent with active tuberculosis are followed by a sputum examination, which is usually based on microscopy rather than culture (75). Only those with a positive chest radiograph and a smear positive for acid-fast bacilli (AFB) are barred from entry until they either complete treatment or are smear negative and obtain a waiver allowing them to continue treatment in the United States. Those whose radiographs are abnormal but are sputum smear negative are allowed to enter the country but are referred to local health departments for further evaluation. Such reevaluation is recommended but is not a legal requirement for continued residence. The underlying philosophy of the overseas screening strategy is to limit entry of persons with infectious TB who pose an acute public health threat and to refer others with suspect TB for further evaluation and treatment in the United States, where generally there are better diagnostic facilities and where the quality of treatment can be more closely monitored. In Canada, the strategy differs slightly. Canada uses repeat radiographs (defined by two radiographs 3 months apart and not more than 6 months old) as part of the routine evaluation process. Individuals with a chest radiograph suggestive of active TB are required to submit sputum, gastric, or laryngeal specimens for smear and culture at the discretion of the immigration medical officer. Those with negative cultures or, at minimum, stable radiographic findings (6 months apart) are allowed to immigrate, while those with radiographic or microbiological evidence of active TB are not admitted to Canada until an adequate treatment regimen (at least 6 months of a regimen including at least isoniazid and rifampin or 12 months or longer of an alternative regimen) has been completed with evidence of three negative sputum cultures and/or evidence of stable or improving chest radiographs (33,76). Individuals who have radiographs consistent with inactive TB are placed under surveillance by the public health authority of the province of destination and are required to report within 30 days of entry into Canada (N. Heywood, personal communication; 77). Australia also uses chest radiograph and clinical examination as the basis of its screening. Smears, cultures, and a repeat radiograph 6 months later are conducted on all people with suspect TB based on clinical and chest radiographic evidence. If active TB is diagnosed, the applicant is not allowed to enter Australia until he receives treatment with standard TB therapy for 6 months with stable radiographic evidence. All immigrants who have a history of TB and have an abnormal chest radiograph must sign a statement before leaving their country of origin that they will agree to undergo surveillance in Australia and must report to health authorities within a specified period after their arrival in Australia (78). Israel, in response to the high case rates seen among Ethiopian immigrants, has instituted a program of preimmigration screening and treatment in that coun-

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try; persons found to have active TB undergo a course of directly supervised treatment prior to immigration (D. Chemtob, personal communication). However, immigrants coming from other areas continue to undergo postarrival, rather than prearrival, screening. Advantages of prearrival screening include prompt identification and treatment of persons who are infectious, stratification by risk of persons who are not currently infectious but might potentially reactivate, and decreasing the burden of screening on the health-care infrastructure of the low-prevalence country. Disadvantages include the difficulty of providing adequate supervision at the screening sites, varying diagnostic and laboratory capabilities (79), potential falsification of information, and possible change in TB status during the interval between the medical examination and arrival at the country of destination. In addition, assuring that postarrival follow-up occurs may be problematic, especially in countries such as the United States where failure to complete follow-up has no legal ramifications. Yield of Prearrival Screening

The yield of screening in terms of cases of active TB detected and the identification of candidates for preventive therapy 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. However, these percentages differ widely by country of origin; among newly arrived immigrants from Mexico, the corresponding figures were
0.005% and 0.07%, and among those from the Philippines, these values were 7.5% and 5.8%, respectively. Similarly, regional data in Canada showed that of the 21,586 immigrants who arrived in Manitoba, 2.4% (523) were placed on surveillance, most because of inactive TB (80). The number who are smear-positive and undergo partial or complete treatment prior to arrival is small; an estimated 50 persons who have been treated and have had a negative smear but have not yet completed a full course of therapy apply for a waiver to complete their therapy in the United States, with an unknown additional number of persons completing therapy and reapplying for entry. A study of radiographic screening followed by sputum microscopy of prospective migrants and refugees from Vietnam bound to the United States, Australia, and Canada showed that of 39,581 persons screened, 322 were smear positive (641 per 100,000), 82% of whom were cured with short-course chemotherapy and directly observed therapy prior to departure (81). A high percentage of those whose radiographs are compatible with both active and inactive TB receive follow-up in the United States (79), though figures vary from state to state and have increased in recent years as a result of increased awareness of the importance of foreign-born TB cases in the United States.

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Among those whose radiographs are compatible with suspect active TB upon follow-up, between 3.3% and 14% were diagnosed as having TB on laboratory and/or clinical grounds. The variation between sites in the United States was due in part to the case definitions used for TB; those that based diagnosis on strict laboratory criteria had lower rates of disease than those that relied more heavily on the accepted clinical criteria (82). For those with radiographs compatible with inactive TB, the percentage diagnosed as having TB ranged from 0.4% to 3.8%. Regional data from Canada show that 3% of persons under surveillance were diagnosed with active TB in the first year and an additional 2% in the 3–5 years following arrival (80). Among those with abnormal radiographs who were not found to have active TB when evaluated in the United States, a number were candidates for potential treatment of latent TB infection by virtue of an abnormal radiograph and a positive tuberculin skin test. A study in Seattle identified over a third of newly arrived immigrants who had an abnormal radiograph but not active TB overseas to be eligible for treatment of latent TB infection (see Chap. 18) (72). Postarrival Screening Methods

In European countries that systematically screen foreign-born persons, the screening is usually conducted after arrival. In the United States, Canada, and Australia, such screening is also performed on persons who have entered the country under other visa categories or who enter as asylum seekers. In the United States in recent years, the number of persons screened postarrival has been similar to the number screened before arrival. In Europe and Israel, immigrants tend to arrive in the country at a limited number of sites and must go through screening to obtain access to health and social benefits and to obtain permission to work, assuring good compliance with the screening. In England, screening is done at the port of entry with a radiograph, with notification to the local health consultant of the name and address of the immigrant. The local health consultant is responsible for ensuring that adequate screening is undertaken. About 50% of new immigrants are adequately screened through the postarrival process (83,84) because very few immigrants get radiographs on arrival and the address they provide is often a staging address. In other countries such as Switzerland, where most immigrants are seeking refugee status (asylum seekers), examination at the border consists of a 3- to 8-day stay where a chest radiograph of those older than 15 years and tuberculin skin testing take place. Those with an abnormal radiograph or positive tuberculin test are referred to local centers for treatment (23). An increasing number of persons in the United States have already been living in the country for several years at the time of their application for permanent residence. This population is also screened, but using methods different from

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those used in the overseas screening. The U.S.-based screening is somewhat different in its focus in that it is based on tuberculin skin testing (TST) (Chap. 12), which has the advantage of identifying not only those with active disease but also those with TB infection who may be candidates for treatment of this latent infection. The screening, which is conducted by licensed physicians appointed by the Immigration and Naturalization Service, consists of a tuberculin skin test, with a low threshold for obtaining a chest radiograph (5 mm reaction). Those with abnormal radiographs and persons with 10 mm induration on TST are to be referred for further evaluation for treatment or for preventive therapy by local health departments (85). Both Canada’s and Australia’s postarrival screening consists of a history and medical exam combined with a chest radiograph (N. Heywood and A. Plant, personal communications). The advantages of postarrival screening are that the control of the quality of the examination process may be easier and a broader range of laboratory services (e.g., culture and susceptibility testing) results in better diagnostic capabilities and more focused treatment. Furthermore, at least in the United States, the supervision of treatment may be better than for immigrants who are screened prearrival and are found to have infectious TB and are responsible for obtaining their own treatment. Finally, persons identified with suspected TB or who are candidates for treatment of latent infection can be more readily referred for initiation of treatment or treatment of latent infection. Disadvantages, however, are that it requires a system that allows the prompt identification of newly arrived persons and may be costly for the health-care system to conduct. Yield of Postarrival Screening

In the Netherlands, 0.3% of asylum seekers in 1996 were found to have active TB (15). In Switzerland, Zellweger et al. found that 1763 (7.2%) of the 24,156 asylum seekers screened in 1993 had abnormal chest radiographs and 83 (0.3%) had active TB (23). A tuberculin reaction of 10 mm was observed in approximately a third of asylum seekers tested, and the distribution of the TST reaction sizes were similar among both subjects with active TB and those with normal chest radiographs. Regional data from England showed that the yield of active TB among immigrants at entry was 6.5 cases per 1000. Of these immigrants, 30% of those under age 30 had negative tuberculin skin tests and were given BCG vaccination. Furthermore, 12% of the children in this population were eligible for chemoprophylaxis (84). Although as many as 400,000 persons undergo postarrival screening in the United States each year, limited data are available on the results of postarrival screening. A study in Denver identified only four cases of active TB from 7500 persons evaluated but found a high crude prevalence (42%) of TB infection among this predominantly Mexican population. In addition, of the approximately 1000 candidates identified as being eligible for treatment of latent infection, 70% completed such treatment (86). The relatively low yield of persons with active TB

Tuberculosis Among Immigrants

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in this group may have resulted from the fact that most were from a moderateprevalence country and many of the applicants applying for permanent residence have been in the United States for a number of years at the time of application and may already have been diagnosed if they had active disease. Furthermore, their risk of new infection during their U.S. residence was likely to have been lower than the risk they may have faced had they remained in their countries of origin. Other Screening Activities

Pre- and postarrival screening programs are useful for identifying new immigrants with active TB. However, foreign-born persons may belong to groups such as students who are not routinely screened, may be illegal immigrants, or may have entered before systematic screening programs were instituted. In Los Angeles, for example, less than 5% of TB cases from Mexico and Central America who had been in the United States less than a year at the time of diagnosis had been identified through prearrival screening (87). Furthermore, a substantial proportion of immigrants from high prevalence countries will have latent TB infection but not disease at the time of immigration and will be at continued risk of developing disease unless they receive treatment for latent infection. Indeed, in the United States, Australia, and the Netherlands (14–16), the majority of foreign-born TB cases occur in persons who have been in the country 5 years or more at the time of diagnosis. The number of infected persons is considerable; in the United States, for example, it is estimated that at least 8 million foreign-born persons (one third of the 24 million total) are latently infected with TB and, conservatively, that 160,000–240,000 (2–3%) will develop disease some time after immigration unless they complete a regimen of preventive treatment of latent infection. The screening of foreign-born persons for disease and infection and the provision of treatment for latent infection in low-prevalence countries with large foreign-born populations are hindered by the large number of persons to be screened, difficulties in gaining access to persons who should be screened, the lack of screening tools with high sensitivity and specificity, and, in the case of tuberculin skin testing, the perceived difficulty of diagnosing TB infection in persons who have been BCG-vaccinated, particularly if they have received multiple doses (see Chap. 19). Furthermore, screening is not recommended unless an intervention is to be undertaken, and even in countries where treatment of latent TB infection is a well-recognized intervention, efforts to initiate large-scale screening programs to identify additional foreign-born persons with TB infection may be impeded by insufficient resources to ensure completion of this treatment. Decisions by low-prevalence prevalence countries regarding screening for active disease and for infection should be based on information about the foreignborn populations of their countries and their risk of disease (88). The screening of foreign-born persons should be selective, however, taking into account not only such factors as country (or region) of origin, age at arrival, and length of residence, all of which appear to influence risk of disease, but also accessibility for

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screening, and likelihood of completing treatment for latent infection if the screening is meant to identify infection as well as disease. Screening sites might include schools, job sites, health departments, private providers’ offices, or community clinics. Possible groups for screening might include new school entrants from high-prevalence countries, adults enrolled in language or other classes for newly arrived immigrants, or possibly persons in occupations with large numbers of foreign-born persons from high-prevalence countries (e.g., food handlers, hotel staff, poultry industry workers). In conducting such screening, care must be taken to avoid stigmatizing those that are foreign-born. For this reason, comprehensive strategies that do not specifically target foreign-born persons (such as screening by occupational category) may be preferable in some countries. In addition, care is needed to assure that screening is conducted in such a way as to avoid a real or perceived fear of deportation among those found to have disease or infection.

B. Provision of Treatment and Preventive Services in ForeignBorn Persons

Because of the high level of drug resistance in some high-prevalence countries, drug-susceptibility testing should be an important component of TB diagnosis among foreign-born persons. In the United States, it is recommended that foreignborn persons be placed on an initial four-drug regimen pending results of susceptibility testing (89,90). Isoniazid resistance is high in many high-prevalence countries, and the issue has been raised of the adequacy of isoniazid for treatment of latent TB infection among the foreign-born population. At present, unless an individual is a contact of a person with known drug resistance, isoniazid remains the drug of choice. In both treatment of disease and latent infection, understanding cultural sensitivities about TB is important. In many cultures, TB is stigmatized (46,91,92), and care should be taken to provide appropriate education to patients and their families about the nature of the disease and its treatment. Treatment of latent infection may be particularly problematic since the concept of treatment for an asymptomatic condition may be new to many foreign-born persons. Outreach workers who speak the same language as the foreign-born patients and who preferably are from the same communities may improve the outcomes of treatment of disease and latent infection. As low-prevalence countries approach the elimination phase for tuberculosis, attention naturally becomes focused on the prevention and treatment of the high-risk populations for TB, including immigrants from high-prevalence areas. In this chapter, we have summarized some shared epidemiological trends among the immigrant populations, but we also have highlighted the many complexities involved with epidemiology of tuberculosis among the foreign-born population

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that make generalizations difficult. Because the characteristics, outcomes, and access to care issues of the immigrant population vary from country to country, and in most cases differ locally, TB control efforts must be tailored to meet these needs locally in a culturally appropriate manner. Furthermore, global efforts are needed to reduce the TB burden in developing or high-prevalence nations if TB elimination is to be achieved in the industrialized or low-prevalence nations. References 1. Daniel TM, Bates JH, Downes KA. History of tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection, and Control. Washington, DC: ASM, 1994:13– 25. 2. Cummins SL. Tuberculosis in primitive tribes and its bearing on the tuberculosis of civilized communities. Int J Public Health 1920; 1:137–171. 3. Brown P, Cathala F, Cajdusek DC. Mycobacterial and fungal sensitivity patterns among remote population groups in Papua New Guinea and in the Hebrides, Solomon and Caroline Islands. Am J Trop Med Hyg 1981; 30:1085–1093. 4. World Bank. World Development Report 1993: Investing in Health. New York: Oxford University Press, 1993. 5. Euro TB (CESES/KNCV) and the national coordinators for tuberculosis surveillance in the WHO European Region. Surveillance of Tuberculosis in Europe. Report on the Feasibility Study (1996–1997). Tuberculosis Cases Notified in 1995. Paris: WHO, 1997. 6. Rieder HL, Zellweger JP, Raviglione MC, Keizer ST, Migliori GB. Tuberculosis control in Europe and international migration. Eur Respir J 1994; 7:1545–1553. 7. McKenna MT, McCray E, Onorato I. The epidemiology of tuberculosis among foreign-born persons in the United States, 1986–1993. N Engl J Med 1995; 332:1071– 1076. 8. Parry C, Davies PDO. The resurgence of tuberculosis. Soc Appl Bacteriol Symp Ser 1996; 25:23s–26s. 9. British Tuberculosis Association. Tuberculosis among immigrants to England and Wales: a national survey in 1965. Tubercle 1966; 47:145–156. 10. Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994; 272:535–539. 11. Reported Tuberculosis in the United States, 1996. Atlanta: Centers for Disease Control and Prevention, 1997. 12. McCray E., Weinbaum CM, Braden CR, Onorato IM. The epidemiology of tuberculosis in the United States. Clin Chest Med 1997; 18:99–113. 13. Centers for Disease Control and Prevention. Tuberculosis morbidity—United States, 1996. MMWR 1997; 46:695–699. 14. Zuber PL, McKenna MT, Binkin NJ, Onorato IM, Castro KG. Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 1997; 278:304–307. 14a. Centers for Disease Control and Prevention. Progress toward the elimination of tuberculosis—United States, 1998. MMWR 1999; 48(33):732–736. 15. Index Tuberculosis 1996. The Hague: Royal Netherlands Tuberculosis Association (KNCV), 1997.

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16. Oliver G, Harvey B. Tuberculosis notification in Australia, 1995. Commun Dis Intell 1997; 21:261–269. 17. Wartski SA. Epidemiology and control of tuberculosis in Israel. Public Health Rev 1995; 23:297–341. 18. Wilkins K. TB incidence in Canada in 1992. Health Reports 1994. Stat Can 1994; 6:301–309. 19. Hansen KA, Faber CS. Current Population Reports: The foreign-born population 1996. U.S. Census Bureau Economics and Statistics Administration, U.S. Dept. of Commerce, 1996. 20. Enarson D., Ashley MJ., Grzybowski S. Tuberculosis in immigrants to Canada. Am Rev Respir Dis 1979; 119:11–18. 21. Israel Ministry of Health. Tuberculosis in Israel. Jerusalem: Ministry of Health, 1994. 22. Wang JS, Allen EA, Enarson DA, Grzybowski S. Tuberculosis in recent Asian immigrants to British Columbia, Canada: 1982–1985. Tubercle 1989; 72:277–283. 23. Zellweger JP, Raeber PA, Desgrandchamps D, Helbling P. Screening for Tuberculosis Among Asylum Seekers Entering Switzerland. Hague: Tuberculosis Surveillance Research Unit, 1997. 24. Ishikawa N. [Tuberculosis among new immigrants in Japan..epidemiological, clinical, and sociological features, and the future of control] [Japanese]. Kekkaku 1995; 70:691–703. 25. Williams HE, Phelan PD. The epidemiology, mortality, and morbidity of tuberculosis in Australia: 1850–94. J Paediatr Child Health 1995; 31:495–498. 26. U.S. Immigration and Naturalization Service. Statistical Yearbook of the Immigration and Naturalization Service, 1996. Washington, DC: U.S. Government Printing Office, 1997. 27. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention, and cost. Bull Int Union Against Tubercl Lung Dis 1990; 65:2–19. 28. British Thoracic and Tuberculosis Association. Tuberculosis among immigrants related to length of residence in England and Wales. BMJ 1975; 3:698–699. 29. Medical Research Council Cardiothoracic Epidemiology Group. National survey of notifications of tuberculosis in England and Wales in 1988. Thorax 1992; 47: 770–775. 30. Zuber PL, Binkin NJ, Ignacio AC, Marshall KL, Tribble SP, Tipple MA, Vogt RL. Tuberculosis screening for immigrants and refugees. Diagnostic outcomes in the state of Hawaii. Am J Respir Crit Care Med 1997; 154:151–155. 31. Styblo K. The relationship between the risk of tuberculous infection and the risk of developing infectious tuberculosis. Bull Int Union Tuberc 1985; 60:117–119. 32. MacIntyre CR, Dwyer B, Streeton JA. The epidemiology of tuberculosis in Victoria. Medical Journal of Australia 1993; 159:672–677. 33. Orr PH, Hershfield ES. Tuberculosis in foreign-born in North America. In: Reichman LB., Hershfield ES., eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, 1993:531–550. 34. McCarthy OR. Asian immigrant tuberculosis-the effect of visiting Asia. Br J Dis Chest 1984; 78:248–253. 35. Kenyon T, Driver C, Haas E, Valway SE, Moser KS, Onorato IM. Immigration and tuberculosis among children on the United States–Mexico Border, County of San Diego, California, from 1985 to 1993 [abstr]. Abstracts of the 35th Interscience Con-

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55. Schneider E, McCray E, Onorato IM. HIV Seroprevalence among TB clinic patients in the U.S., 1986–1996 [abstr]. 1997 American Thoracic Society Meeting, San Francisco, May 16–21, 1997. 56. Granich RG, Zuber PL, McMillan M, Cobb JD, Burr J, Sfakianaki ED, Fussell M, Binkin NJ. Tuberculosis among foreign-born residents of southern Florida. Public Health Reports 1998; 113(6):552–556. 57. Rieder HL. Tuberculosis and human immunodeficiency virus infection in industrialized countries. In: Davies PDO ed. Clinical Tuberculosis. London: Chapman and Hall, 1994:227–233. 58. Alland D, Kalkut GE, Moss AR, McAdam RA, Hahn JA, Bosworth W, Drucker E, Bloom BR. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994; 330:1710– 1716. 59. Agerton T, Valvay S, Gore B, Gore B, Pozsik C, Plikaytis B, Woodley C, Onorato I. Transmission of a highly drug-resistant strain (strain W1) of Mycobacterium tuberculosis. JAMA 1997; 278:1073–1077. 60. Iseman MD, Starke J. Immigrants and tuberculosis control. N Engl J Med 1995; 332:1094–1095. 61. Moore M., Onorato IM, McCray E, Castro KG. Trends in drug-resistant tuberculosis in the United States, 1993–1996. JAMA 1997; Vol. 278:833–837. 62. Lambregts-van Weezenbeek CSB, Jansen HM, Nagelkerke NJD, Van Klingeren B, Veen J. Nationwide surveillance of drug-resistant tuberculosis in the Netherlands: rates, risk factors, and treatment outcome. Int J Tuberc Lung Dis 1998; 2(4):288–295. 63. Hirano K, Y Kazumi, Abe C, Mori T, Aoki M, Aoyagi T. Resistance to antituberculosis drugs in Japan. Tuberc Lung Dis 1996; 77:130–135. 64. Lambregts-van Weezenbeek CSB, Jansen HM, Veen J, Nagelkerke NJD, Sebek MMGG, Van Soolingen D. Origin and management of primary and acquired drug-resistant tuberculosis in The Netherlands; the truth behind the rates. Int J Tuberc Lung Dis 1998; 2(4):296–302. 65. Menzies R, Amyot D. The determinants of the prevalence of tuberculous infection among young adults in Montreal (abstr A396). Am Rev Respir Dis 1989; 139:142. 66. Friedman CR, Stoeckle MY, Kreiswirth BN, Johnson WD Jr., Manoach SM, Berger J, Sathianathan K, Hafner A, Riley LW. Transmission of multidrug-resistant tuberculosis in a large urban setting. Am J Respir Crit Care Med 1995; 152:355–359. 67. Chin DP, DeRiemer K, Small PM, de Leon AP, Steinhart R, Schecter GF, Daley CL, Moss AR, Paz EA, Jasmer RM, Agasino CB, Hopewell PC. 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. 68. Small P, Hopewell P, Singh SP, Samir P, Paz A, Parsonnet J, Ruston D, Schecter GF, CL. Daley, Schoolnik GK. The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703–1709. 69. Borgdorff MW, Nagelkerke N, van Soolingen D, de Haas PE, Veen J, van Embden JD. Analysis of tuberculosis transmission between nationalities in the Netherlands in the period 1993–1995 using DNA fingerprinting (review). Am J Epidem 1998; 147(2):187–195.

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70. Borgdorff MW., Nagelkerke N., van Sooligen D., de Haas PEW, Veen J., van Embden JDA. Transmission Dynamics of Tuberculosis Within and Between Subpopulations in The Netherlands. Hague: Tuberculosis Surveillance Research Unit, 1997. 71. Jasmer RM, Ponce de Leon A, Hopewell PC, Alarcon RG., Moss AR, Paz EA, Schecter GF, Small PM. Tuberculosis in Mexican-born persons in San Francisco: reactivation, acquired infection and transmission. Int J Tuberc Lung Dis 1997; 1(6):536–541. 72. Wells CD, Zuber PLF, Nolan CM, Binkin NJ, Goldberg SV. Tuberculosis prevention among foreign-born persons in Seattle-King County, Washington. Am J Respir Crit Care Med 1997; 156:573–577. 73. Schwartzman K, Culman K, Tannenbaum T, Brassard P, Thibert L, Kunimoto D, Fitzgerald JM, Menzies D. Tuberculosis in young Montrealers, 1992–1994, RFLP analysis [abstr]. Am J Respir Crit Care Med 1997; 155:A227. 74. Workgroup of TB in Foreign-Born Persons. Report of Working Group on TB in Foreign-Born Persons. Atlanta: CDC and State TB Controllers, 1998. 75. Centers for Disease Control and Prevention. Technical Instructions for Medical Examination of Aliens. Atlanta, 1991. 76. Immigration Medical Services. Medical Officer’s Handbook. Ottawa, Canada: Immigration Medical Services, Medical Services Branch, Department of National Health and Welfare, 1995. 77. Canada Communicable Disease Report. Guidelines for the investigation of individuals who were placed under surveillance for tuberculosis post-landing in Canada. Can Med Assoc J 1992; 148:1957–1958. 78. King K, Dorner RI, Hackett BJ, Berry G. Are health undertakings effective in the follow-up of migrants for tuberculosis? Med J Aust 1995; 163:407–411. 79. Binkin NJ, Zuber PL, Wells CD, Tipple MA, Castro KG. Overseas screening for tuberculosis in immigrants and refugees to the United States: current status. Clin Infect Dis 1996; 26:1226–1232. 80. Orr PH, Manfreda J, Hershfield ES. Tuberculosis surveillance in immigrants to Manitoba. Can Med Assoc J 1990; 142:453–458. 81. Centers for Disease Control and Prevention. Case definitions for public health surveillance. MMWR 1990; 39:1–43. 82. Keane VP, O Rourke, TF, Bollini P, S Pampallona, H Siem. Prevalence of tuberculosis in Vietnamese migrants: the experience of the Orderly Departure Program. Southeast Asian J Trop Med Public Health 1995; 26:642–647. 83. Davies PDO. Tuberculosis in immigrants, ethnic minorities and the homeless. In: Davies PDO, ed. Clinical Tuberculosis. London: Chapman and Hall, 1994:191–209. 84. Ormerod LP. Tuberculosis screening and prevention in new immigrants 1983–1988. Respir Med 1990; 84:269–271. 85. Centers for Disease Control and Prevention. Technical instructions for medical examination of aliens in the United States. Atlanta, GA: Centers for Disease Control, 1991. 86. Blum RN, Polish LB, Tapy JM, Catlin BJ, Cohn DL. Results of screening for tuberculosis in foreign-born persons applying for adjustment of immigration status. Chest 1993; 103:1670–1674. 87. Zuber PL, Knowles LS, Binkin NJ, Tipple MA, Davidson PT. Tuberculosis among foreign-born persons in Los Angeles County, 1992–1994. Tuberc Lung Dis 1996; 77: 524–530.

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88. Qualls N, Taylor Z, Binkin N, Saraiya M, Nguyen C. A decision analysis of screening for Tuberculosis among immigrants prior to arriving in the U.S. (abstr). International Union Against Tuberculosis and Lung Disease, North American Region, Vancouver, Canada, February 1998. 89. Centers for Disease Control and Prevention. Tuberculosis among foreign-born persons entering the United States. Recommendations of the Advisory Committee for Elimination of Tuberculosis. MMWR 1990; 39(RR-18):1–21. 90. Centers for Disease Control and Prevention. Tuberculosis among foreign-born persons who had recently arrived in the United States—Hawaii, 1992–1993, and Los Angeles County, 1993. MMWR 1995; 44:703–707. 91. Carey JW, Oxtoby MJ, Nguyen LP, Huynh V, M Morgan, Jeffery M. Tuberculosis beliefs among recent Vietnamese refugees in New York State. Public Health Rep 1997; 12:66–72. 92. Nichter M. Illness semantics and international health: the weak lungs/TB complex in the Philippines. Social Sci Med 1994; 35:649–663. 93. Stehr-Green, JK. Tuberculosis in New Zealand, 1985–90. NZ Med J 1992; 939: 301–303.

26 Coalition Building for Tuberculosis Control The Philippine Experience CAMILO C. ROA, JR.

RODRIGO L. C. ROMULO

University of the Philippines College of Medicine Manila, Philippines

University of Santo Tomas Manila, Philippines

I. Coordinating Tuberculosis-Control Efforts: The Need for Coalitions The control of tuberculosis (TB) remains a formidable task, particularly in developing countries with limited resources. Independent TB-control efforts may be taking place at various levels—national and local, public and private, medical and nonmedical. If these efforts are not coordinated there may be wastage of valuable resources. Organizing these fragmented, uncoordinated, and possibly conflicting movements appears to be crucial in achieving the ultimate objective of TB control. Although the World Bank (1) has shown that the chemotherapy of TB is one of the most cost-effective health interventions available to governments, countries that have high TB prevalence rates would still require significant resources in order to develop effective TB-control programs. Ironically, TB is generally more prevalent in countries where such resources are scarce and there are other competing priorities. One front on which the battle against TB should be fought is in convincing national leadership to invest adequate resources in TB control. The World Health Organization (WHO) (2) has decried that TB is not a priority in most countries, both rich and poor. In many highly endemic countries, national control programs either do not exist or are of limited coverage. Where political will is lacking or when a comprehensive anti-TB program cannot be fully imple693

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mented, TB control will be difficult to attain. One major effort, therefore, in TB control is lobbying within a nation’s governmental structure for resources to develop and optimize a national TB-control program. Where a large private for-profit health provider sector exists, government programs may not reach the upper and middle classes. Such is the situation in the Philippines, India, Pakistan, South Korea, and Taiwan, where independent, popular, and highly influential private for-profit medical practitioners exist. Strengthening the national program under these circumstances should include not only the underprivileged but paying patients as well. This would require recruiting private medical practitioners, traditionally a loosely (if at all) regulated group, to participate in the national program. The WHO’s annual Tuberculosis Notification Update (3) consistently ranks the Philippines among the highest in the world in terms of TB case report rates. Local surveillance studies (4,5) consistently show high rates of multidrug-resistant tuberculosis (MDR-TB) in that country. Clearly, collective TB-control efforts in the Philippines have failed and must be changed. Undoubtedly, the political and socioeconomic milieu has influenced the outcome of previous TB-control efforts, but correcting these factors will take time. The specter of an incurable TB epidemic on the horizon warns us that we cannot merely wait for these changes. Innovative approaches like National Tuberculosis Program (NTP) policy changes and recruiting nongovernmental TB interest groups may provide the necessary shortcut.

II. TB Interest Groups In the Philippines, the organizations with special interest in TB include the government through its Department of Health TB Control Service, physicians groups, medical specialty societies, medical school groups, civic organizations, religious organizations, pharmaceutical companies, and other business organizations. Some of these groups have been organized to do TB work. Others are interested in TB as part of a wider concern. Individual participation is often voluntary, although some groups have salaried administrative staff. In general, all these groups are highly motivated, but their activities are limited to that aspect of the TB problem that crosses their path. Private physicians encounter TB on a case-to-case basis, so physician groups would focus on diagnosing and treating individual patients rather than organizing a coordinated TB-control program. For example, the “consensus on childhood tuberculosis” recently developed by Philippine pediatricians presents simple clinical diagnostic and treatment guidelines for general practitioners. Medical school and medical specialty societies conduct management update work-

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shops and seminars for private physicians and paramedical personnel. The TB-related activities of pharmaceutical companies would naturally be related to promoting their own antituberculosis products, although many may also provide genuine physician education. The importance of private for-profit physicians in countries like the Philippines must be emphasized. Several surveys in the Philippines (6) have consistently shown that roughly one third of those with symptoms compatible with TB who seek health care consult private physicians. In 1997, a National Tuberculosis Prevalence Survey (7) was conducted in which 21,960 Filipinos identified by stratified multistage sampling were studied. In this survey, 36.2% of those with TB-like symptoms who sought health care consulted private physicians. Only 24.5% utilized the government health services. The preference for private physicians may be because they are perceived to be better trained, more accommodating, and have more flexible office hours. In addition, perhaps because of the “privacy,” visiting a private physician’s clinic is less likely to produce stigmatization. However, private medical practitioners in the Philippines do not follow a standard protocol in the diagnosis and treatment of TB. They do not maintain registries of TB cases, nor do they report cases to the Department of Health. They are free to prescribe any anti-TB medication available in the market to patients that they “diagnose” as having TB. Often these diagnoses are based on symptoms or chest radiograph findings alone. Private physicians overwhelmingly prefer chest radiographs to sputum acid-fast smears for diagnosis. The therapeutic regimens used by the private physicians have been noted to vary greatly, frequently qualifying as inappropriate by international standards. The management of TB cases in the private sector is practically unsupervised by any regulatory body. In addition, no effective means of ensuring patient compliance (e.g., directly observed therapy) is available in the private sector. On the other hand, the government TB-control efforts have long been organized into the NTP, which sees around one fourth of those with TB symptoms in the country. Although a standard protocol based on the International Union Against Tuberculosis and Lung Disease (IUATLD) and WHO recommendations is used for diagnosis and treatment, logistic problems have plagued the NTP through the years. These include inadequate drug supply, inefficient distribution of existing drug stocks, and poor supervision of workers at all levels of the NTP. The TB Control Service has recently undertaken measures to correct these deficiencies, but currently these problems may add to the overall confusion suffered by patients and health providers alike. Enlisting the support of interested nongovernment groups is important for TB-control movements because, as already mentioned, government TB programs may not reach all the cases of TB. In fact, community involvement appears to be crucial for a successful control program. But if nongovernmental organizations (NGOs) with anti-TB interest (see Chap. 30) do not coordinate with one another,

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they may become ignorant of or disinterested in each other’s activities. Counterproductive competition and duplication of efforts may result in wasting of resources. Criticisms may trigger unending debates, resulting in loss of man-hours and friction between key personalities. In 1993, during the Eastern Region Meeting of the IUATLD held in Bangkok, Thailand, the head of the Philippine TB Control Service gave a report on the status and prospects of TB control in the Philippines. While this report drew the applause of the delegates from other countries, the Filipinos in the group, most of whom were not in government service, were shocked. Many could not agree with the figures and projections presented. The communication gap between the government and other stakeholders in TB control had long been perceived, but it was only at this meeting that its magnitude was realized. III. Rallying Around a Common Goal A coalition of various anti-TB organizations in the Philippines appeared desirable. However, given the situation in 1993 with several strong protagonists pushing their own ideas, collaboration did not come naturally. Initiatives emanating from one group would not be easily accepted by others. There had already been a failed attempt at public-private collaboration in previous years when government planners attempted to recruit individual private physicians to treat TB patients following NTP policies. The arrangement allowed the private physicians to continue seeing their patients and collect their usual consultation fees. The diagnosis and treatment policies of the NTP were to be adopted, and patients were to get free anti-TB drugs supplied by the government. Despite the soundness of the idea, this pilot project failed to get popular support—an example of groups working against TB unable to work together. An anti-TB coalition had truly become necessary to promote collaboration among various factions working for TB control. The shock that the Filipino delegates felt at that 1993 IUATLD meeting, whether justified or not, was enough to open their minds to paradigms for TB control different from their own. In a hurriedly conducted meeting in a bus stuck in the notorious Bangkok traffic, the group of Filipino delegates resolved to unite and help instead of just criticizing the government program. The idea of a coalition composed of all TB interest groups in the country caught each one’s imagination. All volunteered to be part of the convenor group that would establish the coalition. IV. The Philippine Coalition Against Tuberculosis The Philippine Coalition Against Tuberculosis (PHILCAT) was envisioned to be a coordinating body for all organizations with any anti-TB interest. The members were to include the government TB Control Service, physician groups, academe,

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paramedical specialties, pharmaceutical companies, press and other media organizations, NGOs, and all other TB interest groups. It would not compete with existing organizations since it would not accept individual persons as members. Rather, its strength was to come from the collective efforts of its member groups, among whom PHILCAT would foster communication, encourage complementary work, facilitate sharing of resources, and disseminate data generated by research or experience. The timing was fortuitous in that new leaders were at the helm of many of the anti-TB organizations, mostly unaffected by past rivalries, which had often been characterized by personal animosities between leaders. But what would keep this coalition together? It could not be funds, since there was a dearth of them in the Philippines as in other countries where TB abounds. Convenience, although helpful in bringing people together, would not keep them working together. A deeper reason had to exist to justify the collaboration. The threat of an incurable TB epidemic affecting any or all individuals in the country was believable but possibly too abstract to hold people together in a coalition. If the coalition realizes that the failure to control TB in their country may have resulted from previous control efforts being fragmented, then the goal of coordinating and unifying these efforts could itself be the glue that would keep the coalition together. PHILCAT would thrive only if its key protagonists internalized this idea. V. Formalizing and Expanding The next step for the coalition would be to formalize its existence and clarify its nature and purpose. The legal document containing the coalition’s goals, organizational structure, manner of equitable representation, and similar matters had to be drafted. Creating the coalition’s constitution would be a delicate process requiring diplomacy by its proponents. Care had to be taken not to offend or inadvertently bypass any member during the consultation process. Simultaneously with the drafting of the constitution, the convenor group of PHILCAT worked to expand its membership expeditiously. Target groups or organizations were identified, and key persons in those groups were approached and persuaded to join the coalition as founding members. This process opened new lines of communication between influential organizations and individuals who previously may not have been in touch. A new open-mindedness among stakeholders in TB control in the Philippines emerged, and PHILCAT promised to be a forum for the discussion of important issues in TB control. VI. Generating Resources The necessary preparation required funds. Enough resources were needed immediately to support the flurry of activity and enthusiasm of the convenor group, which

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consisted mostly of busy private physicians. The pharmaceutical industry contributed most of the crucial initial support. The possible scenario that good TB control would significantly reduce sales of anti-TB drugs did not deter such companies from supporting the coalition. Since actual control of TB would not occur in the near future, companies with anti-TB drugs would continue to have a market, and posturing with TB-control advocates would certainly enhance their corporate images. In addition, the first-line anti-TB drugs marketed by the pharmaceutical companies could become obsolete if poor TB treatment remained rampant and led to spread of drug resistance. Membership dues, donations, and fund-raising activities were envisioned as the future sources of funds for the coalition. The membership fee was of special importance. This steady source of funds would not only be crucial in supporting the fledgling coalition but would also be a manifestation of the member group’s commitment. The coalition membership was expected to include groups of various sizes and resources. A “socialized” membership fee scheme was devised in which the pharmaceutical and other business corporations would be assessed the maximum, while nonprofit organizations (including medical specialty groups) would be assessed based on the size of their own membership. Government organizations were not required to pay annual dues because government participation was considered essential for the coalition. The number of votes allocated to the member group was also determined by their respective membership size, except for the government, business, and pharmaceutical groups, who were to have only one vote each. VII. The Birth of PHILCAT The serious TB situation in the Philippines and the specter of an epidemic of incurable, drug-resistant TB was apparently sufficient reason for several key individuals to put aside personal feelings and accept the need to unite for TB control. One morning in June 1994, the representatives of the major anti-TB groups in the Philippines assembled in the office of the Undersecretary of Health. Each signed the document signifying their organization’s commitment to join the coalition. After a short, moving speech, the Undersecretary declared the birth of PHILCAT. After months of hard work and sensitive diplomacy, the principal stakeholders in Philippine TB control were now united in a coalition. But elation among the convenors was tempered with uncertainty and awe of the task at hand. A quick election and induction of interim officers followed. PHILCAT had been legitimately established and government support was assured. Now the coalition could get to work. VIII. Pushing Onwards To capitalize on its momentum, the interim executive board immediately met and decided to pursue the following strategies: 1) expand the membership offering

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founding member status to those joining before the general assembly a few months later, 2) inform the general public of the existence and rationale of the coalition, 3) request member groups to allow PHILCAT to discuss TB in their major meetings, and 4) have member groups co-sponsor the major PHILCAT activities including its annual convention. The last strategy was to assure individual member groups that they do not lose their respective personalities while members of the coalition and that their individual strengths were the strength of the whole coalition. The first annual PHILCAT convention in August 1994 was co-hosted by the Department of Health. The theme was “TB Control: A Shared Responsibility.” For the first time, the government NTP implementers shared a meeting with medical specialists, representatives of medical schools, and nongovernment organizations. Politicians and public officials from the national and municipal levels participated in the successful program. Subsequent annual conventions were co-hosted by the Philippine Society for Microbiology and Infectious Diseases, the Philippine Pediatric Society, and the Philippine Academy of Family Physicians. World TB Day was first organized by WHO in 1996. The Department of Health was the agency contacted by WHO to organize the activity in the Philippines. This task was then delegated to PHILCAT. A series of media interviews and news releases about TB led to the culminating event, which was an early morning march. The march ended at a monument dedicated to a Philippine president, Manuel L. Quezon, who died of TB. For the first time in the country’s history, over a thousand people indignant about TB marched as a united group. Although humbled by the failure of TB control, those present were hopeful that through the coalition success would eventually be attained. With the early successes came the challenge of maintaining the coalition’s momentum. This task lay on the shoulders of its officers and main supporters. While the coalition was composed of organizations, day-to-day activities were run by a core group of individuals on a completely voluntary basis. This dedicated group invested a good deal of time and effort (taken from professional, personal, and family time) into PHILCAT activities. No matter how deeply one may be motivated, the work may not always be perceived as pleasurable, considering the sacrifices entailed. It may be worthwhile considering the motivation of those in the core group who continue to do the work and how this could be reinforced or used to inspire others. Certainly it was not financial remuneration because this was volunteer work. Was it the challenge posed by the magnitude of the TB problem? Was it the instinct for self-preservation, considering that uncontrolled TB may affect oneself and one’s family? Was it prestige or the feeling of importance? Was it a genuine desire to contribute to community and national improvement or compassion towards one’s fellow man? Whatever the reason, those voluntarily continuing the work of the coalition must persist. Propelled by its own momentum, PHILCAT pursued its initial strategy for the first 3 years. It was not until after the third year that the coalition reassessed its

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direction. In early 1997, representatives of PHILCAT members met to formulate its mission and vision statements. An action plan was also developed listing the strategies adopted to address the different problems in TB control. Each strategy had its own objectives, timetable, identified responsible person, resource requirement, and targeted outcome. This action plan was to serve as the yardstick by which accomplishments were to be gauged. Unfortunately, preparations for that year’s main coalition activities (World TB Day, annual convention) appeared to have distracted PHILCAT from the complete execution of the action plan. Although some aspects of the plan were realized on target, other parts have been delayed.

IX. Developing a Unified Strategy: Identifying More Stakeholders The action plan of a coalition to control TB should identify the pressing problems and prioritize their solutions. Part of the above action plan includes developing a “unified strategy” for TB control that all health-care providers in the country could follow whether they are government or private employees. In the Philippines, as stated above, persons with symptoms suggestive of TB who seek medical care will approach either government or private clinics or self-medicate with antituberculosis medications purchased over the counter at a local drug store. A NTP already exists to cater to those who come to the government health facilities. On the other hand, private for-profit health-care providers are not organized in any way for TB control. In addition, according to the 1997 National Tuberculosis Prevalence Survey, half of those with symptoms of TB do not seek any health care. A unified TB-control strategy in the Philippines should integrate the existing NTP with a movement to organize the private for-profit providers into a parallel NTP, as well as with efforts to remove over-the-counter availability of antiTB medications. It should also include a public awareness campaign aimed at both the general public and political leaders. The latter group is targeted in the hope of directing public funds towards TB-control activities. The information campaign for the general public must reach those with TB symptoms who do not take any health-seeking action. In the process of developing the unified strategy, more stakeholders will inevitably be identified and must be recruited into the coalition. To halt the rampant over-the-counter availability of anti-TB medications, the strategy must include measures to understand the problem further, such as sociological studies investigating the knowledge, attitudes, and beliefs of both the parties selling the medications and the individuals purchasing the drugs. Corrective measures need not await the result of such studies. Legislation prohibiting the sale of antimicrobial medications without physician prescription already exists in

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the Philippines. Enforcement of this law has been poor. The new TB-control strategy must include methods of promoting improved enforcement of this law. Existing mechanisms regulating the retailing of pharmaceuticals must be reviewed and possibly modified to improve adherence to the rules. More importantly, pharmacists and pharmacy owners must be involved as part of the TB-control strategy. Pharmacist societies must be convinced to take up the cause of TB control as their own and become part of the solution rather than part of the problem. Perhaps they could develop their own campaigns against the sale of anti-TB drugs without prescriptions and somehow police their own ranks. Pharmacy schools should be convinced to train their students to be TB-control advocates and condemn the over-the-counter dispensing of anti-TB medications. Developing this part of the strategy identifies new stakeholders who must be drawn into the anti-TB coalition: sociologists, law enforcers, pharmacists and their professional societies, pharmacy owners, and pharmacy schools. Organizing the private for-profit physicians (private practitioners) for TB control presents a more difficult problem. In the Philippines, graduates of the 4year medical course who complete an additional year of postgraduate internship are eligible for licensure if they pass the medical board examinations. Once licensed, many begin to establish their private for-profit practices as general practitioners. Others pursue specialty or subspecialty training before starting their private practices. Other new physicians become salaried government physicians. Those who enter private practice are free to prescribe any medication available in the market and are under no supervision. The latter have been noted to have no standard criteria for diagnosing tuberculosis. Furthermore, private practitioners treat their TB patients with a variety of regimens for tuberculosis, ranging from monotherapy with any of the available drugs to five-drug combinations including expensive fluoroquinolones. Often, prescribing practices are heavily influenced by pharmaceutical promotions. The practice of offering physicians “incentives” in the hope of acquiring patronage of a drug product is common. A unified strategy for TB control would require standard diagnostic criteria and treatment regimens. In the Philippines, these two points have been the source of much controversy and disunity for many years. Whereas the government NTP has emphasized the use of acid-fast smears of sputum for diagnosing pulmonary TB, private practitioners rely heavily on chest radiographs, often refusing to obtain sputum smears. One reason given by private practitioners for this preference is the inconvenience (and expense) to the patient of providing several sputum specimens compared with the ease in obtaining a single chest x-ray. Unlike those who consult at government health centers, private patients must pay for sputum examinations and all other diagnostic tests. Another reason is the low sensitivity of sputum smears compared with the perceived higher sensitivity of a single chest radiograph. There has also been much contention as to whether three or four drugs should be used in the intensive phase of treatment regimens.

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A previous attempt had been made to develop a standard in the management of TB in the Philippines. In 1988, an organization of chest physicians called the TriChest Organization gathered local TB experts from the academe, the Department of Health (DOH), the Philippine Tuberculosis Society (PTS), and private practice to develop a national consensus for the management of tuberculosis. The First National Consensus on Tuberculosis was presented the following year. This included standard recommendations on diagnosis and treatment. The treatment regimen recommended for pulmonary TB was a 6-month regimen with a four-drug intensive phase consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol (or streptomycin) for 2 months followed by rifampicin and isoniazid daily for the next 4 months. In spite of the involvement of the PTS and the DOH in the development of the consensus, the government NTP was not altered to reflect the consensus recommendations. The consensus was not widely disseminated, so many private physicians remained unaware of its recommendations. This First National Consensus on Tuberculosis did not succeed in unifying Filipino physicians in the control of TB, but it was an important first step. Currently, two of the member organizations of the Philippine Coalition Against Tuberculosis (PHILCAT) are leading the revision of the National Consensus (the Philippine Society for Microbiology and Infectious Diseases and the Philippine College of Chest Physicians). Many of the participants in the development of the first consensus have again been enlisted in the revision process. The entire process of revising the consensus is being carried out under the official aegis of the PHILCAT. Transforming the National Consensus into a document acceptable to most physicians caring for TB patients in the Philippines is one of the most crucial tasks presently facing the coalition. The new document would provide the details for the coalition’s TB-control advocacy campaign. It would be the focal point around which actual TB-control programs in the private sector could be organized. The new Consensus will not suffer the fate of poor dissemination like its predecessor. The networks of many of the coalition’s members (particularly the Department of Health, medical specialty societies, the Philippine Tuberculosis Society, and pharmaceutical companies) will be the conduits for circulating the new consensus widely.

XI. Coalition Activities: Achieve Objectives and Maintain Member Enthusiasm Aside from the revision of the National Consensus, the main projects of the PHILCAT have been holding an annual scientific convention and preparing ac-

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tivities commemorating World TB Day on March 24 of each year. Each annual convention is co-hosted by PHILCAT and one of its member organizations. As already mentioned, the first convention was co-sponsored by the Department of Health and the subsequent ones by the Philippine Society for Microbiology and Infectious Diseases, the Philippine Pediatric Society, and the Philippine Academy of Family Physicians. Preparations for these activities have been effective in drawing member organizations together to work side by side. These activities have also been helpful in developing the camaraderie and maintaining the enthusiasm necessary for the coalition’s success. Equally important is the fact that the annual convention has been the major source of revenue for the coalition. However, as mentioned above, continuing to focus efforts on the coalition’s “traditional” activities may have distracted PHILCAT’s attention from carrying out its new action plan. A lesson that future coalitions can learn from this experience is to obtain expert assistance on organizational development and fund raising right from the outset. The coalition’s mission, vision, goals, and action plan should be established early, and subsequent efforts should be directed at executing the action plan. This action plan should include clear plans on revenue generation and seek the advice of fund-raising professionals so that the coalition’s concentration on advocacy and TB control would not be diverted. XII. Summary In countries where a dominant and effective NTP does not exist or where existing TB-control efforts are splintered and uncoordinated, the formation of a coalition of anti-TB organizations is a logical, even necessary, strategy. Forming such a coalition is a difficult process requiring commitment, volunteerism, persistence, diplomacy, and creativity from its organizers. Professional assistance in organizational development and fund raising should be sought early after forming the coalition to clearly define the group’s direction, plan of action, and strategy for revenue generation. Once these are set, the coalition can focus on its work of encouraging and coordinating its members in the fight against tuberculosis. References 1. World Bank. World Development Report 1993: Investing in Health. New York: Oxford University Press, 1993:1–329. 2. World Health Organization Global TB Programme. Geneva: Annual Report, 1994. 3. World Health Organization Global TB Programme. Geneva: Tuberculosis Notification Update, December 1996. 4. Mendoza MT, Gonzaga AJ, Roa C, et al. Nature of drug resistance and predictors of multidrug-resistant tuberculosis among patients at the Philippine General Hospital, Manila, Philippines. Int J Tuberc Lung Dis 1997; 1:59–63.

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5. Manalo F. Tan F, Sbarbaro JA, Iseman MD. Community-based short-course treatment of pulmonary tuberculosis in a developing nation. Am Rev Respir Dis 1990; 142: 1301–1305. 6. National Prevalence Survey in Tuberculosis. National Institute of Tuberculosis (Philippine Tuberculosis Society and Department of Health), 1983. 7. Tupasi TE, Radhakrishna S, Rivera AB, Pascual MLG, Quelapio MID, Co VM, Villa MLA, Beltran G, Legazpi JD, Mangubat NV, Sarol Jr, JN, Reyes AC, Sarmiento A, Solon M, Solon FS, Mantala MJ. National Tuberculosis Prevalence Survey. Int J Tuberc Lung Dis 1999; 3(6):471–477.

27 Tuberculosis Education

EILEEN C. NAPOLITANO

ELIZABETH J. STOLLER*

New Jersey Medical School National Tuberculosis Center and International Center for Public Health UMDNJ–New Jersey Medical School Newark, New Jersey

Francis J. Curry National Tuberculosis Center San Francisco, California

I. Introduction Tuberculosis (TB), the “deadly scourge” of the nineteenth and early twentieth centuries, still prevails, albeit considerably attenuated in areas of the world in which resources are plentiful. A number of factors have been suggested for the failure to eliminate TB in the United States, including the ability of the tubercle bacillus to cause disease after a potentially long latency, inadequate economic resources, patients’ lack of adherence with long treatment regimens, immigration from TB-endemic countries, and physician error (1). Strategies have been developed to address each of these factors. TB control programs have concentrated on factors most amenable to intervention; among these are the knowledge base and skills of health-care providers. In the United States, where case rates are now on the decline after a marked upsurge in the late 1980s to early 1990s, educational efforts to assist in the prevention and control of tuberculosis have been intensified. This chapter focuses on why continuous availability of resources for provider education is critical to the elimination of tuberculosis and outlines current educational efforts. Historically, tuberculosis has been managed by fairly discreet groups of providers. In the early twentieth century, TB was prominently featured in medical

*Current affiliation: Institute for Global Health, San Francisco, California.

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and nursing textbooks. Care was provided in large part in the TB sanatoria, and health and social service providers had the opportunity to gain considerable knowledge about management of the disease through direct patient care. As effective chemotherapy became available to render patients noninfectious quickly and to cure the disease, confinement in sanatoria was no longer necessary, and they gradually closed down. Care for TB patients was shifted to public health department outpatient clinics. In the 1970s, public health programs in the United States were virtually dismantled, and in many instances TB patients came to be cared for by providers who had little or no preparation for the management of this disease. With the resurgence of tuberculosis in the 1980s, many providers were encountering patients that they were not equipped to manage. To address this and other deficiencies made manifest by the reappearance of tuberculosis, a group of national experts devised a set of recommendations for tuberculosis elimination in 1989 entitled “A Strategic Plan for the Elimination of Tuberculosis in the United States” (2). One of the efforts stemming from the plan was the National Tuberculosis Training Initiative (3). The purpose of the Initiative was to ensure that adequate, standardized information regarding the care and control of tuberculosis was available to all practitioners and educators. A core curriculum (4) was developed to serve as the basis for planning and preparing educational activities; the Centers for Disease Control and Prevention (CDC), the American Lung Association, and national medical and nursing organizations participated in the development of the document (5) and it is just entering its fourth version. Tuberculosis training and education for health-care providers is presented here as one strategy to prevent and control tuberculosis. In addition to educating those who provide services to TB patients, education is also necessary for patients with tuberculosis and their family and community members both to establish and maintain the necessary activities for completing treatment and preventing further infection and to create a culturally appropriate and compelling context for engaging in treatment and prevention activities. The strategies for, and challenges in, providing education about tuberculosis to patients have been described in the context of promoting patient adherence (6,7). An array of factors, including knowledge deficits, affect patient adherence to and community attitudes towards tuberculosis treatment (8). Many of the educational efforts for high-risk populations are designed to reduce the stigma associated with tuberculosis that is prevalent in many cultures. The following sections address (1) evidence of the need for provider education and training, based on provider, patient factors, and structural factors, (2) the current initiatives on training, (3) the populations in need of training, (4) the methods for developing and delivering training, and (5) future directions for training efforts.

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II. Evidence of the Need for Training and Education for Providers A. Missed Opportunities for Prevention

A substantial literature has developed on missed opportunities for appropriate prevention, diagnosis, and treatment. Failure to perform screening where indicated and to initiate treatment of latent TB infection for persons infected with Mycobacterium tuberculosis has resulted in numerous preventable cases of tuberculosis in children and adults. Mehta et al. reported on an 8-year prospective study of pediatric TB cases in Tennessee: approximately one fifth were preventable and almost half could have been avoided through use of treatment of latent TB infection (9). During a one-year period in Portland, Oregon, recommended procedures were not used in 59% of active cases, e.g., failure to conduct skin testing when indicated (43%), failure to initiate treatment of latent TB infection when it was indicated (8%), failure to complete treatment of latent TB infection (1%), and failure to complete previous treatment for disease (7%) (10). A history of BCG vaccination deterred preventive treatment for certain populations seen by Canadian providers (11), and a study in South Africa found that 69% of pediatric contacts to adult cases were not screened or provided with treatment of latent TB infection (12). B. Diagnostic Delays

Delays in diagnosis result from a variety of factors, including failure to perform sputum microscopy, overreliance on chest radiographs, and a low level of clinical suspicion. An example of a “domino effect” beginning with inadequate detection, leading to inadequate treatment, followed by inadequate case management is presented by Ridzon et al. (13). A case analysis of a high school outbreak with 18 cases of TB found that delayed diagnosis and reporting, incomplete evaluation of suspects, insufficient monitoring of infectiousness, and inadequate attention to therapy all contributed to the perpetuation of the outbreak. Diagnostic delays have also been documented among HIV-infected populations, a group for whom TB infection can progress rapidly to disease. In a review of 52 consecutive HIV-infected patients with culture-positive M. tuberculosis at a Los Angeles hospital, Kramer et al. found that therapy was delayed for nearly 50% of the patients (14). Delays were due to failure to collect an adequate number of sputum samples and resulted in failure to initiate presumptive antituberculosis therapy when radiographic findings suggested mycobacterial disease. In developing countries, delays in diagnosis are also common. For example, a retrospective survey of 100 Ghanaian adults found a median delay to diagnosis of 4 months (mean 7.7 months). Delays attributed to the medical practitioners were associated with the failure to perform sputum microscopy. Patients were also responsible in part for the diagnostic delays, but provider practices in this study

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resulted in twice the length of delay (15). A study of 212 patients in Botswana also found that health service delays surpassed patient delays. While patient delays accounted for part of the problem, health service delays were considerably longer (16). C. Knowledge and Practice Deficiencies

Gaps in provider knowledge, particularly in the private sector in the United States and abroad, are evidenced by inappropriate treatment regimens that can result in prolonged treatment and drug resistance. In New Jersey, Liu and colleagues (17) determined that 36% of TB cases did not receive the recommended four-drug regimen. Mahmoudi and Iseman (18) found numerous practice errors in the management of patients who had developed drug resistance. Many of the errors were deviations from standard recommendations and guidelines. Errors were made in the management of 80% of the 35 patients, with an average of 3.93 errors per patient, resulting in prolonged and costly care. In Pakistan, 23% of university hospital–based providers surveyed incorrectly used sputum results for diagnosis (19), and urban general practitioners in Pakistan failed to follow diagnostic and treatment procedures in accordance with World Health Organization (WHO) guidelines (20). Only 30% of private practitioners in India used National TB Program (NTP) approaches, 90% relying on chest radiographs and only 12% using sputum analysis (21). In another study in India, Uplekar and colleagues (22) found that 105 private practitioners reported using 79 different treatment regimens, few of which were consistent with the NTP recommendations. Hong et al. (23) surveyed a random sample of Korean providers: more than 50% did not consider sputum examination essential in case finding and diagnosis. Despite clear evidence of the efficacy of treatment of latent TB infection, only 43% of the tuberculin skin test–positive physicians at a Minnesota medical center undertook and completed such treatment (24). Reichman suggests that compliance of the physician is a key factor in understanding the modern barriers to effective control measures (25). A provider who does not personally follow recommendations is less likely to be able to inspire patients to adhere to a prescribed regimen. D. Adherence to Published Guidelines

Treatment Guidelines

To help providers offer state-of-the-art care, guidelines on treatment for tuberculosis were developed by the CDC and the American Thoracic Society (ATS) (26). While recommendations and guidelines are important tools for providers, they are unlikely to alter practice norms without additional measures. In a national U.S. survey on physician practices relative to the published CDC/ATS treatment rec-

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ommendations, Sumartojo and colleagues found that 60% of respondents described appropriate regimens for a hypothetical case, 29% selected excessive regimens, and 12% chose insufficient regimens (27). Less than half of the house staff surveyed at Harlem Hospital knew the appropriate four-drug treatment regimen, even though 55% were currently managing active disease or latent infection (28). Adoption of the American Academy of Pediatrics recommendations for TB screening in children was not uniform among 762 pediatricians and family physicians surveyed in five eastern U.S. locations. Cheng et al. recommend that as new guidelines are published, they should be actively promoted to providers to foster changes in clinical practice (29). Leaders in the field can influence practice by supporting new approaches (30). The effect that medical opinion leaders have when they promote new practice behaviors has been characterized as the “contagion response” (31). Institutional Guidelines

Infection control guidelines have been used as tools to educate staff working in institutional settings. These guidelines are essential to reducing the potential for nosocomial infections in outpatient clinic and hospital settings (32). Cleveland et al. report on two AIDS cases with multidrug-resistant tuberculosis in an outpatient HIV dental clinic where staff failed to use universal precautions and conduct appropriate screening on potentially infectious patients (33). Charge nurses in a Texas health-care system had an average score of 48% on a knowledge test designed to measure knowledge of TB, infection control, and acid-fast bacilli (AFB) isolation policies (34). In the year prior to the survey, the health-care system had 5 active cases that resulted in 115 exposures in 15 departments, a marked manifestation of the inadequate administrative and facility controls. In this instance, the survey was conducted to collect baseline data to plan a series of educational interventions; postintervention test scores improved by 49%. E. Social, Cultural, and Structural Factors Contributing to Prevention and Treatment Outcomes

Problems with screening, treatment, and ongoing care are not solely attributable to the provider. The errors and suboptimal outcomes must be viewed in the broader contexts of both the patient-provider encounter and the settings in which the health care is delivered. Various patient-related and structural factors can also influence the process and outcomes. Cultural factors may affect the use of services and the outcome of treatment. For many cultures, there is a stigma associated with tuberculosis that may lead to ostracism of the patient by others in the community. Interviews and focus groups in a Honduras study found that attitudes about tuberculosis among patients and the community interfered with help seeking and adherence (35). Providers need to be

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aware of the stigma of tuberculosis in many communities and how this perception presents a barrier to care. In a study of physician practices in western India, 11% of the practitioners acknowledged that stigma associated with tuberculosis kept them from disclosing the tuberculosis diagnosis to their patients (22). Patient education is needed to dispel myths associated with the stigma and to contradict basic misconceptions such as the belief that patients are infectious while on treatment (35). Utilization of care can be affected by structural barriers, such as lack of the necessary resources to use health-care services (e.g., transportation, release time from work), or the lack of readily available appropriate services. Services that are provided should address other basic survival needs for patients as an inducement to participate in treatment. Community-based organizations have resources and expertise to assist in TB-control efforts. Some organizations have outreach, peer education, and case-management staff with practical expertise in the provision of need-based incentives. These sites can assist providers and public health programs by offering directly observed therapy (DOT). Many organizations can also provide other community and organizational referrals for patients (36). Adherence to the prescribed prevention or treatment regimen is a shared problem of the provider and patient. Successful efforts to promote adherence take into account the issues of patients’ access and the relative value that they place on the need for complete treatment. Directly observed therapy in the United States and directly observed therapy, short course (DOTS) in many other parts of the world represent a concerted attempt to extend program resources to each patient in a culturally sensitive manner. Some programs and providers also provide a more holistic patient care approach, offering short-term housing, food vouchers, and other incentives to the completion of therapy. In areas where traditional medicine and western medicine coexist, some providers have combined approaches to meet the needs of their patients. Studies in both Botswana (16) and Ghana (15) found that patients sought care from traditional healers both before and during their TB diagnosis and treatment. Dialogue was strongly encouraged between traditional healers and modern health-care workers. Successful efforts for prevention and control have addressed some of these social, cultural, and structural barriers in addition to improving provider practices. The effectiveness of any intervention will be enhanced when the range of factors that contribute to treatment and completion success is addressed. A number of training initiatives to foster increased provider knowledge and skill are currently in place. Education for providers on patient management should include an articulation of the access and adherence issues faced by patients and, where appropriate, the community at risk, as well as how to address these issues.

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III. Current Training Initiatives A. Existing Education and Training Resources

Training resources have increased markedly since the resurgence of tuberculosis towards the end of the twentieth century. For many years the National Jewish Medical and Research Center has provided training on tuberculosis for clinicians. The five-day lecture course is offered several times a year. The CDC Division of Tuberculosis Elimination provides print-based materials, slide sets, videotapes, training courses, satellite courses, and Internet World Wide Web-based education, as well as a clearinghouse on TB education materials. The CDC’s Core Curriculum on Tuberculosis serves as a standard clinician’s practice guide for management of patients with tuberculosis (37). B. CDC-Funded Training Initiatives

The CDC’s Public Health Practice Program Office supports the regional sites of the National Laboratory Training Network, which provide training for laboratory personnel on the identification, handling, and reporting of M. tuberculosis. The CDC Division of Tuberculosis Elimination funded the Model Tuberculosis Prevention and Control Centers in 1993 to develop innovative tuberculosis prevention and control strategies and training programs to increase skills for physicians, nurses, epidemiologists, and allied health professionals. The three centers are located in high-morbidity areas: the Francis J. Curry National Tuberculosis Center in San Francisco, California; the Charles P. Felton National Tuberculosis Center at Harlem Hospital, New York, New York; and the New Jersey Medical School National Tuberculosis Center in Newark, New Jersey. Training is a major emphasis of each center. Each center has developed an array of training materials and courses for a variety of providers, including videotapes, print materials, and computer-based learning programs. C. Five-Year Strategic Training Plan

A major training-related effort of the three model centers, in collaboration with the CDC Division of TB Elimination is the Strategic Plan for Tuberculosis Training and Education (38). The plan, released in early 1999, identifies training needs, catalogues existing resources, and provides a blueprint for training efforts through 2003. (See Appendix A for a detailed description of the plan.) D. Academic Educational Initiatives

The TB Academic Awardee program of the National Heart, Lung and Blood Institute of the National Institutes of Health was initiated in 1993. The goal of the program is to promote the principles and practices of tuberculosis prevention,

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management, and control to medical students, house staff, and practicing physicians and nurses. The award provides each recipient with 5 years of funding to develop curricula for their local medical and/or osteopathic school. Important components of this award include focus on educational efforts in areas of high morbidity, the coordination with other agencies providing service to populations in these areas, and the promotion of enhanced awareness of the unique ethnic, cultural, and socioeconomic factors involved in providing effective care (39). E. Local, Regional, and National Efforts

In addition to these categorically funded efforts, several state and large city recipients of CDC funds for tuberculosis control offer a variety of training programs for providers in their respective areas. The American Thoracic Society conducts continuing education programs for providers on tuberculosis through the annual American Lung Association/American Thoracic Society Annual International Conference and through the state Thoracic Society affiliates. Likewise, the American Lung Association provides continuing education opportunities through its state and local affiliates. National, regional, and state tuberculosis controller organizations offer continuing education opportunities through their regular meetings (e.g., the National TB Controllers Association Workshop, the Northeast TB Controllers Meeting, the Southeast TB Controllers Meeting, and the California TB Controllers Association meeting). The North American Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) conducts an annual conference, much of which is devoted to tuberculosis. Finally, the American College of Chest Physicians, the Infectious Diseases Society of America, and the American Public Health Association typically feature sessions or seminars on tuberculosis at their annual meetings. In addition to the forums in which tuberculosis is an integral component, some groups are including tuberculosis as an additional medical and/or administrative concern. The national network of AIDS Education and Training Centers funded by the U.S. Health Resources and Services Administration offer training modules on tuberculosis in geographic locales where TB/HIV co-infection has emerged as an issue. The national justice system and the institution-based correctional medical facilities have included tuberculosis education in response to outbreaks of tuberculosis among inmates and staff. F. International Efforts

Beyond the United States, some of the key international organizations involved with training on tuberculosis influence the morbidity among persons who immigrate to the United States from endemic countries. WHO has developed a tuberculosis guide for low-income countries and hosted a Global Tuberculosis Programme Workshop

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on Tuberculosis Control and Medical Schools, which resulted in a list of knowledge, skills, and attitudes essential for physician management of tuberculosis (40). The IUATLD offers an annual international conference as well as on-location, comprehensive training courses in high-incidence countries for managers and intermediatelevel staff from the respective NTPs. The courses are offered in English, French, or Spanish, depending on the country in which they are offered. The Japanese Anti-Tuberculosis Association (JATA), through the Research Institute on Tuberculosis (RIT), offers courses in English in Tokyo on modern methods of TB control, NTP implementation, and evaluation for key NTP organizers and managers, as well as laboratory methods training. JATA also offers mobile seminars on tuberculosis control in other countries. The Royal Netherlands Tuberculosis Association (KNCV) also offers training and technical assistance in several high-incidence countries. The KNCV has focused on capacity building by providing programmatic and technical support for DOTS implementation. A number of other organizations throughout the world offer training courses. A list of international course offerings can be found on the World Wide Web, www.nationaltbcenter.edu. Finally, the National Institutes of Health’s Fogarty International Center, the World Bank, the Pan American Health Organization, and the U.S. Agency for International Development all fund training and technical assistance for programs and providers in high-incidence countries. The relationship between the U.S.based efforts and the international efforts is a special focus of the Strategic Plan on Tuberculosis Training and Education (see Appendix B). IV. Health-Care Providers in Need of Education and Training A. How Are the Terms “Training” and “Education” Being Used?

Our working definition of training is a planned activity that is designed to increase knowledge, change attitudes, and promote necessary skills for tuberculosis patient care, prevention of M. tuberculosis, and tuberculosis control. Education on tuberculosis for providers is offered as individualized self-study or as training, as part of either preservice instruction, postgraduate education, inservice education, or on-the-job-training. Formal and informal consultation, including dedicated telephone services, curbside consultations, provider-provider interactions, and case reviews, also fosters changes in knowledge and possibly practice, but these changes are difficult to quantify. B. Who Is in Need of Training and Education?

The public health workforce has statutory responsibility for the prevention and control of tuberculosis. Staff are in need of the knowledge and skills for preven-

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tion, management, and control of the disease in individuals and in groups. Private sector providers, professionals in related disciplines, and noncategorical public health-care providers need to know about prevention, management, and control of tuberculosis in individuals. C. Priority Audiences for Training

In 1998, key U.S. public health tuberculosis program personnel were surveyed to identify categories of providers that should be targeted for education in a national collaborative planning effort (A. Green Rush, unpublished). These target populations are: 1. 2. 3. 4.

Providers in the public health public sector* Private sector† and managed care providers Providers in correctional facilities Providers of high-risk populations (HIV-infected, substance-using, and homeless patients) 5. Providers serving foreign-born patients 6. Providers trained in foreign medical institutions 7. Providers in agencies serving international audiences

While these categories are not mutually exclusive, they all describe key foci for the strategic planning process and targets for TB educational programs. V. Methods A. Developing Training

Development of training interventions often follows a public health program planning model: problem analysis/needs assessment, goals and objectives, implementation, and evaluation (41). B. Needs Assessment

A needs assessment is conducted to define the target populations, the knowledge and/or skill areas to be addressed, the appropriate format for the intervention, and * Public sector providers include physicians, nurses, outreach workers, clinicians, engineers, disease investigators, laboratory workers, industrial hygienists, social workers, administrators, health educators, TB case registry staff, clerical staff, and volunteers, including staff of community-based organizations. † Private sector providers include medical and nursing school students, private sector physicians, nurse practitioners, physician assistants, nurses, engineers, industrial hygienists, respiratory therapists, and laboratory workers.

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the baseline knowledge, attitudes, and skill levels of the intended audience. Both qualitative and quantitative data are collected to develop an adequate picture of the current needs and, in particular, to determine which of the identified needs are amenable to training. An important element of this assessment process is the determination of how the changed knowledge and/or skills can (or will) be supported by the organization that the individuals come from. Often, in addition to addressing the core learning objectives, the training curriculum will need to impart knowledge and skills to recipients to help them effect change in their respective work environments, such as setting up a system for referral to, or collaboration with, specialist providers or tailoring services to the socio-medical needs of patients and community members. For example, an assessment conducted to develop a course for medical providers in a tuberculosis program may use data from existing sources, augmented by interviews with representatives of the target population, to help determine: Current reporting practices Completion of therapy rates Relapse rates Whether targeted providers can successfully foster patient adherence to treatment and preventive therapy regimens What, if any, errors are made in treatment and management The data gathered during the needs assessment are used as a baseline for evaluation and are used to help tailor the curriculum to the needs of the participants. C. Goals and Objectives for the Training

These are developed in collaboration with the representatives of the population to be trained. The goals state what the training will achieve overall. Specific educational objectives are developed to address the previously determined needs. Objectives are written to articulate what the participants will gain from each session or module, whether it be case discussions, didactic sessions, or clinical practica. The objectives are specific, measurable statements that specify what is to be done, by how much, by whom, and by when. The objectives form the blueprint for the training plan. D. Implementation of the Training Plan

The training plan spells out what is needed to implement the curriculum, how the curriculum will be implemented, and to whom training will be directed. The plan

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includes: How training participants will be selected Which instructional methods will be used (the training format) What expertise is needed among the teaching faculty The actual training design: how each step will be carried out, by whom, and what resources are needed What measures will be used, and when, for evaluation Training can be provided in a variety of formats. Local—and individual— needs and resources dictate the type of training that is appropriate in any given situation. Training can be provided through: 1. Print materials (such as modules and journal articles), audiotapes and videotapes. This format allows for individual pacing and administration on a schedule at the convenience of the user. 2. Didactic methods, such as inservice presentations, seminars, and training courses. These are more typically tailored to meet the needs of each specific audience and can include applications for practice, such as with the use of case discussions. 3. Clinical and field practica, including patient modeling in standardized clinical scenarios. These experiential formats provide a hands-on approach to both information and skill acquisition, as do some of the more sophisticated offerings of computer-based instruction, such as CDROM and Internet offerings. 4. Distance learning technologies, such as satellite teleconferences, videoconferences, and audioconferences. These formats bring regional or national expertise to providers at the local level in various geographic locales. E. Evaluation

Evaluation measures can begin with the data collected during the assessment phase and continue at strategic points during implementation and follow-up. The evaluation design can utilize a variety of methods to determine if the objectives were met. Data collected for evaluation purposes can include: Baseline data of current program and/or practice status Process data—the effect of the training effort as it is happening Impact data—the immediate results (changes in knowledge, attitudes, and skills) Outcome data—long-term effects in knowledge, attitudes, and skills of trainees and, as applicable, their colleagues (through dissemination), overall structural changes (such as development of new procedures) at-

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tributable to the training intervention, and overall changes in program indicators (e.g., completion rates) Evaluation findings are used for planning future courses and program efforts and can serve as baseline data for subsequent training development cycles. VI. Future Directions for Training Resources and support for current and future training efforts are tied in part to tuberculosis incidence, to the extent that the level of funding will likely decrease more or less in proportion with a decrease in tuberculosis morbidity. The challenge to organizations that emphasize training is to develop mechanisms to ensure the sustainability of each training effort. A. Maximize Use of Each Training Tool

Development of enduring products is one approach to perpetuating training resources. Strategies include: 1.

A syllabus with references to accompany a training course: trainees have the opportunity to review and in some cases, relearn and/or teach others the material at a later date. 2. User-manipulated self-study materials (print, audio, video, computerbased) that can be used by a number of different people on an ongoing basis. 3. Materials that can be used at varying distances from the source (journal articles, audiocassettes, audio-conferences, videoconferences, and computer-based education). These materials maximize the potential for a broad geographic audience to benefit from one concerted effort.

B. Build on Existing Structures

Another approach to maximizing training resources is to foster the integration of the knowledge and skills necessary for continued training efforts by the recipient groups. The train-the-trainer method involves both the delivery of the didactic information as well as imparting skills to the recipients so they can train others. A more comprehensive approach is the capacity-building effort undertaken by the Francis J. Curry National Tuberculosis Center. Staff from the center work with the host jurisdiction to conduct an extensive needs assessment to determine practice deficiencies and the status of program structure and functioning. A determination is made as to which problems or deficiencies are amenable to training and what program changes need to be made to embrace the new knowledge and skills of the program staff. As part of the assessment process, the host program representatives

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are taught how to use a software program to analyze their program data. The planned trainings are designed to involve local staff as faculty to the extent possible. The overall goals of the effort are to build program capacity for conducting training and to enhance program performance through training of staff and, in some cases, key groups from the broader health and social service community (42). C. Model Appropriate Techniques

Teaching by illustration of appropriate techniques is another way to develop abilities in the target group. The New Jersey Medical School National Tuberculosis Center utilizes a standardized patient approach (also known as simulated patients) to training second-year medical students about interviewing techniques. The Center has expanded the scope of this teaching-through-role-play method to train health-care workers about interviewing techniques (43). This New Jersey model has been successfully adapted for use at other locations. The New Jersey Center is one of several programs in the United States that operate a telephone advice line for clinicians, policymakers, and community members. The consultation provided to medical personnel models appropriate clinical decision-making skills (44). D. Collaborate

Finally, it is economically prudent to collaborate with groups who have a shared agenda, such as infectious disease groups, pulmonary and thoracic organizations, and AIDS, emerging infections, and international health organizations in order to maximize use of resources. Cross-training of generalist staff (e.g., communicable disease workers and community outreach workers) offers an opportunity to share public health program skills that can be funded from a variety of sources. VII. Topics for Further Discussion This chapter focused on the needs, resources, and methodologies for training to enhance tuberculosis prevention and control efforts. Several issues remain regarding the orchestration of training efforts. A. Evaluation of Cost-Effective Approaches

As tuberculosis morbidity declines, the merit of educational efforts needs to be continuously demonstrated. The costs of undertaking training, both from the consumers’ perspective and the training providers’ perspective, need to be measured.

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These data can be compared against the known costs of managing patients, including those who were subjected to an inappropriate treatment regimen and those who were misdiagnosed and brought to treatment at an advanced stage of disease. Thus, the relative cost-effectiveness of training can be ascertained. A parallel line of inquiry should reveal the actual outcome of each training offering, so that the most efficacious and cost-effective methods can be used to achieve the desired results. Davis et al. (45) suggest that for continuing medical education, active learning instruction, such as practice-linked or problem-based situations, complemented by in-person “outreach” visits, may be more effective than episodic, didactic programs. However, educational programs offered in the traditional format may serve as a catalyst for behavior change that can further be reinforced by less formal (and in some cases, less costly) efforts, such as reading, consultation, outreach, and detailing (46). B. Integration

Tuberculosis training and continuing education efforts need to be integrated into broader existing education and training activities. The Academic Awardee program of the National Institutes of Health National Heart, Lung and Blood Institute is an example of a concerted effort to address the gaps in professional medical training by building tuberculosis education into the curriculum. Tuberculosis-specific training should also be built into broader postgraduate continuing education efforts for providers, such as pulmonary medicine, AIDS, infectious diseases, laboratory methods, and infection control. C. Build Capacity

Providers of training, to the extent possible, should emphasize resource-building, specifically enhancing the training recipients’ capacity to perpetuate the training process. The CDC and the Model Tuberculosis Centers are focusing on the development of enduring products, such as videotapes, computer-based instruction, and train-the-trainer curricula. Some of the international programs described earlier provide technical assistance to build program infrastructure and capacity in the host country. D. Use Available Resources

Organizations offering training and consumers seeking training and education should review the broad array of existing resources and use or adapt them as necessary. In many cases it isn’t necessary to develop materials from scratch, and often faculty that provide training are available to assist with efforts in other locations. One major effort of the 1999 Strategic Plan for Tuberculosis Training and Education was to collect and catalogue existing training and education resources

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throughout the world. The database includes a listing of organizations, their contact information, and courses and resources that are available. The information is posted on the World Wide Web at www.nationaltbcenter.edu. Evidence of the need for continued availability of training and education resources for providers is clear. While continued emphasis on training and the development of new methodologies is warranted, all new efforts should be consistent with a larger overall plan. The goals of the Strategic Plan for Tuberculosis Training and Education (see Appendix B) provide an overarching framework for development and coordination of training initiatives. Future efforts should address these or similar goals and should be constructed to be consistent with efforts for the elimination of tuberculosis. Acknowledgments We are grateful to Jennifer Flood, Andrea Green Rush, Philip C. Hopewell, and Debra J. Kantor for their comments on this manuscript. References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

Kissner D. Tuberculosis missed opportunities. Arch Intern Med 1987; 147:2037– 2040. Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the United States. MMWR 1989; 38(suppl):1–25. Harris JO. The National Tuberculosis Training Initiative. Chest 1990; 97:770. Core Curriculum on Tuberculosis. Atlanta: Centers for Disease Control and Prevention, 1989. Reichman LB. National tuberculosis training initiative. Ann Intern Med 1989; 111(3):197–198. Sumartojo E. When TB treatment fails: a social behavioral account of patient adherence. Am Rev Respir Dis 1993; 147:1311–1320. Sumartojo E. Adherence to the tuberculosis treatment plan. In: Cohen FL, Durham JD, eds. Tuberculosis: A Sourcebook for Nursing Practice. New York: Springer, 1995. Johnson MP, Helitzer-Allen D. Public education in tuberculosis. In: Improving Tuberculosis Treatment and Control: An Agenda for Behavioral Social and Health Services Research. Proceedings of Tuberculosis and Behavior: National Workshop on Research for the 21st Century, Bethesda, MD, Aug 28–30, 1994. Atlanta-CDC, 1995:129–136. Mehta JB, Bently S. Prevention of tuberculosis in children: missed opportunities. Am J Prev Med 1992; 8(5):283–286. McAnulty JM, Fleming DW, Hawley MA, Baron RC. Missed opportunities for tuberculosis prevention. Arch Intern Med 1995; 155(7):713–716. Menzies D, Adhikari N, Tannenbaum T. Patient characteristics associated with failure of tuberculosis prevention. Tuberc Lung Dis 1996; 77(4):308–314.

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12. Gie RP, Beyers N, Schaaf HS, Donald PR. Missed opportunities in the diagnosis of pulmonary tuberculosis in children. S Afr Med J 1993; 83(4):263. 13. Ridzon R, Kent JH, Valway S, Weismuller P, Maxwell R, Elcock M, Meador J, Royce S, Shefer A, Smith P, Woodley C, Onorato I. Outbreak of drug-resistant tuberculosis with second-generation transmission in a high school in California. J Pediatr 1997; 131(6):863–868. 14. Kramer F, Modilevsky T, Waliany A, Leedom JM, Barnes PF. Delayed diagnosis of tuberculosis in patients with human immunodeficiency virus infection. Am J Med 1990; 89:451–456. 15. Lawn SD, Afful B, Acheampong JW. Pulmonary tuberculosis: diagnostic delay in Ghanaian adults. Int J Tuberc Lung Dis 1998; 2(8):635–640. 16. Steen TW, Mazonde GN. Pulmonary tuberculosis in Kweneg District, Botswana: delays in diagnosis in 212 smear-positive patients. Int J Tuberc Lung Dis 1998; 2(8):627–634. 17. Liu Z, Shilkret K, Finelli L. Initial drug regimens for the treatment of tuberculosis. evaluation of physician prescribing practices in New Jersey, 1994 to 1995. Chest 1998; 113(6):1446–1451. 18. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis. JAMA 1993; 270(1):65–68. 19. Arif K, Ali SA, Amanullah S, Siddiqui I, Khan JA, Nayani P. Physician compliance with national tuberculosis treatment guidelines: a university hospital study. Int J Tuberc Lung Dis 1998; 2(3):225–230. 20. Marsh D, Hashim R, Hassany F, Hussain N, Iqbal Z, Irfanullah A, Islam N, Jalisi F, Janoo J, Kamal K, Kara A, Khan A, Khan R, Mirza O, Mublin T, Pirzada F, Rizvi N. Hussain A, Ansari G, Siddiqui A, Luby S. Front-line management of pulmonary tuberculosis: an analysis of tuberculosis and treatment practices in urban Sindh, Pakistan. Tuberc Lung Dis 1996; 776(5):86–92. 21. Singla N, Sharma PP, Singla R, Jain RC. Survey of knowledge attitudes and practices for tuberculosis among general practitioners in Delhi, India. Int J Tuberc Lung Dis 1998; 2(5):384–389. 22. Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in India. Int J Tuberc Lung Dis 1998; 2(4):324–329. 23. Hong YP, Kwon DW, Kim SJ, Chang C. Kang MK, Lee EP, Moon HD, Lew J.. Survey of knowledge, attitudes and practices for tuberculosis among general practitioners. Tuberc Lung Dis 1995; 76:431–435. 24. Ramphal-Naley L, Kirkhorn S, Lohman WH, Zelterman D. Tuberculosis in physicians: compliance with surveillance and treatment. Am J Infect Control 1996; 24(4):243–253. 25. Reichman LB. Tuberculosis elimination: What’s to stop us? Int J Tuberc Lung Dis 1997; 1(1):3–11. 26. American Thoracic Society. Treatment of tuberculosis and tuberculosis infections in adults and children. Am J Respir Crit Care Med 1994; 149:1359–1374. 27. Sumartojo EM, Geiter LJ, Miller B, Hale BE. Can physicians treat tuberculosis? Report on a national survey of physician practices. Am J Public Health 1997; 87: 2008–2011.

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28. Murrman MK, Souffrant GC, El-Sadr WM. Residency Training: A Unique Opportunity for TB Education. American Lung Association/American Thoracic Society International Conference, CDC/ATS Public Health Poster Session, Chicago, April 26, 1998. 29. Cheng TL, Miller EB, Ottolini M, Brasseux C, Rosenquist G. Tuberculosis testing: physician attitudes and practice. Arch Pediatr Adolesc Med 1996; 150:682–685. 30. Fox W. Compliance of patients and physicians: experience and lessons from tuberculosis. BMJ 1983; 287:101–105. 31. Soumerai SB, Avorn J. Principles of educational outreach (“academic detailing”) to improve clinical decision-making. JAMA 1990; 263(4):549–556. 32. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR 1994; 43(RR-13). 33. Cleveland JL, Kent J, Gooch PF, Valway SF, Marianos DW, Butler WR, Onorato IM. Multidrug-resistant Mycobacterium tuberculosis in an HIV dental clinic. Infect Control Hosp Epidemiol 1995; 16(1):7–11. 34. Cook JD, Lewis L, Thomassen KA. The use of continuous quality improvement to achieve proper isolation of patients with suspected tuberculosis. Am J Infect Control 1995; 23(5):323–328. 35. Mata JI. Integrating the client’s perspective in planning a tuberculosis education and treatment program in Honduras. Med Anthropol 1998; (winter):57–64. 36. Freudenberg N. A new role for community organizations in the prevention and control of tuberculosis. J Community Health 1995; 20:15–28. 37. Core Curriculum on Tuberculosis. 3d ed. Atlanta: Centers for Disease Control and Prevention, 1994. 38. Strategic Plan for Tuberculosis Training and Education. San Francisco: Francis J. Curry National Tuberculosis Center, January 1999. 39. National Heart, Lung and Blood Institute. Bethesda: http://www.nhlbi.nih.gov/ nhlbi/train/ tbaa.htm. 40. Chaulet P, Campbell I, Bolen C. Tuberculosis Control and Medical Schools. Report of a WHO Workshop, Rome, Italy, October 29–31, 1997. Geneva: WHO, 1998. 41. Stoller EJ, Miller CM, Daley CL, Bernstein MC, Wallis K. A catalogue of tools for training on tuberculosis. Int J Tuberc Lung Dis 1997; 1(suppl. 1):S29. 42. Bernstein MC, Miller CM, Stoller EJ. Targeted training to enhance local tuberculosis control efforts. Int J Tuberc Lung Dis 1998; 5(suppl. 1)S377. 43. Kantor D, Reichman LB, Mangura B, Addis J. Beyond didactic lectures: the use of standardized patients (SPs) in training health care workers. Int J Tuberc Lung Dis 1997; 1(suppl. 1):S30. 44. Lardizabal A, Sunderam A, Riegel L, Albino J, Mangura BT, McDonald RJ, Reichman LB. Calls to a 1-800-TB information line may represent public and health care worker misinformation. Am J Respir Crit Care Med 1996; 153:A328. 45. Davies DA, Thomson MA, Oxman AD, Haynes RB. A systematic review of the effect of continuing medical education strategies. JAMA 1995; 274(9):700–705. 46. Escovitz GH, Davis DA. A bi-national perspective on continuing medical education. Acad Med 1990; 65:545–549.

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Appendix A Summary of Strategic Plan for Tuberculosis Training and Education Overview The Strategic Plan for Tuberculosis Training and Education was conceived of as an effort to avoid duplication of services, to coordinate TB training and education resources, and to identify areas of highest need. One major component of this plan is a comprehensive catalogue of training and education tools and resources. The Francis J. Curry National Tuberculosis Center, the New Jersey Medical School National Tuberculosis Center, the Charles P. Felton National Tuberculosis Center at Harlem Hospital, in conjunction with the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, sponsored this collaborative effort. The process involved gathering tuberculosis experts to project future training needs and trends and to identify and catalogue all training and education efforts. The resulting Strategic Plan for Tuberculosis Training and Education established priorities to more effectively target training resources. It provides guidance to agencies and organizations in the United States that provide TB training and education for public and private sector providers for a 5-year period through 2003). The Planning Process Topic-focused workgroups were established to identify resources and develop recommendations. The strategic planning process culminated with a 2-day summit on tuberculosis training and education and the development of the plan document. The goals of the strategic planning process were to: Determine and prioritize provider education needs Identify tuberculosis education and training resources Identify gaps in training resources Foster collaboration among major training providers Develop a master plan for tuberculosis training and education Three groups drove the strategic planning process. The Steering Committee The Steering Committee, composed of representatives of the three Model TB Centers and the Division of TB Elimination, met on an ongoing basis and provided overall guidance for the planning process and ensured that broad, overarch-

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ing issues and concerns were reflected in the plan. Steering Committee members were responsible for: Participating in Steering Committee conference calls Participating in at least one workgroup Reviewing workgroup documents Attending the summit Reviewing the draft strategic plan document Developing a distribution plan for the strategic plan document

Workgroups The workgroups met by conference call on a regular basis. The strategic planning workgroups were 1) private sector/managed care/provider education, 2) public health sector, 3) corrections, 4) special populations (HIV/ TB, homeless, substance abuse), 5) foreign-trained providers/foreign-born patients, and 6) international TB training. Workgroups were responsible for: Developing background information on their topic as it relates to TB training and education Assisting with the identification of existing training resources Identifying gaps in TB training and education Developing recommendations to be integrated into the strategic plan

Advisory Committee The Advisory Committee was responsible for: Reviewing workgroup position papers/recommendations Attending the summit Reviewing the draft strategic plan

Timeline This consisted of: Workgroup conference calls: April–July 1998 Workgroup documents due to Francis J. Curry National Tuberculosis Center: July 31, 1998

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Summary of workgroup documents sent to summit participants: September 21, 1998 Summit: October 22–23, 1998 Plan document completed: December 1998

Appendix B Strategic Plan for Tuberculosis Training and Education, October 22–23, 1998, Summit Meeting Mission Statement The Strategic Plan for Tuberculosis Training and Education promotes and guides training and education efforts to control and eliminate tuberculosis. Five-Year Goals* (1999–2003) Build, strengthen, and maintain collaboration among the key agencies and organizations in training. Build, strengthen, and maintain collaboration with global partners. Develop, improve, and maintain access to and availability of TB training and education resources. Improve and sustain knowledge, skills, and practices tailored to local epidemiological circumstances. Identify and mobilize financial resources for TB training and education.

* Not in order of priority.

28 Political Will The Singapore Tuberculosis Elimination Program

CYNTHIA BIN-ENG CHEE and YEE-TANG WANG Tan Tock Seng Hospital Singapore

It has often been stated, and widely believed, that tuberculosis (TB) can be eliminated if only there was the political will (1,2). The government of Singapore has taken up this challenge and on World Health Day 1997 declared its intention to eliminate TB with the launch of the Singapore TB Elimination Program (STEP).

I. Singapore: An Island City-State The Republic of Singapore consists of the main island of Singapore and some 60 off-shore islands situated approximately 137 km north of the equator. The main island is about 42 km long, 23 km wide, and 645.7 km2 in area. Singapore’s immediate neighbors are Malaysia (peninsular Malaysia to the north and Sarawak and Sabah to the east), Indonesia to the south, and Brunei to the east. Other countries in the Southeast Asian region include the Philippines, Myanmar, Thailand, and Vietnam. In 1819, Sir Stamford Raffles established a British trading post in what was then a small settlement of 150 people living along the banks of the Singapore River. As Singapore grew into a thriving free port, immigrant settlers came from 727

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southern China, the Indian subcontinent, the Malay peninsula, and Indonesia. Singapore remained under British rule until it achieved internal self-governing status in 1959. In 1963, Singapore joined the Federation of Malaysia, but shortly thereafter, on August 9, 1965, it separated from Malaysia to become a fully independent and sovereign nation. Singapore today is a major business, financial, and trading center in the international arena and a service gateway into the Asia Pacific region. It is also the world’s busiest port in terms of shipping tonnage, the world’s top bunkering port, and the third largest oil-refining center. These successes are due to its excellent infrastructure and strategic location at the crossroads of major shipping and aviation routes, good banking and financial services, efficient telecommunications network, stable government, and skilled and disciplined workforce. Singapore is also a major tourist destination and convention city, with 7.29 million visitor arrivals in 1996. A. The Population

The resident population in 1996 was an estimated 3.04 million, with a population density of 4702 residents per km2 (3,4). Chinese made up 77.3%, Malays 14.1%, Indians 7.3%, and persons of other ethnic groups 1.3% of the resident population. In the last decade, the proportion of residents aged 60 years and above increased from 8.3 to 10% and the median age of the resident population from 27.8 to 32.2 years. In 1996, the total number of live births was 48,738, and the number of deaths was 15,586. The general literacy rate (defined as the number of literate residents for every 100 residents aged 15 years and over) was estimated to be 92.2%. English is the language of administration, Malay is the national language and the official languages are Malay, Chinese (Mandarin), Tamil, and English. The standard of living is generally high, the per capita indigenous gross national product being S$34,220 (S$1  ~$0.60 U.S.). The labor force comprises 1.8 million people, with a participation rate of 64.6%. The average unemployment rate for 1996 was 2%. About 86% of the population live in public housing. For every 10,000 people, there were 36 public buses, 15 doctors, and 3084 residential telephone lines. B. The Government

Singapore has experienced political stability with the ruling political party, the People’s Action Party, enjoying an overwhelming majority rule since the country’s independence in 1965. This has enabled sound policies, even those that may temporarily inconvenience the populace, to be implemented for the eventual good of the nation.

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C. Health Care

Singaporeans enjoy a good standard of health care. The infant mortality rate is low at 3.8 per 1000 live births, while the life expectancy at birth for resident males is 74.4 years and for females 78.9 years. The national health-care expenditure in 1996 was S$3.7 billion (S$1,208 per capita) or 3% of the gross domestic product (3,4). The Ministry of Health provides preventive, curative, and rehabilitative health services and coordinates the planning and development of the public and private health sectors. It also works closely with the Ministry of the Environment in the maintenance of environmental hygiene and control of communicable diseases and with the Ministry of Manpower in improving the industrial and occupational health of workers. The Medical Audit and Accreditation Unit (MAAU) licenses, audits, and ensures that there are acceptable standards of health care in hospitals, medical clinics, clinical laboratories, and nursing and maternity homes in Singapore. In terms of health-care services, there is a dual system comprising a government/public health care system, which provides about 20% of primary health care and 80% of hospital care, and a private health-care system, which provides 80% of primary health services and 20% of hospital services. Health-care financing is government-subsidized on a co-payment basis, in which patients pay part of the medical services they use and pay more if a higher level of service is demanded. Three medical financing schemes are also in existence: Medisave, a compulsory savings scheme where funds are automatically deducted from salaries, and which may be used to pay for the hospitalization needs of the individual and immediate family; Medishield, a voluntary insurance scheme that covers medical expenses of major or prolonged illness; and Medifund, an endowment fund set up by the government for the poor and indigent who are unable to pay their hospitalization bills. Every child is immunized against tuberculosis, poliomyelitis, diphtheria, pertussis, tetanus, measles, mumps, rubella, and hepatitis B. Screening programs for adult high-risk groups for early detection of hypertension, diabetes mellitus, heart disease, and certain cancers have also been introduced. The health-education program emphasizes preventive health care and individual responsibility for one’s health, encouraging healthy lifestyle habits. II. Tuberculosis in Singapore A. Historical Perspective

Tuberculosis, together with other infectious diseases, was a major scourge and a leading cause of death in the local population in the early part of this century. The

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mainstay of treatment then was artificial pneumothorax together with prolonged bedrest and good nutrition in the sanatorium. In response to the rising number of TB cases and the unavailability of treatment to many patients at the main civil hospital under the British administration, the Singapore Anti-Tuberculosis Association (SATA) was registered and launched in 1947. In the 1950s, TB remained a formidable problem with 5000 new cases annually, despite available effective treatment with streptomycin, para-aminosalicylic acid, and isoniazid. Mass BCG vaccination was introduced in the mid-1950s. Targeted mass chest x-ray screening was also introduced in the 1950s. The Tuberculosis Control Unit (TBCU) and the TB notification registry was set up in 1957. In the 1960s, joint studies between the British Medical Research Council (MRC) and the TBCU demonstrated the effectiveness of supervised, 6month, rifampicin-containing regimens, and, together with British MRC trials in Hong Kong and East Africa, led to the establishment of short-course TB chemotherapy as it is practiced today (5). B. Epidemiology

In 1960, the incidence rate of TB among Singapore residents numbered 307 per 100,000 population (6). With improved socioeconomic conditions and the institution of short-course TB chemotherapy and TB-control measures, the incidence rate of TB declined steadily to 56 per 100,000 in 1987. Since then it has remained at between 49 and 56 per 100,000. The number of new TB cases reported among Singapore residents in 1997 was 1712, giving an incidence rate of 55 per 100,000. This represented 4,979 more cases since 1987 than would have been expected had the trend of decline continued (Fig. 1). In 1997, most of the new TB cases occurred in males (68.6%) and in persons over 50 years of age (57.8%) (Fig. 2). This trend has changed little over the last 5 years. The incidence rate of TB among children (
15 years) remained low in the last 10 years, at below 5 per 100,000. Of all cases 92.1% were pulmonary TB. Of the extrapulmonary cases, the most common site was the pleura in males and the lymph nodes in females. Of the pulmonary cases, 65% were sputum bacillary positive. Drug-resistance rates for new cases remained low, with 5.8% of cases resistant to one drug (mainly streptomycin) and 1.2% resistant to two or more drugs. There was one case of multidrug-resistant TB (resistance to at least both rifampicin and isoniazid) reported in the new TB cases in 1997. The number of relapsed TB cases has also remained stable (between 243 and 325 cases) in the last 5 years, with 265 cases reported in 1997. As with the new TB cases, these relapsed cases also occurred predominantly in males and among older persons. As expected, there were more drug-resistant cases in this group, with 10.1% resistant to one drug and 6.6% resistant to two or more drugs

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Figure 1 Graph showing the annual incidence rate of TB cases in the resident population of Singapore from 1980 to 1997 expressed as log rate per 100,000 population. The TB incidence rate showed a steady decline from 1950 to 1987, but has since then remained at between 49 to 56 per 100,000. This represents an excess of 4,979 cases since 1987 than would have been expected had the rate of decline continued.

Figure 2 The number of new TB cases for 1997 by age and gender in the Singapore resident population. Most of the TB cases occurred in males and those over the age of 50 years, there being little change in this distribution over the last 5 years. The rate of TB in children over the last 10 years has been low at
5 per 100,000.

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in the 168 cases with pulmonary disease who had bacteriological sensitivity tests done. There were three cases of multidrug-resistant TB (MDR TB) among the relapsed TB cases in 1997. The mortality rate due to TB was 3.4 per 100,000 in 1997, accounting for 0.7% of all deaths in Singapore. This has also remained stable in the last 5 years. BCG vaccination, although not compulsory by law, has been widely accepted and practiced since its introduction in the mid-1950s. BCG coverage of infants and newborns has been over 95% since 1987. There is also a BCG vaccination program for school entrants and leavers for Mantoux nonreactors and those without history of BCG vaccination or a BCG scar. C. HIV

There were 173 cases of HIV infection reported among Singaporeans in 1997, bringing the cumulative number of HIV infection to 731 since the first case was reported in 1985 (6). Among these, 357 had asymptomatic infection, 133 had fullblown AIDS, and 241 had died from the disease. Males formed 91% of the cases, with heterosexual transmission the main mode of transmission. Forty-three percent of the cases were between the ages of 30 and 39 years. D. TB and HIV Co-infection

The Ministry of Health has performed sentinel surveillance of TB cases since 1989, and available data up to 1995 revealed no HIV infection among the TB cases. Of the cumulative AIDS cases through December 1997, the clinical presentation was disseminated TB in 16.2% and pulmonary TB in 14.8%. E. TB Among Foreign Workers

Currently, all foreigners desiring to work in Singapore as blue-collar workers or domestic maids are required to pass health screening checks, including a routine chest x-ray examination, before the work permits are granted. These work permits are also subject to renewal every 2 years. The work permit applications and renewals are not approved if there is radiological evidence of active TB, and they are terminated should the foreign worker develop active TB any time while working in Singapore. These persons are started on appropriate treatment and sent back to their country of domicile for continuation and completion of treatment. Once treatment is successfully completed, they may reapply to come back to Singapore to work. F. TB Treatment

Most of the TB cases in Singapore are treated at the TBCU or the government or restructured hospitals. The TBCU treats about 40% of all TB cases in Singapore.

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Another 20% are treated at the Tan Tock Seng Hospital, a public hospital, while 25% are treated at the other four public hospitals. About 6% of TB cases are treated by SATA and 5% by respiratory physicians in private practice. The majority of general practitioners in Singapore do not treat TB and would refer these cases to specialists at the TBCU or public hospitals for treatment. The main form of treatment is the 6- or 9-month short-course regimen, which is self-administered in the vast majority of cases. Directly observed treatment (DOT) is not yet widely accepted or practiced in Singapore. In recent years, less than 10% of the cases treated received DOT during the initial phase of chemotherapy. DOT as it is carried out in Singapore requires the patient to attend the government polyclinic for administration of treatment. There is at present no system or network of health outreach workers to carry out DOT at the patients’ homes. Generic, single-drug preparations are the main formulations used in the major treatment centers. Fixed-drug combination formulations are widely used only in the private sector. Anti-TB drugs are available only by prescription. Up to the present, there has been no system of nationwide surveillance of treatment completion rates or treatment outcome. A 1993 survey of 152 patients treated for TB in a general medical clinic of a public hospital showed that only about 60% completed their treatment, while in the TBCU 88% of patients completed treatment in 1995. The treatment outcome and completion rates for the other treatment centers are not known. Most of the treatment centers also have no systematic defaulter tracking system. Defaulter tracing in the TBCU entails attempts to contact the patient by phone, letter, and home visits. A survey of home visits (usually carried out during office hours) in 1996 showed that contact with the patient or other person at home was made only 41% of the time. There is in existence an Infectious Diseases Act that allows for confinement of recalcitrant cases of infectious diseases, but this act has never yet been exercised for TB. As Singapore has a relatively high TB-notification rate, the national program has thus far directed most of its attention to treatment of cases and placed little emphasis on contact screening and treatment of latent TB infection. Thus, infected contacts are probably underidentified and treatment of latent TB infection underutilized. Contact screening is done at the TBCU for notified TB cases attending the TBCU for treatment. These index cases are personally interviewed and the household members asked to come for contact screening in the form of an interview for symptoms of disease, chest x-rays for adult contacts, and Mantoux tests for children. Isoniazid treatment for latent TB infection is prescribed for infected childhood contacts. Mantoux testing is not routinely carried out for adult contacts. Isoniazid treatment of latent TB infection of infected adult contacts has not been practiced at the TBCU. For TB cases attending other clinics, a letter is sent out to them upon case notification, requesting them to notify their household members to come for screening. Thus, contact identification depends entirely on this letter in these cases.

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AFB smear examinations are carried out in some designated laboratories around the island, while facilities for TB cultures are available only at the Central TB Laboratory, which participates in several external proficiency programs such as the College of American Pathologists (CAP) Mycobacteriology Survey, U.K. National External Quality Assurance Scheme (NEQAS) for Mycobacteriology, and WHO EQA in Microbiology. The Central TB Laboratory performs fluorescent microscopy for AFB from concentrated deposit, culture isolation using Bactec radiometric or MGIT nonradioactive method, and differentiation and drug susceptibility tests on every positive isolate. Second-line drug susceptibility testing may also be performed on MTC isolates resistant to first-line drugs. The number of specimens examined for TB culture has risen from 28,335 in 1991 to 37,550 in 1996, with the positivity rate ranging between 9 and 11%. III. Rationale for the Singapore Tuberculosis Elimination Program Despite Singapore’s economic progress and improvements in living standards and health care, its TB incidence has remained high (49–56 per 100,000) over the last 10 years, being 5–10 times that of developed countries in the West. We believe that our TB rates have not declined because there is still significant ongoing transmission of TB in the community due to delays in diagnosis and treatment. Moreover, it is also likely that many patients are not adhering to and completing treatment, hence remaining infectious or being at high risk for disease relapse. We are still fortunate that our rates of HIV and TB drug resistance are low, but there is no room for complacency, as Singapore is in one of the high-prevalence regions for HIV as well as MDRTB. There has been, to date, no comprehensive national policy to treat infected contacts to prevent progression of infection to disease. Our national TB program has been in place since 1957, but in view of the current situation, the time had come for a review of the program. It was determined that, in order to bring our TB rates down and to meet the challenge of the global TB and HIV epidemic, the existing TB program had to be tightened and improved. At the same time, it was clear that there were several factors in our country’s favor that may make it possible to not only control but eliminate TB. First, Singapore is very small and geographically compact, with a well-developed infrastructure and advanced health-care system. Second, the society is well organized and disciplined, without the problems of poverty, homelessness, or substance abuse. And, very importantly, we have yet to experience the full impact of the HIV epidemic.

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With this in mind, the government decided to lend its support to the task of eliminating TB in Singapore. The Singapore Tuberculosis Elimination Programme (STEP) was thus launched by the Minister for Health, Yeo Cheow Tong, on World Health Day in 1997. The mission of STEP is to eliminate TB in Singapore with the following goals: 1. 2. 3. 4. 5.

To detect and diagnose all infectious (sputum positive) cases in the community To cure all cases of TB To detect and treat all infected TB contacts To prevent the emergence of multidrug-resistant TB To prevent foreigners and Singaporean returnees from importing TB into Singapore

IV. Organizational Structure of STEP The main components of STEP are the epidemiological component, administered by the Department of Epidemiology and Disease Control (E & DC) of the Ministry of Health, and the clinical component, under the TBCU, which has been part of the Department of Respiratory Medicine of the Tan Tock Seng Hospital since 1995. The Department of E & DC is responsible for the Central TB Notification Registry and the monthly surveillance of all TB cases treated in Singapore. The TBCU is being developed into a model TB center where, in addition to being a national referral center for the treatment of TB cases, the tracing, screening, and treatment of infected contacts and training and education of health-care workers are carried out. STEP is overseen and directed by a Ministry of Health–appointed TB Executive Committee chaired by the Deputy Director of Medical Services (Professional and Service Development) of the Ministry of Health. Its members include the Director of SATA and other senior officials of the Ministry of Health. STEP receives advice and assistance from another Ministry-appointed committee, the STEP Committee, which comprises local experts in the fields relevant to TB. A. International Advisory Panel

An International Advisory Panel comprising four TB experts from the United States and Canada provides expert advice and assistance to STEP. This panel is led by the programme’s National TB advisor, Lee B. Reichman, Executive Director of the New Jersey Medical School National Tuberculosis Center. Its members are Earl S. Hershfield, Department of Medicine and Community Health Science, University of Manitoba, Winnipeg, Manitoba, Canada, Paula Fujiwara, Director, New York Bureau of TB Control, and Ken Castro, Director, Division of TB Elimination, Centers for Disease Control and Prevention, Atlanta. The function of the

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panel includes the following: To advise on national policies on TB control (e.g., BCG vaccination, DOT, contact tracing, and INH prophylaxis) To raise the profile of TB among health professionals in Singapore through lectures and symposia To provide training of health-care workers through attachments for physicians, nurses, and public health workers To involve the TBCU in international multicenter trials B. Interministerial Involvement

The Ministry of Health is involved through the TBCU and government and restructured hospitals, the outpatient polyclinics, the Central TB Laboratory, its Departments of Epidemiology and Disease Control, and Training and Health Education. Other ministries involved are the Ministry of Community Development pertaining to the management of TB in the welfare and nursing homes and the Ministries of Manpower and Home Affairs, which helps in the screening and monitoring of imported TB. C. Involvement of Nongovernmental Organizations

The Singapore Anti-Tuberculosis Association (SATA) celebrated its fiftieth anniversary in 1997 by hosting the 19th Eastern Region Meeting of the International Union Against Tuberculosis and Lung Disease in Singapore and the opening of a new clinic. Since its launch in 1947, SATA has been actively involved in public education and treatment of TB. With the decline in TB cases in the 1970s, it has extended its services to include health screening for the public and work permit applicants. It is funded by donations and proceeds from health screening. Currently, 5.8% of the TB cases are treated by SATA, which continues to treat TB and to play a major role in public education and public health screening. V. Key Factors for the Success of STEP The factors identified for the success of the program are: 1. Strong government support until successful control and elimination of TB. This requires interministry cooperation and coordination and adequate funding 2. Sound treatment strategies: use of proven and accepted treatment regimens by all medical practitioners, optimization of patient compliance with supervised treatment in the form of DOT, and a tight system of defaulter tracing and treatment outcome monitoring 3. Effective detection of infectious TB cases 4. Systematic contact tracing and administration of treatment of latent TB infection

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5.

Infrastructure: good laboratory and radiological support, the Central TB Laboratory, and adequate staffing and training of public health workers 6. Education for modification of human behavior and attitudes via public education and education of health-care givers The two key features of STEP are the monitoring of monthly progress and treatment outcome of individual patients via a central TB registry and the use of the DOTS strategy. Other activities include accurate and prompt diagnosis (via the existing laboratory and radiological services and physician and patient education), improving identification of infected contacts for INH treatment of latent TB infection surveillance of high-risk groups (institutionalized elderly, HIV-infected), monitoring imported TB, and research. A. Central TB Registry

A central registry that receives notification of new TB cases already exists, but the success of a TB program is also measured and monitored by treatment-completion rates. The role of the central registry has been thus expanded to monitor case outcome not only on an annual but also on a real-time basis in order to swiftly detect defaulters for whom action should be taken. The existing TB notification form (which must be completed by the medical practitioner for each case of TB at the time of diagnosis and returned to the Department of Epidemiology and Disease Control, Ministry of Health) has been updated (Appendix A) and fine-tuned to be more user-friendly as well as to include more information pertaining to foreigners with imported TB. Information on the treatment regimen on which the patient has been started has also been included. This allows cross-checking of the drugs prescribed with the drug susceptibility of the infecting organism when they are available to ensure that the patient has been on the appropriate therapy as well as timely modifications to the drug regimen to be made if required. A treatment progress report (Appendix B) has been developed in which the treatment status of every TB patient has to be entered, and this is to be updated and returned monthly to the Department of Epidemiology and Disease Control, Ministry of Health by each treatment center. This not only serves as a means of monitoring national TB treatment-completion rates, but also to heighten each treatment center’s awareness of its own performance, so that appropriate measures may be taken at their level to achieve good treatment results. B. Efforts to Increase the Use of DOT and Improve Patient Adherence to Treatment

A concerted effort has begun at the TBCU and Tan Tock Seng Hospital to change the mindset of doctors, health-care workers, and patients towards increased acceptance and the use of DOT.

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For patients who are physically unable to attend the clinic for DOT, a relative or caregiver is to be made responsible for DOT at the patient’s home. This is to be recorded daily in a DOT record form, which is given to the patient and caregiver at every clinic visit. The supportive role played by the health-care worker in ensuring that the patient adheres to and completes treatment cannot be overemphasized. Every patient is counseled at the beginning of treatment as to the nature of the disease, the importance of adherence and completion of treatment, and the various different medications and their side effects. Every effort is made by the health care worker to establish a rapport with the patient and to understand the patient’s needs and concerns regarding the impact of the disease on their lives. C. Establishment of DOT in Government Polyclinics Nationwide

There is a network of 17 government polyclinics nationwide (Fig. 3) under the jurisdiction of the Public Health Division of the Ministry of Health where DOT is carried out between 7:30 a.m. and 5 p.m. Mondays to Fridays, and between 7:30 a.m. to 1 p.m. on Saturdays. A tight system of communication has been established between the TBCU and these polyclinics. Should any patient fail to turn up for DOT at the clinic, attempts will be made to contact him or her within the next 24 hours, failing which the TBCU is informed and defaulter tracing measures taken.

Figure 3 Map of Singapore with the government family health clinics represented by the points scattered over the island.

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D. Laboratory and Radiological Support

The present high standard of laboratory and radiological support is being maintained with regular quality-assurance monitoring. Peripheral laboratories are subjected to quality-control checks by the Central TB Laboratory, which in turn are assessed by an international reference laboratory. A quick turnaround time for the processing and reporting of positive sputum results (positive sputum results to be reported within 24 hours) and abnormal chest x-rays is being enforced. E. Contact Tracing and Treatment of Latent TB Infection

Under STEP, index cases reported by all treatment centers are interviewed to identify their household, workplace, and social contacts, who are then called up for contact screening. The screening process includes interview for symptoms of TB and any high-risk medical conditions. Mantoux testing, and chest x-ray. Infected contacts are offered isoniazid treatment of their latent TB infection. F. Targeted Mobile Chest X-Ray Screening

The practice of targeted mobile chest x-ray screening (e.g., those with symptoms, 45 years old, diabetics, institutionalized elderly) is being continued. G. Education of Health-Care Workers

Guidelines on TB pathogenesis, diagnosis, principles of treatment, and the facilities and resources available for the management of TB have been published and distributed to all doctors in Singapore. This is aimed at raising the awareness of the problem of TB not only as a disease of the individual, but also as a public health concern, such that early diagnosis of TB will be made. An additional book for clinicians involved in treating TB patients detailing appropriate and effective treatment regimens, emphasizing the importance of patient adherence and completion of treatment, and promoting the practice of DOT has also been published and distributed. Continuing medical education programs for both doctors and nurses pertaining to TB are regularly held. The teaching of TB in the medical school curriculum is being reinforced, with an emphasis on the public health aspects of the disease and its control. VI. Conclusion Singapore is on the threshold of becoming a developed nation but still has the TB rates of a developing country. Its TB incidence, having fallen since the pre–shortcourse chemotherapy era of the 1960s, has remained static since 1987. Although

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the incidences of MDRTB and HIV are both currently low, we are geographically situated in one of the world’s “hot spots” for MDRTB as well as HIV, with the potential for a disastrous rise of both HIV and TB a very real concern. The “Ushaped curve” (7) experienced in the United States in the early 1980s has served as a warning against complacency in our measures for TB treatment and control. Singapore, being a small country with well-developed infrastructure and a relatively disciplined society, is well placed to not only control but also eliminate TB. The government of Singapore has declared its political will and commitment to the elimination of TB in the form of the Singapore Tuberculosis Elimination Program. The task is formidable, but the ultimate goal worthwhile. We have no alternative but to put in our best efforts now, before it is too late. Acknowledgments The authors wish to thank Professor L. B. Reichman, Professor E. Hershfield, Dr. Ken Castro, Dr. P. Fujiwara, Dr. Chen Ai Ju (Director, Medical Services), Dr. Chee Yam Cheng (Deputy Director, Medical Services), Dr. S. C. Emmanuel, Dr. Jane Yap, Dr. Kwek Poh Lian, Ms. Tan Bee Yian, and Dr. Pwee Keng Hoe. Special thanks to Dr. S. C. Emmanuel, Dr. Irving Boudville, and Dr. Lee Hong Huei. References 1. Reichman LB. Tuberculosis elimination—what’s to stop us? Int J Tuberc Lung Dis 1997; 1:3–11. 2. Reichman LB. Defending the public’s health against tuberculosis. JAMA 1997; 278: 865–867. 3. Ministry of Information and the Arts. Singapore 1997—A Review of 1996. Singapore: Ministry of Information and the Arts, 1997. 4. Singapore—Facts and Pictures 1997. Singapore: Ministry of Information and the Arts. 5. Iseman MD, Sbarbaro JA. Short-course chemotherapy of tuberculosis. Am Rev Respir Dis 1991; 143:697–698. 6. Singapore: Department of Clinical Epidemiology, Communicable Disease Centre, Tan Tock Seng Hospital and Ministry of Health. Communicable Disease Surveillance Report 1997. 7. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991; 148:741– 742.

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Appendix A The Singapore Tuberculosis Elimination Programme notification form.

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Appendix B The Singapore Tuberculosis Elimination Programme treatment progress report.

Compliant to treatment: patients who have consumed at least 80% of prescribed medications in the judgment of the attending physician. Completed treatment: patients who have been compliant, as defined above, and who have completed the total prescribed regimen of treatment. Cured: patients with initially smear- or culture-positive pulmonary TB, defined as documentation of at least two negative sputum smears and/or cultures during the continuation phase, one of which is at the end of treatment.

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29 Medical Anthropology An Important Adjunct to International TB Control

DANIEL CHEMTOB, SHERI WEISER, and ISRAEL YITZHAK The National Tuberculosis and AIDS Unit Ministry of Health Jerusalem, Israel

DANIEL WEILER-RAVELL Carmel Medical Center Haifa, Israel

I. Introduction This chapter was written with two audiences in mind: the medical practitioner in the field and the public health policy maker. If it achieves its aims, the practitioner will have sharpened his sensibilities and awareness of the supreme importance of the person behind the patient in the socio-cultural sense. He also might run through a socio-anthropological mental checklist when addressing the needs of his patients, availing himself of expert advice to guide him in providing the best possible treatment for his patients. Likewise, the policy maker will incorporate specific measures of integrated social science research into any program he or she designs or supervises. Health, in the words of the World Health Organization (WHO), is more than absence of disease. “It is a result of a complex mix of social, economic, political and environmental factors, all of which reflect complex issues of power, status and resource distribution . . . To a considerable extent, health depends on the political, social, cultural, economic and physical environment”

The opinions expressed in this article are those of the authors and do not purport to represent the opinions of the agencies with which they are associated.

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(1). Tuberculosis (TB) as a public health issue is a typical example of this interaction. The complexity of TB is also expressed in its epidemiology, which differs from region to region and from society to society (2). There is also heterogeneity within societies with regard to patients and systems of health and social care (3). For example, unemployment influences the incidence of TB in urban areas in the United States (3), whereas in a study of TB in London the average level of notifications was correlated with overcrowding and the proportion of migrants, but not with unemployment or social class (4). In western countries, recent immigrants (5,6) the poor, and the elderly have the greatest morbidity in association with tuberculosis. Consequently, public health officers must devise strategies to target those populations who have the greatest difficulty accessing health care. For recent immigrants, strategies must be adopted to bridge potential cultural gaps between patients and providers, while aiming to reduce other impediments to health care. This chapter discusses some of the strategies adopted in Israel to confront the problem of tuberculosis among Ethiopian immigrants. In what follows, we concentrate on the dynamic interaction between the socio-cultural circumstances of patient populations and the management of TB, with the clinician or public health worker in mind. Our data and discussion relate mainly to a migrant population. However the guiding principles described are probably pertinent to all hard-to-reach populations.* Often, in both developed and developing countries, the implementation of the culturally sensitive aspects of a TB-control program will have low priority for political and financial reasons. Commonly, the treated population will be blamed for poor compliance when structural barriers and a lack of sensitivity to the social, political, and cultural circumstances of the patient are important contributors to program failure (7). Before presenting our experience with Ethiopian Israelis, which illustrates many of the above points, we begin by discussing the applicability of social science tools to public health programs and the need for a multidisciplinary approach in addressing complex problems in public health. II. The Relevance of Social Science to Public Health Many studies have described failed health interventions that did not take into account economic barriers to treatment (7), that were not culturally sensitive (8,9), in which the study population felt manipulated by researchers (8), or in * Homeless, sectarian groups with unique health practices, substance abusers, individuals in crisis situations, or other individuals who have difficulties accessing health and social services.

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which the study community felt forced to commit acts contrary to its religious convictions (9). In this chapter, we argue that the social sciences could be helpful to public health policy makers by doing the following: 1. Delineating the socio-cultural, economic, and political elements of the public health problem; 2. Identifying the central barriers to treatment for the patient population and the interplay between the patients’ health problems and other socioeconomic problems; 3. Analyzing the pitfalls in current public health interventions; 4. Suggesting concrete solutions for overcoming some of these difficulties (this last step is often a very controversial one). Studies addressing the health knowledge, attitudes, practices, and beliefs of patients could be of interest to policy makers; the conclusions of these studies might then be useful in devising public health interventions. But focusing only on these factors, while omitting other equally important social, economic, psychological, and political issues could result in ineffective public health programs. The following example from a multidisciplinary study demonstrates how an understanding of cultural factors (e.g., the beliefs and health practices of patients) is useful but not sufficient for addressing complex public health problems (10,11). Ethiopian Israelis have complex and multifaceted ways of understanding and discussing jaundice, an early manifestation of hepatitis B infection. For many Ethiopian patients, one of the etiological explanations for jaundice is “a bat urinating on the patient.” There is a simple traditional method of treating it, there is no need for prevention, and it is never fatal. Many Ethiopian patients see no connection between jaundice and cirrhosis or hepatic carcinoma (10). With these patients, an attempt to justify systematic follow-up with liver function tests is problematic, since they find little meaning in the notion of an asymptomatic viral carrier state. In addition, since blood has deep-rooted cultural and social meanings for Ethiopian immigrants (for example, it is often said that “blood is the source of the soul”), blood sampling is in itself problematic and is only justifiable in case of overt illness. It was important to consider all these cultural elements when devising a public health strategy to prevent hepatitis B virus (HBV) infection and its complications (cirrhosis and hepatocellular carcinoma) among recent immigrants (11). We later discovered that the Ethiopian aversion to blood drawing was also related in part to a political-religious conflict between the new immigrants and the Israeli Rabbinate (12). When Ethiopian immigrants first came to Israel, they were required to undergo a symbolic conversion ceremony “in an attempt to clarify several anomalies in the personal religious status of Ethiopian Jews” (13). This symbolic conversion, referred to as “conversion in doubt,” included three elements:

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symbolic recircumcision (a process whereby a drop of blood was drawn from the tip of the penis), ritual immersion, and a declaration of willingness to keep the Jewish commandments (12). Many Ethiopian immigrants felt that these policies were humiliating, racist, and an offense to their Judaism, which they had fought so hard to retain in Ethiopia. One of the manifestations of their tension over this conflict was a rumor circulating among some Ethiopian Israelis that blood tests were being used to distinguish between Jews and non-Jews (11). This fear contributed to their reluctance to undergo blood tests. Doctors and rabbis were also viewed as part of the same authoritative system, and therefore the Ethiopian rejection of certain biomedical procedures was in part an expression of their resistance to authoritative structures that they felt were oppressive. The above example demonstrates the importance of social science research not only in identifying cultural gaps between doctors and patients, but also in elucidating political and religious issues that directly impinge upon the health and well-being of patients. Most of the lessons learned in connection to HBV infection have contributed to the development and implementation of a prevention program for AIDS among Ethiopian immigrants, which demonstrates how social science can aid in the development of more effective public health interventions (14,15). With respect to TB control, all who are familiar with the practical aspects of operating in Western countries will appreciate the notion that, for this disease, organization takes precedence over clinical acumen; in the terminology of public health, case management is far more difficult to achieve than case finding. These difficulties are compounded when dealing with a migrant population. The perspective of immigrant patients with respect to the meaning of illness and the effect of the treatment on their lives may differ considerably from that of their health providers. Moreover, the well-intentioned efforts of health providers may not coincide with what is actually needed by the target population. Thus, a health program adapted to an immigrant population should take into account the socio-cultural characteristics of this population (16). In this situation the tools of medical anthropology, which are eminently suitable for the analysis of this type of problem, may be applied. In order to identify the barriers to treatment of TB, it behooves both the health-care worker and health institutions to ask the following questions regarding all patients and the immigrant patient population in particular (17). Are there adequate health facilities? What are advantages and limitations of the services provided? What economic barriers do patients face? Do they have adequate resources to pay for transportation costs, health visits, medications, etc.? Are there other structural barriers such as racism, institutional discrimination, and stigmatization that dissuade patients from seeking treatment? Do patients’ views and understanding of TB coincide with those of the health provider?

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Are their notions about life, well-being, malaise, disease, and death the same as the dominant society? And if not, what are they? What types of healers and medical techniques do patients seek and why? If they are not taking treatment for their disease, why not? What implications do the management of their disease have on the patients’ perception of themselves, their families, and the community structure? What will be the impact of public health interventions on the target population? Some additional issues to consider when working with immigrant populations include: Are there any legal barriers (such as illegal residence) that would prevent patients from seeking care from health institutions? Are there any political or religious conflicts between the immigrant population and the dominant society that impede successful treatment? What type of prevention practices were used in the society of origin, and how did these practices influence the management of the disease? How were attempts at prevention by the absorbing society perceived by the immigrants? How does their disease and its treatment affect their integration process, and in turn how does the integration process into the host society influence their choice of treatments and their experience with TB? To answer in depth this lengthy but not comprehensive list would be, in the context of clinical medicine, an impractical task. However, we recommend that it serve as a checklist for health-care workers for the treatment and prevention of TB among hard-to-reach populations. In addition, we argue that it is relevant to incorporate the above questions in any public health program for TB and to enlist, as soon as possible, the help of social scientists in the design of the program. The effort to deal with these issues in a TB-control program requires extensive cooperation between health institutions, physicians, social scientists, policy makers, and patients. Multidisciplinary expertise is required not only because of the inherent complexity of the problems, but also because the parties involved— the patients, the immediate health-care providers, and the health establishments have different perspectives with respect to the prevention and/or treatment of TB. This type of cooperation is helpful in ensuring that the prevention and treatment strategy adopted addresses mainly the needs of the target population and not, as often inadvertently occurs, those of the provider. The large cultural gap between the immigrant and host country may require an inevitable adaptation on the part of the immigrant in the integration process.

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Concomitantly, a parallel process of change is also called for in the integrating apparatus. This usually occurs as a spontaneous pragmatic process in response to difficulties arising in the field, rather than as part of a concerted cooperative endeavor. Ideally this should be a constructed dialogue (in planning and implementation) in which a paternalistic or authoritative approach should be avoided as much as possible. The target population should be encouraged by health and integration institutions to play an active role in health promotion, and the TB-control program should aim to empower both individuals and the community as a whole to participate in the responsibility for their health promotion. III. Some Basic Concepts in Social Science Social science analysis of disease processes should be multifaceted, placing individual illness episodes within the broader social and historical context of the society in question. The biological aspects of disease comprise only one dimension of the illness experience. The term “illness” also refers to the psychological, social, and cultural dimensions of suffering that shape the experiences of afflicted individuals (18). Social constructs of disease categories and interpersonal support networks often have profound effects on individual symptomatology (19). The social environment molds the experience of the individual and is in itself transformed by the illness process. The suffering of patients directly affects family and close friends (20) and extends, “to the practitioners and institutions who care for them, and to their neighborhoods and the rest of society” who are “affected profoundly yet differently by its consequences” (21). The relevant use of the social sciences in medicine (and in TB control as outlined above) will be enhanced by an understanding of some of the theoretical approaches and concepts of the discipline. An exhaustive introduction to cultural anthropology is beyond the scope of this chapter. Rather, we have chosen a few anthropological examples that should provide our readers with the tools to approach TB control with a broader perspective. One of the main concepts that has been debated in anthropological discourse is the concept of the “representation system” (22), its components and mode of operation, and its role in the interpretation of disease by all involved in the healthcare process. By “representation” we mean the different interpretation that each participant in the process—the patient, the health-care workers, and the system in which they work—may attach to an issue (in our case TB). It brings not only a different understanding and representation of what pathophysiologically is a single entity but, most importantly, input back into the system creating and adding new meanings and often unpredictable dimensions to the issue. According to one school of thought, representation systems may be presented as entities constructed by a society forming its culture, which are detached

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from the individual but specific to the human group sharing them (23). Another approach attributes to certain innate dispositions of the human spirit a cultural representation of the world which, at the core, is the same for all human beings and therefore for all societies, with different expressions for different cultures (24). Defining representation as evolving from either the collective experience of a society or as an expression of the individual spirit could be enlightening and provides an historical, methodological, and theoretical framework for some of the basic tenets of anthropology (25). While examining the history of anthropology, Augé identified two major orientations: meaning-centered analyses and function-centered analyses. He argues that these two orientations (meaning and function) do not encompass the whole of reality. He states that “even if anthropology maintains an essential meaning and function . . . it must, in the end, merge into an established social science where meaning and function, symbolism and history would no longer be at odds” (25). Cathébras discusses two subdisciplines of medical anthropology (26): socio-cultural epidemiology and ethnomedicine. Socio-cultural epidemiology, among other issues, seeks to study the relationship between “modernization” and psychosomatic symptoms as well as numerous socio-cultural aspects pertaining to AIDS* (27,28). Ethnomedicine, on the other hand, focuses on “the set of beliefs and practices relating to illness in each society” (29). It also examines the social uses of illness, namely how a society uses illness to elaborate and maintain its social system. Ethnomedicine has sometimes had the tendency to distinguish between “empirical-rational” and “magico-religious” aspects of medicine. Foster (30) further elaborated this approach in distinguishing between “personalistic medical systems” and “naturalistic medical systems.” In the former type of system, the illness’s etiology lies in the deliberate intervention of a human agent, a nonhuman (spirit, ancestor) or a supernatural being. In this case, the illness is but an expression of the misfortune of which the patient is a victim. Medical and religious practices are thus closely intertwined in order to “reject the aggressor or expel the evil” from the victim (30). In “naturalistic medical systems,” the illness’s etiology lies in the loss of balance between the natural forces or elements (such as cold, heat, humidity, dryness, yin, yang, etc.) contained in the human body. In this case, illness has nothing to do with any form of discontent. The patient is not a victim; on the contrary, he or she is responsible for the illness’s occurrence and could

* The bibliography on this subject is extremely large. Several articles have been published in journals such as Social Science and Medicine and Sociology of Health and Illness. One of the latest calls for multidisciplinary collaboration between public health and social science professionals was made at the Second European Conference on the Methods and Results of Social and Behavioral Research on AIDS, Paris, January 1998.

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have prevented it. In fact, treatment does not involve magic or religion. According to Foster (30), these two types of systems are often present in the same society, although in varying proportions. Cathébras (26) argues that “the distinction between natural and supernatural causality has but a very relative value: to believe in germs (when one has never seen any) and to believe in spirits, comes down to the same thing.” In the view of one theorist, there are at least three distinct levels of causality of illness (31) the immediate cause (such as the germ), the agent that possesses the harmful force (the person who transmitted the germ to me), and the ultimate, personalized, cause (e.g., the violation of a prohibition that made me vulnerable). According to Cathébras, “modern medicine limits its field of investigation and action to the realm of the immediate cause. It is ethnomedicine that teaches us that man is continually seeking, more or less vaguely, for a deeper meaning for his unhappiness: Why is this happening to me, and why today?” (26). Many anthropologists argue against reducing medical systems to a model of either “personalistic medical systems” or “naturalistic medical ones” (26,32,33). Augé argues that these models are reductionistic and ignore the fact that the two systems described co-exist within the same society and even within the same social group (26,32). Moreover, this natural/supernatural dichotomization is oversimplified, ignoring the rich and complex nature of social interactions and the fact that people’s experience with disease is influenced by political, social, and economic factors (32) as well as by cultural conceptions of the body and the self (33). Patients (both in western and nonwestern settings) often view their illness in much broader terms than a simple natural/supernatural polarization. Rather than separating the medical, social, communal, spiritual, and psychological aspects of disease into discrete and fragmented units, patients weave all these various facets of disease together in their response to representation of their illness. Many anthropologists focus on these social dimensions of illness (32,34) and the ways in which illness episodes both influence and are influenced by the surrounding environment. According to Augé (34), both in African and western societies, “the relationship between society and disease should not be reduced to a causal link.” For Kleinman (35), an experience-near approach to illness and suffering must begin with an understanding of “what is at stake for the subjects of study in their local moral worlds.” According to Kleinman (35), confining the discourse on suffering and illness to the domain of the individual precludes a deeper understanding of suffering as an intersubjective phenomenon, which affects and is affected by family, community, and larger social groups. Augé also argues that ethnomedicine highlights an evolutionist perspective in which western efficiency acquires supremacy (32). He claims that western science at times imposes upon other cultures a dichotomy between empirical-rational and symbolic domains, even when the cultures themselves “do not differentiate between a sphere accessible to knowledge and a sphere only accessible to

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faith” (32,32). Augé and others (26,32) argue that this natural/supernatural rift may also be a projection of some anthropologists in support of their theories (32). Other theorists argue that an exploration of the health beliefs of other cultures in an effort to correct misconceptions and alter health behavior can be problematic. For example, Good (33) argues that the word “belief” in the discussion of health cultures often connotes doubt, error, or falsehood and is often juxtaposed to the “knowledge” put forth by the biomedical model of disease. Good points out that, whereas “belief” is often discussed with respect to mistaken understanding of the “natural world,” it is often assumed that science can distinguish knowledge from belief (33). In line with Augé’s critique of the natural/supernatural dichotomy (32), he argues that one of the problems with studying the “health beliefs” of other cultures (as is done in ethnomedicine) is that researchers often presuppose the supremacy of western science and consequently reaffirm the power differential between the researcher and those being studied. As is becoming increasingly clear, the view that medicine and science lie external to culture is no longer tenable. Good (33) argues that “the language of medicine is hardly a simple mirror of the empirical world. It is a rich cultural language, linked to a highly specialized version of reality and system of social relations, and when employed in medical care, it joins deep moral concerns with its more obvious technical functions.” Another problem with the “health-belief” model of disease mentioned by Good is that it is inaccurate to assume that we can always deduce “beliefs” from statements people make about what they think. He states that “discourse is pragmatically located in social relationships, all assertions about illness experience are located in linguistic practices and most typically embedded in narratives about life and suffering” (33). Researchers also point out the difficulty of communicating to physicians the importance of taking into account cultural context in their work. Physicians are often looking for quick formulas on how to deal with culturally diverse groups, whereas the anthropologist feels that such an approach reinforces cultural stereotypes (33). Many anthropologists grapple with the question of how physicians can be taught “cultural competence.” If physicians and anthropologists collaborate, the physician can gain a broader view on culture and on the ways in which illness episodes are both culturally and socially embedded. In line with the views of Augé, Good, and Kleinman, we found it important to understand the social and cultural context of disease for Ethiopian Israelis in order to develop approaches for treating patients in a holistic manner, addressing the social, political, economic, and cultural barriers to treatment. The tools of social science helped us understand the “collective representation” of TB among Ethiopians and how the “shared meanings” surrounding TB were embedded in the larger socio-political context of Israeli society. Ethiopian patients often viewed their disease in broader terms, where moral, spiritual, religious, social, and philosophical concerns were viewed as essential components of the illness experience. As will be shown below,

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we are attempting to encourage physicians to adopt a broader definition of illness, considering the various dimensions of the illness experience in their interaction with patients.

IV. Some Key Perspectives in the Social Science Literature on TB Much of the social science literature to date focuses on the problem of noncompliance and the failure of health-care providers to take into account the perspective of patients. For example, in one study of tuberculosis control, the authors conclude: “Poor patient compliance has been and remains the principle cause of treatment failure in both developing and developed nations” (36). In another study, the authors argue that “effective care of patients also requires understanding of one’s ethnic identity and related conception of illness” (37). Noncompliance is often attributed to the inauspicious knowledge, attitudes, beliefs, and behaviors of patients. According to this paradigm, patients (usually in nonindustrialized, poor settings) harbor a set of traditional beliefs and attitudes that conflict with the biomedical models of their providers. These patients believe their tuberculosis to be caused by witchcraft, sorcery, spirits, voodoo, or God. These beliefs prevent patients from seeking appropriate medical treatment and at the same time lead patients to “default” from chemotherapy treatment regimens. Furthermore, lack of knowledge concerning the cause, modes of transmission, and treatment of tuberculosis greatly contributes to noncompliance. The knowledge, attitudes, and beliefs of the patients lead to “inappropriate” health-seeking behavior and ultimate treatment failure. Interventions should therefore focus on improving compliance by correcting patients’ “misconceptions” and knowledge gaps concerning tuberculosis and making treatment more culturally sensitive by incorporating patients’ beliefs into the treatment process (38–40). The studies outlined above adhere to the “knowledge, attitudes, beliefs, and behavior” model for analyzing the problem of TB compliance. During the 1960s these studies came into vogue and have continued to be popular up to the present day. Focusing primarily on cultural factors intrinsic to patients, these studies are valuable, because physicians have often ignored culture as an important factor in treatment completion. Moreover, these studies are useful in pointing out that patients’ views on tuberculosis and its treatment often differ from those of their providers. It is important to understand these differences when devising health education for patients and in helping doctors and patients overcome communication barriers in the clinical setting. Some TB treatment centers integrated the results of cultural studies and made use of them to develop tools such as foreign language videotapes for refugees (41). Nevertheless, these studies are at times limited in their scope and often have the tendency to blame the problem of treatment non-

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completion entirely on intrinsic aspects of patients, without reflecting upon drawbacks in the treatment facilities themselves. A recent paper by Farmer (7) points out many of the limitations of studies that focus primarily on noncompliance and on the “knowledge, attitudes, beliefs, and behaviors” of patients. Farmer argues that a focus on noncompliance mistakenly assumes that patients have the choice to comply or not comply with treatment. He suggests that calls to change lifestyle and behavior are often made to precisely those persons whose agency is most constrained. He challenges the validity of the statement that noncompliance remains the most significant barrier to tuberculosiscontrol efforts by pointing out that nearly 50% of patients with TB worldwide go undetected because they have no access to medical treatment. Even for those who have access to a medical facility, it is often difficult to make clinic appointments when the patient is employed or needs to travel several hours to the clinic each day. Financial barriers are another reason that people may not comply with therapy, because a TB chemotherapy regimen may consume nearly half of the patient’s income in certain regions (7). Farmer argues that the real barriers to treatment are poverty, malnutrition, political and structural violence, racism, homelessness, and lack of access to medical facilities and poorly planned public health projects (7). In a small community health program in Haiti, where TB medication was provided free of charge, Farmer et al. (42) examined the impact of financial aid, incentives to attend a monthly clinic, and the use of trained village health workers on treatment success. When supplemental food and income were provided, TB outcome significantly improved and cultural factors were not significantly associated with TB treatment completion. The authors argue that anthropological studies into cultural understandings of illness beliefs, albeit interesting, direct attention away from the more significant social and economic inequalities that constitute the prime barriers to successful treatment. Other studies have shown that when supporting the integration of cultural aspects in TB programs, it is important to take into consideration pragmatic issues in order to be effective. For example, a study in Honduras (40) went to great lengths to elucidate why patients ignored recommendations for TB diagnosis and treatment. Little mention was made of the need to facilitate access to care, nor was the adequacy of resources addressed. The lack of attention to accessibility was manifested when the elaborate plans mentioned in the paper for improving sputum collection were frustrated by the government agency’s failure to provide the special sputum cups ordered for the program at the time that they were needed. Although Farmer et al.’s conclusions are central to TB-control programs in developing countries, they mention that cultural factors and social stigma may be relatively more important in westernized settings that have already eliminated economic and structural barriers to treatment (42). As will be shown below, our study on Ethiopian Israelis addresses additional barriers to treatment, which arise when larger economic and financial concerns are eliminated from the equation.

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While agreeing with Farmer that economic, political, structural, and social factors are important determinants of patient adherence, Sumartojo (43) discusses how an understanding of cultural factors may be useful to treating physicians. She states that “the most appropriate use of research findings on cultural factors may be a combination of accurate cultural knowledge and skillful listening, the effective communication of information, and a determination to interact with the patient despite cultural differences” (43). In spite of her support for cultural studies of patient nonadherence, Sumartojo warns researchers and program administrators to avoid simplistic or stereotyped views of culture. Another issue discussed in the literature consistent with the above viewpoints is that patients and health-care workers often have different perspectives concerning the essential barriers to treatment. While doctors often focus on patient-centered factors and attribute treatment failures to social and cultural characteristics of their patients, patients often attribute treatment failures to problems with the treatment facilities. For example, in one early study in San Francisco (44), physicians argued that the prime barriers to treatment were the patients’ lack of education, ignorance, and language problems. Patients, on the other hand, ascribed treatment failures to problems with the clinical facilities themselves such as inconvenient clinical hours, problems with the treating physicians, failure of health services to properly explain their diagnosis and treatment, and prolonged waiting time for clinical appointments (45). When clinical staff became aware of the patients’ viewpoints, clinic work was reorganized and missed appointment rates dropped from 26 to 4% (46). Similarly, in a description of the experience with TB among the Maya Indians in rural Mexico (47), the author describes how change in local religion and the introduction of western medical health care services, including the use of indigenous paramedics, caused an increasing use of these services. Regarding the treatment of TB, nonadherence to treatment was influenced by patient beliefs, but also by poor paramedic supervision. Patients who completed treatment were convinced of the severity of TB and its prolonged course, even though they did not necessarily subscribe to the biomedical model of disease. A positive relationship with the treating paramedic was an important factor for treatment adherence. In addition to the factors mentioned above, some researchers argue that social stigma towards TB patients may contribute both to treatment nonadherence and to delays in seeking appropriate medical treatment (48). For example, in one study conducted in Mexico City, the authors discussed the fact that patients returning home after long hospitalizations found themselves rejected by their families. This enhanced a propensity to ignore or deny overt illness in order to avoid ostracization by the immediate family (47). In another study, the authors point out that rejection by the patient’s family members led to premature termination of treatment, whereas support by the immediate family and the health care provider positively affected treatment (49).

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The perception and interpretation of TB symptoms as triggers for seeking out medical care vary among population groups. For example, in one study conducted in two major Indian cities (50), patients sought medical care on their own initiative in the early stages of the disease. In contrast, in another study conducted among people of Mexican origin in Texas and California, the authors found that patients regularly disregarded early symptoms (51). In a study undertaken in south Texas, patients attributed their early symptoms to easily treatable causes (51). Other studies have highlighted the diversity and variability with respect to understandings of TB for individuals from a particular cultural and social group (45,52). Physicians may therefore need to adopt different strategies for individuals of different cultural backgrounds, while not assuming that all patients from the same cultural or social group will have the same response to, and representation of, TB. Of several types of interventions to improve adherence to TB treatment regimens, Sumartojo (43) stresses the importance of comprehensive services in a TBcontrol program. In her evaluation of a number of TB programs, she argues that the best programs typically have holistic views of patients and their needs and use a variety of different approaches to address treatment adherence. Program successes are often attributed to factors such as specialized medical teams, careful patient follow-up, economic incentives for patients, assistance with social, medical, and financial problems, improved attitudes on the part of professional staff, greater patient convenience, and treating patients with courtesy and respect. Sumartojo also warns that despite an attempt by researchers and policy makers to find one all-encompassing problem to account for treatment nonadherence, “the reasons for poor adherence are many, and many interventions will be needed to address it.” In accordance with Sumartojo, we agree that multiple strategies are needed to improve treatment completion. We consider many of the strategies discussed above in our investigation of barriers to treatment among Ethiopian immigrants in Israel (53,54).

V. An Anthropological Study of TB Among Ethiopian Immigrants in Israel A. Background

The incidence of TB in Israel rose from 50 cases per 100,000 in 1948 to 200 cases per 100,000 by 1951 due to mass immigration (55). TB control was achieved by nongovernmental organization clinics with aid from the Ministry of Health (MOH), and rates fell to 4–5 per 100,000 by 1985. Subsequently the TB infrastructure was dismantled (55). When approximately 7400 new Ethiopian immigrants arrived in 1985, the incidence of TB almost doubled. Due to screening and subsequent treatment, the rate dropped to a low of 4 per 100,000. With a second wave in 1991 of some 14,300 persons, it rose again to 10 per 100,000. (With immigrants coming before, in between, and after these two waves, the total popula-

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tion originating from Ethiopia is 65,000—out of a total Israeli population of 5.9 million at the end of 1996.) The integration process of these last waves of immigration coincided with the entry of a total of 737,000 new immigrants (1990–1996), mostly from the former Soviet Union (56). The increase of the population of Israel by some 15% within a period of 7 years presented a formidable challenge to the country’s absorption capacity in general and to TB-control structures in particular. In addition to the expected difficulties associated with integration into a new country, there were socio-political conflicts between the newcomers and the institutions responsible for their absorption and health management, which undermined their confidence in the treatment provided by health-care personnel (see below). New Ethiopian immigrants were screened upon their arrival with chest xrays and tuberculin skin tests in special absorption centers. Active TB was treated with short-course therapy, and medication was not supervised. A formal prospective historical study of the rate of completion of therapy revealed that for at least 40% of the TB patients notified to the MOH for the period 1990–1992, there was no documentation of treatment completion (57,58). A highly significant association was found between TB treatment outcome and district health offices (as a proxy variable of the regional TB clinics), suggesting that there were deficiencies in the current treatment facilities that partially accounted for the low level of treatment completion. The study showed that the best rates of completion of treatment were obtained by five clinics, and almost 70% of the patients who completed their TB treatment were treated in these clinics” (57). The Ethiopian immigrants were a culturally unique group from a highly endemic TB area (59). As part of the measures we took to contain the rise in TB, we conducted a study on barriers to treatment among Ethiopian immigrants, addressing the cultural, social, political, and economic factors that impeded successful treatment. We were aware that there existed a perception among the Israeli public that the Ethiopians are a “diseased group.” There was also a prevailing negative attitude among health-care workers, who perceived Ethiopian patients as “difficult” to treat for a variety of reasons (60). We were also aware that many Ethiopian patients did not subscribe to western biomedical constructs and treatment (61). We felt there were grounds for a more systematic approach to these problems and therefore resolved to address these issues with the tools and approaches of social science, particularly cultural anthropology, as outlined in the introduction to this chapter. Our objectives in this study were to improve treatment completion among Ethiopians, to uncover deficiencies in the current TB-control apparatus, and to elucidate the problems in communication and cooperation between Ethiopian patients and Israeli health-care providers. Another main objective of our research was to understand the relationship between treatment compliance and problems with integration into Israeli society in general. We sought to understand the psychological, social, spiritual, and religious connotations of TB for Ethiopian Is-

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raelis and to study the reasons underlying both the compliance and noncompliance of Ethiopian patients. Our intent was to use the findings of our study to ensure that directly observed therapy (DOT) would be implemented in a manner that incorporates the expressed concerns and needs of patients. B. Preliminary Results

As it is impossible to elaborate upon most of our findings in this article, we briefly summarize some of the main barriers to treatment discovered in our research (53,54) relevant to the implementation of the new Israeli TB-control program. In our study, the barriers to treatment included cultural, social, structural, and political problems. We outline each of these factors below.* Cultural barriers to treatment were important in the following contexts: (1) There was an overall aversion to ingesting large quantities of antibiotics and a cultural preference for injections over pills. The problem with ingesting large quantities of pills was heightened in the recent past when there was a shortage of 300 mg isoniazid tablets and patients were required to take many 50 mg tablets. (2) When Ethiopian patients felt that health-care worker failed to respect their cultural heritage, they were less likely to comply with the directives of their physicians. (3) There was no direct Ethiopian translation for tuberculosis and therefore there was confusion among patients concerning the severity of their diagnosis. The usual Amharic terms to describe tuberculosis were yesal beshita, translated literally as the coughing disease, or less commonly yesamba beshita, the lung disease. These terms referred to a host of conditions ranging from the common cough to bronchitis to a deadly disease culminating in the vomiting of blood. In Ethiopian medical circles, the term for tuberculosis is yesamba nekeresa, which translates directly into cancer of the lungs. The ambiguity in nosological terms due to the lack of relevant Amharic terminology was unknown to Israeli health-care providers. These confusions created frustrations in the clinical setting on the part of both doctors and patients and may have contributed to treatment noncompliance (53). Although cultural factors created important conflicts in the clinical encounter, other problems seemed to have an even more significant impact on treatment completion. First of all, there were problems in the overall effectiveness of the treatment facilities. Many health-care providers complained that their budgets were limited and there was consequently no organized system of follow-up to ensure that patients diagnosed with tuberculosis were taking their medications. Moreover, patient education was not emphasized in current treatment facilities, and consequently patients were often not fully informed about the etiology, course, and treatment of TB. Although DOT was being implemented in several health facilities, most facilities still relied on patient self-medication, an approach * Much of the material from the following section was summarized from the MA dissertation of Sheri Weiser (53).

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to treatment that has proven less effective in many studies (57,62–64) and which has undoubtedly contributed to treatment failures. We further elaborate upon structural barriers to treatment below when discussing the implementation of the new Israeli TB-control program (65). For Ethiopian Israelis, attitudes towards physicians proved to be one of the most critical determinants of patient adherence (53). If the doctor was perceived to be respectful and caring and took the time to provide a comprehensive physical exam, patients were often willing to comply with their directives. On the other hand, if the doctor was perceived to be rude, impatient, or condescending, patients often lost faith that the doctor’s remedy could help them. Health professionals did not always adequately explain to patients the rationale underlying chemotherapy treatment and why it was essential that they strictly adhere to their treatment. Although most physicians attempted to explain TB treatment to their patients, they were ill equipped to do so because of linguistic, cultural, and other communication barriers. Thus, if Ethiopian patients did not know why it was necessary to take their medications and did not trust their physicians, patients saw no reason to follow the directives of health-care workers and turned instead to traditional healers, who addressed their needs in a more holistic manner. Much of the distrust for physicians was integrally related to problems with integration into Israeli society in general. The often marginalized position of most Ethiopian immigrants in Israeli society, their lack of access to power, and their feelings that authority figures have treated them in a condescending, paternalistic manner contributed indirectly to problems in the clinical setting. It is impossible to isolate the clinical environment from the broader social, political, and historical contexts that characterize the life of Ethiopians in Israel, because problems in society at large are reproduced in the interaction between patients and doctors. For example, the conflict between Ethiopian Israelis and the Chief Rabbinate concerning the validity of their Jewish origins, and Ethiopians’ anger at their discovery that for years their blood donations had been discarded, have important implications in the health-care setting, as discussed elsewhere (see also Ref. 66). Although, as mentioned above, economic constraints are often the primary cause of treatment failure in hard-to-reach populations, in our study economic factors did not play a large role in treatment noncompletion. This is because the Israeli Ministry of Health attempts to eradicate many of the direct economic barriers to treatment by covering the cost of medical treatment (and medication) and most of the transportation costs to and from the clinic (65). There are also a plethora of social, economic, and medical services targeted at new immigrants, helping to ensure that their basic needs in Israel are met. Nevertheless, Ethiopian Israelis are still affected by employment, housing, and educational problems, and these problems may indirectly interfere with adherence to treatment when patients are far less concerned with their disease than with their other overwhelming dayto-day problems.

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Stigma within the Ethiopian community also did not seem to influence treatment completion significantly. On the other hand, stigma in the larger Israeli population, manifested in the widespread perception that Ethiopian Israelis are “primitive, backward, and diseased,” had negative repercussions in the clinical encounter and negatively affected treatment completion. This was particularly the case when physicians harbored negative attitudes towards Ethiopian patients. Table 1 summarizes many of the aforementioned factors that contribute to treatment failure, emphasizing both barriers to treatment relevant to all TB patients and unique barriers to treatment found in the Ethiopian community. It is Table 1 Barriers to Treatment for All TB Patients and Some Unique to Ethiopian Israelis Barriers relevant to most TB patient populations Inadequate TB treatment facilities Difficulty to pay for transportation costs, visits to physicians, and medications (not relevant to the Ethiopian Israeli context) Poor patient follow-up and patient education Discrimination, racism, and other structural problems Patient frustration over the duration of treatment Patients feel well after a few weeks and are therefore not physically motivated to adhere to treatment Difficulty ingesting a large quantity of pills Stomach cramps and additional side effects including dizziness, nausea, and vomiting Difficult to remember medications in the midst of busy daily circumstances; time-consuming and inconvenient to take medications Fear among pregnant women that tablets will harm the baby Lack of a caring, respectful relationship with the health provider Lack of “laying on” of hands during the medical interview Source: Ref. 54.

Additional features specific to Ethiopian immigrants Overall negative attitude towards ingesting tablets Preference for injections over pills Medicine may treat some symptoms but it cannot treat the roots of their suffering: social, economic, religious problems, and disruption of their lives brought about by the dramatic life changes in Israel Problems with integration into Israeli society and major social and political conflicts, which negatively affect treatment completion A sense of mistreatment by Israeli authorities leading to rejection of health behaviors identified with the dominant health model Overall perception of the Ethiopian community as primitive and diseased Problems with translation impede communication between doctors and patients

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clear that although some aspects of the Ethiopian Israeli situation were unique, many of the most important barriers to treatment for Ethiopian patients are probably similar to problems encountered elsewhere. We are using the factors outlined in the table in the creation of educational programs for both Ethiopian patients and Israeli health professionals.

VI. The Contribution of Social Science to the New National Program for the Elimination of TB in Israel We recently had the opportunity to implement some of the principles elucidated above while setting up a new national TB program. Before discussing specific changes in the TB-control program designed for recent immigrants, we summarize some of the main structural problems with existing TB-control services as well as how the new Israeli TB-control program tried to overcome these barriers to treatment. As mentioned above (57), contrary to the opinion of many health workers, it was not possible to explain treatment failures only in terms of the cultural beliefs, attitudes, and practices of the new immigrants. It was found that existing TB services were deficient. Organizational efforts were therefore needed in order to overcome problems with existing TB services. We identified the following problems in TB services (57). TB treatment was self-administered, often in nonspecialized hospital outpatient facilities carrying small TB caseloads or in clinics that lacked expertise for TB management. There were often difficulties in obtaining drugs (particularly some of the second-line drugs), and there was inadequate follow-up of patients. Consequently, drug taking was erratic, increasing the possibility of relapse of active disease or of the emergence of multidrug-resistant strains. The transfer of responsibility for TB management from the MOH to the four Health Management Organizations (HMOs) operating in Israel further compounded these infrastructure problems. It led to dispersion rather than to muchneeded concentration of efforts needed to contain the added TB caseloads (67). In addressing these organizational problems, we have restructured the system of TB control in Israel (65,67,68). First, we are providing DOT for all patients. DOT is being monitored through District Health Offices (DHOs) by the National TB and AIDS unit. We could not afford to provide DOT through health-care providers dedicated solely to the management of TB, as has been done in New York City (69) and other programs in the United States. Therefore, we devised a system whereby DOT is given for the most part in primary health-care clinics managed by the four HMOs active in Israel under the National Health Bill. The DOT is directly organized by the TB clinics and under the supervision of the DHO. All citizens belong to one of the HMOs and have free access to a primary health-care clinic. This means that almost all of the costs associated with admin-

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istering DOT are covered within existing budgets. There is no need for additional manpower since the burden is spread throughout the existing health-care infrastructure and usually no more than one or two patients are cared for at any particular location. Patients receive DOT in an easily accessible clinic in their neighborhood. Additional funding has been allocated to ensure patient accessibility to health facilities (e.g., travel expenses are often reimbursed). When use of a primary care clinic is not feasible for patients, the program covers the costs of home visits for DOT. But this is the exception to the rule. Since we previously found that the best results for completion of treatment were concentrated in clinics with large caseloads (57), we have designated nine centers for the treatment of TB located in geographical areas coinciding with the distribution of TB patients in the country (65,68). These centers are responsible for recommending a medical treatment regimen, providing the treatment, and providing follow-up for patients in that locality. After the initial assessment, patients are followed monthly or more frequently as their situation demands. This approach has done away with the fragmentation of resources that existed previously. It also has enabled us to communicate more efficiently with TB field workers and institute our specific recommendations for Ethiopian patients. Two national TB laboratories have been set up to facilitate accurate and rapid diagnosis of all bacteriological specimens and to screen for multidrug-resistant strains (65,70). To ensure optimal inpatient treatment, all inpatients are hospitalized in two national TB departments (65). Finally, to ensure that there are regular supplies of first- and second-line drugs, centralized purchasing of TB drugs has been arranged (65,68). As part of the program, we are including an ongoing system of evaluation, and we will begin the first stage of evaluation at the end of the first year of the program’s implementation. Since two thirds of TB patients are immigrants from either Ethiopia or the former Soviet Union, we intend to implement additional strategies to eliminate community-specific barriers to treatment. We have formulated a number of practical recommendations for health-care workers involved in care of Ethiopian patients based on the findings of our study and are in the process of implementing them in the new TB-control program. Many of these recommendations may also be valid for other patient populations. Some of the measures we are implementing in response to this study are as follows (53): 1. The provision of comprehensive health education that is both culturally appropriate and empowering to patients. In improving patient education for Ethiopian immigrants, the Ministry of Health has instituted a communitywide education program run by Ethiopian health workers. Seven Ethiopian health educators have been trained under the direct supervision of a nurse/health educator also of Ethiopian origin.

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Chemtob et al. These educators are active within the community, involved in the follow-up of Ethiopian TB patients, and liaise with the TB clinics and the district health offices that monitor the clinics. Medical staffs at the TB clinics have been asked to carefully explain to their patients (with the help of these Ethiopian health workers) the mode of transmission of TB, the rationale for prolonged chemotherapy treatment, and potential side effects of the medications. They should repeat these explanations several times until it is clear that patients understand their explanations. Most of this work is done not by the physician, but by the clinic nurses, who have a much more intimate relationship with the patients since they set up the patients’ treatment DOT program, collect sputum samples, and schedule appointments. We feel strongly that education should aim to present scientific principles in an appropriate fashion and should avoid the assumption that patients are uninterested or unwilling to learn about science. We emphasize the need to avoid paternalistic attitudes and exchanges. 2. Both Ethiopian health workers and other Israeli health-care professionals should immediately address any social or economic barriers to treatment. If patients are unable to make clinic appointments because they conflict with household or work-related duties, there is funding under the new national TB program for creative and flexible solutions for such problems. Nevertheless, it will take time for the staff of our clinics to adjust to these new concepts and to make use of new options offered by the new TB-control program. We stress the importance of a holistic view of patients’ needs, which includes an understanding of the social, political, and economic context under which disease unfolds. Consequently, education about the Ethiopian socio-political situation and culture has been provided to treating staff. 3. Whenever possible, we plan to enlist the support of respected community members, including traditional healers, to assist in persuading patients to visit doctors and strictly adhere to a chemotherapy regimen. We feel that it is important for doctors to cooperate with traditional healers (especially for difficult cases) and to remain open to patients’ choices to use traditional remedies along with antibiotics (this is not particularly relevant for other diseases). If patients wish to attend to the spiritual or social aspects of their illness, Ethiopian interpreters can encourage patients to complement their biomedical regimen with periodic visits to traditional healers. 4. Within the framework of the new centralized management of TB patients, it has become possible to encourage a system of courtesy, tact, respect, and politeness, which hitherto has often been lacking. This implies that doctors may initially need to spend more time

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with each patient, but in the long run a few successful visits will be more time- and cost-effective than many shorter unsuccessful ones. We suggested having bread or enjara, a traditional Ethiopian food, present in waiting rooms to create an atmosphere of comfort and hospitality. We emphasize the importance of treating all patients with dignity. We have therefore been stressing to health providers the importance of displaying sensitivity to the social circumstances, values, cultural expectations, and disease constructs of Ethiopian patients (and other patients whose values differ from those of their providers). The need for laying on of hands, the physical examination, is one of the most important ways to gain trust and confidence in the eyes of these patients. Comprehensive physical exams will both help determine the current health status of patients and greatly contribute to the patient’s confidence in the treatment. When disclosing the diagnosis of TB to patients, the Hebrew word for TB, Shachefet, will be used for all Ethiopian TB patients. This label overcomes some of the aforementioned ambiguities in diagnostic terminology. Treating physicians will use as few tablets as possible for any given dosage in order to make taking large doses of antibiotics as palatable as possible for patients. Health-care professionals are urged to maintain the confidentiality of their patients’ health status. This is a particularly difficult issue for all TB patients, because of the need to screen close contacts when a case of active TB is discovered. We will use social science along with epidemiology to evaluate the qualitative and quantitative outcomes of the program.

VII. Conclusion In this chapter we have tried to portray the complexity and the dynamic nature of social processes related to health and well-being. Using TB as an example of a multifaceted public health issue, we described how social science helped us delineate the socio-cultural, economic, and political elements of the TB problem and analyze the interplay between these different elements. Social science was also helpful in identifying pitfalls in the existing TB-control program and in indicating concrete solutions for overcoming these difficulties. We have shown that although cultural factors are important to consider, political, religious, and economic issues also must be taken into account when devising TB-control programs. Social science can help guide policy makers in weighing the relative importance of each of

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these variables and in ensuring that public health interventions do not ignore crucial barriers to treatment. Cultural misunderstandings, though important, are often overemphasized as a cause of both noncompliance and unsuccessful TB-control programs when, in fact, other pragmatic or logistic factors such as inaccessible health-care facilities or inadequate drug supplies often underlie treatment failure. The tendency to blame treatment failure on factors intrinsic to patients occurs most often in marginalized populations such as minority groups and immigrant populations and often makes it more difficult to uncover all the relevant barriers to treatment. Ideally a TB-control program must take into consideration the different aspects mentioned above and must strive to find unique solutions for the local population in question. When an institutional commitment to combat TB exists and the organizational infrastructure is in place, it becomes fully appropriate to address cultural factors and any concomitant cultural barriers to successful treatment. We have tried to incorporate this approach in the new Israeli TB-control program and will now monitor and evaluate the outcome of this program once again using the principles and theoretical orientation of the social sciences.

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Chemtob et al. Retel-Laurentin A, ed. Etiologie et Perception de la Maladie dans les Sociétés Modernes et Traditionnelles. Paris: L’Harmattan, 1987:329–333. Setel P. AIDS as a paradox of manhood and development in Kilimanjaro, Tanzania. Soc Sci Med 1996; 43:1169–1178. Genest S. Introduction à l’éthnomédecine. Essai de synthèse. Anthropol Soc 1978; 2: 5–28. Foster GM. Disease etiologies in non western medical systems. Am Anthropol 1976; 78:773–782. Zempléni A. La “maladie” et ses “causes.” Introduction. L’Ethnographie 1985; 2:13– 44. Augé M. L’Anthropologie de la maladie. L’Homme 97–98, 1986; 26:81–90. Good B. Medicine, Rationality and Experience. Cambridge: Cambridge University Press, 1994. Augé M, Herzlich C. Le Sens du Mal. Anthropologie, Histoire, Sociologie de la Maladie. Paris: Editions des Archives Contemporaines, 1984. Kleinman A, Kleinman J. Suffering and its professional transformation: toward an ethnography of interpersonal experience. Culture Med Psychiatry 1991; 15:275–301. Grange JM, Festenstein F. The human dimension of tuberculosis control. Tuberc Lung Dis 1993; 74:219–222. Barnhoorn F, Adriaanse H. In search of factor responsible for non-compliance among tuberculosis patients in Wharda District, India. Soc Sci Med 1992; 34:291–306. Bakshi SS, Ali S. Knowledge, attitude and behavior of TB patients. J Publ Health Med 1995; 17:343–348. De Villiers S. Tuberculosis in anthropological perspective. South Afric J Ethnol 1991; 14:69–72. Mata JI. Integrating the client’s perspective in planning a tuberculosis ducation and treatment program in Honduras. Med Anthropol. 1985; 9:57–64. Sower P, Breckenridge-Potterf S. Utah Department of Health: Refugee Tuberculosis Education Program. TB Notes 1991, Division of Tuberculosis Elimination. Atlanta: Centers for Disease Control and Prevention, 1991:7. Farmer P, Robin S, Ramilus SL, Kim JY. Tuberculosis, poverty, and “compliance”: lessons from rural Haiti. Semin Respir Infect 1991; 6:254–260. Sumartojo E. When tuberculosis treatment fails—a social behavioral account of patient adherence. Am Rev Respir Dis 1993; 147:1311–1320. Curry FJ. Neighborhood clinics for more effective outpatient treatment of tuberculosis. N Engl J Med 1968; 279:1262–1267. Jenkins D. Group differences in perception: a study of community beliefs and feelings about tuberculosis. Am J Social 1966; 71:417–429. Curry FJ. Encounters in training clinic support staff. Chest 1975; 68:462–465. Menegoni L. Conceptions of tuberculosis and therapeutic choices in Highland Chiapas, Mexico. Med Anthropol Q 1996; 10:381–401. Rubel AJ, Garro LC. Social and cultural factors in the successful control of tuberculosis. Publ Health Rep 1992; 107:626–636. Barnhoorn F, Adriaanse H. In search of factors responsible for noncompliance among tuberculosis patients in Wardha District, India. Soc Sci Med 1991; 34:291–306. Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Ban-

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galore. A controlled clinical trial of 3- and 5-month regimes in the treatment of sputum-positive pulmonary tuberculosis. Am Rev Respir Dis 1984; 130:1091– 1094. Rubel AJ. Concepts of disease in Mexican-American culture. Am Anthropol 1960; 62:795–814. Schur CL, Bernstein AB, Berk ML. The importance of distinguishing Hispanic subpopulations in the use of medical care. Med Care 1987; 25:641–727. Weiser S. Culture, politics and the debt of the rescued: The experience of tuberculosis among the Ethiopian Israelis. MA dissertation, Cambridge: Harvard Graduate School of Arts and Sciences, 1998. Weiser S, Chemtob D, Weiler-Ravell D, Yitzhak I. Barriers to treatment among Ethiopian patients with tuberculosis in Israel (abstr). Int Tuberc Lung Dis 1997; 1(5):S81–S82. Wartski SA. Epidemiology and control of tuberculosis in Israel. Public Health Rev 1995; 23:297–341. Israeli Ministry of Health. Health in Israel—Selected Data. Health information and computer services, Jerusalem, 1996; and State of Israel, Central Bureau of Statistics. Monthly Bulletin of Statistics, Vol. 49, Jerusalem, January 1998. Chemtob D. Completion of tuberculosis treatment in Ethiopian immigrants compared to other population groups, Israel 1990–1992. MPH dissertation, Hebrew University of Jerusalem, Jerusalem, 1995. Chemtob D, Weiler-Ravell D, Slater PE, Epstein L. Completion of tuberculosis treatment in Israel, 1990–92 (abstr). Tuberc Lung Dis 1996; 77(suppl 2):S73–S74. Wartski SA. Tuberculosis in Ethiopian immigrants. Isr J Med Sci 1991; 27:288–292. Dolberg OT, Alkan M, Schlaeffer F. Tuberculosis in Israel: a 10-year survey of an immigrant society. Isr J Med Sci 1991; 27:386–389. Chemtob D, Rosen H. “Be ‘Gobez’ for the Sake of your Health.” A Cross-Cultural Medical Approach for Communicating with Ethiopian Immigrants about HIV, HBV Infections and Related Diseases. Jerusalem: Multi-agency Committee for Education and Information on HIV Infection and Related Diseases, December 1991 (in Hebrew), January 1992 (in English). Bayer R, Wilkinson D. Directly observed treatment for tuberculosis: History of an idea. Lancet 1995; 345:1545–1548. Iseman MD, Cohn DL., Sbarbaro JA. Directly observed treatment of tuberculosis. We can’t afford not to try it. N Engl J Med 1993; 328:576–578. Kumaresan JA, Maganu ET. Case holding in-patients with tuberculosis in Botswana. BMJ 1992; 305:340–341. Israel Ministry of Health. Regulations for the implementation of the National Program for tuberculosis elimination. Jerusalem: Directive of the Director General, No. 3/97, 30.03.97 (in Hebrew). See the daily Israeli newspapers (Ma’ariv, Ha’aretz, and Ye’diyot A’aharonot) from January 24, 1996 and the following days (in Hebrew). See also the Navon Board of Inquiry’ report (July 1996) and the press release of the United Ethiopian Jewish Organization (July 28, 1996) rejecting the conclusions of the Board of Inquiry on the same day of their publication.

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67. Chemtob D, Weiler-Ravell D, Berlowitz Y, Leventhal A. Circumstances leading to a new TB program in Israel (abstr). Int Tuberc Lung Dis 1997; 1(5):S136–S137. 68. Weiler-Ravell D, Chemtob D, Berlowitz Y, Leventhal A, Lev B, Barbash G. A new national TB program in Israel (abstr). Int J Tuberc Lung Dis 1997; 1(5):S136. 69. Fujiwara P I, Frieden TR. Tuberculosis epidemiology and control in the inner city. In: Rom WN, Garay S, eds. Tuberculosis. Boston: Little Brown and Co., 1996:99–111. 70. Mates A, Weiler-Ravell D, Chemtob D. Regulation of laboratory testing for Mycobacterium tuberculosis in a new national TB program in Israel (abstr). Int J Tuberc Lung Dis 1997; 1(5):S148–S149.

30 The Role of Nongovernmental Organizations

ANNIK ROUILLON and NILS ERIC BILLO International Union Against Tuberculosis and Lung Disease Paris, France

FRANCES R. OGASAWARA* American Lung Association New York, New York

I. Introduction In the fight against tuberculosis, a partnership exists among three important sectors: the public, health professionals, and the government. This chapter will deal with two of these three partners: the public and health professionals. Previous chapters have shown that our present weapons against tuberculosis are effective, are accepted by the population, are affordable by governments, are able to be assimilated by less sophisticated health personnel and, therefore, can be evaluated. They can be coordinated into national tuberculosis control programs in developed countries (see Chap. 3) as well as in developing countries (see Chap. 2). A simple relationship between a patient and the doctor as individuals through community-oriented national tuberculosis programs is part of the global fight against tuberculosis. The responsibility for having a national program rests with the government; it is up to the health authorities to design, staff, implement, assess, and orient the program. Although this is generally accepted and would seem fully logical today, it is remarkable that the first organized effort against tuberculosis (which in many instances led the way to other public health measures) originated from the voluntary combination of the energy of physicians and the public in an attempt to relieve suffering, prevent disease, and disseminate information.

*Retired.

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Thus were created at the end of the nineteenth century and the beginning of the twentieth century voluntary associations that gathered together lay individuals and professionals to develop the first elements for the concerted effort to fight tuberculosis. In most countries, even though governments have taken the responsibility for providing health services in relevant programs, the success of any governmental program continues to depend on the competence and attitudes of professionals who are delivering the programs and on the active and understanding participation by the people in the measures offered them. Voluntary nongovernmental organizations are the best means of ensuring high standards in the application of the professional and governmental measures and the widespread participation of the public in any control program. This includes lobbying for improvements and acting as a “watchdog” for the program. A. What Is a Volunteer?

Since nongovernmental organizations (NGO) originate from the grass-roots level, that is, from ordinary citizens, it is necessary to define the term “volunteer.” Volunteers are persons from any walk of life who are ready to devote, freely and without remuneration, part of their time and effort to a special cause or task to which they feel motivated to commit themselves. Volunteers should not be expected nor requested to work more than a few hours each week (or to give a very sustained effort for more than a limited time). They must know exactly what they have to do and should receive proper training in their approach to the task and to other people and in the procedures to be followed if they will have to apply specific means. Members of an organization are the first level of voluntarism: they are persons who took the step to enlist themselves or to register and to contribute; they are supposed to follow the development of the activities toward the relevant aim and, when necessary, to give their moral, then possibly financial and physical support to action, thereby becoming more and more active volunteers. The work of volunteers is organized and backed by an association, which may exist at the local, national, and international levels. B. What Is a Nongovernmental Organization?

An NGO is an organization or association formed by a group of persons with a common interest, a shared experience, or a similar goal. NGOs may also be called nonprofit organizations or philanthropic organizations, voluntary or community councils, neighborhood groups, women’s organizations, or economic and social development groups. They may be organized for a particular purpose, such as in the field of health/disease–specific organizations or disability-specific organizations. They may be groups of patients, families, and friends suffering from the

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same disease or condition. Also included are professional societies organized by members of the health professions, such as physicians, nurses, or other public health workers or charitable organizations, such as church-related groups who contribute to needy causes. The NGO can be purely local or may have national or international scope. Often a national or international organization may function as a federation of corresponding local or national NGOs. It is at the local level that the association should prove its efficacy and worth. Often, the national body has the role of assisting a local association by providing proper information, training, guidance, and backing. The NGOs are generally directed by the members themselves. The members select a group from the membership to provide leadership and determine how the organization will achieve its goals. Throughout the organization, volunteers do much of the work of leadership and program implementation. When budget allows, staff is hired to carry out the program and to give administrative support. NGOs are funded by one or a combination of the following: membership dues, contributions, service fees, and contracts or grants from private and government sources. Fund raising, however, is a permanent problem for most associations. Because they are independent, NGOs can function in any political climate and usually maintain a neutral position on political matters. They are free to pursue the policies and programs that the governing body, whether it be a board of directors, executive committee, or governing council, has determined will best achieve the mission of the organization. The NGO may determine membership criteria and may have several classes of members, including a category of membership open to any interested person. The NGO usually is a group with specific interest, experience, commitment, and expertise. They have the ability and willingness to respond to the needs of a particular community in innovative and creative ways. Depending on the problem addressed, the community to be served, and the expertise of the NGO, it may have an important role in the formulation of strategies, in planning, implementation, and in providing service. In dealing with health issues, NGOs are a source of ideas and manpower. They can cooperate with, participate in, and help to publicize and to influence public opinion in support of a government health program. They can also pressure governments to address unmet health needs. Grass-roots NGOs, activists representing victims or patients, can vociferously call attention to the needs of such consumers. Those NGOs that are professional societies may provide important technical advice on the scientific aspects of a health program. They may also play an important role in educating professional colleagues about new methods and concepts in treating and controlling disease (1).

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Although they are very diverse in their aims, structure, operation, and size, NGOs are sometimes considered as falling into one of the three following categories (2,3): 1. Service delivery (e.g., running of facilities for diagnosis, treatment, or rehabilitation) 2. Innovation (e.g., developing new approaches to yet unmet or new needs, such as AIDS) 3. Advocacy (campaigning on a specific issue, such as smoking) In fact, many NGOs actually address all three aspects. Nongovernmental organizations are by no means new (4). Trade groups existed in the Roman empire and in ancient eastern, as well as in pre-Columbian, cultures. In Europe during the late Middle Ages, various guilds of merchants or artisans were formed to protect their interests, rule prices, wages and procedures, and introduce codes of ethics. The Industrial Revolution was accompanied by the decline of these guilds in Europe, while at the same time Americans started to show a propensity to band together. One hundred associations were in existence in the United States by 1900, 1000 by the end of World War I in 1918, and currently 21,000 exist. Of these, 3200 have their headquarters in Washington, D.C., 2300 have an office in New York, and 900 in Chicago. One thousand are being created every year. Voluntary health organizations have played an important role in the health programs in most of the countries of Europe and North America (5). They started to emerge over 100 years ago, at a time when the social conditions and the health situation were quite different from what they are today; the countries of Europe and North America were in a process of socioeconomic development, influencing the rural populations that formed the greatest part of the countries’ population at that time. Social and health services were hardly developed; self-reliance was a characteristic feature in most places. The first voluntary associations were founded to fight the most important and feared diseases; tuberculosis was first among these. Tuberculosis or lung associations are nonprofit organizations. Basic financial support for the organizations comes from membership dues, voluntary contributions, and grants. In some countries, associations receive grants from governments to carry out special programs. Some associations may have government contracts to provide medical services and often hire staff to administer and carry out day-to-day activities. At the international level, the International Union Against Tuberculosis and Lung Disease (IUATLD) is the nonprofit, nongovernmental voluntary organization working in the area of tuberculosis and lung disease. Among its constituent members are the national voluntary tuberculosis and lung associations worldwide. In the United States, the constituent member of IUATLD is the American Lung As-

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sociation, which, in turn, has constituent and affiliate associations throughout that country. Having recently (January 2000) established itself as a separate independent corporation, the American Thoracic Society is committed to working closely with the American Lung Association toward the goal of global control of TB. II. National Tuberculosis Associations A. North America

The American Lung Association

The American Lung Association (ALA) was founded in 1904 as the National Association for the Study and Prevention of Tuberculosis. It was the first national, voluntary health agency in America dedicated to fighting a single disease. It was also the first to combine the energies of physicians and lay persons in fighting a public health problem. The association was founded on the idea that citizens could do something about tuberculosis, (6). A few local voluntary societies had been formed to fight tuberculosis as early as 1892. The founders of the national association were leading practitioners of medicine and active in broad projects for social betterment. They formed the new association to study tuberculosis in all its forms; to disseminate knowledge about the causes, treatment, and prevention of tuberculosis; and to encourage the prevention and scientific treatment of tuberculosis. Widespread social organization, actions taken by an informed citizenry, was an important factor in the evolution of the modern public health campaign. A public education program was launched to inform people of the dangers of tuberculosis and the steps required to fight the disease. Pressure was put on lawmakers to build sanatoriums to provide rest, fresh air, and good food—the therapy advocated in 1904. When tuberculosis was recognized as being a contagious, rather than an inherited, disease, the need for sanatoriums to isolate the source of infection from the community became an important public health measure. Tuberculosis control as a public health function was new in 1904, and most communities in the United States did not have organized health departments. Local tuberculosis associations pressured for the establishment of such public health departments with tuberculosis-control programs in every community. Lawmakers were also urged to fund these services with tax money so tuberculosis care would be available to all without cost to the patient. The national association organized state and local associations all over the country to carry out this educational and legislative program at the community level. By 1956, there were about 2700 local associations; hence, programs and fund raising could be conducted in the local community. The Christmas Seal campaign became the primary source of funds to conduct these activities. The first nationwide Christmas Seal campaign was conducted in 1908. By 1920 the national association had shortened its name to National Tuberculosis Association (NTA).

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In the prechemotherapy era, the NTA, its constituents (state associations), and its affiliates (local associations) conducted educational programs to dispel myths about tuberculosis and to encourage early detection and prompt treatment, and they lobbied for adequate services and facilities and the means to finance them. The associations conducted tuberculin testing and mass chest x-rays, provided rehabilitation services for persons with arrested disease, and conducted school health education programs to promote good nutrition and healthy living to build up resistance. These programs were conducted in cooperation with official agencies (health departments, social welfare, departments, education departments) and with private and professional societies. The medical section of the NTA, the American Trudeau Society, was originally founded as the American Sanatorium Association in 1905. Its members included the physicians who were leaders in the field of tuberculosis. The organization supported research to study the tubercle bacillus, to find a cure for the disease, and to study the epidemiology of the disease so that it could be prevented and set standards for treatment. Through its annual meeting and other conferences, the American Trudeau Society provided forums during which research results could be described and successful treatment regimens could be shared. After the discovery of effective chemotherapy for tuberculosis, the association promoted its widespread use and changes in services that were needed for outpatient care. The NTA also changed its goal to the eradication of tuberculosis and, together with other agencies and organizations, devised nationwide plans to achieve that goal. As the tuberculosis problem declined, other lung diseases, especially smoking-related diseases, were increasing. The NTA expanded its program to include all respiratory diseases and changed its name to National Tuberculosis and Respiratory Disease Association in 1968 and the American Lung Association in 1973. The Trudeau Society became the American Thoracic Society (ATS) in 1960. It became separately incorporated in 1999. In the postchemotherapy era, the lung associations, in cooperation with the U.S. Public Health Service and state and local health departments and other agencies and organizations, conducted tuberculosis-eradication projects throughout the United States, promoting the use of chemotherapy and treatment of latent TB infection (chemoprophylaxis). These projects sought not only to cure individual patients, but were viewed as public health measures: to prevent new infections by removing the source of tubercle-bacillus transmission and to prevent the infected from becoming infectious. Associations had programs to address problems in high-incidence and low-incidence communities and to meet the needs of multicultural communities and non–English-speaking persons. As the tuberculosis problem declined in magnitude, programs were targeted to specific high-incidence groups of high-risk individuals, such as unemployed alcoholic men, migrant farmers, and recent immigrants. The ATS, as the medical section of the American Lung Association, issued statements and position papers on numerous aspects of tuberculosis treatment and control to promote optimal

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treatment and to change attitudes about what constitutes modern tuberculosis care. These statements have usually been issued jointly with the U.S. Public Health Service. They are used for professional education and as a guide to communities in planning tuberculosis services and as an indicator of the proper standard of care. The increase in immigration of persons from high-incidence countries provided a source of infected persons at risk of progressing to active TB and becoming infectious and slowed the downward trend of morbidity. The appearance of the acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection, especially in large cities as well as governmental deemphasis, resulted in a reversal in the decline of the tuberculosis problem. The ALA is still committed to the elimination of tuberculosis and is placing continued emphasis on solving the difficult barriers achieving that goal. Their advocacy efforts have largely been responsible for restoration of funding of programs that have led to the current U.S. decline in cases. The mission of the ALA today is “the prevention of lung disease and the promotion of lung health” with strategic emphasis in the areas of tobacco control, asthma, and environmental health. There are also significant efforts to prevent, treat, or eradicate other lung diseases as well, including influenza, pneumonia, and tuberculosis. For example, the ALA is the home of the National Coalition for Elimination of Tuberculosis (NCET), an umbrella group of 80 U.S.-based governmental and nongovernmental organizations involved and concerned about tuberculosis control as a constituent member. It also supports the work of IUATLD through major annual contributions. The ALA conducts its program through education, advocacy, and the support of research. Examples of educational activities include programs directed to the public about steps they can take to fight air pollution; helping in the design of educational materials on asthma for the public, patients, and school personnel; conferences for the media to discuss new reports on lung health issues; conducting a study of a comprehensive school health curriculum; helping new parents learn of the harm to babies and children caused by secondhand (passive) smoking; and information for workers at risk for occupational lung disease. In its advocacy activities, the ALA and ATS provide spokespersons to provide expert testimony before the U.S. Congress on lung health issues, such as indoor and outdoor air pollution; the need to increase funding of the lung research program of the National Institutes of Health (NIH); the importance of grants to state and local communities to support the tuberculosis control programs; and the health effects of secondhand smoke on airlines. The ALA and ATS work through coalitions of other like-minded health organizations. Sometimes ALA and ATS bring together a coalition or invite participation of other interested organizations to solve problems they have in common and to conduct joint programs. The research program of the ALA awards “seed money” research grants to young investigators. It encourages the training and development of future research

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scientists. The professional education program includes the publication of two journals: the American Journal of Respiratory and Clinical Care Medicine (formerly American Review of Respiratory Disease) and the American Journal of Respiratory Cell and Molecular Biology. The ALA-ATS international conference is an annual meeting during which papers on original research, symposia, major lectures, and numerous other educational sessions are presented. Conferences and workshops on specialized subjects are conducted during the year to develop policies, discuss issues, or increase the medical community’s knowledge about a particular disease and its treatment. An important part of the ALA is its communications program. Working through all media, television, radio, and publications, it disseminates information and educates the public on all aspects of lung disease problems. As a voluntary organization with expertise, it is perceived by the public as having credibility and being a source of valid scientific knowledge and accurate information. The ALA is governed by a volunteer board of directors. Volunteers also serve on the council and on numerous committees that guide the operation and program of the organization. The national paid staff, directed by the chief executive officer, is made up of competent trained professionals in all aspects of association health education, communications, fund raising, business management, and organizational development. As of late 1999, serving all communities through the United States are 55 state and 23 local lung associations. Each is independently incorporated, affiliated with the ALA through a contract, and is governed by a volunteer board of directors. Each is staffed by an executive director and other staff members to carry out the activities of the association. The board of directors of each association sets the policies for that association and, working with the staff, develops its program and fund raising following the policies and guidelines of the national association. The number of associations has been declining in recent years, as boards appropriately see economies of scale and cost savings in staff and office sharing, leading to total mergers of programs and then associations. Public financial support comes from many sources: the traditional Christmas Seal campaign, other direct-mail efforts, special events, major corporate and individual gifts, workplace giving, planned gifts, memorials, grants, and in-kind contributions. Membership fees and service fees also help fund activities. Because programs are determined by each state or local association, there is some variation in the particular activities carried out. Programs are usually planned according to the needs identified, and priorities are set and activities chosen according to the resources available. Through expansion of the mission and changes in objectives, ALA, nationally, has continued its role of leading and enlisting citizen action to help solve a health problem. It works with all groups and all sectors of society to identify what needs to be done, to influence those in a po-

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sition to make changes, and to educate and encourage those whose participation or individual action is required. It emphasizes individual responsibility as well as concerted community action. The Canadian Lung Association

The Canadian Lung Association (CLA) was founded in 1900 as that country’s national NGO dealing with tuberculosis. In 1969, the emphasis was changed to include lung diseases under its mandate, and the organization was changed to the Canadian Tuberculosis and Respiratory Disease Association. Finally, in 1977, at its annual meeting in Moncton, New Brunswick, Canada, the association changed its name to the Canadian Lung Association. The medical arm is called the Canadian Thoracic Society (CTS). The major role of the CLA in its relation to the International Union Against Tuberculosis and Lung Disease has been to spearhead international activities through the IUATLD’s Mutual Assistance Program in the form of grants to various projects in developing countries (7,8). This program was instituted at the time of the International Union Against Tuberculosis (IUAT) World Conference held in Toronto in 1961. It consisted primarily of maintaining an IUATs office in Kuala Lumpur, Malaysia, for the Eastern region, in developing regional seminars in the Far East, and to assist in developing provincial and district offices in various countries in the Far East. The CLA has also contributed heavily to tuberculosis educational seminars in various Far Eastern countries, including Sri Lanka, Pakistan, Malaysia and Nepal, Indonesia, India, Thailand, Bangladesh, and the Republic of Korea. In more recent years the CLA has supported the establishment of an international course in tuberculosis microbiology in Ottawa for individuals from developing countries. It has also assisted these countries in establishing and equipping tuberculosis laboratories. Similar to its U.S. counterpart, the CLA is divided into provincial associations who raise funds through a national Christmas Seal campaign. These funds are directed toward education in tuberculosis and lung disease, research in these areas, and to assisting the IUATLD in its operating and mutual assistance budgets. The members of CTS are active in provincial, national, and international organizations, including the IUATLD. B. Latin America

In Latin America, especially in areas where there is not yet full medicosocial protection of the population, “tuberculosis leagues,” as they are most often called, have long been striving to assist poor patients and their families by running outpatient clinics and triggering government interest in the establishment of modern national programs. An extreme case is the Comisión Honoraria para Tuberculosis of Uruguay.

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The Comisión has full technical, financial, and operational responsibility for all antituberculosis activities in the country. Through carefully applied treatment, it is able to cure most of the existing tuberculosis patients in the country. The Comisión also carries on research, mostly epidemiological. It is also responsible for all vaccinations (against any disease) with vaccines provided by the government. Funds necessary for these activities come from a tax on alcoholic beverages and from lotteries. C. Europe

National tuberculosis associations were formed in Austria in 1890, in France in 1891, in Great Britain and Belgium in 1898, and in Portugal and Italy in 1899. A survey of 25 (practically all) European national tuberculosis or lung disease associations showed that, by the mid-1980s, tuberculosis had remained the sole concern of only 2 associations; 18 others kept tuberculosis as their main priority; 23 out of 25 now include other lung diseases or cardiovascular diseases and, in one, aging, in another malnutrition, and another malaria (9). Their approach to dealing with their objectives is through counseling, assessment of control (in 18), and postgraduate education (in 17); 10 have research activities and 7 social and welfare activities. All except 3 hold regular meetings, conferences, and symposia. Almost 90% issue regular journals, yearbooks, selected papers, or other publications. Membership consists mainly of physicians and other medical or paramedical personnel, 8 also enroll lay persons, and 5 enroll institutions. Their source of income is usually membership fees; however, 13 carry out fund-raising campaigns, 10 receive support from official authorities, and 4 manage their own property. No single European association plans to restrict its activity in the future. On the contrary, more than half envisage extension. In the field of tuberculosis, they recommend the promotion of research activities in tuberculosis surveillance, in solving problems with foreign workers and immigrants, and in dealing with nontuberculous mycobacterial diseases. A comparison of associations in two European countries, whose TB surveillance data suggest that they are approaching elimination of tuberculosis, illustrates the differences. The Royal Netherlands Tuberculosis Association

The Royal Netherlands Tuberculosis Association (KNCV) was established in 1903 as the national organization to coordinate the fight against tuberculosis in the Netherlands. Since then, KNCV has grown into a leading NGO in the field of tuberculosis control in the Netherlands and abroad. It is KNCV’s mission to contribute to the global elimination of tuberculosis through the development and enhancement of effective and efficient tuberculosis control activities.

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In the Netherlands KNCV’s main activities are surveillance, technical support, research, and development of policy guidelines. The KNCV acts as the official Tuberculosis Control and Surveillance Unit for the Ministry of Health and the Municipal Health Services. KNCV was instrumental in maintaining a uniform and coherent delivery of tuberculosis-control activities during an extensive health sector reform in the late 1980s. The latter resulted in a decentralization of control services including the responsibility for its funding. Tuberculosis-control activities in the Netherlands have resulted in one of the lowest incidences of the disease in the world. Based upon accurate and detailed epidemiological data, the elimination of tuberculosis as an endemic public health problem is predicted for the year 2030. In high-prevalence countries KNCV supported (financially and technically) an innovative application of tuberculosis control—directly observed treatment, short-course (DOTS)—in Tanzania, Malawi, and Benin, developed by Dr. Karel Styblo of the IUATLD. The DOTS strategy demonstrated in Africa that it is possible to cure 8 out of 10 diagnosed infectious patients. The same approach applied in Vietnam, Indonesia, and China is even more successful, with 9 out of 10 patients cured (see Chap. 2). KNCV Makes DOTS Work

The experience of KNCV with DOTS is widely acknowledged, and there is an ever-increasing demand for program support and technical support by KNCV consultants. The aim of the KNCV is to develop sustainable tuberculosis programs that detect and cure as many infectious sources as possible. The objective of such a program is the implementation of a country-specific DOTS strategy to reduce morbidity and mortality from tuberculosis; to reduce transmission of infection; and to prevent the occurrence of drug resistance. KNCV is involved in programs in Africa, Asia, and Latin America. Long- and short-term support is given in collaboration with several partners to local capacity building in all management aspects of TB programs. Such activities include analysis of the current situation, project identification, technical assistance, and project evaluation. KNCV fosters policy debate and development through its membership of the Coordination Advisory and Review Group (CARG) and the Technical Research and Advisory Sub-Committee (TRAC) of the Global Tuberculosis Program of the WHO. Another important forum for policy development is provided through its membership in the IUATLD. Organization

KNCV is an organization of health professionals, with a director responsible to its board. The director presents the annual and financial report at the general meeting. This meeting also approves of the work plan and financial budget.

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Norway, another European country that will also see the elimination of tuberculosis in the early part of the twenty-first century, has witnessed the transformation of its Tuberculosis and Public Health Association (founded in 1910) into one dealing with cardiovascular diseases, elder care and welfare, and healthy lifestyles (10,11). It kept a small subcommittee on tuberculosis and maintained a constant concern for making others benefit from their efforts and experience in combating tuberculosis, including international advanced training courses; since 1976, the tuberculosis subcommittee has been instrumental in obtaining from the government of Norway substantial support of the IUATLD for its structures and its activities; a first tuberculosis seminar was organized in 1983 in Zimbabwe, gathering 100 delegates from 10 countries of Eastern Africa: it was the first time that the countries of that part of the world had a seminar on tuberculosis. The Norwegian National Health Association, together with another national voluntary agency, The Norwegian Heart and Lung Association, and the Norwegian government technically and financially support the IUATLD collaborative national programs in Nicaragua, Malawi, Sudan, Senegal, and Nepal. Following the example of the Netherlands and Norwegian associations, other European associations in countries such as Switzerland, Finland, France, and Germany now also promote special drives for developing countries through the IUATLD and also provide the IUATLD with the support of their government. The Belgian association has provided special donations from closed former sanatoriums, the British association together with the French association assisted the IUATLD in establishing its nontuberculosis respiratory program. D. Middle East

Tuberculosis associations in the Middle East, besides working for their respective countries, are also contributing to international activities. Examples include the following: 1.

The Syrian association for many years has been reprinting relevant parts of the IUATLD Bulletin into Arabic and distributing it in the region. 2. In 1950, the first International Training and Demonstration Centre for Tuberculosis was established in Istanbul and run by the tuberculosis association. Besides its own national tasks (12), the association has hosted the 15th World Conference of the IUAT in 1959, its annual meetings in 1970 and 1977, and, in 1985 and 1995, the Middle East Regional Meeting. 3. The Egyptian association has also been supporting international activities of the IUATLD: two regional meetings, a regional seminar, and the Conference on Tuberculosis in Animals in Africa and the Middle East

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in 1992, promoted by the Tuberculosis in Animals Scientific Committee of the IUATLD. The IUATLD regional meeting was held in Cairo in 1992. 4. Through the IUATLD, the Kingdom of Saudi Arabia supported the whole National Tuberculosis Program of Yemen for several years. E. Africa

After independence, in western and eastern Africa as well as in north Africa, most of the associations dating from the colonial period were reorganized. Lack of funds and the many problems with which those countries are confronted, as well as the disaster of the HIV epidemic, render their work in sub-Saharan Africa especially difficult, although especially needed. In Ivory Coast (13), the association has been instrumental in promoting the government’s program, disseminating instructions and information to the staff and to the population, and filling gaps in the procurement of drugs and products or repairing vehicles. In Togo and in Senegal, support has been given by more affluent European associations for their issuing of Christmas Seals and conducting education and fund-raising campaigns. The Mali association with the support of the KNCV ran a pilot project of sputum smear case finding and ambulatory treatment. The old Tunisian Antituberculosis League, which had mainly been forming and running dispensaries, was reorganized in 1957, 1965, and 1975 to become in 1981 the National League Against Tuberculosis and Respiratory Disease (14). The association is active in giving clothing, food, and travel assistance to patients in underprivileged districts, in many activities of health education for the public, and in contributing to the efforts of the government in training microscopists and in refresher sessions for physicians. After its 1965 relaunching, it conducted an important pilot project of case detection by sputum smear examination and twiceweekly supervised treatment in a remote area with the IUAT. These principles, demonstrated in different ways and settings in Mali and Tunisia, were to appear in the further resolutions of the World Health Assembly and of the Alma-Ata Primary Health Care Conference of 1978. In Algeria, the Comité Algérien de Lutte contre la Tuberculose (CALT), founded in 1965 (15), has conducted several Christmas Seal campaigns, giving as much material support as possible to the national program through the publication of technical guidelines, registers, and educational materials, the granting of awards to motivate microscopists and treatment supervisors, and through a particularly important activity: the “supervision and evaluation seminars” held once a year in almost every province in which all members of the team with a group from the capital city examine what succeeded and what failed in the application of the program.

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CALT is a member of the Tuberculosis Surveillance Research Unit (TSRU), an advanced research unit linked to the IUATLD (see below): indeed the National Algerian Program is able to provide information for epidemiological and operational analysis useful to assess its own program as well as to assist other countries in their own approaches. It also supports the WHO/IUATLD/Algerian government international training course in tuberculosis control methods held every year in Algeria (16). F. The Far East

Most countries in Asia possess a tuberculosis association, many of which are quite active in running facilities, organizing courses and meetings, and informing the public. Almost all keep tuberculosis as their sole or prominent focus. Asia

In Asia, the association with the broadest scope in its work is the Japan Anti-Tuberculosis Association (JATA) (17). Its major activities are as follows: 1.

2.

3.

4.

5.

Health education and public relations activities on tuberculosis and other related diseases, including providing information through publications such as official bulletins, books, and videos, conducting public assemblies and Tuberculosis Prevention Week, commending local governments with excellent achievements in tuberculosis control, and other promotional activities (e.g., cooperating with antituberculosis women’s societies). Research and surveillance activities at the Research Institute of Tuberculosis (RIT), which conducts comprehensive research on tuberculosis including basic, clinical, and epidemiological studies and operates the national tuberculosis surveillance system. Medical treatment and mass screening examination services in tuberculosis and other diseases provided by two JATA-affiliated hospitals, two clinics, and 47 branches located in each district nationwide. Training activities through operating local tuberculosis training courses in RIT for medical doctors, x-ray and laboratory technicians, public health nurses, and local government. International cooperation activities: a. Technical and research cooperation: providing technical support to NTPs in several countries such as Nepal, Yemen, and Philippines through bilateral technical cooperation projects of the government of Japan and WHO; conducting research cooperation under the United States–Japan Cooperative Medical Science Program and other research programs.

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b. Training courses: conducting international training courses by RIT jointly with WHO and the government of Japan since 1963. Since 1977, four annual international courses have been conducted for medical officers, senior managers, medical technologists, and AIDS control managers with a total number of participants to date of over 1400 from about 80 countries. c. International tuberculosis information center: conducting further analysis and update of epidemiological and tuberculosis control data in the Western Pacific Region (WPR) under the collaboration of WPRO/WHO and basic surveys on tuberculosis drug resistance surveillance system. The revised report of tuberculosis in WPR (1995) was published in 1996. d. Projects: organizing on-site seminars or workshops in Asian countries such as Cambodia, Mongolia, Vietnam for personnel engaged in tuberculosis control; operating pilot projects in tuberculosis control both in Nepal and Indonesia in cooperation with the local antituberculosis organizations. 6. Other international activities, such as the Princess Chichibu Memorial TB Global Award, established by JATA. Since 1998, a person who has shown great achievements in antituberculosis activities has been honored annually. India

The Tuberculosis Association of India was established in 1939 (18). One of the first steps the association took was to evolve a practical approach to the care of tuberculosis patients. The New Delhi Tuberculosis Center, established in 1940, was upgraded with the help of the government, WHO, and the United Nations International Emergency Children’s Fund as a training and demonstration center. In 1948, the association formed its technical committee consisting of 15 senior tuberculosis workers from around the country; the committee acts as a nonofficial advisory body to the government. The National Tuberculosis Program launched in 1962 is periodically revised by the technical committee. The association has a wide program of health education through the production of films, posters, slides, flip charts, and school health brochures. These are distributed through state associations and other voluntary agencies and the government. The Indian Journal of Tuberculosis, a quarterly publication of the association, is the only journal devoted exclusively to tuberculosis in the country. The association also issues textbooks for physicians, blueprints, and the Handbook of Tuberculosis, which covers, in simple language, the essential facts about clinical, epidemiological, and social aspects of the disease and emphasizes aspects con-

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cerning nurses, health visitors, and lay social workers in their day-to-day work. A regular program of the association is holding annual conferences for tuberculosis and chest disease workers, and the organization, together with the Indian Medical Association, holds periodic one-day refresher courses for general practitioners. Funds (approximately $80,000 yearly) come from interest on investment, publication sales, donations, and shares from Christmas Seal collections. Twentyfive state tuberculosis associations are affiliated with the central association; most of them also have tuberculosis associations at the district level. They assist official services in the distribution and administration of drugs. They also organize case finding and immunization camps in remote areas where tuberculosis services are deficient. Many of them hold conferences to supplement the yearly national conference. New Dehli hosted the 14th World Conference of the IUAT in 1957, the first time the Union left Western capitals. Bangladesh

The Bangladesh Tuberculosis Association deals with a population of some 120 million in a country under the handicap of enormous flood and typhoon disasters. Education, information, and demonstration projects are carried out. Indonesia, Thailand, and Singapore

The Indonesian association (19), also dealing with a vast population, received a special award from the IUATLD in 1986. The association of Thailand is a 58-yearold institution which hosted the 29th World Conference of IUATLD in Bangkok in 1998. The Singapore association (SATA) hosted the 26th World Conference of the IUATLD in 1986 and the Eastern Regional Conference of IUATLD in 1997. Korea

The Korean National Tuberculosis Association (KNTA) was founded in 1953 and evolved as the technical arm of the National Tuberculosis Program (NTP) (20). For the launching of the NTP in 1962, the KNTA recruited, trained, and posted supervisory medical officers and nurses for the city and provincial governments and follow-up workers and microscopists for health centers. They became government employees in 1967. The KNTA established a Central Tuberculosis Laboratory and nine city or provincial tuberculosis laboratories. Health centers do microscopy only. In 1988, 400,000 microscopy examinations were done at health centers for case finding, 160,000 cultures were done at the city and provincial and central laboratories, and 5000 drug-sensitivity and 4400 identification tests were performed. Contributions to the nationwide random sample epidemiological surveys started in 1965 and are repeated every 5 years. In 1970, the KNTA established the Korean Institute for Tuberculosis (KIT) to strengthen its role as the technical arm of the national program. Various surveys, trials, assessment of results, and operational research are thus carried out

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jointly. The production of freeze-dried bacille Calmette Guérin (BCG) vaccine is also entrusted to the KIT. The training sessions for all categories of health workers, provided by the KNTA up to 1981, were then transferred to the National Institute of Health, but the staff of the KIT still participates actively. The KNTA has been a member of the International Tuberculosis Surveillance Research Unit (TSRU) since 1984. It has an important health-education program, with a monthly magazine, films, videotapes, and slides distributed to health centers, schools, and relevant agencies. A seal campaign takes place every year. The Korean seals are famous for their design and grace and have almost perpetually won the first prize at the Seal of Year International Contest of the IUATLD.

III. The International Union Against Tuberculosis and Lung Disease The IUATLD (21) is the federation of national tuberculosis and lung disease associations and of individual persons interested in the fight against these diseases from all over the world. It is one of the oldest voluntary international organizations dealing with health. Shaped in its present form in 1920 at a Paris Congress on Tuberculosis, it in fact originated at the Berlin International Tuberculosis Congress of 1902, which decided on the creation of a Central Bureau for the Prevention of Tuberculosis (further called the International Antituberculosis Association). Even this Central Bureau was the result of international concern for tuberculosis, which can be traced back to 1867 when, at the first International Medical Congress in Paris, several sessions were devoted to this disease and the classic work of Villemin demonstrating the contagion of tuberculosis was presented (22). Subsequent international congresses on tuberculosis were held in Paris in 1888, 1891, 1893, and 1898; in Berlin in 1899, when for the first time official representatives from various governments and voluntary agencies were present; in London in 1901; then in Berlin again for the 1902 congress just referred to. It was also at this Berlin congress that, on the proposal of Dr. Gilbert Sisteron, the Secretary General of the Federation of the French Antituberculosis Associations, the double-barred red cross was adopted as the emblem of the fight against tuberculosis.*

* The double-barred cross, the origin of which can be traced back to the second century, was added in 1099 to the banner of the Prince of Lorraine, of France, who raised the first crusades. It thus became the emblem of an enlistment in the service of an ideal, of the rallying of all those committed to an imposing idea. Over the years, certain countries have replaced this emblem with others that they felt corresponded more closely to their countries’ traditions and culture. Some have thus chosen the double red crescent.

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The Central Bureau organized conferences in Paris, The Hague, Vienna, and Philadelphia (in 1908); Stockholm and Brussels (in 1910, where the death of Robert Koch was announced); and Rome and Berlin (1912). A conference was scheduled to take place in Bern, Switzerland, when World War I broke out in 1914 and put a stop to the activities of the international association. The experience and suffering of the war had brought maturity to certain concepts, and when representatives from 31 nations met in October 1920 in Paris to form the IUAT, they moved in an impressive procession in the large lecture hall of the Sorbonne and pledged one by one their wholehearted collaboration in the campaign against tuberculosis and declared their belief in an organization that would impose obligations on its members and centralize all the experience of the disease. The words that Leon Bernard, Secretary of the French Association, pronounced on that occasion remain extraordinarily valid today: “It is necessary for all countries wishing to eradicate tuberculosis to decide among themselves on the methods, to agree on the most effective weapons, and to forge and implement them jointly against the common enemy. Anti-tuberculosis measures must some day be standardised but first it is necessary for the research workers to make a thorough investigation of the problem in order to provide governments with the necessary information. . .” These words were no doubt prophetic, and during the more than three quarters of a century of its modern existence, the “Union”—as its members call it—remained faithful to this description of its mission. In 1973 the IUAT decided to expand its mission from tuberculosis to cover other lung diseases and community health, but it added “and Lung Disease” to its name to become the IUATLD only in 1986; actually in this enlarged field it is cautious not to overlap with others (such as cystic fibrosis) while focusing on lung diseases with both a global and public health significance (acute respiratory infections, a number of aspects of asthma, the fight against smoking, occupational lung diseases, and the consequences of natural disaster on the lung). Sharing knowledge and efforts while backing national associations is the very essence of the IUATLD and it materialized in a permanent program of activities against tuberculosis as well as in various achievements of global practical significance, which will be described in the following sections. A. Program of Activities

Dissemination of Knowledge

Knowledge dissemination is accomplished through meetings, seminars courses, and publications. World conferences are perhaps the most visible part of the program. They were organized initially every second year, then every fourth year, and now they happen each year. The 29th World Conference was held in Bangkok in 1998 and the 30th World Conference on Global Lung Health in 1999 was in

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Madrid. Conferences on Global Lung Health with more than 1000 participants from over 100 countries were held in Paris in 1995, 1996, and 1997. Regional conferences are held every second year in each of the regions of the Union (Africa, Far East, Europe, Latin America, Middle East, North America). Some 80 such meetings have taken place. Several regional or national seminars attract 50–300 participants each year. Five international regular yearly courses on tuberculosis are held in English, French, and Spanish focusing on epidemiology and the delivery of national control programs in Tanzania, Benin, Nicaragua, Vietnam, and France (23). Since 1920, 66 volumes of the Bulletin of the IUATLD have been issued giving in their English, French, and Spanish versions the papers presented at the various Union’s conferences as well as other original articles. For a short time, Tubercle and Lung Disease was and now The International Journal of Tuberculosis and Lung Disease is the official journal of the IUATLD. The journal’s main aim is the continuing education of physicians and other health personnel and the dissemination of the most up-to-date information in the field of tuberculosis and lung health. It is distributed to more than 2000 individuals and libraries. Technical guides and manuals for field workers have been developed and printed in English, French, Spanish, Portuguese, Arabic, and Vietnamese. They are adapted to the specific structure of the health services and the measures decided by each national program. Several guides have been published in recent years and distributed to several thousand colleagues worldwide (24–29). Applied Research

In its concern to answer needs at the consumer level, in 1951, the Union organized itself into six regions to adapt activities to local circumstances. During the same period it also formed a number of scientific committees (30,31). They were composed of the best experts in various fields, and they began a number of surveys and studies. Among these are two studies on the chemotherapy of tuberculosis, grouping centers in 17 and 21 countries, respectively (32,33); the reading of 1100 x-ray films by 100 readers in 10 countries (34); the assessment of treatment results in routine practice in five countries (35); the study on the chemoprophylaxis of fibrotic lesions of the lung (36) with 25,000 participants followed for 5 years in seven countries; and an international survey on BCG complications (37). These various works were the first international multicentric collaborative studies in the world, soon introduced in other fields of health care as well. At the same time, an international unit for advanced epidemiological studies, the Tuberculosis Surveillance Research Unit (TSRU), was created, jointly with the World Health Organization and four constituent members in 1965 (38–40). The work of this unit, as directed by Dr. Karel Styblo, has resulted in the development of a single epidemiological index, the risk of infection, to follow the

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level and the trend of the tuberculosis situation. A separate unit is operating in the Hague [the International Tuberculosis-Surveillance Centre (41)] to train teams and assist countries in collecting data and calculating their risk of infection (42). It has also made important contributions to the understanding and quantification of the natural history of the disease and to the mode of action of our means, thus providing new information, often shaking long-accepted concepts, deep-rooted dogmas, and vested interests. Such longstanding programs were assessed and given their proper significance: the epidemiological role of BCG; the yield of mass x-ray examinations and of regular tuberculin testing of school children; the degree of transmission of the disease; the indefinite systematic follow-up of former patients; the effect of treatment on the epidemiological situation; the defects in diagnosis; the role of migrant workers’ presence on tuberculosis in a country; the proportion of cases diagnosed only after death; the degree of application of the new effective means and approaches; and, more currently, the relationship between HIV and tuberculosis. Several countries such as the Netherlands, Sweden, Germany, and Switzerland changed various aspects of their tuberculosis policy following the TSRU findings. Collaborative National Control Programs

The Mutual Assistance Program of the IUATLD, which started in 1961, represents one further step for the Union in addressing practical problems and trying to remain as close as possible to the “periphery” (43). It was initially aimed at strengthening the voluntary part of the tuberculosis programs in resource-poor developing countries, and it was to be implemented by support from affluent member associations giving through the Union. But it increasingly appeared that, to be really effective, more had to be done than just assist voluntary associations to become and remain true partners of their government and that it would be more rewarding and more efficient if the Union would back governments directly. At that time, national and international interest in tuberculosis had decreased significantly and even WHO had considerably reduced its worldwide support for tuberculosis activities. The Union thus started to work with the governmental tuberculosis units of some developing countries. A few of the Union’s members (essentially the KNCV at the beginning) and the international cooperation departments of a few governments (essentially the Swiss and the Norwegian governments) provided substantial support to these national efforts. Others joined, such as the associations of Finland, France, Norway, Belgium, and the governments of Saudi Arabia, Finland, and France. From 1 million dollars spent in total over the first 15-year period (1961–1976) (“seed” money given to promote association’s work), the Collaborative Program now spends about 3 million dollars per year. The IUATLD currently provides technical collaboration to more than 20 coun-

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tries, intensive support to 14 countries, and occasional and contractual support to 12 countries (23). The work consists in the organization of a system of diagnosis delivery (with sputum smear examination of suspects) and chemotherapy (with the least expensive short-course regimen, proper supervision of treatment, proper recording, and proper assessment of results). Over the last 18 years, in both new and retreatment cases, over 1,200,000 patients have been diagnosed and treated, and there is a documented assessment of cure rates, which reach 85–90%, a level never reached nationwide before in developing countries. It was thus demonstrated that tuberculosis programs conducted under very adverse circumstances could nevertheless be successful in terms of relief of human suffering (decrease in deaths, definitive cure of patients) and be fully documented and permanently assessed through built-in evaluation (44,45). It was the first time that a system evolved that would be reproducibly successful with high levels of treatment results that could be maintained over the years and were easily assessable and that would entail a progressive decrease of the problem. Moreover, at the same time that this demonstration of efficacy was made, an independent analysis by the World Bank, Harvard University, and WHO within the framework of the “Health Sector Priority Review” came to the conclusion that these national programs conducted along the IUATLD prototype ranked among the most cost-effective health interventions, competing, in cost per year of life saved, with measles immunization and oral rehydration for infantile diarrhea (46–48). This system of delivery of effective and efficient tuberculosis programs is relevant for some 30–40 high-prevalence countries with insufficiently developed health infrastructures. As a consequence of the IUATLD’s efficacy and efficiency, governments are induced to undertake such programs; these programs also attract donors, such as international intergovernmental agencies, including the United Nations Development Program and the World Bank, international cooperation and development departments of governments of the more affluent countries, foundations, and all types of nongovernmental organizations. The method of delivery of tuberculosis programs developed within the IUATLD by Dr. Karel Styblo and Dr. Annik Rouillon, as well as the work of TSRU, represent a considerable input in the preparation of the new global strategy against tuberculosis presently implemented in over 100 countries by WHO as the socalled DOTS strategy. This strategy is now accepted by all relevant organizations. They are actively using this approach in several collaborative programs. The importance of first treating already known and diagnosed cases and then only expanding case finding was confirmed in the various national programs. Also, the levels of cure rates and detection rates obtained in the programs constituted useful practical bases for calculating the targets proposed in the Resolution on Tuberculosis adopted in the World Health Assembly in May 1991 (49).

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The WHO with its Global Tuberculosis Program and now as partner in the Stop TB initiative has been instrumental in expanding the DOTS strategy (see Chap. 34), and encouraging results from National Tuberculosis Programs indicate that the DOTS strategy works (50). Liaison with Other Organizations

The IUATLD has had an official relationship with the WHO since the creation of the latter in 1947 (51). It works directly with several governments that entrust to it part of their international collaboration funds (Norway, Switzerland, France, Saudi Arabia). It is “registered” with United States Aid for International Development (US-AID), a privilege rarely given to a non-U.S. voluntary agency. It also maintains collaborative links with many official research institutions such as the U.S. Centers for Disease Control (CDC) in Atlanta, the Medical Research Council of Great Britain, relief institutions such as Misereor in Germany and the International Leprosy Association, NGOs such as the International Union Against Cancer. B. Structure and Budget

The headquarters of the IUATLD are in Paris. Its Board of Directors has been composed of eight individual members and six representatives of the regions. Funds come from a quota share from constituent members and from individual members’ fees. This makes about 25% of the operating budget. The rest is covered by gifts and grants. To run the field projects, seminars, and courses, extra support is often given voluntarily by constituents as well as by departments of governments of several affluent countries who entrust the IUATLD with the use of the grants in underprivileged countries. C. Conclusion

It appears that, among international NGOs, the IUATLD stands, to a great extent, as a unique organization in many respects: 1. It is made up of both national entities—the lung associations and other national bodies—and individual persons in 118 countries. It thereby provides a remarkable tool to spread the word rapidly. 2. It is truly international and apolitical, which often means immense good will, tolerance, and understanding on the part of its members; it has meetings and members everywhere (e.g., the two Vietnams, the two Germanies, and the two Yemen were members when they were joined, and the two Koreas are members). 3. It has always counted among its members, voluntarily and spontaneously, the highest authorities in the field of tuberculosis and lung diseases.

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4. As an independent and flexible organization, the Union can and does do pioneering work in the delivery of health services; as a nongovernmental agency, it can more easily afford to fail than can a government or an intergovernmental agency, and this is one of the reasons its pioneering activities and programs are so important and precious worldwide. 5. Among the pneumological societies, the Union is essentially the only one that is concerned with the Third World countries in direct assistance and for training of personnel in an effort at collaboration and solidarity, the aim of which is to induce final technical and material selfsufficiency. It also encourages not only a north-south dialogue, but a south-south dialogue, which is another form of its vanguardism. 6. It has a permanent work program, and it has succeeded in several difficult undertakings entailing international collaborative work. The most recent and spectacular is the conduct and success of the National Tuberculosis Programs. 7. It has official ties with all the main intergovernmental and nongovernmental international agencies and is recognized by them as a worthwhile partner and adviser in the field of intervention for health. 8. It fulfills a rather difficult and unrewarding, ungratifying, but very useful, role; namely, that of reconciling the often conflicting interests of the government, the medical profession, and the public and of integrating clinical and public health aspects. 9. It addresses the whole spectrum of situations in the world, ranging from those in the most sophisticated countries to those in the least affluent. It is trying to create among all types of nations, with widely different tuberculosis and respiratory disease problems, a constant interchange and stream of ideas, opportunities, and solidarity. For all these reasons, the IUATLD provides a unique forum for discussion; it facilitates exchange between clinicians, research workers, and specialists in the same and other disciplines of health and social welfare. In this respect the Union is an important element for international collaboration, friendship, esteem and stimulation, mutual education, and attenuation of prejudices. IV. Present Trends: Irreplaceable Partners NGOs have played a most important role in many nations of the industrial world as the first promoters of concerted, organized actions for health, which were then taken up by governments and official sociomedical schemes. Consequently, in many of these countries, with the main needs taken care of, the influence of NGOs had tended to somewhat diminish. This was particularly true of NGOs dealing with tuberculosis, the concern for which, in these countries, had almost disappeared among the public as well as professionals. In developing countries, na-

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tional NGOs have had difficulties in emerging, in managing, and in finding funds, and here it is mostly NGOs from developed countries that are taking the first steps to strengthen their counterparts. In recent years, however, NGOs have received increasing prominence. This is the result of an increased understanding of their role and an increased awareness of their potential: in responding to the needs of people, in being credible to them, in translating messages in simple terms, in pioneering new approaches, in complementing governments’ efforts, in advocating, and in bringing financial and manpower support. More and more governments are recognizing NGOs as essential partners in health programs. Some still have some mistrust, and NGOs, on their own side, in general are a bit wary of interference and want to ensure their complete independence. In fact, it is not a matter of governments using NGOs and their multifaceted resources, rather it is a matter of governments facilitating the work of NGOs. In the pneumology field, the resurgence of tuberculosis and a clearer appreciation of the problems it entails and also the occurrence of the HIV pandemic, the consequences of which have been initially, and are still in greater part, tackled by voluntary organizations (52), have reawakened interest in the work of NGOs dealing with tuberculosis. In fact, in early 1976, the IUAT invited the nongovernmental organizations in official relation with the WHO to attend a meeting in Geneva at the time of the 29th World Health Assembly. It called this meeting to exchange views on 1) the role that NGOs may and should play in primary health care (PHC) programs, and 2) the coordination of NGOs’ activities in PHC. Some 18 NGOs took part in that initial meeting and resolved to continue meeting to pursue their common interest in PHC. The group set out to promote PHC as a concept within their affiliated NGOs at the national level, to promote the national debate in those countries, and to assist its national expression and implementation. During 1977 and early 1978, the NGO group assisted in the preparation of a position paper on the role of NGOs in PHC. This paper was later presented at the Joint WHO/UNICEF International Conference on Primary Health Care, held at Alma-Ata in September 1978 (1). Following the Alma-Ata Conference, four emphases emerged in the discussions of this NGO group. A series of meetings focused on the promotion of people’s participation, strengthening the means of communications at all levels, encouraging joint planning among the NGOs within countries, and working for a new style of coordination at the local, regional, and international levels. In 1985, during the 38th World Health Assembly in Geneva, technical discussions took place between WHO and NGOs (over 500 representatives were present) to examine the mechanisms of closer collaboration, to identify and tackle the obstacles to this collaboration, and to indicate the best method of action for the immediate future. The technical discussions resulted in a series of recommendations for NGOS, for governments, and for WHO (53,54). A new era of increased partnership with WHO seems to open. The DirectorGeneral of WHO, Dr. Gro Harlem Brundtland, made the following statement on

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her speach to the 51st session of the World Health Assembly in Geneva in May 1998: “We must reach out to the NGO community. Their reach often goes beyond that of any official body. Where would the battle against leprosy, TB or blindness have been without the NGOs? I will convene a conference with the NGO community to draw up new guidelines for our cooperation to establish new mechanisms for interaction with civil society in Member States.” V. Summary The situation of tuberculosis has worsened and will worsen still more if drastic decisions are not taken everywhere to urgently and energetically apply the means we have (55,56): 1. It has been demonstrated that these means work, and if properly and widely applied, they may even be able to curb the damage caused by HIV to the transmission of tuberculous infection. 2. There are able, dedicated, and enthusiastic people who can apply the means thoroughly. 3. There are donors who wish to invest in productive areas, including research, to make our means still more effective and easier to apply. The future is in the hands of governments of individual countries and the international community to decide whether to have a tuberculosis program. A high responsibility lies with WHO and IUATLD together and, for the latter, together with its national affiliates. They must keep the momentum and maintain the international and national communities closely united to undertake the most formidable battle ever against tuberculosis: the enemy has now enrolled two most dangerous allies, HIV and drug resistance. The conduct and success of the IUATLD Model Tuberculosis Programs led to the DOTS strategy and has shown that what was considered unfeasible is feasible; what was considered insurmountable is surmountable. This is true because mutual assistance is an example of something that is more than only the direct help provided, the reproducible method, or the documented facts. Behind mutual assistance is a spirit of mutual understanding, mutual esteem, and mutual stimulation and solidarity toward progress. The NGOs constitute irreplaceable partners in the national and global fight against tuberculosis. References 1. NGOs’ Group on Primary Health Care. The role of nongovernmental organizations in formulating strategies for health for all by the year 2000 (position paper 1981). (Can be obtained from the Christian Medical Commission, World Council of Churches, 150 route de Ferney, CH-1211 Geneva 20, Switzerland.)

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2. Broadhead T, O’Malley J. NGOs and Third-World Development: Opportunities and Constraints. World Health Organization, GPA/GMC (2) 89.5 Add. 1. WHO, 1989. 3. Moerkek H. The role of non-governmental organizations in AIDS education. Presented at the World Conference on Lung Health, Boston, May 20–24, 1990 (ALA/ ATS/IUATLD). 4. Lee L. A nation of associations. In: Mahoney AI, ed. Leadership (the magazine for volunteer association leaders). Washington, DC: American Society of Association Executives, 1988:17–21. 5. Hastrup B. The role of private organisations in welfare work. The historical perspective. Dan Med Bull 1992; 39(3):228–231. 6. Shryock RH. National Tuberculosis Association 1904–1954. New York: National Tuberculosis Association, 1957. 7. Hershfield E. If preventable, why not prevented? Bull Int Union Tuberc Lung Dis 1991; 56:75–78. 8. Hershfield E. The Canadian Lung Association and international health. Bull Int Union Tuberc Lung Dis 1987; 62:12–16. 9. Trnka L. European constituent members of the IUAT. Their activities in the early eighties. Bull Int Union Tuberc 1984; 59:219–220. 10. Rouillon A. Address for the official ceremony of the 75th anniversary of the NNHA. Bull Int Union Tuberc 1986; 61(1–2):76–79. 11. Wilberg VG. History and development of the Norwegian National Health Association. Bull Int Union Tuberc 1986; 61(1–2):75–76. 12. Özgen ZS. The role of charitable organizations in tuberculosis control in Turkey. Bull Int Union Tuberc Lung Dis 1987; 62:21. 13. Bretton R. The Ivory Coast Committee and its assistance to the state in tuberculosis control. Bull Int Union Tuberc Lung Dis 1986; 61:53–54. 14. Tunisian League against Tuberculosis and Respiratory Disease. Defeat tuberculosis now and forever. Bull Int Union Tuberc 1985; 60:78–79. 15. Larbaoui D. The participation of the Comité Algérien de lutte Contre la Tuberculose in twenty years of tuberculosis control in Algeria. Bull Int Union Tuberc Lung Dis 1987; 62:18–20. 16. Perdrizet S. International training courses in tuberculosis control methods. The WHO/IUATLD/France, Algeria course in French. Bull Int Union Tuberc Lung Dis 1988; 63:39–40. 17. Shimao T. Five major activities of the Japan Antituberculosis Association. Bull Int Union Tuberc Lung Dis 1987; 62:22–24. 18. Pamra PN. The Tuberculosis Association of India. Bull Int Union Tuberc 1984; 59: 217–218. 19. Kusnadi H. Some notes about the activities of the PPTI or Indonesian Tuberculosis Control Association. Bull Int Union Tuberc Lung Dis 1987; 62:17–18. 20. Hong YP. The Korean National Tuberculosis Association. Bull Int Union Tuberc Lung Dis 1990 Dec; 65(4):69. 21. Rouillon A. The International Union Against Tuberculosis. Tubercle 1982; 247–253. 22. Chrétien J. Commemoration du Centenaire de la mort de Jean-Antoine Villemin (1829–1892). Bull Acad Nathe Med 1992; 176(7):1017–1022.

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23. International Union Against Tuberculosis and Lung Disease. Newsletter, September 1997. 24. Enarson DA, Rieder HL, Arnadottir T, Trébucq A. Tuberculosis Guide for Low Income Countries. 4th ed. Paris: IUATLD, 1996. 25. Aït-Khaled N, Enarson DA. Management of Asthma in Adults. A Guide for Low Income Countries. Paris: IUATLD, 1996. 26. Enarson P, Enarson DE. Management of the Child with Cough and Difficult Breathing. A Guide for Low Income Countries. Paris: IUATLD, 1997. 27. Slama K. Tobacco Control and Prevention. A Guide for Low Income Countries. Paris: IUATLD, 1998. 28. Rieder HL, Chonde TM, Myking H, Urbanczik R, Laszlo A, Kim SJ, Van Deun A, Trébucq A. The Public Health Service National Tuberculosis Reference Laboratory and the National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income Country. Paris: IUATLD, 1998. 29. Arnadottir T, Rieder HL, Enarson DE. Tuberculosis Programs. Review, Planning, Technical Support. A manual of methods and procedures. Paris: IUATLD, 1998. 30. Rouillon A. Evaluation of the work of the scientific committees. Bull Int Union Tuberc 1973; 48:10–21. 31. Rouillon A. The IUATLD and its role. Bull Int Union Tuberc Lung Dis 1991; 65:95– 96. 32. Rist N, Crofton J. Drug resistance in hospitals and sanatoria. Bull Int Union Tuberc 1960; 30:2–45. 33. International Union Against Tuberculosis. An international investigation of the efficacy of chemotherapy in previously untreated patients with pulmonary tuberculosis. Bull Int Union Tuberc 1964; 34:1–191. 34. Springett VH. Results of the study on x-ray readings of the ad hoc committees for the study of classification and terminology in tuberculosis. Bull Int Union Tuberc 1968; 41:107–131. 35. Bignall JR and international coordinators. Cooperative international study of the IUAT on evaluation of treatment in routine practice. Bull Int Union Tuberc 1979; 54: 35–46. 36. Krebs A, Farer LS, Snider WE. Five years of follow up of the IUAT trial of isoniazid prophylaxis in fibrotic lesions. Bull Int Union Tuberc 1979; 54:65–69. 37. Lotte A, Wasj-Häckert O, Poisson N. Second IUATLD study on complications induced by intradermal BCG vaccination. Bull Int Union Tuberc Lung Dis 1987; 63: 47–59. 38. Rouillon A. The International Tuberculosis Surveillance Research Unit (TSRU): the first 30 years. Int J Tuberc Lung Dis 1998; 2(1):5–9. 39. Rouillon A. The Tuberculosis Surveillance Research Unit (TSRU). Bull Int Union Tuberc 1978; 53:117–112. 40. Styblo K. Epidemiology of Tuberculosis. Selected Papers 24. The Hague: Royal Netherlands Tuberculosis Association, 1991. 41. Bleiker MA. International Tuberculosis Surveillance Center (ITSC). Its history and objective. Bull Int Union Tuberc 1978; 53:122–124. 42. Bleiker MA, Sutherland I, Styblo K, ten Dam HG, Misljenovic O. Guidelines for es-

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Rouillon et al. timating the risks of tuberculous infection from tuberculin test results in a representative sample of children. Bull Int Union Tuberc Lung Dis 1989; 64:7–12. Rouillon A. The structure of the IUAT, its budget and its scientific committees. Bull Int Union Tuberc 1991; 59:64–66. Enarson D. Principles of IUATLD collaborative tuberculosis programs. Bull Int Union Tuberc Lung Dis 1991; 66:195–200. Herman van Geuns International Union Against Tuberculosis and Lung Disease Memorial Symposium on “10 year collaboration in National Tuberculosis Programs.” Bull Int Union Tuberc Lung Dis 1991; 66(suppl.):41–58. Murray CJL. Social, economic and operational research on tuberculosis: recent studies and some priority questions. Bull Int Union Tuberc Lung Dis 1991; 66:149–156. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, cost and intervention. Bull Int Union Tuberc Lung Dis 1990; 65:6–24. World Bank. World Development Report 1993: Investing in Health. Oxford: Oxford University Press, 1993. World Health Organization Resolution WHA44.8 of 13 May 1991 on the Tuberculosis Control Program. WHO, 1991. Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of worldwide tuberculosis control. Lancet 1997; 350:624–629. Directory of Non Governmental Organizations in Official Relations with the World Health Organization. World Health Organization, 1990. World Health Organization Resolution of 19 May 1989 on nongovernmental organizations and the global AIDS strategy. WHO, 1989. Conclusions and recommendations arising out of the plenary and group discussions of 10 May 1985 on the collaboration with non-governmental organizations in implementing the global strategy for health for all. A38/Technical Discussions/WP.1, World Health Organization, 1985. Resolution WHA 40.25 of 15 May 1987 on the collaboration with non-governmental organizations: Principles governing relations between WHO and non-governmental organizations. World Health Organization, 1987. World Health Organization Statement on AIDS and tuberculosis. World Health Organization in collaboration with International Union Against Tuberculosis and Lung Disease, WHO/GPA/INF/89.4. World Health Organization, 1989. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998; 352:1886–1891.

31 Economic Considerations for Tuberculosis Control

HOLGER SAWERT World Health Organization Bangkok, Thailand

I. Political Commitment and Economic Arguments A. No Money: The Continuing Plight of Tuberculosis-Control Programs

Political commitment is a crucial condition for the implementation of effective tuberculosis-control programs (1). “Commitment” usually entails that national health care providers ensure adequate funding of the various program components, in order to maintain a sufficient supply of drugs and diagnostic materials, the regular training and supervision of staff at all levels, and an effective information and program evaluation system on a long-term basis. Tuberculosis-control programs worldwide have fared rather badly in obtaining this level of commitment. During decades of public neglect of the disease, the programs have often been regarded as pariahs within national health care structures. As a result, underfunding often made the provision of effective interventions impossible. The lack of adequate financial support can be seen as one of the reasons for the reemergence of the disease during the 1980s (2). Fortunately, recent developments have provided an opportunity to improve this situation. Triggered by rising case numbers in a number of industrialized countries, a new interest in the disease has led to a rediscovery of its importance 799

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on a global scale. The sheer magnitude of the problem was one key message that has proved to be useful in arousing the interest of policy makers and the public. The realization that tuberculosis was far from disappearing, but instead had remained the leading killer in adult populations worldwide, made lasting impacts on both professional circles and the general public during recent years. Special events such as the annual World TB Day have been largely successful in putting tuberculosis back on the “international agenda” (see Chap. 34). Nevertheless, popular attention has not regularly translated into adequate funding of control programs. The simple lack of money, besides the continuation of inappropriate policies, remains the most serious impediment for effective tuberculosis-control programs in many countries. B. Common Budgeting Mechanisms and Rational Alternatives

Government budget allocations in most countries are driven by the political power of interest groups. Testimony to this situation in low-income countries is the commonly observed discrepancy between comprehensively equipped tertiary care hospitals in the capitals (where the country’s economic and political elite tries to ensure its well-being) and malfunctioning primary care services throughout the rest of the country. The latter, however, represent the type of service that tuberculosis patients usually have to rely on. These patients tend to be of low socioeconomic status and usually lack the means to access high-level facilities. Their political influence is often negligible. That a large percentage of them is not cured despite the availability of effective treatment, that the epidemic is far from being under control, and that rising case numbers are reported worldwide can thus be seen as one result of resource-allocation mechanisms that are mostly informed by political considerations rather than actual disease burdens and comparative assessments of alternative interventions! Recent years have seen various attempts to overcome this situation and rationalize the provision of health-care services (3). The relevant principles are now introduced by increasing numbers of health-care providers worldwide. Rationalization of political processes usually comprises the specific incorporation of economic principles. The basic notion underlying these principles is that resources are limited and that they should be used in a way that the utility resulting from their use is maximized for all members of a population. Translated to the spending of health-care funds, this notion necessitates the observation of certain basic rules when decisions about funding for alternative projects have to be made: 1. An intervention should be comparatively effective. Among alternative interventions with similar costs, preference should be given to those that produce larger health gains.

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2. An intervention should have comparatively low costs. Among alternative interventions with similar outcomes, preference should be given to those that require smaller expenditures. 3. An intervention should relieve comparatively large burdens to the public health. Among alternative interventions with similar costs and outcomes, preference should be given to those that address diseases of high prevalence and incidence. Rules 1 and 2 are often combined to result in a measure of the cost-effectiveness of interventions. It should be noted that relatively expensive interventions can thus be cost-effective if their outcomes (in terms of health gains) are very large; likewise, an intervention that does not produce large health gains can nevertheless be cost-effective if its costs are very low. Enlarging upon the methods of cost-effectiveness analyses, cost-benefit studies attempt to value outcomes of control interventions in money terms. For example, benefits can be expressed by calculating the income that a patient would earn if death from a disease is prevented through effective interventions (4). If health interventions are evaluated on the basis of cost-benefit analyses, their implementation is recommended if their benefits exceed their costs. From a cost-benefit viewpoint, health-care programs are investments that should result in adequate returns. For example, the modification of an inappropriate tuberculosis-control strategy may require substantial initial expenditures, such as intensive training programs for staff at all levels or the purchase of new equipment, e.g., microscopes. If it can be shown that these investments are exceeded by the benefits resulting from improved patient care, a strong argument for the implementation of the new strategy can be made. The results of an effective control program, such as an overall reduction of case incidence, may not immediately follow the introduction of an improved control strategy. For this reason, tools that allow the evaluation of future scenarios and their relationship to current decisions about control strategies are of specific importance for the conduct of economic analyses. C. Modern Budget Allocation Mechanisms and Tuberculosis Control

How can tuberculosis-control programs be evaluated according to economic principles? The programs (Table 1) address a comparatively large disease burden to societies; in fact, they address the disease causing the largest burden among all infectious diseases worldwide (5). They used to be relatively expensive due to high drug costs and prolonged hospitalizations, but costs have been reduced substantially through the introduction of ambulatory treatment (6) and recent price cuts for drugs (7). The health benefits are very large because curing a case will not only provide individual healthy years of life, but will also prevent new infections and

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Table 1

Modern Resource Allocation Criteria and TB Control

Allocation criteria Large disease burdens Cost-effective interventions

Facts about TB control TB is the leading cause of death from infectious diseases in adults. TB control is among the most cost-effective of all health care interventions.

thus potential future cases. A comparison of these health gains to the cost of the interventions in African countries showed the remarkably favorable cost-effectiveness of tuberculosis control (8). This observation has been used by international funding agencies such as the World Bank, which listed tuberculosis control among the “most cost-effective” health-care interventions available for low- and middle-income countries (3). In a political climate that favors the introduction of rational policy making based on economic considerations, the directors and managers of specific programs within the health care sector will be regularly challenged to demonstrate the “cost-effectiveness” of the interventions they implement. Managers of tuberculosis-control programs are therefore well advised to familiarize themselves with the relevant basic terms and concepts to engage successfully in the competition for limited funds. II. Economic Analysis: Basic Concepts A. Costs

Economists define the word “costs” in a way that differs from its use in ordinary language. The concepts that are used to define the economic cost of an activity are those of “resource consumption” and “opportunity cost” (9,10). While a tuberculosis program manager will normally calculate the cost of an x-ray as the price of the film and developer, the economist notes that, in order to produce the x-ray, several “resources” must be used in addition to film and developer (e.g., the x-ray machine, the time of the x-ray technician, or the space for the dark chamber). To use these resources results in an “opportunity cost,” since an opportunity to use them for an alternative purpose is forgone to produce the x-ray: the x-ray machine could have been sold or rented to another hospital, the technician could have swept the floor and saved the expense for cleaning personnel, and the dark chamber could have been rented as a hotel room. While the examples may be a little farfetched, they illustrate why the costs that economists calculate for a specific activity may differ substantially from the figures that program managers know from their budget and expenditure sheets. The cost that is calculated by dividing the total cost for all resources by the number of output units is known as the average cost of an activity. For example,

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we can calculate the average cost of an x-ray by determining the total cost of the facility for one month and dividing this figure by the number of x-rays that was produced in that period. Apart from total and average costs, there are additional categories of economic costs which are sometimes more appropriate for the assessment of program modifications. Incremental costs are defined as the additional costs of a new activity (which may make use of existing facilities) (10). If a new tuberculosis clinic is set up in a hospital with spare rooms and unused staff time, the costs for buildings and staff will not change if an additional activity is added. In this case, the incremental cost of a new activity will not include building and staff costs. The resulting cost figure may be substantially lower than total costs. Marginal costs are costs for producing more output units for an existing activity, e.g., producing 101 instead of 100 x-rays per day. If the capacity of the existing x-ray facility is sufficient to handle this number, there will be no additional infrastructure costs, and the marginal cost figure may just equal the costs for films and developer. A technically improved intervention may result in cost reductions: if ambulatory tuberculosis treatment is delivered, instead of in hospitals, costs for the health care provider will drop (6). If outcomes are similar (or better) than under the previous strategy, any further analysis would be superfluous, and one may avoid further work on the basis of this least-cost analysis. When cost reductions under alternative strategies are delayed, an analysis of future scenarios will be necessary. When provider costs under a new strategy are higher than under the previous one, an analysis of outcomes is required to assess its economic merits (Table 2). B. Outcomes

Effectiveness

The effectiveness of health interventions is usually measured in time units: if a person were to die from a disease, an effective intervention will provide additional lifetime; if a person lives in a state of disability from disease, curing him will provide additional time of healthy living. Despite these straightforward notions, a bewildering variety of health outcome measures is used in economic analyses, often

Table 2

Forms of Economic Analysis

Least-cost Cost-effectiveness Cost-benefit

Costs

Outcomes

$ $ $

— “Health,” measured in time (QALY, DALY) $

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denoted by acronyms such as years of healthy life lost (YHLL), quality adjusted life year (QALY), or disability adjusted life year (DALY). The differences arise from different assumptions about the “normal” life expectancy, the “economic value” of life years at different ages, or alternative methods for assessing disabilities. Unfortunately, there is currently no universally accepted standard, which complicates the comparison of studies that have used different measures (11–13). Nevertheless, the evaluation of a large number of alternative interventions remains possible if one standard measure were used for all studies. The effectiveness of an intervention can be related to its costs in cost-effectiveness ratios. When uniform methodologies are used for a variety of interventions, decision makers are enabled to maximize the outputs of a health-care system by choosing the interventions with the most favorable cost-effectiveness ratios. In a recent large-scale study, interventions with a cost of less than $150 per year of life saved were regarded as “highly cost-effective” for middle-income countries. The same study denoted an average cost per year of life saved by tuberculosis-control interventions of $5–7 (3). Benefit

Economists have used various methods to express health benefits in monetary terms. A prevented death will result in additional years of productive life. The income that a person could obtain during these years can be counted as the economic benefit of the health-care intervention. This approach to costing health benefits is known as the human capital method (4). An alternative consists in determining people’s willingness to pay for healthy life years (e.g., by observing how much they are willing to invest in safer cars to reduce the risk of death from road accidents) (9). These figures can be used as a measure for the “utility” that people derive from life years and accordingly as the benefit resulting from effective healthcare interventions. We note that figures derived by the “human-capital” and “willingness-to-pay” approaches tend to differ widely, and both methods are fraught with concerns about equality due, for example, to their tendency to place higher economic benefits on providing health care to the rich or young. Again, this observation demands caution when the results of studies with different methodologies are compared. Nevertheless, if similar methods are used to assess alternative interventions, the determination of economic benefits in addition to health outcomes may provide information of crucial interest to policy makers. III. Specific Points for the Analysis of Tuberculosis Control Interventions A. Drug Resistance

Insufficient treatment of tuberculosis cases will result in a high percentage of relapses. Also, there is a danger that remnant mycobacteria have become resistant

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to one or several drugs under treatment, which will make the cure of relapsing cases more difficult to achieve. In its most severe form, drug resistance develops against the two most potent antimycobacterial drugs, rifampicin and isoniazid. The mortality in these multidrug-resistant cases is excessively high, and their successful treatment requires the use of second-line drugs, extensive hospitalization, and sometimes surgical interventions. The associated costs can be extremely high: a U.S. study provided estimates of greater than $180,000 per case (14). The emergence of drug resistance under inadequate control programs has been clearly described (15), as well as the potential reductions of drug resistance resulting from effective treatment strategies (16). This observation has obvious economic implications: the high costs of treatment should make the prevention of drug resistance (through effective treatment of regular cases) the cheaper option (14). To fully assess the costs of ineffective control programs and the benefits of improved strategies, an assessment of future scenarios will be necessary. B. Future Scenarios

Successful tuberculosis control programs have benefits beyond the cure of individual patients (Fig. 1). Since tuberculosis is an infectious disease, the cure of active cases entails a reduction of the risk of new infections for as-yet-unaffected members of the population (8). This, in turn, will lead to an overall reduction of case incidence rates. Lower case incidences, however, mean lower costs for the health care provider. These basic relationships can be usefully exploited for the economic evaluation of tuberculosis-control programs. An inefficient strategy,

Figure 1

Indirect effects of improved TB control.

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run with a minimum of training and supervision expenditures and temporarily ceasing to function when drugs run out, may be regarded as a “low-cost” option by health-care providers. An analysis of future scenarios will show that this is not necessarily the case: since such a strategy is unlikely to reduce the risk of infection, the case load may remain high and can increase dramatically under the influence of external factors such as HIV or social changes. The “cheap” option may turn out to be costly when health-care services are crowded with new tuberculosis cases, the occurrence of which could have been prevented. On the other hand, successful control programs can achieve remarkable reductions of incidence, more recently demonstrated in the wake of the resurgence of the disease in the United States (17). The economic assessment of tuberculosis-control interventions should therefore go beyond the consideration of individual cases to an analysis of alternative scenarios for the overall development of the epidemic and their associated costs and benefits. To perform this task, some modeling of future developments will be necessary. The first models of tuberculosis epidemics were developed by Wade Hampton Frost during the 1930s (18). Since then, a variety of models has been used for epidemiological and economic analyses (19–21). Although most models are based on rather complex mathematics and tend to be inaccessible to politicians or program managers, simpler approaches are possible (e.g., by exploiting the empirically derived relationship between the annual risk of infection and incidence rates) (22). When model projections are applied for practical purposes, such as economic analyses, sensitivity analyses need to be performed to assess the influence of different parameter values on model outputs. This step is necessary, since most of the epidemiological parameters cannot be derived precisely from empirical studies; instead, ranges of values will usually be available from a number of studies, all of which should be explored in model calculations. If changes of parameter values do not result in changes of the basic conclusions of an economic analysis, its results can be described as robust. A complete economic analysis of alternative tuberculosis-control strategies would therefore proceed in the following way: 1) an analysis of the total costs and outputs provides an average cost figure per case treated; 2) if important fixed-cost items exist whose magnitude will not differ with changing case numbers, the marginal cost per case should be determined in addition; 3) a similar analysis is then performed for the new strategy, again using the concept of marginal costs for varying case numbers, as well as the concept of incremental costs if the new strategy will make use of existing health-care infrastructure; 4) modeling is employed to determine the total number of tuberculosis cases and deaths for a certain time period (e.g., 10 or 20 years) under two scenarios—continuation of the current program or implementation of the alternative strategy; 5) case and death numbers may be converted into a standard outcome measure, such as QALYs or DALYs; 6) costs and outcomes for the two strategies are compared and differences calculated; 7) if costs for the new strategy are lower and outcomes are better, the anal-

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ysis concludes with this least-cost result; 8) if costs are higher, cost-effectiveness ratios are calculated and compared to those for alternative health-care interventions; 9) to perform a cost-benefit analysis a money value is associated with case and death numbers under the two scenarios and the difference between the two calculated; 10) if benefits exceed any additional costs for the new strategy, its implementation can be recommended on economic grounds.* IV. Example: Improving Tuberculosis Control in Thailand A. Introduction

Thailand has provided short-course drug regimens free of charge to all tuberculosis patients since 1986. Nevertheless, program outcomes have remained poor. The average cure rate of smear-positive cases is less than 60%, and case detection has recently been estimated to be less than 50% (23). The country has experienced a rise in tuberculosis incidence rates in concurrence with the development of the HIV epidemic. The government is now faced with the choice between either continuing the current control policy or investing in improved services. The key feature of an improved service would be the provision of treatment under direct observation, which would require a decentralization of treatment services from their current concentration at specialized facilities to the district and health center level. In the following we will describe how the decision-making process could be aided by an economic analysis (24). B. Methods

Epidemiological Model

A simple epidemiological model can be used to calculate case and death numbers for four categories of patients (HIV positive and negative, treated and untreated), as well as the proportion of multidrug-resistant (MDR) cases among all detected cases (Fig. 2). For HIV-negative individuals, the model makes use of the relationship between the annual risk of infection and the tuberculosis incidence rate. Incidence rates for HIV-positive individuals have been reported in various studies. The model requires projections of the general population size as well as of the HIV epidemic as inputs. This information is available from national statistical offices or health ministries.

* Whenever future scenarios are evaluated for economic analyses, the discounting of future costs and benefits is an important step. In general, discounting means that future costs do have a lower value than costs that occur today. Since a detailed discussion of the associated concepts would transcend the limits of this chapter, the reader is referred to the specific economic texts listed as references.

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Figure 2 Ref. 24.)

All rates used during model calculations are indicated as circles. All time-dependent model inputs and rates are indicated by arrows (⇓). (From

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Cost Analysis Provider Costs

The average cost per tuberculosis case treated in Thailand was determined in 1995 to be $343. An analysis of cost distributions showed that the largest cost categories were drugs (27% of total costs) and salaries (24.3%). Recurrent costs for diagnostic supplies and stationery accounted for 4.6% of total costs. Maintenance costs, capital depreciation, and recurrent costs for training and supervision together accounted for 44.1%. Since this analysis requires an assessment of the cost implications of changing case numbers, it is necessary to calculate the marginal cost per case treated. While an increase in the workload from tuberculosis at the district level will influence the use of available infrastructure for tuberculosis, it is unlikely that this will have cost implications with respect to the use of the existing health infrastructure for treatment services: the average annual case load per TB clinic at the district level is currently 33 patients, or fewer than 3 patients per month. Model calculations assuming full decentralization and “worst-case scenarios” for increases in total case numbers show that this workload would increase to not more than eight patients per month. This increase is unlikely to require additional infrastructure with respect to treatment services. However, 43% of all patients are currently diagnosed at centralized services and only 33% at district level. If diagnosis is also fully decentralized, additional infrastructure (microscopes, laboratory equipment, and laboratory staff) may be required, since diagnosis also involves the screening of a substantial number of suspects. The marginal cost calculation for diagnostic services therefore includes the costs of personnel and equipment, while marginal costs with respect to treatment activities are calculated as average variable costs for drugs and stationary. The total of these costs is $161 per case. The cost for the treatment of multidrug-resistant cases could not be precisely determined at the district level, because these cases are regularly treated at referral hospitals. Also, the treatment of these cases tends to be highly individual, with various second-line drug regimens, different lengths of hospitalization, and sometimes surgical interventions. For this analysis, we assume a range of $1,000–$10,000 per case, which can be regarded as a conservative estimate when compared to an average cost of $180,000 reported from the United States (14). Indirect Costs

Indirect economic costs resulting from morbidity and mortality due to the TB epidemic can be calculated based on the human capital approach, using the average GDP for Thailand as an indicator of the economic benefit derived from a year of healthy life. Loss of productive time is calculated separately for the morbidity and premature mortality resulting from tuberculosis. With respect to morbidity, it is assumed that a diagnosed and treated case would lose on average 2 months of time

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at the workplace, whereas a patient who remains undiagnosed would lose on average one year of work time. Calculations of the time of productive life lost due to premature mortality are made separately for HIV-infected and non–HIV-infected TB patients. For HIV-infected individuals, it is assumed that death from tuberculosis would on average only lead to the loss of 2 years of productive life, since death would occur from other HIV-related illnesses after cure from TB. For non–HIV-infected individuals, an average age of death of 45 years is assumed, resulting in 15 years of productive life lost if participation in the workforce is supposed to end at age 60. Streams of future life years are discounted at a rate of 5.85%. Taken together, these assumptions mean that the indirect costs resulting from morbidity due to tuberculosis are $317 for a treated patient and $1,900 for a patient who remains undiagnosed. Death of an HIV-infected TB patient causes an economic loss of $3,490 to society, while the death of a non–HIV-infected patient results in a loss of $19,400. C. Results

Epidemiological Projections

Figure 3 shows projections of tuberculosis case numbers in Thailand. Since casedetection rates rise under the new program, the number of detected cases is pro-

Figure 3 Numbers of total (i.e., all incident cases, either detected or undetected) and detected cases for model calculations with the mean parameter values (without uncertainty analysis). Results are shown for a scenario describing the current program policy (“no change”) and a scenario assuming a program modification to achieve target levels of 70% case detection and 85% cure rate (“new program”). (From Ref. 24.)

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Figure 4 The difference in annual direct provider costs between two scenarios: continuation of the current program policy and program modification to reach new target levels for case detection and cure rate. Negative values indicate higher costs under a modified program; positive values indicate higher costs under the current program. Results are presented for a simulation period of 20 years and show the range of possible future scenarios determined by the uncertainty analysis. Cost unit is millions of dollars. (From Ref. 24.)

jected to be higher under improved program conditions until the year 2007. Thereafter, case detection is lower than under the current program due to the decrease in total case numbers. The projections for MDR cases follow the same trend, although initial differences in case detection are less pronounced (data not shown). In brief, from a level of 2000 MDR cases in 1995, 3078 cases are expected in 2015 if no changes in current control practices take place, as opposed to 408 cases under a revised program strategy. Analysis of Future Costs and Savings Direct Costs

Provider cost differences between the two strategies depend on differences in numbers of detected cases (drug sensitive and MDR) between the new policy and the present program. Figure 4 shows projected annual differences in expenditures, indicating possible ranges on the basis of the uncertainty analysis. The new program strategy could require additional costs over the costs under the current strategy for a period of up to 17 years. Thereafter, annual expenditures would be less than those projected under the current strategy for all parameter combinations.

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Figure 5 The figure shows the difference in cumulative indirect costs between two scenarios: continuation of the current program policy and program modification to reach new target levels for case detection and cure rate. Positive values indicate higher costs under the current program, i.e., savings that could be obtained through a restructuring of the program. Results are presented for a simulation period of 20 years and show the range of possible future scenarios determined by the uncertainty analysis. Cost unit is billions of dollars. (From Ref. 24.)

The mean present value* of these streams of future costs and savings is $8.3 million, with a range of uncertainty from $90 million in additional expenditures to $115 million of potential savings. Forty-eight percent of the generated values are greater than $10,000,000: should the restructuring of the program require an additional spending of $10,000,000, there is a 48% probability that future savings will be higher than this initial investment. Indirect Costs

Cumulative figures for the amount of indirect costs that could be avoided through the introduction of intensified control measures are shown in Figure 5. For an evaluation period of 20 years, the mean of the simulation results is $2.5 billion, with a range of simulation results from $65 million to $7.0 billion. Again, if we assume

* Depending on the discount rate, the present value of cost and benefits that occur in the futire is lower than the actual future figure.

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that the required investment in improved services would be $10,000,000, the societal benefit gained from every dollar invested in improved tuberculosis control would be at least $5.50 and probably as much as $700. D. Discussion

In this example, we make the realistic assumption that the establishment of a wellfunctioning tuberculosis-control program would require considerable initial investment. However, the analysis of future scenarios provides important information for the decision-making process. From a societal perspective, the required expenditures are always far outweighed by savings resulting from averted morbidity and mortality. The probability of net savings in direct provider costs is also shown to be high. We made conservative assumptions in order not to overestimate the benefits from improved control measures (e.g., no increase of the annual risk of infection even under the influence of HIV, low estimates of the increase of MDR cases, low-cost estimates for the treatment of MDR cases). The result of the uncertainty analysis with its wide range of possible outcomes shows that increased expenditures within the health-care system are definitely possible under these restrictive conditions. These results are highly sensitive to the assumptions made about the development of MDR cases. In our calculations, the highest values for the initial level and annual increase of MDR cases results in a proportion of 10% MDR cases among all cases after 20 years, which is well below data reported from other areas with high HIV prevalence (15). Since our highest cost estimate for the treatment of an MDR case ($10,000) is also considered to be conservative, we conclude that the probability of net savings to the health system through the implementation of a successful tuberculosis control strategy may be substantially higher than reported here. Previous economic analyses regarding tuberculosis have focused on the cost-effectiveness of the relevant interventions. If the information generated from this study is used to calculate cost-effectiveness ratios, expressed as marginal costs per marginal year of life saved, we are faced with the example of an intervention with negative cost-effectiveness ratios (i.e., years of life are saved while costs are decreasing simultaneously) for the majority of model calculations. For those scenarios that result in higher costs to the health care provider, the highest cost per discounted year of life (DYL) saved is $32, which would confirm the status of tuberculosis control as one of the most cost-effective health-care interventions (3). Although the analysis was made for the situation in Thailand in 1995, we assume that the characteristic factors (existing control program with relatively low efficiency, increasing case numbers due to the HIV epidemic, increasing incidence of multidrug-resistant cases) are paradigmatic for the situation in many countries today. It is therefore likely that similar conclusions about the economic

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effects of improved tuberculosis-control strategies could be drawn for different countries, even though there may be differences in the magnitude of costs and savings. References 1. WHO Global Tuberculosis Programme. Framework for Effective Tuberculosis Control. WHO/TB/94.179 ed. Geneva: WHO, 1994. 2. WHO Global Tuberculosis Programme. TB—A Global Emergency. WHO report on the tuberculosis epidemic. Geneva: WHO, 1994. 3. The World Bank. World Development Report 1993. Investing in Health. Oxford: Oxford University Press, 1993. 4. Rice D, Hodgson TA, Kopstein A. The economic cost of illness: a replication and update. Health Care Financ Rev 1985; 7:61–80. 5. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990; 65:1–20. 6. Barnum HN. Cost savings from alternative treatments for tuberculosis. Soc Sci Med 1986; 23:847–850. 7. Chaulet P. The supply of antituberculosis drugs: price evolution. Tuberc Lung Dis 1995; 76:261–263. 8. Murray CJ, DeJonghe 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. 9. Drummond MF, Stoddart GL, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes. Oxford: Oxford Medical Publications, 1987. 10. Sawert H. Cost analysis and cost containment in tuberculosis control programmes. Geneva: WHO, 1996. 11. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ 1996; 313:275–283. 12. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-Effectiveness in Health and Medicine. JAMA 1996; 276:1253– 1258. 13. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine. JAMA 1996; 276:1339–1341. 14. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis. We can’t afford not to try it. N Engl J Med 1993; 328:576–578. 15. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993; 328:521–526. 16. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330:1179–1184. 17. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333:229–233.

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18. Frost WH. The age selection of mortality from tuberculosis in successive decades. Am J Epidemiol 1995; 141:4–9. 19. Joesoef MR, Remington PL, Jiptoherijanto PT. Epidemiological model and cost-effectiveness analysis of tuberculosis treatment programmes in Indonesia. Int J Epidemiol 1989; 18:174–179. 20. Blower SM, Small PM, Hopewell PC. Control strategies for tuberculosis epidemics: new models for old problems. Science 1996; 273:497–500. 21. Waaler HT. Model simulation and decision-making in tuberculosis programmes. Bull Int Union Tuberc 1970; 43:337–344. 22. Styblo K. The relationship between the risk of tuberculosis infection and the risk of developing infectious tuberculosis. Bull Int Union Tuberc 1985; 60:(app.1)117–119. 23. WHO Global Tuberculosis Programme. Tuberculosis Programme Review Thailand. WHO/TB/95.192. Geneva: WHO, 1995. 24. Sawert H, Kongsin S, Payanandana V, Akarasewi P, Nunn PP, Raviglione MC. Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 1997; 44:1805–1816.

32 The Impact of Managed Care on Tuberculosis Control in the United States

BESS MILLER

SARA ROSENBAUM

Centers for Disease Control and Prevention Atlanta, Georgia

School of Public Health and Health Services George Washington University Washington, D.C.

I. Introduction Health sector reform is occurring in both industrialized and developing countries throughout the world (1). The nature of the reform varies greatly, but it often involves substantial changes in the organization and financing of health services. These changes may have a profound effect on the way tuberculosis (TB)-control activities are carried out. In the United States, the major thrust of reform over the past decade has been a change in the predominant mode of financing and organizing health care, from traditional public and private insurance to managed care. Managed care is a form of insurance that combines the financing and delivery of health services. In this system, managed care companies contract with buyers (e.g., employers or public agencies) to provide a defined set of health services to plan members at a fixed rate, thereby assuming financial risk for the cost of care. Managed care often includes the practice of capitation, where a managed care company’s network providers are paid a single fee that covers the costs of patient care, regardless of the number of encounters. As with insurance in general, an underlying tenet of managed care is that some patients will need very little care, while others will need far more. Providers or organizations that do not manage funds appropriately or ac817

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cept a capitated rate too low to cover costs of services will lose money. Perceived benefits of managed care include cost control, increased access to care, improved quality of care, and the integration of categorical services into primary care (2). This movement towards managed health care has raised concerns among public health officials regarding their ability to sustain good TB-control practices within a managed care framework. On the one hand, managed care may provide an environment conducive to the consistent application of clinical standards of patient care. On the other hand, it is a system that emphasizes cost control and responsibility to individual plan members rather than the community at large. This chapter will describe the effect that managed care has had on TB control in the United States and the response of the public health community to the changes that are taking place. II. Tuberculosis Control in the United States: Current Organizational Structure In the United States, the states are responsible for regulating the provision of health care and financing the delivery of certain communicable disease services, and each state public health department has a unit responsible for TB control. The size of a state’s TB-control program and its organizational structure vary considerably, depending on the size of the TB problem and the organizational and political structure of the state’s public health system. While state arrangements vary, certain aspects of TB control are typical to all states. Thus, TB-control activities at the state level include policy development, supplying drugs for public TB clinics, provision of laboratory services, maintaining information systems, assessment of program performance, training and consultation, performing outbreak investigations, and providing funding to local TB programs. At the local level (county or city), it is also customary to find a public health TB unit or communicable diseases unit. Local level functions include the delivery of clinical services, including directly observed therapy (free of charge to those who cannot afford to pay), and performance of public health functions, including surveillance, contact investigations, infection control, screening high-risk populations for infection, and providing treatment for latent TB infection (3,4). The relationship between the state and local programs varies widely. In some areas the local health departments manage patients and their local programs nearly autonomously, performing many of the duties described above for the state programs; in others the state health department is involved in daily operation of local programs and patient management. In addition, a number of agencies at the federal level play a significant role in TB control by formulating policies, maintaining a national surveillance system, supporting a national framework for program evaluation, conducting research,

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and licensing drugs. The federal government also provides funding to state and local health departments through both direct grants and coverage of low-income persons through entitlement programs, primarily Medicaid (see below). Following the closing of the TB sanatoria in the 1960s and 1970s, typically both clinical care and public health functions for TB control were carried out in the public health department setting (5). However, over the past three decades, there has been an increasing trend toward private sector clinical care for TB patients. By 1995, approximately 50% of patient care for TB patients was provided either partially or totally by the private medical sector (6). This separation of individual patient care from the public health aspects of TB control has created challenges to private health-care providers and health officials alike and has provoked debates as to the optimal setting for TB patient care (7). III. The Advent of Managed Care and Its Impact on TB Control The managed care transformation has increased the movement of TB patients away from clinical care in health department settings (8). Tuberculosis patients may be enrolled in managed care organizations as a result of coverage under employee benefit plans, privately purchased insurance policies, enrollment in Medicaid, or enrollment in Medicare programs. The Medicaid program is a joint federal-state program supplying health care coverage to low-income, aged, and disabled persons. Medicaid, established in 1965 to serve the poor, relies on the states to set eligibility limits, and there is a wide variation in Medicaid benefits from state to state (9). Medicare provides health care coverage to persons over age 65 and covers persons with certain disabilities as well. The Omnibus Budget Reconciliation Act of 1993 (OBRA) permitted states to extend Medicaid coverage to low-income persons with TB otherwise ineligible for coverage, and some states have used this legislation to enroll TB patients in their Medicaid programs (10). Furthermore, in the interest of cost containment, many states have mandated enrollment of Medicaid beneficiaries into managed care plans. As part of this Medicaid managed care restructuring overall, a few states also have expanded coverage to previously uninsured persons (11). The vulnerable populations included among the newly insured may include persons with or at high risk for TB. Paralleling the growth in Medicaid managed care has been an increase in managed care enrollment among the Medicare population. By 1996, three quarters of all privately insured individuals, 40% of all Medicaid beneficiaries, and over 10% of Medicare beneficiaries were members of managed care plans, and these numbers are expected to increase (12). A recent survey of state TB-control programs showed that nearly one fourth of TB patients were enrolled in Medicaid (CDC, unpublished data).

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The shifting of care of patients with TB into managed care plans, with the emphasis on management of costs, has raised new concerns among TB and communicable disease health officials regarding the ability of the private sector to maintain adequate community TB-control efforts and provide optimal patient management. Specific concerns are addressed in the following sections. A. Surveillance

The reporting of communicable disease of public health significance is mandated by state and territorial laws and regulations (13). Managed care organizations may use out-of-state laboratories, which may not be subject to the laws of the state from which the specimen originated. This may lead to poor or delayed reporting and failure to institute treatment, initiate contact investigations, and identify outbreaks in a timely manner. B. Outbreak/Contact Investigations

The duty of managed care is to prevent and cure disease among members of the managed care plan. While managed care organizations are able to follow-up members who have been exposed to persons with active TB, they are not likely to accept the role of identifying nonmember contacts to TB patients enrolled in their plans. Furthermore, frequent disenrollment and reenrollment of patients may hinder the recognition of outbreaks. C. Provision of Clinical Services

In general, managed care organizations have limited experience with vulnerable populations. Most have relatively little experience providing enabling services, such as transportation, interpreter services, social services, and, most crucial for management of TB patients, providing directly observed therapy (DOT). There are no explicit incentives to search for TB patients lost to follow-up. On the contrary, capitated rates may actually create incentives for underservice. D. Laboratory Services

Mycobacteriology services are quite specialized, and extensive guidelines for processing mycobacterial specimens have been developed (14). In many areas with declining TB morbidity, only the state public health laboratories have been able to process enough specimens to maintain the needed expertise. Additionally, current recommendations require antimicrobial drug susceptibility testing of all initial Mycobacterium tuberculosis isolates from patients. In the effort to control costs, managed care organizations may use a variety of private laboratories, local or out

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of state, which may not have sufficient experience in handling mycobacterial specimens and in performing drug susceptibility tests on these isolates. E. Screening High-Risk Persons for TB Infection and Provision of Treatment for Latent TB Infection

Screening populations at high risk and providing treatment for latent TB infection are not of financial benefit to managed care organizations because prevention may be beneficial only in the distant future (except in the case of severely immunosuppressed persons). In reality, the average duration of coverage in any one Medicaid managed care plan is only 8 months (15)! F. Quality Assurance

Assuring the quality of care of TB patients managed in the private medical sector has typically been difficult. A national system of assessing the quality of care provided by managed care plans has been developed (Health Plan Employer Data and Information Set, or HEDIS). However, because TB is considered a rare disease in many areas, performance indicators on TB are not included in this assessment tool. On the other hand, because quality managed care organizations are likely to adopt and enforce the use of clinical standards of care, the quality of TB patient care could actually be an improvement over that provided by a heterogeneous group of private practitioners. G. Health Department Revenue

In many areas, Medicaid funding was used to subsidize activities of some health department programs. As more Medicaid funding is directed toward Medicaid managed care plans, this source of revenue will be lost. In addition, health departments in many areas are continuing to provide services to vulnerable populations, including persons enrolled in Medicaid or Medicare managed care organizations as well as uninsured individuals; in many cases, the health departments are not being reimbursed for these services. Many health departments do not have billing systems that would enable them to be reimbursed by third parties, such as Medicaid, Medicare, or private insurance companies. V. Response of TB Health Officials to the Advent of Managed Care At the state and local level, the response to managed care, and particularly Medicaid managed care, has been varied, depending on such factors as the magnitude of the TB problem, the characteristics of the TB patients, the organizational structure of the health department TB control program, and the degree of penetration

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of managed care into the community. A survey of state and local TB-control programs on the impact of managed care revealed important information. A. Provision of Clinical Services

Over half of the states that have managed care reported that the traditional arrangement, where the health department provides clinical care to the TB patients and receives categorical funding from federal, state, and local sources, still exists. In the remaining states, a combination of the following arrangements exists: 1. Health departments care for some of the patients, by serving as a subcontracting network provider to the managed care organization. The managed care organization pays the health department directly for providing TB clinical service to their enrollees with TB. 2. Health departments serve as nonnetwork “fee-for-service” providers. The health department provides all or some clinical services (e.g., perhaps only DOT) to TB patients enrolled in managed care on a fee-forservice basis. 3. TB services are provided within the managed care organizations. 4. TB services are exempted from managed care agreements. In this situation the health department continues to provide clinical services to TB patients enrolled in managed care organizations, but these arrangements are not included in any written agreements (see Section VI). Health departments are paid directly by the Medicaid agency. This is the case in some of the counties in California, with regard to the provision of DOT. 5. Finally, in a few areas health departments are becoming managed care organizations themselves and providing clinical and public health services. B. Performance of Contact Investigations, Provision of DOT, and Return to Care

The health department continues to perform contact investigations in most states with managed care arrangements and continues to provide DOT as well (under a variety of financial arrangements) in most of these states. Return of lost patients to care also continues to be done by the health department in most areas. These activities are labor intensive and costly. C. Billing and Reimbursement for Services Provided

While approximately two thirds of TB programs have billing systems in place to allow for reimbursement for services, only about one half actually receive such payments (CDC, unpublished data). Many health departments are now develop-

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ing the capability to bill third parties (e.g., Medicaid, Medicare, private insurance companies, managed care organizations) for services provided to TB patients. This requires substantial effort in areas that have not had the information systems, staff, or even the volume of patients to warrant such systems. Assigning charges to certain services, e.g., a DOT visit, is difficult in many areas. In addition, billing may be a disincentive to receiving services for some low-income patients, who may be asked to pay on a “sliding scale” basis. However, in the changing healthcare–delivery system, obtaining reimbursement for services may become increasingly important if health department activities such as contact and outbreak investigations and providing DOT are to be sustained. D. Collecting Information on Source of Care for TB Patients

Information on the source of care for TB patients (e.g., name of provider, name of managed care plan) is not collected in a standard manner around the country and is not currently included in the national surveillance reporting system. In most areas, ideally the name of the provider or managed care plan can be found in the TB register, which may be a hand-written card-based register or an electronic one. A few areas are beginning to include managed care status as one of the variables in their local reporting systems. This may be quite useful in providing oversight of these patients and in assessing the quality of care provided to them (e.g., rates of treatment completion in patients cared for by managed care plans). E. Coordination of Activities Between the Public Health Departments and Managed Care Plans

Clearly, the health department continues to play a leading role in both the provision of clinical services and the performance of public health functions, even in areas heavily penetrated by managed care. However, the need for coordination with new providers and new organizational and financial structures is great. Many areas have identified a specific “case manager” or “case management team” in the health department to serve as coordinators and patient “ombudsmen” for the managed care organizations in their areas. The larger managed care plans may assign specific personnel to oversee management of TB patients or, more broadly, patients with communicable diseases. If the health department is a managed care organization itself, this may solve some coordination problems but at the same time present problems in its oversight functions of other managed care organizations, as it may be seen as a competitor. VI. Role of Contracts and Memoranda of Agreement In response to the new reality of large health-care systems providing care to TB patients, many areas are developing written agreements to clarify the roles and re-

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sponsibilities of the managed care plans and health departments and to formalize the relationship between the two. These may take the form of informal memoranda of agreement, usually between managed care organizations and state or local health departments, describing who will be responsible for the various components of patient care and public health practice. On a more formal level, they may develop legally binding contracts, usually describing the arrangement between the purchasers of managed care, e.g., state Medicaid agencies, and the managed care plans. These contracts may cover only a few aspects of patient care or public health issues, or they may include detailed specifications on all aspects of the management of patients and the safeguarding of the public’s health. The process of developing and negotiating contracts is a new one for the public health community and most are in the learning phase regarding how to be involved in the process of contract development and what specifically should be included in the contracts. Recently, model contract specifications for TB have been developed for use by managed care organizations, purchasers of care (e.g., state Medicaid agencies), and health departments to formalize the relationships between these parties regarding the standards for patient care and public health practice (16). The provisions are of importance to health officials because they attempt to address the multiple points at which public health agencies should interact with managed care organizations and the public health considerations that must be addressed in managed care settings. The model contract specifications are organized around 10 categories, selected because they represent the principal elements of Medicaid managed care contracts. These categories include: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Definitions of terms Covered services Medical necessity (What is medically necessary to cover?) Enrollment and disenrollment procedures Provider network (Which providers, including laboratories, are qualified to provide care?) Access standards (What waiting times [including for laboratory results] and distances for travel to services are acceptable? Relationships with local health departments Quality assurance Data and reporting Confidentiality issues

The model contract includes specifications on providing quality clinical care to TB patients, but also on methods to ensure that the public health aspects of TB control are addressed. It assumes certain standards of care based on nationally accepted guidelines. These include use of bacteriological confirmation to diag-

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nose TB patients; drug susceptibility results on all initial isolates; rapid laboratory methods by laboratories with expertise in mycobacteriology; standard initiation of three- or four-drug regimens with total duration of therapy lasting at least 6 continuous months; directly observed therapy for all patients; recommended infection control practices, including isolations of infectious patients in institutional settings; reporting of all cases to the health department; timely initiation of contact investigations; and screening and preventive therapy for high-risk populations (4,14,17–24). The contract is written to assure continuity of care (enrollment, disenrollment section), provision of drugs free of charge (covered services section); provision of social services, such as drug rehabilitation and housing for the homeless (covered services section); universal DOT (covered services section); hospitalization with isolation in cases where medically necessary to prevent transmission of disease (medical necessity section); and use of providers, including laboratories, with expertise in treating TB (provider network section). Finally, the contract includes performance measures for each of these sections to assure ongoing monitoring of the terms of the contract. It is hoped that these contract specifications will promote currently recommended guidelines for patient care and public health practice in a format that will reach the new health industry. VII. Conclusion Managed care has already had a significant impact on the way TB-control activities are conducted in the United States and will have a continually greater impact as this form of insurance and health service delivery gains momentum in additional areas. The managed care and public health communities are working together to address areas of concern, such as those mentioned here (25). Nevertheless, TB health officials will need to maintain vigilance in assuring that quality TB-control practices are maintained in this era of sweeping change. It is hoped that approaches outlined here, e.g., use of contracts, will assist in this process. References 1.

Cassels A. A Guide to Sector-Wide Approaches for Health Development. WHO/ARA/97.12. Geneva: World Health Organization, 1997. 2. Introduction to Managed Care for State Health Agencies. Washington, DC: Association of State and Territorial Health Officials, 1995. 3. Binkin NJ, Vernon AA, Simone PM, McCray E, Miller BI, Schieffelbein CW, Castro KG. Tuberculosis prevention and control activities in the United States: an overview of the organization of tuberculosis services. Int J Tuberc Lung Dis 1999; 3(8):663–674. 4. Centers for Disease Control and Prevention. Essential components of a tuberculosis prevention and control program. MMWR 1994; 44(No. RR-11):1–16.

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5. Sbarbaro JA. The public health tuberculosis clinic: its place in comprehensive health care. Am Rev Respir Dis 1970; 101:463–465. 6. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 1997. Atlanta, GA: CDC, 1998. 7. Frieden TR, Fujiwara PI, Hamburg MA, Ruggiero D, Henning KJ. Tuberculosis clinics. Am J Respir Crit Care Med 1994; 150:893–894. 8. Tuberculosis control and prevention in a changing managed care environment: challenges and opportunities for local health departments, managed care organizations, and others. Washington, DC: National Association of County and City Health Officials, 1997. 9. Dacso ST, Dacso CC. Managed Care Answer Book. 2d ed. New York: Panel Publishers, 1997. 10. P.L. (Public Law) 103-66 Sec. 13603 (e)(I). 11. Rosenbaum S, Darnell J. Section 1115 Statewide Medicaid Managed Care Demonstrations: Implications for Federal Policy. Washington, DC: Kaiser Commission on the Future of Medicaid, 1997. 12. Rosenblatt R, Law S, Rosenbaum S. Law and the American Health Care System. Old Westbury, NY: Foundation Press, 1997. 13. Chorba TL, Berkelman RL, Safford SK, Gibbs NP, Hull HF. Mandatory reporting of infectious diseases by clinicians. JAMA 1989; 262:3018–3026. 14. Mycobacterium tuberculosis: Assessing Your Laboratory. Atlanta: Association of State and Territorial Public Health Laboratory Directors and Centers for Disease Control and Prevention, 1995. 15. Medicaid HEDIS (Health Plan Employer Data and Information Set). Washington, DC: National Committee on Quality Assurance, 1996. 16. Miller B, Rosenbaum S, Stange PV, Solomon SL, Castro KG. Tuberculosis control in a changing health care system: Model contract specifications for managed care organizations. Clin Infect Dis 1998; 27:677–686. 17. Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the United States. MMWR 1989; 38(suppl. no S-3):1–25. 18. American Thoracic Society/Centers for Disease Control. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990; 142:725–735. 19. American Thoracic Society/Centers for Disease Control. Control of tuberculosis in the United States. Am Rev Respir Dis 1992; 146:1623–1633. 20. American Thoracic Society/Centers for Disease Control. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359–1374. 21. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health care facilities, 1994. MMWR 1994; 43 (No. RR-13):1–132. 22. Centers for Disease Control and Prevention. Screening for tuberculosis and tuberculosis infection in high-risk populations: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1995; 44 (No. RR-11): 19–32. 23. American Academy of Pediatrics. Tuberculosis: In Georges P, ed. Red Book: Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics, 1997:541–562.

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24. Centers for Disease Control and Prevention. 1997 United States Public Health Service/Infectious Diseases Society of America guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 1997; 46 (No. RR-12):1–46. 25. Centers for Disease Control and Prevention. Prevention and managed care: opportunities for managed care organizations, purchasers of health care, and public health agencies. MMWR 1995; 44 (No. RR-14):1–12.

33 The Impact of Health Sector Reform on Tuberculosis Control in Developing Nations

ELIZABETH TAYLER Department for International Development (DFID) British High Commission Abuja, Nigeria

I. Introduction “Health sector reform is a sustained process of fundamental change in policy and institutional arrangements, guided by government, designed to improve the functioning and performance of the health sector, and ultimately the health status of the populations,” (1). Health sector reform is occurring throughout the world in developed and developing countries alike. Major changes in the organization and financing of health services are already happening, which will have a significant impact upon the way in which tuberculosis (TB) control is organized. Health sector reform is not a single entity, and the content of reforms, the motivation behind them, and the process of implementation vary greatly between countries. Despite this, certain themes can be identified in most health systems that are undergoing reform (2), although the extent to which they are actually being implemented in any system will vary (Table 1). In most cases this will also involve a different way of working. Rather than directly managing a package of activities such as training and supervision and supply of drugs, TB program managers may in the future become more concerned with coordinating these activities and ensuring that the functions are properly executed by other people and agencies. They will also be more involved in determining policy, setting standards, and monitoring performance, intervening only 829

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Table 1 Elements and Implications of Health Sector Reform Key elements of health sector reforms Decentralization

Integration

Changing role of the Ministry of Health Increased plurality of providers

Alternative sources and mechanisms of funding

Practical Implications More managerial and/or financial control in the periphery Services may become more tailored to local needs Central unit may have less control over staff, budgets, drug policies, collection of data, etc. Integration of services, staff roles, management and support functions, and organizational components (this can occur at all levels) MOH is more concerned with policy/setting standards Less with direct management Greater involvement of nongovernmental organizations, private providers, and the informal sector User fees Social and private insurance systems Contracts franchising and voucher systems

when things actually go wrong. Responsibilities for some management and/or financial resources are likely to be transferred to more peripheral levels. Another major change is an explicit acknowledgment that people go to many different providers of health care: private physicians, nongovernmental organizations, hospitals, pharmacies, and traditional healers. If they are to have a real impact upon the health of the population, those responsible for TB control will need to influence all of these providers. Some health reforms are primarily concerned with financing. Total revenues available to governments in many developing countries are so low that even the most basic services cannot be made available to all. In practice “informal charging” for health services is already widespread, but now formal user fees are being introduced into most countries in Asia and Africa with obvious implications for equity and accessibility of essential health services. This chapter examines why so many countries are now embarking upon reforms. The likely impact of changes and the greatest challenges to established TB programs are explored. While the challenges may be similar across a wide range of contexts and countries, the optimal solutions are likely to be much more varied. This chapter therefore cannot offer a new “blueprint” for TB control in health systems undergoing reform. It does, however, highlight potential opportunities and

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some of the major challenges that are likely to be faced in many countries undergoing these sorts of process. II. Why Health Sector Reform Is Needed Health systems in many countries function poorly. As a result, people with tuberculosis are mismanaged and many die. Even in countries where TB-control programs run well, they may be an isolated pillar of excellence, reliant upon extensive external inputs, while in the general health system services remain poor. The causes for this include (3): Scarce resources are used inefficiently, on inappropriate and cost-ineffective service. The infrastructure is weak, staff salaries are low and may not be paid regularly, facilities are dilapidated, and the drug supply is unreliable. People cannot access the care that they need—the barriers preventing this may be physical (e.g., distances involved, the costs of seeking care), cultural, or a result of age or sex. The services provided do not respond to what people want: patients face unmotivated and poorly trained staff, long waiting times, inconvenient clinic hours, and a lack of confidentiality and privacy. The health services of developing countries rarely have adequate resources. More than 14 countries spent less than $10 per person on all health services in 1996 (4). In many such countries there is a heavy reliance upon overseas development assistance, and yet this too is currently decreasing. In 1986 the Organization for Economic Cooperation and Development (OECD) countries spent an average of 0.33% on overseas development assistance; by 1995 this had shrunk to 0.27%, and this trend is likely to continue (5). In an attempt to address these problems, national governments and several international donors are moving away from organizing services around specific projects towards a more integrated approach to the health service as a whole (6). Obviously because the identification, diagnosis, and treatment of people with TB occur largely through general health services, initiatives that improve care in these facilities are welcome. However, in the short term there is a significant chance that the emphasis and resources that are given specifically to TB will decrease, which may significantly affect the quality of service. There have been impressive advances in TB control using the International Union Against Tuberculosis and Lung Disease/directly observed therapy, short course (IUATLD/DOTS) model in many countries, e.g., China (7,8), Bangladesh (9), Cambodia (10), Nicaragua (11), and Tanzania (12). However, in almost all these countries there has been extensive, specific donor support of the TB program. Specific programs with dedicated training, vehicles, and distribution and in-

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formation systems may rapidly achieve a system for effective service delivery for particular conditions, such as TB or immunization. However if separate and potentially incompatible systems for every program are allowed to proliferate, coordination of the health sector as a whole becomes more difficult, particularly for a Ministry of Health that itself has very limited capacity (13). Duplication of inputs leads to inefficient use of scarce resources. Sectorwide approaches are of interest to many donors and national governments. These allow them to approach the whole health sector as an entity and to develop shared priorities pooled budgets and a common information and accounting systems (6). The challenge of working in this environment will be to maintain the technical excellence that some TB program have achieved while operating in a more coordinated fashion that supports the more sustained development of the wider health service. III. Impact of Health Sector Reform Upon TB Services The prerequisites for good TB control are much the same as for most other diseases. However, unlike most medical interventions, the risks of allowing drug resistance to develop mean that it is better to do nothing than to implement poor control (14). In addition, the protracted treatment period and the benefits of treatment to the community as a whole—in terms of preventing transmission of disease— mean that certain elements such as the drug supply and the mechanisms for financing treatment will need special consideration in any plans to integrate services. In many countries successful TB programs have been based upon the DOTS or IUATLD system (15). There are five elements to the DOTS package (16): 1. Political commitment to TB control and delivery of care through general health services 2. Effective diagnosis of disease in patients who present with symptoms (smear positive cases given priority for treatment) 3. Standard regimen of short-course chemotherapy (with supervision of treatment) 4. Adequate regular supply of quality drugs 5. Monitoring system that records outcomes of all patients In addition, it is obviously important to have adequate financial and human resources to allow the system to operate. The principal risk in a reformed health service is that there will be less attention to the details that ensure a high-quality service if there is no specific TB focus. Coordinating services can be more difficult than directly managing and paying for them. The key elements of the DOTS package should all be provided

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in any health service, but ensuring coordination and an effective focus on TB will be a major challenge for the TB officer and will require new skills. He or she is likely to have fewer resources under his or her direct control. In addition, even where TB is a high priority for governments and resources are appropriately divided between high-priority programs, total resources are often so low that TB programs will notice a decrease and will have to refine activities if they are to be sustainable. Working out exactly how systems should be adapted and refined—determining which elements do require separate consideration and which, with imagination, can be incorporated completely within the management system of general services—will be difficult. At a global level one cannot stipulate which these are. As TB control becomes more integrated within the system of each country and more adapted to the needs of a particular society, apparent differences will increase. The following discussion is an attempt to outline in broad terms some of the issues that should be considered by TB experts and those concerned with health system design when services are being reorganized. IV. Political Commitment TB control has been neglected for years in many countries. TB is a disease that affects some of the poorest, most marginalized, and least politically powerful members of societies, and although it is a major contributor to the overall burden of disease in most poor countries, within individual communities there are likely to be only a few new cases each year. If strategies for successful TB control are to be developed and maintained, there must be support from people who make and implement policy at all levels. Over the last decade there has been a resurgence of interest and financial support in many countries at the national level. This is in part due to international advocacy by agencies such as the World Health Organization (WHO), The World Bank, and IUATLD (see Chap. 34). A. Community Support for TB Control

Decentralized health services attempt to be responsive to the communities that they serve; in such an environment the support and involvement of the community in TB control will be crucial and is likely to require a different strategy from that which has been developed for largely centralized systems. Community development offers major opportunities for developing sustainable strategies for TB control that really meet the needs of people in these communities. It will, however, take time, tolerance, and a flexible approach if this approach is to be successful.

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Political commitment can be demonstrated through financial support. In nearly all countries provision of TB services is still officially free even though informal charging certainly exists (17). In certain notable exceptions, such as over a large part of China, patients are expected to pay the full costs of their treatment. Elsewhere the “free” government services are so inaccessible, or bad, that even poor people resort to the private sector (18). Although many governments are exploring methods of charging for health care, there are good reasons why the responsibility for funding TB should remain with government: treatment of TB can be very cost-effective (19) and is of benefit to the community as a whole. Bad TB control is counterproductive. Levels of drug resistance increase and the costs of subsequent treatment for individuals and the community are much higher. In providing patients with free treatment, governments increase the chances of proper compliance and good control. In addition to issues around efficiency and equity, there are also practical reasons—a large proportion of TB patients are too poor to pay, and attempts at fee collection are likely to cost almost as much as they collect in fees (20, 21). Within a decentralized system an adequate central allocation to TB is not enough. Where resource allocation decisions are taken at the periphery, some form of “earmarking” is probably necessary to preserve the funding and functioning of essential services (even if this is contrary to an ideological incentive to encourage local autonomy). V. Case Finding and Diagnosis If reforms in a health service achieve their aims of increasing the accessibility and quality of primary health services, then the identification and diagnosis of symptomatics is likely to improve. A. User Fees and TB: Practical Implications

One element of reforms that is generating considerable concern is the widespread introduction of user fees and the risk that they will dissuade many patients from seeking diagnosis and treatment. It is known that the introduction or increase of user fees can cause significant and sustained decreases in utilization, particularly among rural populations and the poor (20,22). In most contexts, exemptions do not seem to work well, as there is confusion over who is exempt, and informal charging occurs anyway (20,23). Because TB patients present with a cough and may not be aware that they have the disease, many patients will be dissuaded from seeking care irrespective of any exemptions policy. If, as is claimed, user fees for general services are unavoidable in many countries and facilities are reliant upon them for

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the extra resources and financial flexibility that they bring, careful consideration of how to safeguard the access of potential TB patients is going to be crucial. B. Fees for Diagnositic Services

Fees are being charged for laboratory services in many countries. Whether TB suspects should be charged for sputum microscopy is controversial. If they are, it may deter people seeking care and prevent the identification of some cases, meaning that they may continue to transmit disease. If charges are not made, then unless adequate extra resources dedicated for TB are made available the resources available to laboratories, the morale of laboratory staff, and the quality of the service may be compromised. Developing and maintaining a system of quality control in the laboratory is always difficult. Laboratory services are rarely a high priority area for policy makers, and although the consequences of laboratory error can be grave, proper systems of quality control are sometimes seen as a luxury. C. Quality Control

Considerable technical expertise is required to supervise laboratory services well, and these skills are not possessed or rapidly acquired by other health staff. This is one of the clearest examples of the need to preserve some vertical linkages to ensure the maintenance of technical standards. It may be, however, that within an integrated system, all the functions of the laboratory, such as malaria and TB diagnosis and hematological investigations, should be supervised together.

VI. Standardized Short-Course Regimen and Supervision of Therapy The impact of reforms upon adherence to guidelines and standard regimens is difficult to predict. Ensuring this and other key elements of the program is likely to depend on good training and supervision. Direct observation of treatment is likely to be more of a problem. It is nearly always the part of the DOTS package that patients and health workers find most difficult. Particularly where health facilities are overstretched and understaffed, it is likely that compromises will be made as to how the treatment of patients is observed. Adequate training (including on the job supervision) is crucial to developing and maintaining good TB control. If TB control is integrated into general services, with teams of multipurpose workers rather than specialist individuals, more people will require some training while fewer dedicated resources will be available.

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One of the strengths of vertical programs has been their ability to spend money on good training. However, frequently the only training offered has been in these specific areas, and the general services have been totally neglected. Directors of health facilities are also concerned about the disruption of service provision through frequent health worker absences for workshops (24). In most countries training for TB control is fairly protracted, reliant upon specialized modules, centrally arranged courses, and per diem training allowances. In the future it is likely that training courses will be driven more by demand (from the district) than supply (from the central program) (25). Districts are therefore likely to demand briefer training courses tailored more to the needs and preexisting skills of their workforce and a more coherent approach to disease control and service delivery. While TB control is not complicated, there are certain basic principles that need to be learned well, and this is likely to be even more important in a decentralized system where disease-specific control and supervision is likely to be less intense. Refining and simplifying training materials and courses will be a major challenge (25). Some form of supervision is crucial, and this area is vulnerable to cuts when savings have to be made. It is true that in a decentralized system there may be less need for managerial and financial links between levels, particularly when extensive capacity building has occurred in these areas. However, in most developing countries technical knowledge is still limited and there is need for support and advice from higher levels. Good supervision is an integral part of continuing training; it is important for identifying and addressing problems in the facilities visited and also in validating the data that they supply (14). (Whether most supervision currently really achieves these objectives is debatable.) If the proposed shift of focus towards monitoring outputs and outcomes occurs, with performance and possibly remuneration dependent upon the results, the temptation to distort data will grow and with it the need to validate it. Without dedicated vehicles and adequate fuel, routine separate supervision is unlikely to be possible. Therefore, innovative solutions and new models of operating are going to become important, such as more integrated supervision, recruiting non–TB workers to perform simple focused checks, and enlisting the assistance of nongovernmental organizations and other agencies. Ensuring that practitioners comply with protocols for effective diagnosis and treatment is difficult, even within government services. Achieving this across the health sector, with practitioners who are either motivated by profit or who have traditionally had little respect for the government service, will be an even greater challenge. New methods and incentives for influencing the behavior of these groups will have to be developed.

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VII. Drug Supply Although drugs are important for all health services, there are important reasons why those for TB need separate consideration. These include: The relatively high costs of a full course of treatment, which means that a service that recovers a significant proportion of costs will be unaffordable for most patients. The risks of developing drug resistance if there is not good adherence to standard regimen by patient, physician, and pharmacist. The protracted treatment period, which increases the vulnerability of all these actors to errors and noncompliance. Given that in most countries TB treatment should be provided free, a strong case can be made for central purchase and provision of these drugs, even if they are then distributed through normal channels. The potential savings through bulk purchase and the importance of proper quality control are additional reasons why centralized procurement should be retained, irrespective of delivery systems within the country or whether drug budgets have been decentralized. Whether the actual procurement is done by the TB service or a specialized procurement unit, there should be active consultation to ensure that the drugs ordered conform with national policies and guidelines and quality issues are properly addressed. VIII. Recording and Reporting If management decisions are being made at a local level and the flow of resources from central level is not dependent upon information being fed upwards, there is little incentive to report on case notifications or treatment outcomes to higher levels. In reality there is little point in collecting information or forwarding it to higher levels if it is not going to affect policy or practice. The system developed for TB programs of monitoring treatment outcomes through cohort analysis is potentially a useful management tool. Many disease-specific programs have developed information systems that give useful management information. The problem is that completing all these forms can be a major burden for health workers, with the attendant risk that either it will not be done properly, compromising data quality, or it will be done instead of other important tasks. Incorporating different information systems into a more coherent and unified form is likely to be difficult. Where it is done well it will preserve the quality of separate disease-control systems and also be an instrument to monitor the overall health service performance and the impact of the reforms. If this is to be achieved, health system planners will

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have to acknowledge that information about specific disease-control activities is crucial to the maintenance of effective services, that good disease surveillance matters. Those concerned with disease control will have to acknowledge the risks of information overload and refine and simplify their systems. IX. Conclusions Health sector reforms are occurring in countries across the world, and their impact upon TB control will be considerable. Changes are going to occur whether those controlling TB programs want it or not. Pleading for special status for TB control in an attempt to maintain the status quo with a separate, semi-autonomous program may not be the best way to sustain high-quality services. A. Maintaining Quality: Issues for Reformers

Certain key challenges are common to most disease-specific programs, and a more common approach by the categorical programs may be of benefit. In many countries the key issues that need to be preserved for all priority areas are: Adequate funding for essential public health programs and effective financial flows that ensure that funds are appropriately spent at the peripheral level Effective technical supervision between levels of service to identify problems, assist and retain staff, and validate performance Some coordination and accountability for performance of specialized services and disease control activities, even where services are primarily coordinated according to function rather than programme Preserving the strengths of the information systems of categorical programs and their measurement of outcomes in the shift towards more integrated systems of monitoring B. Simplifying and Refining: Issues for Those in TB Control

Those involved in the design and implementation of TB programs may need to make significant changes in the ways that services are organized and delivered. While challenges will vary between countries, the following areas are likely to require reorganization, refinement, or simplification: Training and supervision Recording and reporting Supplying drugs and diagnostic equipment Equally important is likely to be the shift towards more collaborative ways of working, with a focus upon TB within the context of the broader health service.

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The potential gains for TB control and improvements in health care in general are great. However, adjusting to these new ways of working may not be easy, and the prospect of such changes may be very threatening to those involved in disease control, who will need to be politically adept and may have to develop new skills of communication, collaboration, and advocacy. C. Future Trends

In many countries it is too early to even speculate upon the impact of the reform process on TB control. In some countries there is a lot of talk of reform, but little is happening; in others there are major differences between the design and implementation of the reforms, often because one wave of reforms is overtaken by another. There is a risk that undue focus upon systems and process can result in the ultimate purpose of improving services being lost. The key components of the IUATLD/DOTS model for good TB control are similar to those for many other diseases: appropriate financial and political support, adherence to evidence-based protocols, and a regular supply of drugs, with the whole process being monitored and refined in the light of treatment outcomes. If these components and this way of thinking become more generalized, it will be good for all areas of health care, including TB control. If in addition resources are shifted towards care in district health services and concentrated upon those conditions that result in the highest burden of disease, the potential for significant and sustainable improvements in TB control is great. Excellent TB control as achieved in some programs will probably be more difficult to attain. However, the epidemiological and health benefits of good control across the sector, incorporating hospitals, and the private services, may still be greater than isolated public clinics achieving excellent cure rates while all other facilities treat huge numbers of patients badly, propagating drug resistance. In many countries the concept of a “program” will become less relevant (as it is in developed countries). Attempts to impose this structure upon more integrated health services is unlikely to be productive or sustainable. There will be problems in many countries, particularly over the transition periods, when resources are inadequate, services fragmented, and accountability is limited. However, such problems are not new, nor are they confined to countries undergoing reform. Evaluating the impact of reforms, sharing experiences, and learning from them will be crucial, but in doing this, people must be aware that context is crucial and not all lessons can be widely generalized. In addition, health systems and health policy are complex, and it is rarely possible to directly attribute changes in one part of the system to alterations elsewhere. Currently there is a great deal of concern about the impact of reforms upon TB control, much of which may be justified. However there is potential for more accessible effective and sustainable services. If this potential is to be realized, peo-

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ple concerned with TB control will need to show flexibility and imagination, develop new skills and allies, and be actively involved in the policy process. References 1. Cassells A. Health Sector Reform in less developed countries. J Int Develop 1995; 7: 329–347. 2. Zwi A, Mills A. Health Policy in less developed countries: past trends and future directions. J Int Development 1995; 7(3):299–329. 3. Nabarro D, Cassells A. Strengthening health management in developing countries. Health Exchange 1994; 6–8. 4. World Bank. Health Nutrition and Population Strategy. Washington, DC: World Bank, 1997. 5. Development Cooperation. Development Assistance Committee Annual Report. 1996 Report edition. Paris: Organisation for Economic Cooperation and Development (OECD) 1997: Table A8. 6. Cassells A. Sectorwide approaches. London: WHO DFID DANIDA, 1997. 7. China Tuberculosis Control Collaboration. Results of directly observed short course chemotherapy in 112, 842 Chinese patients with smear positive tuberculosis. Lancet 1996; 347:358–362. 8. Zhang LX, Kan GQ. Tuberculosis control programme in Beijing. Tubers Lung Dis 1992; 73(3):162–166. 9. Mushtaque A, Chowdhury R, Chowdhury S, Nazur Islam Md, Islam Akramul, Patrick Vaughan J. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997; 350:169–172. 10. Norval P-Y, Kong KimSan, Team Bakhim, Dy Narong Rith, D I Ahn, L Blanc. DOTS in Cambodia. Int J Tuberc Lung Dis 1998; 2:44–51. 11. Cruz JR, Heldal T, Arnadottir R, Juarez I, Enarson D. Tuberculosis case finding in Nicaragua: Evaluation of routine activities in the country programme. Tuber Lung Dis 1994; 75:417–422. 12. Styblo K, Chum HJ. Treatment results of smear positive tuberculosis in the Tanzania national tuberculosis and leprosy programme. 25th World Conference on Tuberculosis and respiratory disease. Professional Postgraduate Services, 1987; 122–126. 13. Cairncross S, Peries H, Cutts F. Vertical health programmes. Lancet 1997; 349 (suppl iii):20–24. 14. Enarson D, Rieder H, Arnadottir T, Trebucq A. Tuberculosis Guide for Low Income Countries. 4th ed. Paris: Verlagsgruppe, 1996. 15. Enarson DA. Principles of IUATLD Collaborative Tuberculosis Programme. Bull Int Union Tuber Lung Dis 1991; 66:195–200. 16. Global Tuberculosis Programme WHO. Framework for Essential TB Control. Geneva: WHO, 1994. 17. Gilson L. Government Health Care Charges. Is Equity Being Abandoned? London: London School of Hygiene and Tropical Medicine, 1988. 18. Pathania V, Almeida J, Kochi A. TB Patients and Private for Profit Health Care Providers in India. Geneva: WHO, 1997.

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19. World Bank. Investing in Health World Development Report. New York: Oxford University Press, 1993. 20. Waddington CJ, Enyimayew KA. A price to pay: the impact of user charges in Ashanti Akim district Ghana. Int J Health Plann Manage 1989; 4:17–47. 21. Creese A, Kutzin J. Lessons from Cost recovery in Health. Form on Health Sector Reform Discussion Paper 2 1995; Geneva: WHO SHS NHP 95.5. 22. Yoder RA. Are people willing and able to pay for health services? Soc Sci Med 1989; 29:35–42. 23. Russell S, Gilson L. User Fees at Government Health Services. Is Equity Being Considered? London: London School of Hygiene and Tropical Medicine, 1995. 24. Sikosana P, Dlamini QQD, Issakov A. Health Sector Reform in Sub Saharan Africa. Vol. WHO ARA cc 97.2. Geneva: WHO, 1997. 25. Kolehmainen-Aitken R, Newbrander W. Decentralizing the Management of Health and Family Planning Programs. Newton, MA: Management Sciences for Health, 1997.

34 Mobilizing Society Against Tuberculosis Creating and Sustaining Demand for DOTS in HighBurden Countries

KRAIG KLAUDT World Health Organization Geneva, Switzerland

This chapter concerns the use of advocacy, social mobilization, and the creation of political will to prevent Mycobacterium tuberculosis from causing further infections, cases, and deaths. In theory, advances in combination therapies, improved diagnosis, and case management should provide tuberculosis (TB) patients with an almost 100% chance of survival. In reality, nearly a third of all tuberculosis patients worldwide die from the disease. There is ample reason to expect that the epidemic will continue to outlast future scientific and medical advances as long as there is minimal public concern and political commitment to address tuberculosis. I. Assessment of the Current Response to the Global TB Epidemic Nearly 80% of the world’s TB cases are found in just 22 large middle-income and low-income countries. Currently, 16 of these countries are not expected to meet the World Health Organization’s global TB targets by the year 2000.* In analyz* Afghanistan, Brazil, Ethiopia, India, Indonesia, Islamic Republic of Iran, Mexico, Myanmar, Nigeria, Pakistan, Philippines, Russian Federation, South Africa, Sudan, Thailand, and Uganda comprise the 16 countries that are making slow progress in controlling tuberculosis, as indicated by low treatment success (1995 data), slow expansion (1996 data), and failure to implement DOTS or to provide complete data. Bangladesh, China, Democratic Republic of Congo, Peru, United Republic of Tanzania, and Vietnam are the eight highburden countries making progress in controlling TB.

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ing the situation in these 16 countries, the World Health Organization has concluded that three main constraints have impeded TB control efforts (1): 1.

Lack of Political Will: Many governments are failing to provide the necessary funding and administrative support for strengthened TB control. 2. Lack of Ownership of DOTS: Many health workers remain uninformed or unconvinced of the usefulness of the DOTS strategy (see Table 1). 3. Lack of Human Resources: Capable technical and managerial staff are not being attracted to TB-control programs, making it difficult to expand use of the DOTS strategy.

In 1998, this analysis was affirmed by two independent committees of international public health experts convened to assess how to more effectively coordinate a response to the TB crisis. In March 1998, the Ad Hoc Committee on the Tuberculosis Epidemic concluded that “the most fundamental constraint is the lack of political will to develop and sustain effective TB programmes. . . . Extraordinary measures now are needed to reverse the insufficient political will which underpins the other constraints” (2). Responding to this challenge 2 months later, representatives of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD), the Royal Netherlands Tuberculosis Association (KNCV), the Centers for Disease Control and Preven-

Table 1

Definition of DOTS

DOTS (directly observed treatment, short-course) is the most effective strategy available for controlling TB, developed from the collective best practices, clinical trials, and programmatic operations of TB control over the past two decades. The World Bank considers DOTS one of the most cost-effective health strategies available. Its five core elements are: Government commitment to sustained TB control activities Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services Standardized short-course chemotherapy (6–8 months) for at least all confirmed sputum smear–positive cases, with direct observation of treatment for at least the initial 2 months A regular, uninterrupted supply of all essential anti-TB drugs A standardized recording and reporting system, which allows assessment of treatment results and overall program performance

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tion (CDC), the American Thoracic Society (ATS), and the American Lung Association (ALA) called for the development of a tuberculosis global action plan that would “engage all relevant parts of civil society and their governments to advocate, mobilize and sustain resources for, and implement, effective tuberculosis programmes, more rapidly and more widely.” It has become clear to an increasing number of public health professionals that the political and managerial challenges currently preventing the control of tuberculosis are more significant than the medical and scientific challenges. By mobilizing greater political commitment for the accelerated use of existing tools and strategies, it is possible for each of the 22 high-burden countries to meet global targets by the year 2010 and for over 30 million deaths to be averted in the next two decades (3). Arguably, there are only two alternatives to mobilizing political will for using DOTS more widely. One is to await the contribution socioeconomic development can make to the control of TB. This argument is based on the experience of most developed countries, where disease incidence and death steadily declined long before the advent of effective medicines. In South Africa, Indonesia, and other emerging economies, however, economic development has yet to yield substantial progress against TB. In all likelihood, such a decline will take decades to materialize, and tens of millions of women, men, and children will needlessly die while the world is waiting. With the emergence of multidrug-resistant strains, it has become even more imperative to intensify control efforts before incurable forms of the disease begin to spread exponentially. A second option is to make the development of an effective vaccine the foremost priority in a global strategy to stop TB. A one-shot vaccine, such as that used to eradicate smallpox and reduce childhood illnesses, would certainly be a welcome replacement for a 6-month course of supervised treatment. However, even in the most favorable scenario, an effective vaccine is unlikely to be discovered, tested, affordably produced, and ready for wide dissemination for at least another 15 years. And even then the present constraint of inadequate political commitment to control the disease is likely to remain if not addressed. It is debatable whether governments currently unwilling to implement a cost-effective strategy to make affordable and effective anti-TB medicines available to a few million TB patients annually would be willing to pay for the widespread testing and inoculation of billions of potentially infected individuals. WHO believes that the creation of greater public demand and political leadership for the wider use of the DOTS strategy is the foremost priority in current efforts to control the global TB epidemic. This is an objective containing many difficult—although not insurmountable—challenges. For example, most international efforts to address the epidemic have only recently begun to address the need for creating political commitment for the control of TB in high-burden countries.

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For political will to emerge, new contributions will be needed from those involved in tuberculosis-related advocacy, country support, and research. First, advocacy strategies need to be systematically applied to help address the unique political constraints preventing the control of TB in each high-burden country. Since it declared a global TB emergency in 1993, WHO has focused its advocacy efforts almost exclusively on increasing donor resources and building global awareness of the DOTS strategy. While accomplishing much in this area, WHO and other organizations must also increasingly use advocacy and social mobilization strategies to help address specific political obstacles facing individual high-burden countries. Second, WHO and other organizations are just beginning to provide intensive technical support to national TB programs in high-burden countries specifically in the areas of developing political support, ownership of DOTS, and human resource development. In assisting countries to quickly adopt DOTS, WHO training modules and courses initially emphasized the technical and managerial aspects of the strategy and have only recently begun placing greater emphasis on the creation of political will. Recently, significant discussion of these three main constraints has begun to appear on agendas of IUATLD regional and global meetings. Other leading providers of international assistance such as KNCV are currently considering ways of providing technical support to national TB programs in the development of political will. And finally, there has been relatively little research into why these three constraints exist in high-burden countries. Not only has TB research been vastly underfunded in comparison to the size of the disease burden, these meager resources have not been focused on the most pressing needs of resource-poor countries. For example, there has been little emphasis on health systems and services research aimed at getting DOTS adopted as policy and then implementing it more efficiently, factors influencing the decision-making process of health policy makers, or attitudes toward TB and DOTS by service providers, patients, and policy makers. If the control of TB is primarily a political and managerial challenge more than a therapeutic or scientific challenge, then it is incumbent upon those involved in advocacy, program support, and research to apply their skills and strategies to address these political and managerial challenges in high-burden countries. II. The Role of Information, Education and Communication, Advocacy, and Social Mobilization Initiatives to increase political commitment typically involve the use of various communication strategies. In general, health communication spans a continuum between strategies intended to reach two distinct audiences (Fig. 1). On one end of the spectrum are those strategies that attempt to influence the health-related be-

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Figure 1 Health communications spans a spectrum between strategies and objectives intended to reach two distinct audiences: health behavior of the general public and political behavior of those who influence the health policy and funding of governments and institutions.

havior of the general public. On the other end of the spectrum are those strategies that attempt to gain the support of those who influence the health policies and funding of governments and institutions. Frequently, similar channels of communication—such as the media, coalitions, and publications—are used to reach both audiences. Generally, health professionals are more familiar with the former strategy— (information, education, and communication) (IEC) campaigns designed to change the health practices of risk groups, patients, and large populations. For example, IEC campaigns often target specific groups such as women whose children would benefit from breast feeding or commercial sex workers who should insist

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on the use of condoms. IEC strategies are also used to reach the general public, as in the case of mass media campaigns designed to encourage better nutrition or to discourage drunk driving. However, the modification of individual health-related behavior is insufficient to prevent many health risks. For example, blood supplies can be more easily protected by changing government policies rather than individual behavior. Other health threats such as premature births are more easily avoided by convincing governments to provide all citizens with access to basic health services. Hence, the importance of advocacy strategies to influence funding, policies, and human resources related to health. Many public health concerns require changes both in personal health behavior and in the commitment of institutions and governments. To prevent the use of tobacco, educators distribute brochures to encourage individuals to quit smoking, while advocates enlist professional lobbyists to convince governments to ban tobacco advertising directed at adolescents. In responding to the AIDS epidemic, public service announcements are used to encourage safe sexual behavior, while letter-to-the-editor campaigns are waged to encourage local school boards to permit sex education in the classroom. The most sustainable advances in public health are usually those that mobilize a wide array of partners and strategies in advocating social change. Social mobilization attempts to involve new individuals and institutions from many sectors of society as a means of changing health behavior, social norms, and political agendas. Indeed, social mobilization could be described as a more sustainable means of both IEC and advocacy; one that relies on the “bottom-up” support of a broad constituency rather than a limited number of actors or events. According to Neill McKee of UNICEF (4): As the process of social mobilization gathers momentum, advocacy is taken up by a whole new range of partners so that early advocacy is magnified many-fold. A host of allies at the national, regional and community level will join in, influencing a wide spectrum of society. . . . Social mobilization, therefore, magnifies advocacy activities and strengthens program communication, for many more societal partners participate in the program, such as NGOs [nongovernmental organizations], grassroots organizations which often have the motivation and skills for involving local communities in programmes.

IEC, advocacy, and social mobilization strategies have individual roles to play in addressing the tuberculosis epidemic. It is important for those involved in tuberculosis-control programs to consider the appropriate use of each of these strategies. The following general principles can be applied. 1.

The education of health workers is an important priority in the DOTS strategy. Where education resources are limited, the first priority should be to improve the compliance of TB-control workers and vol-

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3.

4.

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unteers, educating them to understand the importance of observing patients as they take their medicines and the value of other elements of the DOTS strategy. Many health workers have unrealistic hopes that education strategies directed at patients can greatly increase compliance to treatment. The evidence does not support that intensive patient education by itself can help high-burden countries achieve 85% cure rates (5,6). Patient education through DOTS can improve health-seeking behavior. While patient education is not the main determinant of treatment compliance in the DOTS strategy, it does have an important role to play. Supervision should not only ensure the intake of drugs, but also help the patient and his or her family understand the illness and the steps necessary to bring about a cure. With good supervision, the patient should feel comfortable to ask questions about his or her health. This bond between the patient and the health worker is especially important in the event there are any adverse reactions to the medicines or the patient is at risk of defaulting from treatment. The patient-friendly approach of DOTS also provides health workers the opportunity to provide information and counseling on other concerns, such as reproductive health and AIDS prevention. IEC campaigns for TB should be used where effective DOTS programs are in place. It is appropriate for countries fully implementing the DOTS strategy and achieving high cure rates to use mass media IEC strategies targeted at the general public. Increasing case detection is the greatest challenge facing countries such as Vietnam, Peru, Oman, and Bangladesh, which have fully implemented DOTS. Mass media campaigns that remind the general public that “TB can be cured” and that “free TB-treatment services are available” are an important strategy to help these countries begin to reach the global target of 70% case detection. IEC campaigns for TB should be avoided in countries without effective DOTS programs. Mass media campaigns with messages such as “If you cough for more than 3 weeks, you might have TB” can be counterproductive in countries not using DOTS, serving only to overburden poorly performing health services. Educating the public that “TB can be cured” can undermine the credibility of health services when interruptions in drug supplies, inadequate laboratories, and lack of training make it impossible to provide effective treatment. Inadvertently, these IEC strategies can increase drug resistance and heighten fatalism in the community about the disease. Advocacy strategies are essential in countries not achieving high cure rates. Advocacy strategies—not IEC—are the first priority in countries

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6.

slow to utilize or expand the DOTS strategy. Advocacy is necessary to encourage governments to fund the establishment and expansion of the DOTS strategy. Advocacy media campaigns with messages that highlight the dangers of TB and promote the establishment of DOTS programs are the most critical need. Social mobilization strategies are necessary to sustain support for TB control. The strength of advocacy strategies is their ability to quickly refocus political priorities. However, if only a few key advocates and policy makers are involved, political gains can easily evaporate. Often leading advocates become involved in other issues, and champions within the government are replaced when new political parties come into power. Hence, progress made by advocacy efforts can be short-lived. Sustained advocacy for TB is best accomplished when many partners are mobilized to demand effective TB control for their communities.

Currently, not enough effort is being made to use advocacy and social mobilization strategies to support TB control in high-burden countries. This is in contrast to a rich history of community activism against TB in North America, Europe, and Japan at the beginning of this century through TB crusades and seal campaigns. It is also in contrast to the many vibrant efforts currently underway to mobilize communities against other neglected social concerns, such as AIDS, gender discrimination, land mines, and tobacco, to name a few. Certainly, lessons can be learned from all of these initiatives. The following section briefly examines recent mobilization campaigns for other social concerns, as they have the most contemporary relevance to the political challenges currently facing developing countries with a high burden of TB. III. The C.A.U.S.E. Strategy for Mobilizing Society In considering how to mobilize society to control TB, it is instructive to learn from mobilization efforts that have succeeded in addressing other important causes. Consistently, successful movements are characterized by five salient characteristics that galvanize public opinion and attract support: high profile celebrities, energizing activities, attention surrounding unexpected scandals, memorable symbols, and defining events. The author has coined these highly visible focal points as comprising the C.A.U.S.E. strategy for mobilizing society (Table 2). These five elements serve to attract public attention to a problem and mobilize efforts to find a solution. The C.A.U.S.E. elements emerge in unique ways for every social movement. Some result from local activism, as in the case of protests by Rosa Parks and others who initiated passive resistance strategies in order to further civil rights in

Fasting Passive resistance Burning draft cards Occupation of university buildings

Martin Luther King Rosa Parks

Mahatma Gandhi

Jerry Rubin Abbie Hoffman

Civil rights in the United States

Independence movement in India Vietnam war protests in the United States

Sit-ins

Construction of mock shanty towns Divestment campaigns

Nelson Mandela Desmond Tutu

Anti-apartheid in South Africa

ACT-UP zaps

Activity

Ryan White Magic Johnson Rock Hudson

Celebrity

Ways of Creating a C.A.U.S.E.

AIDS in the United States

Table 2

World AIDS Day

Sun City

Montgomery bus boycott 1963 March on Washington Watts riots 1930 salt march

Chicago riots

ANC colors

“I have a dream” Hooded klansmen

Spinning wheel

Peace symbol

Sharpeville massacre Murder of Stephen Biko Medgar Evers murder

Jallianwala Bagh atrocity “The Pentagon Papers” My Lai massacre Kent State shooting

Event

Red ribbon Quilt

Symbol

Contaminated blood supplies Reports of heterosexual transmission

Unexpected Scandal

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the United States. Others are the result of carefully orchestrated advocacy strategies designed to attract media attention and change public opinion. It is important to note that not every social movement requires all five elements in order to succeed. For example, the visible involvement of Diana, Princess of Wales, was sufficient to propel the campaign to ban land mines onto the international political agenda without, for example, the popularization of a campaign symbol or the development of a grass-roots protest activity. The visible advent of one or more of the C.A.U.S.E. elements makes it easier for a movement to generate other visible initiatives. For example, the initial success of the Band Aid concert and the song “Do They Know It’s Christmas?” in 1984 stimulated other activities to address world hunger, such as the involvement of additional celebrities and corporations in LiveAid and Hands Across America follow-up events. Effective social movements usually have a bandwagon effect, compelling an increasing number of individuals to become involved because of the apparent popularity of the cause. The C.A.U.S.E. elements also appear in most successful initiatives to mobilize a social response to other important health issues, such as reproductive health and child survival. Over the past two decades, UNICEF has been the principal leader in applying the concept of social mobilization for health concerns. A wide range of partners and sectors are typically involved in UNICEF’s social mobilization initiatives in any given country (Table 3). Celebrities such as Audrey Hepburn and Harry Belafonte have attracted visibility to these activities. International associations such as Rotary, Junior Chamber, and Kiwanis have provided a volunteer base in developing countries to conduct special activities during national immunization days. National committees in 37 industrialized countries have supplemented UNICEF’s advocacy activities in publicizing the unexpected scandal of childhood mortality. At the country level, symbols have helped promote immunization, as seen with the moni symbol in Bangladesh. Political leadership has been galvanized at events such as the Bellagio Conference and the World Summit for Children. According to a 1985 planning document, “in practice, political will, as reflected by the attitudes of heads of state, has not been difficult to mobilize. Few leaders remain unenthusiastic when given the promise that their nation’s children can be protected quickly and inexpensively through immunization” (7). The control of TB, however, represents a greater challenge. History has shown that while society can be mobilized to help innocent children, it is less compassionate in helping those children if they have the misfortune of growing up to become impoverished adults. UNICEF has committed substantial resources to mobilizing countries to vaccinate children and protect them from a variety of basic childhood diseases. Currently, UNICEF has about 120 communication and information officers and is spending nearly $50 million annually on these initiatives. This budget is en-

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Table 3 Advocacy and Social Mobilization Activities for Expanded Program of Immunization (EPI) in Bangladesh Partner President/Prime Minister Ministers and Secretaries Cabinet Division Parliamentarians UNICEF Executive Director UNICEF Goodwill Ambassadors Audrey Hepburn, Imran Khan, and Tetsuko Koroyanagi UNICEF Board Chairperson, Deputy Chairperson and other Senior UNICEF officials UNICEF Representative, Special Representative for EPI, Project Director and other staff Rotary International

Centre for Sustainable Development, Press Institute of Bangladesh and Association of Development Agencies in Bangladesh NGOs, large and small Ministry of Education

Ministry of Social Welfare & Women’s Affairs Ministry of Information

Ministry of Religious Affairs Ministry of Communications “We are for Children” arts and entertainment group National Sports Council Corporate Mobilization: Dhaka Match, Bata Shoes, Sparks Ltd. (Kodak), Lever Brothers, General Electric Fans, Fisons (Bangladesh) Ltd. Source: Ref. 4.

Activity Speeches at numerous fora, images on posters Speeches and appearances Directives for involvement to Divisional and District Commissioners Speeches and letters Meetings and interviews with President, Senior Officials, radio, and TV Visits in 1989 and 1990

Visits throughout EPI period

Extensive travel and public appearances in numerous public fora Numerous events, fundraising and seminars on PolioPlus Program, Involvement of youth branch, Rotaract, in social mobilization activities, and mobilizing community members to complete immunizations Numerous training and orientation sessions for journalists, special articles on EPI

Service delivery in cities, field-level training, logistics, surveys, mobilization Numerous directives for school rallies, EPI module for “Primary School Fortnight,” and the placement of EPI in curriculum and supplementary materials Directives to field staff to support EPI Three minutes of free prime time on radio and TV per day, inclusion of EPI in numerous health and family planning programs Imam orientations Issue of stamps and first-day covers on immunization Organization of events, lending of creative talent, time, and images for TV spots, appearances Maa-o-moni football cup tournament Placement of moni logo on millions of packages and signs

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hanced further as UNICEF attempts to fully integrate social mobilization into program activities, rather than to view them as “add-on” activities (8). In comparison, relatively few human and financial resources are currently being devoted to removing the main obstacles preventing the control of tuberculosis. Until recently, only a handful of health organizations, lung associations, and national TB programs had strategies to increase political commitment for the control of TB. To succeed, TB-control organizations must reorient their efforts to also become catalysts for political commitment. Influential leaders and organizations in high-burden countries need to become champions of the DOTS strategy. Civic leaders must demand DOTS services for their community and be backed by vocal public support. Those who care about the control of TB must find a way to make this issue a visible C.A.U.S.E. IV. The Main Components of Advocacy A C.A.U.S.E. seldom emerges—locally or globally—without intensive advocacy planning and activity. What follows is a brief summary of the most important steps for developing and implementing an advocacy and social mobilization strategy for TB.* These steps should be adapted to suit the political protocol, media etiquette, and social values of each country. A. Assess the Political Situation

The first step in TB advocacy is to analyze the political constraints and opportunities confronting expansion of the DOTS strategy. It is often useful to involve skilled advocates for other issues in conducting this analysis, as their fresh perspectives can stimulate a new understanding of the political situation. Examples of common obstacles include lack of financial resources or administrative support, unwillingness of some segments of government to cooperate in the control of TB, political instability, or weak leadership from the national TB program manager. * For a more complete explanation, refer to the World Health Organization’s TB Advocacy: A Practical Guide. This document is available from the Stop TB Initiative, 20 Avenue Appia, CH-1211 Geneva, Switzerland. Other useful advocacy and social resources include Media Advocacy and Public Health, by Lawrence Wallack et al., available from Sage publications, 2455 Teller Road, Newbury Park, CA 91320; Organizing for Social Change, by Kim Bobo et al., available from Seven Locks Press, PO Box 68, Arlington, VA 22210; Public Health Advocacy, by David Altman et al., and How-To Guides on Community Health Promotion, available from Stanford Center for Research in Disease Prevention, 1000 Welch Road, Palo Alto, CA 94304-1895; and Social Mobilization & Social Marketing in Developing Communities, by Neill McKee, available from Southbound, 9 College Square, 10250 Penang, Malaysia.

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Opportunities might include a favorable change in government, knowledge that an influential public figure has TB, or the potential to leverage donor assistance. Specific people are usually responsible for these obstacles and opportunities. The more one can learn about these key decision makers, the more effective one can be in developing persuasive advocacy messages and strategies. Some of this information can be gathered by reviewing speeches, attending public meetings, and talking with others who have worked with the decision maker. In conducting this research, it is important to identify groups and individuals that might be able to influence the decision maker. B. Document the Situation

It is difficult to change the minds and actions of policy makers without good evidence. The most useful information documents the extent and severity of the problem and the benefits and feasibility of the solution. For example, country-specific information related to the threat of multidrug-resistant TB, the success of DOTS demonstration projects, and the cost-effectiveness of DOTS can often influence policy makers. Unfortunately, many public health officials end their advocacy efforts after gathering this information, believing that “the facts will speak for themselves.” In reality, the validity and weight of the evidence alone is rarely enough to bring about political change. Other strategies are usually needed to encourage policy makers to take the correct course of action. C. Package the Message

Two basic messages provide the basis for most advocacy strategies for TB. First, TB is a devastating disease. Advocates need to use compelling language to describe the effects that TB has on individuals, families, whole communities, and national economies. And second, the DOTS strategy can control TB. Advocates need to persuasively argue the effectiveness and cost benefits of using DOTS to address TB. These two messages need to be stated in special ways for different audiences, ensuring their relevance to each stakeholder’s unique concerns and agenda. A minister of finance will be more interested in the economic impact of the TB problem and the cost-effectiveness of the solution, whereas an AIDS organization will want to know how the TB crisis and the DOTS intervention are relevant to HIV-positive individuals. When presenting advocacy messages to policy-minded audiences, health specialists must use an entirely different way of communicating from that appropriate in medical, scientific, and academic settings (Table 4). Overly technical, qualified, and dispassionately presented information is likely to be ignored by nontechnical audiences. Focused messages using memorable language are necessary to effectively communicate to policy makers and journalists. Visual materi-

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Table 4

Differences Between Scientific and Advocacy Communication

Science Detailed explanations are useful. Extensive qualifications can be necessary for scholarly credibility. Technical language can add greater clarity and precision. Several points can be made in a single research paper. Be objective and unbiased. Build your case gradually before presenting conclusions. Supporting evidence is vital. Hastily prepared research and presentations can be discredited. The fact that a famous celebrity endorses your research may be irrelevant. What you know counts, and truth is often seen to be objective.

Advocacy Simplification is preferable. Extensive qualifications can blur your message. Technical jargon confuses people. Restricted number of messages is essential. Present a passionate compelling argument based on fact. State your conclusions first, then support them. Too many facts and figures can overwhelm the audience. Quick, but accurate, preparation and action are often necessary to take advantage of opportunities. The fact that a famous celebrity supports your cause may be of great benefit. Who you know counts, and truth is often seen to be subjective.

als, such as graphs, photos, and videos, are especially important because they are often more likely to be remembered than text or words. D. Apply Pressure Through the Media

If an issue is ignored by the media, it is unlikely to receive sustained political or social attention. Fortunately, the criteria for attracting media attention are quite predictable, even if sometimes difficult to achieve. If presented properly, journalists can be interested in most any story that is new, urgent, sensational, or controversial or that involves celebrities or dramatic personal stories. With the help of individuals skilled in public relations, TB programs can become much more successful in using the media to help set the political agenda. Media strategies are especially important in democracies, where politicians need to maintain a good public image in order to be reelected. The prospects of being publicly acknowledged for taking leadership on an important issue or the threat of being discredited by the media for failing to take action are proven ways of motivating otherwise disinterested political officials into greater involvement.

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E. Involve New Advocacy Partners

In most countries, TB organizations alone have too small a power base to create the political commitment necessary to control TB. Other organizations and sectors need to be involved. The more people from diverse backgrounds who deliver the same message, the more difficult it will be for policy makers to ignore. There are three main ways in which new individuals and partners can become involved. The first is through forming a coalition of stakeholders who are concerned about TB. Organizations representing risk groups such as children, refugees, people who are HIV positive, women, laborers, and prisoners are natural partners in the fight against TB. Second, grass-roots advocacy campaigns can be waged to mobilize the general public to participate in activities that can attract political attention. For example, individuals around the world can be mobilized to draw “Stop TB” postcards and mail them to public officials requesting specific action. This is a creative and accessible activity to involve schools and community and voluntary organizations. Finally, effective TB-control efforts require financial resources. An important part of advocacy is to plan fund-raising strategies that can attract donor support in order to sustain future efforts. The TB seal campaigns of many lung associations represents one of the many ways in which new individuals can be attracted to fund TB-control efforts. F. Use “Insider” Strategies

In politics it is said that it is not what you know, but who you know that really counts. Indeed, there is no substitute for developing a network of influential individuals who have direct personal access to important decision makers. A common example of an insider strategy is to form strategic alliances with other influential individuals for the mutual benefit of all parties. While insider political strategies can provide the most direct means of bringing about change, they also require more compromise, negotiation, and deal making than strategies that create external political pressure. Insider strategies are most effective when they are supported with strong external pressure from the public. A multifaceted approach combining both internal and external pressures and incentives is often required, especially when governments and institutional bureaucracies are reluctant to welcome change and seem intent on preserving the status quo. To break through this inertia, advocates often use “carrots-and-sticks” strategies that provide personal incentive for political advancement, credit, or achievement and simultaneously pose a potential threat to one’s good standing if the necessary action is not taken. G. Evaluate Results and Build on Successes

The ultimate measure of any TB advocacy initiative is whether or not it can contribute to curing greater numbers of infectious TB patients. The effectiveness of advocacy strategies can be measured on three intermediary levels (Table 5).

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Table 5 Indicators for Measuring the Progress of Advocacy and Social Mobilization Strategies 1. Capacity for advocacy activities Advocacy staffing Advocacy budget Formation of an advocacy coalition Production of advocacy materials Planning of media events Frequency of communication with political leaders Availability of relevant epidemiological information 2. Awareness created by advocacy strategies Amount of media coverage Increased awareness of key audiences Change of attitudes in key audiences Involvement of new partners 3. Impact on political will Political statements on TB Establishment of NTP DOTS as national TB-control policy Government resource allocation for TB Appointment of high-caliber TB program management

1. The capacity of organizations to implement advocacy strategies 2. The awareness created by advocacy strategies and messages among target audiences 3. The impact of advocacy strategies on the policy and funding behavior of political institutions Although the impact and results of advocacy strategies are the foremost concern, one should constantly monitor other advocacy indicators to ensure they are sufficient to attain the necessary results. Inevitably, the knowledge and skill of a program’s advocacy staff is one of the surest determinates of subsequent programmatic outcomes. V. Potential Initiatives to Help Mobilize Society to Control TB The preceding section outlined a theoretical framework for TB advocacy. This section presents a number of practical projects that can be components of a country-specific advocacy strategy and help create the conditions for making TB control an attractive social cause.

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A. Indicators That Are Understandable by the General Public

The best popular campaigns have a specific goal in sight. The use of one simple indicator was an important tool in involving new partners to push for the expansion of childhood vaccinations. With one clear goal, childhood vaccination advocates were able to rally support and increase coverage from 20% in the early 1980s to nearly 80% a decade later. The target for a social mobilization campaign against TB should be to increase the percentages of infectious TB patients cured through the DOTS strategy. Currently, nearly 20% of all infectious TB patients worldwide are cured through DOTS. TB advocates should aim to cure at least 70% of all TB patients with DOTS in the next decade. It is important to promote this simple goal as a rallying point by which progress in controlling TB can be measured by non–health experts. The goal of curing 70% of TB patients with DOTS should supplement—not replace—WHO’s programmatic targets of 85% cure rate and 70% case detection. B. The Stop TB Symbol

The Stop TB logo has become a popular and memorable symbol for the TB-control movement (Fig. 2). This image draws upon one of the most commonly, universally recognized symbols—the stop sign. Additionally, the English version compactly contains messages concerning both the urgency of the epidemic and, when turned upside down, the recommended intervention. Groups use this symbol to publicly signal their concern about TB. For example, health workers who administer treatment in Thailand wear this logo on their jackets. Participatory grass-roots activities encourage schoolchildren and community groups to send Stop TB postcards to their government officials encouraging them to make the

Figure 2 The STOP TB logo draws upon a universally recognized symbol—the stop sign. The English language version contains a key message concerning the urgency of the epidemic (STOP TB) and, when turned upside down, the recommended intervention (DOTS).

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DOTS strategy available in their communities. Around the world, creative individuals are finding other unique uses for the Stop TB image—on T-shirts, umbrellas, coffee mugs, bumper stickers, posters, buttons, and billboards. C. Global World TB Day Activism

World TB Day provides many new partners their first opportunity to attempt advocacy and social mobilization strategies against TB. In 1998, nearly 200 organizations conducted public outreach activities on March 24. In the coming years, World TB Day will continue to be a rallying point for mobilizing new partner organizations. A key event in this process has been the World TB Day advocacy planning meetings for NGOs, which KNCV has sponsored the fall of each year since 1995. It is important that additional organizations step forward to host World TB Day advocacy planning meetings for their own regions and countries. D. Market Research

Research is needed to gain a better understanding of knowledge and attitudes toward TB and DOTS among key audiences in high-burden countries as well as the factors policy makers consider in prioritizing a particular disease or health threat. This information is valuable not only for the insight it can provide into the development of advocacy strategies and messages, but also in providing baseline indicators upon which the impact of future advocacy and social mobilization strategies can be measured. E. Surveillance and Operational Research to Produce Advocacy Information

TB-control advocates in many high-burden countries are currently unable to offer answers to many questions asked by policy makers: How serious is TB in our country? How serious is multidrug-resistant TB in our country? What will be the future impact of the dual TB/HIV endemic in our country? What are the projected number of TB cases and deaths we can expect in the future if no action is taken? How much is our country currently spending on TB control? How does this compare to what is spent to address other diseases? Which individuals in what offices control the use of this money? What is the cost per capita for implementing a DOTS program in our country? How much money can our country eventually save by using DOTS? What is the economic impact of TB on the families of patients? What are the economic and social consequences for our country if we ignore TB?

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Research is needed to help advocates more accurately answer these questions. Currently, there is a great imbalance in TB research, with the majority of investigations addressing questions relevant to wealthy, low-burden countries, and a much smaller proportion principally focused on immediate challenges facing low-income countries that are burdened with over 90% of all TB cases (9). F. Advocacy Presentation Materials

Many potential partners would likely become involved if TB-control advocates simply took the time to share the basic facts of the epidemic and request specific action. Concise advocacy booklets and multimedia presentations need to be prepared to help reach these potential supporters and encourage them to take initial steps in TB advocacy. These presentation materials should be designed so they can be utilized by others with a minimal amount of training. G. Building an Advocacy Capacity Within NTPs

In 1996, South Africa’s national TB program (NTP) became the first country to hire a full-time advocacy officer and integrate the development of political will into its yearly planning. This strategy was instrumental in prompting South Africa to declare in 1997 that the TB epidemic was the country’s most urgent health threat. A similar approach should be taken by all national TB programs. Often, there are considerable resources available within the budgets of NTPs for mass public education and IEC activities. In countries not making wide and effective use of DOTS, these resources would be better used to hire staff or consultants skilled in advocacy and social mobilization and to develop materials that can increase the supportive involvement of new partners and help increase political will for the control of TB. H. Advocacy Training Workshops for NTP Managers and Staff

Training workshops are needed to help lay the groundwork for a better appreciation of the importance of advocacy among managers of TB services. TB program managers do not need to become experts in the specifics of executing advocacy and social mobilization strategies; specialists should be hired for this. However, they do need to know how to think strategically in attempting to increase political support for TB control in their country. As social mobilization efforts accelerate, it will also become increasingly important for TB program managers to receive training in how to be effective spokespeople to the media. I. Training Workshops for Journalists

A series of seminars for health reporters could help correct some common misinformation that occurs in the reporting of TB. For example, journalists frequently overstate the usefulness of BCG vaccine and understate the effectiveness of

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the DOTS strategy. As media attention on TB increases, there is also the risk that particular risk groups, such as foreign-born individuals, the homeless, and those who are HIV positive, could become further stigmatized through uninformed reporting. J. Increasing NGO Advocacy Capacity

The Western Cape TB Alliance in South Africa and BRAC in Bangladesh have demonstrated the important role NGOs can play in stimulating TB advocacy efforts in high-burden countries. Workshops and training seminars are needed to equip more lung associations and TB NGOs to become better advocates and to involve health, development, and human rights NGOs with strong advocacy networks in the movement to control TB. K. Creating Patient Organizations

It is possible that patient-based organizations can again be created for TB—such organizations were highly successful in Europe, Japan, and North America in the early part of this century. More recently in the United States, patient organizations such as ACT-UP have been critical for social mobilization to prevent the spread of HIV/AIDS. Family-related organizations have also been important health advocates—MADD (Mothers Against Drunk Driving) and PFLAG (Parents and Friends of Lesbians and Gays) are two of the better-known examples. L. “DOTS Observer” Networks

The most labor-intensive element of the DOTS strategy is the time it takes to observe TB patients swallow their medicines. If this is one of the biggest challenges in implementing DOTS, it could also be its greatest opportunity. NGOs and service organizations with large volunteer networks could assist health services by observing patients as they take their medicines. This social mobilization strategy would be similar to the involvement of Rotary International volunteers to assist with national immunization efforts. Trained members of volunteer organizations could help administer TB treatment. Nonmonetary rewards, such as certificates, trophies, or medals, could be presented to individuals and agencies that reach targets for directly observing treatment and helping to bring about the successful cure of TB patients. Many other strategies will be needed to help mobilize society against tuberculosis. Celebrities must become involved as spokespeople—so far they have been silent, although it is certain many marathon runners, film stars, and musicians have been affected by TB. Industry and corporations need to be encouraged to address the double burden TB places on productivity and economic growth; the disease devastates the age groups that comprise the biggest share of the workforce and the biggest share of potentially emerging middle-class markets.

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VI. Conclusion In analyzing recent technical advances in the prevention and treatment of TB, clinicians and researchers should also note an often-overlooked discovery made by two of this century’s foremost investigators of the epidemic. The late Dr. Karel Styblo, the originator of the DOTS strategy, was widely recognized as being one of the most brilliant and rigorous observers of the technical factors involved in the control of TB. To his credit, while completely immersing himself in the smallest details of operating effective programs, Styblo understood the political context of his activities. Styblo recognized that the creation of political will was one of the most essential considerations for establishing and sustaining an effective TB-control program and incorporated this as one of the five main elements of the DOTS strategy. Considered to be one of this century’s premiere TB researchers, Sir John Crofton perfected the use of combination treatment to increase cure rates and prevent drug resistance. After watching the world squander these advances during his lifetime, Crofton increasingly emphasized that researchers are responsible not only for developing better tools, but also for helping ensure they are put to effective use. According to Crofton, “governments must be persuaded that they have a grim and urgent problem which is, nevertheless, soluble if quite modest national efforts and resources are devoted to it” (10). Far from being an anomaly for health professionals to concern themselves with advocacy, it is a fundamental necessity for those who desire to achieve the greatest impact in preventing Mycobacterium tuberculosis from causing further infections, cases, and deaths in high-burden countries. References 1. World Health Organization Global TB Programme. Programme Director’s Report for CARG. Geneva: World Health Organization, 1997. 2. World Health Organization Global TB Programme. Report of the Ad Hoc Committee on the Tuberculosis Epidemic. WHO/TB/98.245. Geneva: World Health Organization, 1998. 3. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for global tuberculosis control under the WHO DOTS strategy. Lancet 1998; 352:1886–1891. 4. McKee N. Social Mobilization and Social Marketing in Developing Communities: Lessons for Communicators. Penang, Malaysia: Southbound, 1992. 5. Malla P, Gadtaula RP, Bam DS. Impact of repeated health education on treatment outcome in patients with smear-positive tuberculosis. Tuberc Lung Dis 1996; 77:S97. 6. Jin BW, Kim SC, Mori T, Shimao T. The impact of intensified supervisory activities on tuberculosis treatment. Tuberc Lung Dis 1993; 74:267–272. 7. Planning Principles for Accelerated Immunization Activities. Geneva: World Health Organization, 1985.

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Rivera L. 13th World Conference on Health Education. Conference Proceedings 1998; II:221. 9. World Health Organization Global TB Programme. The Global TB Research Initiative: Research to Make a Difference. WHO/TB/98.248. Geneva: World Health Organization, 1998. 10. Crofton J. Tuberculosis: world perspectives and the challenges ahead. J Pharm Pharmacol 1997; 49 (suppl. 1):3–6.

Part Six THE FUTURE

35 Tuberculosis in the Future

RICHARD J. O’BRIEN

MARIO C. RAVIGLIONE

Centers for Disease Control and Prevention Atlanta, Georgia

World Health Organization Geneva, Switzerland

Tuberculosis (TB) is a fascinating and complex disease. Its history is well detailed in the introductory chapter to this text. As the twentieth century draws to a close, it is appropriate to speculate on the future of tuberculosis in the new millennium. The past decade has witnessed remarkable changes, both favoring improved control and eventual elimination of this ancient disease and arousing fears that the epidemic will surely worsen in the decades ahead. In this chapter we will review these changes, both negative and positive, consider what mathematical models might tell us about TB in the future, speculate on the promise and potential impact of new technologies, and conclude with a discussion of the possibility of the elimination of tuberculosis. I. Tuberculosis in the 1990s: Reasons to Be Hopeful Perhaps the most remarkable change during the past decade has been in the public perception of the importance of tuberculosis. In the late 1980s most people throughout the industrialized world believed that the disease had disappeared from their countries. Additionally, many thought that tuberculosis was not of great importance in developing countries. The reasons for this misperception are read867

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ily apparent. While many persons living in the United States may have had grandparents and older relatives who had tuberculosis decades earlier, the disease had retreated from mainstream America. Although cases continued to occur, they did so in marginalized persons who were seldom noticed. In the developing world, tuberculosis was given low priority, as it was assumed that widespread BCG vaccination and provision of inexpensive drugs would keep the epidemic under control. At the same time, funding was being cut from tuberculosis-control programs worldwide. By the mid-1980s the staff of the World Health Organization (WHO) Tuberculosis Unit had been reduced to one statistician and one secretary. Support for research had all but vanished, and there was little incentive for the private sector to invest in development of new control technologies. By the mid-1990s, the majority of people in the United States believed that tuberculosis had returned. The epidemics of multidrug-resistant (MDR) tuberculosis, largely fueled by nosocomial transmission among persons with human immunodeficiency virus (HIV) infection, aroused new fears about incurable tuberculosis (1). Coincident with the MDR TB outbreaks, reported cases of TB began to rise, reversing a steady downward trend of the earlier decades. Contributing to this rise were cases of foreign-born tuberculosis, worsening socioeconomic conditions in larger urban areas, and a public health infrastructure that could not provide optimal control services (2). As press attention to MDR TB picked up, public concern grew and eventually the U.S. Congress responded. Federal support for TB control under categorical grants, which had all but disappeared, increased so that by 1996 the U.S. Centers for Disease Control and Prevention (CDC) was providing about $100 million yearly to state and large city tuberculosis programs. Much of this funding was used for the provision of directly observed treatment (DOT) to ensure that tuberculosis patients were cured. The impact of this increase in resources was obvious. In 1993, cases of tuberculosis in the United States decreased for the first time in nearly a decade (3). This decrease has continued, and in 1998 cases and case rates were at an all-time low (4) and the trend has continued through 1999. Presently, nearly half of all U.S. counties are tuberculosis-free. Even more dramatic were the changes at the global level. The WHO Global Tuberculosis Programme (GTB) was established, and in 1991 the WHO World Health Assembly adopted the year 2000 targets of detecting 70% of new, smearpositive cases and curing 85% of those detected (5). Among the most prominent of GTB activities was a highly successful advocacy campaign to marshal support for improved tuberculosis control in developing countries (see Chap. 34). The pronouncement by the WHO Director General in 1993 that tuberculosis had become a global public health emergency was unprecedented and attracted significant attention from all corners of the world. GTB elucidated its strategy for successful tuberculosis control modeled after the programs developed by Dr. Karel Styblo of the International Union Against Tuberculosis and Lung Disease (IUATLD) (6).

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This strategy was packaged as DOTS (directly observed treatment, short-course), which specifies the essential elements required for effective tuberculosis control (7). In 1997 the Director General of WHO proclaimed DOTS to be the “health breakthrough of the decade.” Largely through the efforts of GTB, donor support for tuberculosis control in resource-poor countries increased through both bilateral contributions and direct contributions to WHO. This enabled GTB to expand its work, focusing on extending DOTS programs to achieve its global targets for case detection and cure rates that would reverse the global epidemic. Several countries and regions also embarked on ambitious plans to eliminate tuberculosis. Unfortunately timed, the U.S. elimination plan was announced by the Advisory Council on the Elimination of Tuberculosis (ACET) in 1989 during the middle of the upsurge in tuberculosis in the United States (8). However, the plan was useful and was adapted into a strategic plan to address the upsurge in MDR TB in the United States. ACET has since revised its elimination plan, emphasizing the importance of continued research to develop new technologies needed for elimination. A group of western European countries, the Persian Gulf States, and Singapore (see Chap. 28) have also discussed elimination strategies. In an effort to attract new parties to the global effort to reduce the toll of tuberculosis morbidity and deaths, several international and national tuberculosis programs are collaborating in the development of the “Stop TB” initiative led by WHO. This initiative is founded on partnership and intended to include the widest possible participation to address the tuberculosis problem throughout the world. The initiative will reach out to the tuberculosis community and also beyond it— to the UN family, the private sector, and civil society. The initiative will develop a global action plan for tuberculosis control that identifies the roles for different partners. It will focus on a global charter to secure commitments to improve tuberculosis control from heads of state of endemic countries, international organizations, and donors. It will develop mechanisms to ensure global access to quality, fixed-dose combination tuberculosis drugs of demonstrated bioavailability. Urgent action focused on high-burden countries, the emerging drug-resistance problem, and management of tuberculosis control in settings of high HIV prevalence is also planned. The initiative will also support a balanced agenda for global tuberculosis research focusing on both short- and long-term objectives. After several decades of a near absence of both basic and applied tuberculosis research aimed at the development of new tools, the decade has seen definite advances. A significant effort is underway aimed at improved understanding of the immunopathogenesis of tuberculosis through studies of both the infecting organism and the human host. We now have an improved understanding of both host and microbial genetic factors related to increased resistance and susceptibility (9–12), and we have advanced our understanding of the human protective immune response to tuberculosis (13).

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Perhaps the most important scientific advance has been the sequencing of the complete genome of Mycobacterium tuberculosis (14). Information from the genome provides an opportunity for the development of innovative approaches to study basic questions of virulence, pathogenesis, and persistence (the ability of bacilli to achieve a long-lasting state of dormancy after infection) and to identify potential protective antigens. Techniques are also being applied to exploit the available information for the development of new diagnostic, therapeutic, and immunological interventions. With the increasing recognition that BCG vaccination has had little impact on the global TB problem (see Chap. 19), much work is aimed at the development of new TB vaccines. New vaccine candidates, including novel subunit vaccines, attenuated strains of living mycobacteria, and DNA vaccines, have been developed (15), and more than 100 have been tested in animal models under the sponsorship of the National Institutes of Health (16). Several candidate vaccines will likely be available for human testing in the near future. Notable advances in applied tuberculosis diagnostics have recently taken place, including the development of new methods to culture and identify mycobacteria that greatly reduce the time needed to detect growth of M. tuberculosis in diagnostic specimens (17). In the United States, several rapid tests for the diagnosis of tuberculosis based on the amplification of nucleic acid have been licensed (see Chap. 14). These tests, which permit the identification of M. tuberculosis in less than 24 hours, are highly specific and more sensitive than microscopy. Unfortunately, they do not appear to be as sensitive as standard culture and at present are rather costly, so that their cost-effective application has not been established (18). Rapid methods of identifying drug-resistant TB are presently under investigation (19). Although there has been little progress in the development of more specific skin test antigens for diagnosing latent TB infection, a new blood test based on the detection of gamma-interferon in persons with TB infection shows promise (20). Several diagnostic tests in simple kit form based on detection of mycobacterial antibodies have been marketed outside the United States, but none has proven to be sufficiently sensitive and specific to be generally useful (21). DNA fingerprinting methods, such as restriction fragment length polymorphism (RFLP) analysis, have been used to identify M. tuberculosis strains implicated in outbreaks and laboratory cross-contamination (22) (see Chap. 11). After over two decades with little activity in TB drug development, progress is now being made. In 1998, rifapentine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of TB, the first such drug approved in the United States in over 25 years (23). Fluoroquinolone antibiotics are now among the most commonly used “second-line” drugs for the treatment of patients with drug-resistant TB (24), although this is not apparent from the product labeling. Several entirely new classes of antimicrobial compounds have shown promising anti-TB activity in laboratory and animal models. Investigators have also found that immunomodulation by drugs or cytokines can improve response to TB treat-

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ment. Clinical trials of “short-course” preventive therapy conducted in HIV-infected patients have led to a recent recommendation from CDC for the use of a 2month regimen of rifampin and pyrazinamide as an alternative to longer courses of isoniazid (see Chap. 18) (25). Experimental studies have also suggested that the combination of rifapentine and isoniazid given once weekly for 3 months may be a highly effective preventive regimen (26). In addition, significant progress has been made in recent years in elucidating mechanisms of drug action and mechanisms of antibiotic resistance. These advances are contributing to identification of novel drug targets and the development of new classes of therapeutic agents. However, one major and unresolved problem is that with the high cost of new drug development, pharmaceutical companies continue to have relatively little interest in TB drugs (27). II.

Problems Looming at the End of the Twentieth Century

Despite significant advances in the last decade, there remain significant impediments to control and ultimately eliminate tuberculosis, not only in low-incidence countries such as the United States, but especially in high-incidence, resourcepoor countries where the great majority of tuberculosis cases reside. Perhaps the most significant problem facing these countries is persistent, grinding poverty complicated by urban migration and lifestyle changes which might facilitate the transmission of tuberculosis. In many developing country settings people are poor, malnourished, and live in crowded, nonhygienic conditions. Epidemiologically, this translates into a vicious cycle of more disease, more transmission of infection, and more persons likely to develop disease, including the young. In this situation, the chain of transmission of tuberculosis cannot be interrupted. Although the argument that only with social improvement and alleviation of poverty will the tuberculosis situation improve has largely been discounted (28), these socioeconomic realities create significant impediments to improved tuberculosis control. Most developing countries cannot afford an efficient health-care system. The result is that tuberculosis patients are not diagnosed rapidly, nor are they treated effectively until cured. Thus, individual patients suffer and transmission continues. The control situation is slowly improving, but it is far from satisfactory. A GTB study has concluded that the application of its DOTS strategy could, if widely applied, halve the global burden of tuberculosis within 10 years (29). However, modeling data for this study based on earlier trends in tuberculosis morbidity in Europe may not be applicable to the situation in developing countries. In addition, the requirement for a disease-specific program, a rather complex system that may be difficult to sustain in many areas without continuing donor assistance,

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and reliance on antiquated tools are factors that suggest that the DOTS approach may not always have the anticipated impact. Although 96 countries were in various stages of implementation of DOTS in early 1997, only 32% of the human population were living in areas where effective tuberculosis-control programs were fully implemented and operational (30). Thus, today probably only a small proportion of all tuberculosis patients are being cured. Recent data show that in areas with good tuberculosis control 78% of cases are successfully treated, but these constitute a fraction of the total 3.8 million cases reported and the 7.4 million estimated to have occurred (30). In addition, it is likely that only one third of the infectious tuberculosis cases are detected and put on treatment worldwide. In 1997 WHO announced that its year 2000 TB objectives would not be met because of slow implementation of DOTS (31). Countries of the former USSR and socialist bloc are suffering from a new wave of tuberculosis cases and deaths (32). In the late 1980s and through the first half of the 1990s in most countries of this area tuberculosis notifications and deaths increased, sometimes markedly. In Russia, for instance, the case-notification rate increased from 34 per 100,000 population in 1991 (the lowest ever) to 75 in 1996, and the tuberculosis death rate rose from 7.7 per 100,000 in 1988 to 15.4 in 1995. Similarly, case-notification rates have increased dramatically in Romania, Belarus, Ukraine, Moldova, the Baltic countries, the Caucasus, and the central Asian republics of the former USSR. A large proportion of cases occurs among young adults, indicating that tuberculosis transmission is ongoing. Various factors are producing this upsurge of tuberculosis in the former USSR. Wars and conflicts are known to be accompanied by an increase of tuberculosis, often as a result of impaired nutrition and stress (33). The deterioration of the public health system, which followed the dissolution of the USSR, resulting in delayed diagnosis and a high rate of defaulting, contributed to ongoing transmission ending in new infections and new cases. Finally, and probably more importantly, almost all these countries are experiencing severe lack of drugs. This translates to high case fatality rates, high rates of relapse or treatment failure, and selection and spread of drug-resistant strains. This latter problem has recently received a great deal of attention. In many areas of Russia, initial resistance to both rifampin and isoniazid (i.e., primary MDR TB) appears to be high. One survey in the northwestern region found the rate of primary MDR TB to be 5% in the general population (34), and the rate in the Ivonovo region where WHO has established a model DOTS program was 4% in 1996 (35). In addition to Russia and some countries in eastern Europe, there are other areas recently identified by WHO as “hot spots” for MDR TB, e.g., portions of India and China, the Dominican Republic, and Côte d’Ivoire. In Russian prisons primary MDR TB is likely an even greater problem (see Chap. 24). In a model DOTS program implemented by the Belgian nongovernmental organization Doctors Without Borders in tuberculosis penal colony in

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Mariinsk, Western Siberia, the failure rate for newly admitted patients treated with the WHO/IUATLD retreatment regimen was 40% (M. Kimmerling, personal communication). Based on results of drug-susceptibility testing for another group of inmates in the same prison, one might expect such a high rate of failure. One expert has recently estimated that there are as many as 67,000 patients with MDR TB in Russia, of which over 50,000 are imprisoned (A. Goldfarb, personal communication). In the bordering country of Azerbaijan, a team of doctors from the International Red Cross has also documented high rates of both initial and acquired drug resistance in prisoners (36). As the century draws to a close, it is uncertain how MDR TB will be addressed. To what extent it can be controlled by proper implementation of standard DOTS programs is unknown. Some experts argue that once a level of initial MDR is reached, DOTS will only worsen the problem because more drug resistance will be created. Some proponents of “DOTS-plus,” which provides second-line drugs for the treatment of MDR TB cases, state that treatment of MDR TB is not only morally imperative but also epidemiologically required (see Chap. 17) (37). Unfortunately, it is difficult to see how countries, such as Russia, that cannot purchase standard drugs for DOTS can afford to care for their MDR TB cases. HIV infection also threatens tuberculosis control in areas where both infections are prevalent (see Chap. 20). Evidence of the interaction between tuberculosis and HIV is provided by HIV seroprevalence surveys, autopsy and clinical studies, and cohort studies of co-infected individuals (38). The HIV epidemic is today a major contributor to the tuberculosis epidemic in an increasing number of developing countries where persons at risk of acquiring HIV infection are equally at risk of being infected with tuberculosis (39). WHO estimates that nearly 11 million people in the world are currently carrying the dual infections, 68% of whom are in sub-Saharan Africa and 22% in South east Asia (WHO, unpublished data). As a consequence, a large number of tuberculosis cases originates from this co-infected pool: in 1995 over 700,000 tuberculosis cases (8.4% of all cases) and over 250,000 tuberculosis deaths (8.9% of all tuberculosis deaths) were attributable to HIV (40). Market reform and health care restructuring (see Chaps. 32 and 33) also threaten tuberculosis control and DOTS implementation. It is a principle of tuberculosis control worldwide that diagnostic and treatment services should be provided free of charge. However, cost recovery in the health sector is being promoted in lower income countries as part of economic reforms required by external lending institutions such as the World Bank and the International Monetary Fund. Unfortunately, requiring tuberculosis patients to pay for drugs has the well-recognized consequence of abandoning treatment, with subsequent failure and acquisition of drug resistance. In the United States, the move to managed care threatens to impede proven measures of tuberculosis control, such as contact investigation and provision of DOT (41).

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In the United States in 1997, over 40% of all newly reported cases occurred in persons born outside the country (4). The proportion of foreign-born cases has steadily increased since 1986, when country of origin was first reported to CDC. Unless immigration from high-incidence countries is drastically curtailed, this trend will surely continue. Early in the next century the United States will likely join other countries, such as Canada, the Netherlands, Switzerland, and Australia, with foreign-born cases outnumbering those in the native born. Finally, as the century draws to a close, we have witnessed a profound structural and philosophical reorganization within WHO. These changes have led to a renewed interest in consolidated control of communicable diseases and the integration of GTB, one of the most successful and prominent disease-specific programs of WHO, into the Communicable Disease Cluster. For some, the loss of GTB’s name and identity has created anxiety. However, it is also hoped that the creation of new dynamics will allow the channeling of new ideas into tuberculosis control and from tuberculosis control to other infectious disease control activities. In this new paradigm, allocation of resources for DOTS may ultimately increase and become sustainable for the decades to come, although the U.S. experience of the 1970s when categorical TB programs were replaced by Block funding, directly leading to the 1985–1992 U.S. TB resurgence should be borne in mind. III. TB in the New Millennium: Clues from Modelers Mathematical models, although imperfect, can shed some light on the potential effect of both currently available and new tools on the tuberculosis epidemic. Two important papers on this topic were published recently. WHO has concluded that without any change in the current status of TB control, the yearly total of incident TB cases will rise from an estimated 7 million in 1995 to nearly 10 million in 2020 (Fig. 1) (29). In this model the application of DOTS to achieve the WHO global objectives for case-detection rate and cure would have a dramatic impact, reducing cases by as much as two thirds by the year 2020. If the global targets were reached by 2010—a not impossible goal—an estimated 43 million cases and 18 million deaths would be averted by the year 2020. However, only 25% of the total burden during this time period will be averted. Therefore, the WHO investigators conclude that new tools are clearly needed but, unfortunately, are unlikely to be available in the next several decades. Using a different model with different approaches and assumptions, investigators at the Harvard School of Public Health have come to similar conclusions about the potential impact of the DOTS strategy on the global tuberculosis problem (42). They estimated that if DOTS were expanded under the most favorable circumstances, 54 million cases and 19 million deaths would be averted by the year 2030, compared with those expected if the current trend in DOTS uptake con-

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Figure 1 Projected annual worldwide incidence of tuberculosis under assumption that WHO targets for case finding and cure are met in 2000, 2010, and 2020, compared with maintenance of current control effort. (From Ref. 29. Copyright 1998 The Lancet Ltd.)

tinues. However, this corresponds to a reduction of only 24% in global TB morbidity and mortality through optimal use of DOTS. Going further, these investigators estimated the impact of additions to DOTS such as active case finding and preventive chemotherapy. Over 90 million cases and 39 million deaths might be averted by active case finding with mass miniature radiography (MMR) and mass preventive therapy (Fig. 2). The remarkable achievements in tuberculosis control in Alaska 40 years ago suggest that these estimates are not beyond the realm of possibility. With active case finding, isolation, and optimal treatment, the annual risk of tuberculosis infection among Alaskan native children fell from 25% in 1950 to 1% in 1960 (43). Ten years later with the addition of village-wide treatment of latent TB infection, transmission appeared to have been virtually eliminated (44). The Harvard investigators also estimated the potential impact of new technologies, including new vaccines. Even allowing for a 15-year developmental delay in implementation, new vaccines would have the greatest impact. For example, a postinfection vaccine that was 80% effective would prevent 52 million cases

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Figure 2 Projections of global deaths from tuberculosis, 1998–2030. Each graph shows the baseline DOTS strategy and alternative strategies incremental to baseline DOTS. The top graph shows expectations of the epidemic given various aggressive applications of existing strategies, including mass preventive therapy (MassPT) and single cycle or continuous active case finding using mass miniature radiography (ACF-MMR-1 and ACF-MMR, respectively). The bottom graph shows the results of strategies using new technologies, including a vaccine preventing breakdown with 50% efficacy (VacBr50), a single-dose treatment regimen for active tuberculosis (UltraSCC), and this single-dose regimen combined with active screening (ACF-MMR  UltraSCC). (From Ref. 42. Copyright 1998 National Academy of Sciences, U.S.A.)

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and 14 million deaths. The combination of ongoing active case finding with MMR and a treatment regimen that required only a single patient contact would prevent 72 million cases and 32 million deaths. The obvious conclusion is that while DOTS must be expanded, DOTS alone is not likely to ensure optimal global tuberculosis control. In addition to the use of other tuberculosis-control measures presently available, such as active case finding and treatment of latent TB infection, new tools are clearly required. Moreover, in the United States current tools are not sufficient to achieve the goal of elimination. Even with optimal tuberculosis screening and diagnosis, many patients with newly diagnosed tuberculosis will have spread the infection to their closest contacts before they are identified and placed on treatment. Environmental control has reduced the transmission of tuberculosis in some settings, notably hospitals, but these measures cannot be easily applied in the households of infectious patients where most tuberculosis transmission is believed to occur. Implementation of these measures in low-income countries with higher rates of tuberculosis is far less feasible. Preventive chemotherapy—the treatment of persons with latent M. tuberculosis infection to prevent the development of active TB—could play a major role in TB elimination. However, the difficulties in identifying those persons at highest risk of disease and problems of nonadherence and drug toxicity limit the effectiveness of this strategy. Although some progress is being made, as exemplified by the rifampin-based “short-course” treatment of latent TB infection regimens that have recently been shown to be effective in HIV-infected persons (25), curative treatment and treatment of latent TB infection as currently practiced are not likely to allow us to reach the goal of tuberculosis elimination.

IV. The Promise of New Technologies It is apparent that new tools will be required to eliminate tuberculosis completely in the United States and internationally. The greatest impact could come from a new vaccine. As noted above, recent technological advances have provided the basis for new vaccine development, and important progress in the development of new vaccines against tuberculosis is being made. However, sustained support is required to move the research from the laboratory to field trials of vaccines and to implement new vaccine programs. Recognizing the importance of TB vaccines, ACET has recommended that public agencies and vaccine manufacturers develop a comprehensive, consensual strategy to achieve these goals. In a report published in 1998, ACET outlined the steps needed to develop a new vaccine and called upon the National Institute of Health (NIH) to develop a more detailed blueprint for vaccine development (45). It is proposed that a Public Health Service (PHS) task force be formed to implement this strategy. Although it is thought that it

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might take several decades before a new, effective vaccine is in use in the field, the impetus to undertake this project has begun. The key to its success will be the marshaling of both private and public sector support for the sustained effort that will be needed. Within a decade it is likely that rapid diagnostic methods will be available for the highly accurate diagnosis of tuberculosis disease and determination of drug susceptibility. Moreover, new methods of diagnosing latent infection and markers to predict progression of infection to disease will be available. However, the availability of tests that are feasible for use in low-income countries is another question. The requirements for new diagnostics for the developing world have been detailed (46), and a number of biotechnology companies are directing significant efforts toward the development of such tests. Given the remarkable progress of the last decade, it is reasonable to expect that the next decade will see the implementation of new diagnostics to both replace cumbersome smear microscopy and greatly improve the diagnosis of paucibacillary tuberculosis. Future progress in the development of new therapeutics is less certain. In the past, great advances in tuberculosis treatment and drug development came about through trials conducted in the public sector or as public-private partnerships. In the United States, the Veterans Administration (VA) and the PHS conducted a notable series of clinical trials to evaluate new drug regimens for both the treatment and prevention of tuberculosis. Unfortunately, U.S. support for the infrastructure required for these studies gradually diminished. With the recent increase in federal support for tuberculosis control and elimination, CDC has returned to the private-public partnership model and has established the TB Trials Consortium (TBTC), which now provides a unique and important resource for further clinical studies. The NIH is increasing its capacity to conduct large-scale clinical TB trials through collaborative partnerships between U.S. academic institutions and centers outside of the United States. The IUATLD has also recently established a clinical trials program aimed at the evaluation of regimens to improve treatment in low-income countries. Clearly, continued public sector support for new drug development will be needed, and innovative collaborative relationships between the public and private sectors, which include sharing of costs, will likely be required to sustain and increase private sector interest in tuberculosis. If successful, the payoff could be enormous.

V. Tuberculosis Elimination: An Impossible Dream? Speculation on the future of tuberculosis invariably invokes the question of tuberculosis elimination or eradication. Such speculation is not new. Fifty years ago, under the sponsorship of the National Tuberculosis Association (now the American

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Lung Association) and the U.S. Public Health Service Tuberculosis Program, a group of experts gathered at the Arden House (a conference center in the United States) to discuss the steps required to eliminate tuberculosis in the United States. At that time, only a decade removed from the introduction of effective chemotherapy for tuberculosis, it was felt that “tuberculosis control within the U.S. as a whole (had) progressed to the point where the virtual elimination of the disease as a public health problem appears to be within reach” (47). However, in a prescient note the conferees stated their concern that the “remarkable progress made against tuberculosis since the advent of chemotherapy has mitigated the fear that used to be felt about the disease (and resulted in) some complacency and loss of interest in finishing a task that once was considered extremely urgent.” Their recommendations were succinct, taking only one printed page and calling for community mobilization and federal support to provide maximal application of chemotherapy together with expanded case detection. Little attention was given to the need for new tools, although, given its feeling that BCG had limited usefulness in the United States, “further search for a new vaccine was encouraged” and the group found early reports from field trials of isoniazid treatment of latent TB infection promising. Less than 2 years later, in a paper prepared for the 16th International Congress on Tuberculosis in Toronto in 1961, George Canetti discussed the possibility of the eradication of tuberculosis (48). He concluded that the likelihood was greatly dependent upon the economic status of the country in question, but that for both low-income, high-incidence countries and high-income, low-incidence countries, the priority was chemotherapy of infectious cases. Canetti felt that the major impediment to progress in developed countries was patient noncompliance with therapy as tuberculosis care was decentralized into general medicine. Perhaps foreseeing the need for DOT, he predicted that “a veritable science of prolonged administration of chemotherapy will evolve.” For developing countries, Canetti stated that the major problem was provision of effective chemotherapy “under conditions where everything is unfavourable for it.” These unfavorable conditions have changed little in the last 40 years. Although Canetti felt that BCG vaccine was of use in both developing and developed countries, he cautioned against overemphasizing vaccination in favor of chemotherapy. Like most Europeans, he opposed large-scale “chemoprophylaxis,” stating that “tuberculosis is not such a grave disease that this disadvantage (the anxiety experienced among healthy people taking a drug for a long period of time) can be lightly accepted.” However, he did advocate studies of short-course treatment of latent TB infection for selected high-risk populations. In his musings about the possibility of tuberculosis eradication, he clearly foresaw several impediments, including migration of persons from high- to low-incidence countries and the threat of primary drug resistance. He concluded that eradication was indeed possible in developed countries but that for moving toward global eradication there was only a single absolute priority: “the perfecting of chemotherapeu-

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tic methods adapted to conditions of ‘developing’ countries.” Despite the efforts of such giants as Wallace Fox and Karel Styblo, it took the rest of the world 30 years to see with clarity what Canetti saw in 1961. Subsequently, there were occasional calls for tuberculosis eradication or elimination, and in 1989 the CDC announced its plan to eliminate tuberculosis from the United States by the year 2010 (8). The plan called for more intensified use of currently available control technologies but also recognized the importance of developing new tools and rapidly transferring research results into practice. The basic elements of the plan, which was announced at the same time that tuberculosis was spiraling out of control, were subsequently used to focus activities in a highly successful effort to regain control over the disease. The same year the U.S. elimination plan was announced, a group of international disease control experts were convened by the Carter Center in Atlanta to discuss the possibility of eradication of diseases of global importance (49). Lessons learned during the successful smallpox eradication program and the earlier failures to achieve yaws and malaria eradication provided criteria for assessing the feasibility of eradication of a specific disease or condition (Table 1). Not surprisingly, the group did not consider tuberculosis to be currently eradicable. Although the group did not consider the persistence of the tubercle bacillus in animal reservoirs and the high prevalence of latent infection to be important obstacles to eradication, it did state that more accurate and rapid diagnostic tests, better

Table 1

Criteria for Accessing Eradicability of Diseases and Conditions

Scientific Feasibility Epidemiological vulnerability (e.g., existence of nonhuman reservoir, ease of spread, natural cyclical decline in prevalence, naturally induced immunity, ease of diagnosis, and duration of any relapse potential) Effective, practical intervention available (e.g., vaccine or other primary preventive, curative treatment, and means of eliminating the vector). Ideally, intervention should be effective, safe, inexpensive, long-lasting, and easily deployed. Demonstrated feasibility of elimination (e.g., documented elimination from island or other geographical unit) Political Will/Popular Support Perceived burden of the disease (e.g., extent, deaths, other effects; true burden may not be perceived; the reverse of benefits expected to accrue from eradication; relevance to rich and poor countries) Expected cost of eradication (especially in relation to perceived burden from the disease) Synergy of eradication efforts with other interventions (e.g., potential for added benefits or savings or spinoff effects) Necessity for eradication rather than control Source: Ref. 50.

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case finding in high-risk persons, and the development of a safer and more effective vaccine were needed before tuberculosis eradication would be feasible. More recently, D. A. Henderson, who directed the WHO smallpox eradication program, stated that it is foolhardy to speak of tuberculosis eradication, at least within the next half century (50). He listed six factors essential to a successful disease-eradication program and found notable deficiencies for tuberculosis. The first is political commitment, where great strides have been made for tuberculosis but, as the slow implementation of DOTS indicates, much more must be done. The second is program leadership, where for tuberculosis there are notable successes. The third is a technically sound and feasible plan, which will remain problematic for tuberculosis for some time until we better understand latency and how to deal with it. The fourth is surveillance as a strategy, for which better means of diagnosing both active and latent tuberculosis are clearly required. The fifth is quality control both for therapeutics, where progress is being made in tuberculosis, and for program performance, which is an element of the DOTS strategy. The last is research, which has received increasing support during the past decade but which will require several more decades for the development of the tools, and specifically an effective vaccine, which might make tuberculosis elimination feasible. However, Lee Reichman has argued that it is only the lack of political will that has stymied our attempts to eliminate tuberculosis (51). He faults the “noncompliance” of multiple sectors in failing to deal adequately with a problem that he sees as readily addressable: communities, physician and other health care professionals, drug companies, governments, the press, international development agencies, and even WHO. Reichman makes a valid point: if all interested and influential partners banded together in a concerted effort, we could and would eliminate tuberculosis. How likely is this to happen? We do have the successful model of smallpox eradication and the legacy of failed global eradication campaigns as cautionary guides. In the smallpox effort, all parties did band together. Political will to do so was achieved, even among the cold war opponents. Can this be done for tuberculosis? Perhaps so, but the time is now. Otherwise, the danger that complacency will again set in is great. Tuberculosis will persist; people will forget. Do we want this to be our legacy? References 1. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988–1991. MMWR 1991; 40:585–591. 2. 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.

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3. McKenna MT, McCray E, Jones JL, Onorato IM, Castro KG. The fall after the rise: tuberculosis in the United States, 1991 through 1994. Am J Public Health 1998; 88: 1059–1063. 4. Centers for Disease Control and Prevention. Progress toward the elimination of tuberculosis—United States, 1998. MMWR 1999; 48:732–736. 5. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991; 72:1–6. 6. Styblo K. Overview and epidemiological assessment of the current global tuberculosis situation: with an emphasis on tuberculosis control in developing countries. Bull Inte Union Against Tuberc Lung Dis 1988; 63:39–44. 7. WHO Tuberculosis Programme. Framework for effective tuberculosis control. WHO/TB/94.179. Geneva: World Health Organization, 1994. 8. Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the United States. MMWR 1989; 38(S-3):1–25. 9. Bellamy R, Ruwende C, Corrah T, McAdam KPWJ, Whittle HC, Hill AVS. Variations in the NRAMPI gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998; 338:640–664. 10. Goldfeld AE, Delgado JC, Thim S, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998; 279:226–228. 11. Berthet F-X, Lagranderie M, Gounon P, et al. Attenuation of virulence by disruption of the Mycobacterium tuberculosis erp gene. Science 1998; 282:759–762. 12. Li Z, Kelley C, Collins F, Rouse D, Morris S. Expression of katg in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. J Infect Dis 1998; 177:1030–1035. 13. Schluger NW, Rom W. The host immune response to tuberculosis. Am J Respir Crit Care Med 1998; 157:679–691. 14. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393:537–544. 15. Orme IM. Progress in the development of new vaccines against tuberculosis. Int J Tuberc Lung Dis 1997; 1:95–100. 16. Baldwin SL, D’Souza C, Roberts AD, et al. Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Infect Immun 1998; 66:2951–2959. 17. Crawford JT. New technologies in the diagnosis of tuberculosis. Seminar Respir Infect 1994; 9:62–70. 18. American Thoracic Society. Rapid diagnostic tests for tuberculosis: What is the appropriate use? Am J Respir Crit Care Med 1997; 155:1804–1814. 19. Drobniewski FA, Wilson SM. The rapid diagnosis of isoniazid and rifampicin resistance in Mycobacterium tuberculosis—a molecular story. J Med Microbiol 1998; 47:189–196. 20. Streeton JA, Desem N, Jones SL. Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection. Int J Tuberc Lung Dis 1998; 2:443–450. 21. Chiang IH, Suo J, Bai KJ, et al. Serodiagnosis of tuberculosis. A study comparing three specific mycobacterial antigens. Am J Respir Crit Care Med 1997; 156:906–911. 22. Behr MA, Small PM. Molecular fingerprinting of Mycobacterium tuberculosis: How can it help the clinician? Clin Infect Dis 1997; 25:806–810.

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INDEX

A Abdominal tuberculosis, 355 Absolute concentration method, 173 Acid-fast bacilli microscopic examination of, 161–166, 347 role of in case finding, 95 Acquired resistance, 404 Activism (see Advocacy and social mobilization) Adherence to directly observed therapy, 710 to treatment, 436–438, 757 Adolescents, tuberculosis in, 573 Advisory Council on the Elimination of Tuberculosis (ACET), 869, 877 Advocacy (see also Social mobilization and community leadership) aims and techniques of, 846–850 evaluation of results of, 857 main components of, 854–858 research and training for, 860–862 successful examples of, 850–854 Aerobiology, 216–221 Africa, nongovernmental organizations in, 783 Age and case rates, in the U.S., 145 effect on childhood infection of, 562 effect on tuberculin reaction of, 287 at immigration, and case rates, 670 as risk factor, 134, 136, 141 Air disinfection, 232–234 Alaska, preventive therapy in, 473 Algiers, drug resistance in, 116–118 Alpha antigen, 190

American Lung Association (ALA) founding of, 16, 775–777 mission of, 775–779 American Thoracic Society (ATS) mission of, 776–779 treatment recommendations by, 419 Amikacin, 415, 417, 460 Amniotic fluid, infection of, 562 Amoxicillin-clavulanate, 461 Anergy in HIV-infected persons, 531–533 and preventive therapy, 489, 543 testing, 288 Animal models, in drug activity testing, 170 Anthropology, relevance to public health of, 750–754 Antigens, 188–192 Antituberculosis medications (see also Chemotherapy; individual drugs; Treatment) in children, 579–581 cost comparisons of, 464 drug–drug interactions of, 408–412 first-line, 405–414, 449 fixed-dose combinations of, 413 future development of, 878 research progress in, 870 resistance to, 448–452 second-line, 414–419, 870 Arabinogalactan, 192 Asia, national tuberculosis associations in, 784–787 Auenbrugger, Leopold, 10 Australia, disease among immigrants to, 665–683 Avicenna, 6

885

886

Index B

Bacille Calmette-Guérin (see BCG) BACTEC method, 173, 349 Baku Declaration, 660 Bangladesh national tuberculosis associations in, 785 social mobilization in, 853 BCG vaccination, 37 administration of, 507 adverse reactions to, 512 causing false-positive tuberculin test, 290–292 in children, 576 contraindications to, 507 controlled trials with, 96 effect on nontuberculous mycobacteria of, 512 effect on serial tuberculin testing of, 303–305 efficacy of, 506, 508 for health care providers, 630 history of development of, 503–505 impact of, 513 policies of, 505–508 BCG vaccines causes for variability of, 509–512 future research goals for, 516 improvements upon, 514–516 manufacturers of, 505 Beijing family strain, 268 Biggs, Herman, 19 Biopsy, 351 Bodington, George, 21 Bone and joint tuberculosis, 354 Breastfeeding, 491 British Medical Research Council, regimen developed by, 419 Bronchoalveolar lavage, 350 Bronchoscopy, 350

C Cabrini Hospital, infection-control measures at, 628 Calmette, Albert, 36 Canada, disease among immigrants to, 665–683 Canadian Lung Association, mission of, 779 Canetti, George, 879 Capreomycin, 415, 417

Case finding (see also Contact tracing) and acid-fast bacilli detection, 95 active, 325–328 in children, 560 community leadership in, 325 as control measure, 58, 61 in correctional facilities, 651–653 definition of, 324 detection strategies for, 119–124 determinants of, 95, 123 estimation of new infections by, 123 indicators for, 120 information sources for, 119 information systems for, 109–111 in low-prevalence countries, 90 methods of, 325–332 passive, 328–332 of persons at risk, 326–328 pragmatic approach to, 124 and radiographic examination, 95, 325 results of, 121 by risk factor, 327, 331 and tuberculosis control, 332 use of screening in, 331 user fees for, 834 Case management model, concept of, 600–605 the Newark experience, 599–601 Caseous tuberculous granuloma, 251 Cattle, tuberculosis in, 33 Cavitation, 252 Cell-mediated immunity, 194–199, 249 and HIV–M. tuberculosis interactions, 530 Cell wall, composition of, 159, 192 Centers for Disease Control and Prevention (CDC) guidelines of, 229, 419 training initiatives funded by, 711 Central nervous system tuberculosis in children, 571–573 diagnosis of, 353 Chemoprophylaxis (see also Prevention) early experience with, 40–42, 70 in low-income countries, 57 Chemotherapy (see also Antituberculosis medications; Treatment, or individual drugs) to contain nosocomial spread, 624 experimental, 171 first trials of, 39 prophylactic, 57 relative activities of drugs, 403 results of, 58, 96

Index Children antituberculosis medications for, 579–581 BCG vaccination of, 505, 576 effect of on tuberculin skin testing, 290 case finding in, 131 clinical presentation in, 554 contact tracing in, 387, 390, 560, 585 corticosteroids in, 583 diagnosis in, 356, 574–578 directly observed therapy in, 584 epidemiology in, 555–560 infection in, 559 acquisition of, 134, 137 influence of age on, 562 lymphohematogenous dissemination in, 570 meningitis in, 572 mycobacteriology in, 576 nucleic acid amplification tests in, 577 pathogenesis in, 560–563 pleural effusion in, 569 positive tuberculin reactions among, 132, 298 preventive therapy in, 479 public health programs for, 584–586 radiographic examination of, 563–569 scrofula in, 573 signs and symptoms in, 567 transmission in, 557 treatment in, 578–586 of latent disease, 479, 491 regimens for, 406, 419–421, 581–586 trends of mortality in, 555 tuberculin skin testing in, 290, 293, 575, 585 tuberculosis in of central nervous system, 571–573 chronic, 569 clinical, 563–574 HIV-related, 558, 583 miliary, 571 multidrug-resistant, 583 pericardial, 570 primary, 344, 560 progressive, 561, 568 resurgence of, 553 skeletal, 573 Chronic renal failure, tuberculosis treatment in, 428 Ciprofloxacin, 415, 417, 460 Clarithromycin, 461

887 Clinical laboratories capabilities of at central level, 101 at intermediate level, 102 at peripheral level, 102 comparison of testing strategies in, 359–363 diagnostic tests in, 343–346 of drug susceptibility, 172–175 immunodiagnostic, 175–177 techniques of, 100, 157–178 and DOTS-Plus programs, 463 function of, 99–105 levels or categories of, 101–103 under managed care, 820 quality-control of, 108, 820, 835 safety considerations in, 158 structure and function of, 101–105 Clinical specimens collection and transport of, 160 microscopic examination of, 161, 347 mycobacterial culture of, 162, 348 non-sputum-containing, 161, 359 nucleic acid amplification testing in, 177, 356 speciation of bacteria in, 165 sputum-containing, 160, 358 Clofazimine, 418, 461 Cohort analysis, 111 types of bias in, 112 Collapse therapy, 31–32 Community leadership (see also Social mobilization and advocacy) role in case finding, 325 Computed tomography, 346 Concentration camps, tuberculosis in inmates of, 645 Concentric circle contact follow-up of, 385–388 definition of, 379 Contact, as risk factor, 131, 377 Contacts as case finding sources, 331 data collection of, 380 definition of, 378 field investigation of, 385–388 of HIV-associated infection, 546 latent infection in, 472 medical evaluation of, 388 positive tuberculin reactions among, 298 preventive treatment in, 472, 491 reporting of, 389 transmission risk by, 381–385

888

Index

Contact tracing (see also Case finding) challenges of, 394 for childhood disease, 560, 585 definition of, 378 methods of, 380–391 reasons for, 379 in Singapore, 743 Control building coalitions for, 696–703 and chemotherapy, 58–60 in correctional facilities, 651 early attempts at, 7–9 early concepts of, 13–16 economic considerations in, 804–807, 813 of HIV-associated infection, 544–547 impact of managed care on, 819 impediments to, 843–846 information system requirements for, 109 the Israeli experience at, 759–765 in low-income countries, 60–65, 871–874 in low-prevalence countries, 81–86 of nosocomial transmission, 617–631 objectives of, 55, 604 the Philippine experience at, 693–703 political commitment to, 799–802, 833 projections for, 874–877 strategies for, 108–111 the Thailand experience at, 807–814 through case finding, 58, 61, 332 through directly observed therapy, 598 Correctional facilities case finding in, 651–653 case study from Russia, 657–660 control in, 651 epidemiology of tuberculosis in, 646–648 preventive treatment in, 653 public health programs for, 654 risk factors for inmates of, 648 surveillance in, 653 transmission of tuberculosis in, 648 treatment in, 653 Corticosteroids, in children, 583 Corvisart, Jean Nicolas, 10 Crofton, Sir John, 863 Culture media, 163–165, 348 Cycloserine, 414, 416, 461 Cytolytic T lymphocytes, 250

D Delayed-type hypersensitivity, 215, 249 Delays in diagnosis, 348, 707 patient-related, 89, 328

[Delays] physician-related, 89, 329 in treatment, 328–330 Developed countries (see Low-prevalence countries) Developing countries (see Low-income countries) Diagnosis advances in, 870 chest radiography in, 343–346 in children, 574–578 computed tomography in, 346 of culture-negative disease, 251 delays in, 348, 707 future progress in, 878 history taking and physical examination in, 341–343 of HIV-associated disease, 345, 531–535 laboratory techniques in, 100 of primary tuberculosis, 344 of reactivated disease, 345 in resource-rich countries, 425 role of clinical laboratories in, 99–105 role of tuberculin skin test in, 343 sputum sampling for, 346–348 surveillance of, 89 tests for early development of, 10, 28–31 invasive, 350 routine, 343 user fees for, 834 Directly observed therapy, 40, 437, 448–452 in children, 584 DOTS-Plus, 453–466 in Israel, 762 as key to control, 598 in low-prevalence countries, 91 and managed care, 822–825 in the Netherlands, 781 problems of adherence to, 710 short-course (DOTS), 438, 831–833 advocacy for, 848–850, 859, 862 creating worldwide demand for, 843–846 definition of, 844 future impact of, 871–881 in Singapore, 736, 742 as standard of care, 601–605 DNA fingerprinting (see also Restriction fragment length polymorphism) analysis of, 265 clinical applications of, 266–270 in control programs, 84, 87 and HIV–M. tuberculosis interactions, 530

Index

889

[DNA fingerprinting] for mycobacterial identification, 29, 168, 262 patterns of, 268 Droplet nuclei, 216–219 control of in health care facilities, 625–627 infectious dose of, 225–227 Drug activity testing, 169–175, 403 in animal models, 170 Drug resistance in Algiers, 116–118 causes of, 172 in Korea, 116 in low-income countries, 62, 70 in low-prevalence countries, 88 mutations associated with, 175 strategies against, 116–118 Drugs (see also specific agents) bacterial resistance to, 116–118, 403, 448 in vivo activity assessment of, 170 susceptibility testing of, 172

E Economics DOTS-Plus program costs, 464 health-related concepts of, 802–804 intervention models of, 804–807 and preservation of free TB services, 834 restraints in low-income countries, 69 of Thailand control program, 807–814 Education early public efforts at, 19–21 of health care providers, 707–718, 743 information, education and communication campaigns, 846–850 initiatives by IUATLD, 711–713 Epidemiology administrative, 141–149 among immigrants, 664–675 in children, 555–560 in correctional facilities, 646–648 of drug-resistance in Peru, 456 etiological, 130–141 in Singapore, 730–732 sociocultural, 751–754 Eradication feasibility of, 878–881 The Strategic Plan for the Elimination of Tuberculosis in the United States, 706, 723–725 Ethambutol, 406, 412 Ethionamide, 414, 416, 461

Ethiopia, immigrants to Israel from, 667, 746–748, 757–765 Ethnomedicine, 751–754 Europe incidence rates in, 79 national tuberculosis associations in, 780–782 Exposure duration of as risk factor, 131 intensity of as risk factor, 131 Extrapulmonary tuberculosis abdominal, 355 among immigrants, 672 in children, 570–573 diagnosis of, 351–356 genitourinary, 354 pleural, 345, 352 treatment of, 427

F Fiberoptic bronchoscopy, 350 Fluoroquinolones, 415, 417, 460, 870 Foreign-born (see Immigrants) Fracastorius, Hieronymus, 7

G Galen, 6 Gender, as risk factor, 134, 138, 141 Genitourinary tuberculosis, diagnosis of, 354 Grady Memorial Hospital, infection-control measures at, 628 Granuloma caseous tuberculous, 251 formation of, 194, 252 Greenland, preventive therapy in, 473 Guérin, Camille, 36

H Health care facilities engineering controls in, 625 patient discharge criteria of, 630 tuberculosis transmission in, 610–631 Health care providers (see also Physicians) BCG vaccination for, 630 control measures for, 610, 621–623 education and training of, 705–720, 743, 848 risk of infection among, 614 sociocultural considerations for, 746–750 tuberculin conversions among, 615, 623

890 Health sector reform elements and implications of, 829–831, 838 future trends in, 839 impact on tuberculosis services of, 832 implications of, 873 in Israel, 762–766 need for, 831 in the Netherlands, 82, 85 political commitment to, 833 and quality assurance, 838 and standardization of therapy, 835–837 and treatment outcomes, 837 in the United States, 817–825 Heat-shock protein antigen, 189 Henderson, D. A., 881 HEPA filtration, 232, 625–627 Hepatitis, and isoniazid preventive therapy, 480 High-prevalence countries (see also Lowincome countries) contact tracing in, 389–391 preventing transmission in, 235 High-risk groups, emergence of, 84 Hindu Vedas, 5 Hippocrates, 6 HIV infection anergy testing in, 288, 531–533 mortality with, 526 present status of, 873 preventive therapy in, 484–490, 494, 541–544 as risk factor, 147, 326 in Singapore, 732 transmission in low-prevalence countries, 81 tuberculin skin testing in, 286–289, 531–533 tuberculosis in annual risk of development of, 483 in children, 558, 583 clinical features of, 533–535 control of, 544–547 incidence of, 525–527 influence of, 545–547 multidrug-resistant, 539–541 secondary infection of, 247 treatment of, 430–432, 535–541 HIV–M. tuberculosis interactions, 202 among immigrants, 675 and cell-mediated immunity, 530 in correctional facilities, 649 diagnostic findings in, 345

Index [HIV–M. tuberculosis interactions] in Singapore, 732 and treatment for latent tuberculosis, 482–491 Hospitals (see Health care facilities) Human Immunodeficiency Virus (see HIV infection) Humoral immunity, 199, 255

I Immigrants access to care by, 674 cases of tuberculosis among, 663 clinical patterns of disease in, 672–674 definition of, 662 drug resistance among, 675–677 epidemiology of tuberculosis among, 664–675 Ethiopians in Israel, 667, 747, 757–765 HIV/TB interactions among, 675 impact of in low-prevalence countries, 78–81, 84 influence of age on case rates among, 670 influence of country of origin among, 669, 672 screening strategies among, 678–686 sociocultural differences among, 745–750 as source for case finding, 331 time of diagnosis in host country of, 671 transmission of disease by, 677 treatment and prevention among, 686 treatment outcomes among, 674 Immune responses, 199, 255 Immunity cell-mediated, 194–199 genetic, 246 humoral, 199 and innate host resistance, 243 Immunoregulation, 200–202 Immunosuppression, as risk factor, 139, 146 Incidence in low-prevalence countries, 82 rates in Europe, 79 Index case, definition of, 378 India, national tuberculosis associations in, 785 Indonesia, national tuberculosis associations in, 785 Industrialized countries (see Low-prevalence countries) Infants, infection in, 562, 574

Index Infecting dose, 225–227, 242 Infection causes of, 130–134 in children, 554, 559 impact of HIV transmission on, 81 impact of immigration on, 78 in newborn infants, 562, 574 in patients with HIV, 531–535 predictive value of positive skin test for, 299–303 preventive therapy in, 478 rates in low-prevalence countries, 75–81 and tuberculin conversion, 306–308 Infection-control guidelines of, 709 in health care facilities, 617–629 Information, education and communication campaigns, 846–850 Information systems aims and strategies of, 846–850 for case finding, 109–111 of district registries, 109 of laboratory registries, 103, 109 Innate host resistance, 243 Institutionalization case rates in, 134 as risk factor, 134 Interferon-gamma, 249 International Union Against Tuberculosis and Lung Disease (see IUATLD) Isolation rooms, 625 Isoniazid, 405–408, 460 development of, 39 preventive therapy with, 472–481, 484–491 risk-benefit analysis of, 480 and risk of hepatitis, 480 as single-drug therapy, 61 Israel disease among immigrants to, 667–683 Ethiopian immigrants in, 667, 746–748, 757–765 public health programs in, 759–765 IUATLD collaboration with national NGOs of, 782–786, 790–792 educational initiatives by, 711–713 establishment of, 16, 55 guidelines of, 422–425, 635 mission of, 774, 792–795 model program developed by, 97–99, 109, 832 preventive study conducted by, 478

891 [IUATLD] programs and activities of, 787–792 structure and budget of, 792

J Japan, national tuberculosis associations in, 784 Joint tuberculosis, 354

K Kanamycin, 415, 417, 460 Koch, Robert, 4, 12–13, 33 Koch phenomenon, 187 Korea drug resistance in, 116 national tuberculosis associations in, 785

L Laennec, Rene, 11 Latin America, national tuberculosis associations in, 779 Levofloxacin, 415, 417, 460 Lipoarabinomannan, 192 Liquefaction necrosis, 215, 252–255 Liver disease, tuberculosis treatment in, 428 Loewenstein-Jensen method, 100, 163 Low-income countries (see also Highprevalence countries) childhood disease in, 563 childhood infection rates in, 560 diagnostic work-up in, 425 drug resistance in, 62, 70 economic restraints in, 69 future challenges in, 68, 871–873 health service maintenance in, 69 management strategies in, 65–68 nosocomial transmission in, 616, 631 public health programs in, 60–68 recognizing tuberculosis threat in, 68 redefining strategy in, 62 treatment of latent disease in, 496 treatment regimen options in, 422–425 tuberculosis control in, 60–65 unsuccessful interventions in, 62 Low molecular weight ESAT-6 antigen, 191 Low-prevalence countries case finding in, 90 childhood disease in, 563 contact tracing in, 380–389

892

Index

[Low-prevalence countries] diagnostic work-up in, 425 directly observed treatment in, 91 disease among immigrants to, 664–669 disease transmission in nosocomial, 616 prevention of, 231–234 risk assessment of, 381–385 drug resistance in, 88 framework for control in, 81–86 impact of HIV infection on, 81 impact of immigration on, 78–81 incidence in, 82 management strategies in, 83–85 public health programs in, 86 surveillance in, 86–92 treatment monitoring in, 425 treatment regimens in, 419–421 tuberculosis elimination in, 75–78 Lymphadenitis, diagnosis of, 353 Lymphohematogenous dissemination, in children, 570

M M. tuberculosis antigens of, 188–192 cell wall composition of, 159 DNA fingerprint of, 168 drugs for in vivo activity assessment of, 170 resistance of, 116–118, 403, 448 susceptibility testing of, 172 evolution of, 4 genome elucidation of, 42, 870 growth of, 159 nucleic amplification testing for, 177 physical and chemical characteristics of, 158–160 speciation of, 166 strain genotyping of, 168, 261–270 variability of affecting BCG vaccination, 511 virulence of, as risk factor, 133 Managed care concerns of health officials about, 820–823 contracts and agreements for, 823–825 impact on tuberculosis control of, 819–821 Management strategies in low-income countries, 65–68 in low-prevalence countries, 83–85 for social mobilization, 846–850

Mantoux testing, 35, 282–285, 296 Marten, Benjamin, 9 Mass miniature radiography, 875 Mass preventive therapy, 875–877 Medicaid, and managed care, 819–824 Medical anthropology, relevant concepts of, 750–754 Medicare, and managed care, 819 Meningitis, in children, 572 Mexico, patient-physician interactions in, 756 Mice, natural resistance to infection of, 246 Microepidemics (see Outbreak investigations) Middle East, nongovernmental organizations in, 782 Miliary tuberculosis in children, 571 diagnosis of, 344, 356 Multidrug-resistant disease in children, 583 DOTS-plus regimens for, 453–462 economic assessment of, 804–807 in HIV-infected persons, 539–541 in immigrants, 675–677 impact of DOTS on, 453, 466 nosocomial transmission of, 612, 868 outbreaks of, 235, 456 in Peru, 450, 456–459 in pregnancy, 429 treatment of, 39, 433–435, 540 failures of, 448–552 preventive, 492, 494 principles of, 433–435 surgical, 435 Mycobacteria antigens of, 159 atypical, 166 control of growth of, 249–251 culture of, 348 dissemination of, 248 early concepts of, 29 genetic alterations of, 268 identification and speciation of, 165–168 isolation of in children, 576 nontuberculous (see Nontuberculous mycobacteria) virulence of, 245 Mycobacterial adjuvants, 193 Mycobacterial polysaccharides, 192 Mycobacterial protein antigens, 188–192

Index

893 N

National Tuberculosis Associations, mission of, 775–787 (see also Nongovernmental organizations) National tuberculosis programs (see also Public health programs) basic principles of, 97–99 informational function of, 104, 109 laboratory network structure, 101–105 in the Philippines, 693–703 registry function of, 103, 109 variation in application of, 124 Native-born cases of tuberculosis among, 663 definition of, 662 Naturalistic medical systems, 751 Natural killer cells, 250 The Netherlands annual risk of infection in, 75–78, 87 disease among immigrants to, 665–684 health sector reform in, 82, 85 impact of HIV transmission on, 81 impact of immigration on, 78–81 nongovernmental organizations in, 780 The Newark experience, 599–605 New York City Health Department, model programs of, 17–21 Nongovernmental organizations (NGOs) in Africa, 783 aims and structure of, 772–775 in Asia, 784–787 in Canada, 779 in Europe, 780–782 future tasks of, 795 international partnerships among, 793–795 in Latin America, 779 in the Middle East, 782 role of in advocacy, 862 in Singapore, 736 in the United States, 776–779 Nonnucleoside reverse transcriptase inhibitors (NNRTIs), 430–432 Nontuberculous mycobacteria effect on tuberculin testing of, 303–305 and false-positive tuberculin test, 291–296 identification and speciation of, 166 infection rates with, 148 Norway, nongovernmental organizations in, 782 Nosocomial transmission, 610–631 containing spread of, 624 control of, 617–631

[Nosocomial transmission] in low-income countries, 616, 631 in low-prevalence countries, 616 of multidrug-resistant disease, 612, 868 prevention of, 617–630 in the United States, 610–615 Notification form used in Singapore, 738–741 rates in low-prevalence countries, 88 Nucleic acid amplification tests, 29, 177 in children, 577 costs and operational requirements of, 359–361 diagnostic utility of, 356–358 recommendations for clinical use of, 361–363

O Occupational Safety and Health Administration enforcement policies of, 631–635 mandates of, 626 Ofloxacin, 415, 417, 460 Open lung biopsy, 351 Outbreak investigations, 83, 87, 227, 392 in correctional facilities, 650 within hospitals, 613–616, 627–629 in multidrug-resistant disease, 235, 456 in Peru, 456–459 Outcome monitoring definitions for, 110 and health sector reform, 837 in low-prevalence countries, 90–92 Outcomes analysis of, 111, 113–115 economic assessment of, 802–804 factors affecting, 709

P Para-aminosalicylic acid, 414, 416, 460 treatment failures with, 449 Pathogenesis, 215–217 in children, 560–563 pathways of, 254 stage 1 invasion, 242–248 stage 2 bacillary growth, 248 stage 3 infection control, 249–252 stage 4 reactivation, 252–254 Patient-provider interaction, 604, 753–762

894 Patients activism by, 862 treatment delays caused by, 89, 328 Pediatric tuberculosis (see Children) Percussion and auscultation, early development of, 10 Pericardial tuberculosis in children, 570 diagnosis of, 356 Personalistic medical systems, 751 Peru, multidrug-resistant disease in, 450, 456–459 Phagocytosis, 243–245, 249 The Philippines Coalition Against Tuberculosis (PHILCAT), 696–703 national tuberculosis program in, 694–696 Phrenic nerve crushing, 32 Phthisis, 6–9 Physical examination, 10, 341–343 Physicians (see also Health care providers) knowledge and practice deficiencies of, 708–710 sociocultural awareness of, 753–756 training and education of, 705–720 treatment delays caused by, 89, 329 Pleural effusion, in children, 569 Pleural tuberculosis, 345, 352 Pliny the Elder, 6 Plombage, 32 Pneumoperitoneum, therapeutic, 32 Pneumothorax, therapeutic, 32 Political commitment to control, 799–802, 833 to health sector reform, 833 strategies for mobilization of, 844–863 Polymerase chain reaction, 262, 357, 577 Pott’s disease, 5 Pregnancy, tuberculosis in transmission to fetus of, 562 treatment of, 429, 491, 494 Prevention in anergic patients, 543 in contacts, 472, 491 in correctional facilities, 653 cost-benefit analysis of, 490 feasibility of, 490 in high-prevalence countries, 235 in HIV-infected persons, 541–544 in immunocompetent hosts, 472–481 mass therapy for, 875–877 missed opportunities for, 707 of nosocomial transmission, 617–630

Index [Prevention] projections for, 877 regimens for, 493–496 intermittent, 482 prophylactic, 57, 472–481 short-course, 481 risk-benefit analysis of, 479 Primary resistance, 404 Proportion method, 173 Protease inhibitors, 430–432 interactions with rifamycins of, 412, 538 Psychosocial stress, as risk factor, 149 Public health programs (see also National tuberculosis programs) budgeting mechanisms of, 800–802 and case management, 598 for children, 584–586 in correctional facilities, 654 early efforts at, 16–21 educational initiatives of, 711–713 for immigrants, 678–686 in Israel, 759–765 in low-income countries, 60–68 in low-prevalence countries, 82, 86 maintenance of, 85 and managed care, 822 in the Philippines, 694–696 relevance of social sciences to, 746–757 renewal of, 42 in Singapore, 729–744 the Thailand experience, 807–814 training initiatives of, 713–720 Purified protein derivative administration of, 280–283 development of, 34 Pyrazinamide, 406, 411

Q Quality assurance of clinical laboratories, 108, 820, 835 and health sector reform, 838 in managed care, 821

R Race case rates by, in the United States, 145 as risk factor, 134, 138, 141 Radiographic examination in children, 563–569 diagnostic findings at, 343–346

Index

895

[Radiographic examination] early uses of, 30 in HIV infection, 534 mass miniature radiography, 876 role in case finding of, 95, 325 Reactivation endogenous, 252 treatment after, 427 Reichman, Lee, 881 Renal failure, tuberculosis treatment in, 428 Resistance ratio method, 173 Respiratory masks, 626 Restriction fragment length polymorphism (see also DNA fingerprinting) role of in contact follow-up, 391 Rifabutin, 418, 461 Rifampin, 405–408 fixed-dose combinations with, 413 Rifamycins interactions with protease inhibitors, 412, 538 resistance to, 537 Rifapentine, 418, 461, 870 Risk assessment in contact tracing, 381–388 in health care facilities, 618–622 Risk factors among immigrants, 664–672 contacts as, 377 in correctional facilities, 648 fibrotic lesions as, 328 for infection, 130–135 for reactivation, 140 recent infection as, 327 source case as, 134, 138 susceptibility as, 135, 148 tuberculin sensitivity as, 514 for tuberculosis, 135–140 Riviere, Clive, 29 Roentgen, Wilhelm Konrad, 10, 30 The Royal Netherlands Tuberculosis Association (KNCV), 780–782 Russia, tuberculosis in in penal system, 657–660, 872 rates of, 872

S Sanatoria controversies about, 26–28 establishment of, 21–28 at Saranac Lake, NY, 23–26

Screening studies among immigrants, 678–686, 732 development of, 42 and managed care, 821 in Singapore, 743 Scrofula, in children, 573 Secondary case, definition of, 378 Singapore family health clinics in, 742–744 geopolitics of, 727–729 health care services in, 729 incidence of tuberculosis in, 729–734 national tuberculosis associations in, 785 treatment modalities used in, 732–734 tuberculosis elimination program in, 734–743 notification form of, 738–741 Single-strand conformational polymorphism, 264 Skeletal tuberculosis, in children, 573 Social mobilization (see also Community leadership and advocacy) practical examples of, 858–864 role of, 846–850 strategies and elements of, 850–854 suggestions for, 858–863 use of communication media for, 856 Social sciences basic concepts of, 750–754 relevance to public health of, 746–750 relevant literature of, 754–757 Socioeconomic status case rates by, in the United States, 146 as risk factor, 134, 140, 141 Source case, as risk factor, 134, 138 Sparfloxacin, 415, 417, 460 Species-specific antigenic protein, 189 Spoligotyping, 169, 264 Sputum collection and transport of, 160 diagnostic value of, 358 examination of, 160–168, 346–349, 534 Stop TB initiative, 859, 869 The Strategic Plan for the Elimination of Tuberculosis in the United States, 706, 723–725 Streptomycin, 406, 413 first use of, 38 treatment failure with, 448 Styblo, Karel, 791, 863, 868 Surgery, thoracic, 32, 435

896

Index

Surveillance among immigrants, 678–686 in correctional facilities, 653 in health care facilities, 622 in low-prevalence countries, 86–92 in managed care, 820 Susceptibility innate variation of, 246 as risk factor, 135, 148 testing of, 100, 172

T Tanzania, control strategy in, 63–66 T cells, 194–199 function of, 243–245, 249 Thailand national tuberculosis associations in, 785 tuberculosis control program in, 807–814 The Royal Netherlands Tuberculosis Association (KNCV), 781 Thioacetazone, 406, 413 Thoracic needle aspiration, 350 Thoracic surgery, 32, 435 Thoracoplasty, 32 Tissue liquefaction, 252 Training evaluation of, 715 future directions of, 717 of health care providers, 707–718 methods of, 714–716 objectives of, 715 target audiences for, 714 Transmission in children, 557 in correctional facilities, 648 determinants of, 56 dynamics of, 56 early concepts of, 12–16 epidemiology of, 221–225 by immigrants, 577 mathematical models of, 222–225 nosocomial, 610–631 prevention of, 228, 230–234 probability of, 56 by released prisoners, 649–651, 654 in Russian penal system, 658 sources of, 325–330 surveillance of, 87 from unsuspected sources, 230

Transthoracic fine needle aspiration, 350 Treatment (see also Antituberculosis medications; Chemotherapy) adherence to, 436–438, 757 after relapse, 427 barriers to, 759–762 in children, 578–586 in chronic renal failure, 428 in correctional facilities, 653 in culture-negative disease, 428 delays in, 328–330 DOT and DOTS, 437, 448–452 DOTS-Plus, 453–462 early trials of, 38–40 evaluation of, 113–116 failures of, 426, 448–452 future of, 438 and health sector reform, 835–838 in HIV infection, 430–432, 535–541 intermittent, 404 in multidrug-resistant disease, 39, 433–435, 540 practical recommendations for, 763–765 in pregnancy, 429 preventive, 471 prospective surveys of, 118 regional outcomes of, 113–115 retreatment regimens, 450 in Singapore, 732–734 sociocultural barriers to, 748–750, 755–761 strategies of, 111–119 surgical, 32, 435 theoretical basis for, 402–405 Treatment regimens, 871 causes of failure of, 449–452 for children, 406, 419–421, 581–586 description of, 419–425 in HIV infected persons, 484–490 in HIV-infected persons, 535–540 individualized, 453, 459 for multidrug-resistant organisms, 540 problems of adherence to, 710 short-course evaluation of, 119 failures of, 451 Trudeau, Edward L., 23–25 Trudeau Institute for Research, 23 Trudeau Society, 776 Tuberculin reaction in children, 132, 575 interpretation of, 296–301

Index [Tuberculin reaction] interval from infection, 307–309 predictive value of, 299–301 and preventive treatment, 488 risk analysis with, 302 as risk factor, 139 Tuberculin skin testing, 40, 175, 343 administration of test, 280–283 adverse reactions to, 285 boosting and conversion, 301–308 in children, 575, 585 conclusions about, 310 of contacts, 388 early development of, 33–36 effect of BCG vaccination on, 291 for health care providers, 615, 623 in HIV-infected persons, 531–533 materials for, 281 reading of test, 283–285 results of false-negative, 286–289 false-positive, 290–295 true-positive, 296–299 reversion, 308 role of in diagnosis, 343 technical aspects of, 280–285 Tuberculomas, 344 in children, 572 Tuberculosis adjunctive therapies, 31–33 in cattle, 33 congenital, 562 development of new vaccines against, 514–517 dream of eradication of, 877–881 early appearances of, 3, 4–7, 129 early public education campaigns, 19–21 effect of HIV infection on, 529–531 evolution of public health campaigns, 16–21 extrapulmonary (see Extrapulmonary tuberculosis; specific sites) history of early, 5–7, 11 the past decades, 867–871 16th–18th century, 7–10 19th–20th century, 10–43 in HIV-infected persons, 533–535 immunodiagnostic tests for, 175–177 modeling future course of, 874–877 multidrug-resistant (see Multidrugresistant disease)

897 [Tuberculosis] new research on, 869 present outlook of, 871–874 prevalence of HIV infection among, 528 primary, 344, 555, 560–562 pulmonary symptoms in, 342–346 reactivation of, 345 sociocultural determinants in, 745–750 spread of, 661 stages of development of, 242–254 Tuberculosis control (see Control) Tuberculosis pathogenesis (see Pathogenesis) Tuberculosis prevention (see Prevention) Tuberculosis transmission (see Transmission) Tuberculous lesions, 248 preventive therapy for, 478 Tuberculous lymphadenitis, 353 Tunisia, preventive therapy in, 473

U Ultraviolet irradiation, 232–235, 625 United States case rates in, 142–146 childhood disease in, 556 disease among immigrants to, 665–686 DOTS-Plus program costs in, 464 education and training needs in, 707–720 health sector reform in, 817–825 nosocomial transmission in, 610–615 prisoner-transmitted disease in, 650 The Strategic Plan for the Elimination of Tuberculosis, 706, 723–725 treatment regimen options in, 419–421

V Vaccination (see also BCG) early trials of, 36 future development of, 875–877 shortcomings of, 57 Variable number tandem repeat, 264 Vesalius, 8 Villemin, Jean Antoine, 12 Volunteerism (see Nongovernmental organizations) definition of, 772

W Wells-Riley equation, 223 experimental ward, 220

898 WHO advocating implementation of DOTS, 845, 874 Expert Committee report by, 63–65, 96–99 Global Tuberculosis Programme of, 868 guidelines of, 61–65, 113–116, 635 partnerships with NGOs of, 794 projections by, 874 proposed goals for year 2000, 107

Index [WHO] treatment recommendations by, 422–425, 427 World Bank, loans to low-income countries by, 68 World Health Organization (see WHO)

Z Ziehl-Neelsen sputum smear microscopy, 96, 100, 161