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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 work-
ing 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 per-
son that this vital, remarkable man will be remembered. He approached his lifes 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 col-
leagues.
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 Nether-
lands Tuberculosis Association (KNCV) were extremely important to him as they sup-
ported him in the demonstration, implementation, and propagation of his concept of tuber-
culosis control throughout the world.
Guan-qing Kan was well known in the tuberculosis community especially as Hon-
orary Director of the Beijing Research Institute for Tuberculosis Control, Honorary Pres-
ident of the Chinese Anti-Tuberculosis Association, and Chief Editor of the Bulletin of the
Chinese Anti-Tuberculosis Association. Based on his international experience and
Chinas situation, he put forward Chinas 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
iii
iv 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 Chinas 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 worlds medical science.

L. B. R.
E. S. H.

To the memory of my father, Dr. C. Sheppy Hershfield (19041989), 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 im-
pact of Robert Kochs announcement in 1882 that he had discovered the tubercle
bacillus: To understand the profound effect of Kochs 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 dif-
ficult to believe that anyone could reach adulthood without at least a touch of con-
sumption.
Since 1950, biomedical research and public health concepts have consider-
ably modified our perspective on tuberculosis. Indeed, no one should fail to rec-
ognize 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 suc-
cesses. 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 under-
standing 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 ad-
dress 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 ad-
dress them. At the very least, we should make full use of what we know works.
v
vi 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 ap-

pears only seven years after the debut of the first edition, which was the first text-
book exclusively devoted to tuberculosis in over twenty years. In response, it ex-
hausted three printingsunprecedented for a book devoted solely to tuberculosis.
Because, since the publication of the first edition in 1993, so much more in-
formation 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 re-
versal of the resurgence of tuberculosis in the United States, which was one of the
greatest public health successes of the twentieth century. This reversal under-
scored the observation that political will is the most critical ingredient in tubercu-
losis 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
worlds population remains infected. A very ominous new problem is the vast in-
crease in documented multiple drug resistant tuberculosis (MDRTB), which is al-
ways 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 stan-
dard of care, is not being utilized enough to prevent multidrug resistance. Fur-
thermore, 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 patients individual drug susceptibility profile
known as DOTS-Plusto control the epidemic.
vii
viii 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 worlds
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 co-
ordinating the work. Our production editor, Moraima Suarez, was of great assis-
tance in helping put the work together and carrying it through production. To
Claude Lenfant, Executive Editor of the Lung Biology in Health and Disease se-
ries, 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 re-
spected. 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 flour-
ished. In the long fight against this disease, treatments often evolved from fear and
ignorance. Individuals with tuberculosis were isolated, treated with various po-
tions, 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 eradica-
tion of this disease was possible.
However, the inability of governments to develop appropriate national tu-
berculosis control programs has hindered the fight against this disease. The lack
of patient adherence to prescribed regimens has led to the development of re-
lapses, often with drug-resistant organisms. Finally, the appearance on the world
scene of widespread human immunodeficiency virus infection has increased tu-
berculosis 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 worlds leading au-
thorities on tuberculosis. Their combined knowledge forms the basis of the cur-
rent principles and practices embodied in this volume. We are especially honored
ix
x 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 Produc-
tion Editor, Elaine Grohman, was of great assistance in helping us put the work to-
gether 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 Preven-
tion, 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, Facult de Mdecine Piti-Salptrire, Universit 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 Hop-

kins University, Baltimore, Maryland
xi
xii Contributors

Pierre Chaulet, M.D.* Professor, Faculty of Medicine, University of

Algiers, Algiers, Algeria

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 Epidemiol-

ogy, 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,
UMDMJNew 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,
UMDNJNew 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, Depart-

ment 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, Mas-
sachusetts

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 Trop-

ical 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,

Facult de Mdicine Piti-Salptrire, Universit Pierre et Marie Curie, Paris,
France

Earl S. Hershfield, M.D., B.Sc., F.R.C.P.(C) Professor, Department of Inter-

nal 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 Fran-
cisco, and Associate Dean, San Francisco General Hospital, San Francisco, Cal-
ifornia

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
xiv 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 Cen-
ter for Public Health, UMDNJNew Jersey Medical School, Newark, New Jersey

Richard I. Menzies, M.D., M.Sc., F.R.C.P.(C) Associate Professor, Depart-

ment 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 Tubercu-
losis 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. Muoz, 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, Tuberculo-

sis 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,
UMDNJNew 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 xv

Hospital, and Tuberculosis Control Officer, Massachusetts Department of Public

Health, Boston and Cambridge, Massachusetts

Richard J. OBrien, 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, Amer-

ican Lung Association, New York, New York

Sharon Perry, Ph.D. Staff Research Associate, Department of Medicine, Uni-

versity 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 Monitor-

ing 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.
xvi 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 Tubercu-

losis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia

Jeffrey R. Starke, M.D. Associate Professor, Department of Pediatric Infec-

tious 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 Coordina-

tor, Department of Health, Department for International Development (DFID),
British High Commission, Abuja, Nigeria

Ralph Timperi, M.P.H. Assistant Commissioner, Massachusetts State Labora-

tory Institute, Massachusetts Department of Public Health, Boston, Massachusetts

Chantal Truffot-Pernot, D.Pharm. Assistant, Department of Bacteriology

and Hygiene, Facult de Mdecine Piti-Salptrire, Universit 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, Tubercu-

losis Control Unit, Department of Respiratory Medicine, Tan Tock Seng Hospi-
tal, 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 v

Preface to the Second Edition vii
Preface to the First Edition ix
Contributors xi

Part One PROGRAMMATIC BACKGROUND

1. A Historical Perspective on Tuberculosis and Its Control 3

Anne L. Davis
I. Early Perceptions and Practices 5
II. Concepts from the Renaissance Through the Eighteenth
Century 7
III. Nineteenth- and Twentieth-Century Developments
and Concepts 10
References 43

2. Tuberculosis Control in Low-Income Countries 55

Donald A. Enarson
I. Introduction 55
II. Objectives of Tuberculosis Control 55
III. The Scientific Basis of Intervention 56
IV. Prevention Through Treatment 57
V. Basic Principles of Tuberculosis Control 58
VI. Adaptations for Low-Income Countries 60
VII. Achieving Success in Low-Income Countries 62
VIII. Effective Strategies for the Management of Tuberculosis 65
xvii
xviii Contents

IX. Future Challenges 68

References 71

3. Tuberculosis Control in Low-Prevalence Countries 75

Jaap F. Broekmans
I. The Prospect of Elimination 75
II. Framework for Tuberculosis Control in Low-Prevalence
Countries 81
III. Surveillance 86
IV. Program Monitoring 89
References 92

4. Tuberculosis Laboratories: The Centerpiece of National

Tuberculosis Control Programs 95
Adalbert Laszlo
I. Introduction 95
II. National Tuberculosis Programs 97
III. Tuberculosis Diagnostic Services 99
IV. Tuberculosis Diagnostic Techniques 100
V. The NTP National Tuberculosis Laboratory Network 101
VI. Structure and Function of the National Tuberculosis
Laboratory Network 101
VII. The National Tuberculosis Laboratory Network as a
Source of Data 103
VIII. The National Tuberculosis Laboratory Network as a Source
of Operational and Epidemiological Information 104
IX. Conclusion 104
References 105

5. Evaluation of Applied Strategies of Tuberculosis Control in the

Developing World 107
Pierre Chaulet and Earl S. Hershfield
I. Introduction 107
II. Prerequisites for Evaluating a Tuberculosis-Control
Strategy 108
III. Evaluation of the Strategies Applied in Tuberculosis
Treatment 111
IV. Evaluation of Strategies Applied in the Detection of
Tuberculosis Cases 119
V. Conclusion 124
References 124
Contents xix

Part Two BASIC ASPECTS

6. Epidemiology of Tuberculosis 129

George W. Comstock
I. Introduction 129
II. Etiological Epidemiology 130
III. Administrative Epidemiology 141
IV. Conclusion 149
References 149

7. Bacteriology of Tuberculosis 157

Jacques Grosset, Chantal Truffot-Pernot, and Emmanuelle Cambau
I. Introduction 157
II. Biological Safety 158
III. General Characteristics of Tubercle Bacilli 158
IV. Bacteriology for Diagnosis and Monitoring Treatment
of Tuberculosis 160
V. Strain Typing of M. tuberculosis 168
VI. Drug Activity Against M. tuberculosis 169
VII. Immunodiagnostic Tests for Tuberculosis 175
VIII. Direct Detection of M. tuberculosis by Nucleic
Acid Amplification 177
References 178

8. Immunology of Tuberculosis 187

Thomas M. Daniel, W. Henry Boom, and Jerrold J. Ellner
I. Introduction 187
II. Mycobacterial Protein Antigens 188
III. The Mycobacterial Cell Wall: Mycobacterial Adjuvants
and Mycobacterial Polysaccharides 192
IV. Granuloma Formation 194
V. Cell-Mediated Immunity 194
VI. Humoral Immunity 199
VII. Immune Spectrum and Immunoregulation 200
VIII. HIVM. tuberculosis Interactions 202
IX. Conclusions 203
References 204

9. Transmission of Tuberculosis 215

Edward A. Nardell and Willy F. Piessens
I. Aerobiology of Tuberculosis 217
II. Epidemiology of Transmission 221
xx Contents

III.Infectious Dose for Humans 225

IV. Recent Outbreaks 227
V. Preventing Transmission 228
VI. Governmental Recommendations: An Overview 229
VII. Preventing Transmission from Unsuspected
Cases of Tuberculosis 230
VIII. Engineering Approaches to Preventing Transmission 231
References 236

10. Pathogenesis of Tuberculosis 241

Willy F. Piessens and Edward A. Nardell
I. Introduction 241
II. Stage 1 (Week 1): Invasion 242
III. Stage 2 (Weeks 2 and 3): Logarithmic Bacillary Growth
and the Early Tuberculous Lesion 248
IV. Stage 3 (After Week 3): Infection Control 249
V. Stage 4 (Months to Years Later): Endogenous
Reactivation and Transmission 252
VI. Clinical Correlates of Immune Events in Human
Tuberculosis 254
VII. Conclusion 255
References 255

11. Mycobacterial Strain Genotyping 261

Nancy D. Connell and Barry N. Kreiswirth
I. Introduction 261
II. Methodologies 262
III. Interpreting Genotypes 265
IV. International Applications of Molecular Fingerprinting 267
V. Implications for Basic Research 269
VI. Clinical Applications of Molecular Fingerprinting 270
References 270

Part Three CLINICAL ASPECTS

12. Tuberculin Skin Testing 279

Richard I. Menzies
I. Introduction 279
II. Technical Aspects 280
Contents xxi

III. Simple Cognitive Aspects: False-Negative and

False-Positive Reactions 285
IV. Complicated Cognitive Aspects: Interpreting
Tuberculin Tests 296
V. Conclusions 310
References 311

13. Case Finding in High- and Low-Prevalence Countries 323

Hans L. Rieder
I. Introduction 323
II. Sources of Transmission and Other Cases 324
III. Identification of Sources of Transmission 325
IV. Factors Modifying the Choice of Case-Finding Methods 331
V. The Role of Case Finding in Tuberculosis Control 332
VI. Conclusions 333
References 334

14. Diagnosis of Tuberculosis 341

Philip A. LoBue, Sharon Perry, and Antonino Catanzaro
I.Introduction 341
II.Medical History and Physical Examination 341
III.Routine Laboratory Tests 343
IV. The Tuberculin Skin Test 343
V. Diagnostic Tests: Pulmonary Disease 343
VI. Extrapulmonary Tuberculosis 351
VII. Pediatric Tuberculosis 356
VIII.Developments in Rapid Diagnosis: Nucleic Acid
Amplification Tests 356
X. Summary 363
References 363

15. Contact Follow-Up in High- and Low-Prevalence Countries 377

Sue C. Etkind and Jaap Veen
I. Introduction 377
II. Definitions 378
III. Need for Contact Tracing 379
IV. Contact Tracing in Low-Prevalence Countries 380
V. Contact Tracing in High-Prevalence Countries 389
VI. New Technology: The Role of Restriction Fragment Length
Polymorphism Testing 391
xxii Contents

VII. Challenges and Unanswered Questions 394

VIII. Summary 395
References 396

16. Treatment of Tuberculosis 401

Paula I. Fujiwara, Patricia M. Simone, and Sonal S. Munsiff
I. Introduction 401
II. History of Tuberculosis Treatment in the Chemotherapeutic
Era 402
III. Antituberculosis Medications 405
IV. Standard Antituberculosis Treatment Regimens in the
United States 415
V. Antituberculosis Treatment Regimens in Resource-Poor
Countries 418
VI. Methods Used to Diagnose Tuberculosis and Monitor
Treatment 420
VII. Special Clinical Situations 423
VIII. Adherence to Treatment 432
IX. The Future of Treatment 435
References 436

17. Responding to Outbreaks of Multidrug-Resistant Tuberculosis:

Introducing DOTS-Plus 447
Paul E. Farmer, Jim Yong Kim, Carole D. Mitnick, and
Ralph Timperi
I.Introduction: Strengths and Limitations of DOTS 447
II.What Is DOTS-Plus? 453
III.Making DOTS-Plus Work: A Case Study 455
IV. Pitfalls in the Planning and Execution of DOTS-Plus
Programs 462
V. Conclusions: DOTS-Plus, We Cant Afford Not to Try It 466
References 466

18. Treatment of Latent Tuberculosis Infection 471

David L. Cohn and Wafaa M. El-Sadr
I. Introduction 471
II. Treatment of Latent Tuberculosis Infection in
Immunocompetent Hosts 472
III. New Regimens for Treatment of Latent Tuberculosis
Infection 481
Contents xxiii

IV. Treatment of Latent Tuberculosis Infection in

HIV-Infected Persons 482
V. Treatment of Latent Tuberculosis Infection in Special
Populations 491
VI. Development of Disease Due to Resistant Organisms 492
VII. Recommendations for Treatment of Latent
Tuberculosis Infection 493
VIII. Conclusions and Future Directions 496
References 497

19. BCG Vaccines and Vaccination 503

Paul E. M. Fine
I. Introduction 503
II. Historical Background 503
III. BCG Vaccines 505
IV. Current BCG Policies 505
V. The Protective Efficacy of BCG 508
VI. Protection Against Diseases Other Than Tuberculosis 512
VII. Adverse Reactions 512
VIII. The Impact of BCG Vaccination Programs 513
IX. Improving Upon BCG 514
X. Immediate Prospects for Vaccination Against
Tuberculosis 516
References 518

Part Four SPECIAL PROBLEMS

20. Tuberculosis and Human Immunodeficiency Virus Infection 525

Philip C. Hopewell and Richard E. Chaisson
I. Risk of Tuberculosis in Persons with HIV Infection 525
II. Prevalence of HIV Infection Among Patients
with Tuberculosis 528
III. Influence of HIV Infection on the Pathogenesis
of Tuberculosis 529
IV. Diagnosis of Tuberculosis Infection and Tuberculosis 531
V. Treatment 535
VI. Tuberculosis Caused by Multidrug-Resistant Organisms 539
VII. Prevention 541
VIII. Infection Control 544
IX. Influence of Tuberculosis on the Course of HIV Infection 545
xxiv Contents

X. Necessary Changes in Approaches to Tuberculosis

Control 545
References 547

21. Tuberculosis in Children 553

Flor M. Muoz and Jeffrey R. Starke
I. Introduction 553
II. Epidemiology 555
III. Pathogenesis 560
IV. Clinical Forms of Tuberculosis 563
V. Diagnosis of Tuberculosis in Children 574
VI. Treatment 578
References 586

22. Case Management: The Key to a Successful

Tuberculosis-Control Program 597
Bonita T. Mangura and Karen E. Galanowsky
I. Introduction 597
II. Directly Observed Therapy 598
III. Clinical Care and Public Health 598
IV. The Newark Experience 599
V. The Nurse Case-Management Model 600
VI. Tuberculosis Therapy by Directly Observed Therapy 601
VII. Incremental Service Delivery Change and DOT 602
VIII. The Interaction: Patient and Health Care Provider 604
IX. Impact on TB Control 604
References 605

Part Five UNIQUE ASPECTS OF TUBERCULOSIS CONTROL

23. Tuberculosis Infection Control 609

Henry M. Blumberg
I. Introduction and Historical Overview 609
II. Trends in Nosocomial Transmission of Tuberculosis 610
III. Institutional Controls in the United States and Other
Developed Countries 617
IV. Hospital Discharge Planning and Standards 630
V. OSHA Requirements for a Tuberculosis-Control Program 631
VI. Institutional Controls in Developing Countries and Areas
with Very Limited Resources 631
References 636
Contents xxv

24. Tuberculosis in Correctional Facilities 645

Naomi N. Bock
I.Introduction 645
II.Epidemiology of Tuberculosis in Correctional Facilities 646
III.Transmission of Tuberculosis in Correctional Facilities 648
IV. Risk Factors for Tuberculosis Among Inmates in
Correctional Facilities 648
V. Correctional Facility Tuberculosis and the Community
at Large 649
VI. Controlling Tuberculosis in Correctional Facilities 651
References 654

25. Tuberculosis Among Immigrants 661

Mona Saraiya and Nancy J. Binkin
I. Introduction 661
II. History of Migration of TB 661
III. Definitions 662
IV. Epidemiology of TB Among Foreign-Born Persons 664
V. Drug Resistance 675
VI. Contribution of Immigration to Transmission of TB in
Low-Prevalence Countries 677
VII. Approaches to TB in the Foreign-Born 678
References 687

26. Coalition Building for Tuberculosis Control: The Philippine

Experience 693
Camilo C. Roa, Jr., and Rodrigo L. C. Romulo
I. Coordinating Tuberculosis-Control Efforts: The Need
for Coalitions 693
II. TB Interest Groups 694
III. Rallying Around a Common Goal 696
IV. The Philippine Coalition Against Tuberculosis 696
V. Formalizing and Expanding 697
VI. Generating Resources 697
VII. The Birth of PHILCAT 698
VIII. Pushing Onwards 698
IX. Developing a Unified Strategy: Identifying More
Stakeholders 700
X. National Consensus on Tuberculosis 702
XI. Coalition Activities: Achieve Objectives and Maintain
Member Enthusiasm 702
xxvi Contents

XII. Summary 703

References 703

27. Tuberculosis Education 705

Eileen C. Napolitano and Elizabeth J. Stoller
I. Introduction 705
II. Evidence of the Need for Training and Education for
Providers 707
III. Current Training Initiatives 711
IV. Health-Care Providers in Need of Education and Training 713
V. Methods 714
VI. Future Directions for Training 717
VII. Topics for Further Discussion 718
References 720

28. Political Will: The Singapore Tuberculosis Elimination

Program 727
Cynthia Bin-Eng Chee and Yee-Tang Wang
I. Singapore: An Island City-State 727
II. Tuberculosis in Singapore 729
III. Rationale for the Singapore Tuberculosis Elimination
Program 734
IV. Organizational Structure of STEP 735
V. Key Factors for the Success of STEP 736
VI. Conclusion 739
References 740

29. Medical Anthropology: An Important Adjunct to International

TB Control 745
Daniel Chemtob, Sheri Weiser, Israel Yitzhak, and
Daniel Weiler-Ravell
I. Introduction 745
II. The Relevance of Social Science to Public Health 746
III. Some Basic Concepts in Social Science 750
IV. Some Key Perspectives in the Social Science Literature
on TB 754
V. An Anthropological Study of TB Among Ethiopian
Immigrants in Israel 757
VI. The Contribution of Social Science to the New National
Program for the Elimination of TB in Israel 762
VII. Conclusion 765
References 766
Contents xxvii

30. The Role of Nongovernmental Organizations 771

Annik Rouillon, Nils Eric Billo, and Frances R. Ogasawara
I. Introduction 771
II. National Tuberculosis Associations 775
III. The International Union Against Tuberculosis and
Lung Disease 787
IV. Present Trends: Irreplaceable Partners 793
V. Summary 795
References 795

31. Economic Considerations for Tuberculosis Control 799

Holger Sawert
I. Political Commitment and Economic Arguments 799
II. Economic Analysis: Basic Concepts 802
III. Specific Points for the Analysis of Tuberculosis Control
Interventions 804
IV. Example: Improving Tuberculosis Control in Thailand 807
References 814

32. The Impact of Managed Care on Tuberculosis Control in the

United States 817
Bess Miller and Sara Rosenbaum
I. Introduction 817
II. Tuberculosis Control in the United States: Current
Organizational Structure 818
III. The Advent of Managed Care and Its Impact on
TB Control 819
IV. Concerns of TB Health Officials About Managed Care 820
V. Response of TB Health Officials to the Advent of
Managed Care 821
VI. Role of Contracts and Memoranda of Agreement 823
VII. Conclusion 825
References 825

33. The Impact of Health Sector Reform on Tuberculosis Control

in Developing Nations 829
Elizabeth Tayler
I. Introduction 829
II. Why Health Sector Reform Is Needed 831
III. Impact of Health Sector Reform Upon TB Services 832
IV. Political Commitment 833
xxviii Contents

V. Case Finding and Diagnosis 834

VI. Standardized Short-Course Regimen and Supervision of
Therapy 835
VII. Drug Supply 837
VIII. Recording and Reporting 837
IX. Conclusions 838
References 840

34. Mobilizing Society Against Tuberculosis: Creating and

Sustaining Demand for DOTS in High-Burden Countries 843
Kraig Klaudt
I. Assessment of the Current Response to the Global TB
Epidemic 843
II. The Role of Information, Education, and Communication,
Advocacy, and Social Mobilization 846
III. The C.A.U.S.E. Strategy for Mobilizing Society 850
IV. The Main Components of Advocacy 854
V. Potential Initiatives to Help Mobilize Society to
Control TB 858
VI. Conclusion 863
References 863

Part Six THE FUTURE

35. Tuberculosis in the Future 867

Richard J. OBrien and Mario C. Raviglione
I. Tuberculosis in the 1990s: Reasons to Be Hopeful 867
II. Problems Looming at the End of the Twentieth Century 871
III. TB in the New Millennium: Clues from Modelers 874
IV. The Promise of New Technologies 877
V. Tuberculosis Elimination: An Impossible Dream? 878
References 881

Index 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 (13), 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 worlds 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 in-
dolent 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 con-
stellation of elusive illnesses of hypothetical etiologies to its final recognition as
a single disease caused by a specific microorganism, it has challenged the imag-
ination 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 en-
countered 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 re-
3
4 Davis

strictive laws (811) and raised legal ethical issues as recently as the 1990s
(1216).
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 (13,17,18). When primitive agricultural practices permitted
permanent settlements, cattle, swine, and sheep became domesticated and often
shared the familys dwelling space, making the spread between animals and hu-
mans 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 immunologi-
cal properties suggest that they are subspecies (20) and that M. tuberculosis
evolved through genetic mutations from M. bovis in humans after the domestica-
tion 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 (2125). The distribution of infection and severity of the disease have var-
ied with the time period and geographic location (3,2631). The epidemiology has
been imperfectly hypothesized from the spotty data available before the develop-
ment 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 sev-
eral thousand or more years, the chronology of its devastating impact in the dif-
ferent populations of the world has yielded differing theories explaining the ob-
served phenomena (1,3234). In addition to exposure to infected cattle, their milk,
and milk products (1,17,18,3437), human herd immunity (38) and migration
and immigration patterns, industrialization, poverty, poor nutrition, overcrowd-
ing, unhealthy lifestyle changes, and concomitant disease [e.g., human immuno-
deficiency 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 ac-
celeration 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 twenti-
eth century provided more accurate ways of detecting the disease, generated vig-
orous public health campaigns, introduced new treatment and prevention strate-
gies, and renewed hope that tuberculosis could be prevented and even cured.
Clinical and laboratory investigations burgeoned and have provided the back-
ground for the present application of sophisticated new tools to the persistent chal-
lenges retarding the conquest of tuberculosis into the next century.
This chapter can only hint at the rich history of this ancient disease and high-
light a few of the events and trendsparticularly in the nineteenth and twentieth
History of Tuberculosis 5

centuriesthat 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 ex-
cretions, were used therapeutically. Sometimes certain stones or colors (red, es-
pecially) were considered beneficial. The sun, moon, and stars were also believed
to influence health. Transference of disease to another object or animal was prac-
ticed (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 (26,4042). 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, arte-
facts, 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 Potts disease (39,4447).
Data from written sources, although scarce, also tend to support the hy-
pothesis 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 cen-
tury when the unity of the disease was established. It was known as phthisis
(wasting disease) or consumption as well as scrofula (the cervical swellings re-
sembling cows udders), lupus vulgaris, lung hemorrhage, chronic diarrhea, and
hectic fever.
The Hindus alluded to consumption. Some historians believe that descrip-
tions of consumption passed orally from generation to generation long before the
Vedas were written (26,39). Hindu drugs were known to the Egyptians, who de-
rived 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 recom-
mended 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
6 Davis

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 de-
tailed descriptions of the cardinal symptomsage, incidence, and prognosis
(18,43,49). The careful observations and interest in scientific inquiry by Hip-
pocrates and his followers removed medicine from the realms of religion and phi-
losophy and began to replace superstition with common sense.
At the end of this era, Rome and subsequently Byzantium assumed impor-
tance, 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 (130200 A.D.), a Greek emigr to Rome, became authoritative in
medicine for about the next 1400 years (43,50). The prior interest in keen obser-
vation 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 al-
most solely on careful observations of the patient. Limited attempts at physical ex-
amination were made. References to rles and to succussion have been found in
the Hippocratic Collection (18,43,49). Human dissection was not permitted, ex-
cept 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 patients 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 ear-
lier times as well as the old Hindu remedies. Bloodletting and cupping were also
employed. Pliny the Elder (2379 A.D.) commented that sea voyages were desir-
able especially for hemoptysis (39), and some specific therapeutic concoctions
such as wolfs liver boiled in wine or boiled crocodile for chronic cough were
History of Tuberculosis 7

mentioned. Later the Kings 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 (318272 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 re-
vived. At last anatomical and pathological studies began to provide a basis for un-
derstanding 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. Fracastoriuss
description in his book, De Contagione, in 1546 of three methods of infection
direct contact, fomites, and airand his postulation of the existence of semi-
naria, 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 orig-
inal 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 af-
fected 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 ster-
ilization, which went unheeded for the next 300 years. In the initial stage of treat-
ment, 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-
8 Davis

berculosis is more than a simple infectious disease and that its effective control re-
quires combat on many fronts (27,5457).
During the seventeenth century the contagious nature of tuberculosis was
accepted and dreaded throughout much of Europe, but by the latter half of the cen-
tury 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 imper-
iled by objects remaining after death of a person infected with the disease of
phthisis (58). Disinfection measures were promptly instituted, including replas-
tering the entire house by the authorities, decontamination or burning of house-
hold goods, and removal of the poor sick to a hospital (59). Furthermore physi-
cians 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 gener-
ally agreed that there was a sharp increase in cases of consumption in Britain
and then throughout western Europe during the 1600s, especially in the over-
crowded cities. Following Luccas attempts at record-keeping, compulsory no-
tification was introduced by Ferdinand VI in Spain and in Naples. Parish regis-
ters 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 con-
trol contagion, and for a while the latters 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 con-
tributed to the demise of these early public health efforts (52,58,59). These argu-
ments 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 (15141564) had established the principal of dissecton

and corrected Galens errors, correlation of post-mortem examination with clini-
cal 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
History of Tuberculosis 9

(14971558), who had stated that these occurred frequently in consumptive pa-
tients (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) (16141672), 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 (16211675) 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 (17411770), 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 Martins amazing book A New Theory of
Consumption, More Especially of Phthisis or Consumption of the Lungs, written
in 1719, 26 years after Leeuwenhoeks opening of a new world of microscopical
vistas. It was remarkable in its anticipation of the germ theory proposed and vali-
dated more than 100 years later. He believed that consumption was not only con-
tagious, but that this infection was possibly due to some certain Species of Ani-
macula 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 under-
stood (51,52,62).
Marten also commented on the liklihood of tuberculosis contagion: by ha-
bitual 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 ap-
peared.
By the end of the eighteenth century, tuberculosis was rampant: early at-
tempts 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.
10 Davis

III. Nineteenth- and Twentieth-Century Developments

and Concepts

The observations and investigations of the next hundred years would establish the
fact that the diverse clinical and pathological manifestations were indeed one dis-
ease, 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 in-
terest in expanding techniques for eliciting physical signs of anatomical patho-
logical 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 innkeepers 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 exper-
imented (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 In-
terni Pectoris Morvos Detegendi, published in 1761.
It took another half century for medical clinicians to recognize the value of
Auenbruggers approach to diagnosis. Only when Jean Nicholas Corvisart, Pro-
fessor of Medicine at the College of France, discovered the work in 1797, trans-
lated and published the original text, and practiced the method did percussion be-
gin 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 an-
cient Greeks, was not practical in obese patients or women or when hospital ver-
min were common (39). He constructed a simple instrument to obviate these ob-
stacles and first published his observations in 1819 in his Traite de
lAuscultation Mediate. The stethoscope was at first ridiculed as a mere me-
chanical toy, and critics considered it ludicrous that a physician would proudly
listen through a long tube applied to the patients 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 Roentgens discovery of x-rays later in
the century. Even with todays more sophisticated tools, percussion and auscula-
tion have not yet been discarded.
History of Tuberculosis 11

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 autopsiesmany
of them on patients he had known at the bedsidehe described phthisis on the ba-
sis 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 Bayles 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 desig-
nate tuberculous excavations (43,51).
Although Stark and Bayle had imperfect glimpses of tuberculosis as possi-
bly 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. Laennecs 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 tu-
bercle 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 in-
fection in children (and subsequently recognized at any age) and supported the
theory that most tuberculosis is acquired by inhalation. The pathogenesis of gen-
eralized tuberculosis was demonstrated by Carl Weigert in 1882, and the mecha-
nisms 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-
12 Davis

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 con-
cerning 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 in-
fection (66). Discussion continues today as molecular techniques suggest that ex-
ogenous reinfection occurs more frequently than was previously believed
(6769), 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 An-
toine Villemans astute observations. Working with military horses, he had ob-
served 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 re-
sult 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 spu-
tum 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 dis-
ease 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 Villemans significant contribution, many in France and England
continued to challenge it, claiming that he was just producing a foreign body re-
action. 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. Experi-
menting within the new science of bacteriology, Koch developed a method of
plate cultivation, which by permitting separation of colonies made possible isola-
tion 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). Kochs postulates and his precise experi-
ments to prove them have served as a model for infectious disease investigators
ever since.
Even though Kochs demonstrations seem indisputable now, there were at
the time still skeptics who clung to their preconceived notions or unproven hy-
History of Tuberculosis 13

potheses. At Kochs momentous presentation before the Physiological Society in

Berlin, the audience looked to Virchow for comment. His silence was cutting. Vir-
chow persisted to the end of his life in claiming that scrofula and pulmonary ph-
thisis 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 evi-
dence that the bovine bacillus is responsible for most tuberculosis in cattle, a vital
step in the subsequent eradication of tuberculosis from bovine herds and conse-
quently 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 re-
covered from pulmonary secretions. Nocard, a French veterinarian, did this by
grasping a cows tongue and swabbing the throatwhen the cow coughed, he
tried to catch the secretions. Ravenel more cleverly constructed a hood, which he
put over the cows nose and mouth. At the bottom was a wooden platform upon
which the cows coughed-up secretions would fall. He then collected and exam-
ined them for the tubercle bacillus (65).
Although contagiousness of tuberculosis had long been suspected, consid-
erable 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 transmissi-
bility 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 Kochs announcement. Osler temporarily perpetuated the idea using
silkworm infestation as an example, saying that even the silkworm egg can be in-
vaded by a parasite, thus providing hereditary transmission. This notion was grad-
ually eroded and finally discounted in Cornets statement that the tubercle bacil-
lus 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 cer-
tain control measures (Fig. 1). Cornet, among others, was a proponent of the dust
14 Davis
History of Tuberculosis 15

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 tuberculo-
sis 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 mate-
rial emanating from the patients cough or by swabbing the floor. Inoculation of
animals with such collected material produced tuberculosis (65). It was later con-
firmed 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 Cornets work was so persuasive that the environment was contami-
nated 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 pa-
tient had died, the walls might be swept down with soft bread if they were white-
washed 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 under-
standing of transmission by droplet nuclei was demonstrated by Wells (79,80) and
further elucidated by Richard Riley (81). Wells exposed animals to various con-
centrations 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 organ-
isms usually died off. Droplet nuclei produced by a single cough in Loudons and
Roberts experiments remained suspended in the air after 30 minutes (82). Such
droplets could be readily inhaled and if they reached an alveolus could initiate pri-
mary 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.)
16 Davis

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 in-
fected droplet nuclei from entering the air, diluting their numbers by adequate
number of air exchanges, preventing dissemination by maintaining negative pres-
sure in the contaminated space relative to the adjoining areas, using devices to fil-
ter or sterilize the air leaving the room, and preventing persons entering the in-
fectious patients room from inhaling infected particles by using particulate
respirators (8789).

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 Villemans 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 Aus-
tria, 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 Penn-
sylvania Society for Prevention of Tuberculosis (90). He wanted to disseminate
the idea of the communicability of tuberculosis and to stop its spread using edu-
cation, 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 Ameri-
can Lung Association, was thus born in 1904 (90,91). By 1914, with the collabo-
ration of its many grass-root affiliates, it had become a powerful force in the cru-
sade 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 tubercu-
losis 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
History of Tuberculosis 17

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. Atten-
tion 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 offi-
cials, 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 antitu-
berculosis association was formed in Shanghai (42). In Korea the first tuberculo-
sis 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 im-
portance of not losing employees. Such motives may have hastened the institution
of preventive measures in South Africa in the early twentieth century as the alarm-
ing 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 publics health as they came in contact with middle and upper class per-
sons as their servants, repairmen, or in other capacities. During the recent resur-
gence of tuberculosis in New York City this threat resurfaced, caught the medias
attention and thus the publics, and undoubtedly stimulated the rapid action of leg-
islators 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 nine-
teenth and even the twentieth century in North America and England, despite
Kochs 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).
18 Davis

Figure 2. Tenement visit by visiting nurse in 1924. The nurse/social worker was an es-
sential link in the antituberculosis campaign, educating families about tuberculosis, expec-
toration, 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 subse-
quent 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 Hospi-
tal 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 cul-
tures and beliefs. New waves of immigrants and refugees in the latter part of the
twentieth century stimulated similar sentiments in some areas, and many immi-
grants do not seek health care for sociocultural, economic, or other reasons, in-
cluding 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 be-
come firmly established among physicians, the question of an adequate campaign
History of Tuberculosis 19

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 or-
ganized system for the control of tuberculosis. In 1887, just 5 years after Kochs
announcement, Phillip opened the first tuberculosis dispensary in the world. It be-
came the nucleus of the Edinburgh Anti-tuberculosis Scheme (37,43). Phillips
dispensary was unique in its organization not only for the treatment of tuberculo-
sis, 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 Ger-
many the sanatorium movement preceded any generally organized antituberculo-
sis effort (98). Phillips 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 antitu-
berculosis structures (99,100) (Fig. 3).
In the United States state health departments began to broaden their man-
dates 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 docu-
ment asserted the validity of Kochs 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 re-
port 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 ac-
cepted 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 physicians request.
20 Davis

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 iden-
tification 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 hos-
pital 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 Cour-
tesy 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.
History of Tuberculosis 21

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 Ameri-
can 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 mu-
nicipal 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 reinsti-
tute the lessons of the past has been painful and costly. The importance of con-
tinuous 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 pre-
venting miasmas, the rise of the Public Health Movement stimulated by the atro-
cious sanitary conditions related to increasing urbanization, and the socioeco-
nomic 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-
22 Davis

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 Rokitanskys 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 exer-
cise 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 disin-
fection system to allay their fears. In addition he added chemistry and bacteriol-
ogy laboratories and an observatory to monitor the meteorological conditions be-
lieved so important to the patients. The sanatorium flourished. By the time of
Brehmers 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 pa-
tients (112).
Brehmers 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 ed-
ucation, rest with graduated exercise only as tolerated without fatigue, and open-
air 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 Spenglers establishment of a sanatorium in Davos (114) initiated a
multiplicity of institutionsincluding Rolliers for heliotherapyhotels, and
History of Tuberculosis 23

boarding houses, which transformed Switzerland into a major health resort and in-
spired Thomas Manns novel The Magic Mountain (107).
In the United States the perception of beneficial effects of altitude and cli-
mate 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 him-
self developed a cold abscess during medical school, but the true nature of his ill-
ness 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 Smiths hunting lodge in the Adiron-
dack 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. Trudeaus 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 con-
struction 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 Kochs work became known separate cottages
seemed plausible as a strategy to minimize transmission.
When Trudeau first obtained an English translation of Kochs 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 Kochs paper, a few lessons from Dr. Prudden in New York, and his own inge-
nuity, 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 cul-
tures, and throughout his life he supplied cultures without charge to other scien-
tists (115). He repeated Kochs experiments and was then able to test for the bacil-
lus in patients 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 Trudeaus death from tuberculosis, the new Trudeau Institute for Re-
24 Davis

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 grand-
son, Francis B. Trudeau, Jr., and many devoted friends. Its contributions to the un-
derstanding 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).
Trudeaus 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 educat-
ing the public as to the safety and value of sanatorium treatment (phthisiophobia
was prevalent in some communities) (117), his influence began to spread. He par-
ticipated in the medical and public health activities going on and evolving around
him in 1904, became the first president of the newly organized National Associa-
tion for the Study and Prevention of Tuberculosis (now the American Lung Asso-
ciation), and later president of the Congress of American Physicians and Surgeons
(107).
His protegs 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 scien-
tific and philosophical issues; Esmond R. Long, a pathologist who later headed the
Henry Phipps Institute in Philadelphia and contributed in collaboration with Flo-
rence Siebert to the additional understanding of immunological aspects of tuber-
culin; and James Alexander Miller, founder of the prestigious Bellevue Hospital
Tuberculosis Service in New York City (now the Chest Service) (107).
Trudeaus epitaphGuerir quelquefois, soulanger souvent, consoler tou-
joursis not only a tribute to the man, but exemplifies the caring spirit of
Trudeaus treatment center. From its simple beginning, it developed into a tu-
berculosis university (118), which included not only the Saranac laboratory for
the study of tuberculosis, but a nursess 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 tuberculo-
sis (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-
History of Tuberculosis 25

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. Fed-
eral 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 com-
ponents 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 dis-
ease 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 repre-
sented 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 en-
vironment 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. Mortal-
ity had already been declining (37,121,122), and improved living conditions, nu-
trition, and economics may have played a role (121,122). The lagging decline in
new case rates, however, despite growing availability of sanatorium beds and de-
clining 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 be-
cause 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).
26 Davis

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 19141920. 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 gen-
eral 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
History of Tuberculosis 27

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 orga-
nized efforts at case finding, isolation of active cases, and emphasis on follow-up
were initiated, and collapse therapies and surgical procedures were added to sana-
torium 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.)
28 Davis

Figure 6. Men enjoying occupational therapy or vocational rehabilitation. These activi-

ties, 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 medi-
cally supervised sheltered environment might reduce relapses. Also, unfortunately, even af-
ter 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 clin-
ical 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 compari-
son to the physical signs (132). Relevant even today in the AIDS era is Rivieres
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-
History of Tuberculosis 29

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 dis-
ease 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 iden-
tified 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 con-
cerned, 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). Rivieres 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 dis-
ease and outbreak patterns and aided in the understanding of transmission and
spread of resistant organisms in the community (21,68) and laboratory cross-con-
tamination (141). Their usefulness and validity in the management of patients,
however, is still being debated and evaluated (141143).
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 Kochs discovery, detection of disease continued to depend pri-
marily on symptoms or physical findings and only seldom on radiographic tech-
30 Davis

niques. When Konrad Roentgen discovered x-rays in 1895, their value in diagno-
sis was, like many previous innovations, received with caution or ridicule. A Lon-
don firm allegedly advertised the sale of x-rayproof 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 find-
ings, performed fluoroscopic examinations on more than 100 patients with pul-
monary tuberculosis and reported correspondence between physical signs and x-
ray examination in a considerable number, but in some the disease was more
extensive than the physical examination indicated. In others, x-ray detected in-
creased 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 reputa-
tions, 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 pul-
monary 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, fre-
quently recognized by roentgenological examination in adults who presented with
tuberculosis but with few or no symptoms or typical apical crackles (65). World-
wide interest in the significance of this early infitrate stimulated many investiga-
tions through the 1940s. Medlar (144) and other eminent pathologists studied post-
mortem material from accident victims and those dying unexpectedly of unknown
causes. The early lesions were shown to be small areas of exudative bronchopneu-
monic 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 mate-
rial. Hope of discovering this early infiltrate in order to detect the disease at its ear-
liest stages to prevent spread prompted the mass x-ray surveys so popular in the
midtwentieth century (65). Even when x-ray screening was abandoned in the
1970s as case rates dropped, radiological examination of patients admitted to hos-
pitals 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-
History of Tuberculosis 31

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 fea-
sible. In such cases sputum smear has been used to detect disease, and when possible tu-
berculin testing has been used to detect distribution and prevalence of infection and to iden-
tify candidates for BCG vaccination. (Photograph Courtesy of the American Lung
Association, New York.)

cent changes in the epidemiology of tuberculosis, the prevalence of impaired im-

mune 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

Roentgens discovery to see cavities during life spurred interest in mechanical
methods of treating tuberculosis. Traction on the walls of cavities from elastic re-
32 Davis

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 col-
lapse 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 Jacobeuss invention of the thorascope in 1911 and his thorascopic cau-
terization of adhesions (intrapleural pneumonolysis), which often prevented ef-
fective 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 (150152) and was best in patients with unilateral disease not respond-
ing to rest alone, although there were heated debates about the indications. Com-
plications included mild serofibrinous pleurisy in about 8090% of patients,
chronic pleural changes leading to trapped lung in some, empyema occasion-
ally, 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 oc-
casionally used in intestinal and peritoneal tuberculosis, and in 1933 Vadja re-
ported possible benefit in patients with pulmonary tuberculosis. About 50% of pa-
tients 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 ap-
plied the procedure to collapse a tuberculous cavity. John Alexander refined the
technique and wrote the first of his famous textbooks at Trudeaus 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 oc-
casionally achieved by introduction of oil, paraffin, or plastic spheres into an ex-
traperiosteal pocket (plombage thoracoplasy) in an attempt to minimize defor-
mity and pulmonary function impairment. Thoracoplasy could achieve cavity
closure and sputum conversion in as many as 80% of selected patients. With col-
lapse therapy mortality rates ranged from 14 to 27% after 120 years, but with-
out 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
History of Tuberculosis 33

sanatorium stays, serious impairment of pulmonary function, and increased mor-

tality (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 success-
fully 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 mor-
bidity from such procedures was 50% or more and mortality 2040% (153). In the
1950s with chemotherapy, resection for localized disease was rather common un-
til 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 animals 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 Kochs work (71,154). Koch later pre-
pared a sterile filtrate of cultured organisms, subsequently termed old tuberculin
(OT), and found that the same Koch phenomenon occurred. Kochs great mis-
take 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). Kochs 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 diag-
nostic agent (156).
Veterinarians were the first to recognize and demonstrate the potential di-
agnostic 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 Kochs 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 dis-
ease 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 cat-
tle industry and the serious threat of bovine tuberculosis to the publics health
prompted establishment of a national program to eliminate tuberculosis in cattle.
34 Davis

The positive tuberculin reaction rate in cattle approached 5% in 1918. Systematic

testing was instituted, along with prompt disposal of infected cattle, adequate dis-
infection, and regulations governing movement of animals. Pasturization of milk
assured further protection for humans (17,36,37). By 1974 tuberculin reactor rates
were 00.03% in the United States (18). Various control measures have been used
in other countries, where infection rates have been as high as 7090%, with
3040% having disease on slaughter (18). Eradication of bovine tuberculosis
worldwide requires continued vigilence, public and legislative support, and ade-
quate availability of veterinarians.
Von Pirquet first demonstrated that reactions to OT in humans could be in-
duced by cutaneous injection and that a response was indicative of prior tubercu-
lous 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 infec-
tion, 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 re-
garding the specificity of the test because some cattle reacted to tuberculin but had
no signs of tuberculosis infection at post-mortem examination. Although varia-
tions 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 tu-
berculin 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 Kochs OT became apparent. The
development of a purified protein derivative (PPD), which was a potent stable tu-
berculin 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 sulfateprecipitated 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) ori-
gin (161,162).
History of Tuberculosis 35

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 Furcolows 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 tu-
berculosis and not place of residence, while with 250 TU the frequency of reac-
tions 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 geo-
graphic 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 626 mm induration (peak 1415 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-re-
actions to tuberculin because of sensitization to other microorganisms was con-
sidered 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 412 mm of induration and false-positive reactions to PPD-S appear
to be related to prevalence of certain nontuberculous mycobacteria in the envi-
ronment (166169).
In the 1960s false-negative results in bacteriologically proven cases of tu-
berculosis 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 inter-
pretation 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 un-
dergoing 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-
36 Davis

Cordick in 1929 (175) challenged this view and Wilson later showed that animals
could be made tuberculin negative without losing their immunity (176).
Kochs initial investigations of tuberculin have spawned numerous ques-
tions and further studies. Tuberculin testing has enhanced knowledge about dis-
tribution 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 Mackanesss
work at the Saranac Laboratory began to elucidate the interaction between cell-
mediated immune response and macrophage activation (178). Host and my-
cobacterial 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 un-
derstanding 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 ex-
plored (184).

J. Vaccine Development

Ever since Kochs 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
Gurin, a veterinary school graduate and associate of Calmette, were working
with a virulent bovine type tubercle bacillus previously isolated from a heifers
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 mi-
croorganism 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 new-
born 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
History of Tuberculosis 37

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 Calmette-
Gurin (BCG) for vaccination of humans and animals, but the deaths of 72 and in-
fection of 135 of 250 children orally vaccinated in Lbeck, Germany, in
19291930 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 Lbeck 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 ef-
fected testing of almost 30 million persons and vaccination of 14 million. After
mid-1951 this work was continued and expanded under joint WHO/UNICEF aus-
pices. 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 pos-
sible reasons for the differences have been discussed by others (189193). The
methodological aspects have also been evaluated (188,194196).
BCG vaccine trials have provided some of the best and most complete in-
formation 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 vac-
cines. The 1949 international campaign was the first large-scale centralized pub-
lic 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 cell-
mediated 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 in-
vestigations of immunostimulation in neoplasia, especially in the therapy of blad-
der cancer.
Attempts to develop better vaccines with novel molecular genetic ap-
proaches are accelerating and will be discussed elsewhere.
38 Davis

K. Drug-Therapy Trials

A search for an effective therapy began almost immediately after the causative
bacillus was identified. Kochs tuberculin had failed, but Ehrlichs magic bullet
for syphilis stimulated interest in other chemical agents for tuberculosis. A num-
ber of these had been tried in animals and some in selected human patients. Am-
bersons clinical trial of gold in 1931 is historically important in that randomiza-
tion 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 Ambersons meticulously detailed critique of previously reported
clinical studies.
A number of trials of sulfanilamide and other related compounds were per-
formed in the late 1930s and early 1940s in experimental animals and humans
with some favorable results, but often with significant associated toxicity (199).
Waksmans Nobel Prizewinning isolation of streptomycin in 1944 to-
gether with Schatzs crucial astute laboratory observations (200) and Feldmans
and Hinshaws first clinical application ushered in the momentous era of modern
chemotherapy of tuberculosis (43,201). Within 12 months of its announced isola-
tion, William Feldman, professor of comparative pathology at the Mayo Founda-
tion of Experimental Medicine, and H. Corwin Hinshaw, a bacteriologist and sub-
sequent consultant physician at the Mayo Clinic, together demonstrated
unequivocably streptomycins 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 (202204) with liasons with
the American Trudeau Society, the Mayo Clinic group, and Walsh McDermotts
group studying toxicity at Cornell University Medical College. Details are sum-
marized 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 pul-
monary and extrapulmonary tuberculosis in humans. Rapid development of drug
resistance and some toxicity became early concerns, however. Although Max Pin-
ner had commented, in relation to evaluation of chemotherapy that the therapeu-
tic effects of a truly efficacious chemotherapeutic agent are not likely to depend for
proof on elaborate control series (205), the British Medical Research Council de-
cided that studies using their precious allocation of streptomycin should be rigor-
ously 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 clin-
ical trial (207). Many attempts to prevent or delay bacterial resistance by varying
dosage, duration, or frequency of medication were, however, to no avail.
History of Tuberculosis 39

The second important landmark in understanding chemotherapy of tubercu-

losis 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. tu-
berculosis, 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 regimensPAS
alone, streptomycin alone, and the combination of streptomycin and PASre-
ported in 1949 and 1950 (209) demonstrated unequivocably the reduction in risk
of developing streptomycin resistance when both were used and broadened the po-
tential application of such treatment.
Nevertheless, chemotherapy was not yet accepted as definitive therapy ex-
cept 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 ad-
ditional clinical trials were carried out with various combinations, dosages, fre-
quencies of administration, and durations of these initial three drugs and others as
they became available in the 1950s and 1960s. By the 1970s experience had dic-
tated 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 VAArmed 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 in-
valuable information to guide therapy today.
Information gained from these trials revolutionized the treatment of tuber-
culosis 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 al-
ways mean drug failure (199). Bed rest and sanatorium care did not add to the ben-
efits 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
40 Davis

without disease, as recommended by an expert group convened at Arden House

by the American Lung Association (105). Ambulatory domiciliary care was fea-
sible, 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 ob-
served 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 resis-
tance became alarmingly apparent in the late 1980s and early 1990s.

L. Chemoprophylaxis

Once isoniazid, an effective, inexpensive oral medication with relatively low tox-
icity, was available, its usefulness in preventing tuberculosis was considered, es-
pecially 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 se-
lected populations and was therefore preferred over BCG vaccination as a pre-
ventive strategy. BCG was not consistently shown to be effective except in pre-
venting serious complications such as miliary tuberculosis and meningitis in
children, and it has not been widely embraced in the United States, to the conster-
nation 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 chemoprophy-
laxis (217). In view of the competing risks of tuberculosis and isoniazid-associ-
ated hepatitis (218), lack of recent data from controlled trials, the possibility of
drug-resistant infection, and the problems of distinguishing initial infection, ex-
ogenous superinfection, long-standing infection, and in some cases latent versus
active disease, the recommendations regarding indications and choice of prophy-
lactic therapeutic regimen continually change (219223).
While during the sanatorium era and beyond much attention was focused on
practical therapies for tuberculosis, fortunately basic research was carried out si-
multaneously 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-
History of Tuberculosis 41

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 ambula-
tory 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 out-
patient setting is now a major control strategy of WHO. (Photograph Courtesy of the Amer-
ican Lung Association, New York.)
42 Davis

sium on the nature of the tubercle bacillus and the reactions of the host tissues.
Arnold Richs prophetic remarks regarding the importance of fundamental re-
search 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 per-
manent 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 re-
lied 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 knowl-
edge 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 ani-
mals, improved cell culture techniques, development of specific monoclonal anti-
bodies, and methods of isolating and identifying genes and gene products are
among many tools facilitating research into the fundamental aspects of tuberculo-
sis. 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 humanitys long struggle against this captain of the men of
death.
Despite the many advances in our understanding and ability to detect, diag-
nose, treat, and prevent tuberculosis and despite repeated admonitions of tubercu-
losis 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 tu-
berculosis 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 in-
fectious persons, and prompt appropriate treatment to completion under directly
observed therapyeven in locked facilities, if necessarybecame important is-
sues. 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 prophylac-
tic treatment were issued. The race for faster methods of diagnosis, a more reliable
History of Tuberculosis 43

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.

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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 1549 years (1) and has
been declared a global emergency. Anyone today may become infected with tu-
berculosis simply by breathing the air in a space through which a tuberculosis pa-
tient 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
56 Enarson

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 unreal-
istic objective. Nevertheless, it may be a reasonable one because of the ineffi-
ciency of the dynamics of tuberculosis (2). Beyond this are the strategic implica-
tions 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 conta-
gious 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 es-
sential to interventions for its control; transmission of the causative microorgan-
ism 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 microor-
ganism enters the environment as an aerosol, a susceptible individual is exposed,
becomes infected, and may subsequently develop disease, which may be conta-
gious, thus passing the organism to others. The individual remains contagious for
a limited period of time, during which transmission may occur. This period is lim-
ited either by the death of the individual or the suppression of growth of the mi-
croorganism 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 dis-
ease, (3) from disease to exposure.

B. Determinants

Key determinants in the transition from exposure to infection are the concentra-
tion of microorganisms in the environment, the degree of susceptibility of the ex-
posed, 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 num-
bers of bacteria in the lung and their access to the airways. The stages in the trans-
mission 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
Tuberculosis Control in Low-Income Countries 57

probabilities of transition in the absence of the intervention) is essential to evalu-

ate 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 tran-
sition from infection to disease in this setting is less than 15%. Finally, the prob-
ability 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 objec-
tive.
A strategy for elimination needs to take account of the fact that Mycobac-
terium 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 devel-
oping 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 tu-
berculosis 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 fre-
quent schedule of administration (shortly after birth) prevents those forms of tu-
berculosis 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 devel-
oped 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 strat-
egy cumbersome to apply at a population level.
58 Enarson

C. Evidence for Case Management as an Effective

Preventive Tool

The possibility that chemotherapy could permanently cure a patient with tubercu-
losis 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 chemother-
apy 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 expo-
sure to the case was not different in the two groups.
The ability of chemotherapy of tuberculosis cases to arrest infection of suc-
ceeding 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 in-
fection 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 exten-
sive application of preventive chemotherapy.

V. Basic Principles of Tuberculosis Control

A. Results of Chemotherapy
Chemotherapy of tuberculosis was associated with an immediate and dramatic ef-
fect 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 fol-
lowing 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 pro-
portions of the general population was performed in the belief that such active
Tuberculosis Control in Low-Income Countries 59

Figure 1. Trend in mortality from tuberculosis in Norway, 19251970, in relation to the

introduction of chemotherapy. (Adapted from Ref. 59.)

measures would remove the infectious cases from the community and prevent fur-
ther 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 fur-
ther 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 occa-
sions) where they had not been diagnosed.
An international, multicenter evaluation of the ability of tuberculosis spe-
cialists 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 com-
munity 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).
60 Enarson

Figure 2. Impact of chemotherapy on prevalence of infectious cases, incidence of in-

fectious 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 pa-
tients using a standardized multidrug regimen under the supervision of a special-
ist, case detection based on examination of individuals presenting themselves to
the general health services with symptoms compatible with tuberculosis, bacteri-
ological 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-
Tuberculosis Control in Low-Income Countries 61

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 eas-
iest 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 sup-
ported by the World Health Organization (WHO) undertaken in the Kolin district
of Czechoslovakia, a broad program of research was undertaken, primarily in In-
dia (20), which provided a scientific basis for discussion. A number of modifica-
tions were proposed.
One of the earliest modifications was the use of isoniazid alone in the treat-
ment 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 devel-
opment 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, inte-
grated within the existing health services, and within the reach of the resources
available. As a consequence of these recommendations, most governments insti-
tuted a national tuberculosis program.
62 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 tu-
berculosis were reported to WHO (26). The number of notified cases of tubercu-
losis 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 underesti-
mated the real number of cases that existed and that, instead of declining, the num-
ber of cases may actually have been increasing (27).
Far from being successful, the interventions were shown to have been con-
tributing to a worsening of the tuberculosis situation (28), an analysis initially pre-
sented 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 bring-
ing the problem under some semblance of control, the ineffective treatment of the
cases was actually making the epidemiological situation far worse than if the pa-
tients 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 al-
ready 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 popula-
tion for health following the successful examples of services in China and of spe-
cific projects in India and Indonesia. It was felt that, when such services were es-
tablished, 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-in-

come 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
Tuberculosis Control in Low-Income Countries 63

and isoniazid for 11 months, with an emphasis on the successful treatment of

newly diagnosed cases, a separate treatment regimen for patients failing to re-
spond 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 tubercu-
lous meningitis virtually disappeared, and subsequent evaluation of tuberculin re-
activity in a cohort of unvaccinated children showed that transmission of tubercu-
losis 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-tu-
berculosis Association to a Meeting on the National Tuberculosis Control Pro-
gram, 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 establish-
ment 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 des-

ignated health worker responsible to ensure that policies are followed,
with support from both an intermediate and central level in order to en-
sure 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 pa-
tients, procedures for bacteriological monitoring of the results of treat-
ment, case finding focusing on microscopic examination of sputum spec-
imens from patients presenting with symptoms to the routine health
services, and vaccination with BCG as part of the expanded program on
immunization.
64 Enarson

Routine evaluation, monitoring activities, and their results using standard-

ized instruments for recording and reporting as an integral part of the rou-
tine activities of the program.
An in-built program of research as an essential component of the activi-
ties 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 medi-
cal 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 dis-
appointing: success in treatment, at the outset just over 30% of sputum smearpos-
itive 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 thioaceta-
zone daily. This was administered under very careful supervision, requiring pa-
tients to be admitted to the hospital for direct observation of swallowing of medi-
cations 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
smearpositive 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 pa-
tients 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 de-
cline 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 1824
months after introduction of the revised strategy (36). Patients treated in the pro-
Tuberculosis Control in Low-Income Countries 65

gram pointed out that the community, at the outset, did not believe that tubercu-
losis 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 demon-
strated to the patients, their families, and the community that individuals were im-
proving and being permanently cured. This factor was determinative in the in-
creasing proportion of patients who followed their treatment to completion. The
health education provided by patient-to-patient interaction was much more pow-
erful 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 pa-
tients was undertaken (37). Among patients never previously treated, the propor-
tion of cases resistant to isoniazid was low (
10%) and did not change over the
three decades evaluated; resistance to both isoniazid and rifampicin (multidrug re-
sistance) 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 di-
rectly 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 com-
mitment of the government to health care as a priority, the centralized organiza-
tion 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 low-
income 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
66 Enarson

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 pro-
grams 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 con-
taining 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 $160217 with hospitalization and
$139196 for ambulatory treatment. The conclusion of this evaluation was that
chemotherapy for sputum smearpositive 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 tu-
berculosis was estimated to cost $13 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 re-
view 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 tuberculo-
sis who had never previously received chemotherapy had been evaluated in col-
laborative 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 con-
taining rifampicin.
The conditions necessary for achieving success in these programs were:
1. Political commitment on the part of government, reflected by the es-
tablishment of an adequate structure. This included a designated man-
ager within the district (serving, on average, 100,000 population), an in-
Tuberculosis Control in Low-Income Countries 67

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.
2. 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.
3. 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 cen-
ter was located at the same site as the district manager.
4. Proper recording and reporting of cases, using a standard set of
forms and registers: the numbers of cases newly diagnosed and the re-
sults 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. Adequate supervision of drug taking during the initial intensive
phase, consisting of observing the swallowing of every dose of medi-
cation during the period in which rifampicin was being administered.
2. 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.
3. 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 collab-
oration 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 procure-
ment with international tender and competitive bidding.
68 Enarson

C. The Importance of Action Beyond Medication

While these results were encouraging, they were not sufficient to stimulate an ad-
equate 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 com-
mitment. The first, and probably most important, was the recognition in the pop-
ular 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 pri-
ority, 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 IU-
ATLD 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 in-
dispensible to the extension of tuberculosis services in low-income countries. The
declaration of a global emergency raised the visibility of tuberculosis in the vari-
ous regions where the disease is particularly frequent. The acceptance of the the-
sis 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 Orga-
nization 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 iden-
tifies 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?
Tuberculosis Control in Low-Income Countries 69

To date there is no incontrovertible evidence that the strategy has dramati-

cally 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 ex-
pected, the prevalence has declined more rapidly than the rate of newly diagnosed
cases. Other indirect evidence comes from Nicaragua (51), where the case-notifi-
cation 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 de-
clined. 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 in-
creasing 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 gener-
ation 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 work-
ers, peripheralized decision making, and encouraged privatization of health ser-
vices. The usual structure of tuberculosis services in the successful models may
require revision. This is particularly true where the numbers of cases of tubercu-
losis are rapidly rising and accessibility to services is already compromised in
consequence. Whether cost-effective tuberculosis services can be provided by the
70 Enarson

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 isoni-
azid 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 ad-
ministration 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 isoni-
azid (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 fol-
lowed (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 min-
imized. 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.
Tuberculosis Control in Low-Income Countries 71

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56. Chonde TM. The role of bacteriological services in the National Tuberculosis and
Leprosy Programme in Tanzania. Bull Int Union Tuberc 1989; 64:3739.
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 19951997. Int J Tuber Lung Dis 1997; 5(suppl.):S28.
58. Rodier G, Gravier P, Sevre J-P, Binson G, Omar CS. Multidrug-resistant tuberculo-
sis in the horn of Africa. J Infect Dis 1993; 168:523524.
59. Bjartveit K. The tuberculosis situation in Norway. Scand J Respir Dis 1978,
102:2835.
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 worlds major public health challenges, causing
more than 2 million (mostly young) adult deaths per year. The scale of the prob-
lem is such that in 1993 the World Health Organization (WHO) was forced to de-
clare tuberculosis a global emergency. This somber picture hides the overall
success of tuberculosis-control efforts in most of the industrialized countries. Af-
ter 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 45% per year between
the two world wars, and with the introduction of modern chemotherapy this de-
cline 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 My-
cobacterium 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 Annual risk of tuberculous infection: the Netherlands, 19101979. (From Ref.
1a.)

Figure 2 Annual risks of tuberculous infection and incidence of new active tuberculosis
in subjects aged 014, 1519, 2024, and 2529 years, the Netherlands, 19521970. (From
Refs. 1b,2.)
Tuberculosis Control in Low-Prevalence Countries 77

Figure 3 Estimated prevalence of tuberculous infection prevalence by age, the Nether-

lands, 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 19731976 to 19931995 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 con-
sidered to be in the elimination phase of the disease. However, elimination in low-
78 Broekmans

Table 1 Average Annual Notification Rates of Bacteriologically Confirmed

Pulmonary Tuberculosis (New Cases Only, Foreigners Excluded) per 100,000
Population, The Netherlands, 19731996

19731976a 19771980a 19811984a 19931996b

(P/100,000) (P/100,000) (P/100,000) (P/100,000)

Male 4.9 3.9 3.5 2.6

Female 2.6 2.4 2.0 1.6
All 3.7 3.2 2.7 2.1
a
Source: Ref. 3a.
b
Source: Ref. 4.

prevalence countries, given the extent of the underlying high prevalence of infec-
tion in older age groups, will take at least another 3050 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,

19731984 and 19931996. (From Ref. 4.)
 Tuberculosis Control in Low-Prevalence Countries

Figure 5 Incidence rate of notified tuberculosis, 1995, WHO European region. (From Ref. 11.)
79
80 Broekmans

Figure 6 Notified tuberculosis cases (all forms), the Netherlands, 19741996. (From
Ref. 4.)

in 19931995 involving all infectious pulmonary cases, it has been concluded that
(1) 17% of native Dutch cases can be attributed to recent transmission from a for-
eign source, (2) 15% of native Dutch cases can be attributed to recent transmis-
sion from a native Dutch source, and (3) 68% of cases had a unique DNA finger-
print (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.

Tuberculosis Control in Low-Prevalence Countries 81

In addition to the excess transmission from foreign sources, native cases in

low-prevalence countries occur due to infection acquired during travel in high-
prevalence countries. For example, it is reported that 61 (2%) of 3070 Dutch cases
reported in 19931996 most likely were due to infection acquired outside the
Netherlands (4).
An extremely rare situation occurred in 19931997 in the Netherlands,
when a single infectious source from outside the country caused at least 400 in-
fections and more than 50 bacteriologically confirmed secondary cases. This on-
going cluster epidemic, which could only be studied with DNA fingerprint tech-
nology, is characterized by an unusually long patients and doctors delay in
diagnosing the source case, which was a rather asymptomatic illness (5). The ini-
tial patients 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 preva-
lence of infection in the indigenous population, however, such migration at cur-
rent 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-preva-

lence countries will depend on the overlap between the prevalence of tubercu-
lous 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 in-
fection. The prevalence of tuberculous infection for those aged 1554 yearsthe
age group most vulnerable for HIV transmissionwas 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 19931996 116 (4.1%) of 2885 Dutch and 146 (4.3%) of 3411 foreign tu-
berculosis patients were reported to be HIV positive (4). However, because HIV
testing is not encouraged, these data are not representative, and the precise inter-
action between the HIV epidemic and the tuberculosis situation in the Netherlands
is not well documented.

II. Framework for Tuberculosis Control in Low-

Prevalence 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 ex-
ists for low-prevalence countries. The decline in disease incidence, the health sec-
82 Broekmans

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 dis-
ease. At programmatic level a categorical tuberculosis network becomes unsus-
tainable and for this reason needs to be integrated with other public health pro-
grams (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 dis-
ease departments of the Municipal Health Services in the early 1990s, 80 multi-
functional public health nurses (instead of 40 previously assigned to tuberculosis
cases only) became responsible for approximately the same number of tuberculo-
sis patients.

B. Consequences of the Health Sector Reform

Most industrialized countries experienced health sector reforms resulting in a de-

centralization 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 decentral-
ized funding (from an earmarked national subsidy to a nonearmarked, multipur-
pose municipal grant) and responsibilities for the tuberculosis program manage-
ment to 45 administratively autonomous Municipal Health Services.

Figure 8 Consequences of the decline of disease incidence.

Tuberculosis Control in Low-Prevalence Countries 83

Figure 9 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 out-
break 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 be-
comes a discernible epidemiological event. Microepidemics require a highly spe-
cialized 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 pa-
tient and/or doctors delay. A specific institutional environment (e.g., dis-
cotheque, school, or prison) may facilitate transmission to a multitude of contacts
(see Chap. 15).

Figure 10 Consequences of shift towards outbreak management.

84 Broekmans

Emergence of High-Risk Groups

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 tubercu-
losis. Identifiable high-risk groups thus become accessible for active case finding.
In the Netherlands a high-risk group is characterized by a registered tuber-
culosis 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
19931996 (Table 2) (7).

Introduction of DNA Fingerprint Technology

DNA fingerprint technology may revolutionize tuberculosis control in low-preva-
lence 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,

19931996

Asylum seekers Tuberculosis cases on entry

Examined Total All cases Infectious PTB

Year N % N N p/100,000 N p/100,000

1993 31,578 (90%) 35,000 137 434 46 146

1994 42,939 (95%) 45,202 149 347 61 142
1995 24,424 (97%) 25,089 94 385 40 164
1996 17,919 (90%) 19,868 52 290 26 145
Source: Ref. 7.
Tuberculosis Control in Low-Prevalence Countries 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 manage-
ment is still limited, but its potential in identifying outbreaks in special settings,
only suspected to occur in earlier decades, makes it potentially an extremely pow-
erful new tool in tuberculosis control in low-prevalence countries. The great chal-
lenge to program management will be to demonstrate the specific role of this tech-
nology 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 consti-
tutes 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 unmis-
takable shift toward outbreak management require urgent reassessment as to
maintain an adequate tuberculosis network during the elimination phase of the dis-
ease (Fig. 11).
In the Netherlands the national support and coordination functions were re-
examined 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.
86 Broekmans

Table 3 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
19561965, 10.4% in 19661979, and 8.3% in 19791991 (Fig. 12). It is esti-
mated that the annual rate of infection in the Netherlands was less than 10 per
100,000 in the mid-1990s.
Tuberculosis Control in Low-Prevalence Countries 87

Figure 12 Prevalence of tuberculous infection and annual risk of tuberculous infection,

the Netherlands, 19561991. (From ITSC/TSRU, unpublished.)

B. Surveillance of Recent Transmission

Introduction of DNA fingerprint technology in control programs in low-preva-

lence 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, 19911997

Number of cases
with identical DNA Notification Cluster
fingerprint from of first growth Nature of cluster
January 1, 1991 source case in 1997 (proportion attributed)

66 July 1991 11 Homeless/Drug abusers (77%)

55 March 1993 10 Related to foreign source (92%)
50 July 1993 6 Homeless/Drug abusers (60%)
41 December 1992 13 Asylum seekers (Ethiopia/
Somalia) (95%)
Source: Ref. 8.
88 Broekmans

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, sig-
nificant intracountry differences exist in the trend and level of notification. Resur-
gent tuberculosis in central Harlem in New York City was attributed to the effects
of HIV transmission, homelessness, and the premature disintegration of the tu-
berculosis 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 2535 (all cases) per 100,000 in major
metropolitan areas to 510 (all cases) per 100,000 in more rural areas.

Notification Rates for Infectious Pulmonary Tuberculosis

Notification rates of infectious pulmonary tuberculosis provide a sensitive mea-
sure for the occurrence of sources of infections in the population and its trend to-
wards elimination (Table 1 and Fig. 4).

Surveillance of Drug Resistance

Systematic surveillance of initial drug resistance in new cases and acquired resis-
tance in retreatment cases may be of importance for both epidemiological surveil-
lance as well as a measure of program performance.
A special study concluded that in the Netherlands three quarters of all drug-
resistant cases occur in foreign-born persons (9). The great majority of these pa-
tients 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, 19931995

Asylum seekers, Other foreigners, Dutch

N  351 N  786 N  1089
(%) (%) (%)

Isoniazid 14 8 3
Streptomycin 14 9 3
Rifampicin 3 2 1
Other anti-TB drugs 4 1 1
Any drug resistance 22 15 6
Source: Ref. 4.
Tuberculosis Control in Low-Prevalence Countries 89

study it was observed that in Dutch patients both acquired and primary drug re-
sistance were rare. The high mean age of Dutch patients with drug-resistant tu-
berculosis suggests that this level of drug resistance mostly reflects program per-
formance of a more distant past (9).

D. Surveillance of Mortality

In low-prevalence countries, mortality rates are of only historical value in indi-

cating 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 stud-
ies, suggest an increased patient and doctor delay for Dutch patients. This obser-
vation 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 foreign-
ers 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, 19731996

19931996b 19931996b
19731976a 19771980a 19811984a Dutch Foreigners

Months N % N % N % N % N %

12 1346 53 1136 52 996 54 326 44 455 56

34 713 28 601 27 469 26 203 27 187 23
5 or more 468 19 450 21 374 20 217 29 165 20
Total 2527 100 2187 100 1839 100 746 100 807 100
No 78 3 52 2 77 4 142 16 156 16
information
a
Source: Ref. 3a.
b
Source: Ref. 4.
90 Broekmans

Table 7 Mode of Detection, The Netherlands, 19931996

19931996

Case finding N %

Active case finding (screening) 1671 25

Passive case finding (complaints) 4482 67
Other/Unknown 492 7
Total 6645 100
Source: Ref. 4.

Mode of Detection
In low-prevalence countries, in addition to passive case finding among self-re-
porting suspects, active case finding by screening of risk groups and the contain-
ment of microepidemics and cluster epidemics has become progressively more
important.
For example, in the Netherlands in 19931996, 25% of cases were detected
by active case finding (Table 7). In the Netherlands in 19931996, 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 in-
fection. 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,

19931996

19931996

Diagnosing physician N %

Chest physician 3294 50

Other specialist 1448 21
TB control officer 1903 29
Total 6645 100
Source: Ref. 4.
Tuberculosis Control in Low-Prevalence Countries 91

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

19931996

Total
1993 1994 1995 1996
Treatment result (%) (%) (%) (%) N %

Total (N) (329) (410) (368) (410) 1517 100

Cured/Completed 74.5 81.2 80.4 84.4 1224 80.3
Interrupted 7.9 5.9 4.3 2.0 74 4.9
Died (TB) 3.3 1.7 3.0 3.7 44 2.9
Died (non-TB) 12.5 11.2 11.7 10.0 171 11.2
Transferred out 1.2 0.5 4 0.4
Source: Ref. 4.

In the Netherlands the treatment success rate in Dutch infectious pulmonary

cases was 80% for the period 19931996 (Table 9). The treatment success rate
would be substantially higher if it was corrected for the relatively high case fatal-
ity due to other diseases than tuberculosis. The treatment success rate in non-
Dutch 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 im-
portance of treatment outcome monitoring in specific subgroups is demonstrated
by the fact that among asylum seekers 10% interrupted treatment in 19931996
(Table 11) (4).

Directly Observed Treatment

The great majority of patients in low-prevalence countries are treated by medica-
tion self-administration. With an increasing proportion of patients coming from

Table 10 Treatment Outcome Monitoring of Infectious Non-Dutch Cases,

The Netherlands, 19931996

Total
1993 1994 1995 1996
Treatment result (%) (%) (%) (%) N %

Total (N) (429) (453) (401) (420) 1703 100

Cured/Completed 79.7 78.4 85.8 86.9 1411 82.6
Interrupted 11.2 12.4 6.5 6.0 155 9.1
Died (TB) 1.2 0.7 0.5 0.7 13 0.8
Died (non-TB) 3.3 2.2 1.5 1.4 36 2.1
Transferred out 4.4 6.4 5.7 5.0 88 5.4
Source: Ref. 4.
92 Broekmans

Table 11 Treatment Outcome Monitoring of Infectious Asylum Seekers Only,

The Netherlands, 19931996

Total
1993 1994 1995 1996
Treatment result (N) (N) (N) (N) N %

Cured/Completed 90 116 128 112 446 85.9

Interrupted 11 18 13 10 52 10.0
Died (TB) 1 1 2 0.4
Died (non-TB) 1 1 0.2
Transferred out 7 6 2 3 18 3.5
Total 109 141 144 125 519 100
Source: Ref. 4.

specific risk groups and proportionally more patients detected by active case find-
ing, 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; 42:5104.
1a. Sutherland I, Bleiker MA, Meijer J, Styblo K. The risk of tuberculous infection in The
Netherlands from 1967 to 1979. Tubercle 1983; 64:241253.
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; 57:1743.
3. Styblo K. The elimination of tuberculosis in the Netherlands. Bull Int Un Tuberc
1990; 65:4955.
3a. van Geuns HA, Hellinga HS, Bleiker MA, Styblo K. Surveillance of diagnostic and
treatment measures in The Netherlands. Comparison between the periods 19711976,
19771980, and 19811985. Tuberculosis Surveillance Research Unit of the Interna-
tional Union Against Tuberculosis. Progress Report 1987; 1:6081.
4. Index Tuberculosis 19931996. 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 interna-
tional source case finding during a large outbreak of tuberculosis in the Netherlands.
Int J Tuberc Lung Dis 1997; 1:239245.
6. Tuberculosis Control in High Risk Groups in The Netherlands. Netherlands Tuber-
culosis Policy Committee/KNCV, The Hague, The Netherlands, 1997.
Tuberculosis Control in Low-Prevalence Countries 93

7. Annual Reports 19931996 Tuberculose-screening asielzoekers in opvangcentra. Re-

gio Noord en Zuid Nederland, Municipal Health Service Tilburg and Municipal
Health Service Lelystad.
8. Data from KNCV/RIVM Surveillance Project, The Hague/Bilthoven, The Nether-
lands.
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 GGDen georganiseerde tuberculosebestrijding. Venlo,
The Netherlands, 1998.
11. Euro TB Surveillance of Tuberculosis in Europe. Report on the feasibility study
(19961997). Tuberculosis cases notified in 1995. European Centre for the Epidemi-
ological Monitoring of AIDS (CESES) and Royal Netherlands Tuberculosis Associ-
ation (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 de-
pressions, this decline was further accentuated during the first half of the twenti-
eth century, probably fueled by improving socioeconomic conditions and the iso-
lation 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 cam-
paigns and bacille Calmette-Gurin (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 pa-
tients diagnosed with pulmonary tuberculosis who, even before the HIV/AIDS
95
96 Laszlo

era, were found to have atypical chest x-ray patterns. Furthermore, observer er-
ror 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 dis-
covered) (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 radiogra-
phy. 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 pro-
vide an indication of the progress of chemotherapy, sputum smear microscopy is
an important diagnostic tool in developed countries (4) and the diagnostic corner-
stone 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 vac-
cination campaigns had been superseded by mass vaccination of newborns and
young children, but by the mid-1970s it became evident that this tuberculosis-pre-
vention measure would not substantially improve the overall epidemiological sit-
uation (7). The main reason for this was that more than 95% of reported tubercu-
losis cases among children are smear negative, and it has been shown that
smear-negative patients are much less infectious than smear-positive ones. Fur-
thermore, 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 ade-
quate 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 1014% in developed countries, whereas in de-
veloping countries, which today carry 95% of the worlds burden of tuberculosis,
the annual decrease rates were very low during the last four decadesas 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 na-
tional 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
Tuberculosis Laboratories 97

prevention could be achieved by adequate chemotherapy and that the detection of

contagious sources of tuberculosis in the community could best be attained by in-
expensive bacteriological means. By that time, tuberculosis in developed coun-
tries 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 Tubercu-
losis and Lung Diseases (IUATLD) activities with respect to tuberculosis has
been the development of an appropriate model for the NTPs of developing coun-
tries (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 as-
sessed 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 in-
fection 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 socioe-
conomic circumstances because the infectious agent has only one ma-
jor reservoirthe diseased patientwho can quickly be rendered non-
infectious. This is particularly true for epidemiologically significant M.
tuberculosis infections, which are almost exclusively confined to hu-
mans 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 im-
prove the epidemiological situation. A sputum smearpositive patient,
if left untreated, will infect on average 1015 close contacts per year; if
98 Laszlo

this patient is properly treated one case will be eliminated and up to 15

cases of tuberculosis will be prevented.
3. Smear microscopy detects almost all sources of infection, and highly
efficient chemotherapy regimens can cure almost all discovered cases.
Experience in IUATLD field programs has shown that maintaining a
detection rate of 70% of smear-positive cases and a cure rate of 85%,
the tuberculosis endemic would, in time, come under control.
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 popula-
tions in developing countries, in spite of rapid urbanization, are
still predominantly rural, the program has to be delivered countrywide.
Due to the diseases transmissibility and the high mobility of popula-
tions, solutions must be found for the entire community; failing this, the
part of the population without coverage will keep transmitting the dis-
ease to the part of the population receiving coverage. This is one con-
dition 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 gov-
ernmental 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 pro-
gram must be permanent. Tuberculosis infection is chronic in charac-
ter, with the possibility of endogenous reactivation many years after in-
fection. 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) populations
rates of infection and disease in 1950 were among the highest ever re-
ported 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-
Tuberculosis Laboratories 99

culosis should be conducted at the district level with supervision, train-

ing, 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 tu-
berculosis control in developing countries (20). The DOTS strategy for tubercu-
losis control in developing countries is meant to provide short-course chemother-
apy 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 smearposi-
tive pulmonary tuberculosis worldwide and 2) to detect 70% of existing cases of
sputum smearpositive pulmonary tuberculosis. The success of this strategy de-
pends on the implementation of the five following points: political will, passive
case finding, short-course chemotherapy for all smear-positive pulmonary tuber-
culosis 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 mil-
lion in 1997 (21).

III. Tuberculosis Diagnostic Services

Tuberculosis bacteriology is a complex and demanding branch of clinical micro-

biology. Unlike in some other infectious diseases, the tuberculosis clinical labo-
ratory plays a critical role, not only in the diagnosis of the disease and the man-
agement 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 ver-
ify 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-re-
sistance 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 iso-
lates.
100 Laszlo

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 or-
der 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 countrys NTP, case finding refers to the di-
agnosis of sputum smearpositive disease and passive case finding, where the first
move toward diagnosis is made by the patient, is the method of choice. From the
NTPs 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 in-
crease case finding by 2030%. Since this mode of diagnosis is considerably more
expensive than smear microscopy, it will probably be introduced when smear mi-
croscopy 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 surveil-
lance 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.
Tuberculosis Laboratories 101

V. The NTP National Tuberculosis Laboratory Network

Implicit in the organization principles enunciated above is the concept of the na-
tional tuberculosis laboratory network as a tool for delivering tuberculosis diag-
nostic 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 com-
mon set of standards, information systems, goods and services offered, and qual-
ity 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 patients home, and with an
assurance of quality. In turn, the network will provide information at all levels re-
quired for the planning and the evaluation of the NTP. This information essen-
tially refers to:
1. Tuberculosis suspects: periodic and continuing information on the
number of people presenting with chest symptoms examined by the net-
work makes it possible to evaluate case-finding activities and to iden-
tify possible difficulties that may arise and the places where they may
occur, in order to take remedial action.
2. Case finding: if coverage is good, the trend in tuberculosis cases de-
tected by smear microscopy is known to be the best indicator of the
NTPs diagnostic effectiveness.
3. Cases diagnosed and treated: comparison of information in the tuber-
culosis laboratory register, the district tuberculosis register, and the pa-
tients treatment cards.
4. Trends in bacteriological confirmation: a good operational indicator of
the quality of the NTPthe higher it is, the better the NTP is likely to
be.
5. Cure rate: negative bacteriology at the end of treatment is the best indi-
cator of the NTPs 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,
102 Laszlo

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, drug-
susceptibility 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 di-
agnostic services of the NTP
Train technical/scientific personnel in all aspects of the networks 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 diag-
nostic 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 mi-
croscopy, and to implement quality-improvement measures in the labo-
ratories 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-
Tuberculosis Laboratories 103

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 labo-
ratory
Participate in the network smear microscopy quality-assurance program

Specimen-collecting units are health establishments that do not possess a labora-

tory; 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 sus-
pects and cases. Proper recording and reporting will facilitate budgeting and plan-
ning, provide better understanding of the epidemiology of tuberculosis, and assist
in developing hypotheses about phenomena observed in the descriptive epidemi-
ology 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 spu-
tum 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 exami-
nation, 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 technologists 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 treat-
ment
Number of smear-negative patients at the middle of the continuation phase
of treatment
Number of smear-negative patients at the end of treatment
104 Laszlo

VIII. The National Tuberculosis Laboratory Network as a

Source of Operational and Epidemiological
Information

The laboratory register can provide useful information on the laboratory work-
load, performance, and demographic characteristics of the examinees (23), for ex-
ample:

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 pre-
vention on laboratory-generated test results than tuberculosis. A tuberculosis lab-
oratory network functioning in concert with a model NTP is an essential tool pro-
viding 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 Patients Treatment Card, provide all the elements
required for program evaluation without which a modern NTP cannot exist. Re-
sults 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 pre-
dict 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
Tuberculosis Laboratories 105

NTPs, since it can be noted that no successful NTP is without an efficient tuber-
culosis laboratory network.

References

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Marcel Dekker, 1993:699717.
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5
Evaluation of Applied Strategies of Tuberculosis
Control in the Developing World

PIERRE CHAULET EARL S. HERSHFIELD

University of Algiers University of Manitoba

Algiers, Algieria 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 evolu-
tion of the global tuberculosis epidemic is therefore dependent on the tuberculo-
sis-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 20002020 the gap be-
tween rich and poor countries will only increase (2). As a result, a careful evalua-
tion 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 reduc-
ing, tuberculosis, and to measure the impact of these strategies.
At the beginning of the 1990s, the World Health Organization (WHO) pro-
posed two goals to be achieved by the year 2000: to cure at least 85% of smear-
positive pulmonary tuberculosis cases and to detect at least 70% of existing in-
fectious 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
108 Chaulet and Hershfield

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 whenbe-
tween 2000 and 2020the 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 (46) and then under the aegis of the
International Union Against Tuberculosis and Lung Disease (IUATLD) in its Mu-
tual Assistance Program (79), 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
countrys districts, and the implementation of an information system (registers
and quarterly reports), which is essential for supervising and evaluating the activ-
ities.

A. A Clearly Defined Control Strategy

Evaluation of results can only be done by respecting the norms set for the tuber-
culosis diagnosis and case-finding procedures and for the recommended
chemotherapy regimens. The national tuberculosis programs (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 us-
ing short-course chemotherapy regimens (of 6 or 8 months) under direct observa-
tion at least during the initial intensive phase of treatment and at least for infec-
tious 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 es-
sential that the patients and/or the health personnel have access to laboratories
Applied Strategies of TB Control 109

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 tuberculosisthey are for the most part multipurpose laboratories
where 1040 samples are examined per week.
In general, a laboratory should be located no further than 1520 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 coun-
try), and a permanent system of quality control is essential for guaranteeing the re-
liability 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 meth-
ods.
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 patients 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 re-
quested (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 im-
portant 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 epi-
demiological analysis (Table 1) and allows the different rates and indi-
cators 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-
110 Chaulet and Hershfield

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: 014, 1524, 2534, 3544, 4554, 5564, 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 accord-
ing 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 ac-
cording to the number of cases recorded the previous year.
3. The report on program management provides a synthesis of the infor-
mation on the application of the program (distribution of recorded tu-
berculosis cases according to type of treatment, rate of smear conver-

Table 2 Definitions of Treatment Outcome in Smear-Positive Pulmonary

Tuberculosis Patients
Cure Patient who is smear-negative at (or one month prior to) the com-
pletion of treatment and on at least one previous occasion
Treatment completed Patient who has completed treatment but without bacteriological
proof of cure
Treatment failure Patient who remains or becomes again smear-positive at 5
months or later during treatment
Died Patient who dies for any reason during the course of treatment
Treatment interrupted Patient whose treatment was interrupted for 2 months or more
(default) any time after registration
Transfer out Patient who has been transferred to another reporting unit and for
whom the treatment outcome is not known
Source: Refs. 11, 12.
Applied Strategies of TB Control 111

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 tu-
berculosis. 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-posi-
tive 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 treat-
ment 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 recom-
mended by the national program
When regimens other than short, standardized chemotherapy are used, they are an-
alyzed 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 analy-
sis excludes those patients who have not received treatment as pre-
scribed, 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 tuberculo-
sis 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-
112 Chaulet and Hershfield

tients recorded who can be defined as cured at the end of treatment) and the suc-
cess 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 recom-
mended by WHO this permits a comparison of the results obtained within a coun-
try 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 re-
port the data collected in the registers (which they themselves have filled in), cer-
tain types of bias can appear in the patient cohort analysis:
Bias in patient selection due to errors in recording (smear-negative mistak-
enly 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 inter-
ruptions 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 be-
tween cured and treatment completed and between treatment inter-
rupted 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 co-
ordinators 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 Al-
geria (15), where the results observed in two groups of districts equal in size and
population coverage were compared. In the districts that were supervised regu-
larly, 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).
 Applied Strategies of TB Control 113

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 Completed Transferred

assessed Cured treatment Failed Died Lost out

Districts supervized 503 69.8 13 2.5 2.2 6.5 6

Districts not supervized 216 48.5 22.2 2 2.3 12 13
Total districts 719 63.3 16 2.3 2.2 8.2 8

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 worlds population lives in these
countries, and all of the most populated countries (more than 40 million inhabi-
tants) 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 coun-
tries 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 strat-
egy 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 19951997 in certain countries where HIV preva-
lence among tuberculosis patients is high (Ivory Coast, Democratic Republic of
Congo), moderate (Guinea, Djibouti), or low (Morocco, the Philippines) (1621)
confirm worldwide trends (Table 5). Success rates of 7886% are observed in
zones where the strategy is applied and are lower in Djibouti, where a large pro-
portion 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 HIV-
negative 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 7580%.
114
Table 4 Treatment Outcome by WHO Region and Applied Strategy of Tuberculosis Control, 1995

Treatment outcome

Number of Treatment
smear-positive Treatment Transferred success
WHO Strategy cases Not Cured completed Defaulted Failed Died out rate
region used registered evaluated (%) (%) (%) (%) (%) (%) (%)

AFR WHO 105, 245 15 52 10 10 1 7 5 62

non-WHO 71, 312 8 38 19 14 2 6 14 57
AMR WHO 53, 517 8 69 8 6 1 5 3 77
non-WHO 74, 945 57 22 10 6 1 2 2 31
EMR WHO 18, 138 1 69 13 9 1 2 5 83
non-WHO 28, 302 2 51 23 15 5 1 4 73
EUR WHO 4, 732 13 50 19 7 2 7 2 69
non-WHO 28,702 14 60 7 4 7 6 2 57
SEAR WHO 26, 574 4 66 8 12 2 4 4 74
non-WHO 291, 836 68 4 25 1 0 0 1 29
WPR WHO 152, 274 1 89 2 2 1 2 3 91
non-WHO 143, 970 22 43 26 5 1 2 2 68
Global WHO 360, 480 6 72 6 6 1 4 3 78
non-WHO 639, 067 45 23 22 5 1 2 3 45
AFR  Africa Region; AMR  America Region; EMR  Eastern Mediterranean Region; EUR  European Region; SEAR  Southeast Asia Region; WPR  West-
ern Pacific Region.
Source: Ref. 11.
 Table 5 Treatment Outcomes in Certain Countries by Tuberculosis-Control Applied Strategy

Treatment outcome

No. of Treatment Treatment Transferred Treatment

Strategy smear-positive Cured completed Died Failed interrupted out success rate
Country applied cases assessed (%) (%) (%) (%) (%) (%) (%)

Ivory Coast non-WHO 7221a 63.5 6 4.4 1.5 17.6 7 69.5

(1995)
Dem. Rep. of WHO 8052 63.9 15.9 5.5 1.4 8.3 5 79.8
Congo (1995) non-WHO 8195 46 23 5.2 1.3 11.2 13.3 69
Guinea WHO 2158 58 20 7 3 10 3 78
(1994)
Morocco WHO 14 621 79.2 6.8 2 1 5 6 86
(1994)
Djibouti WHO
(19901995) HIV 550 52.4 7 11.1 0.5 29 59.4
HIV 5636 64.7 6.5 2.1 0.9 25.8 71.2
Total 7086 63.8 6.6 2.8 0.8 26 70.4
Philippines WHO 769 82.3 1.4 2.6 2.2 8.2 3.3 83.7
(19961997) (pilot areas)
a
HIV seroprevalence in patients  39%.
Source: Refs. 1621.

115
116 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 repre-
sentative patient samples on a regular basis. A direct link exists between the qual-
ity 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 pa-
tients 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 resis-
tance 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 pul-
monary tuberculosis patients treated by the public health services from 1983 to
1995 (24). In 19831984, the main primary treatment consisted of an 18-month
regimen combining isoniazid and ethambutol, with a daily or intermittent supple-
ment of streptomycin. From 1985 to 1990, primary treatment consisted of a 9-
month regimen with isoniazid, rifampicin, and ethambutol. Since 1991, the pri-
mary treatment generally applied is a 6-month regimen combining isoniazid and
rifampicin, supplemented by pyrazinamide and streptomycin (or ethambutol) dur-
ing the first 2 months.
The success rates increased from 6165% in the first period to 6978% 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 im-
proved in efficiency (Table 6).

Treatment Strategies and Evolution of Drug Resistance in Algeria

In Algeria, a similar pattern was observed (2628). 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 1218 months.
Applied Strategies of TB Control 117

Table 6 Prevalence of Drug Resistance in Korea

Resistant strains Resistant strains

Prevalence Old cases New cases
survey tested n (%) tested n (%)

1975 45 33 (73.3) 143 39 (27.3)

1980 55 41 (74.5) 63 15 (23.8)
1985 70 41 (58.6) 100 19 (19.0)
1990 35 19 (54.3) 78 12 (15.4)
1995 28 7 (25.0) 103 6 (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 pyrazi-
namide 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 ef-
fective short-course chemotherapy came into general use (Table 7).

A Complementary Method
Drug-resistance surveillance is a method of epidemiological surveillance that pro-
vides information on the treatment strategy applied in the community in recent

Table 7 Prevalence of Drug Resistance in Algeria

Resistant strains Resistant strains

Old cases New cases
Years tested n (%) tested n (%)

19651970 858 703 (81.9) 145 217 (15)

19711979 1490 917 (61.5) 825 83 (10.1)
19801985 606 145 (35.7) 805 51 (6.3)
19861990 408 86 (21.0) 1111 58 (5.2)
Source: Refs. 26, 27.
118 Chaulet and Hershfield

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 sus-
ceptibility testing, selection of a representative patient sample, and reporting of re-
liable 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 35 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 510 years, confirm or clarify the re-
sults 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 treat-
ment results (depending on the regimens used and the results of initial suscepti-
bility 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, compa-
rable 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 bacteriologi-
cal data collected in a single reference laboratory were analyzed. The survey con-
tinued for 4 consecutive years in 30 districts, covering a population of about 4 mil-
lion (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 supervi-
sion.
Applied Strategies of TB Control 119

Table 8 Results of Evaluation of Smear-Positive New Cases Initially Treated

by Short-Course Chemotherapy Regimens Under National Programme Conditions

Regimen initially prescribed

6 months 8 months Patients analyzed

Results 2 years
after end of chemotherapy n % n % n %

Negative cultures
After 18th month 678 (16) 69 810 (18) 66 1488 (34) 67
Between end of treatment
and 18th month 174 (3) 18 258 (4) 20 432 (7) 19.5
Completed treatment
without control since
end of treatment 66 7 101 (1) 8 167 (1) 7.5
Positive cultures when
last seen after
end of treatment 13 (2) 1 22 (7) 2 35 (9) 1.5
Deaths 46 5 50 4 96 4.5
Total 977 (21) 100 1241 (30) 100 2218 (51) 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 col-
lected 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
120 Chaulet and Hershfield

2. The register of the laboratory where tuberculosis microscopy is per-

formed, 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 quar-
terly 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 un-
der 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 examina-
tions. 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 iden-
tify tuberculosis suspects and to send the necessary samples to the laboratory for
diagnosis of pulmonary tuberculosis.
Applied Strategies of TB Control 121

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 sus-
pects: duration of the symptoms presented by the patients, confirmation
by the number and type of medical examinations (e.g., x-ray). If the res-
piratory symptoms presented by the patient are the only criterion for in-
clusion as a tuberculosis suspect, the proportion will be on average 10%
(range 515%).
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 7585%) if ra-
diological facilities are used appropriately and if smear microscopy is
repeated (at least two series of three smear examinations for those tu-
berculosis suspects who have three negative smears in the first series).
A lower proportion can be observed in HIV-positive patients, particu-
larly 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 extrapul-
monary 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 nu-
merator is the number of new smear-positive cases registered in a year
from within a defined population (district, region, or country). The de-
nominator is the estimated total midyear population of that district, re-
gion, or country. An estimated incidence rate is used in program plan-
ning (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 tuberculo-
sis 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 di-
agnosis than as a means of selection (11).
122 Chaulet and Hershfield

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 pro-
portion 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 con-
siderable 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 com-
pared. 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 strat-
egy 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

No. of new New smear-positive/New

Tuberculosis-control smear-positive pulmonary cases
WHO region strategy cases notified (%)

AFR WHO 155, 146 65

non-WHO 93, 833 32
AMR WHO 52, 220 70
non-WHO 81, 773 64
EMR WHO 21, 651 76
non-WHO 36, 499 45
SEAR WHO 51, 075 64
non-WHO 322, 044 25
WPR WHO 206, 582 68
non-WHO 146, 592 27
AFR  Africa Region; AMR  America Region; EMR  Eastern Mediterranean Region; SEAR 
Southeast Asia Region; WPR  Western Pacific Region.
Source: Ref. 11.
Applied Strategies of TB Control 123

Table 10 Influence of Supervision Activities of Health Staff on Case-Detection Results

Health districts (n  52)

With periodic Without periodic

supervision of activities supervision of activities
(n  27) (n  25)

Population covered 3.4 million 3.2 million

Adjusted population 100,000 100,000
Outpatients attending
health services (per year) 68,578 65,713
Number of smear
examinations performed
in suspects 1,910 1,302
Number of smear-positive
pulmonary tuberculosis
cases identified 47 24
Source: Ref. 15.

tection rate of 70% of infectious cases depends on a number of variables, particu-

larly the health coverage of the population, the populations means of communi-
cation with and accessibility to the health services, and the ability of health work-
ers 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 tu-
berculin 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 moni-
toring 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 con-
siderable increase in numbers of cases, well above the numbers that were pre-
dicted, based on the annual risk of tuberculous infection (33,34).
124 Chaulet and Hershfield

A Pragmatic Approach
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, de-
pending on the district. Based on the make-up of the districts of a particular coun-
try (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 pack-
age of health activities, it will be impossible to detect and treat tuberculosis pa-
tients in rural and periurban areas that are neglected, and particularly in the most
vulnerable sections of the population. As long as peripheral district health activi-
ties 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.

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resistance in the world. The WHO/IUATLD Global project on antituberculosis drug
resistance surveillance 19941997. 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 Ko-
rea, 19831994. Int J Tuberc Lung Dis 1998; 2:365371.
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; 2:2736.
26. Boulahbal F, Khaled S, Tazir M. The interest of follow-up of resistance of the tuber-
cle bacillus in the evaluation of a programme. Bull Int Union Tuberc Lung Dis 1989;
64(3):2325.
27. Chaulet P. Tuberculose et transition pidmiologique: le cas de lAlgrie. AnnInsti-
tut PasteurActual 1993; 4:181187.
28. Cheikh El Ghanami Z. Lorganisation de la chimiothrapie de la tuberculose en Al-
grie. Rsultats dune enqute nationale mene en 1971. Thse de Doctorat en
Mdecine, Universit dAlger, Algiers, 1971.
29. Algerian Working Group/British Medical Research Council cooperative study. Short
course chemotherapy for pulmonary tuberculosis under routine programme condi-
tions: a comparison of regimens of 28 and 36 weeks duration in Algeria. Tubercle
1991; 72:88100.
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 8-
month) short course chemotherapy regimens. In: IUATLD Tuberculosis Surveillance
Research Unit. Progress report. Vol. 1. The Hague: TSRU, 1991:2944.
31. World Bank. World Development Report 1993. Investing in Health. New York: Ox-
ford University Press, 1993:3491.
32. Arnadottir T, Rieder HL, Trbucq A, Waaler HT. Guidelines for conducting tuber-
culin skin test surveys in high-prevalence countries. Tuberc Lung Dis 1996; 77(suppl
1):120.
33. Rieder HL. Methodological issues in the estimation of the tuberculosis problem from
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1998; 2:349359.
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 tuberculo-
sis on the worlds well-being is its concentration among young adults throughout
most of the developing world and its airborne spread from person to person, es-
pecially to household members. As noted in Chapter 1, tuberculosis has been ex-
acting a toll for many centuries. Of particular interest from an epidemiological
point of view is the reported frequency of skeletal lesions suggestive of tubercu-
losis among pre-Columbian populations of North America (2). While such lesions
were occasionally noted in skeletons of the Late Woodland peoples (8001050
A.D.), their successors, the Mississippians, had a much higher frequency of tuber-
culosis-like bony lesions, associated with their coming together in larger and rel-
atively 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
130 Comstock

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 epi-
demiology 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 de-
veloping tuberculous disease; and (3) prevent relapse, disability, and death among
those who have tuberculosis.
Administrative epidemiology will then be reviewed. This aspect of epidemi-
ology deals with the occurrence of tuberculosis based on routine reporting or spe-
cial surveys. These data are vital for tuberculosis control workers and other per-
sons 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 organismsMycobacterium tuberculosis, M. africanum, and M. bo-
visare the necessary causes of tuberculosis. M. tuberculosis is by far the most
common. M. africanum is rarely found outside of northwestern Africa, and dis-
ease due to M. bovis is limited in developed countries by widespread pasteuriza-
tion 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 1721 years, the propor-
tion of positive reactors fell from 6.6% in 194951 to 3.1% in 196768. Subsequent
testing on a routine basis showed the prevalence of positive reactors among all re-
cruits 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
Epidemiology 131

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 repre-
sentative of the total adult population come from the first Health and Nutrition Ex-
amination Survey in 19711972. Among 1494 adults aged 2574 years, 16.1%
were classified as reactors (6).
The likelihood of having been infected among household contacts of infec-
tious cases of tuberculosis has also declined with time, at least in the United States
(7). In Williamson County, Tennessee, in the period 193155, 67% of household
contacts aged 59 years were positive tuberculin reactors. In a large study of con-
tacts 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 through-
out most of the world, most rapidly in industrialized nations and least in sub-Sa-
haran Africa and the Indian subcontinent, where the annual rate of decline is esti-
mated 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-Gurin (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 ru-
ral area of South India (12). Among children 14 years of age at the initial exam-
ination, 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
194951, 62% of children aged 06 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 196364, only 2.4% were in-
fected, and in 196970 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
132 Comstock

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 1721 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 re-
lated 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 be-
cause Indian households were more crowded. For both Indians and whites, infec-
tion 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 spu-
tum of the source case contained so many tubercle bacilli that they were demon-
strable by microscopic examination of a stained sputum smear, the risk of infect-
ing 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 pos-
itive tuberculin reactions among children who are household contacts (14). Extent
of pulmonary involvement was strongly associated with infectivity: 62% of con-
tacts of cases with far advanced disease were reactors compared to only 16% re-

Table 1 Age-Adjusteda Percentages of Positive Tuberculin Reactors Among White and

Indian Children Aged 014 Years in British Columbia and Saskatchewan, by Sputum
Status of Source Case, 19661971

Race and closeness of tuberculosis contact

Indian children White children

Sputum status Intimate Casual Intimate Casual

of source case (n  1012) (n  619) (n  1873) (n  3,031)

Positive smear 44.7 37.4 34.7 10.1

Positive culture only 27.7 15.6 8.9 2.4
Negative culture 25.7 18.7 7.2 3.3
a
Adjusted to age distribution of total study population aged 014 years.
Source: Ref. 14.
Epidemiology 133

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 se-
riously considered in the pathogenesis or epidemiology of human tuberculosis.
During 19941996, 21 cases of tuberculosis developed in a small rural commu-
nity 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 reac-
tors and converters. Environmental investigations revealed no explanation for
these high infection rates. The strain of tubercle bacilli responsible for the out-
break was initially reported to be more virulent than the standard virulent Erdman
strain. However, subsequent laboratory investigations have not been able to con-
firm this finding (Cynthia L. Kelley and Arthur M. Dannenberg, Jr., personal com-
munications, 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 im-
portant 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 devel-
oped countries were only slightly more likely to be tuberculin reactors than life-
time residents of this country (3). At least some of the difference must have re-
sulted 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.
134 Comstock

Age
There is some evidence that the risk of acquiring infections increases with age dur-
ing the period from infancy to early adult life (21), probably because of increas-
ingly 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 5060 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 illus-
trated in a large tuberculin testing program among New York City school em-
ployees (23,24). The prevalence of positive reactors was also higher among non-
whites than whites.
Socioeconomic Status
In the New York City study, the prevalence of positive tuberculin reactors de-
creased 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 tu-
berculous 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 exami-
nations (17,26,27). Although isoniazid-resistant organisms have reduced viru-
lence for guinea pigs, there is no indication that drug resistance per se has any ef-
fect 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 in-
creased 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 tu-
bercle 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
Epidemiology 135

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 (3032).
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 posi-
tive 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 ev-
idence 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 seri-
ous 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 shel-
ters. 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 in-
fected 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 anec-
dotal 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 rel-
evant.
136 Comstock

Reinfection
For the past 100 years, there have been many discussions and opinions about the
relative importance of exogenous reinfection and endogenous reactivation in the
development of clinical tuberculosis following the initial infection with M. tuber-
culosis (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 re-
sponsible 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 be-
coming 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 tubercu-
losis 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, proba-
bly related to intensity of exposure. Among 265,488 tuberculin reactors with neg-
ative chest radiographs who participated in a mass campaign in 195052 in Den-
mark (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 195764 was more than 500 per 100,000 persons with initially negative
chest radiographs, virtually all of whom were tuberculin reactors (43). In Den-
mark in the 1960s, rural tuberculin reactors 1544 years of age had a risk of sub-
sequently 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-
Epidemiology 137

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 spu-
tum 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 re-
cent.
The incidence of tuberculosis among tuberculin reactors by age was inves-
tigated as a by-product of a controlled trial of BCG vaccination in Puerto Rico
(44). Among 82,269 tuberculin reactors aged 118 years who were followed for
1820 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 4-
year 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.)
138 Comstock

(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 tu-
berculosis 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 posi-
tive 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 in-
cidence 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 tu-
berculin 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 19661971

Prevalence (%)

Indian contacts White contacts

Sputum status Intimate Casual Intimate Casual

of source case (n  352) (n  169) (n  412) (n  216)

Positive smear 14.4 10.0 14.0 8.2

Positive culture only 5.1 3.9 5.0 6.2
Negative culture 3.0 0 2.3 0
a
Adjusted to age distribution of total study population aged 014 years.
Source: Ref. 14.
Epidemiology 139

those with the closest contact, the conclusion seems inescapable that persons in-
fected 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 my-
cobacteria 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 re-
actions 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 reac-
tions. The importance of this risk was illustrated by a study of Puerto Rican chil-
dren (50). Children with reactions measuring 16 mm or more in diameter to 1 tu-
berculin unit (TU) of a purified tuberculin had a subsequent risk of tuberculous
disease more than five times greater than children with reactions of 610 mm fol-
lowing 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 infec-
tions 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 av-
erage 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 suscep-
tibility 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).
140 Comstock

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
195062 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 anec-
dotal 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 associ-
ated 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 progno-

sis for persons who develop tuberculosis. Conscientious adherence to an appro-
priate regimen even in the earlier days of chemotherapy came close to guarantee-
ing 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 af-
ter apparent cure (5658). Presence of drug-resistant tubercle bacilli is also an im-
portant risk factor for relapse. In 12 controlled trials of short-course chemother-
apy, 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).
Epidemiology 141

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 introduc-
tion, relapse was most likely to occur shortly after treatment stopped (63,64); af-
ter chemotherapy was introduced, relapses were less likely during the year or two
following adequate treatment (61,64). Long-term risk after adequate chemother-
apy 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 re-
lapse 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 In-
dians 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 per-
sons 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
142 Comstock

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 ad-
ministrative 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 uni-
form 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 Wash-
ington) showed average annual increases of 417% during the period 19841991.
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 (7476). For the seven

Figure 2 Tuberculosis case rates, United States, 19751997, all ages. (Adapted from
Ref. 72.)
Epidemiology 143

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 19841991, and the Rest of the Country

1985 1992 1996

Total 9.4 10.5 8.0

Seven statesa 11.2 16.8 11.9
Rest of United States 8.5 7.4 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. 7476.

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 no-
table 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 tuberculo-
sis case rates were still declining up to 1992. In only a few, however, were tuber-
culosis 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 ar-
eas (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 ac-
tivities 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).
144 Comstock

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 Van-
couver (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 20.372.8 (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, in-
terpretation of geographic variations is more difficult than generally recognized.
Within the United States in 1992, the percentage of pulmonary cases not bacteri-
ologically confirmed varied from 0 to 35.4% among states with 25 or more re-
ported 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,
74,76,84,8694). 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 fe-
males 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,
19801996. *Up to 1993, Hispanics are also included in one of the other groups. (Adapted
from Refs. 7476, 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  His-
panic; W  white; M  male; F  female. (Adapted from Ref. 76.)
145
146 Comstock

cess was noted among unmarried men living in central Copenhagen (97). The sit-
uation 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 coun-
tries; the risk decreases with their duration of stay in their adopted homes
(87,100102).
Based on a survey from 29 states in 19841985, occupational status was
strongly associated with tuberculosis case rates (103). Executives and profession-
als 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 as-
sociation 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 tuber-
cle bacilli as other employees (104).

D. Institutional Living

Because poverty is associated with both crime and tuberculosis, it is not surpris-
ing 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. tuberculo-
sis, studies to substantiate this presumption are few and rarely definitive. By far
the most important is immunosuppression, particularly that resulting from infec-
tion 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 adreno-
corticosteroid therapy, some hematologic and reticuloendothelial diseases such as
leukemia and lymphoma, and end-stage renal disease (107).
Epidemiology 147

Silicosis has long been linked with tuberculosis, so much so that silico-tu-
berculosis is an accepted disease entity. Although the causal nature of this associ-
ation 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 ap-
proximately 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, al-
though 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 tuberculo-
sis sanatoria, since 1030% 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 drugresistant 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 immunosuppres-
sion, crowding, homelessness, drug abuse, and/or poverty, especially in circum-
stances 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 tuber-
culous infection was not the major contributor to the increased risk. In recent
years, there have been frequent reports of localized outbreaks (clusters) of tuber-
culosis 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 fragment-
length polymorphism pattern, strongly suggesting that all cases came from a sin-
gle 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 becom-
ing infected is it reasonable to assume that most HIV-associated tuberculosis is the
result of reactivation of latent infection.
148 Comstock

Two features distinguish the epidemiology of HIV-associated tuberculosis.

First is the speed with which clinical disease becomes manifest following expo-
sure. 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 devel-
oped tuberculosis (40). The likelihood of developing manifest tuberculosis de-
pends 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 hered-
itary 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 Inu-
its 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 hu-
man leukocyte antigen types have also been suspected of playing a role in tuber-
culosis 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 re-
sistance of guinea pigs against tuberculosis (127). Evidence of protection was also
found among British adolescents who reacted only to the 100 TU dose of tuber-
culin and U.S. Navy recruits who reacted to antigens prepared from M. avium-in-
tracellulare 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),
Epidemiology 149

although it is possible that the nonreactors to the strong dose of tuberculin were
like some of Palmers 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 psy-
chological, social, and economic stresses have an adverse effect on tuberculosis
(130132). 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 3040 years ago. Of concern is the current risk of disease fol-
lowing tuberculous infection in a variety of populations. Some way of reliably
identifying persons who continue to harbor tubercle bacilli after having been in-
fected 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 con-
clusion. Increased knowledge of current risks of infection and subsequent disease
could help greatly in efforts to bring tuberculosis back under control and, in devel-
oped countries, could even lead to its elimination in the near future.

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7
Bacteriology of Tuberculosis

JACQUES GROSSET, CHANTAL TRUFFOT-PERNOT, and

EMMANUELLE CAMBAU

Facult de Mdecine Piti-Salptrire

Universit 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 reduc-
tion of the time required for obtaining the results of culture and drug-sensitivity
tests. Nonisotopic probes for the identification of pure cultures and DNA finger-
printing of Mycobacterium tuberculosis for strain typing are important new de-
velopments. In addition, the application of nucleic acidamplification techniques
to the direct detection of M. tuberculosis in clinical specimens and the direct de-
tection 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 tu-
berculosis in a pragmatic approach for developed as well as for developing
countries.
157
158 Grosset et al.

II. Biological Safety

Laboratories processing specimens that could contain tubercle bacilli should en-
sure that safety measures are appropriately implemented and controlled (13).
Even more rigorous safety measures should be followed by technicians perform-
ing identification and drug-susceptibility testing since they work with large inoc-
ula 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 hypochlo-
rite or 2% alkaline glutaraldehyde.
Personnel working in a mycobacteriology laboratory should have annual
health exams including tuberculin testing with appropriate chest x-rays and pre-
ventive 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. bo-
vis, 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, 25 m long and 0.20.3
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 bacil-
lus, appearing under microscope examination as a slightly curved or straight,
small red or pink rod.
Bacteriology of Tuberculosis 159

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 6090 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, tre-
halose-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 proce-
dures 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. tuber-
culosis remains viable for weeks at 4C and for years at 70C.

Mycobacterial Antigens
Soon after the discovery of the tubercle bacillus, Robert Koch prepared a concen-
trated sterile filtrate from heat-killed liquid culture (10), which he named tuber-
culin. It soon became apparent that tuberculosis patients reacted to the injection
of tuberculin more rapidly and intensely than uninfected persons, and the intra-
dermal skin test with tuberculin became part of the diagnosis of tuberculosis in-
fection. Among all antigens of M. tuberculosis and M. bovis that have been de-
scribed, 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 or-
dinary 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 1320 hours on solid as well as in liquid medium.
M. tuberculosis is a strict aerobe equipped with catalase, peroxidase, and su-
peroxide-dismutase, the growth rate of which is highly dependent upon the oxy-
gen concentration. When oxygen concentration is high, as in the tuberculosis cav-
160 Grosset et al.

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 clin-
ical specimens (12).
M. tuberculosis can oxidize an extremely wide range of compounds. The
preferred carbon sources for growth are, by order of preference, glycerol, pyru-
vate, and glucose. The growth of M. bovis, a species closely related to M. tuber-
culosis, 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. tuber-
culosis requires four major inorganic elements for growthpotassium, magne-
sium, sulfur, and phosphorusand a variety of trace elements, such as iron, zinc,
and probably manganese (12). All of these elements are present in common semi-
synthetic 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 con-
tainers should be sterile if the specimen is taken from a closed cavity (cere-
brospinal fluid, pleural effusion, abcess, etc.) and should not contain any fixative
or preservative. The collected clinical specimens should be delivered to the labo-
ratory as soon as possible. If delays in delivery or processing are anticipated, spec-
imens should be kept at 4C to avoid overgrowth by contaminants and to pre-
serve the viability of mycobacteria. In case of transportation, the collection
container must be sealed to prevent leakage and cushioned to prevent breakage ac-
cording 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 ob-
tained by either nebulization with sterile hypertonic saline or gastric lavage or la-
ryngeal swabs. Bronchofibroscopy for collection of aspirates, brushing, or
Bacteriology of Tuberculosis 161

lavages may be necessary for some patients (13). The collection of sputum-con-
taining specimens, especially by nebulization or bronchoscopy, should be per-
formed in a special area and by qualified personnel to minimize the risk of infec-
tious aerosols.

NonSputum-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 decon-
tamination 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 Lysis-
Centrifugation 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 tu-
bercle bacilli in the laboratory. Direct smear prepared from necrotic or blood-
tinged particles of the specimen, usually sputum, is done in most laboratories
worldwide. Often, especially when all specimens are processed for culture, a por-
tion of the digested, decontaminated specimen is used for preparing a concen-
trated 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 fluo-
rochrome dye. After decolorization with an acid-alcohol preparation, the smear is
counterstained with either potassium permanganate, acridine orange, or thiazine
162 Grosset et al.

red, and scanned at a lower magnification with a 25 dry objective and a fluo-
rescent 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
5,00010,000 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 fluo-
rochrome 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 todays tuberculosis-control pro-

grams, culture is much more sensitive than microscopy and enables specific iden-
tification 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 de-
contaminated 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 deter-
gents or enzymes. In practice, both liquefaction and decontamination are accom-
plished 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-cys-
teine (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.
Bacteriology of Tuberculosis 163

Whatever digestion-decontamination procedure is used, the procedure must

be critically timed to minimize the killing of tubercle bacilli by the decontaminat-
ing 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 compati-
ble with the BACTEC culture system and molecular biology tests (18). Some pro-
cedures, using slow-acting compounds, such as pancreatin-desogen or cetylpiri-
dinium chloridesodium 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 decon-
taminated adequately without killing excessive numbers of mycobacteria. A sim-
ple 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
5090% 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 Lwenstein-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 my-
cobacteria and therefore should be placed in plates (Petri dishes) and not in screw-
capped tubes. For all these reasons, egg media are more commonly used in coun-
tries 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 Lwenstein-
Jensen 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.
164 Grosset et al.

Whatever the solid medium used, two to six tubes or plates should be inoc-
ulated with 0.10.5 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 3537C. They should be examined within
35 days after inoculation to enable early recognition of rapidly growing my-
cobacteria 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, 50100, 100200, 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 (Bec-
ton-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 decontam-
inated specimen are added to vials containing 4 mL Middlebrook 7H12 broth
(BACTEC 12B vial) along with an antibiotic mixture. The vials are incubated at
37C 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 pro-
duced, 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 smearpositive specimens and 14 days with AFB smearnegative
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: in-
ability to observe colony morphology, difficulty in recognizing mixed cultures,
overgrowth by contaminants, cost, radioisotope disposal, and extensive use of
needles (3).
Bacteriology of Tuberculosis 165

To reduce the difficulties inherent in the use of radioisotopes, new noniso-

topic 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 de-
tection is longer than with the BACTEC system but shorter than with solid media
(28,29).
The mycobacterial growth indicator tube, or MGIT (BBL, Becton-Dickin-
son, Cockeysville, MD), is a culture broth that contains a fluorescence quench-
ingbased oxygen sensor. Under UV light, bright orange fluorescence at the bot-
tom 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 in-
cubation for 36 weeks at 3537C. 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-
166 Grosset et al.

cobacteria (NTM), may produce pigment after exposure to light (photochro-

mogens, 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, es-
pecially those belonging to nonphotochromogenic species, such as M. terrae com-
plex 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. tu-
berculosis complex and NTM: the heat-stable (68C) catalase test, a niacin test,
and growth on 0.5 g/mL para-aminosalicylic acid (PAS). M. tuberculosis com-
plex has heat-labile catalase and is PAS susceptible; in addition, the species M. tu-
berculosis is niacin-test positive. With few exceptions, NTM give opposite re-
sults.
Two other differential tests are now commonly used: the DNA probe assay
and the BACTEC NAP test. DNA probes complementary to rRNA of M. tuber-
culosis 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 ex-
cellent sensitivity and specificity and low cost, DNA probes have supplanted con-
ventional biochemical tests. Cultures of M. tuberculosis complex in the Bactec
vial can also be identified with the p-nitro- -acetylamino-
-hydroxypropiophe-
none (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 DNA-
DNA hybridization could be considered simple varieties of a single species, M. tu-
berculosis (36). Differentiation between them (Table 1) relies upon colony mor-
phology, 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 cul-
ture, are smooth, tiny (dysgonic), and white. However, after several in vitro sub-
passages, 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.
 Bacteriology of Tuberculosis 167

Table 1 Speciation Among the Mycobacterium tuberculosis Complex

Growtha Colonies Growth on Growth on Virulenceb
rate Niacin Nitrate cycloserine TCHb for
Mycobacteria (weeks) Morphology Pigmentation production reduction (30 mg/L) (2 mg/L) guinea pig

M. tuberculosis 34 Re Buff     
M. bovis 4 Sd White     
M. bovis BCG 4 Re Buff     
M. africanum 4 Rd Matte  to   to    to  
M. microti 34 Re Buff   ?  
a
For primary isolation on solid media.
b
For strain susceptible to isoniazid.
R  rough; S  smooth; e  eugonic; d  dysgonic;   positive;   negative; TCH  thiophene-2-carboxylic hydrazide.

bovis BCG have growth and morphology characteristics similar to those of M. tu-
berculosis.
Different geographic varieties of M. tuberculosis have been observed. In
Europe and the United States the organisms grow slowly in culture into well-de-
veloped (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 re-
ductase. 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. tu-
berculosis, but in West Africa (Dakar variety), they are closer to those of M. bo-
vis. They are often resistant to thiacetazone.
Inoculation into the guinea pig enables one to assess the virulence of the dif-
ferent strains of the M. tuberculosis complex. Lack of virulence is a crucial char-
acteristics of M. bovis BCG, and decreased virulence is a characteristic of the nor-
mally 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 de-
velopment of specific DNA probes (GenProbe, San Diego, CA) and the determi-
168 Grosset et al.

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 tu-
berculosis in a given patient is due to endogenous reactivation or exogenous rein-
fection, and demonstrating laboratory contamination of specimens or even of lab-
oratory workers (see Chap. 11).
Since the beginning of drug therapy for tuberculosis, unusual drug-suscep-
tibility patterns have been used for epidemiological purposes but with great limi-
tations. The development of a phage-typing system based on the use of 12 my-
cobacterial phages raised many expectations (39). Unfortunately, only four phage
types were officially recognized: Ao, Aox, B, and C. Type B was common in Eu-
rope 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 carry-
ing the IS are revealed (Fig. 1). This method is referred to as restriction fragment-
length polymorphism (RFLP) or DNA fingerprinting (42). As the distribution of
IS 6110 is variable from one strain to another in the number of copies (120) 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 band-
ing 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 char-
acterize individual strains of M. tuberculosis and conduct scientifically based epi-
demiological 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.
Bacteriology of Tuberculosis 169

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 pa-
tients. 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 com-
pounds against M. tuberculosis and conversely the susceptibility of different
strains of M. tuberculosis to a given compound became common. Well-defined in
170 Grosset et al.

vitro methods have been developed to measure the minimal inhibitory concentra-
tion (MIC) of drugs with known activity and of compounds with unknown activ-
ity 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 clin-
ical 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 in-
corporated into 10% oleic acid albumin dextrose catalaseenriched 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 80containing 7H9 broth at 37C for 7 days; then the turbidity of the re-
sultant suspension is adjusted with distilled water to match that of a standard sus-
pension 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 com-
pared with the growth on drug-free medium, after incubation at 37C for 2128
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 incorpo-
rated into the broth, with twofold dilutions. Then the drug-free and drug-contain-
ing broths are inoculated with the H37Rv strain and incubated at 37C. 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 tu-
bercle bacilli in clinal specimens. It has also been used to assess the airborne trans-
mission 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 (5255) because it is a small and robust
animal that is easy to reproduce and handle, even though it is far from being as
Bacteriology of Tuberculosis 171

sensitive as the guinea pig to M. tuberculosis. Furthermore, the course of the dis-
ease that follows experimental infection with M. tuberculosis is different from that
of the disease in humans. However, the mouse model is able to reproduce bacil-
lary 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 sophisti-
cated 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 suscep-
tible to all antituberculous drugs, is the strain of choice. After intravenous infec-
tion 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 multiplica-
tion 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 pop-
ulation 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 as-
sessment of all antituberculosis drugs, of standard streptomycin plus isoniazid
long-course therapy, and also of short-course therapy with the combination of iso-
niazid, rifampin, and pyrazinamide. It enabled the demonstration in vivo of the
bactericidal activity of the new fluoroquinolones, especially ofloxacin, lev-
172 Grosset et al.

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 tu-
berculosis, 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 se-
lection and multiplication of resistant mutants preexisting in the tubercle bacillus
population before therapy. Multiple drug resistance is the consequence of se-
quential monotherapies. Drug resistance observed before treatment, designated as
primary resistance, is the consequence of exposure to a drug-resistant source of in-
fection.
As the emergence of secondary drug-resistant M. tuberculosis strains and
even of multidrug-resistant strains, particularly in AIDS patients (64), is increas-
ingly reported from many countries (65), it is essential to determine the drug sen-
sitivity 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 sen-
sitivity of isolates from newly diagnosed, previously untreated patients because
these patients usually harbor drug-susceptible organisms and are started on stan-
dard therapy well before the results of the pretreatment drug susceptibility test
might be known.
However, newly diagnosed patients may have developed disease with pri-
mary drug-resistant organisms. They also may have been previously treated, and
the previous treatment may have remained undetected because it was not dis-
closed by the patients (66) or was forgotten by them. For these reasons, the Amer-
ican 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 tuberculo-
sis. 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 first-
line drugs isoniazid, rifampin, ethambutol, and streptomycin. Although pyrazi-
namide is also a first-line drug, it is not included in the priority list because its sus-
ceptibility 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 110% of the colonies grow in a control medium com-
pared to the number of colonies growing at the usual pH 6.8. Despite the inclusion
Bacteriology of Tuberculosis 173

of control media at pH 6.8 and 5.5, the results of pyrazinamide-susceptibility test-

ing 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 susceptibil-
ities of M. tuberculosis: the proportion method, the radiometric or BACTEC
method, which is based on the same principle as the proportion method, the abso-
lute 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 agar-
based 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 concen-
tration (Table 2) is that which inhibits the growth of susceptible organisms with-
out 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 di-
lutions 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)

BACTEC
Drugs 7H10 7H11 LJ 12B broth

Isoniazid 0.2 0.2 0.2 0.1

Rifampin 1 1 40 2
Pyrazinamide 25 ? 200 100
Ethambutol 5 7.5 2 2.5
Streptomycin 2 2 4 2
PAS 2 8 0.5 4
174 Grosset et al.

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 Lwenstein-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 sus-
pension of the primary culture, the turbidity of which has been adjusted to a Mc-
Farland 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 speci-
men 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 suscepti-
bility tests on solid media are obtained after 36 weeks of incubation at 37C. If a
direct susceptibility test has been performed from the patients specimen, the re-
sults are available at the same time as those of culture, 36 weeks after inocula-
tion (68). Those of an indirect susceptibility test are obtained 2 or 3 months after
the inoculation of the patients specimen.
Using the BACTEC 460 TB system, the results of drug-susceptibility test-
ing 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 (100-
fold 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 reli-

Table 3 Dilutions of Decontaminated Specimen for Inoculation

in Direct Drug Susceptibility Testing by the Proportion Method

No. of AFB observed per field

Suspensions Niehl-Neelsen Fluorochrome

to be inoculated (100) (40)

Undiluted and 102
1 19

101 and 103 19 1099
102 and 104 10 100
Source: Adapted from Ref. 68.
Bacteriology of Tuberculosis 175

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 produc-
tion 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
(7680). Because the mutations are localized in limited regions of the genes en-
coding for the drug target, they can be detected. After PCR amplification, the mu-
tation is identified by sequencing the PCR products or by submitting them to sim-
pler 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 po-
sition on the gel, which depends on the presence or absence of mutations, is then
characterized. In theory, the method is simple and rapid (4872 hr) and may be ap-
plied to smear-positive specimens. In practice, the method is costly, rather so-
phisticated, and above all does not permit detection of all mutations conferring re-
sistance, 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 hy-
bridized 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 Zwijn-
drecht, 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 resis-
tance (83,84).

VII. Immunodiagnostic Tests for Tuberculosis

The tuberculin skin test (see Chap. 12) is well established as an immunodiagnos-
tic test for tuberculosis infection. However, it can distinguish neither between ac-
176 Grosset et al.

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 re-
sistant sequences of the rpoB gene); Lanes 26: 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 infec-
tion and infection with other mycobacteria (85).
Because of the common antigens shared by all species of the genus My-
cobacterium, numerous efforts have been made to obtain and purify antigens spe-
cific to the M. tuberculosis complex. In addition, the most sophisticated proce-
dures to detect corresponding antibodies, such as immunoelectrophoresis,
hemagglutination tests, fluorescent antibody tests, radioimmunoassays, and en-
zyme-linked immunosorbent assays (ELISA), have been used. Despite all efforts,
increased specificity often resulted in decreased sensitivity (8688). Even with the
Bacteriology of Tuberculosis 177

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 recom-
mended for clinical use, research efforts should continue in order to develop an
immunological test which enables the discrimination of patients with active dis-
ease among the sputum smear-negative, symptomatic patients suspected of hav-
ing tuberculosis.

VIII. Direct Detection of M. tuberculosis by Nucleic Acid

Amplification

Because of the lengthy time required for cultivating M. tuberculosis, the applica-
tion of nucleic acid amplification for the rapid detection of M. tuberculosis nucleic
acids in clinical specimens has been extensively studied (3). Of the multiple PCR-
based (18,91) and nonPCR-based (9296) amplification procedures developed,
three have been made commercially available: the Gen-Probe Amplified My-
cobacterium tuberculosis Direct Test, or MTD (Gen-Probe Incorporated, San
Diego, CA), the AMPLICOR Mycobacterium tuberculosis Test (Roche Diagnos-
tic Systems, Inc., Branchburg, NJ), and the LCX Probe System (Abbott Labora-
tories, Diagnostic Division, Chicago). With these tests, and for smear-positive and
smear-negative clinical specimens, the sensitivity has been demonstrated to be
9596% and 4853%; the specificity to be 100% and 9699%; and the positive
predictive value to be 100% and 2458%, respectively (18,92,93,97101).
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 am-
plification 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 tu-
berculosis 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 spec-
imens because of the still lower prevalence of M. tuberculosis complex in ex-
trarespiratory than in respiratory specimens (107,108).
178 Grosset et al.

Although the wise recommendations of FDA emphasize the amount of care

clinicians should take in prescribing and interpreting the nucleic acidamplifica-
tion 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,
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8
Immunology of Tuberculosis

THOMAS M. DANIEL and JERROLD J. ELLNER

W. HENRY BOOM
UMDNJNew Jersey Medical School
Case Western Reserve University School Newark, New Jersey
of Medicine
and University Hospitals of Cleveland
Cleveland, Ohio

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 tu-
berculosis (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 do-
ing 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 ani-
mals could not do. Perhaps this observation led him to his ill-conceived recom-
mendation of tuberculin injections for the treatment of tuberculosis. This therapy
certainly paved the way for von Pirquets 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 re-
counted in review articles (3,4).
Pathologists had long recognized granulomas as the central histopathologi-
cal lesions of tuberculosis, and the role of granulomas in containing the spread of
disease was recognized from studies of clinical pathological material. Kochs ob-

187
188 Daniel et al.

servations provided experimental support for this view. Mackaness and cowork-
ers 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 War-
ren 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 func-
tion of these cells; as noted below, we now recognize diverse subsets of lympho-
cytes 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 factorslymphokinesthat are respon-
sible for the proliferation and activation of other immunoactive cells, a story that
has subsequently unfolded to reveal an extraordinarily complex and highly regu-
lated 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 me-
diated by cellular immunity. In this chapter we will review the immunology of tu-
berculosis, 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 re-
sponsible for the hosts responses to tuberculous infection.

II. Mycobacterial Protein Antigens

Immunologically competent cells of the human host recognize Mycobacterium tu-

berculosis 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 con-
stituents are presented to host cells under circumstances that favor antigenicity.
Following the description of an expression library for the entire genome of M. tu-
berculosis by Young and colleagues (9) and the cloning of genes for mycobacte-
rial 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 identi-
fication of further increasing numbers of antigens. Banks of monoclonal antibod-
ies 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
Immunology of Tuberculosis 189

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 ex-
tensively 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 mycobacte-
ria. The 65,000 dalton unit contains considerable helical structures and hydropho-
bic regions, characteristics typical of highly antigenic proteins. Studies with mon-
oclonal 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 mam-
malian proteins; these have been implicated in adjuvant arthritis and might be re-
lated to human autoimmune diseases (19). Because of the prominence of its non-
specific 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 dal-
tons, 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
190 Daniel et al.

(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 in-
hibition 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 pre-
pared 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 pro-
tein, 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 immu-
nization.

C. Antigens of the 85 Complex: Alpha Antigen

Harboe, Wiker, and colleagues used elegant crossed immunoelectrophoretic tech-

niques to show close immunological relationships between three antigens desig-
nated by them 85 A, B, and C (3437). 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 previ-
ously described as -antigen (38), antigen a2 (39), antigen 6 (40), and MPB-
59/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
Immunology of Tuberculosis 191

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 pro-
tein 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 hypersensi-
tivity, and it is of considerable interest that T lymphocytes of healthy M. tubercu-
losisinfected individuals react strongly to this antigen whereas those of patients
with active tuberculosis do not (49,50). This might suggest that decreased T-lym-
phocyte 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 mycobacte-
ria 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 in-
fected 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 fi-
bronectin-binding, secreted protein. It has a molecular weight of 31,00032,000
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 tubercu-
losis (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 mono-
clonal antibody, it was heterogeneous with respect to molecular mass, with iden-
tification 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
192 Daniel et al.

heterogeneity is presumed to reside with the antigenic protein itself. The molecu-
lar 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 iden-
tified 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 deter-
mined, 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 Calmette-
Gurin (BCG) (56).

III. The Mycobacterial Cell Wall: Mycobacterial

Adjuvants and Mycobacterial Polysaccharides

The mycobacterial cell wall is a complex structure with many elements of im-
munological importance. The external aspect of the cell-wall surface comprises
unique lipids containing long-chain mycolic aids. These are esterified to arabino-
galactan, the principal structural element of the cell wall. Interiorly, linked to the
arabinogalactan by phosphodiester bonds, is muramyl dipeptide. Each of these
three major elementsmycolic acid lipid, arabinogalactan, and muramyl dipep-
tidehas importance to the immunology of tuberculosis. Brennan, whose labora-
tory 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 arabinofura-
nosyl 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 wallassociated arabinomannan. Arabinogalactan readily elicits
antibodies in immunized experimental animals (58,59), but this polysaccharide in-
duces 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 (57,6062). The
Immunology of Tuberculosis 193

carbohydrate structure of this polysaccharide was originally elucidated by Misaki,

and it was shown to share an epitope-bearing polyarabinose side chain with ara-
binogalactan, which is the principal structural polysaccharide of the mycobacte-
rial cell wall (63). Circulating antibodies to lipoarabinomannan are easily demon-
strated 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 cy-
tokines, including transforming growth factor (TGF)-
but not tumor necrosis fac-
tor (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-posi-
tive 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 suggest-
ing 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-isoglu-
tamine) as an extremely potent adjuvant (71). This small peptide is phosphodies-
terified to cell-wall arabinogalactan, with which it forms water-soluble adjuvant.
The extensive studies of analogs of muramyl dipeptide by many workers have ex-
plored the structural features of this small molecule that confer upon it adjuvant
properties. Striking among these studies is the observation of Chedid and cowork-
ers (72) that substitution of the D isomer for L-alanine created an immunosuppres-
sive compound.
194 Daniel et al.

IV. Granuloma Formation

If one phenomenon can be thought of as central among the multiple manifesta-

tions of the immunology of tuberculosis, it is the formation of tubercleshyper-
sensitivity granulomas. These lesions, which characterize and distinguish the tis-
sue 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, al-
though this activation lacked the specificity usually associated with immunologi-
cal 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 my-
cobacterial antigens (75).

V. Cell-Mediated Immunity

Natural immune mechanismsmacrophages, natural killer (NK) cells, neu-

trophilslikely have an important role in the primary response to M. tuberculo-
sis and may suffice to control infection before development of the acquired im-
mune response in few individuals (76). However, in the majority of infected
persons the acquired immune response is responsible for control of M. tuberculo-
sis infection. T cells, as antigen-recognition units, have critical regulatory and ef-
fector roles in the immune response to M. tuberculosis, as demonstrated by stud-
ies in animal models and in humans with cellular immune deficiencies (7781).
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. Anti-
gen-activated T cells then secrete cytokines such as IFN-, which in turn stimu-
late macrophages to become more effective in controlling mycobacterial growth.
Recent observations in basic immunology and in studies of the human immune re-
sponse 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
Immunology of Tuberculosis 195

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. tuberculosisinfected macrophages (83,84). Third, macrophages, upon
exposure to mycobacteria, produce a large number of cytokines such as inter-
leukin (IL)-10, IL-12, IL-15, IL-18, TNF- , IL-1, IL-6, and TGF-
. Secretion of
cytokines with immunoregulatory properties extends the macrophages role be-
yond 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 re-
ceptors by class II major histocompatibility (MHC) molecules on antigen-pre-
senting 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-pro-
cessing 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 T-
cell proliferative responses and brisk IFN- production to soluble mycobacterial
protein antigens such as PPD (50). These memory CD4 T cells not only are re-
sponsible for controlling quiescent foci of infection but probably also provide pro-
tection 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 my-
cobacteria, 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. tu-
berculosis (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-tar-
geting methods, reconfirmed the central role of CD4 T cells in the protective im-
mune response to mycobacteria (93).
CD4 T cells exert their influence in the immune response to M. tubercu-
losis through secretion of cytokines and cytotoxicity for M. tuberculosis-infected
196 Daniel et al.

macrophages. Through cytokines (IFN-, GM-CSF, TNF- /

), CD4 T cells en-
hance the effector function of macrophages and regulate the IL-2mediated ex-
pansion 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 (9496). 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 con-
tactdependent 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. Classifica-
tion 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 as-
sociated with different functions, including macrophage activation and help for B-
cell 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 devel-
opment 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 re-
sponse to M. tuberculosisinfected macrophages. Both CD4 T-cell clones and
bulk T-cell populations stimulated with either PPD or live mycobacteria are effi-
cient cytotoxic effector cells (95,98100).
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 dimin-
ished CD4 T-cell function is reflected in decreased proliferative and IFN- re-
sponses to soluble protein antigens of M. tuberculosis, as well as diminished or ab-
sent 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 in-
hibit 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. tuberculo-
sisspecific 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-
Immunology of Tuberculosis 197

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 infec-
tion 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 im-
mune response to M. tuberculosis is the  T-cell receptor (TCR)bearing T cell
(105). Gamma delta TCRexpressing T cells ( T cells) form a distinct subset of
T lymphocytes, comprising 5% of T cells in lymphoid organs and 15% of circu-
lating 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 anti-
gen 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 my-
cobacterial antigens in footpads or lungs or to live bacteria in the peritoneum had
an expansion of  T cells (106108). 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 (106108). The activation of
 T cells by M. tuberculosis is dependent on antigen-presenting cells, and blood-
derived monocytes are particularly effective in this regard (109). In addition, alve-
olar 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-
198 Daniel et al.

cobacterial antigens have a greater ability to activate T cells in response to M. tu-

berculosis 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 mycobac-
terial antigen(s) recognized by V2  T cells. Increasing evidence suggests
that the V2  T cells are activated by phosphate-containing molecules
(112114). The first of these antigens to be identified were four TUBags isolated
from M. tuberculosis, described by Constant et al., which are small (/500 dal-
ton) phosphorylated molecules (112). Two of these (TUBag4 and TUBag3) con-
tain 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 (1014 kDa) from heat-
treated 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. tu-
berculosis 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 in-
fection in CD8 T-celldepleted mice. Consistent with these observations were
recent studies in which class I MHC restricted CD8 T cells specific for M. tu-
berculosis were found in the alveolar spaces of healthy tuberculin skin testposi-
tive 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 rec-
ognized 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-
Immunology of Tuberculosis 199

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 effec-
tor 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 re-
sponse 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 exclu-

sively determined by host T-lymphocytemediated cellular immune responses. At
the same time, one must acknowledge that B-lymphocytemediated humoral re-
sponses 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) usu-
ally 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 re-
mote healed tuberculosis do not have readily detected IgG antibody to mycobac-
terial antigens.
Many investigators have proposed serodiagnostic tests based upon the iden-
tification of IgG antibody to mycobacterial antigens, and new tests are being pro-
posed 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 di-
agnostic tests as do more highly purified antigens. No test has come into
200 Daniel et al.

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 faculta-

tive 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 T-
cell immune reactivity, little in terms of antibody response, few bacilli, and local-
ized disease. At the lepromatous end of the spectrum there are few and poorly
formed granulomas, specific hyporesponsiveness of T cells to mycobacterial anti-
gens, high titers of antibody, and multibacillary disease.
There have been several attempts to define a spectrum of disease manifes-
tations 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 testpositive donors express vigorous DTH and have low
titers of antibody directed against mycobacterial products. Pulmonary tuberculo-
sis, at least in the United States, usually is characterized by relative hyporespon-
siveness to tuberculin; 2025% of individuals with acute tuberculosis have a neg-
ative 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 self-
cure (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 pe-
ripheral 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 reduc-
tion in CD4 lymphocytes in correlation with reduction in total lymphocyte counts
(127). Active and specific immunosuppression is a factor in the depression of T-
cell blastogenic responses and expression of IL-2 in response to PPD (85,133).
Immunology of Tuberculosis 201

The mechanism of suppression appears to be unique. Monocytes primed during

the course of infection are stimulated directly by PPD or bacterial lipopolysac-
charide 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 pro-
duction 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 com-
partmentalization of antigen-reactive cells to sites of inflammation and/or selec-
tive 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 se-
lectively suppressed in patients with tuberculosis. For example, despite compara-
ble responses to sonicates of M. tuberculosis, 84% of healthy household contacts
and only 52% of treated and 48% of untreated patients with tuberculosis re-
sponded to the MTP40 (14,000 dalton) antigen (137). Similarly, tuberculosis pa-
tients showed selective hyporesponsiveness to the 30,000 dalton antigen. Seven of
eight healthy tuberculin reactors and none of six tuberculosis patients (post 620
weeks of treatment) were responsive to the 30,000 dalton antigen (138). Interpre-
tation of these findings is complicated by the consistent finding that tuberculosis
patients in the United States are hyporesponsive to PPD (139). Supportive obser-
vations are, however, available from Mexico City. None of 10 patients with newly
diagnosed pulmonary tuberculosis and 73% of 21 household contacts showed re-
sponses to the 30,000 dalton antigen of M. tuberculosis, whereas responses to my-
cobacterial 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 in-
dividuals 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 my-
cobacterial polysaccharides such as D-arabino-D-mannan and D-arabino-D-galac-
tan stimulate monocyte-dependent suppression of blastogenesis induced by non-
specific 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).
202 Daniel et al.

The finding that a polysaccharide antigen, presumably a major target of the anti-
body response to tuberculosis itself, suppresses T-cell reactivity is of interest as it
may contribute to the inverse and reciprocal relationships between T-cell re-
sponses and B-cell responses in tuberculosis as considered above.
Therapeutic intervention to modulate the spectral immune response in tu-
berculosis 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 my-
cobacterium originally isolated from soil in Uganda, has been proposed as an im-
munogen potentially capable of augmenting beneficial protective immune re-
sponses 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 re-
treated for chronic disease but not significant effects in patients receiving treat-
ment for the first time (145). Additional trials in Africa, which include HIV-in-
fected patients, are underway as of this writing.

VIII. HIVM. tuberculosis Interactions

HIV infection is the strongest known risk factor for the reactivation of a latent tu-
berculous infection. In a prospective study of a cohort of tuberculin skin testpos-
itive 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 tu-
berculosis in M. tuberculosisinfected, HIV-uninfected persons, which is esti-
mated to be 510% per lifetime. It also is clear that primary infection with M. tu-
berculosis is likely to progress rapidly to active tuberculosis in HIV-infected
persons. The current outbreaks of multidrug-resistant tuberculosis in HIV-in-
fected persons (149) are clear evidence of this phenomenon.
HIV infection increases the likelihood of a negative tuberculin skin test in
M. tuberculosisinfected 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 com-
pared 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 infre-
quent (
10%) in individuals with a CD4 count 500/L; below this level, how-
ever, 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
Immunology of Tuberculosis 203

defined using the CMI-Multitest in 46% of 50 HIV-infected individuals (152). Im-

portantly, 36% of HIV-infected tuberculin-positive persons had active tuberculo-
sis as compared to 8% of the tuberculin-negative persons. The notion that tuber-
culosis 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 testpositive with reaction sizes of 10 mm, as compared to 18% in the un-
matched 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 69 months before other AIDS-defining conditions (154). Atypical radio-
graphic presentations, often suggesting primary tuberculosis, are frequent and are
related to low CD4 cell counts (155). The T-cell dysfunction of HIV-infected in-
dividuals 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 tuberculo-
sis also accelerates the course of HIV disease (156). This effect requires active dis-
ease 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 tu-
berculosis 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 pro-
found impact on public health policy. Certainly, the potential benefits from pre-
ventive therapy for tuberculosis would be enhanced if, besides preventing tubercu-
losis, it prolonged the survival of HIV-infected individuals.

IX. Conclusions

Progress towards understanding the immune response to mycobacteria has accel-

erated in the last decade, but it remains for this progress to be translated into prac-
tical 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 con-
tinue to increase, driven by the magnitude of the global problem compounded by
the pandemic of HIV infection and outbreaks of multidrug-resistant tuberculosis.
204 Daniel et al.

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9
Transmission of Tuberculosis

EDWARD A. NARDELL WILLY F. PIESSENS

Harvard Medical School Harvard School of Public Health

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

From the perspective of the organism Mycobacterium tuberculosis, both trans-

mission 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 im-
portant 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 patho-
genesis.
Transmission begins with a human source, almost always a person with cav-
itary, 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 environ-
ment. 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
216 Nardell and Piessens

Figure 1 Tuberculosis propagationbiomedical model.

and frequency, and poorly defined characteristics of respiratory secretions that

permit effective aerosolization and preserve the viability and infectiousness of or-
ganisms. Effective chemotherapy is the single most important factor in reducing
infectiousness at any stage of the disease. Organisms that have developed resis-
tance 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 in-
fectiousness, assuring propagation in the community (1,2).
Tubercle bacilli are spread as droplet nuclei, the dried residue of larger res-
piratory droplets. Fluid lining the respiratory tract and any microorganisms con-
tained 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 (46). Rehydration on inhala-
tion is another critical environmental stress. Strains of tubercle bacilli undoubt-
edly vary in their innate resistance to environmental stresses, but these aspects of
TB aerobiology have not been investigated. Transmission occurs most efficiently
Transmission of Tuberculosis 217

in enclosed environments where the source, infectious droplet nuclei, and poten-
tial hosts are concentrated. The upper respiratory tract, where most airborne
droplet nuclei greater than 5 m in diameter are likely to impact, is highly resis-
tant 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 13 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 hy-
persensitivity 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 1015 generations, infection is aborted without an immunological record (tu-
berculin skin test negative). How often this occurs is, by definition, unknown.
Successful infection can progress to clinical disease after a 4- to 8-week incuba-
tion period (primary or progressive primary TB) or reactivate after a prolonged pe-
riod of latency (postprimary TB). Reactivation disease may occur at the site of im-
plantation 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 be-
fore 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
Manns 1924 Nobel Prizewinning novel, The Magic Mountain, travels to the
renowned international sanatorium Berghof at Davos, in the Swiss Alps, antici-
pating a 3-week visit with his cousin, Joachim, a patient with pulmonary tubercu-
losis (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, din-
ing, 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 pa-
tient. So common was TB in Europe and other industrialized countries in previous
centuries that infection was presumed to be nearly universal, unavoidable, possi-
bly hereditary, and difficult to link to so many potential exposures. Relative im-
munity derived from infection early in life (i.e., herd immunity), and the often
long latency period between infection and reactivation further blurred the associ-
ation between exposure and disease. Precautions to prevent transmission were un-
218 Nardell and Piessens

known in that era, although sanatoria treatment effectively served to isolate many
patients from the general population. Contrast the cavalier risk perception evident
in Manns novel with the 132-page, 1994 Guidelines for Preventing the Trans-
mission of Mycobacterium tuberculosis in Health-Care Facilities, intended to pre-
vent 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, lim-
ited resources for better control, herd immunity, low health expectations, and in-
adequate 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 Kochs discovery of the tubercle bacillus in 1882,

William Firth Wells, working initially at Harvard University and later at the Uni-
versity 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 ear-
lier 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 ob-
servation, his brilliant intellectual leap was postulated: Respiratory droplets gen-
erated 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-
Transmission of Tuberculosis 219

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.
Rileys 1961 monograph, Airborne Infection, summarized and updated Wellss
earlier work (3). In the 1960s, Loudons group focused on cough and the behav-
ior 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, Rileys 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 stim-
ulated new research focused on air disinfection.
Although investigations on the aerobiology of TB stagnated, the aerobiol-
ogy 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 (46). 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 un-
derlying these phenomena have been explored and mathematical models derived
that correlate well with experimental data (46). These data have potential practi-
cal 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 hu-
man 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 cap-
ture 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).
220 Nardell and Piessens

Nucleic acidamplification technologies have also been applied to air sampling

for TB, with limited success (18). As already noted, it is believed that the vast ma-
jority of airborne tubercle bacilli are inactivated due to the stresses of aerosoliza-
tion, transport, and air sampling, but it is difficult to judge viability, much less in-
fectivity, 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 in-
formation on TB infectivity, its variability, the impact of chemotherapy, and the
potential benefits of air disinfection (in ventilation ducts) with ultraviolet irradia-
tion.

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 viru-
lent human TB. Using quantitative culture methods, aerosols were made so dilute
that inhalation of more than a single infectious droplet by test animals was statis-
tically 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 pa-
tients with potentially infectious TB. These experimental conditions have been es-
tablished only once, during the remarkable 4-year study at the Veterans Adminis-
tration 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 ger-
micidal irradiation in the exhaust duct was a highly effective method of air disin-
fection (19,2124).
The study had limitations. Among 61 untreated patients with drug-suscepti-
ble organisms, only 8 infected any guinea pigs, and among 6 untreated patients
Transmission of Tuberculosis 221

with drug-resistant organisms, only 2 proved infectious to guinea pigs. From a to-
tal of 40 patients under chemotherapy, only 2 infected guinea pigs. Thus, the in-
fectivity of many tuberculosis patients with positive sputum was too low to be de-
tected 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 atten-
tion is called to what Riley called disseminators, individuals who for various
reasons infect a high proportion of their contacts (24,25). Although often the sub-
ject of epidemiological investigations, it is unclear how much these unusually in-
fectious 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 condi-
tions, strain hardiness, virulence, and host susceptibility. While many of these fac-
tors were controlled in the guinea pigexposure 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 re-
actions 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 repre-
sented 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 cal-
culated 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 Rileys 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-
222 Nardell and Piessens

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 cav-
ity 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 posi-
tive, and 54% of the men in the second compartment converted. The rate of con-
version 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 com-
partment. 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 prin-
cipal environmental risk.

B. Mathematical Models of Transmission

In a report on a measles outbreak in a suburban elementary school, the quantita-

tive assessment of airborne infection was further refined (29). The results are di-
rectly 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 cultur-
able 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 re-
peated inhalations during one or more exposure until one inhalation results in in-
fection. 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 infec-
tion during ordinary exposures is statistically unlikely. Poissons law of low-prob-
ability events comes into play. Even when highly susceptible guinea pigs were ex-
posed 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%
Transmission of Tuberculosis 223

became infected (some animals, by chance, inhaling more than one droplet nu-
clei), 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 per-
sons and the virulence of the TB strain. However, for the purpose of mathemati-
cal modeling, we will use Wellss quanta of infection, understanding that for
humans a quantum of infection for TB and most other infections cannot be con-
verted to numbers of droplet nuclei inhaled over one or many exposures. This con-
venience, however, permits useful quantitative insights into transmission and its
control.
In studying the school measles outbreak in upstate New York, Edward Ri-
ley expanded and modified Wellss 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 genera-
tion 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 condi-
tioning (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 out-
break 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 infectious-
ness, as was seen in tuberculosis patients on Rileys experimental ward, but the
rate of production of infectious airborne particles was much higher. The mathe-
matical model developed to analyze the measles outbreak has been applied to sev-
eral episodes of TB transmission, of which two instructive examples will be men-
224 Nardell and Piessens

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 smearpositive 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 sus-
picion 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-Ri-
ley 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 exper-
imental 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 accept-
able 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 212 hours of the pro-
cedures, 10 of 13 susceptible room occupants became infected (31). By calcula-
tion, 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 venti-
lation rate in the intensive care unit was extremely low, and further calculations
predicted substantial improvements by increases in ventilation that were achiev-
able (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-Ri-
ley 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
Transmission of Tuberculosis 225

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 de-
rived from an epidemiological model, the Wells-Riley equation has much in com-
mon 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). Epidemiologi-
cal 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 as-
sumed 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 po-
tentially pathogenic oral-pharyngeal bacteria are routinely aspirated without caus-
226 Nardell and Piessens

ing pneumoniaapparently cleared by lung defenses. In guinea pigs and suscep-

tible strains of inbred rabbits, however, experimental exposure studies using di-
lute aerosols (confirmed by culture) have shown that a single inhaled droplet nu-
cleus, 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 infec-
tion 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 Rileys experimental tuber-
culosis 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 radio-
graphs 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 prob-
ability 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 tu-
bercle 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 rel-
atively little microbicidal capacity or where bacilli are fully virulent even hyper-
virulent, the infecting dose will be low, probably as little as a single droplet nu-
cleus. 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 (3638).
The belief that TB infection is caused by the chance implantation of single
infectious droplet nuclei containing few organisms does not explain epidemiolog-
ical observations over the years that more extensive disease has been associated
with situations of high exposure. For example, in Canada, Grzybowski and col-
Transmission of Tuberculosis 227

leagues observed among both Caucasians and indigenous peoples, that household
contacts of smear-positive tuberculosis cases not only had higher rates of infec-
tion, but were almost three times more likely to go on to active disease (39). Ear-
lier, Grzybowski had also shown more extensive calcifications of primary lesions
(more disease) among children infected through household contact (greater expo-
sure) 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 set-
ting, including homeless shelters, residential AIDS facilities, prisons, and, most
strikingly, health-care facilities (4148). Among the earliest and best studied out-
breaks 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 per-
mitted 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 unclus-
tered 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 3040% 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 hos-
pitals (50). Molecular markers were also used in the investigation of an extensive
outbreak in a rural setting, providing evidence that organisms of increased viru-
lence may have been responsible (25).
While these outbreaks added relatively little to our understanding of the ba-
sic aerobiology of M. tuberculosis, they do teach many lessons about its spread in
communities and congregate settings. Health-care providers, institutional admin-
istrators, and even infection-control practitioners had grown lax about the poten-
tial for transmission in close communities, where most exposed persons are now
fully susceptible to infection. Moreover, no one could have predicted the potenti-
ating effect of HIV co-infection on TB transmission, where newly infected per-
sons progressed rapidly and almost invariably to secondary, infectious disease. In-
effective 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 ex-
ample, it was common to administer aerosolized pentamidine, an effective agent
228 Nardell and Piessens

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 pa-
tients (47). In persons with HIV infection, cough, fever, weight loss, and lung in-
filtrates are common and have a low predictive value for TB, whereas lung cavi-
ties 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 sus-
pected 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 detailparticularly respirator usage and the main-
tenance and testing of isolation rooms. Surgical masks permitted extensive face-
seal 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 germi-
cidal 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 agen-
cies, 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
Transmission of Tuberculosis 229

1992, ultimately revising its testing and classification of respirators to the current
system in 1995 (53). The American College of Chest Physicians and The Ameri-
can 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 com-
pliance 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 publica-
tion 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 guide-
lines, 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 trans-
mission in acute care hospitals. These recommendations, their rationale, and ex-
tensive 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 assess-
ment, institutions are expected to formulate comprehensive TB infectioncontrol
plans, with clear lines of administrative accountability. In the 1994 CDC guide-
lines (9), five levels of risk are defined, ranging from minimal to high, with in-
creasing control measures recommended for each risk level. Staff TB risk-aware-
ness training at all levels is recommended, including knowledge of the signs and
symptoms of TB, to encourage prompt identification of suspect cases. Adminis-
trative controls, including identification and triage of suspect cases, is the corner-
stone of the CDC control strategy. Suspects are to be identified promptly and
placed in special TB isolation rooms. Engineering controls for isolation and pro-
cedure 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 irradia-
tion.
A controversial part of the CDC guidelines (9) has been the role of personal
respiratory protection (5658). Although generally considered least desirable in
the hierarchy of controls in industrial settings, the inability to effectively eliminate
230 Nardell and Piessens

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 ventila-
tion 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 dis-
posable respirators appropriate for droplet nuclei-size particles in clean, nonin-
dustrial 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 sur-
gical masks. While the original concerns over the cost and practicality of indus-
trial-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 effec-
tively (61,62). Many hospital infection-control experts, however, find the practice
burdensome and unlikely to be very effective when applied to disposable respira-
tors that inherently have relatively large percentages of face-seal leak. Critics ar-
gue 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 contri-
bution of each of the componentseducation, early detection, triage, isolation,
skin testing, air disinfection, and respirator useis not known (64,65).

VII. Preventing Transmission from Unsuspected Cases

of Tuberculosis

In the view of many experienced observers, unsuspected cases of infectious, pul-

monary 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
Transmission of Tuberculosis 231

unsuspected cases (67). The nonspecificity of the signs and symptoms of TB,
against a background of extremely common symptoms due to other respiratory ill-
nesses, together with often insensitive and nonspecific diagnostic tests assures that
both underdiagnosis and overdiagnosis will persist as obstacles to effective and ef-
ficient 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 respi-
ratory illnesses. Lowering the index of suspicion for TB isolation is the appropri-
ate 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 underdiag-
nosis 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, of-
ten 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 en-
gineering 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 pas-
sive or active ventilation, is the mainstay of general air disinfection in most insti-
tutions in resource-rich countries (73). However, as noted above, dilutional venti-
lation 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
232 Nardell and Piessens

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 ir-
radiation has been recommended (9). Although air filters less efficient than HEPA
should be highly effective in retaining airborne particles in the range of 15 m
in diameter, HEPA has become the standard for air disinfection in clinical and lab-
oratory settings (75). HEPA filters can be used in the return ducts of central ven-
tilating 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 buildings 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-disinfec-
tion room units and even more efficiently in booths and partial enclosures de-
signed for sputum induction and aerosol therapy. In large rooms, free-standing air-
filtration 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 us-
ing room units of various design have generally shown rapid and effective air dis-
infection (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 disinfec-
tion. The exponential decay curve in Figure 2 suggests that doubling room venti-
lation, 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 reduc-
tions 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 dam-
age to other essential proteins (76). Sublethal genetic mutations may also occur,
some of which are reversible. As depicted in Figure 1, exposure to natural envi-
ronmental irradiation is believed to be one of the stresses that limits airport trans-
Transmission of Tuberculosis 233

port of microorganisms (5). However, indoors, where person-to-person transmis-

sion 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 earths at-
mosphere. Because it cannot pass through ordinary window glass, whatever solar
radiation is present in enclosed spaces is the more penetrating, but much less bio-
logically 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 wave-
length, close to the 260 nm peak of the germicidal action spectrum. The avail-
ability of inexpensive germicidal irradiation provides another attractive supple-
ment 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 com-
pletely absorbed by the outer, dead layer of human skinthe 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 microor-
ganisms 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 be-
cause intensive exposure has caused skin cancer in hairless mice, but in an un-
published presentation at the National Centers for Disease Control in Atlanta, Ur-
bach calculated that human skin cancer under the current exposure limits would
require more than 300 years (79). Likewise, short-wavelength UV cannot pene-
trate 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 acci-
dental direct exposure to high-intensity lamps, most often among maintenance and
other workers. Because the onset of symptoms is delayed for hours, early photo-
conjuctivitis is not a useful warning sign. Well-designed fixtures, proper installa-
tion, metering with a sensitive 254 nm instrument, warning labels, and worker ed-
ucation are the most important ways to assure safe use of germicidal UV.
234 Nardell and Piessens

The efficacy of germicidal UV in killing or inactivating a wide range of mi-

croorganisms is well established, having been quantified by countless experi-
ments over more than 50 years (81). How best to apply germicidal UV in build-
ings to prevent airborne transmission, however, remains controversial. UV has
been employed in ventilation ducts in an effort to reduce the recirculation of in-
fectious airborne organisms and has the advantage over HEPA filtration of adding
little flow resistance to the system. While UV air disinfection in ducts avoids ex-
posure of room occupants, this application has limitations similar to those of ven-
tilation 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 base-
line conditions. For large-volume spaces, such as emergency rooms and homeless
shelters, noise and drafts due to the high flow rates required are significant limi-
tations.
Another approach to the application of germicidal UV is upper room air dis-
infection. The advantages of upper room UV air disinfection have been appreci-
ated 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 cur-
rents 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 (16,8385). 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 se-
rious limitation, as noted above. Perhaps the greatest limitation of upper room UV
air disinfection is the uncertainty over the equivalent germ-free ventilation pro-
duced under field conditions, because this depends on the extent of room air mix-
ing, which is not controlled. Details on the application of upper room UV air dis-
infection 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 en-
gaged in new research intended to fill in missing gaps in our current understand-
ing, particularly with regard to optimal fixture design and deployment in rooms in
relation to mechanical ventilation. In addition to bench-scale and room-scale ex-
periments on such factors as the effects on high humidity, a multicenter, placebo-
controlled trial of upper room UV air disinfection in homeless shelters is under-
way. 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 stud-
ies are essential if the technology is to be used where it is most neededin many
parts of the developing world where institutional transmission of multidrug-resis-
tant TB is common and where alternative technologies are either unaffordable or
unavailable.
Transmission of Tuberculosis 235

B. Transmission in High-Prevalence Countries

Although the recent TB resurgence focused attention on institutional TB trans-

mission 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 out-
side 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 can-
not 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, effec-
tive treatment remains the most important infection-control intervention, espe-
cially when treatment occurs primarily in the community (2). In high-prevalence
countries, respiratory isolation is often difficult but may be possible in some set-
tings. 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 de-
veloping 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 epi-
demiology 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 commu-
nity-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). Sev-
eral other pilot projects utilizing a similar strategy, called DOTS-Plus, are be-
ing initiated by WHO in other focal areas of MDRTB (92). A current barrier are
236 Nardell and Piessens

the considerable financial resources needed to diagnose and effectively treat

MDRTB in developing countries.

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10
Pathogenesis of Tuberculosis

WILLY F. PIESSENS EDWARD A. NARDELL

Harvard School of Public Health Harvard Medical School

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

I. Introduction

Host immune responses determine to a large extent the ultimate outcome of in-
fection with Mycobacterium tuberculosis in at least two disparate ways: by par-
ticipating 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, pre-
vention, and control of human tuberculosis.
In this chapter the mechanisms of innate and acquired resistance to M. tu-
berculosis, various strategies used by tubercle bacilli to survive in this hostile en-
vironment, 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 re-
viewed 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 de-
scribes some of the changes in host immune responses to tubercle bacilli result-
ing from coinfection with HIV. However, it is not intended to be a comprehen-
241
242 Piessens and Nardell

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 proto-
typical 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 ded-
icate this chapter.

II. Stage 1 (Week 1): Invasion

Tuberculosis infection can be initiated by ingesting, inoculating, or inhaling viru-

lent 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 alveo-
lar surface to begin infection through inhalation of droplet nuclei that are small
enough (~12 m) to reach the lower respiratory tract. Three main factors deter-
mine whether exposure to tubercle bacilli results in infection: the infecting dose,
the strength of innate host resistance, and the virulence of the infecting mycobac-
teria. The outcome of the initial contest between the host and M. tuberculosis de-
termines whether infection occurs. If the bacilli are inhibited or killed by the alve-
olar 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 lo-
cal 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 in-
dividuals. Multiple or recurrent inhalations are unlikely, however, unless expo-
sure is prolonged or at close range or the source case is unusually infectious. Un-
der 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 tu-
berculosis ward over a 4-year period (4).
Pathogenesis of Tuberculosis 243

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 bacterio-
static 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 re-
ceptor-mediated phagocytosis, in which cellular pseudopodia move circumferen-
tially around the bacilli and then fuse, leaving M. tuberculosis in a membrane-
lined vacuole, the phagosome. The bacillus is a passive participant in the invasion
process. Alveolar and other types of mononuclear phagocytes possess many dif-
ferent receptors involved in phagocytosis of various particles and pathogens. IgG
antibodycoated 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). Com-
plement receptors interact with C3 deposited on M. tuberculosis when the bacte-
rial 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 re-
ceptors 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 mono-
cytes 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 de-
velops and thus modulate innate resistance. For example, human surfactant pro-
tein A (SP-A), which regulates the level of lung surfactant, enhances phagocyto-
sis 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. tuberculosisspecific T
cells will be discussed below in the context of acquired immunity.
244 Piessens and Nardell

Table 1 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 pro-
teins, 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 nu-
trient and produces picolonic acid, which acts synergistically with IFN- to activate
macrophages.
7. Reactive nitrogen oxides (RNOs) and intermediates (RNIs): Enzymatic conversion of L-
arginine 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 re-
cently (12), but some points deserve emphasis. First, while important in mice, the
role of reactive nitrogen intermediates (RNIs) in the antibacterial activity of hu-
man 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 mecha-
nism 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.
Pathogenesis of Tuberculosis 245

C. Bacillary Virulence

Virulent tubercle bacilli have evolved a wide range of mechanisms to resist host-
defense mechanisms. Historically, many different criteria have been used to de-
fine 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 in-
side nonphagocytic cells has been identified and cloned (15). Its mode of action is
unknown, but different parts of the invasion gene encode the factors responsi-
ble 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 lyso-
somal 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-AT-
Pase (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. tu-
berculosis escapes from fused phagolysosomes into nonfused vesicles or the cy-
toplasm, where virulent but not avirulent bacilli are able to multiply (19).
Mycobacteria also resist digestion by scavenging O2 with LAM, by induc-
ing detoxifying enzymes such as catalase and superoxide dismutase and protec-
tive 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 heat-
shock 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.
246 Piessens and Nardell

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 im-
mune 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 un-
known. 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 ini-
tial tuberculosis infection (25). Others contest this explanation because it is diffi-
cult to separate biological from socioeconomic and demographic risk factors as-
sociated with race (2628). This is perhaps best illustrated by the finding that
racial differences in susceptibility to infection were observed among elderly resi-
dents 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 accumu-
lating.
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 ac-
quired 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-celldependent immune effector mech-
anisms. The mouse gene, which has been renamed the gene for natural-resistance-
associated macrophage protein 1 (Nramp 1), encodes an integral membrane pro-
tein that is expressed only in a late endocytic subcellular compartment. Upon
phagocytosis, the protein is recruited to the membrane of the phagosome and re-
mains 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 elimi-
nate divalent cations from the phagosomal interior and thereby deplete this com-
partment 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
Pathogenesis of Tuberculosis 247

susceptibility to tuberculosis in West Africa (31). One of the variant NRAMP1 al-
leles 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 genelike 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 dif-
ferential permissiveness observed in vitro may have a phenotypic rather than a ge-
netic underpinning, because the difference is magnified when the cells are cul-
tured in medium supplemented with autologous serum, and the permissiveness of
macrophages from African American donors is corrected by addition of 1, 25-
OH 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. in-
tracellulare, 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 resis-
tance 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 al-
lele 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 (3538). This extraordinarily rapid rate of progression
to active disease may reflect the inability of HIV-infected individuals to develop im-
mune 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 hosts
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 al-
ters the pattern of cytokine production, impairs the ability of monocytes and
macrophages to serve as accessory cells for T-cell proliferation, and affects the elab-
oration by resident macrophages of proinflammatory leukotrienes and other
5-lipoxygenase metabolites of arachidonic acid (42,43). The resulting decrease in
248 Piessens and Nardell

macrophage activating cytokines (e.g., IL-12) and the concomitant increase in de-
activating cytokines (e.g., IL-10) combined with defects in chemotaxis, receptor-
mediated 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 at-
tracted to the focus and develop into immature macrophages. The latter cells read-
ily 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 or-
ganisms are present and local cell-mediated immune responses are triggered (2).
In both immunized and nonimmunized guinea pigs, bacillary growth is unim-
peded 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 con-
trols 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 his-
tologically 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 le-
sion 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-
Pathogenesis of Tuberculosis 249

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 co-
incides 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 de-
scribe 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 hypersensitiv-
ity refers to the cytotoxic immune process that kills the nonactivated immature
macrophages that permit intracellular multiplication of tubercle bacilli (48). De-
spite 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 immunol-
ogy 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 (5153).
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. Neu-
tralization and gKO experiments indicate that both IFN- and TNF- are essen-
tial 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 tuber-
culosis as well (54,55). IFN- has been used with success to treat human tubercu-
losis 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 (5860). As noted earlier, the role of RNIs in
the killing of M. tuberculosis by human macrophages remains uncertain.
250 Piessens and Nardell

In the second pathway, M. tuberculosisinfected macrophages are killed by

cytolytic T lymphocytes (CTL). This DTH-like process benefits the host by de-
stroying 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 cen-
ter of the developing granuloma. Released bacilli can also be ingested and killed by
T-cellactivated macrophages in the vicinity and killed intracellularly.
Several types of M. tuberculosisspecific 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 deter-
minants on the target macrophages. The cells kill infected target cells by inducing
Fas-mediated apoptosis; the latter process also can reduce the viability of intra-
cellular 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 CD1-
restricted 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, in-
fected 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 tuber-
culosis. However, studies in mice suggest that these cell populations are not es-
sential 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-ac-
tivating cytokines (65). Alternatively, T cells influence local cellular traffic to tu-
berculous lesions by promoting the influx of monocytes and lymphocytes and lim-
iting 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 acti-
vated 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 be-
lieved 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-
Pathogenesis of Tuberculosis 251

gans, caseation necrosis reduces the bacillary population to a low level of organ-
isms 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 stimu-
lants of caseous necrosis, which involves several poorly defined processes in addi-
tion 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 ac-
tivated 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 chemoat-
tractant 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 pre-
senting mycobacterial antigens by M. tuberculosisspecific 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 in-
hibitor of TNF- mRNA expression, is under investigation. Alternatively, cells in the
center of the granuloma degenerate because they are exposed to concentrations of cy-
tokines that are too low to suppress mycobacterial growth.
3. Ischemia from thrombosed blood vessels: Activated macrophages produce pro-
coagulant 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.
252 Piessens and Nardell

epithelial cells infected with M. tuberculosis (7173). 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 pro-
gressively 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, ep-
ithelioid 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 granu-
lomas are replaced with virgin CD8 cells and granulocytes in the necrotic lesions.
Studies in gKO mice indicate that TNF- and IFN- are essential for granu-
loma formation. These cytokines are not sufficient, however, because their levels
are elevated in SCID mice that do not develop tuberculous granulomas (53). Ad-
ministration 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 de-
creases 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 re-
quired 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 pro-
gressive hydrolysis of protein, lipid, and nucleic acid components of caseated tis-
sues by hydrolytic enzymes from host cells and/or mycobacteria. Exactly what
triggers the onset of liquefaction is unknown, but mycobacterial toxins are be-
lieved 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 Luries rabbits. Host factors also contribute to tissue damage.
Pathogenesis of Tuberculosis 253

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 formedthe characteristic radiographic and pathological
presentation of tuberculosis and other chronic, granulomatous infections. The lo-
cal inflammatory response to the sudden spillage of necrotic, highly antigenic, in-
fectious liquid within the lungs is recognized clinically as a tuberculous pneu-
monitis. 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 eventstress, treatment with steroids or chemother-
apeutic drugs, HIV infection, alcohol, malnutrition, etc.perturbs this equilib-
rium, 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 tis-

Table 4 Effect of Cytokines and Other Mononuclear

Cell Products on Macrophage Activation for M. Tuber-
culosis Control

Activating molecules Deactivating molecules

IL-2 IL-1
IL-4 IL-3
IL-7 IL-6
IL-12 IL-10
GM-CSF TGF-
TNF- Prostaglandin E2
TFN-
IFN-
1,25-(OH)2D3
(Calcitriol)
Information shown is based on a variety of models for human tu-
berculosis.
Source: Adapted from Refs. 22, 85, 86.
254 Piessens and Nardell

sue, but the cavitary fluid permits extracellular multiplication of mycobacteria, of

which large numbers accumulate in tuberculous cavities (108 in Luries 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 infec-

tion 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 dis-
ease occasionally leads to cavitary tuberculosis, this outcome usually results from
a second (postprimary) phase of disease activity that occurs months to decades af-
ter apparent recovery from the initial infectious process. As was noted above, it is
unclear what event triggers this endogenous reactivation at the cellular and molec-
ular 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 ge-
netic methods (see Chap. 11) clearly indicates that exogenous (re)infection can
also lead to cavitary tuberculosis. The relative frequency of endogenous reactiva-
tion 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 sit-
uations of low prevalence and vice versa. Even though they lead to the same clin-
ical endpoint, distinguishing the two pathogenic pathways may be important for
optimal management of tuberculosis. Primary tuberculous lesions occur through-
out the lungs but are most common in the lower lobes because of the air flow dis-
tribution; 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 re-
sistance is weak (68,84). In the guinea pig model on which this hypothesis is par-
tially based, BCG does not protect against a primary infection but reduces the re-
sultant 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 consis-
tent with the results of some human BCG trials.
Liquefaction necrosis is of major public health importance because the re-
sulting cavitation connects the infected site with the environment and thus pro-
Pathogenesis of Tuberculosis 255

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 ac-
tivated 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 others activities via mixtures of sol-
uble 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. Vir-
ulent tubercle bacilli dysregulate this delicate balance and pervert some host re-
sponses 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 dis-
eased human tissues and body fluids. This approach should permit a reappraisal of
concepts based on the older models and improve our understanding of the patho-
genesis 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; 125:2529.
2. Lurie MB. Resistance to Tuberculosis: Experimental Studies in Native and Acquired
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11
Mycobacterial Strain Genotyping

NANCY D. CONNELL BARRY N. KREISWIRTH

New Jersey Medical School Tuberculosis Center

National Tuberculosis Center and Public Health Research Institute
and International Center for Public Health New York, New York
UMDNJNew Jersey Medical School and International Center for Public Health
Newark, New Jersey 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 suscep-
tibility patterns (1). The comparison of strains has evolved from analysis of pro-
tein products (phenotyping) to the analysis of genetic content (genotyping). DNA-
based 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 trans-
mission in cites (68), nosocomial outbreaks (911), and congregate settings
(1214); to study transmission among high-risk populations such as HIV-positive
and homeless persons (16,17); to evaluate cross-contamination in the clinical lab-
oratory (1820); and to analyze sequence changes as they reflect rates of molecu-
lar 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
262 Connell and Kreiswirth

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 030 copies in the M. tuberculosis complex genome. In San Francisco,
clinical strains of M. tuberculosis lacking IS6110 are estimated to occur at a fre-
quency 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 chro-
mosome (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 el-
ement, 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 (ma-
jor 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 re-
action (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).
Mycobacterial Strain Genotyping 263

Figure 1 IS6110-based DNA fingerprint patterns from the collection of isolates of My-
cobacterium tuberculosis maintained by the Public Health Research Institute, New York.
Molecular weight makers are along the right margin. Lanes 112 are examples of the W
strain group from various locales, as follows: 12, Singapore; 37, Russia; 8, Kenya; 911,
New York City; 12, New Jersey. Lanes 1319 are strains reflecting the range of RFLP fin-
gerprint 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.
264 Connell and Kreiswirth

C. Single-Strand Conformational Polymorphism

The analysis of drug-resistant isolates of M. tuberculosis on the basis of compar-

ing 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 au-
tomated 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 57 bp. In addition, the number of spacers is variable: BCG has 49 DR spac-
ers 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 characteris-
tic 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 with-
out waiting for expansion of the culture.
IS6110 fingerprinting becomes less differentiating as a strains copy num-
ber decreases. Clinical strains with fewer than five copies of IS6100 are generally
analyzed by alternate means (see below). Several direct comparisons of spoligo-
typing and IS6110-based RFLP indicate that the DR locus can discriminate among
strains containing as few as one copy of IS6110 (3436). 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-
Mycobacterial Strain Genotyping 265

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 differentia-
tion 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 addi-
tion, the complete H37Rv genome sequence has been annotated and published
(26). The circular chromosome contains 4,411,529 base pairs with 3,918 protein-
coding 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 hy-
bridization 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 Eu-
rope (RIVM in the Netherlands, BA Bilthoven, The Netherlands) to track on an in-
ternational basis the spread of this airborne pathogen. In general, these tools are
able to determine whether the isolates recovered from a localized outbreak of dis-
ease 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 re-
lated as a consequence of recent spread. Examples of related and unrelated IS6110
DNA fingerprint patterns are illustrated in Figure 1. Lanes 112 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 1319), 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-
266 Connell and Kreiswirth

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 signifi-
cance among related strains from geographically diverse regions.
A further limitation in IS6110 subtyping is reflected in large outbreak stud-
ies 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 pat-
tern caused disease in more than 350 patients. In the same outbreak investigation,
eight additional multidrug-resistant strains were identified that shared the major-
ity 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 meth-
ods. 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 pyrazi-
namide-resistant and 51 pyrazinamide-susceptible isolates recovered from diverse
geographical localities and anatomical sites. The pncA gene encodes pyrazinami-
dase, which converts pyrazinamide to the active form pyrazinoic acid. Surpris-
ingly, the wild-type alleles of all 51 susceptible strains were identical: this re-
stricted 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 re-
sistance (katGisoniazid; rpoBrifampin; embBethambutol; rpsLstrepto-
mycin; pncApyrazinamide, rrskanamycin) 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 us-
ing other secondary typing methods. This family is now defined based on all of
Mycobacterial Strain Genotyping 267

Table 1 Antibiotic Resistance Loci Used to Confirm Genetic Relatedness of RFLP

DNA Fingerprint Group W Strains

Antibiotic Genetic locus Alterationa Ref.

Isoniazid katG 315:ST 8

Rifampin rpoB 526:HY 8
Ethambutol embB 306:MI/V 43
Streptomycin rpsL 43:KR 8
Pyrazinamide pncA 47:TA 42
Kanamycin rrs A1400Gb 44
a
The affected codon is indicated, followed by the specific amino acid change from susceptible to re-
sistant.
b
The nucleotide A at position 1400 is changed to G in resistant strains.

the following molecular properties:

1820 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 polymor-

phism 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 signifi-
cantly fewer polymorphisms when compared to strains collected in the Nether-
lands (4749). Similarly, an analysis of clinical M. tuberculosis strain genotypes
was carried out with isolates obtained from the Peoples Republic of China and
Mongolia (50). More than two thirds of the strains evaluated exhibited closely re-
lated IS6110 profiles. The similarities observed in RFLP lengths were analyzed by
IS6110 hybridization and were confirmed when further analyzed by two sec-
ondary genotyping methods, using IS1081 and spoligotyping. Limited polymor-
phisms 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
268 Connell and Kreiswirth

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 de-
scribed. Computer analysis (48) found that genotypes of members of the W-MDR
and W-SUS (susceptible) families had many comigrating bands, suggesting ge-
netic relatedness among these strains (46). Further examination of the specific in-
sertion 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 worlds M. tuberculosis strain col-
lections. 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 se-
quences (2 million base pairs) among 26 different genes in 842 clinical M. tuber-
culosis complex strains representing 40 countries on every continent (21). Three
phylogenetic groups of M. tuberculosis were identified on the basis of two poly-
morphisms 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 evolu-
tionarily 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 chro-
mosome required for initiation of DNA replication. RFLP genotypes and detailed

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

Alterations

M. tuberculosis
Group Species strains Codon changes

1 M. microti W, Houston katG463 CTG (leu)

M. africanum gyrA95 ACC (thr)
M. tuberculosis
2 M. tuberculosis C, Houston katG 463 CGG (arg)
Erdman gyrA95 ACC (thr)
3 M. tuberculosis H37Rv, H37Ra katG463 CGG (arg)
gyrA95 AGC (ser)
Mycobacterial Strain Genotyping 269

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 super-
family, common throughout Asia, including China, South Korea, Thailand, and
the Philippines (5153). 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 ethnic-
ity. 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 (48,5659). On the other hand, group 1
genotypes were found in 16 of 49 (33%) isolates from Singapore, a city with ap-
proximately 40% ethnic Chinese. Scrutiny of the New York and Houston epi-
demiological 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 in-
sertion 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, sug-
gesting 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 be-
tween 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 re-
cent computer-based analysis also indicates that the M. tuberculosis genome con-
tains 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 propo-
sition that transposition of IS6110 and other repetitive elements might be an im-
270 Connell and Kreiswirth

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 in-
terrupting 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 even-
tually shown to be a portion of an operon with two open reading frames (mpcA and
mpcB) encoding proteins homologous to hemolytic phospholipases (20). Remark-
able 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 compre-
hensive 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 immunodefi-
ciency virus (10,7072). Population-based studies of transmission will help define
the risk factors for transmission within communities and within and among coun-
tries. Finally, the behavior of drug-resistant strains can be monitored and ana-
lyzed. In a recent report issued by the World Health OrganizationInternational
Union Against Tuberculosis and Lung Disease Working Group on Anti-Tubercu-
losis 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.

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Part Three
CLINICAL ASPECTS

277
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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 popula-
tions because of aging, HIV infection, intravenous (IV) drug use, and other phe-
nomena.
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 tech-
nique, 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
280 Menzies

in Philadelphia developed a technique of extraction of protein from autoclaved tu-

berculosis bacteria grown on artificial media. Results with this purified protein
derivative (PPD) proved much more reproducible and specific (4). After consider-
able 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 agree-
ment, since that time all tuberculin skin testing material produced must be bioe-
quivalent to this standard lot. North American manufactured tuberculin test mate-
rial, 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 (69).
Injection of tuberculin material intradermally into a person previously in-
fected with M. tuberculosis will result in infiltration of previously sensitized lym-
phocytes circulating in peripheral blood. At the site of injection, CD4 and CD8 T
lymphocytes will accumulate, as well as monocytes and macrophages. These re-
lease inflammatory mediators, which produce edema and erythema. Although
there is increased blood flow, the locally increased metabolic activity of these in-
flammatory 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 (1113), although both result from exposure and
acquisition of infection. New molecular biology techniques (14) could prove use-
ful 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 tu-
berculin 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 tu-

berculin 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 tuber-
culin material is standardized using experimental animals infected with H-37RV
strain against the original batch lot of PPD-S. There are two North American man-
ufacturers: Connaught Laboratories (manufacturing Tubersol) and Parke-Davis
(Aplisol). Earlier studies demonstrated that the Connaught product had signifi-
cantly 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-pos-
itive results using the Parke-Davis product (1618). As a result, the Connaught
Tuberculin Skin Testing 281

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 standardiza-
tion (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 sen-
sitivity 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 RT-
23 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 be-
cause 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.
 282 Menzies

Commonly used methods of tuberculin skin test administration are the Man-
toux 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 sensitiv-
ity: in young healthy volunteers, false-negative rates of up to 15% have been re-
ported (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 read-
ings 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 tuber-
culin 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 sub-
cutaneously, 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
Age
Author (mean or Mantoux Sensitivitya Specificitya
(Ref.) Year range) No. dose Type (%) (%)

Badgder (31) 1962 All ages 1001 5 TU Tine (OT) 3mm 96 73

6mm 78 84
Furcolow (33) 1966 36 670 5 TU Tine-OT 98 92
100 95 83
Fine (165) 1972 54 589 5 TU Tine-OT 98 82
Wijsmuller 1975 Adults 915 5 TU J  T injectormore 73
(35) variable than Mantoux
 amount injected
 both
Donaldson 1976 1569 135 5 TU Tine-OT 84
(166) Tine-PPD 90
Lunn (167) 1980 1821 250 5 TU Imotest-PPD 67 65
(Merieux)
Ackerman 1981 14 6239 10 IU Tine-PPD 76
(168) 2574 Imotest-PPD 75
Hansen (169) 1982 Adults 829 5 TU Tine-OT 69 98
Rudd (170) 1982 Adults 100 10 IU Imotest-PPD 72 94
Biggs (171) 1987 Adults 105 10 TU Imotest-PPD 4mm 33 90
2mm 60 85
a
Mantoux taken as gold standard.
Tuberculin Skin Testing 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, es-
pecially 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 tuberculo-
sis (mean age 51 years), readings were made every day for 7 days following tu-
berculin testing. In total, 296 (97%) had positive reactions 4872 hours following
testing. Reading at 96 hours was almost as sensitive, but by day 7, 21% had re-
verted 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 test-
ing 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 in-
formation regarding risk of tuberculosis is based on tuberculin reactions measured
between 48 and 72 hours after testing. In summary, readings should be made 23
days following administration given the reduced sensitivity and uncertain inter-
pretation 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 be-
tween readings are small (4649), irregardless of reader experience (47,49). Over-
 284 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 signifi-
cant misclassification in 8.5% of Heaf tests (50) and 11% misclassification fol-
lowing 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 tech-
nique. Standard deviation of readings and misclassification errors are considerably
less within than between readers, although differences between readers should av-
erage 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 Reading

Author Age Misclassification

(Ref.) Year No. Type (yr) Standard Deviation (Pos. vs. Neg.)

A. Variability of reaction: 2 tests in same subject

Furcolow 1966 212 Mental hospital 36 04 mm 92%
(33) patients 59 mm 7%
10 mm 1%
Chaparas 1985 1036 General Adults 4.6%
(172) 46 TB patients Adults 0
B. Variability of reading: within readers

Bearman 1964 36 General 1617 4 1.31.9 mm

(53)
Furcolow 1966 670 Mental hospital 1190 2 1.2%
(33) patients
C. Variability of readings: between readers
Loudon 1963 53 Workers 2060 7 9%
(173)
Fine (174) 1972 189 General 54 4 12%
Erdtmann 1974 121 General 1825 4 2.5 mm
(52)
Perez Stable 1985 537 Nursing home 770 6 2.3 mm 4.3%
(175) residents
Howard 1988 806 General Adults 2a 11%
(43)
Pouchot 1997 96 Health workers adults 2 2.73.5 1223%
(176)
a
Patient self-reading compared to trained health professional.
Tuberculin Skin Testing 285

errorsa potentially correctable problem through further training and/or elimina-

tion of such readers. Another potential cause of reader error is terminal digit prefer-
ence or rounding. This problem can result in substantial misclassification, particu-
larly 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 4872 hours. Lymphangitis
has been reported following testing using Mantoux or Heaf techniques (55), usu-
ally associated with strongly positive tuberculin tests with severe blistering and/or
ulceration at the site of injection. Severe anaphylaxis has been reported on one oc-
casion following Mantoux testing. A patient with active tuberculous lymphadeni-
tis 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 re-
actions are not related to true tuberculin reactions.
In approximately 12% of patients with positive reactions, there may be se-
vere 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 un-
documented 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), al-
though the manufacturers product monograph mentioned this as a potential pre-
caution in past years (62).

III. Simple Cognitive Aspects: False-Negative and False-

Positive Reactions

Interpretation of any test in clinical medicine requires understanding of the causes

and likelihood of false-negative and false-positive results in the population being
tested.
286 Menzies

A. False-Negative Tests

As summarized in Table 3, tests may give false-negative results because of tech-

nical 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 tech-
nique in tuberculin testing and reading. Proper storage is important because test
material will deteriorate if exposed to light, heat, or if frozen. However, some mis-
classification is inevitable because of the variability related to differences in ad-
ministration, biological response, and reading.
Biological cause of false-negative results are more difficult to avoid. False-
negative tests may occur in patients with active tuberculosis disease: estimates
range from 58% 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 tu-
berculosis (65), malnutrition (66), and elevated serum creatinine levels (67). Mal-
nutrition 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 pro-
portion of false-negative reactions in dually infected (HIV and TB) patients ranges

Table 3 Causes of False-Negative TST

Technical Biological

Material Poor-quality Viral infection HIV

production Other infections,
Inadequate dose measles, mumps,
(e.g., 1 TU) chickenpox
Improper storage Live virus
(exposure to vaccination
light/heat)
Administration Material not Bacterial or fungal Extensive disease
injected infection
Too long in Tuberculosis Miliary or pleural
syringe forms
Reading Inexperienced or Malignancies Lymphoma,
biased reader leukemia
Error in Therapy Corticosteroids,
recording chemotherapy
Too early, too Age Newborn, elderly
late Other Malnutrition, renal
failure, sarcoidosis,
stress, surgery
Tuberculin Skin Testing 287

Figure 2 Effect of HIV infection on prevalence of TST reactions.

from 1528% in those with CD4 counts greater than 400500 up to 100% in pa-
tients with CD4 counts less than 200 (6972). 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 (71,7375) 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 tu-
berculin 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 num-
ber with reactions diminishes with older age, the size of reaction does not
changea 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 Menzies

Figure 3 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 com-
mon 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 (8385). In another study, neg-
ative tuberculin tests were strongly associated with anergy (69). However, in in-
dividual 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 popula-
tions 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 individ-
ual patients (89).
Figure 4 Effect of age on initial tuberculin reactions in Arkansas nursing home resi-
dents.

Figure 5 Incidence of active tuberculosis in HIV-infected, by tuberculin and anergy test

results.

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-Gurin) vaccination (see Chap. 19). BCG vaccination of tu-
berculin negative individuals will almost invariably result in tuberculin conversion
within 48 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 require-
ment is based on the belief that a positive tuberculin reaction correlates with immu-
nity, a belief based on observations in the preantibiotic era that incidence and mor-
tality from tuberculosis was considerably higher in nursing students who were
initially tuberculin negative (9395). However, this phenomenon was actually the re-
sult of the protective effect of prior tuberculosis infection (96). There is convincing
evidence from many studies that postvaccinal tuberculin reactions have no relation-
ship to protective efficacy (11,9799). The continuing insistence on the part of reg-
ulatory agencies on demonstration of tuberculin reactivity following BCG vaccina-
tion 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 reac-
tions, but many of these relied on the presence of BCG scars, which may not form
in 2025% of recipients (100,101). Also, the effect of BCG vaccination on tuber-
culin reactions will be overestimated in populations with a high prevalence of in-
fection with tuberculosis or nontuberculous mycobacteria (101104). As summa-
rized 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 imma-
turity of the immune system in infancy (105), although protective efficacy is, if
anything, higher (102,106). Of those vaccinated at an older age, tuberculin reac-
tions 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 1525%. The size of tuberculin reactions in this subgroup is simi-
lar 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 tu-
berculosis, BCG vaccination is given routinely at birth and often repeated in pri-
mary school. As shown in Figure 6, among foreign-born schoolchildren and young
Tuberculin Skin Testing 291

Table 4 Effect of BCG Vaccination on TST in General Population Samples

Year Age Age TST

Author of No. of vaccinated tested  10mm
(Ref.) study Setting subjects (yr) (yr) (% pos.)

Lifschitz 1965 Arizona 250 01 16 0

(177)
Margus 1965 Israel 758 01 12 7
(178)
Joncas 1975 Montreal 68 01 1 5
(179)
Karalliede 1985 Sri Lanka 106 01 1 18
(180)
Sepulveda 1988 Chile 40 01 6 10
(181)
1
Friedland 1990 Southern Africa 85 01 /25 13
(182)
Menzies 1992 Montreal 162 01 1117 1.7a
(183)
Comstock 1971 Southern 129 118 1821b 16
(184) United States
Bahr 1987 Lebanon 1200 5 1014 35
(102)
Horowitz 1972 Denmark 955 6 11 6080
(90)
Joncas 1975 Montreal 165 6 7 73
(179)
Menzies 1992 Montreal 469 68 1525 23
(183)
Margus 1965 Israel 241 13 14 14
(178)
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 impor-
tant 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 (110113). The mechanism of
292 Menzies

Figure 6 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 individ-
uals 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 be-
cause 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 nontubercu-
lous mycobacteria (NTM antigens) have been used for the diagnosis of patients
with disease due to these mycobacteria. Sensitivity and specificity vary consider-
ably between studies and NTM antigen cannot, as yet, be recommended for rou-
tine clinical use in the differentiation of nontuberculous mycobacterial disease
(117120).
The NTM are also important because of the similarity of NTM antigens to
tuberculous antigens resulting in cross-reactivity when tuberculin testing. In ex-
perimental 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 un-
infected, infected with M. tuberculosis, or infected with nontuberculous my-
cobacteria (122).
As shown in Table 6, the relative importance of NTM as a cause of false-
positive tuberculin tests depends upon the frequency of sensitization to nontuber-
culous 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

(NonBCG-Vaccinated Only)

Population Positive
Author, reactions
year Age (5 mm)
(Ref.) Country Type (yr) No. Antigen No. (%)

Edwards, United States Military 1722 275,558 PPD-Bb 90,935 33

195865 recruits
(147)
Bleiker, Netherlands, Students 714 13,546 PPD-Scrof a 712 5
196570 Delft students 714 10,312 PPD-Scrof a 2,152 21
198085
(185)
Jeanes, Canada Students 1517 5,552 PPD-Be 817 15
1967 24,763 PPD-Ge 1782 7
(186)
Grzy, Canada, Students 1419 3,917 PPD-Be 426 11
1967 (27) British Columbia 2,884 PPD-Ge 538 19
Paul, Kenya Students 610 477 PPD-Aviumc 86 18
1975 1117 344 213 62
(187)
Karditjo, Indonesia Healthy 21 34 PPD-Scrof d 30 88
1985 adults
(188)
Lind, Sweden Students 89 1,368 RS10a 442 32
1986 1,451 RS15a 554 38
(189)
Menzies, Canada, Students 1117 3,710 PPD-Be 122 3
1987 Montreal foreign-born 1125 875 PPD-Be 57 7
(109)
Ly, Vietnam Students 719 153 PPD-Aviumd 56 37
1989 155 PPD-Scrofd 36 23
(190)
a
Serum Statens Institute, Copenhagen RS10 from M. Avium, RS15 from M. scrofulaceum.
b
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.
294 Menzies

Figure 7 Reactions to PPD-S among populations of guinea pigs with varying propor-
tions 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 sensitiv-
ity 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-
 Table 6 Effect of Nontuberculous Mycobacteria on Tuberculin Reactions (NonBCG-Vaccinated Populations)

Reactions to PPD-T (for MTB)

Reactions to NTMa 59 mm 10 mm

Author, Population
year  5 mm  10 mm Total NTM
PPD-T Total NTM  PPD-T
(Ref.) Setting Age No. Antigenb (N) (N) N (N) (%)c N (N) (%)c

Jeanes, Canada 1517 5,552 PPD-B 817 N/A 52 19 37% 93 8 9%

1967 24,763 PPD-G 1782 N/A 246 128 52% 299 64 21%
(186)
Frappier, Quebec 1519 542 Battey 30 9 9 2 22% 12 0 0
1975
(191)
Lind, Sweden 89 1,368 RS10 442 140 81 58 72% 11 9 82%
1986 1,451 RS95 554 192 80 61 76% 6 6 100%
(189)
Menzies, Montreal 1125 3710 PPD-B 103 34 80 15 19% 90 2 2%
1987 (Can.-born)
(192)
Menzies, Montreal 1125 875 PPD-B 93 57 127 54 42% 393 16 4%
1987 (Foreign-born)
(109)
a
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).
b
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 59 mm or 10 mm which may have been due to cross-reactivity to NTM antigens because they had larger simulta-
neous reactions to the NTM antigens.

295
 296 Menzies

ably, and the nontuberculous mycobacterial antigens used have never been stan-
dardized (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 nonBCG-vac-

cinated populations in North America varies widely. Prevalence is very low in
schoolchildren and young adults, although it is substantially higher in certain eth-
nic minorities (125127). Particularly high rates of infection are found among the
urban poor such as intravenous drug users (IVDU), persons receiving social assis-
tance (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 dur-
ing 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, abso-

Table 7 Prevalence of Positive Tuberculin Reactions (Results of Mantoux Testing with PPD-
5TU or RT23-2TU)

Author, Age, TST positive

year Country Ethnic mean (SD) or No. tested (10 mm)
(Ref.) (city) Population group range (yr) (N) No. %

A. Native-Born, NonBCG-Vaccinated General Population

Comstock, United States Military Whites, 1722 1,125,193 42,757 3.8
195869 recruits blacks 1722 70,550 8,749 12.4
(125)
Reichman, United States Workers, White, 2068 37,224 3,094 8.3
197374 (New York) Board of black, 2068 10,364 2,384 23
(193) Education Hispanic 2068 2,744 706 26
Cross, United States Military All 1722 618,074 8,962 1.5
198086 recruits
(194)
Menzies, Canada School- 95% 11 (1) 1351 17 1.3
1987 (Montreal) children white 16 (2) 628 18 2.9
(192)
Barry, United States School- White, 16 (2) 661 9 1.4
1987 (Boston) children black, 17 (2) 1235 60 4.9
(126) Hispanic 17 (2) 457 29 6.4
Trump, United States Military White, 1724 1,588 12 0.8
1990 recruits black, 1724 386 20 5.2
(127) Hispanic 1724 167 9 5.4
Menzies, Canada University 95% 21 (2) 837 15 1.8
1990 (Montreal) students white
(146)
 Tuberculin Skin Testing 297

Table 7 Continued

Author, Age, TST positive

year Country Ethnic mean (SD) or No. tested (10 mm)
(Ref.) (city) Population group range (yr) (N) No. %

B. Prevalence in Special Populations

Reichman, United States Methadone All N/A 3,788 853 23
1973 (New York) clinic
(129)
Several, United States Nursing All 5074 340 155 46
198289 Canada home 7584 559 156 28
(44,144,195) Holland residents 85 643 112 17
Friedman, United States ETOH/Drug White, 36 (9) 97 17 18
1984 (New York) users, black, 36 (9) 477 158 33
(128) welfare Hispanic 36 (9) 311 95 31
Gzrybowski, Canada Urban poor White 1534 170 28 16
1985 (Vancouver) males 3554 254 113 44
(196)
Paul, United States Homeless All 35 (9) 104 72 69
1993 (New York)
(131)
Zolopa, United States Homeless All 36 843 270 32
1994 (San Francisco)
(130)
C. Foreign-Born Populations
Nolan, United States Southeast Asia Refugees All ages 9328 3300 35
198081
(149)
Morse, United States Southeast Asia Refugees 21 954 424 44
1980
(197)
Veen, Netherlands Southeast Asia Refugees 18 221 86 39
1981
(68)
Fitzpatrick, United States Southeast Asia Refugees 1119 77 40 52
198185
(198)
Omerod, Britain India/ New 014 231 30 13
198388 Pakistan immigrants
(199)
Spinaci, Pakistan Afghanistan Male 8 (1) 1358 187 14
1985 refugees
(200)
Godue, Canada All Refugees 21 865 329 38
1987 countries
(201)
Menzies, Canada TB endemic Schoolchildren, 21 (3) 780 288 37
198788 workers
(109)
Blum, United States 90% from Immigrant All ages 4,840 2039 42
1988 Mexico applicants
(202)
Yuan, Canada All Schoolchildren 13 (5) 720 162 23
1992 countries
(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 interme-
diate (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
General
Author, TST population
year Country Age Tested positive TST
(Ref.) (population) range (yr) (N) (%) (%)

A. Smear-Positive Cases
Close/Household Contact
Zwanenburg, England 014 225 164 73 38
194953 (general)
(204)
Zaki, New York City All Ages 3,330 1732 52 13a
196572 (general)
(205)
Grzybowski, Canada
196671 (white) 019 2,501 1209 48 21
(206) (aboriginal) 019 854 466 55 41
Van Geuns, Holland 014 115 80 70 1
196769 (general)
(207)
Karalus, New Zealand 016 155 37 24
1
1980/84 (general)
(208)
 Tuberculin Skin Testing 299

Table 8 Continued

Contacts
General
Author, TST population
year Country Age Tested positive TST
(Ref.) (population) range (yr) (N) (%) (%)

Casual Contact
Grzybowski, Canada
196671 (white) 019 5,364 1630 30 21
(206) (aboriginal) 019 654 327 50 41
Van Geuns, Holland 014 1,733 519 30 1
196769 (general)
(207)
Karalus, New Zealand 016 898 10 1.1
1
198084 (general)
(208)
B: Smear-Negative, Culture-Positive Cases
Close/Household Contact
Zwanenburg, England 014 96 44 46 38
194953 (general)
(204)
Zaki, New York City All ages 1096 437 40 13a
196572 (general)
(205)
Grzybowski, Canada
196671 (white) 019 1340 399 30 21
(206) (aboriginal) 019 527 237 45 41
Van Geuns, Holland 014 128 45 35 1
196769 (general)
(207)
Karalus, New Zealand 016 146 2 1.4
1
198084 (general)
(208)
Casual Contact
Grzybowski, Canada
196671 (white) 019 2270 442 20 21
(206) (aboriginal) 019 413 161 39 41
Van Geuns, Holland 014 602 141 23 1
196769 (general)
(207)
Karalus, New Zealand 016 307 0 0
1
198084 (general)
(208)
a
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-
 300

Table 9 Predictive Value for TB Infection of a Positive Initial TST (10 mm) in a 20-Year-Old Adult

Expected prevalence of reactions (%)b

History of Predictive value of a
False positive
BCG positive test
Subject born in vaccination Clinical situationa True positive NTM BCG (%)

Northern United States or None Screening 2 2 50

Canada Casual contact 40  2 2 95
Close contact 10  2 2 86
Southern United States None Screening 2 6 25
Casual contact 40  2 6 88
Close contact 10  2 6 67
Western Europe Age of 6 Screening 2 4 15 10
Casual contact 40  2 4 15 69
Close contact 10  2 4 15 39
Southeast Asia Age of 6 Screening 50 6 15 83
(newly arrived) Casual contact 70 (40  50) 6 15 92
Close contact 55 (10  50) 6 15 85
a
Clinical situation: screening means test done in absence of exposure/risk factor; contacts are of smear-positive, culture-positive case of TB.
b
Expected prevalence is prevalence of TB infection in 20-year-olds from general population plus additional prevalence infected depending on clinical situa-
tion (see Table 7 for prevalence in population and Table 8 for prevalence according to the clinical situation).
Menzies
Tuberculin Skin Testing 301

fection is low, such as in screening situations. On the other hand, when the ex-
pected prevalence of tuberculous infection is high, such as in close contacts of
smear-positive cases or immigrants from tuberculous-endemic areas, then the pre-
dictive value of a positive tuberculin test is high even in those with BCG vaccina-
tion 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. Interest-
ingly, 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 nonspe-
cific 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 23
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 phe-
nomenon but could be conversion or boosting. Both terms refer to a newly posi-
tive 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 de-
velopment of new hypersensitivity to mycobacteria following new infection either
with tuberculous or nontuberculous mycobacteria, including BCG vaccination.
This distinction is not merely academicboosting is associated with a substan-
tially 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 Population

author, Follow-up Annual
year period TST incidence of TB
(Ref.) Country Group (yr) Number (criterion) (per 100,000)

HIV-infected
Selywn, 1989 United States IVDU 25 49 5 7,900
(209) 168
5 300
Moreno, Spain IVDU 26 108 5 10,400
1993 268
5b 8,290
(85)
Guelar, Spain IVDU 1.3 (1) 87 5a 11,100
1993 733
5b 2,350
(83)
Antonucci, Italy IVDU 2 197 5 5,420
1995 2,498
5b 2,130
(84)
Abnormal chest x-ray
Hong Kong Hong Kong Elderly men 25 116 10c 5,400
Chest Service, With silicosis
1992
(210)
Nolan, United States Vietnam refugees 5 185 10 650
1980
(149)
IUAT, Eastern Europe Inactive TB
1982 Overall 5 6,990 6 286
(211) Lesions
2cm 4,701 232
Lesions 2cm 2,094
426
Horwitz, Denmark Young adults 12 286,000 6 710
1969 Suspicious 48
(132) Calcified
Contacts and abnormal chest x-ray
Veening Netherlands Contacts of S 128 5
cases First year 7,031
(138) Next 3 years 2,521
Recent conversion
Sutherland Britain Adolescence 2 2,170 5 2600
(137) 20 4250
Normal chest x-ray, no other risk factor
Comstock, Alaska Inuit 5.8 570 5 972
1967 275
5 378
(212)
Nolan, United States Vietnam refugees 5 3,115 10 133
1980 6,028
10 10
(149)
Palmer, United States Military recruits 4 12 377
1968 111 110
(134) 0 36
Comstock, United States Military recruits 4
1974 White 1,082,336 10 79
(125) Black 62,027 10 93
Asian 8,238 10 196
 Tuberculin Skin Testing 303

Table 10 Continued

Risk group Population

author, Follow-up Annual
year period TST incidence of TB
(Ref.) Country Group (yr) Number (criterion) (per 100,000)

Ferebee, United States Mental institution 10 T1  10 122

1959 patients T1  59 82
(135) T2  10 66
T2
5 19
Comstock, Puerto Rico Children 1820 82,269 6d 90
1974
(213)
Horwitz, Denmark Young adults 12 286,000 6e 23
1969
(132)
a
Excludes those still on INH therapy.
b
Anergic and nonanergic combined.
c
94% had reactions of 10 mm to 1 TU of RT23.
d
Tested with 1 or 10 Tu RT20/2 22.
e
Tested with 10 Tu.

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 be-
tween 1 and 5 weeks (135,140,141) and is significantly less frequent if the inter-
val 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 oc-
cur after a third (78) or even a fourth (144) sequential test. This has also been de-
scribed in a group of malnourished Southeast Asian refugees (68).
As shown in Table 12, boosting is strongly associated with BCG vaccina-
tion 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 14% had signifi-
cant reactions to a first test with 5 TU of PPD-T, compared to 1213% 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 south-
ern United States, 70% of whom will be sensitive to NTM antigens (147), only
13% will have positive initial reactions to PPD-T but 79% will demonstrate
 304 Menzies

Table 11 Prevalence of Positive Initial and Second TST from Two-Step Testing

Author No. subjects Percent with positive

Population (Ref.) Setting undergoing T1 Initial testa Second testb

Health-care Thompson (142) United States 750 N/A 5.91

workers
Bass (143) Alabama N/A 8.2 8.31
Valenti (214) Rochester, NY 416 3.1 01
Menzies (146) Montreal 951 2.2 2.51
Gross (215) Maryland 2558 3.8 0.33
Richards (145) Chicago 267 2.6 6.61
Nursing home Slutkin (44) San Francisco 411 35 61
residents
Gordin (78) San Francisco 1726 28 141
Washington
W. Virginia
Alvarez (216) Tennessee 510 30 190
Van den Brande Holland 223 29 141
(144)
Barry (217) Boston 323 26 61
Hospital patients Burstin (218) Boston 162 12 61
HIV-infected Webster (219) United States 709 N/A 2.72
Hecker (220) Uganda 345c 71 292
IVDU Lifson (221) United States HIV 900 13 83
HIV 95 13 122
Foreign-born Morse (222) New York State 211 44 311
Cauthen (141) United States 2469 36 31
Menzies (109) Montreal 323 32 161
Morse (197) New York State 524 46 43
Veen (68) Netherlands 221 39 183
a
Initial test% based on number undergoing T1, considered positive if 10mm.
b
Second test% based on number undergoing T2, considered positive if: 0no definition; 1 6 10; 2T1
5, T2  5;
3
T1
10, T2  10.
c
Number extrapolated from figures given in paper.

Table 12 Effect of BCG Vaccination on the Booster Effect in Two-Step Tuberculin Testing
Author No. of Age Age % with
(Ref.) Year Setting subjects vaccinated (yr) tested (yr) Boostera

Sepulveda (181) 1988 Chile 36 01 6 31

Friedland (223) 1990 Southeast Africa 102 05 114 16
Sepulveda (224) 1990 Chile 73 014 1922 26
Menzies (146) 1994 Montreal 380 01 1725 8
210 28 1725 15
a
Definitions of Booster: T1
10mm; T2  10mm and increased by at least 6mm.
Tuberculin Skin Testing 305

Figure 9 History of BCG vaccination on reactions to second tuberculin test (boosting).

boostingremarkably close to observed results in health-care workers in Al-

abama (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 re-
action 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 No. No. response to NTM Sensitive to NTM

a
(Ref.) Year Place tested N % Boosting N % Boostinga

Richards 1979 Chicago 213 110 1 103 13

(145)
Menzies 1994 Montreal 277 252 1.6 25 12
(146)
a
Initial PPD-T (for MTB)
10mm. Second PPD-T  10mm and increased by at least 6mm.
306 Menzies

from conversionsee 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 prob-
ably 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 tu-
berculosis 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 15 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, particu-
larly if two-step tuberculin testing was performed (143).
But in many situations, it is difficult to distinguish conversion from boost-
ing 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 stud-
ies 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 1113).
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 pastparticularly if prior two-step testing has been
negative. As with initial tuberculin testing, tuberculin conversions should be in-
terpreted 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
Tuberculin Skin Testing 307

test in contact investigationsthe 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 vac-
cination, 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 23 weeks if the bacillary load was small
(156), as it usually is in natural infection. Following inadvertent vaccination with
M. tuberculosis (the Lbeck disaster), tuberculin reactions were positive in all
children within 37 weeks (157). As shown in Figure 10, the interval from expo-
sure 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
(158160).
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 de-
tected 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 docu-
mented time of exposure. (From Refs. 158160.)
308 Menzies

occurrence of false-positive conversions. As shown in Table 14, when two se-

quential tuberculin tests are done, boosting is much more likely to account for ap-
parent conversion in casual contacts in populations where BCG or NTM sensi-
tivity 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 con-
tact investigation.
In most situations, 46 weeks are needed to confirm M. tuberculosis in the
index case, evaluate the close or high-risk contacts, and identify lower-risk ca-
sual contacts. This means that the first tuberculin test is usually given 68 weeks
after the contact is broken. Following current recommendations, tuberculin test-
ing is then repeated 12 weeks after the contact was broken. If all tuberculin con-
versions 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. Per-
forming 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 im-
munocompromised, such as HIV-infected populations, where false-positive re-
sults 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 conver-
sion, the majority later demonstrated reversion (161), although some of the ini-
tial tuberculin conversions may have actually resulted from the booster phe-
nomenon 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 chil-
dren with TST 10 mm who were treated for primary tuberculosis in Houston
between 1953 and 1960 and were retested 310 years later, only 29 (8.4%) re-
verted (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 clini-
cal or epidemiological information is available to allow interpretation of such a
phenomenon.
Table 14 Predictive Value of a Positive Second TST in a 20-Year-Old Adult (Second Test Performed 13 Months After Initial
Negative TST)

Expected Prevalence of Reactions (%)b

History of Predictive value of a
False positive
Tuberculin Skin Testing

BCG positive test

Subject born in vaccination Clinical situationa True positive NTM BCG (%)

Northern United States or None Screening 1 2 33

Canada Close contact 10  1 2 85
Casual contact 2.5  1 2 64
Southern United States None Screening 1 8 11
Close contact 10  1 8 58
Casual contact 2.5  1 8 30
Western Europe Age of 6 Screening 1 5 20 4
Close contact 10  1 20 20 33
Casual contact 2.5  1 5 20 13
Southeast Asia Age of 6 Screening 15 8 20 39
(newly arrived) Close contact 15  10 8 20 54
Casual contact 15  2.5 8 20 43
a
Clinical situation: screening means test done in absence of exposure/risk factor; contacts are of smear-positive, culture-positive case of TB.
b
Expected prevalence is prevalence in general population plus added prevalence infected from clinical situation (screeningno additional; contactsfrom
Table 11).
309
310 Menzies

V. Conclusions

The following can be concluded about tuberculin skin testing:

1. The tuberculin skin test is a testnot 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
diseasespecificity is very low and sensitivity is only 7085%.
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 reac-
tions.
7. The boosting phenomenon is common and in many populations is al-
most as frequent as initial tuberculin reactions. However, it is much
less specific because it is strongly affected by sensitivity to NTM anti-
gens as well as prior BCG vaccination. Therefore, the likelihood of fu-
ture development of tuberculosis is lower than for positive initial re-
actions 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 mycobacte-
rial infection.
10. The best definition of tuberculin conversion remains unclear, because
there are few data from cohort studies. Examination of tuberculin re-
actions 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
Tuberculin Skin Testing 311

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 clini-
cal value in the management of individual patients.
13. After close to 100 years of use, there is an enormous amount of clini-
cal and epidemiological information available to assist in interpreta-
tion of the tuberculin test, but we still cannot identify with certainty
those who will develop the disease. New molecular biology tech-
niques 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.

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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 in-
fectious cases of tuberculosis with appropriate chemotherapy as swiftly as possi-
ble 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 atten-
tion and the delay of health care providers in making the diagnosis and com-
mencing appropriate chemotherapy. These delays are variably attributable to the
patients attitudes towards symptoms and the health-care providers 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
324 Rieder

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 ac-
tive tuberculosis and the arrest of transmission. Patients and doctors 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 identifica-
tion of population segments infected with tubercle bacilli at high risk of develop-
ing 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 sit-
uation 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
(24) that the major sources of infection in the community are patients with tu-
Case Finding in High- and Low-Prevalence Countries 325

berculosis of the respiratory tract who are excreting such large numbers of tuber-
cle bacilli that they can be seen by direct microscopic examination of their spu-
tum. Patients with sputum smearnegative, culture-onlypositive 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 car-
ries 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 identifi-
cation 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 smearpositive patients were discovered on account of their symptoms.
Only some 20% of new cases were found through indiscriminate mass radiogra-
phy 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 (3,8,1013).

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 im-
prove case finding by involving community leaders have been evaluated (1416).
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 in-
vestigation 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-
326 Rieder

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 reg-
istered. 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 rel-
atively little work. A third study was undertaken to evaluate the usefulness of re-
questioning community leaders at shorter intervals.
The third study (16) showed that interrogation of household heads on a sin-
gle occasion produced more than two thirds of all the bacteriologically confirmed
cases found in the community by several case-finding methods combined. How-
ever, 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 question-
ing 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, infec-
tion with the human immunodeficiency virus (HIV) has been identified as the
strongest (17,18). The annual risk of tuberculosis among dually infected persons
Case Finding in High- and Low-Prevalence Countries 327

is some 510% (1820). It appears that 3050% of patients with the acquired im-
munodeficiency syndrome (AIDS) who are also infected with tubercle bacilli de-
velop tuberculosis at some time, and very commonly before the appearance of
other AIDS-defining conditions (21,22). Although screening for disease and sub-
sequent treatment is efficacious and effective, the effectiveness of the therapeutic
consequence of screening for infection, i.e., preventive therapy, is much more am-
biguous. 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
(2629).
As is the case for other population groups, failure to make a diagnosis of tu-
berculosis in this group of patients is not uncommon and may lead to unnecessary
morbidity and fatality (3032). Because HIV-associated tuberculosis often pre-
sents with radiologically unusual pictures (3342) and may be commonly found
at any extrapulmonary site (36,4345), 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 smearnegative pul-
monary tuberculosis among patients with HIV infection or AIDS is more common
than among tuberculosis patients without HIV infection (43,47), large increases in
sputum smearpositive 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 situ-
ation 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 pre-
senting 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 re-
warding. 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 Re-
public were found to have tuberculosis (52). The latter study also showed that tu-
berculosis 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 tu-
berculous infection and tuberculosis proves rewarding in some HIV clinics in in-
dustrialized countries (54,55).
Risk Factor: Recent Infection
The more recent the tuberculosis infection, the greater will be the risk for pro-
gression to tuberculosis (17,56,57). Many hospitals, particularly in the United
328 Rieder

States, where BCG vaccination has never been used routinely, have implemented
screening procedures utilizing the tuberculin skin test to identify recent conver-
sion among hospital employees (58), which is not without difficulties in exclud-
ing false conversions attributable to boosting (5963).

Risk Factor: Fibrotic Lesions

Patients with fibrotic lesions resulting from previous, spontaneously healed tu-
berculosis 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 in-
creased 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 identifi-
cation 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 se-
vere 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 patients de-
lay 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 smearpositive 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 patients delay in seeking medical attention (70). In con-
Case Finding in High- and Low-Prevalence Countries 329

trast, it is conceivable that in resource-poor countries the distance to the next

health-care provider may influence the patients attitude towards seeking medical
attention (71,72).
In Japan, the interval between the occurrence of symptoms and the first con-
tact with a health-care provider was 17 days, but this varied remarkably between
individual patients (70). Patient delay was also influenced by profession and lo-
cation of residence. In Hong Kong, an intensive mass media campaign failed to at-
tract significant numbers of tuberculosis patients and failed to attract older sub-
jects 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 tubercu-

losis cases found through interrogation of community leaders and heads of house-
holds (1416), a rather cumbersome procedure, had actually attended health-care
facilities with complaints but had not been examined bacteriologically or radio-
graphically. Similarly, in Bangalore City in India where both general health insti-
tutions 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 atten-
tion, but when the proper diagnosis is made.
In the Japanese study (70), the median patient delay was 17 days and the me-
dian 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 ra-
diograph 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 in-
creased 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 Dis-
ease Research Centre, Nairobi, and the British Medical Research Council, ap-
proaches to improve case finding by seizing upon opportunities among patients at-
tending health care facilities have been evaluated (72,7678). In the fourth study
(76), similar to the previous three, 90% of suspects without a history of tubercu-
losis 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 bacteri-
ologically.
330 Rieder

In the fifth study (72), careful screening for patients with a cough of 1
months or more duration in general outpatients attending a district hospital iden-
tified 601 (2.9%) suspects among 20,756 new outpatients. Among the suspected
cases, 5.6% had bacteriologically or radiographically active tuberculosis. An ad-
ditional 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 demon-
strated 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 at-
tending as general outpatients four different district hospitals for the first time was
examined. A suspected case was defined as in the earlier studies (1416). 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 de-
creased 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 substan-
tial yield of tuberculosis cases can be obtained from the area surrounding district
hospitals. The major impediment to finding a larger proportion of cases lay, how-
ever, with the complacency of health staff in the periphery. Unless primary health-
care facilities in the periphery were improved, the proportion of identified cases
among all actually newly occurring cases would remain disappointing. Further-
more, it might be added, the failure to interrupt transmission by definitively cur-
ing 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 rel-
evant symptoms referable to the respiratory tract in both resource-poor and in-
dustrialized countries. Second, in resource-poor countries a strengthening of the
primary health care services is imperative. Third, if patients who are being ulti-
mately 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).
Case Finding in High- and Low-Prevalence Countries 331

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 coun-
tries, 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 coun-
tries, 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 coun-
tries 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. Popula-
tion 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-preva-
lence 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 iden-
tify 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 accord-
ingly policy statements have been elaborated to address the issue as an increasing
proportion of cases in industrialized countries is found among foreign-born per-
sons (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.
332 Rieder

Risk Groups: Persons in Correctional Facilities

Tuberculosis outbreaks in correctional facilities, including outbreaks with mul-
tidrug-resistant strains, have alerted the public (9296), 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 preva-
lence 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 find-
ing is often expanded to these groups. In resource-poor countries, most active
case-finding activities that go beyond contact examination are prohibitively ex-
pensive 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 fol-

lowed by treatment, it cannot be deduced that the root cause of the documented in-
efficiency of tuberculosis-control programs in many low-income countries lies
primarily with deficiencies in case finding. On the contrary, there is much evi-
dence 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 epidemiolog-
ically 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 hy-
pothesis has been offered that indeed low cure ratios may even lead to a deterio-
ration 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 hy-
pothesis. 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 (1416), 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
Case Finding in High- and Low-Prevalence Countries 333

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 popu-
lation 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 as-
sured 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 re-
source-rich countries, the problem of delay in diagnosis does not so much lie with
the patients failure to seek medical attention as with the failure of the medical sys-
tem 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 appro-
priately 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 seg-
ments gives a high yield, the emphasis must be placed on continuously educating
health-care providers and physicians so that the diagnosis of tuberculosis can eas-
ily be made once it is considered. Most important for both low-income and high-
income countries is the lesson that all case-finding activitieseven successful
onesare in vain if the patients compliance cannot be assured. In addition to the
failure of improving the epidemiological situation because of inadequate treat-
ment, the threat of losing rather than winning the battle against tuberculosis looms
with the emergence of drug resistance (104), to which noncompliance of the med-
ical system may contribute more than is openly admitted.
334 Rieder

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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 resur-
gence 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 or-
der to interrupt transmission to uninfected hosts and prevent reactivation in in-
fected hosts, respectively. Obviously, accurate and rapid diagnosis of cases of ac-
tive 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 individ-
uals in whom the diagnosis of tuberculosis should be considered. The information
gathered provides the basis for deciding which, if any, diagnostic testing (chest ra-
diograph, sputum sampling, etc.) should be pursued.
341
342 LoBue et al.

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-tu-
berculosis-prevalence countries and/or refugee status), low income, and home-
lessness (14). Certain occupations, such as health care workers, are associated
with a greater risk of tuberculosis (510). Two other high-risk populations are el-
derly residents of nursing homes and inmates of correctional facilities (1114).
Biological risk factors are basically underlying medical conditions in which cell-
mediated immunity is depressed, such as HIV infection (the greatest risk factor)
(15). Other medical conditions that result in greater risk for contracting tubercu-
losis 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, there-
fore, received the greatest attention. Because tuberculosis is generally insidious in
onset, symptoms may be minimal or completely absent until the disease is ad-
vanced. 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 progres-
sive, 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 Rass-
mussens aneurysm (an exposed dilated blood vessel within a cavity) (22). Dysp-
nea is more likely to occur from pleural involvement (effusion), but with exten-
sive 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 non-
specific and may be seen with other lung infections or malignancies. They cannot
be used to differentiate active tuberculosis from old inactive disease with any cer-
tainty, 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 bac-
terial superinfection.
The physical exam is not particularly helpful in diagnosing pulmonary tu-
berculosis because physical signs, like symptoms, are both insensitive and non-
Diagnosis of Tuberculosis 343

specific. In the early phases of active disease, there are often no abnormal physi-
cal findings. As tuberculosis becomes advanced, physical exam may reveal sys-
temic 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 hemato-
logical 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 710% 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 epidemi-
ological tool, and it should not be considered a diagnostic test for active tubercu-
losis. The vast majority of individuals with a reactive TST do not have active tu-
berculosis. Conversely, 1025% 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 tu-
berculosis 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-Gurin (BCG), and prior infection with nontuberculous my-
cobacteria (28). Nevertheless tuberculin skin testing should be performed on all pa-
tients with suspected active tuberculosis. A TST, which is indicative of tuberculo-
sis 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 pa-
tients with active pulmonary tuberculosis, but may be normal in about 1015% of
HIV-infected patients.
344 LoBue et al.

Primary Tuberculosis

Primary tuberculosis refers to the initial pulmonary infection occurring in a patient

due to inhalation of M. tuberculosiscontaining droplets from an infectious
source. In most cases of primary tuberculosis infection, the patient is asymp-
tomatic or minimally symptomatic and the chest radiograph is normal. This is par-
ticularly the case when the person is young and healthy at the time of infection.
However, patients can develop significant illness with marked radiographic ab-
normalities with progressive primary tuberculosis. There are five major radio-
graphic manifestations of active primary pulmonary tuberculosis: parenchymal
consolidation, atelectasis, lymphadenopathy, pleural effusion, and miliary disease
(30).
Parenchymal consolidation is usually unifocal with multilobar disease oc-
curring in up to 25% of cases (31). It can occur in any lobe, and there is contro-
versy 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 find-
ings 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 endo-
bronchial obstruction or extrinsic compression from lymphadenopathy, with the
most common sites being the anterior segment of the upper lobe or the medial seg-
ment 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 67% 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 17% of all forms of tuber-
culosis and may occur as a manifestation of primary tuberculosis (30,34). The ra-
diographic 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 gen-
erally thought to be residua of healed primary disease (36). A review of the liter-
ature has revealed that they are found in 79% 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).
Diagnosis of Tuberculosis 345

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 infil-
trates 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 aver-
age in about 50% of cases (30). Cavities are more frequently multiple than soli-
tary 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 surround-
ing 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, inac-
tive, or healed tuberculosis. Chest radiography, by itself, cannot be used to deter-
mine 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 con-
tributes 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 tuber-
culosis (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 tu-
berculosis most commonly resembles that of primary disease, i.e., hilar and me-
diastinal adenopathy with or without noncavitating parenchymal infiltrates
346 LoBue et al.

equally likely to occur in the upper or lower lobes (41). In one study of Haitian pa-
tients 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 1214% of HIV-infected patients with active
pulmonary tuberculosis confirmed by a positive sputum AFB smear or culture
(41,43). Pleural effusions are seen in 712% 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 619% of HIV-infected patients with tuberculosis
(41,44).

Computed Tomography Scan

Computed tomography scanning of the chest can be helpful in making the diag-
nosis 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 sus-
pected 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 morn-
ing, 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 pro-
duce 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
Diagnosis of Tuberculosis 347

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 ini-
tial 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 consid-
ered. 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 im-

portant 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 com-
pared 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 re-
view of the literature found that the sensitivity of a single sputum AFB smear was
3040%, but increased to 6575% with multiple specimens (50). Another key fac-
tor that affects the diagnostic yield of direct microscopy is the extent of dis-
ease/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 exam-
ination 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 sen-
sitivity and negative predictive value.
Because direct microscopy cannot distinguish between M. tuberculosis and
nontuberculous mycobacteria, e.g., M. avium-intracellulare complex (MAC), an-
other 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 environ-
ment 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
348 LoBue et al.

published studies show the AFB smear to continue to have excellent specificity
(99%) and positive predictive value (91.598%) for the diagnosis of tuberculo-
sis (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 pa-
tients. 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 inci-
dence of infection with MAC resulted in concerns about lower specificity in these
patients. Both of these issues have been addressed. Studies comparing the sensi-
tivity of the AFB smear in HIV patients (5566%) and non-HIV patients
(5579%) have demonstrated no significant difference between these two groups
(5456). Similarly, the positive predictive value of the AFB smear from expecto-
rated 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 tubercu-
losis than is AFB smear. Determining its true sensitivity and specificity is some-
what difficult. In the United States a diagnosis of active tuberculosis may be re-
ported 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 evalua-
tion, 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 lim-
itations, two studies have reported the sensitivity for sputum culture to be ap-
proximately 81% in pulmonary tuberculosis, with a significantly higher sensitiv-
ity 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 ac-
tive 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 re-
sults. Using conventional methods in which mycobacteria are inoculated in egg-
based (Lowenstein-Jensen, L-J) or agar-based (Middlebrook 7H11) media and in-
cubated, cultures may not grow for 38 weeks or more. In the late 1970s new
culture methods were developed in order to shorten the delays inherent in culture.
Diagnosis of Tuberculosis 349

The most widely used system, BACTEC (Becton Dickinson, Sparks, MD), em-
ploys 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 814 days (30). In terms of sensitivity, BACTEC is at least as good as conven-
tional culture methods (46). Some authors have recommended using BACTEC in
conjunction with conventional media (L-J or M 7H11) as this combination pro-
duces 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, pig-
ment 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 57 days and has been found to be up to 99% accu-
rate (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 limita-
tion 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. bo-
vis). 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 per-
formed 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 com-
pared 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. Ob-
taining 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 accu-
rate test for the diagnosis of tuberculosis (see Sec. VIII).
350 LoBue et al.

C. Invasive Testing: Bronchoscopy, Transthoracic Needle

Aspirate, and Open Lung Biopsy

In certain instances it may not be possible for a patient to produce a sputum sam-
ple, 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 23 months. This is particularly true when alternative diagnoses, such as ma-
lignancy 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 tuber-
culosis who either had three negative AFB smears or were unable to produce spu-
tum, fiberoptic bronchoscopy (FOB) provided a diagnosis of mycobacterial in-
fection in 22 (39%) cases (59). Transbronchial biopsy had the highest yield for
immediate microscopic diagnosis. Another study showed that of 89 sputum AFB
smearnegative patients eventually diagnosed with tuberculosis, 67.4% were di-
agnosed 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 diag-
nosis 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 tuberculo-
sis in HIV-infected patients. The diagnostic yield was found to be similar to that
for nonHIV-infected patients, with transbronchial biopsy providing additional
yield, especially for immediate diagnosis (62,63). Based on these studies and oth-
ers, 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 per-
sonnel, 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 tuber-
culosis (64). Compared with FOB, little has been written about the efficacy of this
procedure for diagnosing tuberculosis. In one study 10 patients ultimately diag-
nosed with tuberculosis who had negative AFB smears from sputum or broncho-
scopic brushings underwent ultrasound guided transthoracic FNA (with a Tru-cut
needle biopsy if initial AFB smear from aspiration was negative) (65). FNA/
Diagnosis of Tuberculosis 351

biopsy yielded the diagnosis of tuberculosis in 9 of 10, with an immediate diag-

nosis 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 diag-
nosing 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 di-
agnosed 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 pre-
sent 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 cul-

ture. The combination of a reactive TST and a chest radiograph consistent with tu-
berculosis with or without symptoms often leads a physician to begin antituber-
culous 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 (13 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 ac-
tive 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 nonimmuno-

compromised 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 be-
ing diagnosed with tuberculosis (7072). The occurrence of atypical presenta-
tions of tuberculosis in HIV-seropositive patients appears to be related to the de-
gree 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).
352 LoBue et al.

The most common sites of extrapulmonary tuberculosis are peripheral

lymph nodes, the pleura, the bones and joints, the genitourinary system, the ab-
domen (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 tu-
berculosis, a compatible clinical and/or radiographic presentation are usually suf-
ficient 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 tu-
berculosis and CNS toxoplasmosis). In these cases, if there is deterioration or fail-
ure to respond to tuberculosis therapy at the extrapulmonary site, additional diag-
nostic 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 anal-
ysis 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 particu-
larly abundant in activated T lymphocytes. High pleural fluid ADA activity has
been associated with tuberculous pleuritis. In one study of 221 patients with pleu-
ral 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 investi-
gation 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 diagno-
sis 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 com-
mon and therefore the positive predictive value of this test may be lower in the
United States.
Diagnosis of Tuberculosis 353

High pleural fluid levels of interferon-gamma (IFN-), another lymphocyte

product, are also seen in tuberculosis pleuritis. One study of 80 patients with pleu-
ral effusions found that the mean IFN- level was 90 in individuals with tuber-
culous 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% (7577,81). 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 fre-
quently involved lymph node groups are the inguinal and axillary (83). For diag-
nosis 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 (8385).

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
1618% of individuals, respectively (8688). CT scan and MRI usually show
basal enhancement and hydrocephalus with meningitis (89,90). The lumbar punc-
ture often shows a lymphocytic pleocytosis with elevated protein and a low glu-
cose (86,88). The cerebrospinal fluid (CSF) AFB smear is usually negative
(8688). 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 menin-
gitis 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 con-
trast (89,90). If characteristic brain lesions are seen on CT or MRI in a patient sus-
354 LoBue et al.

pected of having tuberculosis, some advocate an empiric trial of therapy, reserv-

ing biopsy for those patients who do not respond (92). However, as the radio-
graphic 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
Potts disease), which accounts for 5060% of cases (94). Within the spine the
lower thoracic and thoraco-lumbar regions are the most commonly involved, com-
prising 4867% of spinal lesions. Tuberculosis typically infects the vertebra (os-
teomyelitis) and the adjacent joint space (arthritis), resulting in inflammation and
destruction (95). With time the infection may spread to the adjacent soft tissue, re-
sulting 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 clin-
ically 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 re-
ported to be present in up to 2458% of cases (96,97). With very advanced dis-
ease, 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 10,00020,000 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 includ-
ing 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). Con-
stitutional symptoms, such as fever and weight loss, are less frequent. The finding
Diagnosis of Tuberculosis 355

of sterile pyuria should alert the clinician to the possibility of urological tubercu-
losis. For urological tuberculosis, urine AFB smears and cultures are usually the
first test of choice. Urine cultures have a sensitivity of 8090% (102,103). Ultra-
sound 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 (105107). Ascites is
detectable on physical exam in 75100% of cases (106,107). Analysis of the as-
citic fluid generally reveals a high protein content and an elevated white blood cell
(WBC) count with a lymphocytic predominance (105,107). AFB smears are al-
most 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 pro-
cedure is on the order of 80100% (109111).
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
5280% of enteric tuberculosis (108,112114). 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 pal-
pated (usually in the right lower quadrant) (113). Enteric tuberculosis may present
as a small bowel obstruction or (rarely) as a perforation (113). Radiological stud-
ies (barium enema and CT scan) often show bowel wall abnormalities, but the
findings are nonspecific and may be confused with other entities such as Crohns
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 (116118).

H. Pericardial Tuberculosis

Pericardial tuberculosis is uncommon. It generally presents as a pericardial effu-

sion, often with tamponade, or constrictive pericarditis (119,120). Chest radio-
graph, EKG, and echocardiogram findings are not specific (119121). Pericardial
fluid is most often serosanguinous and characterized by an elevated WBC count
356 LoBue et al.

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 (119121).

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) (122125).

VII. Pediatric Tuberculosis

The diagnosis of tuberculosis in infants and children is particularly challenging.

Even in pulmonary disease, bacteriological confirmation of the diagnosis is es-
tablished 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 con-
tact to a source case, a positive tuberculin skin test, and a compatible chest radio-
graph (127). In suspected pulmonary tuberculosis, if cultures are necessary, the
best method for obtaining specimens in infants and children is aspiration of gas-
tric contents (127129). For suspected extrapulmonary tuberculosis, the diagnos-
tic 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 re-
sults may be delayed for 25 weeks (130), and in most developing countries rou-
tine confirmation by culture is not feasible. In the interim, critical decisions re-
garding 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 radio-
graphic 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
Diagnosis of Tuberculosis 357

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 (133135). 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 (137139).
Recent advancements in molecular biology have greatly accelerated the de-
velopment of more accurate rapid tests. At the present time, this research is pro-
ceeding along two basic lines. Nucleic acid amplification tests (NAAs) combine
probe and genetic amplification technology in an assay system which can be per-
formed 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 million-
fold, thus providing sensitivities for probe to within 1100 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 spectrophoto-
metric 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 adapt-
able to multiplex designs enabling simultaneous testing of several mycobacterial
species. More experimental procedures such as multiplex strand displacement am-
plification (143,144) and spoligotyping (148) are increasingly encountered in the
laboratory literature. NAAs require sophisticated laboratory infrastructure, in-
cluding 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 820 copy numbers in
most but not all M. tuberculosis strains, was the first rapid diagnostic test format
to be widely reported (148150) and remains the most popular basis for so-called
home-brew preparations. Commercial kits, using standardized controls and of-
fering integrated amplicon/oligonucleotide detection systems, have also been de-
358 LoBue et al.

veloped. Among the more extensively tested at the present time are the Mycobac-
terium Tuberculosis Direct Test (MTD, Gen-Probe, Inc., San Diego, CA)
(151161), which uses transcription-mediated amplification of ribosomal RNA in
conjunction with the manufacturers Accu-Probe test for culture (151,157,
162165), and the Amplicor (Roche Molecular Systems, Branchburg, NJ), a poly-
merase chain reaction system targeting DNA of genes encoding rRNA
(155,166175). The LCx MTB assay (Abbott Laboratories, Chicago, IL), which
utilizes a semi-automated ligase chain reaction system to target Antigen b, a con-
stituent of the species-specific 38 kDa protein, is currently undergoing demon-
stration trials (176178). A Q-beta replicase system (Gene-Trak, Framingham,
MA), targeting the 23S subunit of ribosomal RNA, has also been described
(179181). 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, in-
cluding quality control and specimen-preparation procedures, can affect test per-
formance 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 collec-
tively 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 gener-
ally 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%. False-
negative 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 tu-
berculous target (158,165,188). The best sensitivity has been achieved in smear-
positive samples where the tests have detected 95100% of culture-positive spec-
imens. Depending on the proportion of specimens containing nontuberculous
mycobacteria (NTM), perhaps 5075% 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-
Diagnosis of Tuberculosis 359

ity in smear-negative samples has been more variable, ranging from 40 to 75%, al-
though specificity in these samples is similar to that achieved overall, or about
95%. As a result estimated positive predictive values have been lower, around
5060%, 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 an-
tituberculous 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 ampli-
fication systems in extrapulmonary specimens (156,187,190192) and for detec-
tion of disease in children (193196) warrants continued investigation. With the
exception of pleural effusions, for which results have been inconclusive
(160,197), performance in cerebrospinal fluid (159,198202), blood, urine
(203205), 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 sensi-
tivities across a range of body fluids in a group of AIDS patients with tuberculo-
sis (204). A few studies in children, using an IS6110-targeted in-house PCR as-
say, 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 sensitiv-
ity 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 dis-
ease 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 sensi-
tivity 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 Soci-
ety, 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,
360 LoBue et al.

discordant results occurred, which were resolved in conjunction with other clini-
cal 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. com-
pared three NAA assays as a tool for screening within the first 24 hours of hospi-
tal 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 clin-
ical reference standards of diagnosis and comparing alternative testing strategies
under appropriately randomized and blinded conditions. Among the many ques-
tions 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 in-
fluenced by the physicians prior suspicion of disease, the American Thoracic So-
ciety 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 de-
velop guidelines for special groups, such as children, the elderly, and HIV-posi-
tive patients. Additional studies are also needed to characterize utility for differ-
ent 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 de-
termination 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 re-
search. The potential impact of the NAAs on resource utilization has been simu-
lated in theoretical models. One preliminary study modeling costs for a U.S. in-
patient setting, illustrated overall savings for a scenario in which the enhanced
specificity of rapid diagnosis led to reduction of unnecessary isolation and treat-
ment (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-
Diagnosis of Tuberculosis 361

ports for Kenyas 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 de-
velop models of diagnostic technology assessment that are more relevant to de-
veloping countries. The contribution of delayed diagnosis to tuberculosis epi-
demics 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 ten-
tative recommendations for clinical use of the NAAs (214). These guidelines as-
sume a high level of proficient laboratory resources and would not necessarily ap-
ply 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 infor-
mation 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 propor-
tion of all test positive results) can exceed 20% in some regions of the United
States (216219). We suggest that it is most effective in geographic areas or pop-
ulations 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 pre-
dictive values are likely to exceed those reported in laboratory trials. In combina-
tion with other clinical evidence, a positive NAA, particularly when it is repeated
362 LoBue et al.

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 el-
evated (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 3060% depending on the skill of the clinician. The probability of dis-
ease 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 fol-
lowed up with an AFB smear to quantitate mycobacterial load and culture to re-
cover 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 re-
peated 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.
Diagnosis of Tuberculosis 363

tive, the diagnostic plan should be reformulated on the basis of other medical ev-
idence 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 ac-
tive 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 radio-
graph, bacteriological reports, and physical examination, this assessment requires
attention to the patients 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 re-
ceived the greatest attention. With the changing epidemiology of tuberculosis, in-
cluding such factors as the HIV epidemic and the higher incidence among indi-
viduals 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 evalu-
ating 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 sen-
tinel 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.

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

SUE C. ETKIND JAAP VEEN

Massachusetts Department of Public Royal Netherlands Tuberculosis

Health Association (KNCV)
Boston, Massachusetts 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 approx-
imately 9 contacts identified for each case. Of these, 21% are expected to be in-
fected 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 per-
sons 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
(712), and for follow-up of multidrugresistant 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
378 Etkind and Veen

characteristics of the organism, the nature of the contact, and the environments
that they share (1618).
Contact tracing is an integral part of any tuberculosis program. This activ-
ity encompasses all aspects of tuberculosis control, including surveillance, case
containment, and prevention. In many respects, contact tracing corresponds to ba-
sic epidemiological methodology, particularly as it relates to surveillance and out-
break control. However, contact tracing is in fact much more. Successful contact
tracing requires skills in patient assessment, interviewing, counseling, and evalu-
ation. The quality of contact tracing has been shown to markedly affect the abil-
ity 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 popula-
tion (e.g., geographic and risk-behavior groups), it has become necessary to mod-
ify traditional contact-tracing methods in order to address the specific needs of
these individuals. Although the basics of epidemiology and follow-up are un-
changed, 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 todays multifaceted tu-
berculosis problem for both high- and low-prevalence countries. It will also intro-
duce newer technologies and discuss their additive value to contact-tracing pro-
cedures. 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 casea person with or suspected of having tuberculosis.
Index casethe infectious individual who is believed to have transmitted
infection to another person(s) (may also be referred to as the source
case).
Secondary caseTB disease in a contact as a result of transmission from an
identified index case.
Contact investigationthe process of conducting an epidemiological in-
vestigation into a case (or suspected case) of tuberculosis in order to
Contact Follow-Up 379

identify contacts, screen them for infection and TB disease, and give
therapy as indicated.
TB contactsthose persons who may have a risk of acquiring TB because
they have shared air with the presenting case. The degree of risk is de-
pendent on the duration and frequency (times) of exposure and is influ-
enced by the degree of infectiousness of the patient. The risk is also in-
fluenced by characteristics of the environment, the organism, and the
new hosts (contact) susceptibility to tuberculosis infection or disease.
Close contactsindividuals 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 contactsindividuals 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 fol-
lowing:
To identify persons who have been exposed to the presenting case and who,
therefore, are at greater risk of developing tuberculosis infection and dis-
ease than the general population.
To identify persons who are infected with the TB bacillus through appro-
priate screening of these individuals.
To ensure access to medical evaluation and preventive therapy as appropri-
ate for these infected individuals in order to prevent disease from occur-
ring.
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 in-
fected persons or more tuberculosis cases are discovered during the investigation
380 Etkind and Veen

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 de-
partment, infection control nurse, etc.). Prioritizing which tuberculosis cases re-
quire contact tracing can be difficult. In some areas, investigations are restricted
to contacts of smear-positive pulmonary or laryngeal cases, whereas in other ju-
risdictions a broader definition may apply. In addition, as children are rarely in-
fectious, 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 re-
lated to the reported case, the investigation should begin as soon as possibleide-
ally, 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 informa-
tion 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 ob-
tained 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 re-
sult(s) in millimeters, clinical signs and symptoms (presence of coughproduc-
tive/nonproductive, duration?), and anti-TB drug regimen including dosages and
date initiated.
Armed with this background information, the investigator can then com-
plete the preliminary data-collection process by interviewing the presenting case.
This patient interview may be conducted in the hospital, at the patients 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 con-
tact information will determine the success or failure of the epidemiological in-
vestigation. Good interviewing skills can elicit important information that other-
wise might not be forthcoming.
Contact Follow-Up 381

The presenting case interview has many purposes. These include providing
opportunities to:
1. Establish rapport and trust with the client (face-to-face contact facili-
tates building a relationship between the client and the health care
provider).
2. Obtain information relative to the presenting cases 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 lo-
cation of potential exposures.
4. Identify potentially exposed contacts.
5. Obtain locating/demographic/risk factor and environmental informa-
tion (living quarters/work/school or leisure activities) for the identified
contacts. Environmental factors may include such things as the ventila-
tion, 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 treat-
ment for latent TB infection.
7. Assess compliance elements as they may relate to the presenting case
(i.e., are there any factors in the cases 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 immunodefi-
ciency 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 inves-
tigative efforts will be diluted and limited resources are likely to be spent on de-
livering 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 as-
sessment of the risk of TB transmission to the identified contacts can be done prior
382 Etkind and Veen

to the actual field investigation. Transmission risk assessment is best accom-

plished by organizing the background information into the basic epidemiological
categories of person, time, and place. For this chapter, these categories will be de-
fined as (1) person factorsthe infectiousness of the presenting case(2) time
factorsthe duration and frequency of exposureand (3) place factorsthe
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 signif-
icant factors are disease site and sputum smear positivity. For example, if the pre-
senting case has been shown to have only extrapulmonary disease and no respira-
tory symptoms, the likelihood of TB transmission is very low. If however, the
presenting case is shown to have cavitary disease, hemoptysis, and heavily posi-
tive 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 immunocompe-
tent contact who has been previously infected with tuberculosis is rarely rein-
fected 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 High Low

TB disease location Laryngeal Extrapulmonary alone

Pulmonary
Smear status Positive Negative
Smear source Spontaneous specimen Induced or clinical
(bronchoscopy, etc.)
Chest x-ray Cavitary Noncavitary
Symptoms Cough No cough
Anti-TB drug No Yes (2 weeks or more)
Contact Follow-Up 383

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 (2325). 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 ex-
ample, 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 trans-
mission. When the contact is unable to remember reliably when his or her symp-
toms began, some jurisdictions elect to define the period of infectiousness as be-
ginning at least 3 months before treatment started. The period of infectiousness
ends when all of the following criteria are met: symptoms have improved, the pa-
tient 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 of-
fices (26), airplanes (27), crackhouses (28), HIV respite facilities (29), drug reha-
bilitation 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
384 Etkind and Veen

definition of family may be required to adequately define the limits of the ini-
tial investigation (33).
In addition to establishing the exact locations of potential exposures, addi-
tional 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 af-
fect 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 sun-
light, the risk of transmission is further increased.
During the interview process, the investigator may discover that the pre-
senting 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 like-
lihood 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 ob-
tain information from the presenting case and the contacts and to make a visual as-
sessment of the surrounding area in order to further narrow the limits of the in-
vestigation.
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
cases 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 High Low

Volume of air common Low High
to the case/contacts Poor Good
Adequacy of ventilation
10 CFM*/person 20 CFM/person
Yes No
Recircularized air Not present Present
Upper room UV light

*CFM, cubic feet per minute.

Contact Follow-Up 385

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 shel-
ter, an institution, etc., will assist in establishing rapport and trust between these
individuals and the health-care provider. The same principles that were sug-
gested for the presenting case interview apply to the contact interview. Because
prevention of both further disease transmission and further progression from in-
fection to active disease are among the purposes of contact tracing, the timeli-
ness in which the field investigation is conducted is paramount. Current recom-
mendations 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) inter-
view and skin test the identified contacts, (2) observe the contacts for any signs or
symptoms suggestive of tuberculosis, (3) collect sputum samples from any con-
tact 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 contacts environment for po-
tential transmission factors (crowding, ventilation, etc.), (8) assess the contacts
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 high-
est 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 con-
tact investigation. Although mathematical models exist to analyze potential trans-
mission of tuberculosis (34), the factors affecting both transmission and the ac-
quisition 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 Etkind and Veen

Table 3 Contacts at Highest Risk for Progression to Disease

Contacts at high risk

Contacts most likely to be infected
Contacts exposed to the patient during
the period of infectiousness
Contacts exposed to the patient in:
small rooms
poorly ventilated or dark areas
areas without HEPA filters or
ultraviolet lights
Contacts who:
routinely spend a lot of time with
the patient
have been physically close to the
patient
have never had TB infection
of developing TB disease once infected
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.
Contact Follow-Up 387

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 in-
vestigation 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 in-
fection than is expected for the general community. If the inner-circle close con-
tact 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 investi-
gation 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 con-
tact 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 dif-
ficulties in orchestrating the concentric circle approach. Problems encountered in-
clude difficulties in narrowing down just who is a part of the inner circle, a reluc-
tance to identify individuals in certain settings, the desire on the part of the
employees or administration to overtest individuals in order to ameliorate the hys-
teria 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
388 Etkind and Veen

identify and understand the sources of concern. Once this is known, an educa-
tional 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 4872 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 possi-
bility 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 resultsContacts who
have a documented prior positive PPD who are not known or likely to
be immunosuppressed or have other medical risk factors need no fur-
ther 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 evalu-
ation. In some countries, close contacts who have been intensely ex-
posed 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 pre-
ventive therapy.
3. For those persons who were skin test negative initiallyAll other con-
tacts who are skin test negative initially should be retested in approxi-
mately 812 weeks in order to allow time for skin test reactivity to oc-
cur (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 1012 weeks pos-
texposure is referred to as the window period. Persons found to be
Contact Follow-Up 389

skin test positive at the second testing are considered to be newly in-
fected and require further medical evaluation.
The total contact tracing process should be completed within 3 months un-
less concentric circle testing results require further expansion of the testing. Con-
tact 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 health-
care provider for the duration of their treatment.

E. The Contact Investigation Report

The contact-tracing investigation should be well documented and the results ana-
lyzed. 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 iden-
tification, number, and percentage of newly positive, previously positive, docu-
mented 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, inter-
ruptions 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-preva-
lence 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, tu-
berculosis 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 over-
crowded, usually poorly lighted and ill-ventilated. It is therefore likely that tuber-
culosis 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 trans-
mission taking place.
390 Etkind and Veen

Studies have differing conclusions about the importance of contact investi-

gations 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 smearpositive cases and
high tuberculin reactor rates compared to the general population. Children aged
05, 69, and 1019 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 con-
tacts 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 finan-
cial 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, how-
ever, that 64% of 282 children who lived in the household with at least one smear
sputumpositive 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
smearpositive adults could be more infectious than HIV-negative sputum
smearpositive patients. Reports from Zaire and Malawi (10) showed no differ-
ence 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-in-
come 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 test-
ing. Positive tests need to be interpreted with care. Most children were BCG vac-
cinated 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
Contact Follow-Up 391

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 inves-
tigation can also be restricted to persons with symptoms suggestive of tuber-
culosis.
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 per-
son 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 resource-
poor 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 symp-
toms, 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 microbiolog-
ical 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 sugges-
tive 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 interven-
tion. Fingerprinting has also produced new insights in the development of tuber-
culosis. New infections generally result in active tuberculosis in only 510% 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 out-
break where DNA fingerprinting showed that the clustering of patients in place
and time was due to recent transmission (29). This has implications for the orga-
nization of contact investigation.
Small (41) recognized three current trends contributing to the increase of tu-
berculosis: geographic disparity in tuberculosis case rates, the emergence of mul-
tidrug resistance, and population mobility. He stated that the knowledge of M. tu-
392 Etkind and Veen

berculosis genotypes characteristic of specific geographic areas would signifi-

cantly facilitate the international tracking of tuberculosis.
The following examples show that the combination of conventional and
molecular epidemiology in outbreak investigations contributes to the understand-
ing 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 Har-
lingen, 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 de-
tected, 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 tu-
berculosis 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, transmis-
sion to other geographic areas may not be as likely as expected, espe-
cially 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 out-
break among HIV-infected persons (44). The common place of trans-
mission turned out to be a local bar, which could not have been identi-
fied 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 re-
flect the fact that most contacts are effectively identified and prophy-
laxed 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
Contact Follow-Up 393

the results are similar to San Francisco. It has therefore been suggested that cur-
rent tuberculosis-control strategies have important limitations in contemporary ur-
ban 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 inter-
ventions.
Another contribution to prevention is by identifying unexpected transmis-
sion caused by lapsed compliance with procedures. Examples are laboratory-ac-
quired 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 in-
dividual 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, de-
pending on the size of the inoculum, may take 38 weeks to grow. The typing it-
self 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 re-
cent 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 finger-
printing are useful for the evaluation of interventions. Epidemiological linking
will explain the chain of transmission and thereby contribute to redirected inter-
ventions. 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 mycobac-
teria and therefore are unable to detect infections before disease occurs. Early de-
tection of infection and ensuing preventive chemotherapy still remain very im-
portant and powerful tools of tuberculosis control.
394 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 (12,25,27,49,5155). 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 programmat-
ically and individually, a lack of education for physicians (particularly those
in the private sector) about concentric circles and the need for contact investiga-
tion 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-carede-
livery 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 fol-
lowed until completion of therapy (56). These include the following: establish-
ment of a priority system at the clinics for identified contacts; outreach worker as-
signments 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 fol-
low-up during routine case conferences.
The transmission risk-assessment process is based on a number of assump-
tions 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)?
Contact Follow-Up 395

2. Presenting Infectious Case: Is smear status a useful indicator for con-

tact 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 epi-
demiology in intervention and control efforts (29,4247)?
When is a presenting infectious patient a superspreader? Are these mark-
ers 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-vac-
cinated persons (64)?
4. The Environment: Is there a better way to identify and quantify envi-
ronmental factors related to transmission? How much does the type of
setting affect transmission? What are the benefits of engineering con-
trols?

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 infec-
tion to disease. This chapter has illustrated that contacts of infectious cases of tu-
berculosis are such a high-risk group and should be priorities for tuberculosis-con-
trol 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 trans-
mission, 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 investi-
gation beginning with the notification of a case or suspect case of tuberculosis. It
396 Etkind and Veen

has described the collection of needed epidemiological data for planning pur-
poses, the establishment of investigational priorities based on this data, the
methodology for contact tracing in the field setting, the utilization of the concen-
tric circle approach in order to set the limits of the investigation, and the docu-
mentation of the procedures and results of the investigation. In addition, this chap-
ter has discussed the differences in contact tracing between high- and low-
prevalence 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.

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16
Treatment of Tuberculosis

PAULA I. FUJIWARA PATRICIA M. SIMONE

New York City Department of Health Centers for Disease Control and Prevention
New York, New York, and 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 in-
ternational collaborations, the most notable of which were developed by the
British Medical Research Council and colleagues in East Africa, India, Hong
Kong, and Singapore (13).
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
402 Fujiwara et al.

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 re-
sistance and the role of intermittent regimens, will be discussed. The drugs avail-
able 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 du-
ally infected with the human immunodeficiency virus (HIV) and Mycobacterium
tuberculosis, the treatment of persons with and exposed to multidrug-resistant tu-
berculosis, and the role of surgery. The chapter will end with a discussion of ad-
herence 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 strepto-
mycin in 1944. Used alone, streptomycin was found to be highly effective at pro-
ducing 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 discov-
ered that the emergence of resistance could be prevented by using two or more
drugs in combination (7). Standard regimens of 1824 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 ri-
fampin 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 ac-
tivity (see Table 1) (10). Drugs that are highly active in the prevention of drug re-
sistance 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 403

Table 1 Relative Activities of Antituberculosis Medications

Preventing
Early bactericidal activity
drug Sterilizing
In vitro In vivo resistance activity Activity

INH INH INH RIF High

RIF RIF PZA
SM
EMB SM INH
EMB RIF
PZA EMB SM
SM THA EMB
PZA
THA THA
PAS PAS PZA THA Low
INH  isoniazid; RIF  rifampin; PZA  pyrazinamide; EMB  ethambutol; THA  ethionamide.

which the last few viable bacteria are killed (12). Drugs with potent sterilizing ac-
tivity 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 resis-
tance, 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 spon-
taneously in wild-type strains of M. tuberculosis (13). These mutations occur at
different rates for the antituberculosis medications. For example, mutations pro-
ducing 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 multiply-
ing the rates for the individual drugs. For instance, mutations producing isoniazid-
and 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 re-
sistant 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 107109 organisms and thus are likely to include a few mutants re-
sistant 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 or-
ganisms 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
404 Fujiwara et al.

strain. In a large population of resistant mutants, further mutations can occur, pro-
ducing doubly resistant organisms.
Drug resistance in tuberculosis may be classified as either primary or sec-
ondary (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 emer-
gence of drug resistance. This is followed by a consolidating, continuation phase
containing sterilizing agents to kill the less active, intermittently dividing popula-
tions. A 9-month regimen of isoniazid and rifampin, with ethambutol or strepto-
mycin in the first 2 months, provides excellent bactericidal and sterilizing activity
(15). Furthermore, the potent sterilizing activity of rifampin and pyrazinamide re-
duces the duration of treatment from 9 to 6 months, while maintaining the ability
to retain low relapse rates (1619). Even when pyrazinamide is added for only the
first 2 months of treatment, highly successful regimens of only 6 months are pos-
sible (17). Ethambutol or streptomycin are added initially before susceptibility re-
sults are available to prevent the emergence of rifampin resistance if there is un-
recognized 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 ther-
apy. Nonadherence has been recognized as the major cause of treatment failure,
relapse, and the emergence of drug resistance (2022). Researchers began to study
the feasibility of two methods to enhance adherence: supervised treatment and in-
termittent treatment (23,24). Supervised therapy (watching the patient swallow
each dose of medication) was discovered to be an effective way to address non-
adherence. To improve the cost-effectiveness of treatment, the possibility of in-
termittent (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 in-
terval. 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 (2628). In another study, a fully intermittent reg-
imen of four drugs given three times weekly for the full course of treatment has
Treatment of Tuberculosis 405

also been found to be effective, even in the presence of initial resistance to isoni-
azid 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 di-
viding 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 adminis-
tration 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 hep-
atitis (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 recom-
mended for adults starting therapy with isoniazid. Measurements should be re-
peated 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 inhibitorlike 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 lev-
els (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 ac-
tivity against semidormant bacilli. It works primarily by inhibiting DNA-depen-
dent 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
Table 2 First-Line Antituberculosis Drugs: Dosages

Dose in mg/kg (United States)

(maximum dose)
Dose in mg/kg (WHO and IUATLD)
Daily 2 times/weeka 3 times/weeka (range mg/kg)

Drug Route Child Adult Child Adult Child Adult Daily 2 times/weekb 3 times/week

Isoniazid Oral 10 5 2040 15 2040 15 5 15 10

(300 mg) (300 mg) (900 mg) (900 mg) (900 mg) (900 mg) (46) (1317) (812)
Rifampin Oral 1020 10 1020 10 1020 10 10 10 10
(600 mg) (600 mg) (600 mg) (600 mg) (600 mg) (600 mg) (812) (812) (812)
Pyrazinamide Oral 1530 1530 5070 5070 5070 5070 25 50 35
(2 g) (2 g) (4 g) (4 g) (3 g) (3 g) (2030) (4060) (3040)
Ethambutol Oral 1525 1525 50 50 2530 2530 15 45 30
(1520) (4050) (2535)
Streptomycin IM or 2030 15 2530 2530 2530 2530 15 15 15
IV (1 g) (1 g) (1.5 g) (1.5 g) (1.5 g) (1.5 g) (1218) (1218) (1218)
Thioacetazone Oral N/A N/A N/A N/A N/A N/A 2.5c
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.
Treatment of Tuberculosis 407

Table 3 First-Line Antituberculosis Drugs: Adverse Reactions and Monitoring

Drug Adverse reactions Monitoring Comments

Isoniazid Hepatic enzyme elevation Baseline measurements of Hepatitis risk increases with age
Hepatitis hepatic enzymes for and alcohol consumption
Peripheral neuropathy adults
Mild effects on central Repeat measurements: Pyridoxine can prevent peripheral
nervous system if baseline results are neuropathy
Drug interactions abnormal
if patient is at high risk
for adverse reactions
if patient has symptoms
of adverse reactions
Rifampin GI upset Baseline measurements for Significant interactions with:
Drug interactions adults: methadone
Hepatitis CBC and platelets birth control pills
Bleeding problems hepatic enzymes many other drugs
Flu-like symptoms Repeat measurements: Colors body fluids orange
Rash if baseline results are May permanently discolor soft
abnormal contact lenses
if patient has symptoms
of adverse reactions
Pyrazinamide Hepatitis Baseline measurements for Treat hyperuricemia only if
Rash adults: patient has symptoms
GI upset uric acid
Joint aches hepatic enzymes
Hyperuricemia Repeat measurements:
Gout (rare) if baseline results are
abnormal
if patient has symptoms
of adverse reactions
Ethambutol Optic neuritis Baseline and monthly tests: Not recommended for children
visual acuity too young to be monitored
color vision for changes in vision unless
TB is drug resistant
Streptomycin Ototoxicity (hearing loss Baseline and repeat Avoid or reduce dose in adults
or vestibular dysfunction) monthly: 60 years
Renal toxicity hearing
kidney function
Thioacetazone Severe dermatological Skin exam Do not use if HIV or clinical
reactions: symptoms of AIDS
Stevens-Johnson syndrome
toxic epidermal necrolysis
exfoliative dermatitis
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 gas-
trointestinal upset. Hepatotoxicity occurs less frequently than with isoniazid ad-
ministration. Some adverse reactions, such as hypersensitivity reactions, throm-
 408 Fujiwara et al.

bocytopenia, and renal failure, occur only rarely but appear to occur more fre-
quently with intermittent rather than daily administration. Rifampin is a potent in-
ducer 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 ri-
fampin. Rifampin also interacts significantly with protease inhibitors and non-nu-
cleoside 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 short-
course chemotherapy regimens (40). It is most active in acid environments, espe-

Table 4 Rifamycins, Protease Inhibitors (PI), and Nonnucleoside Reverse

Transcriptase Inhibitors (NNRTIs)

Rifabutin Rifampin

Effect of Effect of PI or Effect of Effect of PI or

rifabutin on AUC NNRTI on AUC rifampin on AUC NNRTI on AUC
HIV drug of PI or NNRTIa of rifabutina of PI or NNRTIa of rifampinb

Saquinavir 40% NR 80% NR

(Invirase)
Saquinavir soft 47% 44% 70% NR
gel capsules
(Fortovase)
Ritonavir NR 4c 35% Unchangedd
Indinavir 24% 270% 90% NR
Nelfinavir 32% 207% 82% NR
Amprenavir 14% 204% 81% NR
Nevirapine Unchanged NR () 58% Unchanged
Delavirdine 75% 150% 90% Unchanged
Efavirenz Unchanged 38%e 26% 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. 8998.
Treatment of Tuberculosis 409

cially in the intracellular environment of macrophages. The precise mechanism of

action of pyrazinamide on tubercle bacilli is not known. The daily dose of pyraz-
inamide is 1530 mg/kg given by the oral route.
Hypersensitivity reactions and gastrointestinal upset may occur with pyraz-
inamide administration. Hepatotoxicity occurs infrequently with current recom-
mended dosages. Pyrazinamide often produces elevated uric acid serum levels, al-
though 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 se-
lection 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
1525 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 ethambutols
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 gener-
ally 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 ad-
ministration 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 re-
lapse in patients with initially isoniazid-resistant strains. It is usually given at a
dosage of 150 mg daily, commonly in a combination tablet with 300400 mg of
410 Fujiwara et al.

isoniazid. Gastrointestinal upset is common, but the most significant side effects
are cutaneous reactions. These reactions may be severe, including exfoliative der-
matitis, 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-ad-
ministered therapy to prevent monotherapy and the emergence of drug resistance
(43,44). Combinations of isoniazid and rifampin (Rifamate) and isoniazid, ri-
fampin, and pyrazinamide (Rifater) are available in the United States. Combina-
tion tablets of isoniazid and thioacetazone and isoniazid and ethambutol are avail-
able in other countries (4446).
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 con-
tain more rifampin than the recommended dosage of rifampin given in the single
drug preparation. Fixed-dose combinations of antituberculous drugs have the ad-
vantage 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 dis-
advantages 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 pa-
tient takes fewer tablets than prescribed, and the incorrect prescriptions written
and filled because of the similarity of trade names (Rifadin for rifampin alone; Ri-
finah 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 bioavail-
ability 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.
 Table 5 Second-Line Antituberculosis Drugs
United States WHO
daily dosea daily dose
{maximum dose} {maximum dose} Adverse
Drug (usual dose) (usual dose) reactions Monitoring Comments
Cycloserine 1520 mg/kg po in 1520 mg/kg po in Psychosis Assess mental status Start with low dosage and
divided doses divided doses Convulsions Measure serum drug increase as tolerated
{1 g} (500750 mg po in Depression levels Pyridoxine may decrease
(250500 mg BID) divided doses) Headaches CNS effects
Rash
Drug interactions
Ethionamide 1520 mg/kg po in 1520 mg/kg po in GI upset Measure hepatic enzymes Start with low dosage and
divided doses divided doses Hepatotoxicity increase as tolerated
{1 g} {1 g} Hypersensitivity May cause hypothyroid
(250500 mg BID) (250500 mg BID) Metallic taste condition, especially if
Bloating used with PAS
para-Amino- 150 mg/kg po in 150 mg/kg po in GI upset Measure hepatic enzymes Start with low dosage and
salicylic acid divided doses divided doses Hypersensitivity Assess volume status increase as tolerated
(PAS) {16 g} (56 g BID) Hepatotoxicity Monitor cardiac patients
(4 g TID) May cause hypothyroid
condition, especially if
used with ethionamide
Capreomycin 1530 mg/kg 20 mg/kg qd Toxicity: Assess: After bacteriologic
IM or IV qd {1 g} auditory vestibular function conversion, dosage may
{1 g} vestibular hearing function be reduced to 23 times
renal Measure: per week
Hypokalemia blood urea nitrogen
Hypomagnesemia creatinine
potassium, magnesium
continues

411
 Table 5 Continued
United States WHO

412
daily dosea daily dose
{maximum dose} {maximum dose} Adverse
Drug (usual dose) (usual dose) reactions Monitoring Comments

Kanamycin/ 1530 mg/kg 15 mg/kg IM qd Toxicity: Assess: After bacteriological

Amikacin IM or IV qd {750 mg1 g} auditory vestibular function conversion, dosage may
{1 g} vestibular hearing function be reduced to 23 times
renal Measure: per week
blood urea nitrogen
creatinine
Fluoroquinolonesb,c GI upset
Dizziness
Hypersensitivity
Drug interactions
Headaches
Restlessness
Ciprofloxacin 7501500 mg/day po 10001500 mg/day in
(750 mg BID) single or divided
doses

Ofloxacin 600800 mg/day po 600800 mg/day po in

(400 mg BID; 800 single or divided
qd) doses

Levofloxacin 500 mg/day Photosensitivity

Sparfloxacin 200 mg/day may occur with
sparfloxacin
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.
Treatment of Tuberculosis 413

Cycloserine
Cycloserine interferes with mycobacterial cell wall synthesis. The usual dosage is
1520 mg/kg daily up to 1000 mg/day in divided doses by the oral route. Cy-
closerine not infrequently causes dose-related neurological or psychiatric distur-
bances, 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 excre-
tion of the drug and can exacerbate adverse reactions.

Ethionamide
Ethionamide is a derivative of isonicotinic acid that appears to interfere with pep-
tide synthesis. The usual daily dosage is 1520 mg/kg up to 1000 mg/day by
mouth in divided doses. Ethionamide frequently causes gastrointestinal side ef-
fects, such as abdominal pain, nausea, vomiting, and anorexia. Bedtime dosing,
taking the medication with food, or gradually increasing to the full dose may im-
prove tolerance. Rarely, ethionamide may cause hepatitis. It can cause hypothy-
roidism, 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 dis-
ease 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 cur-
rently 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 dis-
turbances. Hypersensitivity reactions, hepatitis, and thyroid dysfunction may oc-
cur; 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 1530
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 func-
tion should be monitored closely, especially in elderly patients. Capreomycin may
414 Fujiwara et al.

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 1530 mg/kg. They have complete cross-resistance, and cross-re-
sistance 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 monitor-
ing 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 in-
hibit 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 500750 mg twice a day, and the daily
dosage of ofloxacin is 600800 mg/day. Levofloxacin is the L-isomer of ofloxacin
and has approximately twice the potency. The maximum recommended dose
is 500 mg daily, although 7501000 mg/day has been used by some clinicians for
the treatment of tuberculosis. Sparfloxacin has even greater potency than lev-
ofloxacin; 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 fluoro-
quinolones are well tolerated (54). Animal studies have reported arthropathies
in juvenile animals, suggesting that fluoroquinolones should not be used in chil-
dren. 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
Treatment of Tuberculosis 415

these organisms. It is occasionally used in the treatment of multidrug-resistant tu-

berculosis, although its usefulness has not been clearly demonstrated. Clofazimine
causes an orange-bronze discoloration of the skin and may also cause gastroin-
testinal 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 achiev-
able 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 ri-
fampin, and its usefulness in the treatment of rifampin-resistant tuberculosis has
not been clearly demonstrated. However, because it is a less potent inducer of cy-
tochrome 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 ther-
apy. A preliminary analysis showed an unexpected finding of relapse with ri-
fampin-monoresistant tuberculosis in a disproportionate number of HIV-infected
patients who were treated with once-weekly isoniazid and rifapentine (57). En-
rollment of HIV-infected patients was stopped and further analysis is underway,
although this may be related to the increasing prevalence of experience with ri-
fampin 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 sus-
ceptibility 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 ar-
eas 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 recom-
mended 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, in-
tensive phase of the recommended regimen contains four drugs: isoniazid, ri-
fampin, pyrazinamide, and either ethambutol or streptomycin. The first option is
 Table 6 Regimen Options for Treatment of Tuberculosis in the United States

416
Intensive phase Continuation phase
Total
duration Interval and Interval and
Option Indication (weeks) Drugs duration Drugs Option duration Comments

1 Pulmonary and 24 HRZ (E or S)c Daily for 8 weeks HR 1 Daily or 2 or 3 Ethambutol or steptomycin should be
extrapulmonary times/weeka continued until susceptibility to
TB in adults and for 16 weeksb isoniazid and rifampin is
children 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 Pulmonary and 24 HRZ (E or S)c Daily 2 times/ HR 2 2 times/weeka After the initial phase, continue
extrapulmonary for 2 weeka for 16 weeksb ethambutol or streptomycin until
TB in adults and weeks for 6 susceptibility to isoniazid and
children and then weeks rifampin is demonstrated, unless
drug resistance is unlikely.
3 Pulmonary and 24 HRZ (E or S)c 3 times/weeka for 6 3 Continue all four drugs for 6 months.d
extrapulmonary monthsb This regimen has been shown to be
TB in adults and effective for isoniazid-resistant TB.
children
4 Smear and 16 HRZ (E or S)c Follow option 1, 2, HRZ 4 Daily or 2 or 3 Continue all four drugs for 4 months.
culture-negative or 3 for 8 weeks (E or S)c times/weeka If drug resistance is unlikely (primary
pulmonary TB for 8 weeks isoniazid resistance
4% and
in adults patient has no individual risk factors
for drug resistance), ethambutol or
steptomycin may not be necessary
and pyrazinamide may be
discontinued after 2 months.
 5 Pulmonary and 36 HR (E or S)c Daily for 48 weeks HR 5 Daily or 2 or 3 Ethambutol or streptomycin should be
extrapulmonary times/weeka continued until susceptibility to
TB in adults and for 2832 isoniazid and rifampin is
children when weeksb demonstrated.
pyrazinamide is In areas where primary isoniazid
contraindicated 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 ther-
apy 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.

417
418 Fujiwara et al.

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-admin-
istered 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 reg-
imen 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 pri-
mary 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-effec-
tive. 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 ob-
servation (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 toler-
ated and effective, even in the presence of isoniazid resistance.

V. Antituberculosis Treatment Regimens in Resource-

Poor Countries

In resource-poor countries, not all cases of tuberculosis are given the same prior-
ity for treatment. Both the World Health Organization (WHO) and the Interna-
tional 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 prior-
ity. 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.

Treatment of Tuberculosis 419

419
420 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 smear-
negative 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 medi-
cations 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 IUATLDs recommendation to use isoniazid and
thioacetazone throughout the treatment of previously untreated AFB smear-nega-
tive tuberculosis and in the continuation phase for previously untreated patients
with AFB smear-positive tuberculosis. Thioacetazones chief advantage is its low
cost, but severe, potentially fatal, drug reactions, such as Stevens-Johnson syn-
drome and toxic epidermal necrolysis (6365), 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 im-
proved 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 recom-
mending 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 pri-
ority 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 pa-
tients 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 deter-
mine infectiousness and need for rapid isolation and contact investigation, the
gold standard for diagnosis of tuberculosis is a positive culture for M. tuberculo-
 Table 7 World Health Organization and International Union Against Tuberculosis and Lung Disease Recommended Treatment Regimens

World Health Organization IUATLD

phase phase
Treatment
category Intensive
(see text for (daily or thrice
explanation) Patients weekly) Continuation Intensive Continuation

I Never previously treated: 2 HRZE (HRZS) 6HE or 2 HRZE 6 HTc

Sputum smear () 4HRa, or
Sputum smear () with extensive 4H3R3 2 HTc (S or E) 10 HTc
parenchymal involvementb
Severe forms of extrapulmonary TBb
II Sputum smear (): 2 HRZES/1HRZE 5 H3R3E3, or 2 HRZES/1 HRZE 5 HRE
Relapse 5 HRE
Treatment failure
Treatment after interruption
III New smear () [other than Category I]b 2 HRZ 6 HE, or 12 HTc
New less severe forms of 4 HR, or
extrapulmonary TB 4 H3R3
IV Chronic case (still sputum smear-positive Referral to specialized treatment center Not applicable
after supervised retreatment) (see text)
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.

421
Source: Adapted from Refs. 45 and 62.
422 Fujiwara et al.

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 re-
nal 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 symp-
toms 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 af-
ter 24 months of treatment (59,71). Monthly liver function tests should be per-
formed 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 tuberculo-
sis (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 cul-
tures for tuberculosis, a chest x-ray should be obtained after 3 months of treat-
ment. 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 tuber-
culosis is not needed (59). They should, however, be advised to return for evalu-
ation if they develop symptoms consistent with tuberculosis. Persons who should
be considered for periodic posttreatment evaluation include: (1) those with mul-
tidrug-resistant tuberculosis; (2) those who did not have a rifamycin in the regi-
men; (3) persons on self-administered treatment where there was doubt as to ad-
herence; 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 tu-
berculosis or extrapulmonary tuberculosis, clinicians should monitor increase in
weight and overall improvement. The routine use of blood chemistries, chest x-
rays, and sputum culture and susceptibility testing is not recommended (45,62).
Treatment of Tuberculosis 423

VII. Special Clinical Situations

A. Treatment Failure
Treatment failure ensues when a person continues to have a culture positive for M.
tuberculosis despite 46 months of a treatment regimen to which the organism is
known to be susceptible. When cultures are unavailable or pending, treatment fail-
ure 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 di-
rectly observed therapy; (2) repeating specimens for smear, culture, and suscepti-
bility; and (3) continuing the current regimen until susceptibility results are avail-
able, 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 ad-
justed once susceptibility results are available (59,71).
In countries that monitor sputum smears for response to treatment, treat-
ment 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 af-
ter 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 23
months, followed by 6 months of rifampin and ethambutol. If the strain is resis-
tant to isoniazid and ethambutol (streptomycin), 3 months of rifampin, an
aminoglycoside, pyrazinamide, and ethambutol are followed by 6 months of ri-
fampin 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
424 Fujiwara et al.

(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 iso-
niazid and rifampin in the initial regimen, drug resistance to the previously used
agents should be presumed until proven otherwise. In all situations, drug suscep-
tibility tests should be performed and treatment regimens modified according to
the results.
In resource-poor countries, where cultures are not routinely available, a re-
lapsed 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 recom-
mendation to extend the continuation phase for certain forms (see Table 6). Chil-
dren with miliary tuberculosis, bone or joint tuberculosis, or tuberculous menin-
gitis should be treated for at least 12 months (59). Compared with pulmonary
tuberculosis, cases of extrapulmonary tuberculosis may require surgery more of-
ten 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 smearnegative
(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 smearpositive, 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 seri-
ously 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, prefer-
ably 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.
Treatment of Tuberculosis 425

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 ethion-
amide can be given in normal doses in renal failure. Antituberculosis drugs are
cleared to a variable degree by hemodialysis; therefore, on days dialysis is per-
formed, 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 re-
nal 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 ad-
vised 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, cy-
closerine, and the fluoroquinolones) should be used until the liver function im-
proves. Serum drug concentrations may be beneficial in the management of pa-
tients 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 isoni-
azid and rifampin with streptomycin and ethambutol followed by 6 months of
isoniazid and rifampin or (2) two months of isoniazid, streptomycin, and ethamb-
utol 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 regi-
men of drugs with low potential for liver toxicity such as ethambutol and strepto-
mycin can be used for up to 3 months, followed by isoniazid and rifampin for an-
other 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
426 Fujiwara et al.

infection to the fetus and the newborn. WHO and IUATLD recommend that the
standard short-course regimens containing pyrazinamide be used during preg-
nancy (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 suscepti-
ble. Pyridoxine supplementation should be given to prevent peripheral neuropa-
thy 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 child-
bearing age with MDRTB should be counseled to use birth control. Pregnant
women with MDRTB should be counseled about the potential effects of the med-
ications 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 recom-
mended 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 nurs-
ing 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 iso-
niazid, 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 sim-
ilar low rates of relapse for a group that received a standard 6-month regimen com-
pared 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
Treatment of Tuberculosis 427

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 tu-
berculosis were modified in 1994 to state that individuals with tuberculosis with or
without HIV infection could be treated for 6 months (the previous recommenda-
tion 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 medica-
tions 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 im-
portant 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 tuber-
culosis (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 livers
cytochrome P450 system, but have opposing effects. Rifamycins induce the cy-
tochrome 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 (8993a). Likewise,
because of similar interactions with rifampin, the NNRTIs nevirapine and delavir-
dine should not be used with rifampin. Efavirenz levels are decreased when used
with rifampin, but the clinical significance of this is unclear (94). Although ri-
fabutin has been reported to decrease NNRTI levels less than rifampin, the level
of interaction between delavirdine and the rifamycins is such that their use to-
gether is contraindicated (95,96). Nevirapine can be used with rifabutin without
any dose adjustment (97). Efavirenz decreases rifabutin levels, and the dose of ri-
fabutin 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 substi-
tuted 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:
 428

Figure 2 New York City Department of Healthrecommended treatment regimens for HIV-infected persons with drug-susceptible tu-
berculosis.
Fujiwara et al.
Treatment of Tuberculosis 429

1. Can the use of the PI or NNRTI be delayed? If delay is possible, the

ATS/CDC recommendations for the treatment of tuberculosis de-
scribed 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 con-
tinuation phase, rifampin should be switched to rifabutin and an appro-
priate PI or NNRTI can be used.
2. If the use of a PI or NNRTI cannot be delayed until the end of the in-
tensive phase of treatment for tuberculosis, nonrifampin-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 para-
meters 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 nonrifamycin-
containing 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 con-
trol 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 tubercu-
losis depends upon the clinician knowing susceptibility results and having avail-
able the antituberculosis medications to which the strain of M. tuberculosis is sus-
ceptible. 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 pyraz-
inamide is recommended (59). For other drug-resistance patterns, it is difficult to
develop standardized treatment regimens because good efficacy data are not avail-
able and because the side effects of the second-line medications can be so intoler-
able as to preclude their use for the recommended period of time. The most diffi-
cult 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 ar-
mamentarium. 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
430 Fujiwara et al.

expensive drugs and do not have ready access to the more sophisticated laboratory
procedures needed to monitor the patient. However, WHO has published guide-
lines 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 re-
liable susceptibility testing (see Sec. VII. A) (73). WHO has also endorsed DOTS-
Plus (see Chap. 18).

MDRTB Treatment Principles

All persons with MDRTB should be treated using directly observed therapy.
As this is the patients 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 strains re-
sistance 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 sus-
ceptible. An aminoglycoside or capreomycin should be one of the medi-
cations because of evidence that the duration of treatment with this fam-
ily of drugs is the strongest predictor of culture conversion and survival;
it should be used for at least 46 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 per-
sons 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 patients M. tuberculosis culture remains positive after 45 months of
treatment, the most recent positive specimen should be sent to the labo-
ratory 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 pa-
tient is acutely ill, at least two new drugs should be added while contin-
uing 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 ef-
fect 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.
Treatment of Tuberculosis 431

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 high-
est 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 con-
tacts risk of being exposed to persons with drug-susceptible tuberculosis (a nurse
working on a hospital tuberculosis ward versus a tuberculin skin testpositive
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 rec-
ommended. 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 treat-
ment (103,104) In New York Citys tuberculosis-control program, which has had
considerable experience in this area, persons who are immunosuppressed or chil-
dren under 5 years of age are offered 12 months of two drugs to which the infect-
ing 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 radio-
graphs 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
432 Fujiwara et al.

thought to decrease the amount of oxygen available for the survival of M. tuber-
culosis, 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 tu-
berculosis was abandoned (106). Surgery for tuberculosis was used to correct the
consequences of severe disease, such as major bronchial obstruction, a bron-
chopleural 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 46 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 be-
ing sufficient drug activity to diminish the mycobacterial burden enough to fa-
cilitate probable healing of the bronchial stump (107,108). In its series of 130 pa-
tients 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 tu-
berculosis, Wallace Fox, one of the architects of the widely influential British
Medical Research Trials on tuberculosis treatment, reported the difficulty of get-
ting 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
Treatment of Tuberculosis 433

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, transporta-
tion 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, ex-
panding 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. An-
other important practice is to have staff treat patients as if they are the most im-
portant 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 nonad-
herent, studies have shown that nonadherence is difficult to predict. Ones age,
sex, race or ethnicity, socioeconomic status, level of education, occupation, in-
come, 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 out-
comes from intermittent treatment also meant that fewer doses needed to be super-
vised (23,24,112). Despite this early evidence, U.S. physicians and public health of-
ficials 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 (117120). The adoption by one community in Texas of al-
most universal DOT, whereby patients ingest medications under the direct ob-
servation 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 in-
creased 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 pe-
riod (118,121). Chaulk and colleagues showed that the implementation of DOT
434 Fujiwara et al.

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 immi-
gration 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 com-
munity 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 pro-
grams, 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 modi-
fied DOT (78.6%); in nine programs where treatment was not supervised, an av-
erage 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 epi-
demic, WHO adopted the successful strategy of the International Union Against
Tuberculosis and Lung Diseases tuberculosis mutual assistance program to de-
velop 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 func-
tioning 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 be-
ing 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 tuberculosis-
control 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 observa-
tion 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 infras-
tructure, lack of acceptance by staff, and the need to travel long distances.
Treatment of Tuberculosis 435

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 en-
sures 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 in-
gestion 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 guar-
antee 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 un-
derstanding 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 medica-
tions 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, im-
plantable, sustained-release forms of existing and new drugs would be useful. Pri-
mary prevention, in the form of an effective vaccine, should be given high prior-
ity on the research agenda, for what respiratorily transmitted disease has been
controlled without one? New effective measures to prevent the pool of already in-
fected 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 in-
fection. In the final analysis, however, political commitment, in the form of eco-
nomic support for tuberculosis-control programs and funding for basic and ap-
plied 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.
436 Fujiwara et al.

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Appendix Drug Interactions with Antituberculosis Medications

Antituberculosis
medication Drug or drug type Interaction

Isoniazid Acetaminophen toxic metabolites

Antacids isoniazid absorption
Anticoagulants (oral) anticoagulant effect
Benzodiazepines benzodiazepine toxicity
Carbamazepine toxicity of both drugs
Cycloserine central nervous system
effect of cycloserine
Disulfiram Severe psychotic episodes
(avoid concurrent use)
Enflurane nephrotoxicity (avoid
concurrent use)
Haloperidol haloperidol toxicity
Ketoconazole ketoconazole effect
Phenytoin phenytoin toxicity
Theophylline theophylline toxicity
Valproate hepatic and central nervous
system toxicity
Rifampin and Aminosalicylic acid rifampin absorption
rifabutin Amprenavir Possible rifabutin toxicity,
marked amprenavir effect
Anticoagulants (oral) anticoagulant effect
Antidepressants antidepressant effect
(tricyclic, barbiturates,
benzodiazepines)

-Adrenergic blockers (most) beta blockade
Benzodiazepines benzodiazepine effect
continues
444 Fujiwara et al.

Appendix Continued

Antituberculosis
medication Drug or drug type Interaction

Chloramphenicol chloramphenicol effect

Clofazimine Possible rifampin effect
Clofibrate clofibrate effect
Contraceptives (oral) contraceptive effect
Corticosteroids Marked corticosteroid effect
Cyclosporine cyclosporine effect
Dapsone Possible dapsone effect
Delavirdine Marked delavirdine effect,
rifabutin effect
Digitoxin digitoxin effect
Digoxin digoxin effect
Diltiazem diltiazem effect
Disopyramide disopyramide effect
Efavirenz efavirenz effect,
rifabutin effect
Estrogens estrogen effect
Fluconazole fluconazole effect
Haloperidol haloperidol effect
Indinavir Possible rifabutin toxicity,
marked indinavir effect
Itraconazole itraconazole effect
Ketoconazole ketoconazole and rifampin
effect
Mephenytoin mephenytoin effect
Methadone methadone effect with
rifampin
Metoprolol Possible beta blockade
Mexiletine antiarrhythmic effect
Nelfinavir Possible rifabutin toxicity,
marked nelfinavir effect
Nevirapine Probable rifabutin effect
Nifedipine antihypertensive effect
Nisoldipine antihypertensive effect
Phenytoin phenytoin effect
Probenecid Possible rifampin effect
Progestin progestin effect
Propafenone propafenone effect
Quinidine quinidine effect
Ritonavir rifabutin toxicity,
ritonavir effect (rifampin),
unknown ritonavir effect
(rifabutin)
Treatment of Tuberculosis 445

Appendix Continued

Antituberculosis
medication Drug or drug type Interaction

Saquinavir Marked saquinavir effect

(rifampin), saquinavir
effect (rifabutin), rifabutin
toxicity (gel form)
Sulfonylurea sulfonylurea effect
Tetracyclines tetracycline effect
Theophyllines theophylline effect
Tocainide Possible tocainide effect
Trimethoprim- Possible rifampin toxicity
sulfamethoxazole
Verapamil verapamil effect
Aminoglycosides Amphotericin Nephrotoxicity (synergistic)
Bumetanide ototoxicity
Capreomycin oto- and nephrotoxicity
(additive)
Cephalosporins nephrotoxicity
Cisplatin nephrotoxicity
Cyclosporine nephrotoxicity
Enflurane Possible nephrotoxicity
Ethacrynic acid ototoxicity
Furosemide oto- and nephrotoxicity
Gallium nephrotoxicity
Methotrexate Possible methotrexate
toxicity with kanamycin
Neuromuscular neuromuscular blockade
blocking agents
Vancomycin oto- and nephrotoxicity
(additive)
Pyrazinamide Allopurinol Failure of allopurinol to
serum uric acid level
Pyridoxine Barbiturates barbiturate effect
Levodopa levodopa effect
Phenytoin phenytoin effect
Cycloserine Alcohol alcohol effect and seizures
Ethionamide central nervous system effect
of cycloserine
Isoniazid central nervous system effect
of cycloserine
Fluoroquinolones Antacids with metal absorption of
cations (Ca, Mg, Al, Fe) fluoroquinolones
Sucralfate absorption of
fluoroquinolones
continues
446 Fujiwara et al.

Appendix Continued

Antituberculosis
medication Drug or drug type Interaction

Drugs metabolized by effect of additional drug

cytochrome P450
(cyclosporine,
theophylline, warfarin,
phenytoin, sulfonylurea)
Nonsteroidal central nervous system
anti-inflammatory stimulation and possible
agents convulsions
Probenecid serum level of
fluoroquinolones
Sparfloxacin Anti-arrhythmics such torsades de pointes secondary to
as disopyramide and prolongation of QTc interval
amiodarone; other drugs
such as terfenadine,
astemizole, clarithromycin,
azithromycin,
erythromycin,
ketoconazole,
itraconazole,
cisapride, or
phenothiazines
para-Aminosalicylic Digoxin Possible digoxin effect
acid
Ethionamide Cycloserine central nervous system effect
of cycloserine

Source: Adapted from Ref. 71.

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 scien-
tific and medical communities were convinced that tuberculosis (TB) was an air-
borne infectious disease and that only isolation of those with active pulmonary dis-
ease 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 (14). 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.
447
448 Farmer et al.

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
agentswas never realized: TB remains the leading single infectious cause of
adult deaths in the world today (6). Since the introduction of highly effective ther-
apy 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 noncompli-
ance (79). But the rigorous application of directly observed therapy (DOT) vir-
tually 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 observedis 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 rec-
ognized rapidly in the 1940s, when patients who had initially responded to
monotherapy with streptomycinat the time, the only available medication
later relapsed with disease that was clearly resistant to the new agent (1013). 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 drugs manufacturer,
Merck, admitted that, when streptomycin was administered alone, in most cases
highly drug sensitive strains become highly resistant in 24 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
Introducing DOTS-Plus 449

could be resected, the patient was not cured and the disease took its courselead-
ing, 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 regi-
mens 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 intro-
duction. In recent years, many DOTS-based regimens have comprised rifampin,
isoniazid, ethambutol, and pyrazinamide; some have contained thiacetazone in-
stead 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 in-
fectious 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 un-
treatable 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 re-
spond 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 treat-
ment 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 abbre-

Table 1 Commonly Used Antituberculous Drugs and Their Time of Introduction

Drug Abbreviation Date of introduction

Streptomycin S 1944
Isoniazid H 1952
para-Aminosalicylic acid PAS 1948
Thiacetazone T 1946 (discovery date)
Pyrazinamide Z 1955
Ethambutol E 1961
Rifampin (rifampicin) R 1966
450 Farmer et al.

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 symptom-
free 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 man-
aged? 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 re-
sistance, 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 sub-
sequently 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 resis-
tant 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 womans resistance ap-
pears 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 (16a19). 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.
Introducing DOTS-Plus 451

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 docu-
mented its contribution to a large outbreak of MDRTB in urban Peru (16a). Fig-
ure 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 re-
treatment regimens.
Adding a single agent to a failing regimen is well known to lead to acquired
resistance (2022); consecutive empiric short-course regimens in patients with
MDRTB result in treatment failure through the same mechanismsinadvertent

Figure 1 Sequential short-course chemotherapy amplifying drug resistance in a 23-year-

old 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.
452 Farmer et al.

monotherapy. Treating patients after they have experienced the amplifier effect
is far more difficultand far more costlythan 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-resis-
tant 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 au-
thors conclude that inadequate treatment regimens are likely to lead to amplifi-
cation of resistance . . . creation of additional resistance is also likely with Cate-
gory 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 re-
treatment regimens. Instead, the amplifier effect of SCC will iatrogenically render
these patients the unwilling incubators of highly resistant strains of M. tuberculo-
sis. Novel strategies, such as DOTS-Plus, are now required in these and other
MDRTB hot spots.
Introducing DOTS-Plus 453

II. What Is DOTS-Plus?

The history of DOTS-Plus is brief. The concept arose in response to two ques-
tions: 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 man-
ner that would take into account MDRTB. In April 1998, representatives of these
bodies came together in Cambridge, Massachusetts, in order to evaluate the exist-
ing 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 evalua-
tions 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 ef-
fective 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 second-
and third-line drugs. The strengths and weaknesses of each of these approaches
are compared in Table 2. The first approachin which ITRs are designed
according to the resistance pattern of the strain infecting each patienthas
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 patients

Table 2 Attributes of DOTS-Plus Models

Attribute ITRs Standardized

Maximum Very high Moderatehigh

Cost High Moderatehigh
Risk of amplification Very low Lowmoderate
Toxicity Moderate Moderate
Technical capacity required High Moderate
454 Farmer et al.

strain is susceptible are incorporated into the definitive treatment regimen. Am-
plification of drug resistance is thus a less likely sequela of ITRs since clinicians
are aware of each patients drug-susceptibility pattern and inadvertent monother-
apy 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 stan-
dardized regimens.
ITRs do have drawbacks, however. They require labor-intensive laboratory
testing, multiple adjustments of each patients treatment regimen, and nonstan-
dardized 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 pre-
sumed 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 pop-
ulation surveillance data. In this case, regimens would be designed and adminis-
tered 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 ad-
ministration and management, since all patients receive standardized doses of the
same drugs. Thus the demand for technical expertise is less when using standard-
ized retreatment regimens. The Peruvian National TB Programme is currently pi-
loting 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 pre-
viously 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 ex-
pensive, drawing resources away from the treatment of pan-susceptible disease;
that it is technically difficult and yields low cure rates; and that treatment of drug-
resistant strains, when improperly monitored, gives rise to even more resistant or-
ganisms. Other claims include those about decreased virulence and transmissibil-
ity 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 ob-
servation is incorrectly applied to the treatment and, by extension, to the preven-
tion costs of tuberculosis cases in general. If the drug-resistance pattern is un-
Introducing DOTS-Plus 455

known, the cost is not predictable. Available cost-effectiveness data do not ad-
dress 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 pub-
lic 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 il-
lustrates 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 consulta-
tions 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-drugresistant TB
(6 months for the injectable).
456 Farmer et al.

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 su-
pervised 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 preva-
lence of patients with drug-resistant organisms (29). In 1985, the same team eval-
uated 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 12-
month 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 ac-
quired, the report also cited a study of tubercle bacilli isolated from 83 consecu-
tive 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 re-
garding 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 ther-
apy completion, in large part because of the adoption of DOTS. Furthermore, the
NTP has recently increased access to TB services in previously underserved re-
gions 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,
Introducing DOTS-Plus 457

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 fluo-
roquinolones, 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 RHEZprecisely
those medications used in Perus DOTS program (16). The northern Lima epi-
demic has been felt beyond Peruvian borders as well: cases of TB resistant to all
first-line drugs, all acquired in Limas 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, Limas 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 antitubercu-
lous drug, and 15.7% had isolates resistant to both H and R (37).
458 Farmer et al.

B. A Public-Private Partnership to Address MDRTB in Lima,

Peru

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 Labora-
tory 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 ex-
panded to serve three districts with a total population estimated at 757,000 inhab-
itants (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 noso-
comial transmission, which often occurs when TB patients are hospitalized.
The treatment strategy used in the Lima project includes ITRs for all pa-
tients. 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 aggres-
sive, multidrug therapy for 1824 months. Dosing, with a minimum of five drugs,
is generally at the high end of recommended ranges. Each regimen includes a par-
enteral antimycobacterial agent, which is administered until at least 6 consecutive
months of smear- and culture-negativity are documented. Patients undergo regu-
lar bacteriologic, radiographic, and clinical monitoring. All doses of medication
are directly observedin 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 459

1% 7% 7%
1%

84%

cured or culture-negative culture-positive

failed abandoned
died

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 in-

ternational TB clinician-specialist, based on suspected resistance patterns, and ad-
justed 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 individuals infecting strain has demonstrated susceptibil-
ity. 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 re-
ceived 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-posi-
tive 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-nega-
tivity were achieved among patients who initiated treatment with smear- and cul-
ture-positive MDRTB. If, as Styblo has suggested (41), a patient with active pul-
 Table 3 Chemotherapeutic Agents Used in the Treatment of Multidrug-Resistant Tuberculosis
460
Drug name Description
Isoniazid (high dose) Nicotinic acid hydrazide. Bactericidal.
Inhibits mycolic acid synthesis most
effectively in dividing cells. Hepatically
metabolized.
Amikacin Aminoglycoside. Bactericidal.
Kanamycin Aminoglycoside. Bactericidal. Inhibits
protein synthesis through
disruption of ribosomal function. Less
effective in acid, intracellular
environment. Renally excreted.
para-Aminosalicylic Bacteriostatic. Hepatic
acid acetylation, renally excreted.
Fluoroquinolones: Likely bactericidal. DNA-gyrase inhibitor.
Ciprofloxacin Levofloxacin appears to be active
Sparfloxacin moiety, and may well be the drug of
Ofloxacin choice. Not FDA-approved for use
Levofloxacin during pregnancyassociated with
arthropathies in studies with immature
animals. Renally excreted. Cross-
resistance among fluoroquinolones
thought to be near complete.
Administration
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.
15 mg/kg IM or IV QD
Adjust for renal insufficiency
1 g IM QD
4 g PO TID
Delayed-release granules should be
administered with acidic food or drink.
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.
Side effects
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.
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 effects in 10%. GI upset (nausea, vomiting,
diarrhea), hypersensitivity in 510% of patients;
rarely, hepatitis.
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.
 Capreomycin Polypeptide isolated from Streptomyces
capreolus. Renally excreted. Varying
degrees of cross-resistance reported
between KM and CM; no cross-
resistance reported between SM and CM.
Frequent cross-resistance between
viomycin and CM.
Cycloserine
Alanine analogue. Bacteriostatic. Interferes
with cell-wall proteoglycan synthesis.
Renally excreted.
Ethionamide
Prothionamide Derivative of isonicotinic acid.
Bacteriostatic. Cross-resistance with
thiacetazone occurs. Hepatically
metabolized, renally excreted.
Amoxicillin-clavulanate
Beta-lactam antibiotic with a beta-
lactamase inhibitor.
Clarithromycin
Semisynthetic erythromycin derivative.
Efficacy shown against M. avium complex.
In vitro killing of susceptible strains of
M. tuberculosis.
Clofazimine
Substituted iminophenazine bright-red dye.
Bacteriostatic. Transcription inhibition
by binding guanine residues of
mycobacterial DNA.
Rifabutin/Rifapentine
461
Rifamycin spiropiperidyl derivative. Cross-
1 g IM QD Ototoxicity and nephrotoxicity dose related (both
Adjust for renal insufficiency. cumulative and peak concentrations).
Increased risk with renal insufficiency.
Pain at injection site.
Rarely, electrolyte abnormalities, eosinophilia,
hypersensitivity, neuromuscular blockade.
7501000 mg PO QD Neurological and psychiatric disturbances, including
Administer with pyridoxine 150300 mg QD. 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.
7501000 mg PO QD GI upset (nausea, vomiting, abdominal pain, loss of
Increase gradually to maximum dose. appetite) and metallic taste in mouth common. May
cause hypothyroidism when taken with PAS.
Rarely, hepatitis, arthralgias, impotence,
gynecomastia, photosensitive dermatitis.
500 mg PO TID GI upset. Administer with food.
Hypersensitivity reactions.
500 mg PO BID Well tolerated. GI side effects (abdominal pain,
diarrhea, abnormal taste) less common than with
erythromycin. Ototoxicity extremely rare.
May cause metallic taste.
200300 mg PO QD Discoloration of skin, GI upset, and crystal deposition
Initiate dose at 300 mg; may lower to 200 mg causing discoloration of the eye. Less commonly,
when skin begins to bronze. phototoxicity reactions, malabsorption, and severe
abdominal distress.
150300 mg PO QD Considered to be of comparable or lesser toxicity as R.
Hepatotoxicity, GI upset, hypersensitivity.
462 Farmer et al.

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
projects operations.
The Lima DOTS-Plus initiative has also resulted in enhanced community
capacity to respond to threats to the communitys health (42). One of the hidden
benefits of DOTS-Plus has been a process of community-capacity building. Train-
ing previously unemployed community members to respond to this epidemic has
had surplus value in many other arenasfrom education to primary health
careand has helped to promote cooperation between NGOs, community-based
organizations, and public health authorities. Previously unemployed young peo-
ple have found jobs as community-health workers and received extensive training
in tuberculosis prevention, detection, and managementin skills ranging from
administering parenteral drugs to identifying symptoms of disease, understanding
drug-susceptibility reports, to advocating for and counseling patients. These de-
velopments stand all participantsand, ultimately, all community residentsin
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 re-
sources 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 Limitations

High efficacy High cost

Uses local resources
Publicprivate initiative
Builds community capacity
Population-based
Detailed documentation
Under the aegis of the National
Tuberculosis Programme
Requires international laboratory and drug-supply
effort
Demands elaborate coordination and power sharing
Most appropriate for small outbreaks
National coverage and treatment in rural popula-
tions pose greater logistical problems
Documentation requires significant technical train-
ing
Any NTP weaknesses could impact DOTS-Plus ini-
tiative
Introducing DOTS-Plus 463

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 pre-
vious failures occurred in patients with evidence of the amplifier effect: failures
were also most likely to occur in patients with longstanding disease and signifi-
cant parenchymal destruction. These conditions seemed to be more predictive of
poor outcomes than was the number of drugs to which a patients isolate was re-
sistant. Other causes of treatment failure include failure of DOT, failure to man-
age side effects, and failure to provide social and psychological support.
Numerous socioeconomic factors also shape a patients likelihood of con-
tinuing, and responding to, therapy. In the Lima effort, community health work-
ers were responsible for ensuring full adherence with therapy and also for re-
sponding 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, col-
laboration with a supranational reference laboratory helps to ensure that the most
reliable data are made available to the DOTS-Plus team. For example, sample-to-
sample discrepancies in susceptibility testing are a source of frustration for pa-
tients 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 sys-
tems. The existence of high positivity rates of specimens and of individual speci-
mens with high concentrations of viable organisms is associated with occasional
cross-contamination, which can occur more frequently in labs without technolog-
ically 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 sig-
nificant information becomes available.
464 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 ma-
jor expense, and the cost of second-line drugs varies widely, as Figures 5
and 6 suggest.
For illustrative purposes, lets consider the case of capreomycin, a corner-
stone 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. More-
over, the true demand for MDRTB drugs is not felt by the pharmaceutical indus-
try, 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 comparisonsecond-line antituberculous drugs.

Introducing DOTS-Plus 465

Figure 6 Cost comparisoncapreomycin (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 out-
break 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 in-
creasingly resistant strains to destroy more and more lung parenchyma in individ-
ual patients and, for these patients to infect many others.

*Previous efforts to lower the prices of second-line drugsby the IUATLD, for example
were disappointing. For an overview of the pitfalls facing those who would finance such
efforts, see Ref. 48.
466 Farmer et al.

V. Conclusions: DOTS-Plus, We Cant 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 tuberculosiswe cant 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 pro-
gressing, unchallenged as yet by any coherent strategy. Only DOTS-Plus can re-
spond 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 sup-
ply advantages of DOTS. DOTS-Plus builds on all the strengths of DOTS, incor-
porating 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 commit-
ment at the highest national level and, at times, at supranational levels. DOTS-
Plus 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 TBre-
gardless of drug-susceptibility patternsis tantamount to striking a blow for eq-
uity and universal treatment as the primary goal of modern public health.

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Peru: Cuanto S.A, 1997.
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Meeting Community Needs. Proceedings of the International Union Against Tuber-
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18
Treatment of Latent Tuberculosis Infection

DAVID L. COHN WAFAA M. EL-SADR

University of Colorado Health Columbia University College of

Sciences Center and Physicians and Surgeons and
Denver Public Health Harlem Hospital Center
Denver, Colorado New York, New York

I. Introduction

In the context of tuberculosis (TB) control, the term preventive therapy is a mis-
nomer 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 isoni-
azid), 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 rel-
atively 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-con-
471
472 Cohn and El-Sadr

trol programs and is usually offered to recent contacts of active cases, recent tu-
berculin skin test converters, patients with abnormal chest x-rays and inactive dis-
ease, 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-ef-
fectiveness of such strategies.
The first section of this chapter includes a review of older studies of pre-
ventive therapy that were largely conducted in immunocompetent populations. In
subsequent sections, more recent studies in HIV-infected persons as well as pre-
ventive 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 acquisi-
tion of infection, including contacts of TB cases and residents of communities
with high rates of TB. Other studies included individuals with remote or long-
standing infections, including residents of mental institutions and individuals with
chest radiographic evidence of inactive lesions. Thus, the studies assessed the ef-
ficacy 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 groups high risk of infection and for
the development of disease (Table 1). In the largest of these studies, the U.S. Pub-
lic 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 demon-
strated a 60% reduction in the rates of development of TB. In addition, the study
Treatment of Latent Tuberculosis Infection 473

showed that untreated contacts were at highest risk during the year after the diag-
nosis 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 (69). With the exception of the study con-
ducted in Japan, all of these studies demonstrated a protective effect associated
with IPT (range 4092%). 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 one-
year 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 ev-
idence 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 Tu-
nis 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.
 Table 1 Prospective Randomized Clinical Trials of Preventive Therapy of Tuberculosis in Largely Immunocompetent Populations

474
Author (Ref.) Outcomes
Location Unit of
Years of study/ Study subjects randomization/ Drug %
publication (n) endpoints regimen(s) TB rates Reduction Comments

Close Contacts of TB Cases

Ferebee (5) Contacts of new Family 10-year rate
United States, cases per 1000
Puerto Rico, (25,033) Placebo 15.4
Mexico INH for 1 year 6.2 60
19571959/1962 Reactors
Placebo 26.9
INH for 1 year 11.1 60
Bush (6) Contacts of cases Individual Placebo 1.0%
Japan (2,238) INH for 1 year 0.7% 30
1957/1968
Egsmose (7) Contacts of cases Endpoints: Nonreactors
Kenya (775) pulmonary lesions Placebo 10.8%
19591963/1965 INH for 1 year 5.0% 54
Reactors
Placebo 4.8%
INH for 1 year 2.1% 56
Pulmonary lesions
Placebo 9.1
INH for 1 year 0 100
Del Castillo (8) Household contacts Endpoints: 2-year follow-up
Philippines (327) chest x-ray Placebo 13.9%
19611965 abnormality INH for 1 year 8.2% 41
 Veening (9) Contacts of cases Individual 7-year follow-up
Netherlands (261) Placebo 9.4%
19601964/1968 INH for 1 year 0.8% 92
Chiba (10) Railway workers Individual Placebo 1.03%
Japan (548) INH for 1 year 0.39% 62
19511962/1963
Community Trials or Institutions
Comstock (11,12)
Alaska 30 communities 6-year rate per 1000
19571963/1967, (6,275) Household Placebo 46.1
1979 INH for 1 year 19.0 59
Groth-Peterson (13) Adults without TB Village 6-year rate per 1000
Greenland (8,081) Placebo 82.7
1956/1960 INH for 26 57 31
Horowitz (14) weeks: twice
1966 weekly 13 wks
alternating
with 13 wks
no Rx Random urine
Nyboe (15) Entire suburb Housing blocks Rate per 1000 checks; poor
Tunisia Persons without TB Placebo 3.1 compliance
1958/1963 (15,910) INH for 1 year 2.3 26

(continued)

475
 Table 1 Continued

476
Author (Ref.) Outcomes
Location Unit of
Years of study/ Study subjects randomization/ Drug %
publication (n) endpoints regimen(s) TB rates Reduction Comments

Ferebee (20) Mental institutions, Ward or building 10-year rate per 1000
United States reactors and non-
19571960/1963 reactors (27,924) Overall
Placebo 9.6
INH for 1 year 3.6 62
10 mm
Placebo 12.2
INH for 1 year 3.9 68
59 mm
Placebo 8.2
INH for 1 year 4.7 47
Abnormal chest x-ray
Placebo 36.0
INH for 1 year 18.4 49
Normal chest x-ray
Placebo 6.9
INH for 1 year 2.1 70

Patients with Inactive Lesions on Chest X-Ray

IUAT (16) Tuberculin skin test 5-year rate per 1000 Pill calendars
Czechoslovakia, positive and Individual All assigned participants: given; symptoms
Finland, German fibrotic lung Placebo 14.3 of hepatitis moni-
Democratic disease, consis- INH for 12 wks 11.3 21 tored; urine test
Republic, tent with TB and INH for 24 wks 5.0 65 for INH q3
months
 Hungary, stable for prior INH for 52 wks 3.6 75
Poland, year Completers-compliers
Romania, (27,830) Placebo 15.0
Yugoslavia INH for 12 wks 10.4 31
19691977/1982 INH for 24 wks 4.7 69
INH for 52 wks 1.1 93
Small lesion
2 cm2
Placebo 11.6
INH for 12 wks 9.2 20
INH for 24 wks 4.0 66
INH for 52 wks 4.2 64
Large lesions 2 cm2
Placebo 21.3
INH for 12 wks 16.2 24
INH for 24 wks 7.0 67
INH for 52 wks 2.4 89
Ferebee (17) Inactive lesions Placebo 2-year rate per 1000
United States 2/3 prior active TB Individual INH for 1 year 19.0
19601964/1970 1/3 inactive (4,575) 7.0 63
Katz (18,19) Mental patients 6-year rate per 1000
United States with inactive TB Ward
19581964/1965 (513)
225 pts no prior TB Placebo 93.0
in hospital INH for 2 years 76.0 18
288 pts prior TB Placebo 245.0
in hospital INH for 2 years 132.0 46

477
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 pre-
ventive 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 Inter-
national 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 Yu-
goslavia. This placebo-controlled trial had several unique characteristics includ-
ing 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 prescrib-
ing 24 weeks rather than 52 weeks of IPT.
In another study among 4575 patients with inactive pulmonary lesions con-
ducted 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
1012 months, there was a 68% reduction in TB, compared to a 23% reduction in
those who took 79 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 in-
fection was investigated as well. In the late 1950s, a study was initiated among
Treatment of Latent Tuberculosis Infection 479

27,924 residents of 37 mental hospitals in the United States (20). These individu-
als 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 tu-
berculin 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 re-
actions  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% re-
duction). 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 acquisi-
tion of infection. Of note, among 90% of the study participants who were tuber-
culin 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 46 mg/kg daily for 12 months or
matching placebo. Ten years after the initial detection of primary TB in these chil-
dren, 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 lymphadenopa-
thy or parenchymal disease.

B. Adverse Events and RiskBenefit Analyses

The relative risks and benefits of IPT have been debated for over three decades. Al-
though isoniazid is generally considered a well-tolerated medication, concern has
been expressed regarding the development of isoniazid-associated hepatitis. Dur-
ing 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 is-
sue received particular attention when 19 of 2321 participants in a study of pre-
ventive 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
480 Cohn and El-Sadr

about signs and symptoms of hepatitis on a regular basis. Among 13,838 partici-
pants 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 1020% of pa-
tients initiating IPT and that this was not associated with increased risk of hepati-
tis (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 anal-
ysis 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 reg-
ular 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 ar-
rived 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 magni-
tude of their risk of TB.
To further evaluate the association between the use of isoniazid and the de-
velopment 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 481

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 monitor-
ing 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 riskbene-
fit, Fitzgerald et al. performed a cost-effectiveness analysis (37). This study sug-
gested that the costs incurred per case of TB prevented were reasonable from a so-
cietal 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 posi-
tive tuberculin skin tests irrespective of age.
The issue of the benefits versus risks associated with IPT remains contro-
versial. The risk to the individual associated with the development of TB are com-
pounded 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 toxi-
city 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 abil-
ity of patients to adhere with and complete therapy. Finally, as more programs im-
plemented 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 Cohn and El-Sadr

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 con-
duct 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 ra-
diographs.
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 ri-
fampin for 3 months and rifampin plus pyrazinamide for 2 months were more ef-
fective than isoniazid for 6 months (41). In tuberculin-positive patients with sili-
cosis 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 in-
terest in the use of directly observed preventive therapy (DOPT) regimens, pri-
marily 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 per-
sons, clinics in high schools, and in programs for released jail inmates (4347). 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 dissemina-
tion after exposure. Indeed, underlying HIV infection is considered the greatest
single risk factor for the development of TB, with severalfold greater risk than pre-
viously recognized risk factors, i.e., silicosis, hemodialysis, diabetes mellitus, im-
munosupressive conditions or therapies, and fibrotic chest x-ray lesions (50).
Rates of TB among HIV-infected patients are 50100 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.) PPD

Location PPDa not tested for PPD
Years of study PPDa Anergic anergy not anergic Total

Selwyn (52) 7.9 (49)b 0.3 (166) 2.1 (215)

USA/IDUb
19851987
Selwyn (53) 9.7 (25) 6.6 (68) 7.7 (93)
USA/IDUc
19881990
Markowitz (51) 3.5 (66) 0.7 (603) 0.2 (429) 0.7 (1107)
USA/23% IDUd
19881994
Moreno (54) 10.4 (84) 12.4 (112) 5.4 (151) 9.1 (374)
Spain/80% IDUc
19851990
Guelar (55) 16.2 (26) 2.6 (235) 0 (87)
Spain/60% IDUc
19881992
Antonucci (56) 5.4 (197) 3.0 (1649) 0.45 (849) 2.2 (2695)
Italy/72% IDU
19901993
Braun (57) 3.1 (249)
Zaire/women
19871989
Allen (58) 5.5 (73) 2.1 (221) 2.4 (401)
Rwanda/women
19881992
a
PPD  purified protein derivative; PPD  5 mm; PPD 
5 mm; IDU  injection drug user.
b
73% did not receive isoniazid preventive therapy (IPT).
c
Did not receive or complete IPT.
d
55% did not receive IPT.
Source: Adapted and updated from Ref. 65.
484 Cohn and El-Sadr

cal studies (5158), and in Table 3, showing rates of TB in placebo recipients in

clinical trials (5964). The risk of TB varied by tuberculin status, population stud-
ied, 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 1.216.2 per 100 person-years (65). Tuberculin-negative persons
who were anergic appear to be at intermediate risk with an estimated risk of
012.4 per 100 person-years, whereas HIV-infected persons who were tuberculin-
negative and not anergic were at lower risk, with an estimated risk of 05.4 per
100 person-years. This is in contrast to the estimated 10% lifetime risk in tuber-
culin-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 519 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 mononu-
clear 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 pre-
vious opportunistic infections, CD4 cell counts, and antiretroviral therapy (69).
Hence the rationale for the prevention of TB in HIV-infected persons is con-
siderable, 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 re-
sult 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 sug-
gested that TB was less commonly noted in patients who received IPT than those
Treatment of Latent Tuberculosis Infection 485

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 rela-
tive contraindication developed TB compared with none of 27 patients who com-
pleted 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 de-
veloped 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 per-
son-years among patients who received IPT (72). There was also a mortality dif-
ference, 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, re-
spectively (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 tuber-
culin-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 dura-
tion. In a prospective single-blind study in Zambia, 23 of 246 (9%) vitamin B6 re-
cipients (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. per-
formed 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-neg-
ative 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 signifi-
cant 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-
 486 Cohn and El-Sadr

Table 3 Prospective, Randomized Clinical Trials of Preventive Therapy of

Tuberculosis in HIV Infection

Author (Ref.) CD4 cell

Location Study subjects counts or Drug regimen
Years of study PPD status (n) percent (months)

Pape59 PPD (25)a Placebo, qD (12))

Haiti PPD (38) INHb 300 mg, qD (12)
19861992 PPD (35)a Placebo, qD (12)
PPD (20) INH 300 mg, qD (12)
Wadhawan60 NTa (246) Placebo, qD (6)
Zambia NTa (298) INH 300 mg qD (6)
19881992
Halsey73 PPD (370) 22.5% INH, 600800 mg biwb (6)
Haiti PPD (380) 22.2% RIFb 450600 mg/PZAb
19901994 15002500 mg biw (2)
Whalen61 PPD (464) Placebo, qD (6)
Uganda PPD (536) INH 300 mg, qD (6)
19931997 PPD (556) INH 300 mg/RIF 600 mg qD (3)
PPD (462) INH 300 mg/RIF 600 mg/PZA
2000 mg, qD (3)
Anergic (323) Placebo, qD (6)
Anergic (395) INH 300 mg, qD (6)
Mwinga62 PPD/ (350)c Placebo (INH), biw (6)
Zambia PPD/ (352)c INH 900 mg, biw (6)
19921996 PPD/ (351)c RIF 600 mg/PZA 3500
mg biw (3)
Hawken63 PPD/ (342) 346/mm3 Placebo, qD (6)
Kenya PPD/ (342) 321/mm3 INH 300 mg, qD (6)
19921996 PPD (67) Placebo, qD (6)
PPD (69) INH 300 mg, qD (6)
PPD (235) Placebo, qD (6)
PPD (224) INH 300 mg, qD (6)
Gordin64 Anergic (257) 247/mm3 Placebo, qD (6)
United States Anergic (260) 233/mm3 INH 300 mg, qD (6)
19911996
Gordin74 PPD (792) 427/mm3 INH 300 mg, qD (12)
United States, PPD (791) 454/mm3 RIF 600 mg/PZA 20 mg/kg,
Mexico, Haiti, qD (2)
Brazil 19911997
a
PPD  purified protein derivative; PPD  PPD 5 mm; PPD  PPD
5 mm; NT  not tested.
b
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.
 Treatment of Latent Tuberculosis Infection 487

No. TB TB Relative No. Relative risk of

cases rate/ 100 risk of TB deaths Death rate/ death
(%) p-years (95% CI) (%) 100 p-years (95% CI)

6 (24) 10.0 1 7 (28) 3.6 (1.012.4)

2 (5) 1.7 0.17 (0.030.83) 3 (8) 1
5 (14) 5.7 1 6 (17)
2 (10) 3.2 0.56 (0.112.5) 2 (10)
23 (9) 11.3 1 1
7 (2) 2.6 0.4 (0.200.82) 0.64 (0.391.03)

14 (4) 1.7 1 72 9.1

19 (5) 1.8 1.1 71

21 (5) 3.41 1 64 (14) 10.2 1

7 (1) 1.08 0.32 (0.140.76) 58 (11) 8.9 0.9 (0.61.2)
9 (2) 1.32 0.41 (0.190.89) 57 (10) 8.3 0.8 (0.51.2)
10 (2) 1.73 0.42 (0.200.92) 58 (13) 9.8 0.9 (0.71.4)

10 (3) 3.06 1 76 (23) 22.3 1

9 (2) 2.53 0.75 (0.301.89) 86 (22) 23.5 1.05 (0.771.42)
44 (13) 8.06 1 58 (17) 9.62 1
27 (8) 4.94 0.62 (0.380.99) 59 (17) 10.02 1.05 (0.731.50)
25 (7) 4.65 0.58 (0.350.95) 68 (19) 11.76 1.24 (0.871.76)

23 (7) 3.86 1 57 (17) 9.58 1

25 (7) 4.29 0.92 (0.491.71) 62 (18) 10.64 1.11 (0.771.58)
8.03 1 1
5.59 0.60 (0.231.60 0.33 (0.091.23)
2.73 1 1
3.28 1.23 (0.552.76) 1.39 (0.902.12)
6 (2) 0.9 1 126 (49) 17.8 1
3 (1) 0.4 0.48 (0.121.91) 129 (50) 17.7 0.96 (0.751.23)

29 (4) 1.2 1 159 (20) 6.5 1

28 (4) 1.2 0.95 (0.561.16) 139 (18) 5.7 0.87 (0.691.11)
488 Cohn and El-Sadr

Table 4 Criteria for Tuberculin Positivity, by Risk Group

5 mm induration 10 mm induration 15 mm induration

HIV positive Recent arrival (
5 years) from high-prevalence Persons with no risk
Recent contact of country factors for TB
TB case Injection drug user
Fibrotic changes on Residents and employees of high-risk
chest X-ray congregate settings: prisons and jails, nursing
consistent with homes and other long-term facilities for the
old TB elderly, hospitals and other health-care
Patients with organ facilities, residential facilities for AIDS
transplants and patients, and homeless shelters
other Mycobacteriology lab personnel
immunosuppressed Persons with high-risk medical conditions
patients (receiving other than HIV infectionb
the equivalent of Children
4 years of age or infants, children,
15 mg/day of and adolescents exposed to adults in
prednisone)a high-risk categories
a
Risk of TB in patients with corticosteroids increases with higher dose and longer duration.
b
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.

fampin and pyrazinamide. Unlike the prior study in Haiti, there were no differ-
ences in survival in the two groups. Adherence rates were better in the individu-
als 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 com-
pared twice-weekly isoniazid for 6 months and rifampin and pyrazinamide twice
weekly for 3 months (62). Both tuberculin-positive and tuberculin-negative pa-
tients were enrolled, and similar to the aforementioned study in Kenya 24% of pa-
tients were tuberculin-positive. Both isoniazid (4.94 per 100 person-years) and ri-
fampin 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 ef-
fect 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
Treatment of Latent Tuberculosis Infection 489

(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 iso-
niazid 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 ele-
vated liver function tests were more common with isoniazid (3%) than with ri-
fampin and pyrazinamide (1%). Of note, as in the Haiti study of twice-weekly reg-
imens of 2 months versus 6 months, adherence to the 2-month regimen (defined
as taking drugs for 60 days) was greater80%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 sur-
vival, although confidence intervals were wide (61). Not surprisingly, the death
rate was higher in the anergic cohort (22%) than in the PPD-positive groups
(810%). Similarly, in a study by Gordin et al. in the United States in anergic pa-
tients 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 2.53.1%
per year) and a low-incidence country (United States, TB rate 0.40.9% 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 612 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 iso-
niazid, 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. Medica-
tions are generally well tolerated, and adherence is better with regimens of 23
490 Cohn and El-Sadr

months than 612 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 im-
pact of preventive therapy may be small. In a study from Uganda, Aisu and col-
leagues 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 re-
turned 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 tuber-
culin testing, a larger percentage initiated IPT and 6070% 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 cost-
benefits 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 (bene-
fit/cost ratio  1.71) (77). Other scenarios suggested that it would be cost-effec-
tive if targeted programs could access significant populations of risk, such as in se-
lected occupational settings. Data from feasibility studies suggest that about 1570
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 pa-
tients, including self-administered (daily) and directly observed (twice-weekly),
and 2-month (rifampin and pyrazinamide) and 12-month (isoniazid) regimens (79).
Treatment of Latent Tuberculosis Infection 491

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 ri-
fampin for 3 months, and rifampin and pyrazinamide for 2 months used in HIV-in-
fected 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 un-
til after delivery. Additionally, some experts prefer delay in initiation of IPT until
23 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 imme-
diate postpartum period (34). However, among certain groups of pregnant women
at substantial risk of TB, IPT has been recommended during pregnancy. These in-
clude pregnant women who are HIV infected, those with recent skin test conver-
sion, 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 appropri-
ate counseling regarding risks and benefits.

B. Children

Children who are recently infected and infants are at significant risk for develop-
ment 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 stud-
ies 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 ri-
fampin 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-
492 Cohn and El-Sadr

tant TB. A decision analysis and Delphi methodology were used to recommend ei-
ther 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 strep-
tomycin, 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 iso-
niazid-resistant TB, none had developed TB after 2 years (89). However, one
episode of rifampin prophylaxis failure was reported among contacts of an isoni-
azid-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 pre-
ventive therapy for individuals exposed to such cases (91). This is particularly im-
portant when there is exposure to a TB case with organisms resistant to both iso-
niazid 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 612
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 immunocom-
petent patients who utilized isoniazid, the data were reassuring with a low risk of
development of isoniazid-resistant TB (17). However, a small proportion of iso-
lates was available for susceptibility testing, and some were obtained after initia-
tion of therapy for active disease rather than at time of diagnosis.
More recently concern has been expressed in relation to the potential for de-
velopment of resistant TB with more widespread use of rifampin-containing pre-
ventive therapy regimens. In the international study by Gordin et al. of the 19 cul-
ture-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, sug-
gesting prior infection with drug-resistant TB. Among the 26 cases of TB that oc-
curred in those assigned to the isoniazid, one was due to an isolate resistant to iso-
Treatment of Latent Tuberculosis Infection 493

niazid, rifampin, and streptomycin. In the Haiti study by Halsey et al., suscepti-
bility 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 popula-
tion who had not received preventive therapy (73). Thus, the available informa-
tion is reassuring, although more extensive data are needed to assess the risk of de-
velopment 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. Sig-
nificant risk factors include HIV infection, recent contact with infectious cases or
skin test conversion, an abnormal chest x-ray consistent with old healed TB, in-
jection drug use, and several other medical conditions. These conditions, most of
which are associated with decreases in cellular immunity and/or local host de-
fenses 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 fac-
tors, 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 per-
sons with radiographic evidence of old TB, 5 mm is considered positive.
In the past, for persons without the above risk factors and a positive tuber-
culin 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-ben-
efit analyses discussed earlier, whereby hepatotoxicity of IPT increases with age.
Owing to the controversy and the different decision analyses, some experts sug-
gested a lower age cut-off than 35 years (e.g., 20 years of age) and others recom-
mend 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 ex-
ception 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 under-
served 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).
494 Cohn and El-Sadr

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 admin-
ister 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. Pre-
viously, 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 HIV-
infected 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 iso-
niazid 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 etham-
butol or pyrazinamide and a quinolone (e.g., ofloxacin) for 612 months are rec-
ommended (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 regi-
mens, which have been associated with gastrointestinal side effects and liver func-
tion abnormalities (94).
 Table 5 Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection
Ratingf

Drug regimena Interval and duration Comments HIV HIV

INH 300 mg (5 mg/kg) Daily for 9 monthsbc In HIV-infected patients, INH may be administered concurrently with AII AII
NRTIs, protease inhibitors, or NNRTIs.
INH 900 mg (15 mg/kg) Twice weekly for 9 monthsb,c DOT must be used with twice-weekly dosing. BII BII
INH 300 mg (5 mg/kg) Daily for 6 monthsed Not indicated for HIV-infected persons, those with fibrotic lesions on BI CI
chest radiographs, or children.
INH 900 mg (15 mg/kg) Twice-weekly for 6 monthsc DOT must be used with twice-weekly dosing. BII CI
RIF 600 mg Daily for 2 months May also be offered to persons who are contacts of patients with INH- BII AI
PZA 15002000 mg resistant, RIF-susceptible TB.
(1520 mg/kg) In HIV-infected patients, protease inhibitors or NNRTIs should not be
administered concurrently with RIF; an alternative is the use of ri-
fabutin for patients treated with indinavir, nelfinavir, soft-gel
saquinavir, amprenavir, nevirapine, or efavirenz.e
RIF 600 mg Twice-weekly for 23 months DOT must be used with twice-weekly dosing. CII CI
PZA 20003000 mg
RIF 600 mg Daily for 4 months For persons who cannot tolerate PZA. BII BIII
For persons who are contacts of patients with INH-resistant, RIF-sus-
ceptible TB, and cannot tolerate PZA.
PZA (2530 mg/kg) Daily for 612 months For persons who are contacts of patients with MDR-TB CIII CIII
EMB (1525 mg/kg) (resistant to INH and RIF).
PZA (2530 mg/kg) Daily for 612 months
OFLX (400 mg bid) or CIII CIII
LEVO (500 mg daily)
a
INH  isoniazid; RIF  rifampin; PZA  pyrazinamide; EMB  ethambutol; OFLX  ofloxacin; LEVO  levofloxacin; bid  twice daily; DOT  directly observed therapy; NRTIs 
b
nucleoside reverse transcriptase inhibitors; NNRTIs  non-nucleoside reverse transcriptase inhibitors. Recommended regimen for children
18 years of age.
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

495
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.
496 Cohn and El-Sadr

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 Organiza-
tion (WHO) and International Union Against Tuberculosis and Lung Disease (IU-
ATLD) recommended IPT for 612 months in tuberculin-positive (5 mm) indi-
viduals 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 re-
sources can be devoted to completion of therapy. In low- or middle-income coun-
tries 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 de-
crease 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., 12-
month regimens, or life-long therapy should be evaluated, especially in areas
where antiretroviral therapy may not be readily available. Finally, new regimens
Treatment of Latent Tuberculosis Infection 497

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 im-
proving 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.

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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 re-
ceived BCG than have received any other vaccine) and most controversial of to-
days 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 Gurin) was derived at the Institut Pas-
teur in Lille, by serial passage (231 times, from 1906 to 1919, in a medium con-
taining ox bile) of an isolate of Mycobacterium bovis. The strain was found to lose
virulence to calves over this period and, following Pasteurs tradition of the de-
velopment 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 Lbeck, Germany, in 1929, when a laboratory error led to 72 deaths
503
504 Fine

among 251 children given virulent Mycobacterium tuberculosis instead of BCG

vaccine. At about the same time, the early evidence supporting BCGs utility was
strongly criticized in the medical press (1), and the combined effect of these prob-
lems 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 ef-
fectiveness 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 em-
ployed in the United Kingdom (a Copenhagen strain BCG, given to tuberculin-
negative 13-year-olds) was providing high efficacy against tuberculosis (3),
whereas that in the United States (Tice strain, given to tuberculin negatives of var-
ious ages) provided little or no protection (4). On the basis of these results, the re-
spective public health agencies did the logical thingBCG 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 in-
troduced routine BCG vaccination according to various schedules (e.g., at birth,
school entry, school leaving), whereas the Netherlands and the United States de-
cided 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 ob-
served 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 dif-
ferent manufacturers differed in microbiological properties (6), and hence it was
not unreasonable to suggest that these might be reflected in differences in im-
munogenicity (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 my-
cobacteria. It was thus proposed, originally by Palmer and colleagues, that expo-
sure 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).
BCG Vaccines and Vaccination 505

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 Coun-
cil 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 my-
cobacterial exposure. A companion trial was to have been set up in an area in north-
ern 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 pro-
tection 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 observa-
tion 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 inter-
national market are Pasteur-Merieux-Connaught, the Danish Statens Serum insti-
tut, 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 propor-
tion 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 re-
gion 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-
506 Fine
BCG Vaccines and Vaccination 507

munization (EPI)/Global Programme on Vaccines of the WHO, which recom-

mends 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 evalua-
tions of the relative effectiveness of these different BCG policies. A particular ex-
ample 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 re-
cently 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 Eu-
rope, as its benefit /cost ratio decreases in the face of continued declines in tuber-
culosis 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 fol-
lowed 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 impor-
tant enough to reintroduce routine BCG vaccination for all children.

A. Contraindications

In general, the worlds wealthier countries have more strict guidelines on con-
traindications to all vaccines than do the poorer countries, reflecting the different
abilities of the health services to ascertain relevant information and to provide alter-
native preventive services to individuals in particular categories. As an example,
BCG is contraindicated in the United Kingdom to individuals with impaired immu-
nity (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 dis-
ease], 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 vari-
ation reported within and between the various outcomes and study designs.
508 Fine

going general radiation therapy) or with malignant conditions such as lymphoma,

leukemia, Hodgkins 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 con-
traindication 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 sensi-
tive 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 vacci-
nees. By far the most common method of administration is by intradermal injec-
tion, 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 tuber-
culosis, 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 vac-
cines show some degree of protection against pulmonary tuberculosis. This fact,
along with their consistent protection against the severe systemic forms of tuber-
culosis, in addition to protection against leprosy, has supported their continued use
in countries with high prevalence of these diseases.
The great variation in BCGs effectiveness should be obvious, but it still
needs to be emphasized. A recent review of the subject failed to point out this het-
erogeneity 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-
BCG Vaccines and Vaccination 509

munological and public health communities, as it implies that the variability ob-
served 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 op-
timally, let alone to develop an improved tuberculosis vaccine.
There is a large literature exploring various hypotheses for the variable be-
havior of BCG vaccines (2123). The major themes are summarized briefly here.

A. Methodological Flaws

Though undoubtedly some of the observed variation can be attributed to differ-

ences 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 varia-
tion (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 rel-
atively 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 re-
infection or reactivation, long after an initial infection. This idea was consistent
with the observed low incidence of tuberculosis among individuals who were ini-
tially tuberculin negative, but it was not supported by subsequent animal experi-
ments (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 epidemio-
logical 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 experi-
ments show that extreme nutritional deficiencies affect susceptibility to tubercu-
losis, but there is little direct evidence that nutrition has affected BCGs 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-
510 Fine

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 re-
sponse.

D. Genetic Differences Between Host Populations

This idea keeps haunting the literature, though with very little direct support. Pro-
tection 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 sta-
tistically significant (4). Case-control studies carried out in the United Kingdom
indicate that BCG vaccines protect Asians in that environment better than in Chin-
gleput (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 res-
olution to the BCG controversyjust 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 reana-
lyzed data from case-control studies in Indonesia and Colombia and found evi-
dence 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 ef-
fectively 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 Comstocks 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.
BCG Vaccines and Vaccination 511

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 inter-
preted 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 in-
duced lymphadenopathy. This is an interesting suggestion, but the result is con-
founded 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 low-
passage 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 ex-

posure 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 vari-
ous 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 environ-
mental 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 tu-
berculosis, 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 expla-
nation for the crude latitude trend observed in BCGs effectiveness. It is interest-
ing 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-
512 Fine

ral areas are more likely to have skin test evidence of prior mycobacterial expo-
sure than do individuals from urban environments (3941).

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 pro-
tection 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 chil-
dren 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 malig-
nancies, 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 more-
or-less characteristic round, depressed scar. These scars have often been used in
vaccine uptake surveys and as indicators of prior vaccination in case-control stud-
ies. It should be emphasized that though some BCG vaccination scars are distinc-
tive, 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
BCG Vaccines and Vaccination 513

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 evi-
dence 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 impor-
tance 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 in-
fants 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 dif-
fers in this regard from all of the other widely used vaccines (diphtheria, tetanus,
pertussis, polio, measles, rubella, mumps, and Haemophilus). There are four rea-
sons for the difficulty in demonstrating BCGs overall impact. First, BCG vac-
cines were introduced in developed countries against a background of already
falling tuberculosis incidence and coincided with other improvements in tubercu-
losis case finding and treatment, which has made it difficult to demonstrate a spe-
cific BCG effect. Second is the fact that the main burden of tuberculosis is pul-
monary disease in adults, in particular older adults, whereas BCG has been
administered mainly to children. This means a delay of many years before vacci-
nated 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-at-
tributable effects from declines attributable to other tuberculosis-control mea-
sures. 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 pul-
monary cases in endemic communities has meant that introduction of BCG has
had little impact upon infection incidence (53).
514 Fine

Despite the difficulty in identifying an obvious impact of BCG on global dis-

ease 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 Scandi-
navia showed a rapid decline in tuberculosis among young adults subsequent to in-
troduction 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 in-
creases 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 pro-
tection 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 pro-
tect 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 in-
fection. 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 dis-
eases in this respect (with the possible exception of varicella-zoster and hepatitis
B, both of which are associated with chronic infections). In vaccinating against tu-
berculosis, we are thus trying to improve upon nature.
The second obstacle against an improved tuberculosis vaccine is our igno-
rance of the immunological mechanism of protection against tuberculosis (see
Chap. 8), which is in turn manifested in the absence of any known correlate of pro-
tective 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 re-
sponse than had been appreciated (32,56). Many studies have shown that strong tu-
berculin 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-
BCG Vaccines and Vaccination 515

terestingly, several studies have suggested that a low degree of tuberculin sensi-
tivity 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 anti-
gens common to the tuberculin reagent and to other mycobacteria or even other re-
lated 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 delayed-
type hypersensitivity at all (58)! Such confusion, on top of the recognized difficul-
ties associated with the standardization, batch variation, administration and read-
ing 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 measur-
able 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 pur-
suing the development of new tuberculosis vaccines. Three broadly different ap-
proaches 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 de-
velopment of mutant or auxotrophic strains of various mycobacteria, which might
set up time-limited infections in the host but still induce protective immune re-
sponses (60). Yet a third approach involves the delivery of DNA encoding vari-
ous 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 evalua-
tion 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 mod-
els, 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 obser-
vation that at least some BCG vaccines behave differently in different human pop-
ulations 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).
516 Fine

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 par-
ticular 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 tuberculo-
sis 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 fore-
seeable future, and these vaccines appear to be providing reasonable protection
against the childhood forms of tuberculosis, in particular meningitis. In addi-
tion, more than 90% of the worlds tuberculosis is in developing countries, and
developed countries are moving away from BCG vaccines, even where they ap-
pear 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 pul-
monary 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 al-
ready 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 per-
haps M. tuberculosis itself and which could provide an appropriate boost to the
immune response in such individuals. Whether such an approach is immunologi-
cally feasible is by no means clear. Research employing animal models is cur-
rently exploring the feasibility of various approaches to booster vaccination; if any
are successful, this may open a window onto a new approach to immunoprophy-
laxis 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 in-
clude the following actions.
1. Future evaluations of the effectiveness of BCG vaccines should not at-
tempt simply to provide another point estimate of efficacy in another
population, but should be designed to explain this estimate, in so far as
BCG Vaccines and Vaccination 517

is possible, in terms of the various current hypotheses relating to BCGs

variable behavior. Thus, it is now possible to explore whether any of the
human genetic determinants newly recognized to be associated with tu-
berculosis, 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 BCGs behavior.
2. There needs to be a concerted effort to identify measurable immuno-
logical correlates of BCGs 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 pol-
icy, 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.
3. Vaccine program managers should consider the important implications
of changing vaccines. Changing vaccines often implies a change in re-
actogenicity, and this needs to be recognized in order to avoid excessive
local reactions such as have occurred in several populations in recent
years.
4. Insofar as is possible, it would be helpful to set up additional compar-
isons between different vaccines, such as was carried out in Hong
Kong. Such comparisons could be organized in some countries rela-
tively easily and would ultimately provide valuable data on the relative
efficacy of different vaccines.
5. 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 oncein the recent trial in Malawi. A trial is
currently underway in Brazil to evaluate a second BCG given to sec-
ondary school students. Similar evaluations should be carried out in
other countries.
6. 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 understand-

ing 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 ulti-
mate evaluation of any new tuberculosis vaccine.

Acknowledgment

The author is grateful to Dr. Ilona Carneiro for assistance in preparation of the fig-
ure.
518 Fine

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1928; i:793795.
2. Heimbeck J. Tuberculosis in hospital nurses. Tubercle 1936; 18:9799.
3. Hart PDA, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuber-
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Part Four
SPECIAL PROBLEMS
20
Tuberculosis and Human Immunodeficiency
Virus Infection

PHILIP C. HOPEWELL RICHARD E. CHAISSON

University of California, San Francisco Johns Hopkins University

and San Francisco General Hospital Baltimore, Maryland
San Francisco, California

Throughout the industrialized and developing world, tuberculosis and HIV dis-
ease are closely linked in mutually disadvantageous synergy: HIV infection pro-
motes 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 re-
quires dealing with HIV infection, and vice versa. This chapter will review the in-
teractions 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
526 Hopewell and Chaisson

Figure 1. 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) tuber-
culin skin test reactions and one tuberculin-negative subject developed tuberculo-
sis in a 2-year period (7.9 cases per 100 person-years of observation). These find-
ings 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 seronega-
tive 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 tu-
berculous 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 child-
bearing 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.
Tuberculosis and HIV Infection 527

In a prospective study conducted in 23 hospital infectious disease units in

Italy, Antonucci and coworkers (6) reported that the 12-month rate of tuberculo-
sis 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 per-
sons who were anergic (failed to respond to seven intradermal antigens), the inci-
dence 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 tu-
berculosis in HIV-infected injecting drug users in a cohort from Baltimore. These
investigators reported an overall annual rate of tuberculosis of 0.22%, substan-
tially 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 pa-
tients with tuberculosis (8). In the northern region 5.6% of AIDS patients are re-
ported 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 as-
sociated with the incidence of tuberculosis in multivariate analyses was the geo-
graphic 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 tu-
berculosis has also been observed in the United States.
In perhaps the most intensive study reported to date, Markowitz and associ-
ates (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 approxi-
mately 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 per-
son-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 fig-
ure 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 popula-
tion 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 inci-
dence of tuberculosis.
528 Hopewell and Chaisson

II. Prevalence of HIV Infection Among Patients with

Tuberculosis

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 Cen-
ters for Disease Control and Prevention (CDC) in 14 urban tuberculosis clinics (9).
The median seropositivity rate in 4301 persons with or suspected of having tuber-
culosis 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 19891991 interval, HIV seroprevalence among males in-
creased 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 2544 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 (1318). 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 cowork-
ers (19), various studies have reported the prevalence of HIV infection among tu-
berculosis patients in sub-Saharan African countries to range from 20 to 67%. In
1998, however, the WHO and the United Nations AIDS Program (UNAIDS) esti-
mated 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. Al-
though 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
Tuberculosis and HIV Infection 529

Figure 2. Tuberculosis cases and cases with HIV infection, San Francisco, 19801996.
(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 tuberculo-

sis rates has been monumental. In a survey of national tuberculosis programs in
sub-Saharan Africa, Cantwell and Binkin (20) found increases in tuberculosis in-
cidence in virtually all countries. The increases were largest in countries with the
highest HIV prevalences and with the poorest quality National Tuberculosis Pro-
grams. 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 us-
ing 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 Chi-
ang 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 commu-
nity 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 infec-

tion or reactivation of latent infection. In areas of low prevalence of tuberculosis,
530 Hopewell and Chaisson

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 (pro-
viding 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 con-
tained tuberculous infection is kept quiescent (23). Because of the effect HIV in-
fection has on cell-mediated immunity, the likelihood of reactivation of latent tu-
berculous infection leading to clinical tuberculosis is greatly increased. For this
reason persons with latent tuberculous infection are at greatly increased risk of de-
veloping 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 in-
fection 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 infec-
tion) 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 con-
cept is unsubstantiated, it has been clearly demonstrated that once an HIV-in-
fected person becomes infected with M. tuberculosis, the infection can progress
very rapidly to cause clinical disease (27,28). In situations where groups of HIV-
infected 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 per-
son with infectious tuberculosis developed active tuberculosis within 120 days
(27). By the use of DNA fingerprinting it was confirmed that tuberculosis was
Tuberculosis and HIV Infection 531

caused by the same strain of M. tuberculosis in all 11 of the culture-positive pa-

tients.
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 un-
infected persons, large clusters are more likely to involve persons with HIV in-
fection (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), tu-
berculosis 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 mycobac-
teremia (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 infec-
tion (see Chap. 14). The sensitivity of tuberculin skin testing is substantially re-
duced 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-
532 Hopewell and Chaisson

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 reactiv-

ity 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 nonHIV-infected injecting drug users and 12% among homosex-
ual/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.)
Tuberculosis and HIV Infection 533

Chin and associates (33) described the results of serial skin testing using can-
dida 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 an-
ergic to being reactive, counter to what would be expected as HIV infection pro-
gressed. 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 con-
cluded 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 re-
commended 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 substan-
tially increased in persons with reaction sizes 5 mm compared with the risk in
persons with 15 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 14 mm the rate was 0, with 59 and
1019 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-in-
fected 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 pneu-
monia 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-
534 Hopewell and Chaisson

tures (30). Clinical reports have emphasized that tuberculosis in advanced HIV in-
fection 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 re-
ported a clear association between low CD4 cell counts and an increased fre-
quency of extrapulmonary tuberculosis, positive blood cultures for M. tuberculo-
sis, 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 HIV-
infected patients. These include central nervous system involvement with brain
abscesses, tuberculomas and meningitis, bone (including vertebral) disease, peri-
carditis, gastric tuberculosis, tuberculous peritonitis, and scrotal tuberculosis. In
addition, M. tuberculosis has been cultured from the blood as well as bone mar-
row. However, despite the increased frequency of unusual forms of tuberculosis
in persons with HIV infection, standard pulmonary disease tends to predominate
in most series (1,2931).

C. Radiographic Findings

The unusual findings on chest radiographs of HIV-infected patients who have tu-
berculosis 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 pul-
monary tuberculosis in persons with HIV infection and noted that, in general,
there was rapid improvement with little residual scarring after completion of ther-
apy. 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,
Tuberculosis and HIV Infection 535

although this finding has not been universal (14,29,40). In some instances, sputum
induction or bronchoscopic procedures have been necessary to diagnose pul-
monary 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 cul-
ture. Potential high-yield sources include lymph nodes, bone marrow, urine, and
blood (42). The value of nucleic acid amplification assays for diagnosis HIV-re-
lated 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 ef-
fective in treating HIV-infected patients with tuberculosis (see Chap. 16), al-
though this has been questioned (4448). 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 Patients (N) Regimen Relapses (%)

Perriens Zaire HIV (119) 2IRZE/4IR 8

HIV (121) 2IRZE/7IR 1
HIV (180) 2IRZE/4IR 5
Kassim Cote Dlvoire HIV1 (106) 6IR/2ZE 3
HIV2 (86) 6IR/2ZE 4
HIV1/2 (138) 6IR/2ZE 7
HIV (198) 6IR/2ZE 3
Chaisson Haiti HIV (129) 2 I3R3Z3E3/4 I3R3 5
HIV (212) 2 I3R3Z3E3/4 I3R3 3
El-Sadr United States HIV (51) 2IRZELevo/4 IR 4
HIV (50) 2IRZELevo/7 IR 2
536 Hopewell and Chaisson

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 ethambu-
tol 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 2-
month induction phase of four or five drugs. Of 102 patients enrolled, only one pa-
tient 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 2030
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 (4852). Reg-
imens using DOT have been advocated by the WHO as the key to controlling tu-
berculosis in developing countries (53). DOT can be facilitated by twice-weekly
drug administration after an initial phase of daily treatment or even, as demon-
strated in Haiti, a thrice-weekly regimen throughout the course of treatment. A
study in Baltimore demonstrated that mortality was lower for HIV-infected tuber-
culosis patients who received DOT rather than self-administered therapy (31).
For patients with pulmonary tuberculosis, response to therapy should be de-
termined by bacteriological examination of sputum as well as by clinical and ra-
diographic examinations. In patients with less accessible sites of disease, gener-
ally only clinical and radiographic evaluations can be used to determine the
response. It should be kept in mind that worsening clinical and radiographic find-
ings may be caused by other HIV-related diseases. There is probably less of a mar-
gin for error (i.e., missed doses) in patients with HIV infection, thus, the thresh-
old 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-
Tuberculosis and HIV Infection 537

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 pa-
tients with tuberculosis caused by organisms that are resistant to isoniazid or ri-
fampin.
There are several areas in which therapy for tuberculosis in persons with
HIV infection differs from that for HIV-negative persons. Although rates of re-
lapse do not seem to be increased, some data suggest at least an ecological asso-
ciation between HIV infection and acquired drug resistance, especially resistance
to rifampin alone (54). The data indicated that having HIV infection, having gas-
trointestinal 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-re-
sistant 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 tu-
berculosis patients treated with rifapentine, a new rifamycin with a long serum
half-life, had an unusually high rate of relapse (10%) with acquired rifampin re-
sistance. 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 pro-
phylaxis for M. avium complex disease in a person who is not recognized as hav-
ing 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 in-
fection is the potential interaction of the antituberculosis agents with other drugs.
Of particular concern is an interaction between rifamycin derivatives and the pro-
tease inhibitor class of antiretroviral agents (59). Similar problems are expected
with nonnucleoside reverse transcriptase inhibitors. The interaction is bidirec-
tional with rifamycins, inducing hepatic P450 cytochrome oxidases, which accel-
erates 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
538 Hopewell and Chaisson

preferred when antiretroviral drug interactions are of concern. Guidelines for us-
ing 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 combi-
nation antiretroviral therapy. These so-called reversal or paradoxical reactions
are similar to the Type 1 reactions of lepromatious forms of leprosy and repre-
sent reconstitution of the immune response to mycobacteria. Typical presenta-
tions involve the new onset of fever, lymphadenopathy, new or worsening infil-
trates, effusions, and, less often, abscesses. Narita and coworkers (62) found that
36% of patients with HIV infection being treated with combination antiretrovi-
ral therapy had paradoxical reactions, compared to only 7% of patients not re-
ceiving antiretroviral drugs. Symptoms and signs generally begin about 36
weeks after antiretroviral therapy is initiated. Patients who have paradoxical re-
actions typically have initially very low CD4 levels, which rise modestly with
therapy. Treatment is supportive (e.g., antipyretics, drainage of effusions or ab-
scesses), 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 con-
sidered but has not yet been initiated: administer a complete regimen containing ri-
fampin 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 treat-
ment 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.
Tuberculosis and HIV Infection 539

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 pa-
tients (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 health-
care facilities (25,6365). 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 reser-
voir of MDR organisms. Second is the effect of HIV on the host response to tu-
berculous infection. As noted earlier, recently acquired infection with M. tuber-
culosis 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-in-
fected persons may not be easily recognizable. For this reason the disease may go
undiagnosed, perhaps in a hospital or clinic environment, for a relatively pro-
longed 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 stan-
dard 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-
540 Hopewell and Chaisson

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
Suggested Duration
Resistance regimen of therapy Comments

Isoniazid, streptomycin, Rifampin 69 months Anticipate 100% response

and pyrazinamide Pyrazinamide rate and less than 5%
Ethambutol relapse
Amikacina
Isoniazid and ethambutol Rifampin 612 months Efficacy should be
( streptomycin) Pyrazinamide comparable to above
Ofloxacin or regimen
ciprofloxacin
Amikacina
Isoniazid and rifampin Pyrazinamide 1824 months Consider surgery
( streptomycin) Ethambutol
Ofloxacin or
ciprofloxacin
Amikacina
Isoniazid, rifampin, and Pyrazinamide 24 months after Consider surgery
pyrazinamide Ofloxacin or conversion
( streptomycin) ciprofloxacin
Amikacina
Plus 2b
Isoniazid, rifampin, and Ethambutol 24 months after Consider surgery
pyrazinamide Ofloxacin or conversion
( streptomycin) ciprofloxacin
Amikacina
Plusb
Isoniazid, rifampin, Ofloxacin or 24 months after Surgery, if possible
pyrazinamide, and ciprofloxacin conversion
ethambutol, Amikacina
( streptomycin) Plus 3b
a
If there is resistance to amikacin, kanamycin, and streptomycin, capreomycin is a good alternative. Injectable agents
are usually continued for 46 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 ri-
fabutin are unlikely to be active (see text).
Source: Ref. 68.
Tuberculosis and HIV Infection 541

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 HIV-
uninfected 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 com-
pleted therapy and 7 were in remissionstill 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 un-
infected 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 bet-
ter 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 in-
fected with both HIV and M. tuberculosis has been substantiated in two con-
542 Hopewell and Chaisson

Figure 6. Kaplan Meier survival plot in persons with HIV infection and multidrug-re-
sistant 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 tu-
berculin 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 tuberculin-
negative 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 pro-
gression 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 ob-
served) 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-
Tuberculosis and HIV Infection 543

imens was protective in anergic subjects. All regimens were well tolerated, al-
though 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, ran-
domizing 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 regi-
mens, and there was no difference in survival. Gordin and associates (75) com-
pared 2 months of daily rifampin and pyrazinamide to 12 months of daily isoni-
azid: 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 2-
month regimen of rifampin and pyrazainmide is as efficacious as 612 months of
isoniazid for preventing tuberculosis in people with HIV infection and offers con-
siderable 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 reac-

Table 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 screen-
ing.
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
544 Hopewell and Chaisson

tions of 5 mm to 5 tuberculin units of purified protein derivative should be con-

sidered as having tuberculous infection and be offered preventive therapy. Treat-
ment with isoniazid for 12 months is recommended in the presence of HIV infec-
tion (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 regi-
mens 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 test-
ing. 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 nonHIV-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 transmit-

ted 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 apply-
ing infection-control measures in persons with HIV infection. In patients who are
being evaluated because of respiratory symptoms and/or findings, respiratory pre-
cautions should be applied until tuberculosis is excluded. Sputum induction and
bronchoscopy should be performed in areas with adequate ventilation or ultravio-
let air sterilization with the exhausted air not being recirculated to other parts of
the building. Similar considerations should apply to areas in which other poten-
tially cough-inducing procedures are performed. Transmission of tuberculous in-
fection has occurred in a poorly ventilated clinic where aerosol pentamidine pro-
phylaxis for P. carinii pneumonia was being administered to two patients whose
sputum contained M. tuberculosis (78). Guidelines for the prevention of nosoco-
mial 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 infec-
tions 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
Tuberculosis and HIV Infection 545

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 re-
duced 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, how-
ever, 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 dis-
ease. In a case-control study Whalen and colleagues (2) demonstrated that the in-
cidence rate of new opportunistic infections among HIV-infected patients with tu-
berculosis 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 pre-
ventive therapy with isoniazid in tuberculin-positive Haitian adults seemed to de-
lay 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 vi-
ral replication (8385). Tuberculosis leads to activation of mononuclear cells, re-
sulting 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 oth-
ers, 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 dis-
ease 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 tuber-
culosis. No longer can it be assumed that only approximately one third of close
546 Hopewell and Chaisson

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 per-
sons 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 pro-
gression, case fatality rates for tuberculosis are much higher than in nonimmuno-
compromised 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 pa-
tients 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 tubercu-
losis control measures must be applied more quickly and with greater intensity in
order to be effective. Specific applications of the principles discussed can be sum-
marized 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 ini-
tial isolates as quickly as possible.
3. Screening investigations of persons in contact with a new case of tu-
berculosis should be initiated immediately upon identification of a pre-
sumed (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 re-
sults; 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 pat-
terns.
If it is suspected or known that the contact is HIV infected, careful ques-
tioning regarding possible symptoms of tuberculosis should be under-
Tuberculosis and HIV Infection 547

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 deter-
minant of outcome, directly observed therapy is the preferable treat-
ment 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 pat-
terns 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 ex-
cluded.
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.

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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 tu-
berculosis infection and disease acquire the organism from adults in their envi-
ronment, the epidemiology of childhood tuberculosis follows that in adults. The
most important reasons for this recent worldwide resurgence of pediatric tubercu-
losis include (1) increased population migration, (2) the human immunodefi-
ciency virus (HIV) epidemic, (3) the emergence of drug resistance (5,6), (4) con-
tinued poverty and poor access to medical care, and (5) inadequate public health
infrastructure required to prevent tuberculosis in children. The World Health Or-
ganization (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
554 Muoz and Starke

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 tubercu-
losis 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 tu-
berculosis 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 dif-
ferent in infants, children, and adolescents from what they are in adults. Most adult
pulmonary tuberculosis is caused by reactivation of dormant organisms that be-
come lodged in the apices of the lung lobes during lymphohematogenous dissem-
ination at the time of initial infection. Pediatric tuberculosis disease usually occurs
as a direct consequence of the initial infection with M. tuberculosis, which in chil-
dren 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 investiga-
tion (see Chap. 15)examining persons close to a suspected case of pulmonary
tuberculosisis the activity that identifies exposed children (8). The most fre-
quent 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, ow-
ing to the short incubation period (several weeks to several months) of tuberculo-
sis in infants and young children, children less than 5 years old in the exposure
stage are treated with a single drugusually isoniazidto prevent the rapid de-
velopment of disseminated or meningeal tuberculosis (1113).
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 in-
fection should receive treatment (see Chap. 18), usually with isoniazid, to prevent
the development of disease.
Tuberculosis disease occurs when the child with tuberculosis infection be-
comes symptomatic or radiographic manifestations caused by M. tuberculosis be-
Tuberculosis in Children 555

come apparent. The risk of a child acquiring tuberculosis infection is directly re-
lated to the probability of exposure to infectious adults or adolescents in his envi-
ronment; the progression to disease is determined by the hosts 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 diseaseoften serious, life-threatening formswithin 12
years. The majority of milder cases of tuberculosis disease in children in most de-
veloping countries are not diagnosed because of the lack of appropriate resources
(14). Even in countries with modern clinical and laboratory facilities, the diagno-
sis 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 pul-
monary tuberculosis that arises as a complication of the initial infection. Unfortu-
nately, this term also has been used to describe the initial infection, even in the ab-
sence 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 dis-
ease 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 tuber-

culosis because of scarce and incomplete data and because of the difficulty of di-
agnosing childhood tuberculosis with certainty in many countries. Reported dis-
ease 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 world-
wide, 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 in-
fection in children is 25% (18), with 820% of the deaths caused by tuberculo-
sis occurring in children. There is no indication that tuberculosis rates among chil-
dren 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 be-
low 0.08 per 100,000 in 1977, (14). The mortality rates for children from newborn
556 Muoz and Starke

to 4 years of age have been and are still about twice that for children ages 515
years, mostly because of the higher incidence of tuberculous meningitis and dis-
seminated disease in the younger population. Some European countries have ex-
perienced 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 an-
nual 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 tu-
berculosis cases had risen by 40% since 1985 (2). Case numbers remained ele-
vated until 1995, when a discrete 2.4% decline to 1558 cases was observed. This
increasing and persistently elevated incidence means that transmission of infec-
tion 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 foreign-
born 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 in-
frastructure in some regions and cities causing slow identification and examina-
tion 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 influ-
enced by either; however, both influence the risk of an infected child developing ac-
tive 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 tradi-
tionally 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 af-
fects the anatomical site of involvement with tuberculosis. Younger children are
more likely to develop meningeal, miliary, or lymphatic tuberculosis, whereas ado-
lescents more frequently present with pleural, peritoneal, or genitourinary disease
(Table 1). Although tuberculosis in adults occurs for the most part among men, his-
torical evidence implies that during the latter part of childhood and during adoles-
cence, 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.
Tuberculosis in Children 557

Table 1 Median Age of Tuberculosis by Predominant Site

in Persons Younger Than 20 Years of Age: United States,
1988
Percentage of
Site cases Median age (yr)
Pulmonary 77.5 6
Lymphatic 13.3 5
Pleural 3.1 16
Meningeal 1.9 2
Bone/Joint 1.2 8
Other 1 12
Miliary 0.9 1
Genitourinary 0.8 16
Peritoneal 0.3 13
Not stated 0.1

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 8087% of child-
hood tuberculosis cases in the United States occur among African Americans,
Hispanics, Asian Americans, and Native Americans, with a relatively higher num-
ber 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 for-
eign-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 de-
creasing 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 mu-

cus that become airborne when the individual coughs, sneezes, laughs, or sings.
Studies performed in orphanages and childrens 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 childrens hospital, it almost invariably has come from an
adult staff member, parent, or visitor with undiagnosed pulmonary tuberculosis
558 Muoz and Starke

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

(2325). 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 Preven-
tion (CDC) guidelines for hospitals state that children with typical pediatric tu-
berculosis do not need respiratory isolation unless they have an uncontrolled pro-
ductive 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 ur-
ban centers. Among adults, tuberculosis has retreated into pockets of high-risk in-
dividuals (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 (2830). In the northern hemisphere, childhood tu-
berculosis 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 VirusRelated Tuberculosis in

Children

The ongoing epidemic of infection with HIV has had a profound effect on the epi-
demiology 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 in-
fections, and those who encounter M. tuberculosis after HIV-related immune sup-
pression has progressed have a more rapid progression to disease (31,32). The
Tuberculosis in Children 559

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 tuberculo-
sis 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 pre-
cedes other opportunistic infections (35). The impact of the HIV epidemic on pe-
diatric tuberculosis has been reported in several studies. A retrospective popula-
tion 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 Abid-
jan, Cote dIvoire, 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. Tu-
berculosis is probably underdiagnosed in HIV-infected children because of the
similarity of its clinical presentation to other opportunistic infections and the dif-
ficulty 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 (4143). There may
be an increased tendency for extrapulmonary or disseminated disease, but data are
limited. Unusual presentations such as chronic fever, tachypnea, or lobar infil-
trates may be found in HIV-infected children, making more difficult the diagno-
sis of tuberculosis (41,44). Children who acquire HIV infection by vertical trans-
mission 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 worlds population is in-
fected 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 inter-
pret. 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 tuber-
culosis infection among 5- and 6-year-olds was about 0.2%.
560 Muoz and Starke

The most efficient method of finding children infected with M. tuberculo-

sis is through contact investigations of adults with infectious pulmonary tuber-
culosis. On average, 3050% of household contacts have a reactive tuberculin
skin test. Even in countries where BCG vaccine is used extensively, a positive tu-
berculin 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 pop-
ulation average 2050%. Among most children in the United States, the preva-
lence of tuberculosis infection is less than 1%. However, in some urban popula-
tions, the rates are much higher. Several surveys conducted in the late 1980s in
Boston, Los Angeles, and Houston demonstrated positive tuberculin skin tests
among 29% of school-age children and adolescents (4648). In these and other
surveys, the majority of children with positive tuberculin skin tests were foreign-
born (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 in-
fection 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 en-
try 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 en-
ter the body and the development of cutaneous hypersensitivity is usually 212
weeks, most often 48 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 hypersensi-
tivity develops, the inflammatory response becomes more intense and the regional
lymph nodes often enlarge. The parenchymal portion of the primary complex of-
ten heals completely by fibrosis or calcification after undergoing caseous necro-
sis and encapsulation. Occasionally, the parenchymal lesion may continue to en-
Tuberculosis in Children 561

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 in-
volve either large numbers of bacilli, which leads to disseminated disease, or
small numbers of bacilli that leave microscopic tuberculous foci scattered in var-
ious tissues. Initially, these metastatic foci are clinically inapparent, but they are
the origin of both extrapulmonary tuberculosis and reactivation pulmonary tuber-
culosis in some children.
The tubercle foci in the regional lymph nodes develop some fibrosis and en-
capsulation, 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 re-
gional 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 ra-
diographic findings of this process have been called epituberculosis, collapse-
consolidation, and segmental tuberculosis.

B. Timetable of Childhood Tuberculosis

There is a fairly predictable timetable of events related to the primary tuberculo-

sis infection and its complications (56). This timetable is very useful for the clin-
ician, 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 36 months after the initial infection, leading to miliary disease and tubercu-
lous 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 525 years later. The interval
562 Muoz and Starke

between the initial infection and reactivation of pulmonary tuberculosis is ex-

tremely variable, depending on the age of the child at initial infection; in adoles-
cents, 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 ef-
fect on the occurrence of both primary and reactivation tuberculosis. Hilar lym-
phadenopathy and subsequent segmental disease complicating the primary infec-
tion occur most often in younger children (58). Approximately 40% of untreated
children less than 1 year of age develop radiographically significant lym-
phadenopathy or segmental lesions, compared with 24% of children 110 years of
age and 16% of children 1115 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 expe-
rience complications of the primary infection but have a much higher risk of de-
veloping 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 tu-
berculosis are no longer used as they were based on autopsy findings (6). Hage-
man 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 infants mother commonly has tuberculous
pleural effusion, meningitis, or miliary disease during pregnancy or soon after
(6163). However, in many cases, the diagnosis of tuberculosis in the newborn
has led to the discovery of the mothers disease. Hematogenous dissemination
may also lead to infection of the placenta, with transmission to the fetus (64), al-
though even massive involvement of the placenta does not always give rise to con-
genital tuberculosis. In either event, bacilli first reach the fetuss liver, where a pri-
mary 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 aspi-
ration or ingestion of infected amniotic fluid in utero. Amniotic fluid can be in-
fected 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).
Tuberculosis in Children 563

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 of-
ten impossible to differentiate postnatal infection from true congenital tuberculo-
sis 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 babys environment.

IV. Clinical Forms of Tuberculosis

In the developing world, the only way children with tuberculosis disease are dis-
covered is when they present with a profound illness that is consistent with tuber-
culosis. 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 (7073). 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 con-
tact investigation usually is higher than from cultures from the child. The second
way is discovery of a child with pulmonary tuberculosis during the contact inves-
tigation 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 ab-
normal 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 lym-
phadenitis. Almost 70% of primary foci are subpleural, and localized pleurisy is a
common part of the primary complex. Infection begins with the deposition of in-
fected 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-
564 Muoz and Starke

ized, nonspecific infiltrate may be seen. The infection spreads within days to re-
gional lymph nodes. When tuberculin hypersensitivity develops, within 310
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 adeni-
tis compared with the relatively small size of the initial parenchymal focus. Be-
cause of the patterns of lymphatic drainage, a left-sided parenchymal lesion often
leads to bilateral adenopathy, whereas a right-sided focus is associated with right-
sided adenopathy only. Hilar or mediastinal lymphadenopathy is invariably pre-
sent with primary tuberculosis but may not be distinct (from the atelectasis and in-
filtrate) 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 ap-
pears 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 indis-
tinct borders (70).

Figure 1. A segmental pulmonary lesion in a child with primary tuberculosis. The com-
plex includes hilar adenopathy, atelectasis, and localized pleural reaction.
Tuberculosis in Children 565

(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 nor-
mal, 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 par-
tial or complete obstruction of the bronchus (51,53). The common radiographic
sequence is hilar adenopathy, followed by localized hyperaeration and, eventu-
ally, 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.
566 Muoz and Starke

(b)
Figure 2. Continued

Obstructive hyperaeration of a lobar segment may accompany bronchial ob-

struction. 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 fan-
shaped segmental lesion (Fig. 1), which results from a combination of the primary
pulmonary focus, the caseous material from an eroded bronchus, the host inflam-
matory response, and the subsequent atelectasis. Up to 43% of children younger
Tuberculosis in Children 567

than 1 year of age who are infected with M. tuberculosis develop a segmental le-
sion, compared with 25% for children ages 110 years, and 15% for children ages
1115 years (58). Segmental lesions and obstructive hyperaeration can occur to-
gether.
Physical signs and symptoms caused by hilar adenopathy and segmental le-
sions 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 bac-
terial 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 subcla-
vian vein, producing edema of the hand or arm. Nodes may rupture into the me-
diastinum 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 Older children
young children and adolescents
Symptom:
Fever Common Uncommon
Night sweats Rare Uncommon
Cough Common Common
Productive cough Rare Common
Hemoptysis Never Rare
Dyspnea Common Rare
Sign:
Rales Common Uncommon
Wheezing Common Uncommon
Dullness Rare Uncommon
Diminished breath sounds Common Uncommon
568 Muoz and Starke

disease, and future chronic pulmonary tuberculosis. Without early therapy, calci-
fication 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 chil-
dren 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.
Tuberculosis in Children 569

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 dissemi-
nation. Rupture into the pleural space can lead to bronchopleural fistula or pyo-
pneumothorax.
Unlike segmental lesions, significant symptoms and signs usually accom-
pany 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 chemother-
apy, prognosis was poor with a fatality rate of 3050%. However, with current
therapy the prognosis for complete recovery is excellent.

Chronic Pulmonary Disease

Chronic pulmonary tuberculosis (adult or reactivation type) represents en-
dogenous reactivation of a site of tuberculosis infection established previously.
Even before the discovery of antituberculosis drugs, chronic pulmonary tubercu-
losis occurred in only 67% of pediatric patients (78). Children with a healed pri-
mary tuberculosis infection acquired before 2 years of age rarely develop chronic
pulmonary disease; it is more common among those who acquire the initial infec-
tion 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 (Simons 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 36
months after infection. The effusion is usually unilateral but can be bilateral (81).
Clinically significant pleurisy with effusion occurs in 530% of tuberculosis cases
in young adults but is infrequent in children younger than 6 years of age and al-
most 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-
570 Muoz and Starke

though corticosteroids may reduce or shorten the duration of associated symp-

toms, they have little effect on the ultimate outcome (80). Diagnosis can be diffi-
cult because the acid-fast stain of the pleural fluid is usually negative and the cul-
ture is positive in only 3050% 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. Scolio-
sis 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). Tubercu-
lous 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 present-
ing symptoms are nonspecific, including low-grade fever, malaise, and weight
loss. Chest pain is unusual in children with tuberculous pericarditis. As the infec-
tion progresses, a pericardial friction rub or distant heart sounds with pulsus para-
doxicus develop. Congestive heart failure is rare. An acid fast smear of the peri-
cardial fluid rarely reveals the organism, but cultures are positive in 3070% of
cases. Pericardial biopsy may be necessary to confirm the diagnosis. Partial or
complete pericardiectomy may be required when constrictive pericarditis is pre-
sent.

B. Lymphohematogenous Dissemination

It is suspected that tubercle bacilli are disseminated to distant sites from the pri-
mary 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 pro-
duces no symptoms, but it is the event that causes extrapulmonary foci that can be-
come 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.
Tuberculosis in Children 571

Miliary tuberculosis arises when massive numbers of tubercle bacilli are re-
leased into the bloodstream, resulting in simultaneous disease in two or more or-
gans. This usually is an early complication of the primary infection, occurring
within 36 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 of-
ten, the onset is insidious with weight loss, anorexia, malaise, and low-grade fever
developing over weeks. Within several weeks, hepatosplenomegaly and general-
ized lymphadenopathy develop in 5070% of children. Initially, the chest radio-
graph may be normal or show evidence of only the primary complex. Within 34
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 2030% 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 fre-
quency.
The diagnosis can be difficult to establish, requiring a high index of suspi-
cion by the clinician. The key is often establishing an epidemiological link to a re-
cently diagnosed case of pulmonary tuberculosis in an adult. Up to 30% of chil-
dren 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 diag-
nosis. The diagnosis can be confirmed by culture in about 33% of cases (86). With
proper chemotherapy, the prognosis of miliary tuberculosis in children is excel-
lent. However, resolution may be slow, with fever declining in 23 weeks and
chest radiograph abnormalities persisting for months.

C. Central Nervous System

Involvement of the central nervous system is the most serious complication of tu-
berculosis in children. Before the development of chemotherapy, tuberculous
meningitis was uniformly fatal. The pathogenesis of central nervous system tu-
berculosis 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 ex-
udate infiltrates the cortical or meningeal blood vessels, producing inflammation,
obstruction, or infarction. The brain stem usually is the site of greatest involve-
ment, which accounts for the frequent dysfunction of cranial nerves III, VI, and
VII. Eventually, the basilar cisterns may become obstructed, leading to a commu-
nicating hydrocephalus.
572 Muoz and Starke

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 36 months of the initial infection.
The clinical onset of tuberculous meningitis in children usually is gradual,
but may be abrupt (8991). 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 12
weeks, is characterized by nonspecific symptoms such as fever, irritability,
headache, sleepiness, and malaise. There are no focal neurological signs, but in-
fants 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, ab-
normal 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 radio-
graph is normal in up to 50% of cases (98). The cerebrospinal fluid (CSF) leuko-
cyte cell count ranges from 10 to 500/mm3; polymorphonuclear cells may be pre-
ponderant early, but a lymphocyte preponderance is more typical. The CSF
glucose level is typically between 20 and 40 mg/dL, whereas the CSF protein con-
centration 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 diag-
nosis 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 chil-
dren younger than 10 years of age. Whereas most tuberculomata in adults are
supratentorial, many in children are infratentorial, most often located at the base
Tuberculosis in Children 573

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 to-
mography (CT) and magnetic resonance imaging (MRI), has shown that tubercu-
lomata are more common than previously realized. The distinction in children be-
tween 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 (90101). 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 antituberculo-
sis 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 mani-
festations (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 dis-
crete, most often unilateral, but they can be bilateral. Other than low-grade fever,
systemic signs and symptoms are usually absent (104). Although the nodes gen-
erally enlarge slowly, there may be rapid enlargement associated with high fever,
tenderness, and fluctuance. If untreated, necrosis of the node usually occurs, ac-
companied 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). Ex-
trapulmonary 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 child-
hood that is exacerbated during adolescence (106). Most commonly, recently in-
fected adolescents develop a classic primary complex, with relatively few signs or
574 Muoz and Starke

symptoms (107). Occasionally, the primary complex may progress rapidly to

chronic pulmonary tuberculosis while the hilar lymph node involvement charac-
teristic of primary tuberculosis is still present.
A primary tuberculosis infection in infancy rarely leads to chronic tubercu-
losis in adolescence. A primary infection acquired between ages 7 and 10 years is
more likely to result in reactivation during adolescence. When primary tuberculo-
sis is acquired during adolescence, chronic pulmonary tuberculosis often develops
within 13 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 tu-
berculosis, 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 accord-
ing 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 respira-
tory 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 sep-
sis and other congenital infections, such as syphilis and cytomegalovirus. Diagno-
sis 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 abnor-
mal chest radiograph, 50% with a miliary pattern. Fewer than 50% of infected new-
borns 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 gas-
tric 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 (109112) 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 tubercu-
losis in children consists of finding the triad of a positive tuberculin skin test, an
Tuberculosis in Children 575

abnormal chest radiograph, and history of exposure to an adult with probable or

proven tuberculosis. Although the only definitive way to diagnose active tubercu-
losis 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 diffi-
cult and uncommon.

B. Tuberculin Skin Test

The tuberculin skin test has been reviewed extensively in Chapter 12. The place-
ment 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 chil-
dren often helps. The skin tester anchors his or her hand along the longitudinal
axis of the childs arm, which enhances stability and allows the last two fingers to
form a fulcrum to guide inoculation of the solution. The tuberculin is injected lat-
erally across the arm. A wheal of 610 mm should be raised after injection. The
test is interpreted at 4872 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 environmentthe 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 Infants No risk factors

infectious persons
Persons with an abnormal
chest radiograph
HIV-infected and other
immunosupressed
patients
Children in contact with adults at
high risk
Foreign-born persons from high-
prevalence 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
576 Muoz and Starke

Correctly classifying a childs reaction supposes that the risk factors of the adults
around the child have been considered (115117). The American Academy of Pe-
diatrics (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 reac-
tions 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 1020% 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 lim-
ited usefulness in children. In most cases (other than those with HIV infection or
other ongoing immunosuppression), the reaction becomes positive as the child re-
covers on chemotherapy. Incubating or manifest viral infections are a frequent
cause of false-negative results in children.
Previous inoculation with a bacille Calmette-Gurin (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 re-
alize 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 prelimi-
nary information and establishing a presumptive diagnosis of tuberculosis. How-
ever, smears may not detect the relatively small number of mycobacteria that are
characteristically present in children with tuberculosis, and sputum is rarely pro-
duced by children under 10 years of age. Acid-fast stains of gastric washings ob-
tained in lieu of sputum in children have a sensitivity below 25% (125). Obtain-
Tuberculosis in Children 577

ing three consecutive early morning gastric aspirates for culture increases this sen-
sitivity to 3050% 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 (127129). Gas-
tric aspiration should be performed early in the morning as the child awakens be-
fore 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, 5075 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 col-
lection, but one recent survey suggested that the yield from early morning outpa-
tient 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 at-
tempted when extrapulmonary tuberculosis is suspected.
In practice, the difficulty of isolating M. tuberculosis from a child with tu-
berculosis disease does not greatly influence the approach to therapy. If the epi-
demiological, tuberculin skin test, clinical and radiographic information are com-
patible 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. tu-
berculosis from the child if the diagnosis is in question, no source case confirma-
tion 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 meth-
ods 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 var-
ied from 80 to 100% (134136). 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
578 Muoz and Starke

pulmonary tuberculosis in young children and immunocompromised patients, es-

pecially 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 re-
sult, 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 chil-
dren and increased concern about the development of resistance to antituberculo-
sis 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 chil-
dren 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 de-
pends primarily upon the size of the bacillary population, resistance that emerges
during therapy, secondary drug resistance, is rare in children. Most resistance en-
countered in children is primary (i.e., infection was by an already resistant organ-
ism). Second, children have a higher propensity than adults to develop extrapul-
monary forms of tuberculosis, particularly disseminated disease and meningitis. It
is important that antituberculosis drugs used in children penetrate a variety of tis-
sues and fluids, especially the meninges. Third, the pharmacokinetics of antitu-
berculosis drugs differ between children and adults. In general, children tolerate
larger doses per kilogram of body weight and have fewer adverse reactions than
adults (137139). Although higher serum concentrations of the antituberculosis
drugs are achieved in children, it is unclear whether they provide a therapeutic ad-
vantage (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 ri-
fampin, 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). Prob-
lems or difficulties taking the several medications required should be anticipated
 Tuberculosis in Children 579

and resolved, especially at the beginning of therapy, to avoid delays and interrup-
tions 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 tol-
erate antituberculosis drugs very well, and adverse reactions are rare. Isoniazid
(INH) is the mainstray of treatment of tuberculosis in children because it is effec-
tive 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 ef-
ficacy 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

Twice-weekly
Daily dose dose Maximum
Drugs Dosage forms (mg/kg) (mg/kg/dose) dose
First-line drugs
Isoniazida Scored tablets: 1015 2040 Daily: 300 mg
100 mg Twice-weekly: 900 mg
300 mg
Syrup: 10 mg/mLb
Rifampina Capsules: 1020 1020 600 mg
150 mg
300 mg
Syrup: formulated
from capsulesc
Pyrazinamide Scored tablets: 2040 5070 2g
500 mg
Streptomycin (IM) Vials: 1 g, 4 g 2040 2040 1g
Ethambutol Scored tablets: 1525 50 2.5 g
100 mg
400 mg
Second-line drugs
Ethionamide Tablets: 250 mg 1020 1525 1g
Kanamycin (IM) Vials: 1 g 15 1g
Cycloserine Capsules: 250 mg 1020 1g
para-Amino 200300 10 g
salicylic acid
a
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 gas-
trointestinal complaints, especially diarrhea.
c
Marion Merrell Dow issues directions for preparation of this extemporaneous syrup.
580 Muoz and Starke

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 childrenteenagers with inadequate diets, children from ethnic
groups with low milk or meat intake, and breastfeeding babiesrequire pyridox-
ine supplementation (146,147). Of children taking INH, 310% have transiently el-
evated liver transaminase levels, but clinically significant hepatitis is exceedingly
rare (139). Adolescents are more likely than younger children to experience hepa-
totoxicity (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 anticon-
vulsants), 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, thrombocy-
topenia, 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, effec-
tive, 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 re-
ported. The adult dose of 3040 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 discontin-
ued within 13 months if clinical improvement is documented. Ethambutol can
cause dose-related reversible optic neuritis or alterations in red/green color dis-
crimination. 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 con-
cern 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 first-
line 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 neuro-
logical complaints; clofazimine and rifabutin, used most often in children with
Tuberculosis in Children 581

AIDS and M. avium-intracellulare infections (153); and the fluoroquinolones

(ciprofloxacin and levofloxacin), which can be used in multidrug-resistant tuber-
culosis 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 ex-
posed to potentially infectious adults with pulmonary disease. In these patients se-
vere 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 bro-
ken (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 pre-
vent the development of tuberculosis disease is an established practice. In infected
children, the effectiveness of isoniazid therapy has approached 100%, and the pro-
tective 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 du-
ration of 9 months of therapy with INH in children. Rifampin can be used in chil-
dren with asymptomatic infection with INH-resistant M. tuberculosis. These
drugs can be taken daily under self-supervision or twice weekly under direct su-
pervision 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
582 Muoz and Starke

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 (158164). 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 stan-
dard therapy for presumed or confirmed drug-susceptible intrathoracic tubercu-
losis (pulmonary and/or hilar adenopathy) (147,165). It is well tolerated, less ex-
pensive, and results in increased adherence to therapy and decreased
development of drug resistance. Daily administration of three medications dur-
ing the first 2 weeks to two months is preferable, followed by twice-weekly ad-
ministration 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 susceptibil-
ity 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 com-
munity where the child lives has a rate of resistance greater than 4%, a fourth an-
tituberculous 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, par-
ticularly in countries where using parenteral preparations is difficult or risks HIV
transmission. Streptomycin is a second alternative, but since it has to be adminis-
tered by intramuscular injections, it is not the preferred choice for children.

Extrapulmonary Tuberculosis

Controlled clinical trials comparing treatment regimens for various forms of ex-
trapulmonary 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 912 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 912 months (147).
Tuberculosis in Children 583

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 in-
clude at least two bactericidal drugs to which the organism is susceptible to pre-
vent the development of more secondary resistance (173175). Duration of ther-
apy is usually 912 months if either INH or RIF can be used and 1824 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 VirusRelated 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 immuno-
compromising 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 dura-
tion of 612 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. Corticos-
teroids 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 mediasti-
nal lymph nodes that result in respiratory difficulty or bronchial obstruction, en-
dobronchial disease, miliary disease, and pleural or pericardial effusions
(128,179). A frequently used regimen includes prednisone (12 mg/kg/day) for
584 Muoz and Starke

46 weeks with gradual taper over 12 weeks. Although there is no convincing

evidence that one form of corticosteroid is more beneficial than others, some ex-
perts 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 fail-
ure of treatment. Routine laboratory testing is not necessary given the low rates of
adverse reactions observed in children. Radiographic improvement of intratho-
racic 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 con-
trol because of the long-term nature of treatment (180). Many children with tu-
berculosis 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 drug-
resistant tuberculosis. By ensuring patient compliance, DOT decreases the rates of
drug resistance, relapse, and treatment failures. However, DOT requires that a
health-care worker observes the patient 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 tuberculosisfor a com-
munity and for individualsdepends 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 chil-
dren 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 in-
tervention 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,
Tuberculosis in Children 585

however, prevents few cases of pediatric tuberculosis, especially if the screening

is centered on school-age children (who rarely develop primary disease). The ma-
jor 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
yieldon average, 3050% of childhood household contacts are infectedbut
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 vir-
tually 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 popula-
tions at low risk, has a low yield of positive results or a large number of false-pos-
itive results, representing an inefficient use of limited health care resources. Chil-
dren 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 identify-
ing risk factors for a child being in a group with a high prevalence of infection. Lo-
cal 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, so-
cial 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 work-
able and generally acceptable policy. Local clinicians can be extremely helpful to
586 Muoz and Starke

health departments in advancing prudent and reasonable tuberculosis control poli-

cies, particularly when other government or public agencies are involved.

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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 New Jersey Department of Health

National Tuberculosis Center and and Senior Services
International Center for Public Health Trenton, New Jersey
UMDNJNew Jersey Medical School
Newark, New Jersey

I. Introduction

The well-known U-shaped curve (1) reflected the fall and resurgence of tuber-
culosis (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 re-
sponsible 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 pa-
tient. How this mandate was applied and implemented varied in different TB-
control programs. This chapter will describe the application of this concept in
many cities while focusing on the specific organization of one of the more suc-
cessful 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, cate-
597
598 Mangura and Galanowsky

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. hospi-
tals (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 Tu-
berculosis 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. Dis-
appearance of TB expertise among physicians servicing multiple health services
compounded the problem. Old tuberculosis concepts of physical isolation by sana-
torium care were no longer practical. Ambulatory care was apparently insuffi-
cient, 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 ther-

apy 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 super-
vised therapy in the 1970s was first suggested in Denver (7) and applied in the
New Jersey Medical Schools Lattimore Clinic (8) in a selected group of patients.
The city of Baltimore (9), a decade before New York City turned the tide of tu-
berculosis (10), used community workers to deliver DOT. Subsequently, the Tar-
rant 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 Re-
search 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 ther-
apy 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 ac-
tivities model. This refers to a system in which clinical services were directed and
provided separately from outreach (governmental) TB-control activities. Self-ad-
ministered 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-
Case Management 599

tive. There was very little synchronization between the clinical follow-up and TB-
control activities, thus accountability for a patient treatment outcome was ad-
dressed 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 as-
signed 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 (mis-
timing) would often adversely impact on the clinic schedule, patient flow, and per-
sonnel 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 eventu-
ally 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

Newarks unique patient population is the largest of any city in New Jersey (esti-
mated 258,751 in 1997), of which 84% are classified as minority black and His-
panic. 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 assis-
tance), 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 (19851992) (9), only about half of the total cases in Newark com-
pleted 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 self-
administered and selective DOT in 1993 to universal DOT in 1994 was insti-
tuted. However, transition to selective DOT and subsequently universal DOT only
showed minimal improvement (19) in contrast to the other successful reports
(17,18).
600 Mangura and Galanowsky

V. The Nurse Case-Management Model

Because of the difficulties described above, the Nurse Case-Management Model

was implemented. The infrastructure, objectives, and function of this model ad-
dressed 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 sys-
tem of case management with common goals. The organizational tree and man-
agement 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 man-
aged in community-based settings. Visiting nurses used some case-management
models in the 1930s (21), while public health nurses utilized the process for com-
munity-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 en-
tities such as tuberculosis. Similar management models had been adopted in the
medical world from the business sector. Businesses addressed optimization of ef-
ficiency 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 patients family or significant other persons,
and coordination of available resources for the patients 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, implemen-
tation, 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 ac-
cording 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.
Case Management 601

The objectives of our case-management model are (1) to identify actual or

potential health and nonhealth-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 ulti-
mately the application of case management. The first intervention was service de-
livery change: case management that involved clinical record review and redefi-
nition of tasks and responsibilities by structuring of roles and functions of all the
staff. During the succeeding periods of time, incremental changes were imple-
mented 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 pre-
scribed 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 pro-
gram to program. The New Jersey Medical School National TB Center specifi-
cally 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-ad-
ministered fixed-dose combination treatment.
In the transition phase, incremental modifications of role definitions, intro-
duction of a team concept, skill-enhancing sessions, mentoring, discharge plan-
ning, and archiving of inactive charts occupied some of the staff activities. Review
of adequacy of treatment, identification of barriers to adherence, and establish-
ment 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 ob-
viously very difficult to manage, confirmed cases were given DOT with an aver-
age adherence rate of 62% each month. Addition of outreach workers to deliver
universal DOT surprisingly did not improve the adherence rate (63%) in 1994.
602 Mangura and Galanowsky

VII. Incremental Service Delivery Change and DOT

Review of the New Jersey Medical School National TB Centers 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. Case-
management teams were created and assigned to each postal zone. The teams were
responsible for 3560 patients with active TB as well as their contacts and asso-
ciates as indicated. By patients 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, as-
signment to nurse case manager, baseline assessment including TB-control ser-
vice interview and contact investigation, physician visit, nurse postcounseling,
HIV counseling and testing, social assessment and intervention, field work inves-
tigations, 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 investiga-
tions. The clinic physician as well as private sector physicians [including pedia-
tricians (28)] worked with the nurse case manager on a continuing basis. The pa-
tients 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 out-
come 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 ad-
dition, 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 short-
course ATS/CDC treatment regimen (26). The baseline length of time for com-
pletion of treatment was 11.6 months, and over the 3-year period the time to com-
pletion improved from an average length of 10.5 months to 7.8 months in 1996.
Case Management 603

Community
Correctional Health Care Drug Treatment Hospital Managed Care Nursing Home Private MD Shelter
Facility Organization Center Organization

Figure 1. The case-management process.

604 Mangura and Galanowsky

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 en-
couraged 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 sys-
tem were no longer possible. Specific problem patients and patients problems
clinical, social, personal, and public health relatedwere subsequently addressed
as they arose. During the first 2 months of the medication-initiation phase, patient-
outreach relationship was optimized to promote bonding, building, and strength-
ening of the unique relationship. DOT was carried out at the patients 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 patients needs were used liberally for all patients. Incentives included Sus-
tacal (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 diag-

nosis, sputum conversion, optimum lengths of treatment, and good adherence as
shown by high completion rates are benchmarks of a successful TB control pro-
gram (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 programs failure to address if not alleviate the mul-
tiple human problems of a once-treatable infectious case. Innovative strategies
and practical variation of existing models, applicable to each location and popu-
lation, 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 levelservice delivery. Therefore, management policies should in-
Case Management 605

clude one person accountable for each patients 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 hard-
to-reach patients with tuberculosis is achievable and replicable in areas with ap-
propriate 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.

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16. Brudney K, Dobkin J. A tale of two cities: Tuberculosis control in Nicaragua and
New York City. Sem Respir Infect 1991; 6:261272.
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;
151:14861490.
18. Fujiwara P, Larkin C, Frieden TR. Directly observed therapy in NYC: history imple-
mentation, results and challenges. Clin Chest Med 1997; 18(1):135148.
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 adher-
ence. Am Rev Respir Dis 1993; 147:13111320.
21. Cesta TG, Tahan HA, Fink LF. The Case Managers Survival Guide: Winning Strate-
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22. Knollmueller RW. Case management: Whats in a name? Nursing Manage 1984;
20(10):3842.
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; 149:13591374.
27. Lardizabal A, Mangura BT, Reichman LB. Directly observed therapy (DOT): varia-
tions 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 man-
agement in developing adherence to TB control. Am J Respir Crit Care Med 1996;
153(4):A490.
29. CDC. Tuberculosis morbidityUnited States, 1997. JAMA 1998; 279(19):1515
1516.
30. Voelker R. Shoe leather therapy is gaining on TB. JAMA 1996; 275(10):743744.
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tive therapy for an inner city population. Int J Tuberc Lung Dis 1997; 1(6):576578.
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 Mycobac-
terium 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 physi-
cians 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 tu-
berculin skin test converted their skin test by graduation, and 22% developed clin-
ical 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 com-
pared to nonhealth-care workers (1,57).
609
610 Blumberg

Myers in 1930 made a series of recommendations for the control of tuber-

culosis transmission in hospitals, and some of his recommendations are still ap-
plicable (4,8):
1. Perform tuberculin skin testing and chest radiographs on all new em-
ployees.
2. Do follow-up skin testing every 612 months.
3. Exclude tuberculosis in all new patients admitted to the hospital, in-
cluding 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 effec-
tive chemotherapy in the 1950s to treat those with active disease, the use of treat-
ment of infection among those with tuberculosis infection, and the progressive de-
cline 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 out-
breaks in the 1960s, 1970s, and early 1980s (912).
As the incidence of tuberculosis declined in the United States and risk of oc-
cupational exposure and infection continued to decline, less and less attention was
paid to infection-control practices in hospitals (13). Thus, few institutions were pre-
pared for the changing epidemiology of the disease (14) and the resurgence of tu-
berculosis in the United States that occurred beginning in the mid-1980s. This resur-
gence 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 (1622) and around the world (2334) 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 multidrug-
resistant (MDR) strains of TB and were associated with a high morbidity and mor-
tality, most often involving HIV-infected individuals. Effective infection-control
strategies are needed to have a safe workplace in the health-care arena and to pro-
tect 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
Tuberculosis Infection Control 611

in the United Statesa 20% increase in the number of cases between 1985 and
1992was due in large part to decay of the public health infrastructure (due to un-
derfunding) and the HIV epidemic (36,37). Other factors included immigration
from areas where tuberculosis is endemic, increasing poverty, homelessness, sub-
stance 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 ap-
propriate 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 oc-
cur in the United States. The major burden of tuberculosis care today is usually pro-
vided 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 patient-
to-patient or patienttohealth-care worker transmission, although one report doc-
uments health-care workertohealth-care worker transmission (22). Health-care
workertopatient 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 dis-
ease was the lack of adequate procedures to identify patients with possible tuber-
culosis and the failure to isolate such patients immediately once tuberculosis was
suspected (35,42). In many urban settings co-infection with HIV and M. tubercu-
losis 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 clas-
sic 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 non-
classic 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
612 Blumberg

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 immunocompro-
mised patients on AIDS wards of large urban hospitals
Delayed recognition of TB in HIV-infected patients because of atypical pre-
sentation 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 iso-
lates
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 com-

mingling 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 lab-
oratory 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 tu-
berculosis include inadequate engineering controls (e.g., lack of negative pres-
sure, recirculation of air from respiratory isolation rooms to other parts of the hos-
pital), 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 tele-
vision, 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 subse-
quently 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-
Table 2 Characteristics of Nosocomial MDR-TB Outbreaks Investigated by CDC, 19881992
Median
interval
from TB No.
Patients with isolation Mortality HCW TST
Hospital Outbreak HIV infection to death rate Resistance conversions
location period Patients (%) (weeks) (%) pattern (%) Ref.
Tuberculosis Infection Control

1 Miami 19881991 65 93 7 72 INH, RIF (EMB, ETA) 13/39 (33) 18, 19

2 New York City 19891991 35 100 16 89 INH, SM (RIF, EMB) 11/60 (18) 20
3 New York City 19891992 70 95 4 77 INH, RIF, SM (EMB, 88/352 (25) 118
ETA, KM, RBT)
4 New York City 19901991 29 91 4 83 INH, RIF (EMB, ETA) 6/12 (50) 119
5 New York State 19901991 7 14 4 43 INH, RIF, SM (EMB, 46/696 (6.6) 120
ETA, KM, RBT)
6 New York City 19901991 16 82 4 82 INH, RIF, SM (EMB, Unknown 121
ETA, KM, RBT)
7 New Jersey 19901992 13 100 4 85 INH, RIF (EMB) 5/10 (50) 122
8 New York 19911992 37 96 NA 93 INH, RIF Unknown 123
9 New York Prisons 19901992 42 98 NA 79 INH, RIF NA 41

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.
613
614 Blumberg

volved HIV-infected patients and mortality was striking. At most of the institu-
tions investigated, the mortality rate was 7090% 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 nosoco-
mial 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 sus-
ceptible cases. Patients with MDR-TB were more likely to have had a previous ad-
mission to the respective hospital and, while hospitalized, a significantly greater
likelihood of exposure to a patient with infectious MDR-TB than did control pa-
tients (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. tuberculo-
sis (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 in-
fection-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 signifi-
cant for health-care workers in addition to patients. In these MDR-TB outbreaks,
6.650% 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
Tuberculosis Infection Control 615

nonoutbreak setting, has been incompletely defined. The reported incidence of tu-
berculin skin test conversion among U.S. health-care workers varies widely, rang-
ing from 0.1 to 10% (13,47). Several national surveys of U.S. hospitals with tuber-
culin skin testing programs have reported rates that range from 0.33 to 5.5% per year
(4851). Several reports have noted that if the number of patients admitted to an in-
stitution 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 medi-
cal 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 im-
plementation of expanded infection-control measures (53,53a,54).
It is usually assumed that all tuberculin skin test conversions among health-
care 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 em-
ployees of Barnes Hospital in St. Louis in 1994 (55). Twenty-nine of 3106 em-
ployees 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 employees 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 proba-
bly 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 in-
stitution. Efficacy of infection-control measures also influences conversion rates.
Despite the limitations of the tuberculin skin test (see Chap. 12), it remains an im-
portant component of an infection-control program in the United States and in as-
sessing the efficacy of the infection-control program.
616 Blumberg

B. International

Nosocomial transmission of tuberculosis has also been reported from a variety of

areas around the world over the past decade including EuropeSpain (32), Italy
(27,56), France (25,30), Netherlands (29), England (16)South AmericaAr-
gentina (23,31)AfricaSouth Africa (33), Malawi (28)AsiaJapan (34)
and Australia (57).
Undoubtedly, nosocomial transmission of tuberculosis is occurring in de-
veloping countries around the world as well but has not been reported or likely re-
mains undetected because of inadequate surveillance systems and/or lack of re-
sources, including laboratory facilities. In developing countries, hospital
admissions of persons with TB are more frequent, HIV infection is more preva-
lent, 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 trans-
mission in developing countries because of the methodological difficulty of study-
ing it in high-incidence areas and the fear of adverse effects on staff motivation
and program function if documented. Further investigations of nosocomial trans-
mission of tuberculosis in developing countries is clearly needed, and preventing
such transmission, if documented, would be an important public health interven-
tion 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 nosoco-
mial 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 co-
infected with HIV, outbreaks often occurring on a HIV-dedicated ward, an ex-
tremely high mortality rate (often approaching 100%) for these patients, my-
cobacteria 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 in-
fections (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 in-
volved 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 tu-
berculosis and HIV) and involved 100 patients with HIV co-infection hospital-
ized in 1994 and 1995. RFLP analysis of MDR-TB strains from the outbreak re-
vealed two closely related patterns, suggesting they had a clonal origin and recent
transmission. At the time the article was written, the infection-control measures
Tuberculosis Infection Control 617

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 im-
portance of an effective tuberculosis infection-control plan is emphasized by the
outbreaks of tuberculosis at health-care facilities throughout the world and the pre-
vention 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. tuberculo-
sis in health-care facilities (1,6163), and practical recommendations for develop-
ing and implementing an effective infection-control program have recently been
published (64). Major goals in the control and prevention of nosocomial tubercu-

Table 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 ap-
propriate regimen including at least two drugs to which the organism is likely to be sus-
ceptible. (Generally, a four-drug regimen will be employed.)
3. Comply with isolation procedures during the patients hospitalization until laboratory
and clinical evidence eliminates the possibility of tuberculosis or the risk of transmis-
sion.
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 health-
care workers.
6. Discharge tuberculosis patients from acute care only when they are no longer infec-
tious 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 re-
sources 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.
618 Blumberg

losis are outlined in Table 3. In addition, the Occupational Safety and Health Ad-
ministration (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 revi-
sion, by 2000 (66). The basic elements of an effective tuberculosis-control program
are outlined in Table 4 and discussed below.

A. Assignment of ResponsibilityAssemble a Task Force

The first step in establishing an infection-control program is for an institution to as-

sign a specific person or group of persons the responsibility for developing a tuber-
culosis-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 sub-
committee 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 institu-
tions 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 fre-
quency of review of the program as part of that health-care institutions tubercu-
losis infection-control plan (61). Elements of tuberculosis risk assessment are
shown in Table 4. The first step is to review the community profile for tuberculo-
sis (e.g., incidence and prevalence of tuberculosis in the community, drug-sus-
ceptibility 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 num-
ber of patients with active disease admitted to each area or ward of the hospital,
Tuberculosis Infection Control 619

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, ad-
ministration, engineering are identified and included.
II. Elements of tuberculosis risk assessment
A. Review community TB profile (incidence and prevalence of TB and drug-sus-
ceptibility patterns).
B. Review facilitys 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 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 ar-
eas.
G. Exhaust TB isolation room air to outside or, if not possible, recirculate only af-
ter HEPA filtration.
VII. Respiratory protection
A. Respiratory protection should be used by people entering rooms in which pa-
tients with known or suspected infectious TB are being isolated, by HCWs
when performing cough-induced or aerosol-generating procedures on such pa-
tients, 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.
VIII. 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 require-
ments for TB isolation.
C. After completion of procedures, TB patients should remain in the booth or spe-
cial enclosure until their coughing subsides.
IX. HCW TB training and education
A. All HCWs should receive periodic TB education appropriate for their work re-
sponsibilities 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 occupa-
tional risk for TB.
D. Training should describe work practices that reduce the likelihood of trans-
mitting M. tuberculosis.
X. 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.
XI. Evaluate HCW PPD test conversions and possible nosocomial transmission of
M. tuberculosis
XII. 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.
Tuberculosis Infection Control 621

analysis of tuberculin skin testing results by area or occupational group to detect

any clustering, and an evaluation of current tuberculosis infection-control prac-
tices (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 outpa-
tient clinic or emergency room
Low: areas or occupational groups in which the tuberculin skin test conver-
sion 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 oc-
cupational 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 oc-
cupational group and epidemiological evaluation suggests nosocomial
transmission; or possible person-to-person transmission of M. tuberculo-
sis has been detected
Recommendations for the minimal and very-low-risk facilities have been pub-
lished (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 rec-
ommended 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 workerdirected 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)
622 Blumberg

These include administrative controls, engineering controls, and personal respira-

tory 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, es-
pecially at institutions where resources are limited. Administrative controls in-
clude measures to reduce the risk of exposure to persons with infectious tubercu-
losis. 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 ther-
apy is initiated (68). This includes careful screening and early identification of pa-
tients 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 (espe-
cially 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 HIV-
infected patients with tuberculosis have included in their protocols that all HIV-
infected patients who have clinical symptoms that could be consistent with tuber-
culosis (e.g., fever and cough or an abnormal chest radiograph) be isolated. Other
patients who should be isolated upon admission include those admitted with tu-
berculosis in the differential diagnosis, patients for whom respiratory specimens
for AFB smear and culture have been ordered, and patients with known active pul-
monary tuberculosis. Patients admitted to respiratory isolation should remain in
isolation while hospitalized unless tuberculosis (or at least a high likelihood of in-
fectiousness) 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 ba-
sis (e.g., every 812 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.
Tuberculosis Infection Control 623

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 rou-
tinely used. Testing should be done at baseline (when the health-care worker ini-
tiates 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 ar-
eas 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 institutions 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 indi-
cated (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 oc-
cupational 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 ad-
dition, when initiating a tuberculin skin testing program and for new health care
workers joining a facility, two-step testing [a second test performed 13 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 conver-
sion rate. At one U.S. hospital in New York City that has a relatively high pro-
portion 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 pre-
vious 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 vac-
cination (72).
Health-care worker education is of course an important and crucial compo-
nent 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 noso-
comial transmission of tuberculosis, and they must be able to effectively imple-
ment 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-
624 Blumberg

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 re-
quires 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 con-
trols. 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 out-
breaks of tuberculosis including those involving MDR strains (46). Broth culture
techniques (e.g., BACTEC system) have been demonstrated to significantly re-
duce (by 1014 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 effi-
ciency of isolation room use and to provide cost savings by allowing AFB smear-
positive 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 impor-
tant control measure. While the exact time that it takes to render a patient non-
infectious is unclear (75), effective therapy to patients with drug-susceptible tu-
berculosis can rapidly decrease the degree of infectiousness of these patients.
Therefore, beginning effective therapy in patients in whom tuberculosis is sus-
pected 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).
Tuberculosis Infection Control 625

Engineering Controls

The second level of controls consists of engineering controls that reduce or elim-
inate TB droplet nuclei in the air. These include (164):
1. Direct source control using local exhaust ventilation (e.g., isolation
room, sputum induction booths, etc.)
2. Controlling the direction of air flow to prevent contamination of adja-
cent areas (i.e., negative pressure isolation rooms so air flows from the
hall or adjacent areas into the respiratory isolation room)
3. Dilution and removal of contaminated air by general ventilation (a min-
imum of 6 air exchanges per hour is recommended by CDC for iso-
lation rooms and 12 air exchanges per hour for new construction or
renovations)
4. Air filtration with high-efficiency particulate air (HEPA) filters
5. 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 ex-
hausted 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 air-
borne contaminants for various removal efficiencies (e.g., 90%, 99%, 99.9%) de-
pending 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 non-
portable 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 institu-
tional transmission of M. tuberculosis has been somewhat controversial. CDC and
the American Thoracic Society have recommend UVGI as a supplementary mea-
sure 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
626 Blumberg

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-pres-
sure, 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 sys-
tem ducts can be used as an adjunctive measure to disinfect air before it is recir-
culated, but this is not recommended as a substitute for HEPA filtration of recir-
culated 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 my-
cobacteria. 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. fed-
eral 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 res-
piratory protective devices or masks should be worn in areas where the risk of ex-
posure 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 res-
pirator 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 ex-
ist to support their use over other types of respirators (e.g., when caring for a pa-
tient 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 In-
stitute 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-
Tuberculosis Infection Control 627

tection program that includes medical evaluation, training, and individual fit test-
ing of health-care workers is required by OSHA. Developing a respiratory pro-
tection program including fit testing can be time-consuming, expensive, and lo-
gistically 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 can-
not be certified for fit testing under the current OSHA regulations because of face-
seal leakage. OSHA regulations require bearded health-care workers to use a pos-
itive 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. tu-
berculosis (Table 6) (67,9193). 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 institu-
tions 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 (35,67,9193).

Table 6 Reports on the Control of Outbreaks of Nosocomial Tuberculosis at Acute

Health-Care Facilities
Control measure(s) used
Administrative Engineering
Location, hospital measures measures PPE masks Ref.
Miami, Jackson Memorial Extensive Extensive Submicron 92
New York, Cabrini Extensive Exhaust fansa Molded Surgical 93
Mask
New York, Roosevelt Extensive Laterb Surgical Mask 91
Atlanta, Grady Memorial Extensive Exhaust fansa Submicron 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 res-
piratory isolation rooms.
Source: Adapted from Ref. 35.
628 Blumberg

At Cabrini Hospital in New York, Maloney et al. reported that the propor-
tion 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 pe-
riod 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 de-
creased 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 suffi-
cient number on workers.
At Grady Memorial Hospital in Atlanta following implementation of ex-
panded infection-control measures, which consisted chiefly of administrative con-
trols, there was a marked reduction in tuberculosis exposure episodes and health-
care worker tuberculin skin test conversion rates. Early identification and isolation
of patients was facilitated by the development of an expanded respiratory isola-
tion policy based on the prevalence and demographic profile of the tuberculosis
patients in the community and served by the institution. Following implementa-
tion of the protocol in March 1992, the number of tuberculosis exposures (patients
with AFB smear-positive pulmonary tuberculosis who were not admitted into res-
piratory 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). Con-
comitant with the decrease in the number of tuberculosis exposure episodes, there
was a marked and significant decrease in the number of tuberculin skin test con-
versions from 3.3% to 0.4% among the hospitals health-care workers during 6-
month testing periods.
Other institutions have also reported decreases in tuberculin skin test con-
versions among health-care workers after implementation of tuberculin infection-
control measures (9496). In all of these reports, multiple control measures (i.e.,
administrative, engineering, and personal respiratory protection) were imple-
mented at about the same time, making it more difficult to identify the most cru-
cial aspect of the program. No actual field trials assessing the independent impor-
tance 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 pro-
gram 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-
Tuberculosis Infection Control 629

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 tubercu-
losis infection-control measures has been a critical component along with en-
hanced community-control measures such as expansion of directly observed ther-
apy 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 defi-
nition including improving the efficiency of infection control measures and deter-
mining the most cost-effective strategies. For example, while tuberculosis infec-
tion-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 tu-
berculosis 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 tu-
berculosis, 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) identi-
fied 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 devel-
oped. 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 iden-
tify 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-Gurin (BCG) vaccination for the prevention of

tuberculosis disease has been somewhat controversial (see Chap. 19). BCG vac-
630 Blumberg

cination has long been proposed by some for use in health-care workers for pre-
venting 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 to-
day (and prior to implementation of tuberculosis infection-control measures) sug-
gest that BCG may reduce the risk of developing active disease in vaccinated
health care workers compared to that among nonvaccinated health care workers
(106112). 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 ex-
cept in situations where there may be high rates of MDR-TB and infection-con-
trol measures cannot be implemented (61). Use of BCG interferes with interpre-
tation 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 coor-
dination of activities among the wide variety of organizations involved in TB pa-
tient 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 hos-
pitals and public health agencies. A written policy or critical pathway manage-
ment of tuberculosis patient discharges that provides guidance as to what consti-
tutes an appropriate discharge is important (35). Patients with tuberculosis should
(1) be discharged on an appropriate antituberculosis regimen (e.g., four-drug reg-
imen), (2) have arrangements to ensure close follow-up after discharge (for ex-
ample, at Grady Memorial Hospital all TB patients have their discharge endorsed
Tuberculosis Infection Control 631

in the chart by the hospitals TB social worker and the local county health depart-
ment 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 liai-
son 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 occupa-

tional 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, OSHAs authority to conduct inspections for oc-
cupational exposure to tuberculosis comes from the general duty clause of the Oc-
cupational 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 de-
veloping 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, correc-
tional facilities, homeless shelters, and drug-treatment centers. It is anticipated that
the final standard will be issued in 2000. The proposed requirements of the stan-
dard 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 de-

veloping countries, although the extent of this has not been fully evaluated (58).
In most of the developing world infection-control or tuberculosis infection-con-
trol measures are minimal or nonexistent (47). The extent of control measures rec-
ommended 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
632 Blumberg

Table 7 Occupational Safety and Health Administrations 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 iden-
tify 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 haz-
ardous 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 pre-
cautions (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.
Tuberculosis Infection Control 633

Table 8 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 abusetreatment 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, emer-
gency 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 in-
fectious 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 identifi-
cation, isolating and managing care, list of high hazard procedures, and schedule for
inspection and maintenance of engineering controls
634 Blumberg

Table 8 Continued
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 Lab-
oratories
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 635

Table 8 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. Medi-
cal removal protection, including all earnings, job status, and seniority, shall be main-
tained 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 spe-
cific knowledge and skills.
Record Keeping
Records must be kept for all medical evaluations, exposure incidents, training, and engi-
neering 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 tubercu-
losis 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 includ-
ing 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. Am-
bulatory 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 con-
firmed (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 tubercu-
losis wards closed and windows open to the outside; exhaust fans are use-
ful 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, ex-
cluding 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).

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lapse in tuberculosis. N Engl J Med 1994; 330:11791184.
117. WHO/IUATLD. Control of tuberculosis transmission in health care settings. Joint
Statement of the WHO Tuberculosis Programme and the International Union
Against Tuberculosis and Lung Disease (IUATLD). WHO Weekly Epidemiol Rec
1993; 50:369371.
118. Jereb JA, Klevens RM, Privett TD, Smith PJ, Crawford JT, Sharp VL, Davis BJ,
Jarvis WR, Dooley SW. Tuberculosis in health care workers at a hospital with an
outbreak of multidrug-resistant Mycobacterium tuberculosis. Arch Int Med 1995;
155:854859.
119. Pearson ML, Jereb JA, Frieden TR, Crawford JT, Davis BJ, Dooley SW, Jarvis WR.
Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis. A
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GP, Morse DL. Nosocomial tuberculosis: an outbreak of a strain resistant to seven
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Woodley CL, Kilburn JO, Crawford JT, Frieden TR. Transmission of multidrug-re-
sistant Mycobacterium tuberculosis among persons with human immunodeficiency
virus infection in an urban hospital: epidemiologic and restriction fragment length
polymorphism analysis. J Infect Dis 1993; 168:10521055.
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M. tuberculosis among intravenous drug users with human immunodeficiency virus
infection. In: Abstracts of the Third Annual Meeting of the Society for Hospital Epi-
demiology of America, Chicago, April 1820, 1993.
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124. Pugliese G. OSHAs proposed standard on occupational exposure to TB. J Health-
care Saf Compliance Infect Control 1998; 2(1):914.
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 Wochen-

schrift described tuberculosis among former concentration camp inmates in East-
ern 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 just-
released 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 post-
primary 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
646 Bock

among the postprimary cases, 2) a high rate of transmission in the camps, as evi-
denced 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 postpri-
mary 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 incarcer-
ated 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 malnutri-
tion. And tuberculosis incubated in jails and prisons is not confined there, but be-
comes 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 tuber-
culosis to be higher among inmates in prisons and jails than in the nonincarcer-
ated population. This finding persists across high-, low-, and increasing-preva-
lence (Eastern Europe and the former Soviet Union) (2) countries (see
Appendix). In the BouakO prison, Ivory Coast, an average annual incidence of
3,600 per 100,000 was reported for 19901992 (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 countrys largest prison, Maison dArret et de
Correction dAbidjan (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 tubercu-
losis 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
Tuberculosis in Correctional Facilities 647

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 Azer-
baijan, 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 high24% 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 in-
stitution to a Barcelona jail over a 9-month period in 19891990 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 neigh-
borhood of Barcelona inhabited primarily by gypsies (2036%) 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 19931994, the incidence of tuberculosis was 2,283 per 100,000 (10).
In the United States, increasing rates of tuberculosis in correctional facili-
ties 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 19901991 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 aver-
age annual general population rate of 12 per 100,000 (14).
Many state prison systems in the United States conduct active case find-
ing among new inmates. This is a useful tool for tuberculosis control (see be-
low), 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 ad-
mission 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 19841985, 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 com-
bination 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
648 Bock

cases in cohorts followed over time and those detected during case-finding pro-
grams.

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 transmis-
sion. The overcrowding of inmates within prisons and jails further enhances trans-
mission (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) tuberculo-
sis were linked in a transmission chain by epidemiological data and drug resis-
tance and RFLP patterns (12). In Antananarivo prison, the authors propose that the
decrease in rates over time following the initiation of effective standard, interna-
tionally recognized treatment regimens may have been due to decreased trans-
mission within the prison (6).
Two decades ago Stead documented previous incarceration as an indepen-
dent 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 in-
mates 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 develop-
ment of tuberculosis disease among persons with latent tuberculosis infection
(20). Among tuberculin skin testpositive, 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).
Tuberculosis in Correctional Facilities 649

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 of-
fenders, 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 in-
fected (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 nondrug 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 coun-
tries are increasingly reported to be associated with HIV infection. Braun et al. re-
ported 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 in-
fected, 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 af-

fects the general community in several ways. First, as discussed above, correc-
tional facilities are environments of transmission, and many inmates become in-
fected while incarcerated. Once released back to the community they may develop
650 Bock

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 de-
tected 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 demon-
strated 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, be-
tween 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 19911995, 38% of inmates un-
der 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 in-
mates started on isoniazid preventive therapy in Seattle, Washington, were never lo-
cated after release from jail despite an aggressive outreach program (35).
A New York State prison employee developed MDR tuberculosis and sub-
sequently died after exposure during an outbreak in the prison system in
19901991 (12). Employees of jails and prisons have been noted to have high
rates of tuberculosis infection (36,37), and periodic surveillance for infection
Tuberculosis in Correctional Facilities 651

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 sys-
tem 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 investiga-
tion 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 In-
ternational Committee of the Red Cross (39; see Appendix B for The Baku Dec-
laration). 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 iden-
tification, isolation, and effective treatment of persons who have active tubercu-
losis, 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 collabora-
tion 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 preva-
lence of infection and disease, and the environment they are entering facilitates
transmission of M. tuberculosis. Screening for disease should be done upon ad-
mission 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 long-
term inmates can detect incident cases; prompt medical evaluation and a high in-
dex 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-
652 Bock

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 fa-
cilities, 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 tubercu-
losis disease should be placed in a respiratory isolation room and further evalua-
tion, with chest radiography or sputum smear microscopy, conducted. Facilities
without adequate respiratory isolation should have a plan for transfer of tubercu-
losis suspects to a facility equipped to isolate, evaluate, and treat them. For symp-
tom 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 weeks 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 spu-
tums 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 smear-
negative cases diagnosed. These screening methods, the first reported in a correc-
tional 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 com-
pared 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 pre-
viously 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
Tuberculosis in Correctional Facilities 653

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-con-
trol 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 confine-
ment since, depending on the air flow in the facility, droplet nuclei produced in
those cells may be recirculated throughout the facility. Also, having infectious tu-
berculosis 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 treat-
ment, (3) no financial cost to the patient, and (4) a plan for recognizing and man-
aging drug-resistant cases.
The International Committee of the Red Cross documented too few antibi-
otics 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 med-
ical services in the prison camp of BouakO, Ivory Coastan 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 drug-
resistant tuberculosis is generally beyond the resources of most national tubercu-
losis programs outside of the industrialized countries. The World Health Organi-
zation (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 out-
breaks where special interventions are necessary.
In countries where resources are available, routine periodic tuberculin test-
ing 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 tuberculo-
sis infection. As noted above, inmates are at increased risk of progression to tuber-
culosis once infected because of the high prevalence of HIV infection and intra-
654 Bock

venous drug use in the population. Few inmates have access to preventive health ser-
vices outside of the correctional system (16). Although the priority for prison tuber-
culosis control is to decrease transmission by detection, isolation, and treatment of
cases, effective treatment of latent infection for infected inmates is another compo-
nent 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 com-
pleted treatment (32). Once the inmate is released, however, completion of treat-
ment for latent infection in the community is much less successful (43).
Preliminary data on the use of primary isoniazid prophylaxis for HIV-in-
fected 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 prisoners 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 de-
tection 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 treat-
ment are at increased risk of being lost to follow-up (14,34). For cases detected on ad-
mission 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.

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Intern Med 1993; 118:139145.
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.
656 Bock

26. Magis C, Del Rio A, Gonzalez G, Garcia ML, Valdespino JL, Sepulveda J. HIV in-
fection 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
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28. Khan AD, Vernon A, Stetler H, Page R, Askew T, DeVoe B. HIV-related tuberculo-
sis (HIV-TB) in Georgia (abstr). Am Rev Respir Crit Care 1996;153:A132.
29. Chaves F, Alonso-Sanz M, Dronda F, Fernandez-MartOn I, Lpez-Cubero L, Cata-
lan 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, in-
stitutions, agencies and paroling authorities. Laurel, MD: American Correctional As-
sociation, 1992:XXII.
31. Correctional Populations in the United States, 1991. Washington, DC: Bureau of Jus-
tice Statistics, August 1993. U.S. Department of Justice document No. NCJ-142729.
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correctional facilitiesselected U.S. sites, 19901991. MMWR 1993; 42:210213.
33. Pelletier AR, DiFerdinando GT, Greenberg AJ, Sosin DM, Jones WD, Bloch AB,
Woodley CL. Tuberculosis in a correctional facility. Arch Intern Med 1993;
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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 assess-
ment. Tuberc Lung Dis 1996; 77:199206.
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; 155:583586.
36. Bock NN, Toomey KE, DeVoe B, Tapia JR, Blumberg HM. High prevalence of tu-
berculosis infection among employees of an urban jail (abstr). Am Rev Respir Crit
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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, Is-
mailov A, Mirzoev F, de Haller R, Portaels F. Drug resistant tuberculosis in prisons
in Azerbaijan: case study. BMJ 1998; 316:14231425.
40. Puisis M, Feinglass J, Lidow E, Mansour M. Radiographic screening for tuberculosis
in a large urban county jail. Public Health Rep 1996; 111:330334.
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; 87:13351337.
42. Barker A. UN urges steps to limit HIV, TB in Europes jails. Reuters Health Infor-
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43. Ijaz K, Stead WW. INH prophylaxis in HIV positive persons before exposure to tu-
berculosis (abstr). National TB Controllers Workshop, Atlanta, 1996.
Tuberculosis in Correctional Facilities 657

Appendix A Case Study of Tuberculosis in the Russian

Correctional System*
Background
Tuberculosis case rates and mortality rates in Russia have been steadily increas-
ing 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 so-
cial 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, 19601997.

*This case study was prepared by Sasha Chapkovsky and Naomi Bock.
658 Bock

thanks to the active involvement of several international nongovernmental orga-

nizations working in close collaboration with the prison medical services and ad-
ministration, particularly in western Siberia.
In 1997 the incidence rate of new tuberculosis cases was 74 per 100,000 per-
sons 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 re-
ported 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. En-
try 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 evalua-
tion, 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 isoni-
azid and rifampin. The duration of incarceration in the detention centers ranges
from 18 months to 5 years. Inmates undergo fluorography every 612 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 medi-
cation 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 deten-
tion center known to have active tuberculosis are transferred to a specialized tu-
berculosis prison colony, where they are treated with four- or five-drug treatment
regimens. The transfer to the specialized tuberculosis colony can take 68 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 612 months, and
any newly detected tuberculosis cases are then sent to the specialized tuberculo-
sis colony, via the transit system, if beds are available. Currently the specialized
Tuberculosis in Correctional Facilities 659

tuberculosis colonies are filled, and newly diagnosed cases in the general penal
colonies are neither isolated from the rest of the population nor given standard-
ized treatment or in many cases no treatment while awaiting transfer. More wor-
risome is the fact that many receive mono-therapy with whatever inexpensive
drugs the colony medical staff can obtain or whatever antibiotics the inmates
family can purchase and send. The time to transfer can be months, and some in-
mates 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 sev-
eral years. However, preliminary drug susceptibility results from early 1998 indi-
cated 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 sus-
ceptibility 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 an-
nual per capita expenditures are $26 and food rations are limited. All three lev-
els of correctional facilities are overcrowded and poorly ventilated, but the IVS
is the worst.
660 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 tu-
berculosis, 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 try-
ing 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 follow-
up. Many inmates become infected with tuberculosis while incarcerated and only
develop disease once released. In Kemerovo oblast, the civilian tuberculosis pro-
gram reported that one third of their new 19971998 cases were among former in-
mates. As described above, many of these former inmates were exposed to inade-
quately 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 be-
come 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 in-
fectious 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 incur-
able 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 tu-
berculosis (TB), an increasing proportion of cases in many of these countries oc-
cur 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 un-
known 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 worlds TB cases, while countries that
once had a high prevalence of TB now have low prevalence. Furthermore, the
661
662 Saraiya and Binkin

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 devel-
oping world (1).

III. Definitions

For purposes of this chapter, low-prevalence country will refer to the industri-
alized 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 for-
eign-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, Scandi-
navia, 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 def-
inition, 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 sub-
stantial 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-
 Tuberculosis Among Immigrants 663

Table 1 Tuberculosis Cases Among the Foreign-Born (FB) and Native-Born (NB) for Se-
lected Countries
How % of TB Crude
is FB cases Incidence Incidence rate ratio
Country (year of data) defined? among FB rateFBa rateNBa FB:NB

North America
United States (1996)b COB 37 31.3 8.1 3.9
Canada (1995)c COB 53 20.4 1.9 10.7
Western Europed
Austria (1995) COC 24
Belgium (1995) COC 33 43.7 10.7 4.3
Denmark (1995) COB 55
Finland (1995) COB 30 95.1 13.0 7.3
France (1995) COC 28 60.0 10.2 5.9
Germany (1995) COC 29 66.8 13.5 4.9
Iceland (1995) COB 1
Italy (1995) COC 10
Luxembourg (1995) COB 50
Netherlands (1996)e COC 52 120 5.5 22
Norway (1995) COB 41 57.2 4.2 13.5
Sweden (1995) COB 56 40.5 3.6 11.3
Switzerland (1995) COC 53 35.2 9.2 3.8
United Kingdom (1988)f Ethnicity 39 25.934.6 4.7 5.528.6
Israel (1993)g COB 93
Asia/Pacific
Australia (1995)h COB 75 17.3 1.7 10.4
Japan (19871992)i COB 1.2 76 39 1.9
New Zealand (19851990)j Ethnicity 42 19.629.7 1.9 10.315.6
a
Rates are per 100,000 population.
b
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 nonIsraeli 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 popula-
tion was separated by Asian ethnicityannual incidence of 29.7 (97% of whom were foreign-born) and Pacific Islander eth-
nicityannual incidence of 19.6 (87% of whom were foreign-born) (93).
664 Saraiya and Binkin

sify the native-born population into aboriginal and nonaboriginal populations

since the TB experience of the two may be quite heterogeneous. Extrapul-
monary TB refers to other than pulmonary TB, while nonrespiratory, often
used in the British literature, refers to other than one or any combination of pul-
monary 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 de-
cline, and drug resistance (8). While TB among foreign-born persons in low-
prevalence 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 rou-
tinely 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 in-
creased 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 Ice-
land and Japan to more than 50% in Canada, the Netherlands, Israel, and Aus-
tralia. In all countries for which data are available, TB rates among foreign-born
persons are approximately 230 times higher than those of the native-born
population.
Both the absolute number and the percentage of total cases among foreign-
born 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 avail-
able 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
Tuberculosis Among Immigrants 665

(a)

(b)
Figure 1 Trends in (a) number and (b) percentage of TB cases among foreign-born per-
sons for selected countries (foreign-born defined by country of birth except for Nether-
lands, 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 be-
gan 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-
666 Saraiya and Binkin

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. Nether-
lands data from Ref. 15.)

mated 67% 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 (1214). In ad-
dition, during 19921998, 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 in-
crease 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 popula-
tion. By 1996, 52% of all TB cases were among non-Dutch persons, and the TB
Tuberculosis Among Immigrants 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 rela-
tively stable since the mid-1980s. While the case rate among persons born in Aus-
tralia 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 per-
sons are not readily available, the 1995 rate is more than 10 times that of the na-
tive-born Canadians.
In Israel (Fig. 3), the number of TB cases and the case rate declined sub-
stantially 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 de-
creased to a low of 3.5 per 100,000 in 1989 but rose to 10.2 in 1991 with the ar-
rival 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, 19601996, 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.)
668 Saraiya and Binkin

year for which a detailed breakdown of country of birth is available, the vast ma-
jority of cases were among foreign-born persons (D. Chemtob, personal commu-
nication).
The reasons behind the differences between low-prevalence countries in
the percentage of cases among foreign-born persons, the rates between the for-
eign-born and indigenous populations, and the trends are complex. As described
below, they involve the overall percentage of the population in the low-preva-
lence 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 re-
cent 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 num-
ber of TB cases reported that year (17). In other countries, the effect is more sub-
tle, but the increase in TB seen in the United States between 1986 and 1992 par-
allels 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 contribu-
tion 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 com-
munication). 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%.
Tuberculosis Among Immigrants 669

Figure 4 Number of legal immigrants according to year of admission (bars) and tuber-
culosis 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 im-
migrants from Ref. 26.)

B. Country of Origin

The countries of origin of the foreign-born population differ for each low-preva-
lence 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 sev-
eral factors: proximity, their countries previous colonial ties, family, work, and
ease of immigration. Interestingly, some countries have a greater diversity of im-
migrants than others, which increases the complexity and amount of resources re-
quired for conducting timely identification of persons with TB infection and
disease.
Rates in foreign-born populations in industrialized countries tend to paral-
lel 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 19901996 (Fig. 5) (7). The age-adjusted rates
of TB in immigrants from these countries range from 43.6 per 100,000 among per-
sons 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.
670 Saraiya and Binkin

Figure 5 Reported tuberculosis cases by country of origin, United States, 19901996

(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 mag-
nitude of the difference observed in Table 1 between TB case rates in the indige-
nous 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,
Tuberculosis Among Immigrants 671

this partially reflects the age structure of the immigrant population (26). Addi-
tionally, 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 im-
migrants. 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 char-
acteristics of migrant populations over time (14).
Age at immigration also plays a role in the risk of TB among the foreign-
born 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 low-
prevalence 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 ex-
posure 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), approxi-
mately 1030% of the foreign-born cases were diagnosed in the first year of resi-
dence in the country, and a total of 5160% were diagnosed within 5 years of ar-
rival. 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.
672 Saraiya and Binkin

The relationship between birthplace, age, and time elapsed since immigra-
tion is complex. Fig. 6 shows 19861994 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. How-
ever, persons from the Philippines had rates of TB higher than 50 per 100,000 per-
son-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 (3537).

F. Clinical Patterns of Disease

Immigrants are more likely to have extrapulmonary TB than the indigenous pop-
ulations. British studies have consistently reported over the past three decades a
higher rate of nonrespiratory TB among persons of Indian subcontinent (ISC) eth-
nicity (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 eth-
nicity had rates of nonrespiratory TB 50 times higher than persons of white eth-
nicity (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 extrapul-
monary 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 ex-
trapulmonary cases varied greatly among Asian immigrants, from 20% among
those from Japan to 54% among those from the Philippines. Additionally, the pre-
 Tuberculosis Among Immigrants 673

B C

Figure 6 Rates of reported tuberculosis by place of birth, age, and length of residence in
the United States, 19861994. (From Ref. 14.)
674 Saraiya and Binkin

dominant types of extrapulmonary TB differed as well; TB lymphadenitis ac-

counted 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 labora-
tory 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 pul-
monary 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 Foreign-

Born Persons

Many immigrants are faced with obstacles to seeking care and completing treat-
ment 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 (4245). In ad-
dition, decreased access to care as a result of cultural, linguistic, and socioeco-
nomic barriers, anti-immigrant sentiments and legislation (47,48), and fear of de-
portation (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 in-
creased TB risk in patients from high-prevalence countries (51).
Despite delays, the mortality rates were lower among foreign-born TB pa-
tients 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 none-
mergency care to undocumented immigrants and to report them to government of-
ficials (53). Such legislation and its associated media attention might actually lead
Tuberculosis Among Immigrants 675

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 res-
idents of low-prevalence countries. In Israel, 15 (1%) of all patients tested be-
tween 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-in-
fected 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 medi-
cal condition for entry into the United States, however, some HIV-positive immi-
grants 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.
HIVs 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, low-
prevalence 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 com-
mon in the foreign-born populations than in the indigenous populations of low-
prevalence 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 pri-
mary 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).
676 Saraiya and Binkin

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

% of new TB patients
Country (year of data) with drug resistance

United States (19931996) a

Overall native-born 10.1
Overall foreign-born 17.6
Mexico 16.1
 1 year 18.9
 1 year 16.3
Unknown time 14.5
Philippines 18.4
 1 year 20.4
 1 year 18.4
Unknown time 16.3
Vietnam 27.4
 1 year 29.7
 1 year 27.2
Unknown time 24.9
Netherlands (19931994)b
Overall native-born 9.0
Overall foreign-born 18.0
Somalia 26.0
Turkey 20.0
Morocco 13.0
Japan (1992)c
Overall native-born 5.6
Overall foreign-born 4.8
a
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.
Tuberculosis Among Immigrants 677

States, a higher proportion of resistance was seen among immigrants from the
Philippines and Vietnam than among those from Mexico (61), while in the Nether-
lands, a higher proportion of resistance was seen among immigrants from Soma-
lia, Turkey, and Morocco (64). Furthermore, in the United States, rates of drug re-
sistance 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 ar-
rived 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 in-
teraction between the foreign-born and indigenous populations. In many commu-
nities, first-generation immigrants live primarily in communities consisting of in-
dividuals 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 pop-
ulation 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 indige-
nous 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 sur-
vey of schoolchildren, health-care profession students, and young adults em-
ployed in various sectors was performed also failed to demonstrate a relationship
between tuberculin positivity and contact with the foreign-born population as de-
termined by various indices (65).
DNA fingerprinting techniques using restriction fragment length polymor-
phism (RFLP) have proven useful in examining transmission between the for-
eign-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 for-
eign-born population disease is more likely the result of activation of remotely ac-
quired infection (6668). By contrast, in the Netherlands, where foreign-born per-
sons 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 re-
cent study in the San Francisco area identified transmission between the U.S.-born
678 Saraiya and Binkin

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 immi-
gration 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 organiza-
tions 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 se-
ries 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 em-

ployed, either alone or in combination. These strategies include prearrival screen-
ing, postarrival screening (including at the port of entry), and screening of foreign-
born populations that is done for other purposes but that potentially identifies
foreign-born persons with infection or disease (e.g., school-based or preemploy-
ment screening).
Foreign-born persons who are applying for immigration or who have re-
cently arrived are the principal focus of active case-finding activities in many
countries. As documented elsewhere in this chapter, TB rates are highest among
 Tuberculosis Among Immigrants 679

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 coun-
tries therefore conduct some form of pre- and/or postarrival screening of foreign-
born persons, although the populations screened and the methods used vary con-
siderably (Table 3). Most countries limit their screening to persons intending to

Table 3 Tuberculosis Screening Programs for Immigrants and Refugees for Selected Countries
Utilization
Time of Mandatory
Screening Screening Target of preventive notification
Country system* method** group screening chemotherapy system

North America
United Statesa A CXR Immigrants Prearrival Contacts Physicians
TST Postarrival Children Laboratories
Adults
Canadab A CXR Immigrants Prearrival Contacts Physicians
Long-term Postarrival Children Laboratories
visitors (6 mos) Adults
Western Europec
Austria A CXR, TST Foreign workers At entrance Contacts Physicians
(asylum seekers) Children
Adults
Belgium A CXR Asylum seekers At entrance Fibrotic Physicians
Foreign workers lesions
Denmark P CXR All entering Not used Physicians
foreigners
Finland A CXR Asylum seekers At entrance Children Physicians
Foreign workers Laboratories
France A CXR All entering At entrance Children Physicians
foreigners
Germany A CXR Asylum seekers At entrance (Children) Physicians
TST in Foreign workers Before residence (Adults) Laboratories
children
Iceland A CXR All entering At entrance Children Physicians
TST foreigners Before residence Adults Laboratories
Ireland P CXR All entering Variable Children Physicians
TST foreigners Adults
Italy A CXR Foreign workers At entrance Children Physicians
Adults
Luxembourg A CXR All entering At entrance Contacts Physicians
TST foreigners Before residence Children Laboratories
Netherlands A CXR Asylum seekers At entrance Contacts Mandatory
(TST) Foreign workers Before residence Children (no details)
Norway A CXR All entering At entrance No policy Physicians
TST foreigners Before residence Laboratories
Portugal A CXR Asylum seekers At entrance Contacts Physicians
TST Foreign workers Before residence Children
Spain A CXR Contacts
TST Children
Adults
continues
 680 Saraiya and Binkin

Table 3 Continued
Utilization
Time of Mandatory
Screening Screening Target of preventive notification
Country system* method** group screening chemotherapy system

Sweden A TST Asylum seekers At entrance Contacts Physician

CXR Some foreign Children Laboratories
workers Adults (voluntary)

All entering Contacts

CXR foreigners outside Children Physicians
Switzerland A (TST) EU and EFTA, At entrance Adults Laboratories
North America, Before residence
New Zealand, and
Australia
United Kingdom A CXR All entering At entrance Children Physicians
foreigners Before residence Adults (laboratories)
Israeld A CXR Some immigrants After entrance Contacts Physicians
TXT Children
Adults
Asia/Pacific A CXR All immigrants from Prearrival No policy Physicians
Australiae high risk countries Postarrival Laboratories
Students 3 mos

* In all countries, some refugees might be screened before entrance if the medical procedures are organized through the Interna-
tional 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 pre-
arrival screening in which applicants must undergo a medical history, physical ex-
Tuberculosis Among Immigrants 681

amination, and a chest radiograph prior to being allowed to enter the country. Cri-
teria 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 com-
plete treatment or are smear negative and obtain a waiver allowing them to con-
tinue 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 lo-
cal 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 fur-
ther evaluation and treatment in the United States, where generally there are bet-
ter diagnostic facilities and where the quality of treatment can be more closely
monitored.
In Canada, the strategy differs slightly. Canada uses repeat radiographs (de-
fined 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 evi-
dence of active TB are not admitted to Canada until an adequate treatment regi-
men (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 ra-
diographs (33,76). Individuals who have radiographs consistent with inactive TB
are placed under surveillance by the public health authority of the province of des-
tination and are required to report within 30 days of entry into Canada (N. Hey-
wood, 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 radio-
graphic evidence. If active TB is diagnosed, the applicant is not allowed to en-
ter 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-
682 Saraiya and Binkin

try; persons found to have active TB undergo a course of directly supervised treat-
ment prior to immigration (D. Chemtob, personal communication). However, im-
migrants coming from other areas continue to undergo postarrival, rather than pre-
arrival, screening.
Advantages of prearrival screening include prompt identification and treat-
ment 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. Disad-
vantages 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, assur-
ing 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 identifica-
tion of candidates for preventive therapy varies by country of origin of the immi-
grant, 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 consid-
ered to have radiographs compatible with active TB and 2.1% with inactive TB.
However, these percentages differ widely by country of origin; among newly ar-
rived 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 immi-
grants who arrived in Manitoba, 2.4% (523) were placed on surveillance, most be-
cause of inactive TB (80).
The number who are smear-positive and undergo partial or complete treat-
ment 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 ap-
ply 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 ac-
tive 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.
Tuberculosis Among Immigrants 683

Among those whose radiographs are compatible with suspect active TB upon fol-
low-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 lab-
oratory criteria had lower rates of disease than those that relied more heavily on
the accepted clinical criteria (82). For those with radiographs compatible with in-
active TB, the percentage diagnosed as having TB ranged from 0.4% to 3.8%. Re-
gional data from Canada show that 3% of persons under surveillance were diag-
nosed with active TB in the first year and an additional 2% in the 35 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 posi-
tive 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 el-
igible for treatment of latent TB infection (see Chap. 18) (72).

Postarrival Screening
Methods
In European countries that systematically screen foreign-born persons, the screen-
ing 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 re-
cent 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 so-
cial 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 im-
migrant. 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 radio-
graphs 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 liv-
ing 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
684 Saraiya and Binkin

those used in the overseas screening. The U.S.-based screening is somewhat dif-
ferent 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 infec-
tion. 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 ab-
normal radiographs and persons with 10 mm induration on TST are to be re-
ferred for further evaluation for treatment or for preventive therapy by local health
departments (85). Both Canadas and Australias 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 treat-
ment. 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 sys-
tem 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 asy-
lum 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 ra-
diographs. 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 chemopro-
phylaxis (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 685

in this group may have resulted from the fact that most were from a moderate-
prevalence 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 stu-
dents who are not routinely screened, may be illegal immigrants, or may have en-
tered 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 identi-
fied 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 dis-
ease unless they receive treatment for latent infection. Indeed, in the United States,
Australia, and the Netherlands (1416), the majority of foreign-born TB cases oc-
cur in persons who have been in the country 5 years or more at the time of diag-
nosis. The number of infected persons is considerable; in the United States, for ex-
ample, 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
160,000240,000 (23%) will develop disease some time after immigration un-
less they complete a regimen of preventive treatment of latent infection.
The screening of foreign-born persons for disease and infection and the pro-
vision of treatment for latent infection in low-prevalence countries with large for-
eign-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 foreign-
born 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 resi-
dence, all of which appear to influence risk of disease, but also accessibility for
686 Saraiya and Binkin

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 com-
munity 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, ho-
tel staff, poultry industry workers). In conducting such screening, care must be
taken to avoid stigmatizing those that are foreign-born. For this reason, compre-
hensive strategies that do not specifically target foreign-born persons (such as
screening by occupational category) may be preferable in some countries. In ad-
dition, 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 Foreign-

Born 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 foreign-
born persons be placed on an initial four-drug regimen pending results of suscep-
tibility testing (89,90). Isoniazid resistance is high in many high-prevalence coun-
tries, 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 in-
dividual 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 sen-
sitivities 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 in-
fection 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 treat-
ment of disease and latent infection.
As low-prevalence countries approach the elimination phase for tuberculo-
sis, 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
Tuberculosis Among Immigrants 687

that make generalizations difficult. Because the characteristics, outcomes, and ac-
cess 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 elimina-
tion is to be achieved in the industrialized or low-prevalence nations.

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26
Coalition Building for Tuberculosis Control
The Philippine Experience

CAMILO C. ROA, JR. RODRIGO L. C. ROMULO

University of the Philippines University of Santo Tomas

College of Medicine Manila, Philippines
Manila, Philippines

I. Coordinating Tuberculosis-Control Efforts: The Need

for Coalitions

The control of tuberculosis (TB) remains a formidable task, particularly in devel-

oping countries with limited resources. Independent TB-control efforts may be
taking place at various levelsnational 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 or-
der to develop effective TB-control programs. Ironically, TB is generally more
prevalent in countries where such resources are scarce and there are other com-
peting 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 imple-

693
694 Roa and Romulo

mented, TB control will be difficult to attain. One major effort, therefore, in TB

control is lobbying within a nations governmental structure for resources to de-
velop 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, popu-
lar, and highly influential private for-profit medical practitioners exist. Strength-
ening 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 partici-
pate in the national program.
The WHOs 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-resis-
tant 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 epi-
demic on the horizon warns us that we cannot merely wait for these changes. In-
novative 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 gov-
ernment 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 or-
ganizing 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. Med-
ical school and medical specialty societies conduct management update work-
TB Control in the Philippines 695

shops and seminars for private physicians and paramedical personnel. The TB-re-
lated activities of pharmaceutical companies would naturally be related to pro-
moting their own antituberculosis products, although many may also provide gen-
uine physician education.
The importance of private for-profit physicians in countries like the Philip-
pines must be emphasized. Several surveys in the Philippines (6) have consis-
tently 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 physi-
cians may be because they are perceived to be better trained, more accommodat-
ing, and have more flexible office hours. In addition, perhaps because of the pri-
vacy, visiting a private physicians 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 reg-
istries 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 quali-
fying 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 ther-
apy) is available in the private sector.
On the other hand, the government TB-control efforts have long been orga-
nized 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 defi-
ciencies, 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,
696 Roa and Romulo

they may become ignorant of or disinterested in each others activities. Counter-

productive competition and duplication of efforts may result in wasting of re-
sources. 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 plan-
ners attempted to recruit individual private physicians to treat TB patients follow-
ing NTP policies. The arrangement allowed the private physicians to continue see-
ing 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 supportan 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 con-
trol 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 ones 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,
TB Control in the Philippines 697

paramedical specialties, pharmaceutical companies, press and other media orga-

nizations, NGOs, and all other TB interest groups. It would not compete with ex-
isting 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 coalitions goals, organi-
zational structure, manner of equitable representation, and similar matters had to
be drafted. Creating the coalitions constitution would be a delicate process re-
quiring diplomacy by its proponents. Care had to be taken not to offend or inad-
vertently 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 or-
ganizations 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 stake-
holders 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 immedi-
ately to support the flurry of activity and enthusiasm of the convenor group, which
698 Roa and Romulo

consisted mostly of busy private physicians. The pharmaceutical industry con-

tributed most of the crucial initial support. The possible scenario that good TB con-
trol 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 postur-
ing 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 envi-
sioned 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 groups 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 busi-
ness 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 pharma-
ceutical 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 incur-
able, 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 morn-
ing 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 organizations commitment to join the coalition. After a short, mov-
ing speech, the Undersecretary declared the birth of PHILCAT. After months of
hard work and sensitive diplomacy, the principal stakeholders in Philippine TB con-
trol 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 in-
terim officers followed. PHILCAT had been legitimately established and govern-
ment 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
TB Control in the Philippines 699

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 ma-
jor meetings, and 4) have member groups co-sponsor the major PHILCAT activ-
ities 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 med-
ical specialists, representatives of medical schools, and nongovernment organiza-
tions. Politicians and public officials from the national and municipal levels par-
ticipated 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 Philip-
pines. 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 presi-
dent, Manuel L. Quezon, who died of TB. For the first time in the countrys his-
tory, over a thousand people indignant about TB marched as a united group. Al-
though 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 coalitions
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 mo-
tivated, the work may not always be perceived as pleasurable, considering the sac-
rifices 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 vol-
unteer 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 af-
fect oneself and ones family? Was it prestige or the feeling of importance? Was
it a genuine desire to contribute to community and national improvement or com-
passion towards ones fellow man? Whatever the reason, those voluntarily con-
tinuing 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
700 Roa and Romulo

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 require-
ment, and targeted outcome. This action plan was to serve as the yardstick by
which accomplishments were to be gauged. Unfortunately, preparations for that
years main coalition activities (World TB Day, annual convention) appeared to
have distracted PHILCAT from the complete execution of the action plan. Al-
though 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 Philip-
pines, as stated above, persons with symptoms suggestive of TB who seek medi-
cal 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 exist-
ing NTP with a movement to organize the private for-profit providers into a par-
allel NTP, as well as with efforts to remove over-the-counter availability of anti-
TB 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 so-
ciological studies investigating the knowledge, attitudes, and beliefs of both the
parties selling the medications and the individuals purchasing the drugs. Correc-
tive measures need not await the result of such studies. Legislation prohibiting the
sale of antimicrobial medications without physician prescription already exists in
TB Control in the Philippines 701

the Philippines. Enforcement of this law has been poor. The new TB-control strat-
egy must include methods of promoting improved enforcement of this law. Exist-
ing 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 ad-
vocates 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 4-
year medical course who complete an additional year of postgraduate internship
are eligible for licensure if they pass the medical board examinations. Once li-
censed, many begin to establish their private for-profit practices as general prac-
titioners. Others pursue specialty or subspecialty training before starting their pri-
vate practices. Other new physicians become salaried government physicians.
Those who enter private practice are free to prescribe any medication avail-
able in the market and are under no supervision. The latter have been noted to have
no standard criteria for diagnosing tuberculosis. Furthermore, private practition-
ers 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 ob-
tain 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.
702 Roa and Romulo

X. National Consensus on Tuberculosis

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 Tri-
Chest 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 Na-
tional 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 inten-
sive 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 rec-
ommendations. The consensus was not widely disseminated, so many private
physicians remained unaware of its recommendations. This First National Con-
sensus on Tuberculosis did not succeed in unifying Filipino physicians in the con-
trol of TB, but it was an important first step. Currently, two of the member orga-
nizations of the Philippine Coalition Against Tuberculosis (PHILCAT) are
leading the revision of the National Consensus (the Philippine Society for Micro-
biology 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 doc-
ument 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 coalitions 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 dis-
semination like its predecessor. The networks of many of the coalitions members
(particularly the Department of Health, medical specialty societies, the Philippine
Tuberculosis Society, and pharmaceutical companies) will be the conduits for cir-
culating 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-
TB Control in the Philippines 703

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 al-
ready 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 enthu-
siasm necessary for the coalitions 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 coalitions
traditional activities may have distracted PHILCATs attention from carrying
out its new action plan. A lesson that future coalitions can learn from this experi-
ence is to obtain expert assistance on organizational development and fund rais-
ing right from the outset. The coalitions mission, vision, goals, and action plan
should be established early, and subsequent efforts should be directed at execut-
ing the action plan. This action plan should include clear plans on revenue gener-
ation and seek the advice of fund-raising professionals so that the coalitions con-
centration 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 organi-
zational development and fund raising should be sought early after forming the
coalition to clearly define the groups direction, plan of action, and strategy for
revenue generation. Once these are set, the coalition can focus on its work of en-
couraging and coordinating its members in the fight against tuberculosis.

References

1. World Bank. World Development Report 1993: Investing in Health. New York: Ox-
ford University Press, 1993:1329.
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; 1:5963.
704 Roa and Romulo

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:
13011305.
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 Tu-
berc Lung Dis 1999; 3(6):471477.
27
Tuberculosis Education

EILEEN C. NAPOLITANO ELIZABETH J. STOLLER*

New Jersey Medical School National Francis J. Curry National Tuberculosis Center
Tuberculosis Center San Francisco, California
and International Center for Public
Health
UMDNJNew Jersey Medical School
Newark, New Jersey

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 re-
sources, patients lack of adherence with long treatment regimens, immigration
from TB-endemic countries, and physician error (1). Strategies have been devel-
oped 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 ef-
forts to assist in the prevention and control of tuberculosis have been intensified.
This chapter focuses on why continuous availability of resources for provider ed-
ucation is critical to the elimination of tuberculosis and outlines current educa-
tional 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.

705
706 Napolitano and Stoller

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 ef-
fective 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 de-
partment 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 en-
countering 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 Tubercu-
losis Training Initiative (3). The purpose of the Initiative was to ensure that ade-
quate, 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 engag-
ing in treatment and prevention activities. The strategies for, and challenges in,
providing education about tuberculosis to patients have been described in the con-
text of promoting patient adherence (6,7). An array of factors, including knowl-
edge deficits, affect patient adherence to and community attitudes towards tuber-
culosis 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 educa-
tion 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 meth-
ods for developing and delivering training, and (5) future directions for training
efforts.
Tuberculosis Education 707

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 pre-
vention, diagnosis, and treatment. Failure to perform screening where indicated
and to initiate treatment of latent TB infection for persons infected with Mycobac-
terium tuberculosis has resulted in numerous preventable cases of tuberculosis in
children and adults. Mehta et al. reported on an 8-year prospective study of pedi-
atric 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 com-
plete previous treatment for disease (7%) (10). A history of BCG vaccination de-
terred 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 pre-
sented 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 popula-
tions, 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
708 Napolitano and Stoller

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 ac-
counted 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 col-
leagues (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 hospitalbased 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 Organi-
zation (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 col-
leagues (22) found that 105 private practitioners reported using 79 different
treatment regimens, few of which were consistent with the NTP recommenda-
tions. Hong et al. (23) surveyed a random sample of Korean providers: more
than 50% did not consider sputum examination essential in case finding and di-
agnosis.
Despite clear evidence of the efficacy of treatment of latent TB infection, only
43% of the tuberculin skin testpositive 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 con-
trol 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 tubercu-
losis 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-
Tuberculosis Education 709

ommendations, Sumartojo and colleagues found that 60% of respondents de-

scribed appropriate regimens for a hypothetical case, 29% selected excessive reg-
imens, 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 physi-
cians 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 conta-
gion response (31).

Institutional Guidelines
Infection control guidelines have been used as tools to educate staff working in in-
stitutional 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 ap-
propriate screening on potentially infectious patients (33). Charge nurses in a
Texas health-care system had an average score of 48% on a knowledge test de-
signed 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 mani-
festation of the inadequate administrative and facility controls. In this instance, the
survey was conducted to collect baseline data to plan a series of educational in-
terventions; 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
710 Napolitano and Stoller

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 ed-
ucation is needed to dispel myths associated with the stigma and to contradict ba-
sic misconceptions such as the belief that patients are infectious while on treat-
ment (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 in-
ducement to participate in treatment. Community-based organizations have re-
sources 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 pub-
lic health programs by offering directly observed therapy (DOT). Many organi-
zations can also provide other community and organizational referrals for pa-
tients (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 ap-
proaches 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 pa-
tients and, where appropriate, the community at risk, as well as how to address
these issues.
Tuberculosis Education 711

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 CDCs Core Curricu-
lum on Tuberculosis serves as a standard clinicians practice guide for manage-
ment of patients with tuberculosis (37).

B. CDC-Funded Training Initiatives

The CDCs Public Health Practice Program Office supports the regional sites of the
National Laboratory Training Network, which provide training for laboratory per-
sonnel on the identification, handling, and reporting of M. tuberculosis. The CDC Di-
vision 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, epidemiol-
ogists, and allied health professionals. The three centers are located in high-morbid-
ity areas: the Francis J. Curry National Tuberculosis Center in San Francisco, Cali-
fornia; 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, in-
cluding 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, cat-
alogues 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 In-
stitute 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,
712 Napolitano and Stoller

management, and control to medical students, house staff, and practicing physi-
cians and nurses. The award provides each recipient with 5 years of funding to de-
velop curricula for their local medical and/or osteopathic school. Important com-
ponents 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, cul-
tural, 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 recip-
ients of CDC funds for tuberculosis control offer a variety of training programs for
providers in their respective areas. The American Thoracic Society conducts con-
tinuing 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 Amer-
ican Lung Association provides continuing education opportunities through its
state and local affiliates. National, regional, and state tuberculosis controller or-
ganizations offer continuing education opportunities through their regular meet-
ings (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 Tuberculo-
sis 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 Associ-
ation 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 adminis-
trative 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 correc-
tional medical facilities have included tuberculosis education in response to out-
breaks 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
Tuberculosis Education 713

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, compre-
hensive training courses in high-incidence countries for managers and intermediate-
level 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-Tu-
berculosis 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 con-
trol 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 Healths Fogarty International Center, the
World Bank, the Pan American Health Organization, and the U.S. Agency for In-
ternational 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 tuber-
culosis 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 tele-
phone 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-
714 Napolitano and Stoller

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 popula-
tions are:
1. Providers in the public health public sector*
2. Private sector and managed care providers
3. Providers in correctional facilities
4. 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 plan-

ning model: problem analysis/needs assessment, goals and objectives, implemen-
tation, 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, engi-
neers, disease investigators, laboratory workers, industrial hygienists, social workers, ad-
ministrators, health educators, TB case registry staff, clerical staff, and volunteers, includ-
ing staff of community-based organizations.
Private sector providers include medical and nursing school students, private sector
physicians, nurse practitioners, physician assistants, nurses, engineers, industrial hygien-
ists, respiratory therapists, and laboratory workers.
Tuberculosis Education 715

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 de-
termination of how the changed knowledge and/or skills can (or will) be sup-
ported by the organization that the individuals come from. Often, in addition to ad-
dressing 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 pa-
tients 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, aug-
mented by interviews with representatives of the target population, to help deter-
mine:

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 partici-
pants.

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 ed-
ucational objectives are developed to address the previously determined needs.
Objectives are written to articulate what the participants will gain from each ses-
sion 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
716 Napolitano and Stoller

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. Localand individual
needs and resources dictate the type of training that is appropriate in any given sit-
uation. 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 train-
ing 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 ap-
proach to both information and skill acquisition, as do some of the more
sophisticated offerings of computer-based instruction, such as CD-
ROM and Internet offerings.
4. Distance learning technologies, such as satellite teleconferences, video-
conferences, and audioconferences. These formats bring regional or na-
tional expertise to providers at the local level in various geographic lo-
cales.

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 datathe effect of the training effort as it is happening
Impact datathe immediate results (changes in knowledge, attitudes, and
skills)
Outcome datalong-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-
Tuberculosis Education 717

tributable to the training intervention, and overall changes in program in-

dicators (e.g., completion rates)
Evaluation findings are used for planning future courses and program ef-
forts 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 tu-
berculosis incidence, to the extent that the level of funding will likely decrease
more or less in proportion with a decrease in tuberculosis morbidity. The chal-
lenge 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 re-

sources. 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, computer-
based) 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 in-
formation 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
718 Napolitano and Stoller

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 possi-
ble. 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 Tubercu-
losis Center utilizes a standardized patient approach (also known as simulated
patients) to training second-year medical students about interviewing tech-
niques. 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 de-
cision-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 organiza-
tions, and AIDS, emerging infections, and international health organizations in
order to maximize use of resources. Cross-training of generalist staff (e.g., com-
municable disease workers and community outreach workers) offers an oppor-
tunity 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 re-
garding 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 con-
sumers perspective and the training providers perspective, need to be measured.
Tuberculosis Education 719

These data can be compared against the known costs of managing patients, in-
cluding 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 pro-
gram 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-spe-
cific training should also be built into broader postgraduate continuing education
efforts for providers, such as pulmonary medicine, AIDS, infectious diseases, lab-
oratory 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 de-
velopment of enduring products, such as videotapes, computer-based instruction,
and train-the-trainer curricula. Some of the international programs described ear-
lier 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 nec-
essary. In many cases it isnt necessary to develop materials from scratch, and of-
ten faculty that provide training are available to assist with efforts in other loca-
tions. One major effort of the 1999 Strategic Plan for Tuberculosis Training and
Education was to collect and catalogue existing training and education resources
720 Napolitano and Stoller

throughout the world. The database includes a listing of organizations, their con-
tact 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 re-
sources for providers is clear. While continued emphasis on training and the de-
velopment of new methodologies is warranted, all new efforts should be consis-
tent 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.

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Tuberculosis Education 723

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 Tuberculo-
sis Center at Harlem Hospital, in conjunction with the Division of Tuberculosis
Elimination, Centers for Disease Control and Prevention, sponsored this collabo-
rative 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 es-
tablished priorities to more effectively target training resources. It provides guid-
ance 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 sum-
mit on tuberculosis training and education and the development of the plan docu-
ment.
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 pro-
vided overall guidance for the planning process and ensured that broad, overarch-
724 Napolitano and Stoller

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, sub-
stance abuse), 5) foreign-trained providers/foreign-born patients, and 6) interna-
tional TB training.
Workgroups were responsible for:
Developing background information on their topic as it relates to TB train-
ing 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: AprilJuly 1998
Workgroup documents due to Francis J. Curry National Tuberculosis Cen-
ter: July 31, 1998
Tuberculosis Education 725

Summary of workgroup documents sent to summit participants: September

21, 1998
Summit: October 2223, 1998
Plan document completed: December 1998

Appendix B Strategic Plan for Tuberculosis Training

and Education, October 2223, 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* (19992003)

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 epi-
demiological 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 elimi-
nated 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. Singapores im-
mediate 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 coun-
tries 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
728 Chee and Wang

southern China, the Indian subcontinent, the Malay peninsula, and Indonesia. Sin-
gapore remained under British rule until it achieved internal self-governing status
in 1959. In 1963, Singapore joined the Federation of Malaysia, but shortly there-
after, on August 9, 1965, it separated from Malaysia to become a fully indepen-
dent and sovereign nation.
Singapore today is a major business, financial, and trading center in the in-
ternational arena and a service gateway into the Asia Pacific region. It is also the
worlds busiest port in terms of shipping tonnage, the worlds top bunkering port,
and the third largest oil-refining center. These successes are due to its excellent in-
frastructure and strategic location at the crossroads of major shipping and aviation
routes, good banking and financial services, efficient telecommunications net-
work, 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 ev-
ery 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 lan-
guages are Malay, Chinese (Mandarin), Tamil, and English.
The standard of living is generally high, the per capita indigenous gross na-
tional 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 ev-
ery 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
Peoples Action Party, enjoying an overwhelming majority rule since the coun-
trys 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.
Political Will 729

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 dis-
eases and with the Ministry of Manpower in improving the industrial and occupa-
tional health of workers. The Medical Audit and Accreditation Unit (MAAU) li-
censes, 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 gov-
ernment/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 exis-
tence: Medisave, a compulsory savings scheme where funds are automatically de-
ducted 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 en-
dowment 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 indi-
vidual responsibility for ones 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
730 Chee and Wang

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 treat-
ment 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 an-
nually, despite available effective treatment with streptomycin, para-aminosali-
cylic 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, 6-
month, 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 institu-
tion 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 per-
sons 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 bacil-
lary 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
Political Will 731

Figure 1 Graph showing the annual incidence rate of TB cases in the resident popula-
tion 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 res-
ident 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.
732 Chee and Wang

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 re-
lapsed 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 ac-
cepted and practiced since its introduction in the mid-1950s. BCG coverage of in-
fants and newborns has been over 95% since 1987. There is also a BCG vaccina-
tion 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 full-
blown AIDS, and 241 had died from the disease. Males formed 91% of the cases,
with heterosexual transmission the main mode of transmission. Forty-three per-
cent 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 pre-
sentation 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 re-
newals 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 work-
ing 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.
Political Will 733

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 ma-
jority 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 treat-
ment (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 ma-
jor 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 com-
pleted 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 at-
tempts 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 ex-
istence 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 pro-
gram has thus far directed most of its attention to treatment of cases and placed lit-
tle emphasis on contact screening and treatment of latent TB infection. Thus, in-
fected contacts are probably underidentified and treatment of latent TB infection
underutilized. Contact screening is done at the TBCU for notified TB cases at-
tending 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 in-
fected 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.
734 Chee and Wang

G. Laboratory Support Services for TB

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. Na-
tional 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 nonra-
dioactive method, and differentiation and drug susceptibility tests on every posi-
tive 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 Singapores economic progress and improvements in living standards and

health care, its TB incidence has remained high (4956 per 100,000) over the last
10 years, being 510 times that of developed countries in the West. We believe
that our TB rates have not declined because there is still significant ongoing trans-
mission 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 deter-
mined 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 im-
proved. At the same time, it was clear that there were several factors in our coun-
trys 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 in-
frastructure and advanced health-care system. Second, the society is well orga-
nized and disciplined, without the problems of poverty, homelessness, or sub-
stance abuse. And, very importantly, we have yet to experience the full impact of
the HIV epidemic.
Political Will 735

With this in mind, the government decided to lend its support to the task of
eliminating TB in Singapore. The Singapore Tuberculosis Elimination Pro-
gramme (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 Singa-
pore with the following goals:
1. To detect and diagnose all infectious (sputum positive) cases in the
community
2. To cure all cases of TB
3. To detect and treat all infected TB contacts
4. To prevent the emergence of multidrug-resistant TB
5. 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 Min-
istry 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 na-
tional 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 Healthappointed TB Ex-
ecutive Committee chaired by the Deputy Director of Medical Services (Profes-
sional 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 programmes National TB advisor, Lee B. Reichman, Executive Direc-
tor 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 Elim-
ination, Centers for Disease Control and Prevention, Atlanta. The function of the
736 Chee and Wang

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 physi-
cians, 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 re-
structured hospitals, the outpatient polyclinics, the Central TB Laboratory, its De-
partments of Epidemiology and Disease Control, and Training and Health Educa-
tion. 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 mon-
itoring of imported TB.

C. Involvement of Nongovernmental Organizations

The Singapore Anti-Tuberculosis Association (SATA) celebrated its fiftieth an-
niversary 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. Cur-
rently, 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 ade-
quate funding
2. Sound treatment strategies: use of proven and accepted treatment regi-
mens by all medical practitioners, optimization of patient compliance
with supervised treatment in the form of DOT, and a tight system of de-
faulter tracing and treatment outcome monitoring
3. Effective detection of infectious TB cases
4. Systematic contact tracing and administration of treatment of latent TB
infection
Political Will 737

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 in-
fection 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 out-
come 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 medi-
cal practitioner for each case of TB at the time of diagnosis and returned to the De-
partment of Epidemiology and Disease Control, Ministry of Health) has been up-
dated (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, Min-
istry of Health by each treatment center. This not only serves as a means of mon-
itoring national TB treatment-completion rates, but also to heighten each treat-
ment centers 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 ac-
ceptance and the use of DOT.
738 Chee and Wang

For patients who are physically unable to attend the clinic for DOT, a rela-
tive or caregiver is to be made responsible for DOT at the patients home. This is
to be recorded daily in a DOT record form, which is given to the patient and care-
giver at every clinic visit.
The supportive role played by the health-care worker in ensuring that the pa-
tient 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 im-
portance of adherence and completion of treatment, and the various different med-
ications and their side effects. Every effort is made by the health care worker to
establish a rapport with the patient and to understand the patients needs and con-
cerns 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 ju-

risdiction 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.
Political Will 739

D. Laboratory and Radiological Support

The present high standard of laboratory and radiological support is being main-
tained with regular quality-assurance monitoring. Peripheral laboratories are sub-
jected 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 iden-
tify 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 facili-

ties 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 com-
pletion of treatment, and promoting the practice of DOT has also been published
and distributed.
Continuing medical education programs for both doctors and nurses per-
taining to TB are regularly held. The teaching of TB in the medical school cur-
riculum 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 preshort-
course chemotherapy era of the 1960s, has remained static since 1987. Although
740 Chee and Wang

the incidences of MDRTB and HIV are both currently low, we are geographically
situated in one of the worlds hot spots for MDRTB as well as HIV, with the po-
tential for a disastrous rise of both HIV and TB a very real concern. The U-
shaped 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 rela-
tively 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 Pro-
gram. The task is formidable, but the ultimate goal worthwhile. We have no alter-
native 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. Spe-
cial thanks to Dr. S. C. Emmanuel, Dr. Irving Boudville, and Dr. Lee Hong Huei.

References

1. Reichman LB. Tuberculosis eliminationwhats to stop us? Int J Tuberc Lung Dis
1997; 1:311.
2. Reichman LB. Defending the publics health against tuberculosis. JAMA 1997; 278:
865867.
3. Ministry of Information and the Arts. Singapore 1997A Review of 1996. Singapore:
Ministry of Information and the Arts, 1997.
4. SingaporeFacts 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; 143:697698.
6. Singapore: Department of Clinical Epidemiology, Communicable Disease Centre, Tan
Tock Seng Hospital and Ministry of Health. Communicable Disease Surveillance Re-
port 1997.
7. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991; 148:741
742.
Political Will 741

Appendix A The Singapore Tuberculosis Elimination Programme notification form.

742 Chee and Wang

Appendix A Continued
Political Will 743

Appendix A Continued
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 com-
pleted 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.

744
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 pos-
sible treatment for his patients. Likewise, the policy maker will incorporate spe-
cific measures of integrated social science research into any program he or she de-
signs 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 repre-
sent the opinions of the agencies with which they are associated.

745
746 Chemtob et al.

(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 notifi-
cations 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 so-
cio-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 cir-
cumstances 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 address-
ing 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 ac-
count 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.
Medical Anthropology 747

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 socio-
economic 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, psycho-
logical, and political issues could result in ineffective public health programs. The
following example from a multidisciplinary study demonstrates how an under-
standing of cultural factors (e.g., the beliefs and health practices of patients) is use-
ful 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 uri-
nating 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 con-
nection between jaundice and cirrhosis or hepatic carcinoma (10). With these pa-
tients, an attempt to justify systematic follow-up with liver function tests is prob-
lematic, 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 devis-
ing 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 sev-
eral anomalies in the personal religious status of Ethiopian Jews (13). This sym-
bolic conversion, referred to as conversion in doubt, included three elements:
748 Chemtob et al.

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 con-
tributed to their reluctance to undergo blood tests. Doctors and rabbis were also
viewed as part of the same authoritative system, and therefore the Ethiopian re-
jection of certain biomedical procedures was in part an expression of their resis-
tance to authoritative structures that they felt were oppressive. The above exam-
ple demonstrates the importance of social science research not only in identifying
cultural gaps between doctors and patients, but also in elucidating political and re-
ligious 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 de-
velopment 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, or-
ganization 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 per-
spective of immigrant patients with respect to the meaning of illness and the ef-
fect 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 co-
incide with what is actually needed by the target population. Thus, a health pro-
gram adapted to an immigrant population should take into account the socio-cul-
tural characteristics of this population (16). In this situation the tools of medical
anthropology, which are eminently suitable for the analysis of this type of prob-
lem, 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 regard-
ing 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 discrimina-
tion, and stigmatization that dissuade patients from seeking treatment?
Do patients views and understanding of TB coincide with those of the
health provider?
Medical Anthropology 749

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 pa-
tients perception of themselves, their families, and the community
structure?
What will be the impact of public health interventions on the target popula-
tion?
Some additional issues to consider when working with immigrant popula-
tions 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 popula-
tion 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 exten-
sive 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.
750 Chemtob et al.

Concomitantly, a parallel process of change is also called for in the integrating ap-
paratus. This usually occurs as a spontaneous pragmatic process in response to dif-
ficulties arising in the field, rather than as part of a concerted cooperative en-
deavor. 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 commu-
nity 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 indi-

vidual illness episodes within the broader social and historical context of the so-
ciety in question. The biological aspects of disease comprise only one dimension
of the illness experience. The term illness also refers to the psychological, so-
cial, 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 so-
cial environment molds the experience of the individual and is in itself trans-
formed 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 pro-
foundly 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 ap-
proach 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 health-
care process. By representation we mean the different interpretation that each
participant in the processthe patient, the health-care workers, and the system in
which they workmay attach to an issue (in our case TB). It brings not only a dif-
ferent 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 pre-
sented as entities constructed by a society forming its culture, which are detached
Medical Anthropology 751

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 rep-
resentation 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 so-
ciety or as an expression of the individual spirit could be enlightening and pro-
vides an historical, methodological, and theoretical framework for some of the ba-
sic tenets of anthropology (25).
While examining the history of anthropology, Aug identified two major
orientations: meaning-centered analyses and function-centered analyses. He ar-
gues that these two orientations (meaning and function) do not encompass the
whole of reality. He states that even if anthropology maintains an essential mean-
ing 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).
Cathbras discusses two subdisciplines of medical anthropology (26): so-
cio-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 so-
cial system. Ethnomedicine has sometimes had the tendency to distinguish be-
tween 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 sys-
tem, the illnesss 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 reli-
gious practices are thus closely intertwined in order to reject the aggressor or ex-
pel the evil from the victim (30). In naturalistic medical systems, the illnesss
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 vic-
tim; on the contrary, he or she is responsible for the illnesss 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 sci-
ence professionals was made at the Second European Conference on the Methods and Re-
sults of Social and Behavioral Research on AIDS, Paris, January 1998.
752 Chemtob et al.

have prevented it. In fact, treatment does not involve magic or religion. Accord-
ing to Foster (30), these two types of systems are often present in the same soci-
ety, although in varying proportions.
Cathbras (26) argues that the distinction between natural and supernatu-
ral 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
Cathbras, 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 con-
tinually 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).
Aug 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 so-
cial group (26,32). Moreover, this natural/supernatural dichotomization is over-
simplified, ignoring the rich and complex nature of social interactions and the fact
that peoples experience with disease is influenced by political, social, and eco-
nomic 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 sepa-
rating the medical, social, communal, spiritual, and psychological aspects of dis-
ease into discrete and fragmented units, patients weave all these various facets of
disease together in their response to representation of their illness. Many anthro-
pologists focus on these social dimensions of illness (32,34) and the ways in
which illness episodes both influence and are influenced by the surrounding envi-
ronment. According to Aug (34), both in African and western societies, the re-
lationship 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 fam-
ily, community, and larger social groups.
Aug also argues that ethnomedicine highlights an evolutionist perspective
in which western efficiency acquires supremacy (32). He claims that western sci-
ence at times imposes upon other cultures a dichotomy between empirical-ratio-
nal and symbolic domains, even when the cultures themselves do not differenti-
ate between a sphere accessible to knowledge and a sphere only accessible to
Medical Anthropology 753

faith (32,32). Aug 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 cul-
tures in an effort to correct misconceptions and alter health behavior can be prob-
lematic. 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 Augs critique of the natural/supernatural di-
chotomy (32), he argues that one of the problems with studying the health be-
liefs of other cultures (as is done in ethnomedicine) is that researchers often pre-
suppose the supremacy of western science and consequently reaffirm the power
differential between the researcher and those being studied. As is becoming in-
creasingly 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 sim-
ple 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 func-
tions. 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 prag-
matically 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 of-
ten looking for quick formulas on how to deal with culturally diverse groups,
whereas the anthropologist feels that such an approach reinforces cultural stereo-
types (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
Aug, 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, eco-
nomic, and cultural barriers to treatment. The tools of social science helped us un-
derstand 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,
754 Chemtob et al.

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 noncom-
pliance and the failure of health-care providers to take into account the perspec-
tive of patients. For example, in one study of tuberculosis control, the authors con-
clude: 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 understand-
ing of ones ethnic identity and related conception of illness (37). Noncompli-
ance is often attributed to the inauspicious knowledge, attitudes, beliefs, and be-
haviors 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 behav-
ior and ultimate treatment failure. Interventions should therefore focus on im-
proving compliance by correcting patients misconceptions and knowledge
gaps concerning tuberculosis and making treatment more culturally sensitive by
incorporating patients beliefs into the treatment process (3840).
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 pa-
tients views on tuberculosis and its treatment often differ from those of their
providers. It is important to understand these differences when devising health ed-
ucation 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-
Medical Anthropology 755

completion entirely on intrinsic aspects of patients, without reflecting upon draw-

backs 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 mistak-
enly 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 tuberculosis-
control 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, be-
cause a TB chemotherapy regimen may consume nearly half of the patients in-
come 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 asso-
ciated with TB treatment completion. The authors argue that anthropological stud-
ies into cultural understandings of illness beliefs, albeit interesting, direct atten-
tion 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 spu-
tum collection were frustrated by the government agencys 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.
756 Chemtob et al.

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 de-
spite cultural differences (43). In spite of her support for cultural studies of pa-
tient 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 view-
points is that patients and health-care workers often have different perspectives
concerning the essential barriers to treatment. While doctors often focus on pa-
tient-centered factors and attribute treatment failures to social and cultural char-
acteristics 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, as-
cribed 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 Indi-
ans 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 rela-
tionship with the treating paramedic was an important factor for treatment
adherence.
In addition to the factors mentioned above, some researchers argue that so-
cial 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 re-
turning home after long hospitalizations found themselves rejected by their fami-
lies. 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 patients family members led to premature termination of
treatment, whereas support by the immediate family and the health care provider
positively affected treatment (49).
Medical Anthropology 757

The perception and interpretation of TB symptoms as triggers for seeking

out medical care vary among population groups. For example, in one study con-
ducted 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 under-
standings of TB for individuals from a particular cultural and social group (45,52).
Physicians may therefore need to adopt different strategies for individuals of dif-
ferent 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 reg-
imens, Sumartojo (43) stresses the importance of comprehensive services in a TB-
control 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 suc-
cesses are often attributed to factors such as specialized medical teams, careful pa-
tient 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 dis-
cussed above in our investigation of barriers to treatment among Ethiopian immi-
grants 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 45 per 100,000 by 1985. Subsequently the TB infras-
tructure was dismantled (55). When approximately 7400 new Ethiopian immi-
grants 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 im-
migrants coming before, in between, and after these two waves, the total popula-
758 Chemtob et al.

tion originating from Ethiopia is 65,000out of a total Israeli population of 5.9

million at the end of 1996.) The integration process of these last waves of immi-
gration coincided with the entry of a total of 737,000 new immigrants
(19901996), mostly from the former Soviet Union (56). The increase of the pop-
ulation of Israel by some 15% within a period of 7 years presented a formidable
challenge to the countrys absorption capacity in general and to TB-control struc-
tures in particular. In addition to the expected difficulties associated with integra-
tion into a new country, there were socio-political conflicts between the newcom-
ers and the institutions responsible for their absorption and health management,
which undermined their confidence in the treatment provided by health-care per-
sonnel (see below).
New Ethiopian immigrants were screened upon their arrival with chest x-
rays and tuberculin skin tests in special absorption centers. Active TB was treated
with short-course therapy, and medication was not supervised. A formal prospec-
tive 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 19901992, there was
no documentation of treatment completion (57,58). A highly significant associa-
tion 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 treat-
ment 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 en-
demic 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, address-
ing 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 diffi-
cult 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 pa-
tients 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 psy-
chological, social, spiritual, and religious connotations of TB for Ethiopian Is-
Medical Anthropology 759

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 incor-
porates 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 polit-
ical 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 cul-
tural preference for injections over pills. The problem with ingesting large quan-
tities 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 bron-
chitis to a deadly disease culminating in the vomiting of blood. In Ethiopian med-
ical circles, the term for tuberculosis is yesamba nekeresa, which translates di-
rectly 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 doc-
tors and patients and may have contributed to treatment noncompliance (53).
Although cultural factors created important conflicts in the clinical en-
counter, other problems seemed to have an even more significant impact on treat-
ment 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 en-
sure 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 disserta-
tion of Sheri Weiser (53).
760 Chemtob et al.

to treatment that has proven less effective in many studies (57,6264) 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 doctors 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. Al-
though most physicians attempted to explain TB treatment to their patients, they
were ill equipped to do so because of linguistic, cultural, and other communica-
tion 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 fol-
low 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, pa-
ternalistic 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 Rab-
binate concerning the validity of their Jewish origins, and Ethiopians anger at
their discovery that for years their blood donations had been discarded, have im-
portant 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 fac-
tors did not play a large role in treatment noncompletion. This is because the Is-
raeli Ministry of Health attempts to eradicate many of the direct economic barri-
ers 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 day-
to-day problems.
Medical Anthropology 761

Stigma within the Ethiopian community also did not seem to influence treat-
ment completion significantly. On the other hand, stigma in the larger Israeli pop-
ulation, manifested in the widespread perception that Ethiopian Israelis are prim-
itive, 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 pa-
tients 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 Additional features specific to

patient populations Ethiopian immigrants

Inadequate TB treatment facilities Overall negative attitude towards

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.
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
762 Chemtob et al.

clear that although some aspects of the Ethiopian Israeli situation were unique,
many of the most important barriers to treatment for Ethiopian patients are prob-
ably 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 summa-
rize 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 be-
liefs, 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 prob-
lems in TB services (57). TB treatment was self-administered, often in nonspe-
cialized 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 fol-
low-up of patients. Consequently, drug taking was erratic, increasing the possi-
bility 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 com-
pounded these infrastructure problems. It led to dispersion rather than to much-
needed concentration of efforts needed to contain the added TB caseloads (67).
In addressing these organizational problems, we have restructured the sys-
tem of TB control in Israel (65,67,68). First, we are providing DOT for all pa-
tients. DOT is being monitored through District Health Offices (DHOs) by the Na-
tional 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-
Medical Anthropology 763

istering DOT are covered within existing budgets. There is no need for additional
manpower since the burden is spread throughout the existing health-care infras-
tructure and usually no more than one or two patients are cared for at any partic-
ular location. Patients receive DOT in an easily accessible clinic in their neigh-
borhood. Additional funding has been allocated to ensure patient accessibility to
health facilities (e.g., travel expenses are often reimbursed). When use of a pri-
mary 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 pro-
viding follow-up for patients in that locality. After the initial assessment, patients
are followed monthly or more frequently as their situation demands. This ap-
proach 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-resis-
tant strains (65,70). To ensure optimal inpatient treatment, all inpatients are hos-
pitalized 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 on-
going system of evaluation, and we will begin the first stage of evaluation at the
end of the first year of the programs implementation. Since two thirds of TB pa-
tients 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 fol-
lows (53):

1. The provision of comprehensive health education that is both cultur-

ally appropriate and empowering to patients. In improving patient ed-
ucation for Ethiopian immigrants, the Ministry of Health has instituted
a communitywide education program run by Ethiopian health work-
ers. Seven Ethiopian health educators have been trained under the di-
rect supervision of a nurse/health educator also of Ethiopian origin.
764 Chemtob et al.

These educators are active within the community, involved in the fol-
low-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 explana-
tions. 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 un-
willing to learn about science. We emphasize the need to avoid pater-
nalistic attitudes and exchanges.
2. Both Ethiopian health workers and other Israeli health-care profes-
sionals 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 un-
folds. Consequently, education about the Ethiopian socio-political sit-
uation and culture has been provided to treating staff.
3. Whenever possible, we plan to enlist the support of respected com-
munity 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 pe-
riodic 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
Medical Anthropology 765

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.
5. 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 ex-
pectations, and disease constructs of Ethiopian patients (and other pa-
tients whose values differ from those of their providers).
6. 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 deter-
mine the current health status of patients and greatly contribute to the
patients confidence in the treatment.
7. 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 ter-
minology.
8. 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.
9. 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.
10. 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 de-
lineate 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 sci-
ence can help guide policy makers in weighing the relative importance of each of
766 Chemtob et al.

these variables and in ensuring that public health interventions do not ignore cru-
cial 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. Ide-
ally a TB-control program must take into consideration the different aspects men-
tioned above and must strive to find unique solutions for the local population in
question. When an institutional commitment to combat TB exists and the organi-
zational 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 prin-
ciples and theoretical orientation of the social sciences.

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30
The Role of Nongovernmental Organizations

ANNIK ROUILLON and

NILS ERIC BILLO FRANCES R. OGASAWARA*

International Union Against Tuberculosis American Lung Association

and Lung Disease New York, New York
Paris, France

I. Introduction

In the fight against tuberculosis, a partnership exists among three important sec-
tors: 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 tuberculo-
sis 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, as-
sess, and orient the program. Although this is generally accepted and would seem
fully logical today, it is remarkable that the first organized effort against tubercu-
losis (which in many instances led the way to other public health measures) orig-
inated from the voluntary combination of the energy of physicians and the public
in an attempt to relieve suffering, prevent disease, and disseminate information.

*Retired.
771
772 Rouillon et al.

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 tuber-
culosis. In most countries, even though governments have taken the responsibil-
ity for providing health services in relevant programs, the success of any govern-
mental program continues to depend on the competence and attitudes of
professionals who are delivering the programs and on the active and understand-
ing 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 in-
cludes 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. Vol-
unteers are persons from any walk of life who are ready to devote, freely and with-
out 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 fol-
lowed if they will have to apply specific means.
Members of an organization are the first level of voluntarism: they are per-
sons 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 sup-
port 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 lo-
cal, 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, womens organizations, or economic and social
development groups. They may be organized for a particular purpose, such as in
the field of health/diseasespecific organizations or disability-specific organiza-
tions. They may be groups of patients, families, and friends suffering from the
The Role of Nongovernmental Organizations 773

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 cor-
responding 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 pro-
viding 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 govern-
ment sources. Fund raising, however, is a permanent problem for most associa-
tions.
Because they are independent, NGOs can function in any political climate
and usually maintain a neutral position on political matters. They are free to pur-
sue the policies and programs that the governing body, whether it be a board of di-
rectors, 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 mem-
bership 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 repre-
senting 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).
774 Rouillon et al.

Although they are very diverse in their aims, structure, operation, and size,
NGOs are sometimes considered as falling into one of the three following cate-
gories (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 ex-
isted in the Roman empire and in ancient eastern, as well as in pre-Columbian, cul-
tures. In Europe during the late Middle Ages, various guilds of merchants or arti-
sans were formed to protect their interests, rule prices, wages and procedures, and
introduce codes of ethics. The Industrial Revolution was accompanied by the de-
cline 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 finan-
cial support for the organizations comes from membership dues, voluntary con-
tributions, and grants. In some countries, associations receive grants from gov-
ernments 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 organiza-
tion 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-
The Role of Nongovernmental Organizations 775

sociation, which, in turn, has constituent and affiliate associations throughout that
country. Having recently (January 2000) established itself as a separate indepen-
dent 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 As-
sociation 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 pub-
lic education program was launched to inform people of the dangers of tuberculo-
sis and the steps required to fight the disease. Pressure was put on lawmakers to
build sanatoriums to provide rest, fresh air, and good foodthe 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. Lo-
cal 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 cam-
paign became the primary source of funds to conduct these activities. The first na-
tionwide Christmas Seal campaign was conducted in 1908. By 1920 the national
association had shortened its name to National Tuberculosis Association (NTA).
776 Rouillon et al.

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, pro-
vided 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 depart-
ments) and with private and professional societies.
The medical section of the NTA, the American Trudeau Society, was orig-
inally founded as the American Sanatorium Association in 1905. Its members in-
cluded the physicians who were leaders in the field of tuberculosis. The organiza-
tion 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 associa-
tion promoted its widespread use and changes in services that were needed for out-
patient 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, es-
pecially smoking-related diseases, were increasing. The NTA expanded its pro-
gram to include all respiratory diseases and changed its name to National Tuber-
culosis and Respiratory Disease Association in 1968 and the American Lung
Association in 1973. The Trudeau Society became the American Thoracic Soci-
ety (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 agen-
cies 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 multi-
cultural communities and nonEnglish-speaking persons.
As the tuberculosis problem declined in magnitude, programs were targeted
to specific high-incidence groups of high-risk individuals, such as unemployed al-
coholic 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
The Role of Nongovernmental Organizations 777

treatment and to change attitudes about what constitutes modern tuberculosis care.
These statements have usually been issued jointly with the U.S. Public Health Ser-
vice. 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 pro-
vided a source of infected persons at risk of progressing to active TB and becom-
ing 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 deempha-
sis, 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 em-
phasis 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 gov-
ernmental and nongovernmental organizations involved and concerned about tu-
berculosis 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 sup-
port 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; conduct-
ing 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 pro-
vide expert testimony before the U.S. Congress on lung health issues, such as in-
door 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 or-
ganizations. Sometimes ALA and ATS bring together a coalition or invite partic-
ipation 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
778 Rouillon et al.

scientists. The professional education program includes the publication of two

journals: the American Journal of Respiratory and Clinical Care Medicine (for-
merly American Review of Respiratory Disease) and the American Journal of Res-
piratory Cell and Molecular Biology. The ALA-ATS international conference is
an annual meeting during which papers on original research, symposia, major lec-
tures, and numerous other educational sessions are presented. Conferences and
workshops on specialized subjects are conducted during the year to develop poli-
cies, discuss issues, or increase the medical communitys knowledge about a par-
ticular 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 or-
ganization 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 execu-
tive officer, is made up of competent trained professionals in all aspects of asso-
ciation 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 direc-
tors. 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 to-
tal mergers of programs and then associations.
Public financial support comes from many sources: the traditional Christ-
mas 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 cho-
sen according to the resources available. Through expansion of the mission and
changes in objectives, ALA, nationally, has continued its role of leading and en-
listing 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-
The Role of Nongovernmental Organizations 779

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 countrys na-
tional NGO dealing with tuberculosis. In 1969, the emphasis was changed to in-
clude 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 Cana-
dian Thoracic Society (CTS). The major role of the CLA in its relation to the In-
ternational Union Against Tuberculosis and Lung Disease has been to spearhead
international activities through the IUATLDs 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 develop-
ing 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, in-
cluding Sri Lanka, Pakistan, Malaysia and Nepal, Indonesia, India, Thailand,
Bangladesh, and the Republic of Korea. In more recent years the CLA has sup-
ported 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 associa-
tions 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 organi-
zations, including the IUATLD.

B. Latin America

In Latin America, especially in areas where there is not yet full medicosocial pro-
tection of the population, tuberculosis leagues, as they are most often called,
have long been striving to assist poor patients and their families by running out-
patient clinics and triggering government interest in the establishment of modern
national programs. An extreme case is the Comisin Honoraria para Tuberculosis
of Uruguay.
780 Rouillon et al.

The Comisin has full technical, financial, and operational responsibility

for all antituberculosis activities in the country. Through carefully applied treat-
ment, it is able to cure most of the existing tuberculosis patients in the country.
The Comisin also carries on research, mostly epidemiological. It is also respon-
sible for all vaccinations (against any disease) with vaccines provided by the gov-
ernment. Funds necessary for these activities come from a tax on alcoholic bever-
ages 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 dis-
ease associations showed that, by the mid-1980s, tuberculosis had remained the
sole concern of only 2 associations; 18 others kept tuberculosis as their main pri-
ority; 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 publica-
tions. Membership consists mainly of physicians and other medical or paramedi-
cal 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 non-
tuberculous mycobacterial diseases.
A comparison of associations in two European countries, whose TB surveil-
lance 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 tu-
berculosis control in the Netherlands and abroad. It is KNCVs mission to con-
tribute to the global elimination of tuberculosis through the development and en-
hancement of effective and efficient tuberculosis control activities.
The Role of Nongovernmental Organizations 781

In the Netherlands KNCVs main activities are surveillance, technical sup-

port, research, and development of policy guidelines. The KNCV acts as the offi-
cial 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 sec-
tor reform in the late 1980s. The latter resulted in a decentralization of control ser-
vices 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 controldirectly 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 pos-
sible 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 pa-
tients 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 pro-
grams 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 in-
fection; 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 activ-
ities include analysis of the current situation, project identification, technical as-
sistance, and project evaluation.
KNCV fosters policy debate and development through its membership of
the Coordination Advisory and Review Group (CARG) and the Technical Re-
search and Advisory Sub-Committee (TRAC) of the Global Tuberculosis Pro-
gram 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 meet-
ing. This meeting also approves of the work plan and financial budget.
782 Rouillon et al.

Norway
Norway, another European country that will also see the elimination of tubercu-
losis 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 deal-
ing 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 tu-
berculosis 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 coun-
tries of that part of the world had a seminar on tuberculosis. The Norwegian Na-
tional Health Association, together with another national voluntary agency, The
Norwegian Heart and Lung Association, and the Norwegian government techni-
cally 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 sana-
toriums, 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 as-
sociation. 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 Re-
gional Meeting.
3. The Egyptian association has also been supporting international activi-
ties of the IUATLD: two regional meetings, a regional seminar, and the
Conference on Tuberculosis in Animals in Africa and the Middle East
The Role of Nongovernmental Organizations 783

in 1992, promoted by the Tuberculosis in Animals Scientific Commit-

tee 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 es-
pecially difficult, although especially needed.
In Ivory Coast (13), the association has been instrumental in promoting the
governments 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 twice-
weekly 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 Pri-
mary Health Care Conference of 1978.
In Algeria, the Comit Algrien 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 par-
ticularly 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.
784 Rouillon et al.

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 ev-
ery 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-Tu-
berculosis Association (JATA) (17). Its major activities are as follows:
1. Health education and public relations activities on tuberculosis and
other related diseases, including providing information through publi-
cations such as official bulletins, books, and videos, conducting public
assemblies and Tuberculosis Prevention Week, commending local gov-
ernments with excellent achievements in tuberculosis control, and other
promotional activities (e.g., cooperating with antituberculosis womens
societies).
2. Research and surveillance activities at the Research Institute of Tuber-
culosis (RIT), which conducts comprehensive research on tuberculosis
including basic, clinical, and epidemiological studies and operates the
national tuberculosis surveillance system.
3. Medical treatment and mass screening examination services in tuber-
culosis and other diseases provided by two JATA-affiliated hospitals,
two clinics, and 47 branches located in each district nationwide.
4. Training activities through operating local tuberculosis training courses
in RIT for medical doctors, x-ray and laboratory technicians, public
health nurses, and local government.
5. 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 StatesJapan Cooperative Medical Science Program and
other research programs.
The Role of Nongovernmental Organizations 785

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 coun-
tries such as Cambodia, Mongolia, Vietnam for personnel engaged
in tuberculosis control; operating pilot projects in tuberculosis con-
trol both in Nepal and Indonesia in cooperation with the local anti-
tuberculosis 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 hon-
ored 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 tu-
berculosis patients. The New Delhi Tuberculosis Center, established in 1940, was
upgraded with the help of the government, WHO, and the United Nations Inter-
national Emergency Childrens Fund as a training and demonstration center. In
1948, the association formed its technical committee consisting of 15 senior tu-
berculosis 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 asso-
ciations and other voluntary agencies and the government.
The Indian Journal of Tuberculosis, a quarterly publication of the associa-
tion, is the only journal devoted exclusively to tuberculosis in the country. The as-
sociation 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-
786 Rouillon et al.

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. Twenty-
five state tuberculosis associations are affiliated with the central association; most
of them also have tuberculosis associations at the district level. They assist offi-
cial 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-year-
old 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 su-
pervisory 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 lab-
oratories, 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 sur-
veys, trials, assessment of results, and operational research are thus carried out
The Role of Nongovernmental Organizations 787

jointly. The production of freeze-dried bacille Calmette Gurin (BCG) vaccine is

also entrusted to the KIT. The training sessions for all categories of health work-
ers, provided by the KNTA up to 1981, were then transferred to the National In-
stitute 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 as-
sociations and of individual persons interested in the fight against these diseases
from all over the world. It is one of the oldest voluntary international organiza-
tions 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, sev-
eral sessions were devoted to this disease and the classic work of Villemin demon-
strating 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 rep-
resentatives 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 Associa-
tions, 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 ral-
lying of all those committed to an imposing idea. Over the years, certain countries have re-
placed this emblem with others that they felt corresponded more closely to their countries
traditions and culture. Some have thus chosen the double red crescent.
788 Rouillon et al.

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 represen-
tatives 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 tu-
berculosis and declared their belief in an organization that would impose obliga-
tions on its members and centralize all the experience of the disease. The words
that Leon Bernard, Secretary of the French Association, pronounced on that oc-
casion remain extraordinarily valid today: It is necessary for all countries wish-
ing 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 Unionas its members call itremained
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 ac-
tivities 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 pro-
gram. 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
The Role of Nongovernmental Organizations 789

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 at-
tract 50300 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 giv-
ing in their English, French, and Spanish versions the papers presented at the var-
ious Unions conferences as well as other original articles. For a short time, Tu-
bercle and Lung Disease was and now The International Journal of Tuberculosis
and Lung Disease is the official journal of the IUATLD. The journals main aim
is the continuing education of physicians and other health personnel and the dis-
semination 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 de-
cided by each national program. Several guides have been published in recent
years and distributed to several thousand colleagues worldwide (2429).

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 com-
posed 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, group-
ing 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 fi-
brotic 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 stud-
ies, the Tuberculosis Surveillance Research Unit (TSRU), was created, jointly
with the World Health Organization and four constituent members in 1965
(3840). 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
790 Rouillon et al.

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 for-
mer 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 be-
tween 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, repre-
sents 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 de-
veloping countries, and it was to be implemented by support from affluent mem-
ber 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 be-
come and remain true partners of their government and that it would be more re-
warding 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 Unions 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 (19611976) (seed money given to promote associations
work), the Collaborative Program now spends about 3 million dollars per year.
The IUATLD currently provides technical collaboration to more than 20 coun-
The Role of Nongovernmental Organizations 791

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 record-
ing, and proper assessment of results). Over the last 18 years, in both new and re-
treatment cases, over 1,200,000 patients have been diagnosed and treated, and
there is a documented assessment of cure rates, which reach 8590%, a level never
reached nationwide before in developing countries. It was thus demonstrated that
tuberculosis programs conducted under very adverse circumstances could never-
theless 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
(4648). This system of delivery of effective and efficient tuberculosis programs
is relevant for some 3040 high-prevalence countries with insufficiently devel-
oped health infrastructures.
As a consequence of the IUATLDs efficacy and efficiency, governments
are induced to undertake such programs; these programs also attract donors, such
as international intergovernmental agencies, including the United Nations Devel-
opment 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 IU-
ATLD 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 so-
called DOTS strategy. This strategy is now accepted by all relevant organizations.
They are actively using this approach in several collaborative programs. The im-
portance of first treating already known and diagnosed cases and then only ex-
panding case finding was confirmed in the various national programs. Also, the
levels of cure rates and detection rates obtained in the programs constituted use-
ful practical bases for calculating the targets proposed in the Resolution on Tu-
berculosis adopted in the World Health Assembly in May 1991 (49).
792 Rouillon et al.

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 Devel-
opment (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 Coun-
cil of Great Britain, relief institutions such as Misereor in Germany and the Inter-
national 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 indi-
vidual 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 entitiesthe lung associations and other
national bodiesand 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 sponta-
neously, the highest authorities in the field of tuberculosis and lung
diseases.
The Role of Nongovernmental Organizations 793

4. As an independent and flexible organization, the Union can and does do

pioneering work in the delivery of health services; as a nongovernmen-
tal 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 assis-
tance and for training of personnel in an effort at collaboration and sol-
idarity, the aim of which is to induce final technical and material self-
sufficiency. 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 diffi-
cult undertakings entailing international collaborative work. The most
recent and spectacular is the conduct and success of the National Tu-
berculosis Programs.
7. It has official ties with all the main intergovernmental and nongovern-
mental international agencies and is recognized by them as a worth-
while partner and adviser in the field of intervention for health.
8. It fulfills a rather difficult and unrewarding, ungratifying, but very use-
ful, role; namely, that of reconciling the often conflicting interests of
the government, the medical profession, and the public and of integrat-
ing 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 tu-
berculosis 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 disap-
peared among the public as well as professionals. In developing countries, na-
794 Rouillon et al.

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 in-
creasing 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 peo-
ple, in being credible to them, in translating messages in simple terms, in pio-
neering 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 indepen-
dence. 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 appre-
ciation 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 deal-
ing 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 discus-
sions of this NGO group. A series of meetings focused on the promotion of peo-
ples participation, strengthening the means of communications at all levels, en-
couraging 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 dis-
cussions took place between WHO and NGOs (over 500 representatives were pre-
sent) 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 im-
mediate 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 Director-
General of WHO, Dr. Gro Harlem Brundtland, made the following statement on
The Role of Nongovernmental Organizations 795

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 com-
munity to draw up new guidelines for our cooperation to establish new mecha-
nisms for interaction with civil society in Member States.

V. Summary

The situation of tuberculosis has worsened and will worsen still more if drastic de-
cisions 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 re-
search, to make our means still more effective and easier to apply.
The future is in the hands of governments of individual countries and the in-
ternational 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 inter-
national 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 fea-
sible; 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 as-
sistance is a spirit of mutual understanding, mutual esteem, and mutual stimula-
tion and solidarity toward progress. The NGOs constitute irreplaceable partners in
the national and global fight against tuberculosis.

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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 tu-

berculosis-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 reg-
ular 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 fi-
nancial support can be seen as one of the reasons for the reemergence of the dis-
ease 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
800 Sawert

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 re-
mained 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 tuber-
culosis 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, re-
mains 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 com-
monly observed discrepancy between comprehensively equipped tertiary care
hospitals in the capitals (where the countrys 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 tubercu-
losis patients usually have to rely on. These patients tend to be of low socioeco-
nomic status and usually lack the means to access high-level facilities. Their po-
litical 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 as-
sessments of alternative interventions!
Recent years have seen various attempts to overcome this situation and ra-
tionalize the provision of health-care services (3). The relevant principles are
now introduced by increasing numbers of health-care providers worldwide. Ra-
tionalization of political processes usually comprises the specific incorporation
of economic principles. The basic notion underlying these principles is that re-
sources are limited and that they should be used in a way that the utility result-
ing 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 cer-
tain 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.
Economic Considerations of Tuberculosis Control 801

2. An intervention should have comparatively low costs. Among alterna-

tive interventions with similar outcomes, preference should be given to
those that require smaller expenditures.
3. An intervention should relieve comparatively large burdens to the pub-
lic health. Among alternative interventions with similar costs and out-
comes, 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-effec-
tiveness 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 nev-
ertheless 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 ex-
ample, 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 im-
plementation is recommended if their benefits exceed their costs. From a cost-ben-
efit 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 pro-
grams 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 strat-
egy can be made. The results of an effective control program, such as an overall re-
duction of case incidence, may not immediately follow the introduction of an im-
proved 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 prin-
ciples? The programs (Table 1) address a comparatively large disease burden to
societies; in fact, they address the disease causing the largest burden among all in-
fectious diseases worldwide (5). They used to be relatively expensive due to high
drug costs and prolonged hospitalizations, but costs have been reduced substan-
tially 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
802 Sawert

Table 1 Modern Resource Allocation Criteria and TB Control

Allocation criteria Facts about TB control

Large disease burdens TB is the leading cause of death from infectious

diseases in adults.
Cost-effective interventions 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-effec-
tiveness of tuberculosis control (8). This observation has been used by interna-
tional 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 man-
agers of specific programs within the health care sector will be regularly chal-
lenged to demonstrate the cost-effectiveness of the interventions they imple-
ment. Managers of tuberculosis-control programs are therefore well advised to
familiarize themselves with the relevant basic terms and concepts to engage suc-
cessfully 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 tubercu-
losis 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 far-
fetched, they illustrate why the costs that economists calculate for a specific ac-
tivity 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,
Economic Considerations of Tuberculosis Control 803

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 as-
sessment of program modifications. Incremental costs are defined as the addi-
tional 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 build-
ing 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 ac-
tivity, e.g., producing 101 instead of 100 x-rays per day. If the capacity of the ex-
isting 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 ambu-
latory 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 pro-
vide additional time of healthy living. Despite these straightforward notions, a be-
wildering variety of health outcome measures is used in economic analyses, often

Table 2 Forms of Economic Analysis

Costs Outcomes

Least-cost $
Cost-effectiveness $ Health, measured in time (QALY, DALY)
Cost-benefit $ $
804 Sawert

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 disabil-
ities. Unfortunately, there is currently no universally accepted standard, which
complicates the comparison of studies that have used different measures (1113).
Nevertheless, the evaluation of a large number of alternative interventions re-
mains possible if one standard measure were used for all studies.
The effectiveness of an intervention can be related to its costs in cost-effec-
tiveness ratios. When uniform methodologies are used for a variety of interven-
tions, decision makers are enabled to maximize the outputs of a health-care sys-
tem 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 tu-
berculosis-control interventions of $57 (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 in-
come 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
peoples 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 acci-
dents) (9). These figures can be used as a measure for the utility that people de-
rive from life years and accordingly as the benefit resulting from effective health-
care 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 method-
ologies are compared. Nevertheless, if similar methods are used to assess alterna-
tive 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 re-

lapses. Also, there is a danger that remnant mycobacteria have become resistant
Economic Considerations of Tuberculosis Control 805

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 devel-
ops against the two most potent antimycobacterial drugs, rifampicin and isoni-
azid. The mortality in these multidrug-resistant cases is excessively high, and
their successful treatment requires the use of second-line drugs, extensive hos-
pitalization, 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 re-
sistance resulting from effective treatment strategies (16). This observation has
obvious economic implications: the high costs of treatment should make the pre-
vention 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 indi-
vidual patients (Fig. 1). Since tuberculosis is an infectious disease, the cure of ac-
tive 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.

806 Sawert

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 infec-
tion, the case load may remain high and can increase dramatically under the in-
fluence 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 tuberculo-
sis 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 alter-
native 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 (1921). 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 ex-
ploiting the empirically derived relationship between the annual risk of infection
and incidence rates) (22). When model projections are applied for practical pur-
poses, such as economic analyses, sensitivity analyses need to be performed to as-
sess the influence of different parameter values on model outputs. This step is nec-
essary, 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 strat-
egy 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 scenarioscontinuation of the current pro-
gram 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 calcu-
lated; 7) if costs for the new strategy are lower and outcomes are better, the anal-
Economic Considerations of Tuberculosis Control 807

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 interven-
tions; 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 im-
plementation 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 tuberculo-
sis 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 con-
tinuing the current control policy or investing in improved services. The key fea-
ture of an improved service would be the provision of treatment under direct ob-
servation, 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 rela-
tionship between the annual risk of infection and the tuberculosis incidence rate.
Incidence rates for HIV-positive individuals have been reported in various stud-
ies. 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 of-
fices 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 eco-
nomic texts listed as references.
808
Figure 2 All rates used during model calculations are indicated as circles. All time-dependent model inputs and rates are indicated by arrows (). (From
Ref. 24.)
Economic Considerations of Tuberculosis Control 809

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 diag-
nostic supplies and stationery accounted for 4.6% of total costs. Maintenance
costs, capital depreciation, and recurrent costs for training and supervision to-
gether accounted for 44.1%.
Since this analysis requires an assessment of the cost implications of chang-
ing 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 in-
fluence 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 infras-
tructure 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 in-
creases 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 in-
frastructure with respect to treatment services. However, 43% of all patients are
currently diagnosed at centralized services and only 33% at district level. If diag-
nosis 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 refer-
ral hospitals. Also, the treatment of these cases tends to be highly individual, with
various second-line drug regimens, different lengths of hospitalization, and some-
times 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 epi-
demic 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
810 Sawert

at the workplace, whereas a patient who remains undiagnosed would lose on av-
erage one year of work time. Calculations of the time of productive life lost due to
premature mortality are made separately for HIV-infected and nonHIV-infected
TB patients. For HIV-infected individuals, it is assumed that death from tubercu-
losis 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
nonHIV-infected individuals, an average age of death of 45 years is assumed, re-
sulting in 15 years of productive life lost if participation in the workforce is sup-
posed 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 nonHIV-infected patient
results in a loss of $19,400.

C. Results
Epidemiological Projections
Figure 3 shows projections of tuberculosis case numbers in Thailand. Since case-
detection 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 de-
tected 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.)
Economic Considerations of Tuberculosis Control 811

Figure 4 The difference in annual direct provider costs between two scenarios: contin-
uation 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 pro-
gram; 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 deter-
mined 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. There-
after, 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, al-
though 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 un-
der 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 pro-
gram strategy could require additional costs over the costs under the current strat-
egy 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.
812 Sawert

Figure 5 The figure shows the difference in cumulative indirect costs between two sce-
narios: 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 fu-
ture 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 mil-
lion, 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 ad-
ditional 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 eval-
uation 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 fu-
tire is lower than the actual future figure.
Economic Considerations of Tuberculosis Control 813

that the required investment in improved services would be $10,000,000, the so-
cietal 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 well-
functioning tuberculosis-control program would require considerable initial in-
vestment. However, the analysis of future scenarios provides important informa-
tion for the decision-making process. From a societal perspective, the required
expenditures are always far outweighed by savings resulting from averted mor-
bidity 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 re-
strictive 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 im-
plementation 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 inter-
vention 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 high-
est 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 as-
sume that the characteristic factors (existing control program with relatively low
efficiency, increasing case numbers due to the HIV epidemic, increasing inci-
dence of multidrug-resistant cases) are paradigmatic for the situation in many
countries today. It is therefore likely that similar conclusions about the economic
814 Sawert

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 Con-

trol. WHO/TB/94.179 ed. Geneva: WHO, 1994.
2. WHO Global Tuberculosis Programme. TBA Global Emergency. WHO report on
the tuberculosis epidemic. Geneva: WHO, 1994.
3. The World Bank. World Development Report 1993. Investing in Health. Oxford: Ox-
ford University Press, 1993.
4. Rice D, Hodgson TA, Kopstein A. The economic cost of illness: a replication and up-
date. Health Care Financ Rev 1985; 7:6180.
5. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, in-
tervention and cost. Bull Int Union Tuberc Lung Dis 1990; 65:120.
6. Barnum HN. Cost savings from alternative treatments for tuberculosis. Soc Sci Med
1986; 23:847850.
7. Chaulet P. The supply of antituberculosis drugs: price evolution. Tuberc Lung Dis
1995; 76:261263.
8. Murray CJ, DeJonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost effec-
tiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African
countries. Lancet 1991; 338:13051308.
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 eco-
nomic submissions to the BMJ. BMJ 1996; 313:275283.
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; 276:13391341.
14. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis. We
cant afford not to try it. N Engl J Med 1993; 328:576578.
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;
328:521526.
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; 330:11791184.
17. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York
Cityturning the tide. N Engl J Med 1995; 333:229233.
Economic Considerations of Tuberculosis Control 815

18. Frost WH. The age selection of mortality from tuberculosis in successive decades.
Am J Epidemiol 1995; 141:49.
19. Joesoef MR, Remington PL, Jiptoherijanto PT. Epidemiological model and cost-ef-
fectiveness analysis of tuberculosis treatment programmes in Indonesia. Int J Epi-
demiol 1989; 18:174179.
20. Blower SM, Small PM, Hopewell PC. Control strategies for tuberculosis epidemics:
new models for old problems. Science 1996; 273:497500.
21. Waaler HT. Model simulation and decision-making in tuberculosis programmes. Bull
Int Union Tuberc 1970; 43:337344.
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)117119.
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; 44:18051816.
32
The Impact of Managed Care on Tuberculosis
Control in the United States

BESS MILLER SARA ROSENBAUM

Centers for Disease Control and Prevention School of Public Health and Health
Atlanta, Georgia 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 in-
volves 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 of-
ten includes the practice of capitation, where a managed care companys 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 ac-
817
818 Miller and Rosenbaum

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 pa-
tient care. On the other hand, it is a system that emphasizes cost control and re-
sponsibility 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 states TB-control program and its organizational structure vary consid-
erably, depending on the size of the TB problem and the organizational and polit-
ical structure of the states 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 clin-
ics, provision of laboratory services, maintaining information systems, assess-
ment of program performance, training and consultation, performing outbreak in-
vestigations, 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 communi-
cable 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,
Managed Care and Tuberculosis Control 819

and licensing drugs. The federal government also provides funding to state and lo-
cal 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 pa-
tients. 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 in-
dividual patient care from the public health aspects of TB control has created chal-
lenges 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 em-
ployee benefit plans, privately purchased insurance policies, enrollment in Medi-
caid, or enrollment in Medicare programs. The Medicaid program is a joint fed-
eral-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 Rec-
onciliation 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 en-
rollment of Medicaid beneficiaries into managed care plans. As part of this Med-
icaid managed care restructuring overall, a few states also have expanded cover-
age to previously uninsured persons (11). The vulnerable populations included
among the newly insured may include persons with or at high risk for TB. Paral-
leling the growth in Medicaid managed care has been an increase in managed care
enrollment among the Medicare population. By 1996, three quarters of all pri-
vately 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, un-
published data).
820 Miller and Rosenbaum

IV. Concerns of TB Health Officials About Managed Care

The shifting of care of patients with TB into managed care plans, with the em-
phasis on management of costs, has raised new concerns among TB and commu-
nicable disease health officials regarding the ability of the private sector to main-
tain 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 out-
breaks 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 mem-
bers who have been exposed to persons with active TB, they are not likely to ac-
cept the role of identifying nonmember contacts to TB patients enrolled in their
plans. Furthermore, frequent disenrollment and reenrollment of patients may hin-
der 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 con-
trary, capitated rates may actually create incentives for underservice.

D. Laboratory Services

Mycobacteriology services are quite specialized, and extensive guidelines for pro-
cessing 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
Managed Care and Tuberculosis Control 821

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 immuno-
suppressed persons). In reality, the average duration of coverage in any one Med-
icaid 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 pro-
vided 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 de-
partments in many areas are continuing to provide services to vulnerable popula-
tions, including persons enrolled in Medicaid or Medicare managed care organi-
zations 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 Medi-
caid managed care, has been varied, depending on such factors as the magnitude
of the TB problem, the characteristics of the TB patients, the organizational struc-
ture of the health department TB control program, and the degree of penetration
822 Miller and Rosenbaum

of managed care into the community. A survey of state and local TB-control pro-
grams 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 ar-
rangement, 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 sub-
contracting network provider to the managed care organization. The
managed care organization pays the health department directly for pro-
viding 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., per-
haps only DOT) to TB patients enrolled in managed care on a fee-for-
service basis.
3. TB services are provided within the managed care organizations.
4. TB services are exempted from managed care agreements. In this situ-
ation the health department continues to provide clinical services to TB
patients enrolled in managed care organizations, but these arrange-
ments 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 provi-
sion of DOT.
5. Finally, in a few areas health departments are becoming managed care
organizations themselves and providing clinical and public health ser-
vices.

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 ac-
tivities 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-
Managed Care and Tuberculosis Control 823

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 health-
caredelivery system, obtaining reimbursement for services may become increas-
ingly important if health department activities such as contact and outbreak in-
vestigations 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 ar-
eas, 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 provi-
sion 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 man-
aged care organizations in their areas. The larger managed care plans may assign
specific personnel to oversee management of TB patients or, more broadly, pa-
tients with communicable diseases. If the health department is a managed care or-
ganization 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-
824 Miller and Rosenbaum

sponsibilities of the managed care plans and health departments and to formalize
the relationship between the two. These may take the form of informal memo-
randa of agreement, usually between managed care organizations and state or lo-
cal health departments, describing who will be responsible for the various com-
ponents of patient care and public health practice. On a more formal level, they
may develop legally binding contracts, usually describing the arrangement be-
tween the purchasers of managed care, e.g., state Medicaid agencies, and the man-
aged 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 publics health. The pro-
cess 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 re-
garding the standards for patient care and public health practice (16). The provi-
sions are of importance to health officials because they attempt to address the mul-
tiple points at which public health agencies should interact with managed care
organizations and the public health considerations that must be addressed in man-
aged care settings.
The model contract specifications are organized around 10 categories, se-
lected because they represent the principal elements of Medicaid managed care
contracts. These categories include:
1. Definitions of terms
2. Covered services
3. Medical necessity (What is medically necessary to cover?)
4. Enrollment and disenrollment procedures
5. Provider network (Which providers, including laboratories, are quali-
fied to provide care?)
6. Access standards (What waiting times [including for laboratory re-
sults] and distances for travel to services are acceptable?
7. Relationships with local health departments
8. Quality assurance
9. Data and reporting
10. 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-
Managed Care and Tuberculosis Control 825

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 con-
tinuous months; directly observed therapy for all patients; recommended infection
control practices, including isolations of infectious patients in institutional set-
tings; reporting of all cases to the health department; timely initiation of contact
investigations; and screening and preventive therapy for high-risk populations
(4,14,1724).
The contract is written to assure continuity of care (enrollment, disenroll-
ment section), provision of drugs free of charge (covered services section); provi-
sion of social services, such as drug rehabilitation and housing for the homeless
(covered services section); universal DOT (covered services section); hospitaliza-
tion 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 in-
cludes performance measures for each of these sections to assure ongoing moni-
toring 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 activi-
ties 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 addi-
tional areas. The managed care and public health communities are working to-
gether to address areas of concern, such as those mentioned here (25). Neverthe-
less, 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: Associa-
tion 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):663674.
4. Centers for Disease Control and Prevention. Essential components of a tuberculosis
prevention and control program. MMWR 1994; 44(No. RR-11):116.
826 Miller and Rosenbaum

5. Sbarbaro JA. The public health tuberculosis clinic: its place in comprehensive health
care. Am Rev Respir Dis 1970; 101:463465.
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 clin-
ics. Am J Respir Crit Care Med 1994; 150:893894.
8. Tuberculosis control and prevention in a changing managed care environment: chal-
lenges and opportunities for local health departments, managed care organizations,
and others. Washington, DC: National Association of County and City Health Offi-
cials, 1997.
9. Dacso ST, Dacso CC. Managed Care Answer Book. 2d ed. New York: Panel Publis-
hers, 1997.
10. P.L. (Public Law) 103-66 Sec. 13603 (e)(I).
11. Rosenbaum S, Darnell J. Section 1115 Statewide Medicaid Managed Care Demon-
strations: 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; 262:30183026.
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 or-
ganizations. Clin Infect Dis 1998; 27:677686.
17. Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the
United States. MMWR 1989; 38(suppl. no S-3):125.
18. American Thoracic Society/Centers for Disease Control. Diagnostic standards and
classification of tuberculosis. Am Rev Respir Dis 1990; 142:725735.
19. American Thoracic Society/Centers for Disease Control. Control of tuberculosis in
the United States. Am Rev Respir Dis 1992; 146:16231633.
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;
149:13591374.
21. Centers for Disease Control and Prevention. Guidelines for preventing the transmis-
sion of Mycobacterium tuberculosis in health care facilities, 1994. MMWR 1994; 43
(No. RR-13):1132.
22. Centers for Disease Control and Prevention. Screening for tuberculosis and tubercu-
losis infection in high-risk populations: recommendations of the Advisory Council
for the Elimination of Tuberculosis. MMWR 1995; 44 (No. RR-11): 1932.
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, 1997:541562.
Managed Care and Tuberculosis Control 827

24. Centers for Disease Control and Prevention. 1997 United States Public Health Ser-
vice/Infectious Diseases Society of America guidelines for the prevention of oppor-
tunistic infections in persons infected with human immunodeficiency virus. MMWR
1997; 46 (No. RR-12):146.
25. Centers for Disease Control and Prevention. Prevention and managed care: opportu-
nities for managed care organizations, purchasers of health care, and public health
agencies. MMWR 1995; 44 (No. RR-14):112.
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 func-
tioning 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 sec-
tor 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 ex-
ecuted by other people and agencies. They will also be more involved in deter-
mining policy, setting standards, and monitoring performance, intervening only
829
830 Tayler

Table 1 Elements and Implications of Health Sector Reform

Key elements of health sector reforms Practical Implications

Decentralization More managerial and/or financial control in the

Integration
Changing role of the Ministry of
Health
Increased plurality of providers
Alternative sources and
mechanisms of funding
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 fi-
nancial 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 or-
ganizations, 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 rev-
enues 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 re-
forms. 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 sys-
tems undergoing reform. It does, however, highlight potential opportunities and
Health Sector Reform in Developing Nations 831

some of the major challenges that are likely to be faced in many countries under-
going these sorts of process.

II. Why Health Sector Reform Is Needed

Health systems in many countries function poorly. As a result, people with tuber-
culosis are mismanaged and many die. Even in countries where TB-control pro-
grams run well, they may be an isolated pillar of excellence, reliant upon exten-
sive 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-ineffec-
tive service. The infrastructure is weak, staff salaries are low and may not
be paid regularly, facilities are dilapidated, and the drug supply is unre-
liable.
People cannot access the care that they needthe barriers preventing this
may be physical (e.g., distances involved, the costs of seeking care), cul-
tural, or a result of age or sex.
The services provided do not respond to what people want: patients face un-
motivated 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 devel-
opment assistance, and yet this too is currently decreasing. In 1986 the Organiza-
tion for Economic Cooperation and Development (OECD) countries spent an av-
erage 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 pro-
gram. Specific programs with dedicated training, vehicles, and distribution and in-
832 Tayler

formation systems may rapidly achieve a system for effective service delivery for
particular conditions, such as TB or immunization. However if separate and po-
tentially incompatible systems for every program are allowed to proliferate, coor-
dination 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 pro-
gram 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 dis-
eases. However, unlike most medical interventions, the risks of allowing drug re-
sistance to develop mean that it is better to do nothing than to implement poor con-
trol (14). In addition, the protracted treatment period and the benefits of treatment
to the community as a wholein terms of preventing transmission of disease
mean that certain elements such as the drug supply and the mechanisms for fi-
nancing 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 gen-
eral 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 at-
tention 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
Health Sector Reform in Developing Nations 833

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 di-
vided 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 refineddeter-
mining which elements do require separate consideration and which, with imagi-
nation, can be incorporated completely within the management system of general
serviceswill 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 in-
crease. 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 af-
fects some of the poorest, most marginalized, and least politically powerful mem-
bers of societies, and although it is a major contributor to the overall burden of dis-
ease 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 advo-
cacy 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 com-
munity 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, how-
ever, take time, tolerance, and a flexible approach if this approach is to be
successful.
834 Tayler

B. Preservation of Free TB Services at a Policy Level

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. Else-
where 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 bene-
fit 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, gov-
ernments increase the chances of proper compliance and good control. In addition
to issues around efficiency and equity, there are also practical reasonsa 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 function-
ing of essential services (even if this is contrary to an ideological incentive to en-
courage 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 symp-
tomatics 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 charg-
ing 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
Health Sector Reform in Developing Nations 835

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, mean-
ing that they may continue to transmit disease. If charges are not made, then un-
less adequate extra resources dedicated for TB are made available the resources
available to laboratories, the morale of laboratory staff, and the quality of the ser-
vice 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 mak-
ers, and although the consequences of laboratory error can be grave, proper sys-
tems 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 en-
sure the maintenance of technical standards. It may be, however, that within an in-
tegrated system, all the functions of the laboratory, such as malaria and TB diag-
nosis 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 dif-
ficult 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 pa-
tients 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 develop-
ing 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.
836 Tayler

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. Di-
rectors of health facilities are also concerned about the disruption of service pro-
vision 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 al-
lowances. In the future it is likely that training courses will be driven more by de-
mand (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 con-
trol 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 decen-
tralized 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 exten-
sive capacity building has occurred in these areas. However, in most developing
countries technical knowledge is still limited and there is need for support and ad-
vice from higher levels. Good supervision is an integral part of continuing train-
ing; 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 fo-
cus towards monitoring outputs and outcomes occurs, with performance and pos-
sibly 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 op-
erating are going to become important, such as more integrated supervision, re-
cruiting nonTB workers to perform simple focused checks, and enlisting the as-
sistance 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.
Health Sector Reform in Developing Nations 837

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 unafford-
able 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 cen-
tral purchase and provision of these drugs, even if they are then dis-
tributed through normal channels.
The potential savings through bulk purchase and the importance of proper
quality control are additional reasons why centralized procurement should be re-
tained, irrespective of delivery systems within the country or whether drug bud-
gets 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 lev-
els. 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 po-
tentially a useful management tool. Many disease-specific programs have devel-
oped 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 qual-
ity, or it will be done instead of other important tasks. Incorporating different in-
formation 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 sys-
tems 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
838 Tayler

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 pro-
gram 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 finan-
cial flows that ensure that funds are appropriately spent at the peripheral
level
Effective technical supervision between levels of service to identify prob-
lems, assist and retain staff, and validate performance
Some coordination and accountability for performance of specialized ser-
vices and disease control activities, even where services are primarily co-
ordinated 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 re-
quire 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.
Health Sector Reform in Developing Nations 839

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 imple-
mentation of the reforms, often because one wave of reforms is overtaken by an-
other. 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 sup-
port, 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 con-
ditions 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 con-
trol 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 coun-
tries 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-
840 Tayler

ple concerned with TB control will need to show flexibility and imagination, de-
velop new skills and allies, and be actively involved in the policy process.

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34
Mobilizing Society Against Tuberculosis
Creating and Sustaining Demand for DOTS in High-
Burden 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 infec-
tions, cases, and deaths. In theory, advances in combination therapies, improved di-
agnosis, and case management should provide tuberculosis (TB) patients with an al-
most 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 worlds 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 Organizations global TB targets by the year 2000.* In analyz-

* Afghanistan, Brazil, Ethiopia, India, Indonesia, Islamic Republic of Iran, Mexico, Myan-
mar, Nigeria, Pakistan, Philippines, Russian Federation, South Africa, Sudan, Thailand,
and Uganda comprise the 16 countries that are making slow progress in controlling tuber-
culosis, 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 high-
burden countries making progress in controlling TB.

843
844 Klaudt

ing the situation in these 16 countries, the World Health Organization has con-
cluded 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 unin-
formed 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 in-

ternational public health experts convened to assess how to more effectively co-
ordinate 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. . . . Ex-
traordinary 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 pro-
grammatic operations of TB control over the past two decades. The World Bank consid-
ers DOTS one of the most cost-effective health strategies available. Its five core ele-
ments 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 (68 months) for at least all confirmed sputum
smearpositive 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
Mobilizing Society Against Tuberculosis 845

tion (CDC), the American Thoracic Society (ATS), and the American Lung As-
sociation (ALA) called for the development of a tuberculosis global action plan
that would engage all relevant parts of civil society and their governments to ad-
vocate, 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 tu-
berculosis are more significant than the medical and scientific challenges. By mo-
bilizing 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 tar-
gets 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 us-
ing DOTS more widely. One is to await the contribution socioeconomic develop-
ment 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 sub-
stantial 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 fore-
most 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 wel-
come 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 bil-
lions of potentially infected individuals.
WHO believes that the creation of greater public demand and political lead-
ership 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
difficultalthough not insurmountablechallenges. For example, most interna-
tional 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.
846 Klaudt

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 mo-
bilization strategies to help address specific political obstacles facing individual
high-burden countries.
Second, WHO and other organizations are just beginning to provide inten-
sive technical support to national TB programs in high-burden countries specifi-
cally in the areas of developing political support, ownership of DOTS, and human
resource development. In assisting countries to quickly adopt DOTS, WHO train-
ing modules and courses initially emphasized the technical and managerial as-
pects of the strategy and have only recently begun placing greater emphasis on the
creation of political will. Recently, significant discussion of these three main con-
straints 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 con-
straints exist in high-burden countries. Not only has TB research been vastly un-
derfunded 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 effi-
ciently, 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-
Mobilizing Society Against Tuberculosis 847

Figure 1 Health communications spans a spectrum between strategies and objectives in-
tended 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 institu-
tions.

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 commu-
nicationsuch as the media, coalitions, and publicationsare 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 ex-
ample, IEC campaigns often target specific groups such as women whose children
would benefit from breast feeding or commercial sex workers who should insist
848 Klaudt

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 insuffi-
cient to prevent many health risks. For example, blood supplies can be more eas-
ily protected by changing government policies rather than individual behavior.
Other health threats such as premature births are more easily avoided by convinc-
ing 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 be-
havior and in the commitment of institutions and governments. To prevent the use
of tobacco, educators distribute brochures to encourage individuals to quit smok-
ing, 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 per-
mit sex education in the classroom.
The most sustainable advances in public health are usually those that mobi-
lize a wide array of partners and strategies in advocating social change. Social mo-
bilization 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 activi-
ties and strengthens program communication, for many more societal partners par-
ticipate in the program, such as NGOs [nongovernmental organizations], grassroots
organizations which often have the motivation and skills for involving local com-
munities 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-
Mobilizing Society Against Tuberculosis 849

unteers, educating them to understand the importance of observing pa-

tients as they take their medicines and the value of other elements of the
DOTS strategy. Many health workers have unrealistic hopes that edu-
cation strategies directed at patients can greatly increase compliance to
treatment. The evidence does not support that intensive patient educa-
tion by itself can help high-burden countries achieve 85% cure rates
(5,6).
2. Patient education through DOTS can improve health-seeking behavior.
While patient education is not the main determinant of treatment com-
pliance in the DOTS strategy, it does have an important role to play. Su-
pervision should not only ensure the intake of drugs, but also help the
patient and his or her family understand the illness and the steps neces-
sary to bring about a cure. With good supervision, the patient should
feel comfortable to ask questions about his or her health. This bond be-
tween 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 infor-
mation and counseling on other concerns, such as reproductive health
and AIDS prevention.
3. 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 cam-
paigns 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 detec-
tion.
4. 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 counterpro-
ductive 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 interrup-
tions 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.
5. Advocacy strategies are essential in countries not achieving high cure
rates. Advocacy strategiesnot IECare the first priority in countries
850 Klaudt

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 high-
light the dangers of TB and promote the establishment of DOTS pro-
grams are the most critical need.
6. 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 advo-
cates and policy makers are involved, political gains can easily evapo-
rate. Often leading advocates become involved in other issues, and
champions within the government are replaced when new political par-
ties 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 mo-
bilization strategies to support TB control in high-burden countries. This is in con-
trast to a rich history of community activism against TB in North America, Eu-
rope, 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 characteris-
tics that galvanize public opinion and attract support: high profile celebrities, en-
ergizing activities, attention surrounding unexpected scandals, memorable sym-
bols, 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 move-
ment. 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
Table 2 Ways of Creating a C.A.U.S.E.

Unexpected
Celebrity Activity Scandal Symbol Event

AIDS in the Ryan White ACT-UP zaps Contaminated Red ribbon World AIDS
United States Magic Johnson blood supplies Quilt Day
Rock Hudson Reports of
heterosexual
transmission
Anti-apartheid in Nelson Mandela Construction of Sharpeville ANC colors Sun City
South Africa Desmond Tutu mock shanty massacre
towns Murder of Stephen
Divestment Biko
campaigns
Mobilizing Society Against Tuberculosis

Civil rights in the Martin Luther King Sit-ins Medgar Evers I have a dream Montgomery bus
United States Rosa Parks murder Hooded klansmen boycott
1963 March on
Washington
Watts riots
Independence Mahatma Gandhi Fasting Jallianwala Bagh Spinning wheel 1930 salt march
movement in Passive resistance atrocity
India
Vietnam war Jerry Rubin Burning draft cards The Pentagon Peace symbol Chicago riots
protests in the Abbie Hoffman Occupation of Papers
United States university My Lai massacre
buildings Kent State shooting
851
852 Klaudt

the United States. Others are the result of carefully orchestrated advocacy strate-
gies 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 suc-
ceed. For example, the visible involvement of Diana, Princess of Wales, was suf-
ficient to propel the campaign to ban land mines onto the international political
agenda without, for example, the popularization of a campaign symbol or the de-
velopment of a grass-roots protest activity.
The visible advent of one or more of the C.A.U.S.E. elements makes it eas-
ier for a movement to generate other visible initiatives. For example, the initial
success of the Band Aid concert and the song Do They Know Its 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 mo-
bilize a social response to other important health issues, such as reproductive
health and child survival. Over the past two decades, UNICEF has been the prin-
cipal leader in applying the concept of social mobilization for health concerns. A
wide range of partners and sectors are typically involved in UNICEFs social mo-
bilization initiatives in any given country (Table 3). Celebrities such as Audrey
Hepburn and Harry Belafonte have attracted visibility to these activities. Interna-
tional associations such as Rotary, Junior Chamber, and Kiwanis have provided a
volunteer base in developing countries to conduct special activities during na-
tional immunization days. National committees in 37 industrialized countries
have supplemented UNICEFs advocacy activities in publicizing the unexpected
scandal of childhood mortality. At the country level, symbols have helped pro-
mote immunization, as seen with the moni symbol in Bangladesh. Political lead-
ership 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 re-
flected by the attitudes of heads of state, has not been difficult to mobilize. Few
leaders remain unenthusiastic when given the promise that their nations children
can be protected quickly and inexpensively through immunization (7). The con-
trol 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 im-
poverished 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-
 Mobilizing Society Against Tuberculosis
Table 3 Advocacy and Social Mobilization Activities for Expanded Program of Immuniza-
tion (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 & Womens
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.
853
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 pub-
lic fora
Numerous events, fundraising and seminars on PolioPlus
Program, Involvement of youth branch, Rotaract, in so-
cial 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 plan-
ning 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
854 Klaudt

hanced further as UNICEF attempts to fully integrate social mobilization into

program activities, rather than to view them as add-on activities (8). In com-
parison, relatively few human and financial resources are currently being de-
voted to removing the main obstacles preventing the control of tuberculosis. Un-
til 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 orga-
nizations 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 emergeslocally or globallywithout 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 strat-
egy 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 opportu-
nities confronting expansion of the DOTS strategy. It is often useful to involve
skilled advocates for other issues in conducting this analysis, as their fresh per-
spectives 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 Organizations TB Advocacy:
A Practical Guide. This document is available from the Stop TB Initiative, 20 Avenue Ap-
pia, CH-1211 Geneva, Switzerland. Other useful advocacy and social resources include
Media Advocacy and Public Health, by Lawrence Wallack et al., available from Sage pub-
lications, 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; Pub-
lic 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.
Mobilizing Society Against Tuberculosis 855

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 opportuni-
ties. 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 meet-
ings, and talking with others who have worked with the decision maker. In con-
ducting 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 evi-
dence. The most useful information documents the extent and severity of the prob-
lem 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 ef-
forts after gathering this information, believing that the facts will speak for them-
selves. 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 de-
scribe the effects that TB has on individuals, families, whole communities, and na-
tional 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 audi-
ences, ensuring their relevance to each stakeholders 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 appro-
priate 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 neces-
sary to effectively communicate to policy makers and journalists. Visual materi-
856 Klaudt

Table 4 Differences Between Scientific and Advocacy Communication

Science Advocacy

Detailed explanations are useful. Simplification is preferable.

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.
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, journal-
ists can be interested in most any story that is new, urgent, sensational, or contro-
versial or that involves celebrities or dramatic personal stories. With the help of
individuals skilled in public relations, TB programs can become much more suc-
cessful in using the media to help set the political agenda.
Media strategies are especially important in democracies, where politi-
cians 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.
Mobilizing Society Against Tuberculosis 857

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 be-
come 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 natu-
ral 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 ac-
tion. 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 individu-
als 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 indi-
viduals 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 bring-
ing about change, they also require more compromise, negotiation, and deal mak-
ing 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 ones 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 con-
tribute to curing greater numbers of infectious TB patients. The effectiveness of
advocacy strategies can be measured on three intermediary levels (Table 5).
858 Klaudt

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 tar-
get 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 con-
cern, one should constantly monitor other advocacy indicators to ensure they are
sufficient to attain the necessary results. Inevitably, the knowledge and skill of a
programs advocacy staff is one of the surest determinates of subsequent pro-
grammatic 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 coun-
try-specific advocacy strategy and help create the conditions for making TB con-
trol an attractive social cause.
Mobilizing Society Against Tuberculosis 859

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 expan-
sion of childhood vaccinations. With one clear goal, childhood vaccination advo-
cates 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 in-
crease 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 nonhealth experts.
The goal of curing 70% of TB patients with DOTS should supplementnot re-
placeWHOs 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-con-
trol movement (Fig. 2). This image draws upon one of the most commonly, uni-
versally recognized symbolsthe 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 sym-
bol 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 symbolthe 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).
860 Klaudt

DOTS strategy available in their communities. Around the world, creative indi-
viduals are finding other unique uses for the Stop TB imageon T-shirts, um-
brellas, 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 ad-
vocacy and social mobilization strategies against TB. In 1998, nearly 200 organi-
zations 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 or-
ganizations. 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 to-

ward 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 devel-
opment of advocacy strategies and messages, but also in providing baseline indi-
cators upon which the impact of future advocacy and social mobilization strate-
gies 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 coun-
try?
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?
Mobilizing Society Against Tuberculosis 861

Research is needed to help advocates more accurately answer these ques-

tions. Currently, there is a great imbalance in TB research, with the majority of in-
vestigations 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 pre-
pared 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 Africas 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 countrys 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 in-
crease 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 apprecia-
tion 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 misinfor-
mation that occurs in the reporting of TB. For example, journalists frequently over-
state the usefulness of BCG vaccine and understate the effectiveness of
862 Klaudt

the DOTS strategy. As media attention on TB increases, there is also the risk that par-
ticular 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 ef-
forts in high-burden countries. Workshops and training seminars are needed to
equip more lung associations and TB NGOs to become better advocates and to in-
volve health, development, and human rights NGOs with strong advocacy net-
works in the movement to control TB.

K. Creating Patient Organizations

It is possible that patient-based organizations can again be created for TBsuch
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 ad-
vocatesMADD (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 ob-
serve 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 ser-
vice 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 tar-
gets 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 tuber-
culosis. Celebrities must become involved as spokespeopleso far they have
been silent, although it is certain many marathon runners, film stars, and musi-
cians 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.
Mobilizing Society Against Tuberculosis 863

VI. Conclusion

In analyzing recent technical advances in the prevention and treatment of TB, clin-
icians and researchers should also note an often-overlooked discovery made by
two of this centurys 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 tech-
nical factors involved in the control of TB. To his credit, while completely im-
mersing himself in the smallest details of operating effective programs, Styblo un-
derstood 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 centurys premiere TB researchers, Sir John
Crofton perfected the use of combination treatment to increase cure rates and pre-
vent 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 effec-
tive 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 Directors Report for

CARG. Geneva: World Health Organization, 1997.
2. World Health Organization Global TB Programme. Report of the Ad Hoc Commit-
tee on the Tuberculosis Epidemic. WHO/TB/98.245. Geneva: World Health Organi-
zation, 1998.
3. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for global tuberculosis con-
trol under the WHO DOTS strategy. Lancet 1998; 352:18861891.
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; 74:267272.
7. Planning Principles for Accelerated Immunization Activities. Geneva: World Health
Organization, 1985.
864 Klaudt

8. Rivera L. 13th World Conference on Health Education. Conference Proceedings

1998; II:221.
9. World Health Organization Global TB Programme. The Global TB Research Initia-
tive: Research to Make a Difference. WHO/TB/98.248. Geneva: World Health Orga-
nization, 1998.
10. Crofton J. Tuberculosis: world perspectives and the challenges ahead. J Pharm Phar-
macol 1997; 49 (suppl. 1):36.
Part Six
THE FUTURE
35
Tuberculosis in the Future

RICHARD J. OBRIEN MARIO C. RAVIGLIONE

Centers for Disease Control and World Health Organization

Prevention Geneva, Switzerland
Atlanta, Georgia

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 con-
trol and eventual elimination of this ancient disease and arousing fears that the epi-
demic 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 elim-
ination of tuberculosis.

I. Tuberculosis in the 1990s: Reasons to Be Hopeful

Perhaps the most remarkable change during the past decade has been in the pub-
lic 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 read-
867
868 OBrien and Raviglione

ily apparent. While many persons living in the United States may have had grand-
parents 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, tu-
berculosis was given low priority, as it was assumed that widespread BCG vacci-
nation 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 sec-
tor 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) tubercu-
losis, largely fueled by nosocomial transmission among persons with human im-
munodeficiency virus (HIV) infection, aroused new fears about incurable tuber-
culosis (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 con-
ditions in larger urban areas, and a public health infrastructure that could not pro-
vide optimal control services (2).
As press attention to MDR TB picked up, public concern grew and eventu-
ally the U.S. Congress responded. Federal support for TB control under categori-
cal grants, which had all but disappeared, increased so that by 1996 the U.S. Cen-
ters 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 tuber-
culosis 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, smear-
positive 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 pro-
nouncement by the WHO Director General in 1993 that tuberculosis had become
a global public health emergency was unprecedented and attracted significant at-
tention 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).
Tuberculosis in the Future 869

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 di-
rect contributions to WHO. This enabled GTB to expand its work, focusing on ex-
tending 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 elimi-
nate tuberculosis. Unfortunately timed, the U.S. elimination plan was announced
by the Advisory Council on the Elimination of Tuberculosis (ACET) in 1989 dur-
ing 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, em-
phasizing 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 tu-
berculosis 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 tu-
berculosis control from heads of state of endemic countries, international organi-
zations, and donors. It will develop mechanisms to ensure global access to qual-
ity, 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 preva-
lence 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 tubercu-
losis 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 or-
ganism and the human host. We now have an improved understanding of both host
and microbial genetic factors related to increased resistance and susceptibility
(912), and we have advanced our understanding of the human protective immune
response to tuberculosis (13).
870 OBrien and Raviglione

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 avail-
able information for the development of new diagnostic, therapeutic, and immuno-
logical 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 my-
cobacteria 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 di-
agnosis of tuberculosis based on the amplification of nucleic acid have been li-
censed (see Chap. 14). These tests, which permit the identification of M. tubercu-
losis 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 pre-
sent are rather costly, so that their cost-effective application has not been estab-
lished (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 polymor-
phism (RFLP) analysis, have been used to identify M. tuberculosis strains impli-
cated 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-
Tuberculosis in the Future 871

ment. Clinical trials of short-course preventive therapy conducted in HIV-in-

fected patients have led to a recent recommendation from CDC for the use of a 2-
month 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 mecha-
nisms 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 impedi-
ments to control and ultimately eliminate tuberculosis, not only in low-incidence
countries such as the United States, but especially in high-incidence, resource-
poor 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. Epidemiologi-
cally, this translates into a vicious cycle of more disease, more transmission of in-
fection, and more persons likely to develop disease, including the young. In this
situation, the chain of transmission of tuberculosis cannot be interrupted. Al-
though the argument that only with social improvement and alleviation of poverty
will the tuberculosis situation improve has largely been discounted (28), these so-
cioeconomic 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). How-
ever, modeling data for this study based on earlier trends in tuberculosis morbid-
ity in Europe may not be applicable to the situation in developing countries. In ad-
dition, the requirement for a disease-specific program, a rather complex system
that may be difficult to sustain in many areas without continuing donor assistance,
872 OBrien and Raviglione

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 vari-
ous stages of implementation of DOTS in early 1997, only 32% of the human pop-
ulation were living in areas where effective tuberculosis-control programs were
fully implemented and operational (30). Thus, today probably only a small pro-
portion 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 es-
timated to have occurred (30). In addition, it is likely that only one third of the in-
fectious 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-notifica-
tion 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 Roma-
nia, Belarus, Ukraine, Moldova, the Baltic countries, the Caucasus, and the cen-
tral 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 tuber-
culosis, 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 transmis-
sion ending in new infections and new cases. Finally, and probably more impor-
tantly, almost all these countries are experiencing severe lack of drugs. This trans-
lates 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 Cte dIvoire.
In Russian prisons primary MDR TB is likely an even greater problem (see
Chap. 24). In a model DOTS program implemented by the Belgian nongovern-
mental organization Doctors Without Borders in tuberculosis penal colony in
Tuberculosis in the Future 873

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 com-
munication). In the bordering country of Azerbaijan, a team of doctors from the
International Red Cross has also documented high rates of both initial and ac-
quired drug resistance in prisoners (36).
As the century draws to a close, it is uncertain how MDR TB will be ad-
dressed. 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). Un-
fortunately, it is difficult to see how countries, such as Russia, that cannot pur-
chase standard drugs for DOTS can afford to care for their MDR TB cases.
HIV infection also threatens tuberculosis control in areas where both infec-
tions are prevalent (see Chap. 20). Evidence of the interaction between tuberculo-
sis and HIV is provided by HIV seroprevalence surveys, autopsy and clinical stud-
ies, 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 de-
veloping countries where persons at risk of acquiring HIV infection are equally at
risk of being infected with tuberculosis (39). WHO estimates that nearly 11 mil-
lion 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-in-
fected 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 tuber-
culosis control worldwide that diagnostic and treatment services should be pro-
vided free of charge. However, cost recovery in the health sector is being pro-
moted 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-rec-
ognized consequence of abandoning treatment, with subsequent failure and ac-
quisition of drug resistance. In the United States, the move to managed care threat-
ens to impede proven measures of tuberculosis control, such as contact
investigation and provision of DOT (41).
874 OBrien and Raviglione

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 struc-
tural and philosophical reorganization within WHO. These changes have led to a
renewed interest in consolidated control of communicable diseases and the inte-
gration of GTB, one of the most successful and prominent disease-specific pro-
grams of WHO, into the Communicable Disease Cluster. For some, the loss of
GTBs 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 19851992 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 ef-
fect 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 2010a not impossible goalan es-
timated 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, inves-
tigators at the Harvard School of Public Health have come to similar conclusions
about the potential impact of the DOTS strategy on the global tuberculosis prob-
lem (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-
Tuberculosis in the Future 875

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 mor-

bidity 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 remark-
able 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 tech-
nologies, including new vaccines. Even allowing for a 15-year developmental de-
lay in implementation, new vaccines would have the greatest impact. For exam-
ple, a postinfection vaccine that was 80% effective would prevent 52 million cases
876 OBrien and Raviglione

Figure 2 Projections of global deaths from tuberculosis, 19982030. 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 ex-
isting strategies, including mass preventive therapy (MassPT) and single cycle or continu-
ous 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, in-
cluding a vaccine preventing breakdown with 50% efficacy (VacBr50), a single-dose treat-
ment 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.)
Tuberculosis in the Future 877

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 find-
ing 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 elimina-
tion. Even with optimal tuberculosis screening and diagnosis, many patients with
newly diagnosed tuberculosis will have spread the infection to their closest con-
tacts 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 pa-
tients 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 chemotherapythe treatment of persons with latent M. tubercu-
losis infection to prevent the development of active TBcould play a major role
in TB elimination. However, the difficulties in identifying those persons at high-
est risk of disease and problems of nonadherence and drug toxicity limit the ef-
fectiveness of this strategy. Although some progress is being made, as exempli-
fied 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
878 OBrien and Raviglione

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 avail-
ability of tests that are feasible for use in low-income countries is another ques-
tion. The requirements for new diagnostics for the developing world have been de-
tailed (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 implemen-
tation 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 no-
table 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 fed-
eral support for tuberculosis control and elimination, CDC has returned to the pri-
vate-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 tri-
als 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 in-
crease 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 tuber-

culosis elimination or eradication. Such speculation is not new. Fifty years ago, un-
der the sponsorship of the National Tuberculosis Association (now the American
Tuberculosis in the Future 879

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 chemother-
apy 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 pub-
lic health problem appears to be within reach (47). However, in a prescient note
the conferees stated their concern that the remarkable progress made against tu-
berculosis 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 fin-
ishing a task that once was considered extremely urgent. Their recommendations
were succinct, taking only one printed page and calling for community mobiliza-
tion 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 re-
ports 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 pos-
sibility 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-inci-
dence countries, the priority was chemotherapy of infectious cases. Canetti felt
that the major impediment to progress in developed countries was patient non-
compliance with therapy as tuberculosis care was decentralized into general
medicine. Perhaps foreseeing the need for DOT, he predicted that a veritable sci-
ence 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 chemoprophy-
laxis, 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 im-
pediments, including migration of persons from high- to low-incidence countries
and the threat of primary drug resistance. He concluded that eradication was in-
deed possible in developed countries but that for moving toward global eradica-
tion there was only a single absolute priority: the perfecting of chemotherapeu-
880 OBrien and Raviglione

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 tuberculo-
sis 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 inter-
national 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 ear-
lier failures to achieve yaws and malaria eradication provided criteria for assess-
ing 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 an-
imal reservoirs and the high prevalence of latent infection to be important obsta-
cles 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, cu-
rative 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.
Tuberculosis in the Future 881

case finding in high-risk persons, and the development of a safer and more effec-
tive vaccine were needed before tuberculosis eradication would be feasible.
More recently, D. A. Henderson, who directed the WHO smallpox eradica-
tion 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 dis-
ease-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 sec-
ond is program leadership, where for tuberculosis there are notable successes. The
third is a technically sound and feasible plan, which will remain problematic for tu-
berculosis 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 sev-
eral 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 non-
compliance of multiple sectors in failing to deal adequately with a problem that
he sees as readily addressable: communities, physician and other health care pro-
fessionals, drug companies, governments, the press, international development
agencies, and even WHO. Reichman makes a valid point: if all interested and in-
fluential partners banded together in a concerted effort, we could and would elim-
inate 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 tubercu-
losis? 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?

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INDEX
A American Lung Association (ALA)
Abdominal tuberculosis, 355
Absolute concentration method, 173
Acid-fast bacilli
microscopic examination of, 161166, 347
role of in case finding, 95
Acquired resistance, 404
Activism (see Advocacy and social
mobilization)
Adherence
to directly observed therapy, 710
to treatment, 436438, 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, 846850
evaluation of results of, 857
main components of, 854858
research and training for, 860862
successful examples of, 850854
Aerobiology, 216221
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, 232234
Alaska, preventive therapy in, 473
Algiers, drug resistance in, 116118
Alpha antigen, 190
founding of, 16, 775777
mission of, 775779
American Thoracic Society (ATS)
mission of, 776779
treatment recommendations by, 419
Amikacin, 415, 417, 460
Amniotic fluid, infection of, 562
Amoxicillin-clavulanate, 461
Anergy
in HIV-infected persons, 531533
and preventive therapy, 489, 543
testing, 288
Animal models, in drug activity testing, 170
Anthropology, relevance to public health of,
750754
Antigens, 188192
Antituberculosis medications (see also
Chemotherapy; individual drugs;
Treatment)
in children, 579581
cost comparisons of, 464
drugdrug interactions of, 408412
first-line, 405414, 449
fixed-dose combinations of, 413
future development of, 878
research progress in, 870
resistance to, 448452
second-line, 414419, 870
Arabinogalactan, 192
Asia, national tuberculosis associations in,
784787
Auenbrugger, Leopold, 10
Australia, disease among immigrants to,
665683
Avicenna, 6
885
886 Index

B Case finding (see also Contact tracing)

and acid-fast bacilli detection, 95
Bacille Calmette-Gurin (see BCG) active, 325328
BACTEC method, 173, 349 in children, 560
community leadership in, 325
Baku Declaration, 660
as control measure, 58, 61
Bangladesh
in correctional facilities, 651653
national tuberculosis associations in, 785
definition of, 324
social mobilization in, 853
detection strategies for, 119124
BCG vaccination, 37
determinants of, 95, 123
administration of, 507
estimation of new infections by, 123
adverse reactions to, 512
indicators for, 120
causing false-positive tuberculin test,
information sources for, 119
290292
information systems for, 109111
in children, 576
in low-prevalence countries, 90
contraindications to, 507 methods of, 325332
controlled trials with, 96 passive, 328332
effect on nontuberculous mycobacteria of, of persons at risk, 326328
512 pragmatic approach to, 124
effect on serial tuberculin testing of, and radiographic examination, 95, 325
303305 results of, 121
efficacy of, 506, 508 by risk factor, 327, 331
for health care providers, 630 and tuberculosis control, 332
history of development of, 503505 use of screening in, 331
impact of, 513 user fees for, 834
policies of, 505508 Case management
BCG vaccines model, concept of, 600605
causes for variability of, 509512 the Newark experience, 599601
future research goals for, 516 Caseous tuberculous granuloma, 251
improvements upon, 514516 Cattle, tuberculosis in, 33
manufacturers of, 505 Cavitation, 252
Beijing family strain, 268 Cell-mediated immunity, 194199, 249
Biggs, Herman, 19 and HIVM. tuberculosis interactions, 530
Biopsy, 351 Cell wall, composition of, 159, 192
Bodington, George, 21 Centers for Disease Control and Prevention
Bone and joint tuberculosis, 354 (CDC)
Breastfeeding, 491 guidelines of, 229, 419
British Medical Research Council, regimen training initiatives funded by, 711
developed by, 419 Central nervous system tuberculosis
Bronchoalveolar lavage, 350 in children, 571573
Bronchoscopy, 350 diagnosis of, 353
Chemoprophylaxis (see also Prevention)
early experience with, 4042, 70
C in low-income countries, 57
Chemotherapy (see also Antituberculosis
Cabrini Hospital, infection-control measures medications; Treatment, or individual
at, 628 drugs)
Calmette, Albert, 36 to contain nosocomial spread, 624
Canada, disease among immigrants to, experimental, 171
665683 first trials of, 39
Canadian Lung Association, mission of, 779 prophylactic, 57
Canetti, George, 879 relative activities of drugs, 403
Capreomycin, 415, 417 results of, 58, 96
Index
Children
antituberculosis medications for, 579581
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, 574578
directly observed therapy in, 584
epidemiology in, 555560
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, 560563
pleural effusion in, 569
positive tuberculin reactions among, 132,
298
preventive therapy in, 479
public health programs for, 584586
radiographic examination of, 563569
scrofula in, 573
signs and symptoms in, 567
transmission in, 557
treatment in, 578586
of latent disease, 479, 491
regimens for, 406, 419421, 581586
trends of mortality in, 555
tuberculin skin testing in, 290, 293, 575,
585
tuberculosis in
of central nervous system, 571573
chronic, 569
clinical, 563574
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,
359363
diagnostic tests in, 343346
of drug susceptibility, 172175
immunodiagnostic, 175177
techniques of, 100, 157178
and DOTS-Plus programs, 463
function of, 99105
levels or categories of, 101103
under managed care, 820
quality-control of, 108, 820, 835
safety considerations in, 158
structure and function of, 101105
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, 3132
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, 385388
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, 385388
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, 381385
888
Contact tracing (see also Case finding)
challenges of, 394
for childhood disease, 560, 585
definition of, 378
methods of, 380391
reasons for, 379
in Singapore, 743
Control
building coalitions for, 696703
and chemotherapy, 5860
in correctional facilities, 651
early attempts at, 79
early concepts of, 1316
economic considerations in, 804807, 813
of HIV-associated infection, 544547
impact of managed care on, 819
impediments to, 843846
information system requirements for, 109
the Israeli experience at, 759765
in low-income countries, 6065, 871874
in low-prevalence countries, 8186
of nosocomial transmission, 617631
objectives of, 55, 604
the Philippine experience at, 693703
political commitment to, 799802, 833
projections for, 874877
strategies for, 108111
the Thailand experience at, 807814
through case finding, 58, 61, 332
through directly observed therapy, 598
Correctional facilities
case finding in, 651653
case study from Russia, 657660
control in, 651
epidemiology of tuberculosis in, 646648
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, 163165, 348
Cycloserine, 414, 416, 461
Cytolytic T lymphocytes, 250
D DNA fingerprinting (see also Restriction
Delayed-type hypersensitivity, 215, 249
Delays
in diagnosis, 348, 707
patient-related, 89, 328
Index
[Delays]
physician-related, 89, 329
in treatment, 328330
Developed countries (see Low-prevalence
countries)
Developing countries (see Low-income
countries)
Diagnosis
advances in, 870
chest radiography in, 343346
in children, 574578
computed tomography in, 346
of culture-negative disease, 251
delays in, 348, 707
future progress in, 878
history taking and physical examination in,
341343
of HIV-associated disease, 345, 531535
laboratory techniques in, 100
of primary tuberculosis, 344
of reactivated disease, 345
in resource-rich countries, 425
role of clinical laboratories in, 99105
role of tuberculin skin test in, 343
sputum sampling for, 346348
surveillance of, 89
tests for
early development of, 10, 2831
invasive, 350
routine, 343
user fees for, 834
Directly observed therapy, 40, 437, 448452
in children, 584
DOTS-Plus, 453466
in Israel, 762
as key to control, 598
in low-prevalence countries, 91
and managed care, 822825
in the Netherlands, 781
problems of adherence to, 710
short-course (DOTS), 438, 831833
advocacy for, 848850, 859, 862
creating worldwide demand for,
843846
definition of, 844
future impact of, 871881
in Singapore, 736, 742
as standard of care, 601605
fragment length polymorphism)
analysis of, 265
clinical applications of, 266270
in control programs, 84, 87
and HIVM. tuberculosis interactions, 530
Index 889

[DNA fingerprinting] Ethiopia, immigrants to Israel from, 667,

for mycobacterial identification, 29, 168, 746748, 757765
262 Ethnomedicine, 751754
patterns of, 268 Europe
Droplet nuclei, 216219 incidence rates in, 79
control of in health care facilities, 625627 national tuberculosis associations in,
infectious dose of, 225227 780782
Drug activity testing, 169175, 403 Exposure
in animal models, 170 duration of as risk factor, 131
Drug resistance intensity of as risk factor, 131
in Algiers, 116118 Extrapulmonary tuberculosis
causes of, 172 abdominal, 355
in Korea, 116 among immigrants, 672
in low-income countries, 62, 70 in children, 570573
in low-prevalence countries, 88 diagnosis of, 351356
mutations associated with, 175 genitourinary, 354
strategies against, 116118 pleural, 345, 352
Drugs (see also specific agents) treatment of, 427
bacterial resistance to, 116118, 403, 448
in vivo activity assessment of, 170
susceptibility testing of, 172 F
Fiberoptic bronchoscopy, 350
E Fluoroquinolones, 415, 417, 460, 870
Foreign-born (see Immigrants)
Fracastorius, Hieronymus, 7
Economics
DOTS-Plus program costs, 464
health-related concepts of, 802804 G
intervention models of, 804807
and preservation of free TB services, 834 Galen, 6
restraints in low-income countries, 69 Gender, as risk factor, 134, 138, 141
of Thailand control program, 807814 Genitourinary tuberculosis, diagnosis of, 354
Education Grady Memorial Hospital, infection-control
early public efforts at, 1921 measures at, 628
of health care providers, 707718, 743 Granuloma
information, education and communication caseous tuberculous, 251
campaigns, 846850 formation of, 194, 252
initiatives by IUATLD, 711713 Greenland, preventive therapy in, 473
Epidemiology Gurin, Camille, 36
administrative, 141149
among immigrants, 664675 H
in children, 555560
in correctional facilities, 646648 Health care facilities
of drug-resistance in Peru, 456 engineering controls in, 625
etiological, 130141 patient discharge criteria of, 630
in Singapore, 730732 tuberculosis transmission in, 610631
sociocultural, 751754 Health care providers (see also Physicians)
Eradication BCG vaccination for, 630
feasibility of, 878881 control measures for, 610, 621623
The Strategic Plan for the Elimination of education and training of, 705720, 743,
Tuberculosis in the United States, 848
706, 723725 risk of infection among, 614
Ethambutol, 406, 412 sociocultural considerations for, 746750
Ethionamide, 414, 416, 461 tuberculin conversions among, 615, 623
890
Health sector reform
elements and implications of, 829831,
838
future trends in, 839
impact on tuberculosis services of, 832
implications of, 873
in Israel, 762766
need for, 831
in the Netherlands, 82, 85
political commitment to, 833
and quality assurance, 838
and standardization of therapy, 835837
and treatment outcomes, 837
in the United States, 817825
Heat-shock protein antigen, 189
Henderson, D. A., 881
HEPA filtration, 232, 625627
Hepatitis, and isoniazid preventive therapy,
480
High-prevalence countries (see also Low-
income countries)
contact tracing in, 389391
preventing transmission in, 235
High-risk groups, emergence of, 84
Hindu Vedas, 5
Hippocrates, 6
HIV infection
anergy testing in, 288, 531533
mortality with, 526
present status of, 873
preventive therapy in, 484490, 494,
541544
as risk factor, 147, 326
in Singapore, 732
transmission in low-prevalence countries,
81
tuberculin skin testing in, 286289,
531533
tuberculosis in
annual risk of development of, 483
in children, 558, 583
clinical features of, 533535
control of, 544547
incidence of, 525527
influence of, 545547
multidrug-resistant, 539541
secondary infection of, 247
treatment of, 430432, 535541
HIVM. tuberculosis interactions, 202
among immigrants, 675
and cell-mediated immunity, 530
in correctional facilities, 649
diagnostic findings in, 345
Index
[HIVM. tuberculosis interactions]
in Singapore, 732
and treatment for latent tuberculosis,
482491
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, 672674
definition of, 662
drug resistance among, 675677
epidemiology of tuberculosis among,
664675
Ethiopians in Israel, 667, 747, 757765
HIV/TB interactions among, 675
impact of in low-prevalence countries,
7881, 84
influence of age on case rates among, 670
influence of country of origin among, 669,
672
screening strategies among, 678686
sociocultural differences among, 745750
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, 194199
genetic, 246
humoral, 199
and innate host resistance, 243
Immunoregulation, 200202
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, 225227, 242
Infection
causes of, 130134
in children, 554, 559
impact of HIV transmission on, 81
impact of immigration on, 78
in newborn infants, 562, 574
in patients with HIV, 531535
predictive value of positive skin test for,
299303
preventive therapy in, 478
rates in low-prevalence countries, 7581
and tuberculin conversion, 306308
Infection-control
guidelines of, 709
in health care facilities, 617629
Information, education and communication
campaigns, 846850
Information systems
aims and strategies of, 846850
for case finding, 109111
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, 405408, 460
development of, 39
preventive therapy with, 472481,
484491
risk-benefit analysis of, 480
and risk of hepatitis, 480
as single-drug therapy, 61
Israel
disease among immigrants to, 667683
Ethiopian immigrants in, 667, 746748,
757765
public health programs in, 759765
IUATLD
collaboration with national NGOs of,
782786, 790792
educational initiatives by, 711713
establishment of, 16, 55
guidelines of, 422425, 635
mission of, 774, 792795
model program developed by, 9799, 109,
832
preventive study conducted by, 478
891
[IUATLD]
programs and activities of, 787792
structure and budget of, 792
J
Japan, national tuberculosis associations in,
784
Joint tuberculosis, 354
K
Kanamycin, 415, 417, 460
Koch, Robert, 4, 1213, 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, 252255
Liver disease, tuberculosis treatment in, 428
Loewenstein-Jensen method, 100, 163
Low-income countries (see also High-
prevalence 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, 871873
health service maintenance in, 69
management strategies in, 6568
nosocomial transmission in, 616, 631
public health programs in, 6068
recognizing tuberculosis threat in, 68
redefining strategy in, 62
treatment of latent disease in, 496
treatment regimen options in, 422425
tuberculosis control in, 6065
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, 380389
892 Index

[Low-prevalence countries] Mantoux testing, 35, 282285, 296

diagnostic work-up in, 425 Marten, Benjamin, 9
directly observed treatment in, 91 Mass miniature radiography, 875
disease among immigrants to, 664669 Mass preventive therapy, 875877
disease transmission in Medicaid, and managed care, 819824
nosocomial, 616 Medical anthropology, relevant concepts of,
prevention of, 231234 750754
risk assessment of, 381385 Medicare, and managed care, 819
drug resistance in, 88 Meningitis, in children, 572
framework for control in, 8186 Mexico, patient-physician interactions in,
impact of HIV infection on, 81 756
impact of immigration on, 7881
Mice, natural resistance to infection of, 246
incidence in, 82
Microepidemics (see Outbreak
management strategies in, 8385
investigations)
public health programs in, 86
surveillance in, 8692 Middle East, nongovernmental organizations
treatment monitoring in, 425 in, 782
treatment regimens in, 419421 Miliary tuberculosis
tuberculosis elimination in, 7578 in children, 571
Lymphadenitis, diagnosis of, 353 diagnosis of, 344, 356
Lymphohematogenous dissemination, in Multidrug-resistant disease
children, 570 in children, 583
DOTS-plus regimens for, 453462
economic assessment of, 804807
M in HIV-infected persons, 539541
in immigrants, 675677
M. tuberculosis impact of DOTS on, 453, 466
antigens of, 188192 nosocomial transmission of, 612, 868
cell wall composition of, 159 outbreaks of, 235, 456
DNA fingerprint of, 168 in Peru, 450, 456459
drugs for in pregnancy, 429
in vivo activity assessment of, 170 treatment of, 39, 433435, 540
resistance of, 116118, 403, 448 failures of, 448552
susceptibility testing of, 172 preventive, 492, 494
evolution of, 4 principles of, 433435
genome elucidation of, 42, 870 surgical, 435
growth of, 159
Mycobacteria
nucleic amplification testing for, 177
antigens of, 159
physical and chemical characteristics of,
atypical, 166
158160
speciation of, 166 control of growth of, 249251
strain genotyping of, 168, 261270 culture of, 348
variability of affecting BCG vaccination, dissemination of, 248
511 early concepts of, 29
virulence of, as risk factor, 133 genetic alterations of, 268
Managed care identification and speciation of, 165168
concerns of health officials about, 820823 isolation of in children, 576
contracts and agreements for, 823825 nontuberculous (see Nontuberculous
impact on tuberculosis control of, 819821 mycobacteria)
Management strategies virulence of, 245
in low-income countries, 6568 Mycobacterial adjuvants, 193
in low-prevalence countries, 8385 Mycobacterial polysaccharides, 192
for social mobilization, 846850 Mycobacterial protein antigens, 188192
Index
N [Nosocomial transmission]
National Tuberculosis Associations, mission
of, 775787 (see also
Nongovernmental organizations)
National tuberculosis programs (see also
Public health programs)
basic principles of, 9799
informational function of, 104, 109
laboratory network structure, 101105
in the Philippines, 693703
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, 7578, 87
disease among immigrants to, 665684
health sector reform in, 82, 85
impact of HIV transmission on, 81
impact of immigration on, 7881
nongovernmental organizations in, 780
The Newark experience, 599605
New York City Health Department, model
programs of, 1721
Nongovernmental organizations (NGOs)
in Africa, 783
aims and structure of, 772775
in Asia, 784787
in Canada, 779
in Europe, 780782
future tasks of, 795
international partnerships among, 793795
in Latin America, 779
in the Middle East, 782
role of in advocacy, 862
in Singapore, 736
in the United States, 776779
Nonnucleoside reverse transcriptase
inhibitors (NNRTIs), 430432
Nontuberculous mycobacteria
effect on tuberculin testing of, 303305
and false-positive tuberculin test, 291296
identification and speciation of, 166
infection rates with, 148
Norway, nongovernmental organizations in,
782
Nosocomial transmission, 610631
containing spread of, 624
control of, 617631
893
in low-income countries, 616, 631
in low-prevalence countries, 616
of multidrug-resistant disease, 612, 868
prevention of, 617630
in the United States, 610615
Notification
form used in Singapore, 738741
rates in low-prevalence countries, 88
Nucleic acid amplification tests, 29, 177
in children, 577
costs and operational requirements of,
359361
diagnostic utility of, 356358
recommendations for clinical use of,
361363
O
Occupational Safety and Health
Administration
enforcement policies of, 631635
mandates of, 626
Ofloxacin, 415, 417, 460
Open lung biopsy, 351
Outbreak investigations, 83, 87, 227, 392
in correctional facilities, 650
within hospitals, 613616, 627629
in multidrug-resistant disease, 235, 456
in Peru, 456459
Outcome monitoring
definitions for, 110
and health sector reform, 837
in low-prevalence countries, 9092
Outcomes
analysis of, 111, 113115
economic assessment of, 802804
factors affecting, 709
P
Para-aminosalicylic acid, 414, 416, 460
treatment failures with, 449
Pathogenesis, 215217
in children, 560563
pathways of, 254
stage 1 invasion, 242248
stage 2 bacillary growth, 248
stage 3 infection control, 249252
stage 4 reactivation, 252254
Patient-provider interaction, 604, 753762
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,
456459
Phagocytosis, 243245, 249
The Philippines
Coalition Against Tuberculosis
(PHILCAT), 696703
national tuberculosis program in, 694696
Phrenic nerve crushing, 32
Phthisis, 69
Physical examination, 10, 341343
Physicians (see also Health care providers)
knowledge and practice deficiencies of,
708710
sociocultural awareness of, 753756
training and education of, 705720
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, 799802, 833
to health sector reform, 833
strategies for mobilization of, 844863
Polymerase chain reaction, 262, 357, 577
Potts 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, 541544
in immunocompetent hosts, 472481
mass therapy for, 875877
missed opportunities for, 707
of nosocomial transmission, 617630
Index
[Prevention]
projections for, 877
regimens for, 493496
intermittent, 482
prophylactic, 57, 472481
short-course, 481
risk-benefit analysis of, 479
Primary resistance, 404
Proportion method, 173
Protease inhibitors, 430432
interactions with rifamycins of, 412, 538
Psychosocial stress, as risk factor, 149
Public health programs (see also National
tuberculosis programs)
budgeting mechanisms of, 800802
and case management, 598
for children, 584586
in correctional facilities, 654
early efforts at, 1621
educational initiatives of, 711713
for immigrants, 678686
in Israel, 759765
in low-income countries, 6068
in low-prevalence countries, 82, 86
maintenance of, 85
and managed care, 822
in the Philippines, 694696
relevance of social sciences to, 746757
renewal of, 42
in Singapore, 729744
the Thailand experience, 807814
training initiatives of, 713720
Purified protein derivative
administration of, 280283
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, 563569
diagnostic findings at, 343346
Index
[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, 405408
fixed-dose combinations with, 413
Rifamycins
interactions with protease inhibitors, 412,
538
resistance to, 537
Rifapentine, 418, 461, 870
Risk assessment
in contact tracing, 381388
in health care facilities, 618622
Risk factors
among immigrants, 664672
contacts as, 377
in correctional facilities, 648
fibrotic lesions as, 328
for infection, 130135
for reactivation, 140
recent infection as, 327
source case as, 134, 138
susceptibility as, 135, 148
tuberculin sensitivity as, 514
for tuberculosis, 135140
Riviere, Clive, 29
Roentgen, Wilhelm Konrad, 10, 30
The Royal Netherlands Tuberculosis
Association (KNCV), 780782
Russia, tuberculosis in
in penal system, 657660, 872
rates of, 872
S 706, 723725
Sanatoria
controversies about, 2628
establishment of, 2128
at Saranac Lake, NY, 2326
895
Screening studies
among immigrants, 678686, 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, 742744
geopolitics of, 727729
health care services in, 729
incidence of tuberculosis in, 729734
national tuberculosis associations in, 785
treatment modalities used in, 732734
tuberculosis elimination program in,
734743
notification form of, 738741
Single-strand conformational polymorphism,
264
Skeletal tuberculosis, in children, 573
Social mobilization (see also Community
leadership and advocacy)
practical examples of, 858864
role of, 846850
strategies and elements of, 850854
suggestions for, 858863
use of communication media for, 856
Social sciences
basic concepts of, 750754
relevance to public health of, 746750
relevant literature of, 754757
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, 160168, 346349, 534
Stop TB initiative, 859, 869
The Strategic Plan for the Elimination of
Tuberculosis in the United States,
Streptomycin, 406, 413
first use of, 38
treatment failure with, 448
Styblo, Karel, 791, 863, 868
Surgery, thoracic, 32, 435
896
Surveillance
among immigrants, 678686
in correctional facilities, 653
in health care facilities, 622
in low-prevalence countries, 8692
in managed care, 820
Susceptibility
innate variation of, 246
as risk factor, 135, 148
testing of, 100, 172
T DOTS-Plus, 453462
Tanzania, control strategy in, 6366
T cells, 194199
function of, 243245, 249
Thailand
national tuberculosis associations in, 785
tuberculosis control program in, 807814
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, 707718
methods of, 714716
objectives of, 715
target audiences for, 714
Transmission
in children, 557
in correctional facilities, 648
determinants of, 56
dynamics of, 56
early concepts of, 1216
epidemiology of, 221225
by immigrants, 577
mathematical models of, 222225
nosocomial, 610631
prevention of, 228, 230234
probability of, 56
by released prisoners, 649651, 654
in Russian penal system, 658
sources of, 325330
surveillance of, 87
from unsuspected sources, 230
Index
Transthoracic fine needle aspiration, 350
Treatment (see also Antituberculosis
medications; Chemotherapy)
adherence to, 436438, 757
after relapse, 427
barriers to, 759762
in children, 578586
in chronic renal failure, 428
in correctional facilities, 653
in culture-negative disease, 428
delays in, 328330
DOT and DOTS, 437, 448452
early trials of, 3840
evaluation of, 113116
failures of, 426, 448452
future of, 438
and health sector reform, 835838
in HIV infection, 430432, 535541
intermittent, 404
in multidrug-resistant disease, 39,
433435, 540
practical recommendations for, 763765
in pregnancy, 429
preventive, 471
prospective surveys of, 118
regional outcomes of, 113115
retreatment regimens, 450
in Singapore, 732734
sociocultural barriers to, 748750,
755761
strategies of, 111119
surgical, 32, 435
theoretical basis for, 402405
Treatment regimens, 871
causes of failure of, 449452
for children, 406, 419421, 581586
description of, 419425
in HIV infected persons, 484490
in HIV-infected persons, 535540
individualized, 453, 459
for multidrug-resistant organisms, 540
problems of adherence to, 710
short-course
evaluation of, 119
failures of, 451
Trudeau, Edward L., 2325
Trudeau Institute for Research, 23
Trudeau Society, 776
Tuberculin reaction
in children, 132, 575
interpretation of, 296301
Index
[Tuberculin reaction]
interval from infection, 307309
predictive value of, 299301
and preventive treatment, 488
risk analysis with, 302
as risk factor, 139
Tuberculin skin testing, 40, 175, 343
administration of test, 280283
adverse reactions to, 285
boosting and conversion, 301308
in children, 575, 585
conclusions about, 310
of contacts, 388
early development of, 3336
effect of BCG vaccination on, 291
for health care providers, 615, 623
in HIV-infected persons, 531533
materials for, 281
reading of test, 283285
results of
false-negative, 286289
false-positive, 290295
true-positive, 296299
reversion, 308
role of in diagnosis, 343
technical aspects of, 280285
Tuberculomas, 344
in children, 572
Tuberculosis
adjunctive therapies, 3133
in cattle, 33
congenital, 562
development of new vaccines against,
514517
dream of eradication of, 877881
early appearances of, 3, 47, 129
early public education campaigns, 1921
effect of HIV infection on, 529531
evolution of public health campaigns,
1621
extrapulmonary (see Extrapulmonary
tuberculosis; specific sites)
history of
early, 57, 11
the past decades, 867871
16th18th century, 710
19th20th century, 1043
in HIV-infected persons, 533535
immunodiagnostic tests for, 175177
modeling future course of, 874877
multidrug-resistant (see Multidrug-
resistant disease)
897
[Tuberculosis]
new research on, 869
present outlook of, 871874
prevalence of HIV infection among, 528
primary, 344, 555, 560562
pulmonary symptoms in, 342346
reactivation of, 345
sociocultural determinants in, 745750
spread of, 661
stages of development of, 242254
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, 232235, 625
United States
case rates in, 142146
childhood disease in, 556
disease among immigrants to, 665686
DOTS-Plus program costs in, 464
education and training needs in, 707720
health sector reform in, 817825
nosocomial transmission in, 610615
prisoner-transmitted disease in, 650
The Strategic Plan for the Elimination of
Tuberculosis, 706, 723725
treatment regimen options in, 419421
V
Vaccination (see also BCG)
early trials of, 36
future development of, 875877
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 Index

WHO [WHO]
advocating implementation of DOTS, 845, treatment recommendations by, 422425,
874 427
Expert Committee report by, 6365, World Bank, loans to low-income countries
9699 by, 68
Global Tuberculosis Programme of, 868 World Health Organization (see WHO)
guidelines of, 6165, 113116, 635
partnerships with NGOs of, 794 Z
projections by, 874 Ziehl-Neelsen sputum smear microscopy, 96,
proposed goals for year 2000, 107 100, 161