Tuberculosis

TUBERCULOSIS CONTENTS Preface Neil W. Schluger Global Epidemiology of Tuberculosis Dermot Maher and Mario Raviglione ...

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TUBERCULOSIS

CONTENTS

Preface Neil W. Schluger Global Epidemiology of Tuberculosis Dermot Maher and Mario Raviglione

ix

167

This article provides an overview of the current scale of the global tuberculosis epidemic. It describes the global tuberculosis situation as measured by reported and estimated cases and deaths. The increasing threats of HIV-related tuberculosis and drug-resistant tuberculosis receive particular attention. There is a brief review of the extent of implementation of effective tuberculosis control using the directly observed treatment, short-course (DOTS) strategy. The article ends with a summary of the approaches needed to accelerate progress in global tuberculosis control.

Epidemiology of Tuberculosis in the United States Eileen Schneider, Marisa Moore, and Kenneth G. Castro

183

After decades of decline, an unprecedented resurgence in tuberculosis occurred in the late 1980s and early 1990s. Deterioration of tuberculosis program infrastructure, the HIV/AIDS epidemic, drug-resistant tuberculosis, and tuberculosis among foreignborn persons contributed to the resurgence. Since then, tuberculosis case numbers have declined, but the decline in 2003 was the smallest since the resurgence. Key challenges remain, and efforts must focus on identifying and targeting interventions for high-risk populations, active involvement in the global effort against tuberculosis, developing new tools, and maintaining adequate resources.

The DOTS Strategy for Controlling the Global Tuberculosis Epidemic Thomas R. Frieden and Sonal S. Munsiff

197

This article reviews the principles, scientific basis, and experience with implementation of the directly observed treatment, short-course (DOTS) strategy for tuberculosis. The relevance of DOTS in the context of multidrug-resistant tuberculosis and the HIV epidemic also is discussed.

The Origin and Evolution of Mycobacterium tuberculosis Serge Mostowy and Marcel A. Behr

207

This article introduces the tools and terminology used for the classification of specific isolates of the Mycobacterium tuberculosis complex (MTC). The utility of these tools and

VOLUME 26 • NUMBER 2 • JUNE 2005

v

terminology is illustrated by discussing work from independent laboratories that have established a genome-based phylogeny for the MTC. It considers the use of these markers to distinguish atypical isolates not conforming to attributes of traditional MTC members. Finally, it discusses the current genomic evidence regarding the origin and evolution of M. tuberculosis in the context of its relevance for tuberculosis control in humans and other mammalian hosts.

Molecular Epidemiology: A Tool for Understanding Control of Tuberculosis Transmission Charles L. Daley

217

One of the primary goals of tuberculosis control programs is to interrupt the transmission of Mycobacterium tuberculosis. The development of several genotyping tools has allowed tracking of strains of M. tuberculosis as they spread through communities. Studies that have combined the use of genotyping with conventional epidemiologic investigation have increased the understanding of the transmission and pathogenesis of tuberculosis. This article reviews some of the lessons learned using these new epidemiologic tools.

Genetic Susceptibility to Tuberculosis Richard Bellamy

233

Host genetic factors are important in determining susceptibility and resistance to Mycobacterium tuberculosis. The etiology of tuberculosis is complex, and several host genes have been shown to contribute to the development of clinical disease. The success of the strategies used to investigate host genetic susceptibility to mycobacterial infections can serve as a model for the investigation of host susceptibility to other infectious diseases.

The Diagnosis of Tuberculosis Daniel Brodie and Neil W. Schluger

247

Diagnostic testing for tuberculosis has remained unchanged for nearly a century, but newer technologies hold the promise of a true revolution in tuberculosis diagnostics. New tests may well supplant the tuberculin skin test in diagnosing latent tuberculosis infection in much of the world. Tests such as the nucleic acid amplification assays allow more rapid and accurate diagnosing of pulmonary and extrapulmonary tuberculosis. The appropriate and affordable use of any of these tests depends on the setting in which they are employed.

Treatment of Active Tuberculosis: Challenges and Prospects Behzad Sahbazian and Stephen E. Weis

273

This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and several special situations that clinicians are likely to encounter in medical practice.

Issues in the Management of HIV-Related Tuberculosis William J. Burman

283

This article focuses on the ways in which HIV infection and the associated immunodeficiency affect the management of active tuberculosis. Controversies in the management of HIV-related tuberculosis can be grouped into issues about tuberculosis treatment itself and

vi

CONTENTS

issues posed by the use of combination antiretroviral therapy. The author reviews these controversies and makes recommendations for the management of HIV-related tuberculosis.

Tuberculosis in Children Kristina Feja and Lisa Saiman

295

The epidemiology of pediatric tuberculosis (TB) is shaped by risk factors such as age, race, immigration, poverty, overcrowding, and HIV/AIDS. Once infected, young children are at increased risk of TB disease and progression to extrapulmonary disease. Primary disease and its complications are more common in children than in adults, leading to differences in clinical and radiographic manifestations. Difficulties in diagnosing children stem from the low yield of mycobacteriology cultures and the subsequent reliance on clinical case definitions. Inadequately treated TB infection and TB disease in children today is the future source of disease in adults.

Treatment of Latent Tuberculosis Infection: Challenges and Prospects Kelly E. Dooley and Timothy R. Sterling

313

This article reviews the treatment of latent tuberculosis infection in HIV-seropositive and HIV-seronegative persons.

New Drugs for Tuberculosis: Current Status and Future Prospects Richard J. O’Brien and Mel Spigelman

327

This article reviews two classes of compounds that have advanced into phase II and III clinical trials, long-acting rifamycins and fluoroquinolones, and a number of other drugs that have entered or may enter clinical development in the near future.

The Global Alliance for Tuberculosis Drug Development—Accomplishments and Future Directions Charles A. Gardner, Tara Acharya, and Ariel Pablos-Méndez

341

The Global Alliance for Tuberculosis Drug Development (TB Alliance) aims to stop the spread of tuberculosis by developing new, faster-acting, and affordable tuberculosis drugs. The TB Alliance is a public–private partnership, a not-for-profit enterprise, that draws upon the resources of both private and public institutions to help address this urgent health need. This article summarizes some of the achievements of the TB Alliance to date and outlines potential future directions.

Index

CONTENTS

349

vii

Clin Chest Med 26 (2005) 349 – 353

Index Note: Page numbers of article titles are in boldface type.

A

tuberculosis in, 295 – 312 diagnosis of smear for acid-fast bacilli and mycobacterial culture, 306 epidemiology of, 295 – 297 extrapulmonary, 300 – 302 in newborns, 302 – 303 latent clinical and radiographic manifestations of, 299 – 303 diagnosis of, 303 – 306 infectious, 299 risk factors for, 297 – 298 treatment of, 306 – 309 pathogenesis of, 298 – 299 prevalence of, 295 public health aspects of, 309 – 310 pulmonary, 299 – 300 tuberculous disease, 299

Age as factor in tuberculosis, 186 Aminoglycoside(s) for active tuberculosis, 277 Amplification phage in pulmonary tuberculosis diagnosis, 261 – 262 Antimycobacterial agents for active tuberculosis, 274 – 277 Antiretroviral therapy with tuberculosis treatment challenges of, 286 – 292

B Bacille Calmette-Guerin vaccination effect on tuberculin skin test, 306 Bronchoscopy fiberoptic in pulmonary tuberculosis diagnosis, 256 – 257

Culture(s) in pulmonary tuberculosis diagnosis, 257 – 258

D Diarylquinolones (R207910) for tuberculosis, 333 Dihydroimidazo-oxazoles (OPC-67683) for tuberculosis, 335

C Chemotherapy for active tuberculosis axioms of, 273 – 274 standardized short-course in DOTS strategy for controlling global tuberculosis epidemic, 198 – 199 Children latent Mycobacterium tuberculosis infection in treatment of, 322

1,25-Dihydroxyvitamin D3 in genetic susceptibility to tuberculosis, 238 Directly observed treatment, short-course (DOTS) strategy for controlling global tuberculosis epidemic, 197 – 205 administrative commitment to, 197 drug quality in, 199 for multi-drug resistant TB, 200 – 201 HIV infection and, 201 – 202

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/S0272-5231(05)00042-0

chestmed.theclinics.com

350

INDEX

political commitment to, 197 results of, 200 sputum microscopy of patients attending health facilities, 198 standardized short-course chemotherapy, 198 – 199 systemic monitoring and accountability, 200 DOTS. See Directly observed treatment, short-course (DOTS) strategy. Drug(s) for tuberculosis, 327 – 340 new agents. See also specific drug and Tuberculosis, treatment of, drugs in. tuberculosis resistant to, 175 – 176 Drug resistance in pulmonary tuberculosis diagnosis rapid detection of, 261 – 262 tuberculosis effects of transmission- and pathogenesis-related, 222

Global Alliance for Tuberculosis Drug Development, 341 – 347 described, 341 – 342 future directions for, 346 global product development public – private partnerships, 346 strategy of, 342 – 345 Global product development public – private partnerships in Global Alliance for Tuberculosis Drug Development, 345 – 346

H HIV. See Human immunodeficiency virus (HIV) infection. HLA-DR2 in genetic susceptibility to tuberculosis, 238 Human immunodeficiency virus (HIV) infection tuberculosis and. See Tuberculosis, HIV-related.

I E Ethambutol for active tuberculosis, 276 Ethnicity as factor in tuberculosis, 186

F Fiberoptic bronchoscopy in pulmonary tuberculosis diagnosis, 256 – 257 Fingerprinting patterns in Mycobacterium tuberculosis complex study, 208 Fluoroquinolones for active tuberculosis, 276 – 277

Interferon gamma signaling pathway in genetic susceptibility to tuberculosis, 237 – 238 Isoniazid for active tuberculosis, 275 for latent Mycobacterium tuberculosis infection, 316 – 319 rifampin with for latent Mycobacterium tuberculosis infection, 320 – 321

L Large-sequence polymorphisms in Mycobacterium tuberculosis complex study, 210 Line probe assays in pulmonary tuberculosis diagnosis, 261 LL3858 for tuberculosis, 335

G

Luciferase reporter phages in pulmonary tuberculosis diagnosis, 262

Genetic susceptibility to tuberculosis, 233 – 246. See also Tuberculosis, genetic susceptibility to.

M

Genome(s) sequenced in Mycobacterium tuberculosis complex study, 208

Macrolide(s) for tuberculosis, 335 – 336 Mannan-binding lectin (MBL) in genetic susceptibility to tuberculosis, 238

351

INDEX

MBL. See Mannan-binding lectin (MBL). Molecular beacons in pulmonary tuberculosis diagnosis, 261 Moxifloxacin for tuberculosis, 331 – 333 Mycobacterium tuberculosis dissemination of, 226 geographic distribution of, 226 origin and evolution of, 207 – 216 Mycobacterium tuberculosis complex characteristics of, 207 deletions from, 212 – 214 genetic resources in study of, 207 – 210 fingerprinting patterns, 208 large-sequence polymorphisms, 210 sequenced genomes, 208 single-nucleotide polymorphisms, 208 – 210 origin and evolution of chronologic, 211 – 212 ecologic, 211 – 212 genomic deletions and, 210 – 211 geographic, 211 – 212 Mycobacterium tuberculosis infection latent diagnosis of, 223 treatment of, 313 – 326 challenges of, 322 – 323 difficulties with, 322 – 323 implementation-related issues in, 323 importance of, 314 in children, 322 in contacts of persons with drug-resistant tuberculosis, 322 in special situations, 322 indications for, 313 – 314 isoniazid in, 316 – 319 with rifampin, 320 – 320 monitoring for toxicity in, 323 prospects for improvements in, 323 regimens in, 314 – 316 rifampin in, 321 with pyrazinamide, 319 – 320 TNF-a antagonists and, 322 treatment completion rates in, 322 – 323 treatment initiation problems in, 322

N National tuberculosis surveillance system, 184 Natural resistance – associated macrophage protein in genetic susceptibility to tuberculosis, 235 – 237

Newborn(s) tuberculosis in, 302 – 303 Nitroimidazopyran(s) (PA-824) for tuberculosis, 333 – 335 Nucleic acid amplification assays in pulmonary tuberculosis diagnosis, 258 – 260

O OPC-67683 for tuberculosis, 335 Oxazolidinones for tuberculosis

P PA-284 for tuberculosis, 333 – 335 Phage(s) lucifer reporter in pulmonary tuberculosis diagnosis, 262 Phage amplification in pulmonary tuberculosis diagnosis, 261 – 262 Polymorphism(s) large-sequence in Mycobacterium tuberculosis complex study, 210 single-nucleotide in Mycobacterium tuberculosis complex study, 208 – 210 Pyrazinamide for active tuberculosis, 277 rifampin with for latent Mycobacterium tuberculosis infection, 319 – 320 Pyrrole (LL3858) for tuberculosis, 335

R R207910 for tuberculosis, 333 Race as factor in tuberculosis, 186 Rifampin for latent Mycobacterium tuberculosis infection, 321

352

INDEX

isoniazid with for latent Mycobacterium tuberculosis infection, 320 – 321 pyrazinamide with for latent Mycobacterium tuberculosis infection, 319 – 320 Rifamycins for active tuberculosis, 275 – 276 Rifapentine for tuberculosis, 328 – 331

S Single-nucleotide polymorphisms in Mycobacterium tuberculosis complex study, 208 – 210 Sputum in pulmonary tuberculosis diagnosis, 255 – 256 SQ109 for tuberculosis, 336 – 338

T TNF-a antagonists. See Tumor necrosis factor-a (TNF-a) antagonists. Tuberculin skin test bacille Calmette-Guerin vaccination effects on, 306 in active tuberculosis diagnosis, 255 in latent tuberculosis diagnosis, 248 – 251 in latent tuberculosis in children, 305 – 306 Tuberculosis active diagnosis of tests in, 254 – 255 treatment of, 273 – 282 aminoglycosides in, 277 antimycobacterial agents in pharmacology and toxicity of, 274 – 277 chemotherapy in axioms of, 273 – 274 ethambutol in, 276 fluoroquinolones in, 276 – 277 guidelines in, 277 – 280 in special situations, 279 – 280 isoniazid in, 275 pyrazinamide in, 277 rifamycins in, 275 – 276

control of, 214 diagnosis of, 247 – 271 rapid detection of drug resistance in, 261 – 262 drug-resistant, 175 – 176 contacts of persons with latent Mycobacterium tuberculosis infection treatment in, 322 in U.S. epidemiology of, 189 – 190 genetic susceptibility to, 233 – 246 1,25-dihydroxyvitamin D3 and, 238 HLA-DR2 and, 238 host genetics in, 234 – 235 identification of, 235 interferon gamma signaling pathway and, 237 – 238 MBL and, 238 natural resistance – associated macrophage protein and, 235 – 237 global epidemic of control of acceleration in progress of, 179 – 180 DOTS strategy in, 197 – 205. See also Directly observed treatment, shortcourse (DOTS) strategy, for controlling global tuberculosis epidemic. status of, 178 – 179 deaths due to, 170 – 171, 175 epidemiology of, 167 – 182 new cases, 176 – 178 prevalence of, 170 – 171, 172 – 174 review of, 167 – 178 HIV-related, 171 – 172, 190 – 191 DOTS strategy in control of, 201 – 202 treatment of adherence to, 287 antiretroviral therapy with, 286 – 292 drug – drug interactions in, 288 immune reconstitution inflammatory events in, 289 – 290 issues in, 283 – 294 optimal duration of therapy in, 284 – 286 overlapping adverse event profiles in, 287 – 288 recommendations in, 286, 292 in children, 295 – 312. See also Children, tuberculosis in. in U.S. elimination of, 192 epidemiology of, 183 – 195 age and, 186 foreign-born persons and, 186 – 189 historical background of, 183 – 184 post-resurgence, 185 – 192

353

INDEX

treatment of diarylquinolones (R207910) in, 333 dihydroimidazo-oxazoles (OPC-67683) in, 335 drug development for, 328 Global Alliance for, 341 – 347. See also Global Alliance for Tuberculosis Drug Development. drug(s) in new, 327 – 340 pipeline of, 333 – 338 macrolides in, 335 – 336 moxifloxacin in, 331 – 333 nitroimidazopyrans (PA-284) in, 333 – 335 oxazolidinones in, 336 pyrrole (LL3858) in, 335 rifapentine in, 328 – 331 SQ109 in, 336 – 338 widely spaced intermittent, 328 – 331

race/ethnicity factors, 186 resurgence, 184 – 185 latent diagnosis of beyond tuberculin skin test in, 251 – 254 tests in, 248 – 254 tuberculin skin test in, 248 – 251 multi-drug resistant global epidemic of control of DOTS strategy in, 200 – 201 new tools for, 191 – 192 pathogenesis of drug resistance effects on, 222 lessons learned regarding, 219 – 226 pulmonary diagnosis of cultures in, 257 – 258 fiberoptic bronchoscopy in, 256 – 257 line probe assays in, 261 luciferase reporter phages in, 262 methods in, 255 – 260 molecular beacons in, 261 nucleic acid amplification assays in, 258–260 phage amplification in, 261 – 262 sputum in, 255 – 256 tuberculin skin test in, 255 in children, 299 – 300 transmission of community epidemiology and, 224 contact investigations, 222 – 223 control of genotyping methods in, 217 – 219 molecular epidemiology and, 217 – 231 future of, 226 drug resistance effects on, 222 exogenous reinfection and, 220 – 222 infectiousness of patients and, 219 – 220 lessons learned regarding, 219 – 226 mixed infection and, 220 – 222 outbreak investigations, 222 – 223 risk factors for clustering in, 224

Tuberculosis control program performance of measurement of, 224 – 226 Tuberculosis disease case definitions of, 303 – 305 Tuberculosis infection latent treatment of, 313 – 326. See also Mycobacterium tuberculosis infection, latent, treatment of. Tuberculosis/HIV coinfection, 190 – 191 Tumor necrosis factor-a (TNF-a) antagonists latent Mycobacterium tuberculosis infection treatment and, 322

V Vaccination(s) bacille Calmette-Guerin effect on tuberculin skin test, 306

Clin Chest Med 26 (2005) 183 – 195

Epidemiology of Tuberculosis in the United States Eileen Schneider, MD, MPHa,*, Marisa Moore, MD, MPHa,b, Kenneth G. Castro, MDa a

Division of Tuberculosis and Elimination, Centers for Disease Control and Prevention, 1600 Clifton Road, MS E-10, Atlanta, GA 30333, USA b TB Control Program, San Diego County Health and Human Services, Department of Public Health Services, 3851 Rosecrans Street, MS P511D, San Diego, CA 92110, USA

Historical background The epidemiology of tuberculosis (TB) in the United States has changed remarkably over the last 2 centuries. In the nineteenth century, TB was the leading cause of death. As the nineteenth century progressed, TB mortality decreased, partly because of improved socioeconomic conditions [1,2], especially in urban settings, and partly owing to the natural behavior of epidemics [3]. After the tubercle bacillus was identified as the causative agent of TB by Robert Koch in 1882, the approach to TB control changed greatly, and the concepts of public health, prevention, and segregation of TB patients gained more acceptance. As a result, in industrialized countries, the prescribed treatment of rest, isolation, nutrition, and fresh air for TB patients was achieved with long stays in sanatoria [1,2]. By the late 1800s, TB was more than ever considered a public health issue, even though there were few well established local or state public health departments [1,2,4]. More resources became available, and public health programs dedicated to TB control were established. In 1904, the first voluntary health agency dedicated to TB, the National Tuberculosis Association (now the American Lung Association), was organized [1,5]. TB surveillance and

This work was funded by the Division of Tuberculosis and Elimination, Centers for Disease Control and Prevention. * Corresponding author. E-mail address: [email protected] (E. Schneider). 0272-5231/05/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.ccm.2005.02.007

data collection was a priority for the National Tuberculosis Association. As the mortality rate continued to decrease, attention focused on TB case finding. Armed with a new diagnostic tool, the chest roentgenogram, mass chest radiograph screenings were conducted beginning in the early 1930s and continuing into the 1950s, enabling the diagnosis of TB patients before they became symptomatic [2]. The need to expand data collection to include TB morbidity in addition to TB mortality was acknowledged [1,2]. Reliable and complete morbidity data would allow TB experts to measure more accurately the magnitude of the TB problem and the effectiveness of control efforts. In 1920, the National Tuberculosis Association published its first Diagnostic Standards and Classifications of TB to assist health care providers and standardize diagnostic criteria [5,6]. National TB mortality and morbidity data, coordinated by the National Tuberculosis Association, became available in 1933. In 1944, a United States Public Health Service Act mandated the creation of a national TB control program [1]. With the introduction of the therapeutic agents streptomycin (1947), p-aminosalicylic acid (1949), isoniazid (1952), and pyrazinamide (1952) TB mortality rates decreased dramatically. Between 1930 and 1960, the mortality rate decreased by 92%, from 71 to 6 deaths per 100,000 population. Because of the widespread use of chemotherapy, long hospitalizations for TB were no longer needed, and TB sanatoria and hospitals began to close [1,2,5]. Having a standard definition for a reportable case of TB for surveillance purposes became paramount [7],


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and in 1951, a committee consisting of state TB control officers and sanatoria directors published recommendations for TB case reporting and counting procedures [8]. In 1952, the United States Public Health Service (USPHS) Tuberculosis Control Program instituted procedures to report new cases of TB. Not until 1953, through the cooperation of the states, did the USPHS receive reports from the entire United States, heralding the birth of the national TB surveillance system [1,2]. National tuberculosis surveillance system Since 1953, the national TB surveillance system has been modified several times to monitor and respond better to changes in TB morbidity. Data are collected on TB cases that have been verified and have met the Centers for Disease Control and Prevention (CDC) public health surveillance case definition for TB [9,10]. TB is a reportable disease in each state [11]. In 1985, the national TB surveillance system changed: originally collecting aggregate data, the CDC began collecting individual case reports on a form called the Report of Verified Case of Tuberculosis (RVCT). Currently, data are collected by reporting areas (the 50 states, the District of Columbia, New York City, Puerto Rico, and jurisdictions in the Pacific and Caribbean) using the RVCT. An RVCT is completed for each reported new TB disease case and contains patient demographic, clinical, and laboratory information. An RVCT is completed by the health department for each confirmed TB case and transmitted to the CDC to be included in the national TB surveillance database. The CDC annually publishes a report summarizing national TB statistics [10]. Also included in this annual report are the ‘‘Recommendations for Counting Reported TB Cases,’’ which were last revised in 1997. The CDC has maintained a computer database on TB surveillance data since 1985. State and local TB programs have been able to collect, manage, and transfer TB surveillance data (i.e., RVCT) electronically to the CDC first through software for expanded TB surveillance (SURVS-TB, 1993 – 1997) and currently through the Tuberculosis Information Management System (TIMS, 1998 – present). In 1993, the RVCT was expanded to collect additional information (eg, drug resistance, HIV infection) in response to the TB epidemic of the mid-to-late 1980s and early 1990s. The most recent modification was implemented in January 2003 to meet federal standards for the classification of race and ethnicity. Additional changes for the national TB surveillance system are on the horizon with a revision of the RVCT.

Reporting of RVCT data to the CDC also will be modified with the transitioning of the TIMS to the Web-based National Electronic Disease Surveillance System.

Tuberculosis resurgence Noting that extraordinary strides against TB have been made both in treatment and surveillance since the 1950s, many TB experts have believed that TB elimination in the United States is within reach [1,2]. In 1959, the historic Arden House Conference, sponsored by the National Tuberculosis Association and the USPHS Tuberculosis Control Program, brought together TB experts to formulate a plan on how to eliminate TB; this plan served as a basis for future TB control efforts [12]. TB incidence continued to decrease. From 1953 through 1985, TB case numbers decreased by 74%, from 84,304 to 22,201 cases, and the case rate decreased by 82%, from 53.0 to 9.3 cases per 100,000 population. As a result, many no longer considered TB to be a major problem. In the early 1970s, federal funding allocated for TB control began to decrease, and, as a result, many TB control services were dismantled [13,14]. Although TB funds were decreasing, the cost of treating TB was increasing. In 1981, only $3.7 million was appropriated to the CDC to fight TB nationally. In 1987, the Advisory Committee (now Council) for Elimination of Tuberculosis (ACET) was established, and its membership was directed to develop a strategic plan for TB elimination [15]. The ACET and the CDC published this plan, proposing a TB incidence interim goal for the year 2000 of 3.5 or fewer TB cases per 100,000 population and an elimination target of less than 1 TB case per million population by 2010. In the mid-to-late 1980s, however, the longstanding downward trend in TB incidence was interrupted. In 1986, a 2.6% annual increase in the case number was documented, signaling the beginning of the TB resurgence (Fig. 1). In the late 1980s, after decades of decreasing TB incidence, TB once again became a major threat. The resurgence had a significant impact on TB control strategies in the United States. Because of newly identified risk groups, the focus of many TB control strategies had to be shifted, and many programs needed to be overhauled. CDC researchers concluded that the resurgence had resulted in an estimated 52,100 excess TB cases from 1985 through 1992 [16]. Several factors have been linked to the resurgence, including the deterioration of the TB program infrastructure, the HIV/AIDS epidemic,

epidemiology of tuberculosis in the united states

185

Number of TB Cases

28,000 26,000 24,000 22,000 20,000 18,000 16,000 14,000 12,000 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Year Fig. 1. Reported tuberculosis cases in the United States from 1981 to 2003.

drug-resistant TB, TB among foreign-born persons, and an increase in transmission, especially in congregate and institutional settings [16 – 19]. The degree to which each of these factors affected TB control at the local level varied, but two of these factors, the HIV/AIDS epidemic and TB among foreign-born persons, strongly influenced the TB resurgence in the United States. HIV infection is considered to be the greatest risk factor known today for TB. Several large outbreaks of multidrug-resistant TB (MDR-TB) (ie, TB resistant to at least isoniazid and rifampin) among persons infected with HIV were documented in Florida and New York City [20 – 22]. In 1991, 41% of culture-positive TB patients in New York City were also infected with HIV, and 19% had MDR-TB [23]. Early diagnosis of TB among persons infected with HIV was difficult because of the lack of specific clinical findings, such as a positive tuberculin skin test result and an abnormal chest radiograph. Ineffective isolation precautions also contributed to nosocomial transmission of MDR-TB among patients and health care providers [24 – 26]. HIV-related TB outbreaks were also documented in other congregate settings [27] such as correctional facilities [28] and homeless shelters [29,30]. Another important factor fueling the TB resurgence was the immigration of persons from countries that have high rates of TB [19]. The proportion of reported TB cases among foreign-born persons increased from 22% in 1986 (the first year birthplace data were collected by the national TB surveillance system) to 30% in 1993. In the early 1990s, the newly established Federal Tuberculosis Task Force revaluated existing TB strategies and formulated the National Action Plan to Combat MDR-TB [31]. In the United States, a monumental public health effort to control TB was initiated [32,33]. Federal funding was increased and used to rebuild the TB infrastructure, strengthen sur-

veillance, augment case finding and contact investigations, advance laboratory capacity (eg, drugsusceptibility testing and new diagnostic tools), and ensure each patient completed therapy through the use of directly observed therapy (DOT).

After the tuberculosis resurgence, 1993 – 2003 During the resurgence, the national TB incidence peaked in 1992 at 26,673 cases (10.5 cases per 100,000 population). The aggressive attack on TB in the United States resulted in the annual TB case number and case rate decreasing in 1993 to 25,108 cases, 9.7 cases per 100,000 population. Tuberculosis became more localized to well-defined risk groups and geographic areas [34,35]. In response, strategic plans were revised to help prioritize efforts and outline updated recommendations for TB elimination in the United States [36,37]. From 1993 to 2002, the average year-to-year decrease in TB rate was 6.9%. In 2003, however, the CDC reported the smallest annual decrease in the TB rate (1.9%) and TB case numbers (184) since the resurgence, raising concern about a possible slowing of the progress against TB. For 2003, 14,874 TB cases were reported in the United States, with a rate of 5.1 per 100,000 population that remains higher than the national interim goal of 3.5 cases per 100,000 population set for 2000. Moreover, despite the decline in TB nationwide, rates have increased in certain states, and elevated TB rates continue to be reported in certain populations (eg, foreign-born persons and racial/ethnic minorities). In 2003, 12 states and the District of Columbia reported case rates above the national average, and 20 states reported increases in case number compared with 2002 [10].

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Age The distribution of TB cases and case rates among age groups remained relatively stable. In 2003, 34.2% of TB patients were 25 to 44 years old, 28.9% were 45 to 64, 20.2% were 65 years and older, 10.6% were 15 to 24 years, and 6.2% were children under 15 years. In contrast, 2003 TB case rates (cases per 100,000 population) were highest (8.4) among persons 65 years and older, followed by a rate of 6.3 for those 45 to 64, 6.0 for those 25 to 44 years, 3.8 for those 15 to 24 years, and 1.5 for children under 15. Although TB case rates among children under 15 are low, certain groups of children (eg, younger children, racial and ethnic minorities, and foreign-born children) are at higher risk for TB [38]. Children pose unique challenges to TB control: 1. TB in children is considered a sentinel event, usually indicating recent transmission. 2. TB diagnosis in children, especially in children under 5 years of age, can be more difficult because they often have nonspecific signs and symptoms and fewer positive bacteriologic tests because of the paucity of mycobacteria. 3. Children, especially infants, are at an increased risk for progressing from latent TB infection (LTBI) to active and sometimes severe TB disease [38]. Race/ethnicity Disparities in TB rates persist among racial and ethnic minority populations (Table 1). Overall, the highest TB rates are seen among Asian/Pacific Islanders, in large part because of the high proportion of foreign-born persons in this population. Among foreign-born persons, non-Hispanic blacks had the highest case rate in 2003 and were the only group with an increase in case rate from 1998 to 2003. In 2003, among TB patients born in the United States, case rates for non-Hispanic blacks and for American Indian/Alaska Natives were 7.7 and 6.8 times, respectively, that of non-Hispanic whites. Local, state, and federal public health partners, including the CDC and the ACET, are collaborating to develop effective strategies to reduce racial disparities in TB [39]. Foreign-born tuberculosis patients National TB surveillance for patient country of birth began in 1986, when 4925 (21.8%) new cases were reported among foreign-born persons. The pro-

portion of foreign-born TB patients remained relatively stable at 22% to 23% until 1990, when the proportion and number of cases among foreign-born persons began to increase (Fig. 2). Since then, the proportion has increased steadily, with foreign-born persons accounting for 53.4% of the national case total in 2003. This trend results from the relatively stable case count in foreign-born persons since the mid 1990s, with 7902 cases reported in 2003, coupled with the significant decrease in cases among US-born persons (Fig. 3). In 1992, 19,225 cases among US-born persons were reported in the United States; this number decreased to 6903 in 2003. TB case rates among foreign-born persons have been consistently higher than among US-born persons [40]. The 2003 TB rate among all foreign-born persons (23.6 cases per 100,000 population) was 8.8 times greater than that among US-born persons (2.7 cases per 100,000 population). Six birth countries of foreign-born TB patients have consistently accounted for approximately 60% of the foreignborn TB cases reported in the United States annually. In 2003, Mexico accounted for 25.6% of foreignborn patients; the Philippines, 11.5%; Viet Nam, 8.4%; India, 7.6%; China 4.8%; and Haiti 3.3%. The number of states reporting 50% or more of their TB cases among foreign-born persons has also been increasing, from two states in 1986, to 14 states in 1998, and to 25 states in 2003 (Fig. 4). Five states have consistently reported the most foreign-born TB patients: California, New York, Texas, Florida, and New Jersey. In 2003, these states combined reported almost two thirds of the total cases in foreignborn TB persons (California, 30.6%; New York, 12.4%; Texas, 9.0%; Florida, 5.9%; and New Jersey, 4.4%). Within each state, the birth-country composition often varies. In 2003, the most common birth country for reported foreign-born TB patients from California and Texas was Mexico; for New York, it was China; for Florida, it was Haiti; and for New Jersey, it was India. In addition, TB patients from certain countries were concentrated in certain states. For example, in 2003, New York reported 63.5% of the national total of TB patients born in the Dominican Republic and 55.7% of those born in Ecuador. Florida reported 60.0% of the TB patients born in Cuba and 49.2% of those born in Haiti; California reported 52.0% of the TB patients born in the Philippines and 48.6% of the patients born in Laos; and Minnesota reported 55.2% of TB patients born in Somalia. This diversity poses unique challenges to state and local TB control programs and must be addressed to facilitate case finding and contact investigations and to ensure completion of therapy.

US-born 1998 Race/ethnicitya Hispanic Non-Hispanic Black Asian/Pacific Islanderc Asian Native Hawaiian and Other Pacific Islander White American Indian/Alaska Native Totald a

No.

Totalb

Foreign-born 2003 Rate

No.

Rate

1282

6.6

1015

4.3

4968 213 ... ...

16.0 5.8 ... ...

3086 204 155 49

3914 248 10,633

2.1 12.6 4.3

2358 173 6903

% change 1998 – 2003

1998

2003

% change 1998 – 2003

1998 No.

2003 Rate

No.

Rate

% change 1998 – 2003

No.

Rate

No.

Rate

33.8

2785

26.0

3073

19.6

24.7

4091

13.5

4115

10.5

22.2

9.2 5.4 4.4 15.7

42.6 6.9 ... ...

841 3411 ... ...

48.5 55.4 ... ...

1048 3288 3252 36

52.0 41.2 41.1 48.6

7.2 25.6 ... ...

5816 3637 ... ...

17.8 36.9 ... ...

4145 3510 3425 85

11.7 29.8 30.0 22.1

34.4 19.3 ... ...

1.2 8.1 2.7

40.6 36.3 38.2

550 ... 7598

8.5 ... 30.2

427 ... 7902

6.1 ... 23.6

27.7 ... 21.8

4473 254 18,287

2.3 12.7 6.8

2790 176 14,874

1.4 8.1 5.1

38.6 36.2 24.4

In 2003, two modifications were made to the tuberculosis report form: (1) multiple race entries were allowed, with 0.3% selecting more than one race, and (2) the previous category of Asian/Pacific Islander was divided into ‘‘Asian’’ and ‘‘Native Hawaiian or Other Pacific Islander.’’ b Persons included for whom country of birth was unknown: 56 in 1998 and 69 in 2003. c For comparison with 1998, data for 2003 Asian/Pacific Islander = Asian plus Native Hawaiian and Other Pacific Islander. d Persons included for whom race/ethnicity was unknown: 16 for all, 8 for US-born, and 5 for foreign-born persons in 1998; 101 for all, 58 for US-born, and 35 for foreign-born persons in 2003. In 2003, persons included who selected multiple races: 37 for all, 9 for US-born, 28 for foreign-born persons.


Table 1 Number and rate per 100,000 population of tuberculosis cases in the United States in 1998 and 2003

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schneider et al Number of Foreign-born TB Cases

Percentage of Foreign-born TB Cases

10,000

60

8,000

50 40

6,000 30 4,000 20 2,000

10

0

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year Number of Foreign-born TB Cases

Percentage of Foreign-born TB Cases

Fig. 2. Trends in tuberculosis cases in foreign-born persons in the United States from 1986 to 2003.

requirements for persons seeking permanent residency in the United States [43]. TB among foreign-born persons is a major component of TB morbidity in the United States [40] and reflects the global TB situation, defined in 1993 by the World Health Organization (WHO) as a global emergency [44,45]. The WHO estimated that in 2002 there were 8.8 million new cases of TB (141 cases per 100,000 population) [46]. Among the 22 high-burden countries, India and China accounted for 46% of the total. Among the 15 countries that have the highest TB rates (>400 cases per 100,000 population), 13 are in Africa, and 12 of these had high TB/HIV incidence rates (>100 cases per 100,000 population) among adults 15 to 49 years

Most TB cases among foreign-born persons are caused by Mycobacterium tuberculosis complex infections acquired abroad [41]. Among foreign-born children, aged younger than 15 years, who had TB, 60% were diagnosed within 18 months of arrival in the United States [38]. Prompt evaluation of foreignborn persons for TB following their arrival in the United States can help identify persons who have LTBI and are eligible for preventive therapy; prompt evaluation can prevent development of active TB disease [41,42]. Foreign-born TB patients are also more likely to have drug resistance and are less likely to be HIV infected than US-born TB patients [40]. The lower proportion of foreign-born TB patients infected with HIV results in part from HIV screening

Number of US-born TB Cases

Percentage of US-born TB Cases

100

20,000

90 80

15,000

70 60 50

10,000

40 30

5,000

20 10

0

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year Number of US-born TB Cases

Percentage of US-born TB Cases

Fig. 3. Trends in tuberculosis cases in persons born in the United States from 1986 to 2003.

189

Number of states with ≥50% TB cases in foreign-born persons


30 25 22

23

22

20 15

2

2

3

3

4

4

5

15

10

9

10

14

6

2

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year

Fig. 4. Number of states with 50% or more of tuberculosis cases in foreign-born persons in the United States from 1986 to 2003.

old, highlighting the magnitude of the TB/HIV epidemic and the influence of HIV/AIDS on TB [46]. Therefore, immigration from regions that have high rates of drug-resistant TB (eg, Eastern Europe) as well as from regions that have high rates of HIV infection (eg, sub-Saharan Africa) substantially affect the epidemiology of TB in the United States. The CDC is collaborating with partners such as the US Agency for International Development, the International Union Against TB and Lung Disease (IUATLD), the KNCV TB Foundation (formerly the Royal Netherlands Tuberculosis Association), and WHO to assist countries that have high burdens of TB. Collaborations have focused on building program capacity, operational research, and programmatic evaluation to address problems such as TB/HIV and drug resistance in TB patients. TB screening among immigrant and refugee visa applicants is being improved through the development of new diagnostic tools [47] and updated medical screening guidelines [43]. In addition, because Mexico contributes the largest number of foreign-born TB patients in the United States, the CDC has been collaborating with partners in the United States and Mexico to help control TB along the United States – Mexico border. These efforts include an innovative new initiative that uses a binational health card to track and manage binational TB patients who cross the border to ensure continuity of TB care and completion of treatment [48,49]. Worldwide, TB is a recognized cause of morbidity and mortality in children. A renewed interest by domestic and international health agencies has focused on mobilizing and strengthening global efforts to improve surveillance, and to promote program and research initiatives to reduce the burden of TB on children [50,51].

Drug-resistant tuberculosis Drug-resistant TB, especially MDR-TB, places an increased burden on all aspects of TB control, including diagnosis, case management, treatment, and cost [52 – 54]. MDR-TB is defined as resistance to at least isoniazid and rifampin, two of the most effective antituberculosis agents in the TB arsenal. When used in conjunction with other antituberculosis agents, rifampin can significantly shorten the treatment course of TB. Although many factors have been associated with the development of drug resistance, including naturally occurring spontaneous mutations, two of the most commonly encountered and preventable factors are nonadherence to therapy and inappropriate use of antituberculosis drugs. Poor infection-control practices within hospitals caring for patients who have drug-resistant TB have also played an important role in the nosocomial transmission of MDR-TB [20 – 22]. Collection of drug-susceptibility results became part of routine national TB surveillance in 1993, in part because of the recommendations outlined by the National Action Plan to Combat MDR-TB [31]. Before 1993, several regional and national drug susceptibility surveys on TB patients were conducted [52]. In 1991, findings of a nationwide survey revealed 14.2% of cases were resistant to at least one drug and 3.5% were resistant to at least isoniazid and rifampin (MDR-TB) [55]. The strongest risk factor for drug resistance was geographic location. New York City had the highest MDR-TB rate (13%) and accounted for 61% of the total MDR-TB cases reported in the United States. Analysis of national TB surveillance data collected from 1993 through 1996 revealed a 13.5%,

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incidence of resistance to at least one drug, and the incidence of MDR-TB was 2.2% [56]. Higher drugresistance rates were seen among TB patients who have had a previous episode of TB, foreign-born persons, HIV-infected persons, and persons residing in specific geographic areas (eg, New York City). In the mid-to-late 1990s, several outbreaks involving highly drug-resistant strains of M. tuberculosis (ie, strain W) were investigated [57 – 59]. These strains share a common drug resistance to first-line antituberculosis medications (eg, isoniazid, rifampin, ethambutol, and, at that time, streptomycin) as well as resistance to some second-line medications, making treatment difficult and costly. The majority of strain W TB cases were reported by New York City [57,59], although outbreaks have occurred elsewhere, including one that was attributed to bronchoscope contamination in South Carolina [58]. To facilitate early detection of strain W isolates, the CDC began recommending that health departments notify the CDC of all M. tuberculosis isolates that have strain W – resistance patterns [59]. Since 1998, overall multidrug resistance among culture-positive TB patients, who do not have a prior history of TB, has been relatively stable (~1%) (Fig. 5), although outbreaks and regional differences continue to occur. Historically, overall drugresistance rates among those who have a previous history of TB have been higher than for those who do not have a previous history of TB. In 2003, among TB patients who had a prior history of TB, 12.6% had resistance to at least isoniazid and 3.6% had MDR-TB, whereas 7.9% of TB patients who did not have a prior history of TB had resistance to

at least isoniazid and 0.9% had MDR-TB. Additionally, drug resistance (MDR-TB and resistance to at least isoniazid) has been seen more commonly in foreign-born TB patients (2003: MDR-TB, 1.2%; isoniazid, 10.6%) than in US-born TB patients (2003: MDR-TB, 0.6%; isoniazid, 4.6%). Knowledge of drug-resistance rates worldwide is critical to controlling the global epidemic and has direct implications for TB control in the United States [60,61]. A more comprehensive understanding of global drug resistance was made possible with the formation of the Supranational Reference Laboratory Network in 1994 and the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Newly released data reveal that TB patients in parts of Eastern Europe and Central Asia are 10 times more likely to have MDR-TB than patients in the rest of the world, with some MDR-TB incidence rates higher than 10% (Israel, 14.2%; Kazakhstan,14.2%; Tomsk Oblast [Russian Federation], 13.7%; Uzbekistan, 13.2%; Estonia, 12.2%; and Liaoning [China], 10.4%) [61]. Tuberculosis/HIV coinfection Today, any discussion about TB is incomplete without a discussion about HIV/AIDS. Knowing a TB patient’s HIV status is critical to management, treatment, contact investigation, and prevention [62 – 67]. The CDC recommends that all TB patients, independent of risk factors, should undergo voluntary HIV counseling, testing, and referral [64,65,67]. Nonetheless, HIV status is not reported nationally for many TB patients in the United States. This in-

Number of MDR TB Cases

Percentage of MDR TB Cases

450

3.0

400 350 300

2.0

250 200 150

1.0

100 50 0.0

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Year Number of MDR TB Cases

Percentage of MDR TB Cases

Fig. 5. MDR-TB among persons without a history of tuberculosis in the United States from 1993 to 2003. MDR-TB is defined as resistance to at least isoniazid and rifampin.


complete reporting of HIV status probably reflects several factors including concerns about confidentiality, interpretation of laws and regulations in certain states and local jurisdictions, and reluctance by health care providers to report HIV test results to the TB surveillance program staff [10]. Information on HIV status was added to the national TB surveillance system in 1993, in response to the TB resurgence. HIV test results (ie, negative, positive, or indeterminate) were reported for 45.7% of TB patients aged 25 to 44 years in 1993 and for 65.3% in 2002. In this group, positive HIV test results were reported for 29.1% in 1993 and for 15.9% in 2002. Historically, reported TB/HIV coinfection rates and case numbers have been relatively high in a few states and urban areas. In 2002, 60% of the positive HIV test results among TB patients aged 25 to 44 years were reported from five areas: California, Florida, Georgia, New York City, and Texas. Crossmatching of state TB registries and HIV/AIDS registries in 1993 and 1994 revealed that 14% (range, 0% – 31%) of persons reported to have TB in the United States were also listed in HIV/AIDS registries [68]. TB-AIDS cases were more likely to be in persons aged 25 to 44 years, male, culture-positive for M. tuberculosis, and USborn. In geographic areas where the prevalence rates of HIV-infected persons were high, drug resistance, especially MDR-TB (6%) and rifampin monoresistance (3%), was reported among TB-AIDS patients. HIV coinfection has several key implications for the overall treatment and management of TB. HIV infection increases the risk of (1) TB disease progression among persons who have LTBI, (2) rapid progression of those newly infected with M. tuberculosis to active TB disease, and (3) reinfection with M. tuberculosis [67,69]. Many of the TB outbreaks among persons infected with HIV that occurred during the resurgence were complicated by high drug-resistance rates and resulted in mortality rates reaching 70% [21 – 23]. TB outbreaks among HIVinfected persons have illustrated the continued need for appropriate treatment and monitoring of this population [70 – 73]. The use of antiretroviral therapy has significantly decreased mortality and morbidity, including the development of opportunistic infections (eg, TB) among HIV-infected persons. New concerns have developed, however, concerning the potential for drug – drug interactions, development of resistance to rifamycin, and paradoxical reactions. Drug – drug interactions, primarily between rifamycin and protease inhibitors and nonnucleoside reverse transcriptase inhibitors, have resulted in new treatment guidelines and recommendations [66,66a]. Acquired rifampin monoresistance has been docu-

191

mented in HIV-infected patients who have low CD4+ T-lymphocyte counts, extrapulmonary disease, and concomitant antifungal therapy [74,75]. Clinicians treating TB-HIV – coinfected persons should be familiar with current diagnostic, management (eg, DOT), and treatment modalities to maximize therapeutic success and minimize TB transmission, drug resistance, adverse effects, and treatment failures [64,67]. Globally, the HIV/AIDS epidemic has had an immense impact on TB control, especially in subSaharan Africa, where an estimated two thirds of persons who have HIV/AIDS live, and has contributed significantly to TB morbidity and mortality [76 – 78]. In these countries, TB incidence and case fatality are strongly associated with HIV prevalence. The prevalence of drug-resistant TB is expected to increase greatly as the HIV epidemic spreads to areas of the world where drug-resistant TB is more prevalent (eg, Asia, Eastern Europe) [61,76]. The scaling up of treatment programs providing antiretroviral therapy will require patient and health care provider education and close monitoring to optimize therapy, reduce transmission, and reduce drugresistant TB [79]. Development of new tools An important component of disease control is the development of new diagnostic tests, pharmacologic agents, and vaccines. The resurgence of TB in the mid-to-late 1980s to 1992 was associated with delays in the diagnosis and identification of drug resistance. This situation generated renewed interest in the development of several new diagnostic tools and the subsequent genomic sequencing of M. tuberculosis. During the past few years, TB diagnostic capabilities have improved through new techniques for the rapid detection of M. tuberculosis complex (eg, nucleic acid amplification tests) [80], identification of M. tuberculosis (eg, nucleic acid probe), rapid detection of latent TB infection (eg, whole-blood interferon gamma assay [QuantiFERON (Cellestis Inc., Valencia, California)]) [81,82], the investigational enzyme-linked immunospot test (ELISPOT) [83], and differentiation of M. tuberculosis strains (eg, DNA fingerprinting) [84,85]. In the 1990s, molecular genetic typing (genotyping) of M. tuberculosis strains became a commonly used tool to understand outbreaks and transmission dynamics. In 1996, the CDC established the National TB Genotyping and Surveillance Network to determine the usefulness of molecular genotyping in more routine TB control settings using the IS6110-based restriction fragment length polymorphism (RFLP)

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technique supplemented with spacer oligonucleotide typing (spoligotyping) on M. tuberculosis isolates [86,87]. Genotyping, in conjunction with epidemiologic investigation, has proven a useful adjunct to epidemiologic investigations in tracing the chain of transmission [88]. The techniques are particularly useful in outbreaks and institutional settings, identifying groups at risk for TB (eg, homeless persons), identifying contacts and social networks, understanding exogenous reinfection, and confirming laboratory cross-contamination [89,90]. To refine the understanding of TB transmission and epidemiology and to advance TB control, the CDC has launched the National TB Genotyping Program, which provides the capacity to genotype M. tuberculosis isolates from all culture-positive TB patients in the United States. Two polymerase chain reaction – based genotyping tests (spoligotyping, mycobacterial interspersed repetitive units analysis) will be supplemented with IS6110 RFLP testing for selected specimens [91]. The goal of this program is to improve the characterization of TB transmission dynamics and to use the results to improve the efficiency of public health interventions. In 1995, following a several-year hiatus in the USPHS-sponsored clinical trials, the CDC reinstated clinical TB research, creating the TB Trials Consortium (TBTC). The TBTC currently is coordinating several studies, including efficacy trials for the use of moxifloxcin as a first-line drug in the treatment of TB disease. Information gained from the earliest of these studies contributed to the Food and Drug Administration licensure of rifapentine, a longacting rifampin and the first anti-TB drug approved in 25 years [92]. Additional studies include a comparison of several generations of QuantiFERON with the tuberculin skin test in the diagnosis of LTBI [81]. In 2001, the CDC established the TB Epidemiologic Studies Consortium to conduct multicenter epidemiologic, behavioral, and operational research studies. Furthermore, recognizing the need for TB prevention globally, a renewed interest, fueled by generous funding has resulted in actively revisiting vaccine development [93,94]. Numerous organizations, both in the public and private sectors, are conducting major research efforts to develop a safe and effective TB vaccine.

Elimination of tuberculosis in the United States: remaining challenges After decades of decline, an unprecedented resurgence in TB began in 1986 and continued through

1992, with case numbers increasing by 20%. Following an intensive campaign and mobilization of new resources, TB cases once again began to decline. Remarkable gains have been made since the early 1990s, with efforts being concentrated on maintaining control of TB, speeding the decline of TB, and developing new tools [37]. Key TB epidemiologic features that have been identified include an increasing proportion of TB cases among persons born in countries where TB is endemic, racial and ethnic disparities, and localized unique epidemiologic profiles in areas throughout the United States. Development of new tools, such as vaccines, antituberculosis drugs, and rapid diagnostic tests have also been identified as vital measures needed to eliminate TB in the United States. The smallest decline since the resurgence was seen in 2003, raising the concern about a possible slowing of the progress against TB or even a reversal of the decline. Despite increasing health care costs and demands for increased programmatic and operational efforts, funding for TB control has not increased [95]. The elimination of TB in the United States will require sustained efforts such as identifying and targeting populations at high risk for TB, remaining actively involved in the global effort against TB, and maintaining adequate resources.

Acknowledgments The authors thank the state and local tuberculosis control officials in health departments throughout the United States who collected and reported the national surveillance data presented in this article, the surveillance staff at the Division of TB Elimination, Centers for Disease Control and Prevention, who maintain the database, Ann H. Lanner for her editorial review of the manuscript, and Dr. Thomas Navin and Dr. Michael Iademarco for their critical review of the manuscript.

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Clin Chest Med 26 (2005) 233 – 246

Genetic Susceptibility to Tuberculosis Richard Bellamy, MRCP, DPhil James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK

Genetic factors are important contributors to the development of a wide range of complex or multifactorial diseases. For example, if one has a close relative who died of ischemic heart disease, one will be at increased risk of developing ischemic heart disease oneself. It is not inevitable that one will develop the same condition, because other factors such as cigarette smoking, diet, exercise, and ‘‘bad luck’’ also contribute to the risk of developing ischemic heart disease. A positive family history simply indicates that one is at increased risk of developing heart disease compared with a person of the same age and sex who does not have a positive family history. Patients and their doctors recognize the importance of family history for a wide range of multifactorial, noncommunicable diseases such as cancer, cardiovascular disease, and diabetes mellitus. Much of the clustering in families that occurs in these conditions, however, probably results from shared environmental risk factors. Although there is much debate about the importance of nature versus nurture, few scientists would dismiss the importance of host genetics in the development of chronic noncommunicable diseases. In contrast, host genetic factors are often given little attention in infectious disease. The familial clustering that is frequently observed for infectious diseases is commonly dismissed as the result of transmission of infection among household members. This assumption is unfair, because host genetic factors are probably at least as important in determining the outcome of infection as they are in other complex diseases. Studies on adoptees are sometimes used to help eliminate the effects of shared environment when

E-mail address: [email protected]

considering the contribution of genetic factors to observed familial clustering of disease. In a study of almost 1000 adoptees, Sorensen et al [1] found that the host genetic component of susceptibility to premature death from infection was greater than for cancer or cardiovascular disease. This finding does not mean that if one’s father dies of tuberculosis, one inevitably will succumb to the same disease. Rather, it indicates that a person who has such a family history has a higher probability of dying from tuberculosis than a person who does not have a positive family history. Thus the statement that host genetic factors make a person susceptible to a particular infectious disease simply means that the risk of developing the disease is higher than for someone who has not inherited the genetic risk factor (ie, who can be described as resistant). Someone whose genetic constitution makes him or her susceptible to Mycobacterium tuberculosis will not necessarily develop clinical disease after exposure to the microorganism. Conversely someone whose genetic constitution makes him or her resistant to M. tuberculosis may still develop clinical disease after exposure. The term ‘‘susceptible’’ simply indicates a genetic make-up with a higher risk of developing tuberculosis than a resistant one. In 1949, Haldane [2] suggested that microorganisms have been the main agents of natural selection among human populations for the past 5000 years. He believed that the recent evolution of the human genome was driven primarily by the need to resist pathogens because infectious diseases were the most important cause of premature death. This hypothesis proposes that most of the genetic diversity found within human populations has been selected for and maintained by pathogenic microorganisms. Until recently, progress in identifying the host genes con-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.006


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ferring resistance to infectious diseases was limited to malaria. Geographic variations in the prevalence of malaria facilitated the identification of several gene variants conferring resistance to malaria, including sickle cell hemoglobin, a- and b-hemoglobin, and glucose-6-phosphate dehydrogenase deficiency [3,4]. Genetic mutations conferring malaria resistance are common in populations originating in areas where malaria is endemic and are rare among populations where malaria does not occur. Historically, tuberculosis has not shown the marked geographic variation shown by malaria. This lack of variation has made the task of identifying the host genes conferring tuberculosis susceptibility and resistance more difficult to identify. It has been estimated that M. tuberculosis was responsible for more than one fifth of all deaths in Western Europe after the industrial revolution [5]. It is therefore logical to expect that M. tuberculosis would have been among the microorganisms that have had the most important effects on the evolution of the human genome. It has been estimated that approximately one third of the world’s population is infected with mycobacteria, but among those infected only about 10% will ever develop clinical disease [6]. Much scientific research has focused on proving that host genetic factors are important in determining why only a minority of those infected by M. tuberculosis develops clinical disease. This article provides a brief summary of this research and describes the strategies that have been used to identify the host genes involved in tuberculosis resistance.

Evidence showing the importance of host genetics in tuberculosis susceptibility In 1926, in Lubeck, Germany, a tragic accident occurred during the bacille Calmette-Guerin (BCG) vaccination program: 249 babies were injected with the same live dose of virulent M. tuberculosis bacteria. Seventy-six babies died; 173 babies survived [7]. This experience showed that there is wide variation in the degree of innate immunity against M. tuberculosis. The babies who died presumably had weaker resistance to M. tuberculosis than the babies who managed to clear the infection. This difference in host immunity could not have resulted from variation in acquired resistance to M. tuberculosis, because the babies were too young to have had significant prior exposure to mycobacteria, and they had not previously been vaccinated with BCG. The difference could also not be explained by variation in virulence or infectivity of the bacteria, because all the infants

received direct inoculation with the same dose of the same strain of M. tuberculosis. Therefore the difference in outcome of the infection is probably explained by host genetic factors. It has been suggested that a population’s resistance to M. tuberculosis is determined by its history of previous exposure [8]. Resistance is built up over a number of generations by selection pressure in favor of mycobacteria-resistant gene variants. When the selection pressure is strong, gene variants conferring disease-resistance can rise to high population frequencies in relatively short periods of time. The most striking example of a population acquiring resistance to tuberculosis has been described by Motulsky [9]. At the end of the nineteenth century the Qu’Appelle Indians suffered their first cases of tuberculosis. The disease spread rapidly through the population and caused the deaths of 10% of the total population annually. After two generations (40 years), half of the families had been lost, but the annual death rate from tuberculosis had fallen to 0.2% [9]. This striking reduction in tuberculosis-specific mortality is believed to have resulted from the strong selection pressure in favor of M. tuberculosis – resistant gene variants [9]. Tuberculosis has been a major cause of premature death in Europe since the Industrial Revolution. In Africa it is believed that tuberculosis did not become widespread until the start of the twentieth century [10 – 12], when the building of densely populated towns and cities facilitated the spread of M. tuberculosis. Haldane’s theory would therefore predict that present-day people of European origin would have greater resistance to tuberculosis than people of African origin. A study of 25,000 nursing home residents in Arkansas confirmed that black residents were twice as likely to become infected with M. tuberculosis as white residents of the same nursing homes [13]. This difference could not be explained by environmental or social factors, indicating that it was most likely caused by host genetics [13]. Twin studies are the most reliable method of determining whether genetic factors are involved in determining who will develop a particular disease. Monozygotic twins inherit identical genomes, whereas dizygotic twins share only 50% of the genes they inherit. If monozygotic twins have higher concordance for a disease than dizygotic twins, this finding indicates that genetic factors are important in the etiology of the disease. Several studies have compared the concordance for tuberculosis in monozygotic twins with that in dizygotic twins. These studies have shown concordance rates among monozygotic twins to be approximately twice as high as

genetic susceptibility to tuberculosis

concordance rates among dizygotic twins [14 – 16]. This evidence that host genes are important in determining susceptibility/resistance to tuberculosis has led to the development of several strategies to attempt to identify the genes involved.

Strategies to identify host genes determining tuberculosis susceptibility Identifying the genes influencing susceptibility to multifactorial diseases is a complex process. No single strategy could identify all of the genes of interest, because each study design has advantages and limitations. Genome-wide linkage studies are used to identify regions of the genome that contain major diseasesusceptibility loci. This approach involves typing a large number of genetic markers (usually more than 300) covering the whole human genome. Sibling-pair families that contain two or more siblings affected by the disease of interest are usually used in studies of multifactorial diseases. These families are preferred to large, extended families (which are generally used for single-gene Mendelian disorders), because they are believed to be more representative of the disease in the general population. Large numbers of sibling-pair families must be typed to provide sufficient power to detect genes exerting a large effect on population-wide disease risk. The approach is systematic and comprehensive and in theory should detect any genomic region that contains a major disease-susceptibility locus. This approach has relatively low power, however, and it cannot detect gene loci that confer only a moderate effect on population-wide disease risk. For example if a disease-susceptibility allele has a frequency of 0.5 (ie, 50% of the alleles in the population are of this type) and exerts a twofold increased risk of disease compared with the resistant wild-type allele, 2498 sibling-pair families are required to provide an 80% probability of identifying this effect by linkage analysis [17]. It would be difficult to collect and type this number of families in a genomewide screen. Association-based candidate gene studies have much greater power. Only 340 cases are required to have the power to detect the effect of the diseasesusceptibility locus described previously [17]. Association-based candidate gene studies can therefore detect genetic effects that would be overlooked in a genome-wide linkage study. The simplest form of association study is the case-control study, but more

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complex, family-based designs are also occasionally used. Association studies generally involve typing individual gene variants that are believed to be potentially important because of previous work on animal models of the disease or for theoretical reasons. Association between a genetic marker and a disease can be caused by either the genetic variant itself conferring disease susceptibility/resistance or the genetic variant being in linkage disequilibrium with the true disease-susceptibility locus. Linkage disequilibrium occurs only when two gene variants are located close together (within 1 centi-Morgan) on the same chromosome. A genome-wide association study would require typing more than 3000 genetic markers; this approach would be time-consuming and expensive and therefore generally is not feasible. Because association studies are usually restricted to candidate genes, this approach cannot be used alone. Regardless of how many candidate genes are typed, the genes that exert the largest effects on population-wide disease risk could be overlooked. Candidate gene studies and genome-wide linkage studies are therefore complementary, and both are generally required when investigating a multifactorial disease. Animal models have several advantages for the study of multifactorial diseases. Animal models can be used in breeding experiments, targeted gene disruption can be performed, and the animals can be challenged with pathogens. Identifying genes that confer susceptibility to individual pathogens in animal species is a useful strategy for identifying candidate genes for case-control studies in human populations. Human patients who suffer from extreme susceptibility to specific opportunistic infections can also provide insight into the host immune response to common infectious disease. For example, individuals who have developed overwhelming infection following BCG infection or who have developed disseminated atypical mycobacterial infections have provided insight into host resistance to M. tuberculosis. This article describes how several of these methods have been used to identify some of the host genes involved in susceptibility to tuberculosis.

Natural resistance – associated macrophage protein More than 20 years ago, innate susceptibility to infection with M. bovis BCG was shown to be determined by a single genetic factor in inbred strains of mice [18]. Gros and colleagues [18] named this putative gene Bcg. Following a single inoculation

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with BCG-Montreal, mice carrying the resistant allele (Bcgr ) had between 100- and 1000-fold fewer splenic colony-forming units than mice carrying the susceptible gene variant (Bcgs ) [19]. The Bcgr allele was found to be dominant over the Bcgs allele [18]. The Bcg locus was mapped to murine chromosome 1 by linkage analysis [20]. Linkage analysis also showed that Bcg was the same gene that determined resistance to Leishmania, salmonella, and other mycobacterial species such as M. lepraemurium and M. intracellulare [21 – 28]. In vitro studies showed that macrophages from mice carrying the Bcgs allele had decreased ability to restrict the growth of mycobacteria, salmonella, and Leishmania compared with Bcgr macrophages [29 – 32]. As a result, Bcgs mice had impaired ability to control the initial stage of mycobacterial infection, but the genetic susceptibility does not affect the later stages of an infection, which are determined by the acquired immune response [19]. A high-resolution linkage map of murine chromosome 1 enabled the Bcg locus to be pin-pointed to a 0.3 – centi-Morgan region [33,34]. The search for the Bcg gene itself was then vigorously pursued by Gros’ group. They produced a 400 – kg-base (kb) bacteriophage and cosmid contig of the region surrounding the Bcg gene [35] and used a molecular method called exon trapping to isolate potential candidate genes for Bcg [36]. One gene was expressed solely in macrophage populations and encoded a polypeptide with characteristics suggestive of a transport protein. This gene was believed to be the Bcg gene, because it contained a nonconservative base change (glycine to aspartic acid at position 169: designated G169D) in the Bcgs strains studied [36]. The group named this gene the natural resistanceassociated macrophage protein gene (Nramp, later re-named Nramp1) [36]. Three experiments were then performed to demonstrate that Nramp1 is the putative Bcg gene. Twenty inbred strains of mice with the Bcgr phenotype and seven inbred strains of mice with the Bcgs phenotype were typed for the Nramp1 G169D variant [37]. All 20 strains with the Bcgr phenotype were found to be Nramp1G169/G169 wildtype homozygotes, and all seven Bcgs strains were Nramp1D169/D169 gene-variant homozygotes [37]. The second experiment involved the production of an Nramp1 gene-disrupted knock-out mouse [38]. This knock-out mouse, designated Nramp1/ , was mated with the homozygous gene-variant mouse Nramp1 D169/D169 . The resulting offspring all had the compound genotype Nramp1D169/- [38]. If the Nramp1D169 allele is a nonfunctional (or null) allele, mice with the genotypes Nramp1D169/D169 ,

Nramp1D169/ , and Nramp1/ should have identical phenotypes. Gros’ group found that mice with these three Nramp1 genotypes had indistinguishable resistance to mycobacteria, confirming that Nramp1D169 is a null allele [38]. In the third experiment the normal Nramp1G169 allele was transferred onto the background of a mouse with the homozygous Nramp1D169/D169 genotype [39]. Macrophages from this transgenic mouse expressed the Nramp1 protein, and the BCG-resistant phenotype was restored [39]. These experiments proved beyond doubt that Nramp1 is the putative Bcg gene. The Nramp1 gene consists of 15 exons spanning 11.5 kb. The gene encodes a 90- to 100-kiloDalton membrane-bound protein containing 12 hydrophobic transmembrane domains [36,40,41]. Macrophages from Nramp1D169/D169 mice do not produce detectable Nramp1 protein [42]. The human homolog of Nramp1 was originally designated NRAMP1 but has now been renamed Slc11a1 (solute carrier family 11 member 1). In this article the name NRAMP1 is retained to avoid confusion. NRAMP1 maps to chromosome 2q35, contains 15 exons spanning 12 kb of DNA, and encodes a polypeptide consisting of 550 amino acids [43,44]. There are several Nramprelated proteins in humans, mice, and many other species. In mice, Nramp2 and Nramp-rs have been mapped to chromosomes 15 and 17, respectively [45, 46]. The human homologue of Nramp2 (NRAMP2) has been cloned and mapped to chromosome 12q13 [47,48]. Evidence is now accumulating to suggest that the NRAMP1 protein is a transmembrane iron transporter. It was first suggested in 1996 that Nramp1 may be a metal cation transporter because of its structural similarity to a known manganese transporter in Saccharomyces cerevisiae [49]. A missense mutation in the Nramp2 gene (glycine to arginine at position 185; G185D) was subsequently found to be responsible for microcytic anemia in a murine model [50]. The same Nramp2G185D mutation is also responsible for microcytic anemia in the Belgrade rat [51]. Murine Nramp2 and human NRAMP2 are integral membrane glycoproteins located at the plasma membrane and at recycling endosomes [52,53]. In contrast, Nramp1 is localized to the late endosomal compartment of resting macrophages and is recruited to the phagosome on phagocytosis [54]. In the presence of excess iron, macrophages from Nramp1D169/D169 mice have the same ability to limit intracellular M. avium replication as macrophages from wild-type Nramp1G169/G169 mice [55]. This finding suggests that Nramp1 may be an iron transporter that becomes saturated at high concentration.

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Nramp2 function in epithelial

Nramp1 function in macrophages

and other cells Iron

Iron Bacteria

Transferrin receptor

Nramp2

H+ Nramp2

Iron

H+

Iron Nramp1 Iron Iron

Nramp2

H+

Nramp1

H+

Fig. 1. Nramp1 and Nramp2 function as hypothesized by Gruenheid et al [52]. The ubiquitous Nramp2 is a membrane glycoprotein that becomes internalized to endosomes with iron. Acidification of the endosome activates Nramp2 resulting in the transport of iron and protons into the cytoplasm. Nramp1 is recruited to the macrophage phagosome after bacteria and iron are ingested. Following acidification, Nramp1 transports iron and protons out of the phagosome into the macrophage cytoplasm. Presumably mycobacterial Mramp competes with Nramp1 for the available intraphagosomal iron.

M. tuberculosis possesses a member of the Nramp protein family called Mramp [56]. Mramp is a transporter of iron and other divalent metal cations [56]. Mycobacterial Mramp is probably competing with host Nramp for control of the iron concentration within the host phagosome (Fig. 1). The identification of several polymorphisms in the human NRAMP1 gene [57] has enabled linkage and association studies to be used to study the importance of the NRAMP1 gene in explaining individual variability in susceptibility to tuberculosis in human populations. Weak evidence of linkage was found between NRAMP1 polymorphisms and tuberculosis in 98 Brazilian families [58] and 173 African sibling-pairs [59]. Strong evidence of linkage between NRAMP1 and tuberculosis was found in a single large aboriginal Canadian family [60]. These results suggested that NRAMP1 is involved in susceptibility to tuberculosis in humans, but that the effect is too small for NRAMP1 to be the major gene involved. Association studies have greater power than linkage studies to evaluate the effects of a candidate gene on disease susceptibility. Association-based case-control studies are therefore more useful than linkage-based family studies for assessing the effects of NRAMP1 on the population-wide variability in risk of tuber-

culosis. In a case-control study of more than 800 persons from Gambia, West Africa, individuals that had tuberculosis had more than four times the odds of carrying the disease-associated NRAMP1 genotype than ethnically matched controls [61]. The association between NRAMP1 polymorphisms and tuberculosis has since been confirmed in further patient populations from Gambia [62], Japan [63], Korea [64, 65], and Guinea-Conakry [66]. One of the NRAMP1 polymorphisms, a (GT)n repeat in the 50-untranslated region, influences gene expression following lipopolysaccharide or interferon gamma (IFNg) stimulation [67]. Persons who possess the less actively expressed allele are more likely to develop tuberculosis. Although these studies confirm that NRAMP1 influences susceptibility to tuberculosis in human populations, it is likely that NRAMP1 accounts for only a small proportion of the total genetic component of tuberculosis susceptibility.

Interferon gamma signaling pathway In 1995, Levin et al [68] described four children from a village in Malta who had suffered from severe

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and recurrent infections with the atypical mycobacteria M. fortuitum, M. chelonae, and M. aviumintracellulare. Three of the children were related, suggesting that they had inherited the same genetic immune defect [68]. Leukocytes from the affected children had impaired IFNg production in response to mycobacterial antigens [68]. A genome-wide screen identified a single region of homozygosity on chromosome 6q in the three related children [69]. The region identified contains the gene encoding the IFNg receptor ligand binding chain (IFNgR1). Sequencing the IFNcR1 gene identified a single-base transversion at position 395 of the coding sequence, which produced a premature stop codon. The three related children were all homozygous for this single-base transversions, and the IFNgR protein was absent from the children’s leukocytes. This finding established that IFNgR1 deficiency could be a cause of increased susceptibility to mycobacterial infections. Independently of Levin’s group, Casanova and colleagues [70] identified IFNgR1 deficiency as a cause of disseminated BCG infection. They identified 121 French children who developed disseminated BCG infection following vaccination. Sixty-one of the children had an identifiable underlying immune defect such as severe combined immune deficiency, chronic granulomatous disease, Di George syndrome, or HIV infection. Casanova and colleagues attempted to find an underlying immune deficiency in the remaining 60 children. They screened a number of candidate genes and found that autosomal recessively inherited mutations in the IFNcR1 gene could lead to disseminated BCG infection following vaccination [71]. Complete IFNgR1 deficiency is caused by gene mutations that abolish receptor expression [69, 71 – 76] or binding of the receptor to IFNg [77,78]. There are two reports of dominant IFNcR1 gene mutations in patients suffering from disseminated atypical mycobacterial infections [79,80]. There is also a report of partial IFNgR1 deficiency in two siblings, one of whom developed disseminated BCG infection and the other tuberculosis [81]. This report led to speculation that the existence of other common gene variants of the IFNcR1 gene might explain the population variability in susceptibility to tuberculosis. When six common IFNcR1 gene polymorphisms were typed in a case-control study of 640 persons from Gambia, however, no association with tuberculosis was found [82]. Mutations in four other genes in the interleukin-12 (IL-12) – IFNg signaling pathway have been found to lead to disseminated mycobacterial infections. Patients have been identified who have complete or partial deficiency of the IFNgR signal transduction

chain (IFNgR2) because of IFNcR2 gene mutations [83,84]. Deficiency of signal transducer and activator of transcription-1 (STAT-1) protein can lead to decreased response to IFNg stimulation [85]. A patient was described who had a dominant mutation in the STAT1 gene causing partial STAT1 deficiency resulting in impaired immunity to atypical mycobacteria [85]. Some patients who have disseminated atypical mycobacterial infections have been found to have abnormal IFNg production in response to IL-12 stimulation but normal cellular responses to IFNg. This result can be caused by complete deficiency of the IL-12 receptor b1 chain (IL12Rb1) caused by recessive mutations in the IL12Rb1 gene [86 – 91] or by deficiency of the IL-12 p40 subunit caused by mutations in the IL12B gene [92,93]. Patients inheriting one of the gene mutations causing abnormal IL-12 – IFNg signaling suffer recurrent infections with mycobacteria that are usually nonpathogenic, such as M. bovis BCG, M. aviumintracellulare, M. kansasii, M. chelonae, and M. smegmatis [94]. The immune deficiency is relatively specific, because, although recurrent salmonella infections occur, there does not seem to be increased susceptibility to a wider range of pathogens [94]. Mendelian susceptibility to mycobacterial infections is rare. Most persons who develop tuberculosis do not have a recognized IL-12 – IFNg signaling pathway defect. Although common gene variants in the IFNcR1 gene were not found to be associated with tuberculosis [82], mutations in other IL-12 – IFNg signaling pathway genes might partly explain population variation in susceptibility to tuberculosis [95]. Lio et al [96] genotyped 45 Sicilian patients who had tuberculosis and 97 controls for a single nucleotide polymorphism in the INFc gene and found the genotype associated with high IFNg production was under-represented among the tuberculosis patients. Case-control studies of the same gene variant in tuberculosis patients from Spain [97] and South Africa [98] found results consistent with this finding, indicating it is unlikely to result from chance. The population-wide effect of the IFNc gene polymorphism on susceptibility to tuberculosis is comparable to that of NRAMP1 [99]. Therefore these gene variants can explain only a small percentage of the total genetic component of the host variability in susceptibility to tuberculosis. A provisional association has also been described between common IL-12Rb1 gene variants and tuberculosis in Japanese patients [100]. It is therefore possible that several genes in the IL-12 – IFNg signaling pathway may contribute to the population-wide variability in tuberculosis susceptibility.


Other candidate genes Several genes have now been suggested to have a role in host variability in susceptibility to tuberculosis. This section focuses on the gene loci for which there is the most convincing evidence. Mannan-binding lectin (MBL) is an important component of the innate immune system. MBL is a calcium-dependent C-type lectin that forms a bouquetlike structure similar to C1q [101]. The lectin domain of MBL can bind to repetitive carbohydrate structures on microorganisms. This action activates complement independently of the classic and alternative pathways and promotes opsonophagocytosis [102]. Deficiency of MBL has been described as the world’s most common immune deficiency [103]. It is caused by one of three nonconservative singlenucleotide polymorphisms at codons 52, 54, or 57 of the gene encoding MBL protein, which is called mbl2 [104 – 106]. These polymorphisms produce variant MBL polypeptides that are unstable and nonfunctional [104 – 106]. MBL deficiency does not have a close relationship with susceptibility to specific pathogens [107]. Rather, it seems to confer an increased risk of susceptibility to a wide range of pathogens during infancy [108,109] and possibly also during adulthood [110,111]. If MBL deficiency predisposes a person to a large number of potentially fatal diseases, there must be some selective advantage in carriage of the variant alleles to explain their high population frequency. The most plausible explanation is that heterozygote carriers of mbl2 variant alleles have some protection against mycobacterial infections [112]. This theory has been given support from case-control studies of tuberculosis [113 – 116], leprosy [112], and M. avium [117]. There is also, however, some limited contradictory evidence that MBL deficiency is a risk factor for tuberculosis [118,119]. Further work is required to confirm whether mbl2 variant alleles confer resistance against tuberculosis and other mycobacterial infections. 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) is an important immunomodulatory hormone that activates monocytes and suppresses lymphocyte proliferation, immunoglobulin production, and cytokine synthesis [120 – 122]. In vitro, 1,25(OH)2D3 enhances the ability of human monocytes to restrict the growth of M. tuberculosis [120,123,124]. Epidemiologic evidence suggests that vitamin D deficiency may be a risk factor for tuberculosis [125 – 127]. Vitamin D exerts its effects through the vitamin D receptor (VDR), which is present on monocytes and on activated T and B lymphocytes [128,129]. If vitamin D

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deficiency is a risk factor for tuberculosis, VDR gene polymorphisms could contribute to genetic variability in susceptibility to tuberculosis. VDR gene polymorphisms were analyzed in the Gambian case-control study in which NRAMP1 variants were found to be associated with tuberculosis. The VDR genotype that produces higher circulating levels of 1,25(OH)D3 [130] was significantly underrepresented among patients who had tuberculosis compared with ethnically matched controls [131]. VDR gene polymorphisms were also found to be associated with tuberculosis among Gujerati Indians in London [132] and with leprosy type in patients from India [133]. Further work is required to investigate the association between VDR gene polymorphisms, vitamin D intake, and host susceptibility to tuberculosis. The class II HLA DR2 has been found to be associated with tuberculosis and leprosy in several populations [134 – 137], but HLA-DR2 has not been associated with tuberculosis in all populations studied [138]. In Cambodia, a provisional association has been described between HLA-DQB1*0503 and tuberculosis [139]. In India, multidrug-resistant tuberculosis also has been found to be associated with HLA-DQB1*0503 as well as with HLADQB1*0502 and HLA-DRB1*14 [140]. In a further case-control study, Indian patients who had pulmonary or miliary tuberculosis were found to be more likely to possess HLA-A3 – like peptide-binding motifs [141]. The mechanisms underlying these associations are uncertain. HLA associations with tuberculosis could be explained by particular HLA types being more effective at recognizing specific mycobacterial antigens. Alternatively, the observed associations may be cause by linkage disequilibrium with other genes in the major histocompatibility complex region of chromosome 6, such as the gene for tumor necrosis factor-a. Genome-wide linkage studies are an effective way of screening for the genes that exert the greatest population-wide effect on variability in susceptibility to a multifactorial disease. A genome-wide screen on 173 sibling-pairs from Gambia and South Africa found evidence suggestive of linkage to tuberculosis for markers on chromosomes 15q11-13 and Xq26 [59]. The size of the observed linkage effect would suggest that the putative tuberculosissusceptibility genes in these regions would exert a much greater population-wide effect than that caused by NRAMP1 or IFNg signaling pathway gene variants. Ongoing studies are attempting to identify the tuberculosis-susceptibility genes in these regions [142].

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Table 1 Putative mycobacteria-susceptibility genes/loci Description of genetic variation associated with disease

Source of information suggesting the gene is involved in susceptibility to tuberculosis or other mycobacterial infections

Relevance to susceptibility to tuberculosis or other mycobacterial infections

NRAMP1

Several polymorphisms described function of these remains uncertain

Studies of inbred strains of mice with increased susceptibility to mycobacterial infections

Common gene polymorphisms are associated with susceptibility to tuberculosis

[61 – 66]

IFNcR1

Gene mutations result in severe deficiency of the protein

Maltese family with Mendelian susceptibility to mycobacterial infections and rare individuals with disseminated BCG infections

The rare condition of partial or complete deficiency leads to disseminated infections with BCG and atypical mycobacteria

[69,71 – 81]

IFNcR2


Rare individuals with disseminated BCG and atypical mycobacterial infections


[83,84]

STAT1


Single individual with disseminated atypical mycobacterial infection

The rare condition of partial deficiency leads to disseminated infections with atypical mycobacteria

[85]

IL12Rb1




[86 – 91]

IL12B




[92,93]

Referencesa

bellamy

Gene or chromosome region

Gene polymorphism described, function of this remains uncertain

Rare individuals with IFNgR1 deficiency suggested IFNg is important in tuberculosis

A common gene polymorphism is associated with susceptibility to tuberculosis

[96 – 98]

Mbl2


Children with recurrent infections and inability to opsonize Baker’s yeast

Carriers of MBL-variant alleles have been found to have increased resistance to tuberculosis, leprosy and M. avium

[112 – 117]

VDR

Several polymorphisms described function of these remains uncertain

Epidemiologic and in vitro data suggested vitamin D is important in immunity to tuberculosis

Common gene polymorphisms are associated with susceptibility to tuberculosis

[131 – 133]

HLA class II

Large number of different HLA types

Case-control studies performed because the HLA system is known to be a key component of the acquired immune system

HLA-DR2 associated with tuberculosis and leprosy in several populations

[134 – 137]

HLA class I

Large number of different HLA types

Case-control studies performed because the HLA system is known to be a key component of the acquired immune system

Several different HLA class I types have been found to be associated with tuberculosis

[139 – 141]

X chromosome

Minisatellite markers on chromosome Xq26

Genome-wide linkage analysis carried out on sibling-pair families with tuberculosis

Suggestive evidence of linkage to tuberculosis for Xq26 in Africans

[59]

Chromosome 15

Minisatellite markers on chromosome 15q11-13

Genome-wide linkage analysis carried out on sibling-pair families with tuberculosis

Suggestive evidence of linkage to tuberculosis for 15q11-13 in Africans

[59]

Abbreviations: BCG, bacille Calmette-Guerin; IFNgR1, interferon-g receptor ligand binding chain; MBL, mannan-binding lectin. a Studies assessing the relevance of the gene to susceptibility to tuberculosis or to other mycobacterial infections.


IFNc

241

242

bellamy

Summary The development of disease following infection with M. tuberculosis depends on a complex interaction between the host, the pathogen, and environmental factors. Many host genes are likely to be involved in the complex etiology of clinical tuberculosis. Substantial progress has already been made in advancing the understanding of genetic susceptibility to tuberculosis (Table 1). The host genes identified to date, however, account for only a small part of the total component of the genetic variability in individual susceptibility to tuberculosis. It is likely that there are many more tuberculosis-susceptibility genes remain to be identified, and several of these may have much greater importance than those that have been discovered to date.

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Clin Chest Med 26 (2005) 167 – 182

Global Epidemiology of Tuberculosis Dermot Maher, BM, BCh, DM, Mario Raviglione, MD* Stop TB Department, World Health Organization, Avenue Appia, CH1211 Geneva 27, Switzerland

In 1993, the World Health Organization (WHO) declared tuberculosis a global emergency because of the scale of the epidemic and the urgent need to improve global tuberculosis control [1,1a]. Since then, WHO has promoted the strategy for global tuberculosis control known as DOTS (a name derived originally from directly observed treatment, shortcourse) [2,3] and its adaptations (eg, as part of a strategy of expanded scope where HIV prevalence is high [4] and as DOTS-Plus in areas where the prevalence of multidrug-resistant [MDR] tuberculosis is high) [5]. This article provides an overview of the current scale of the global tuberculosis epidemic. It describes the global tuberculosis situation as measured by reported and estimated cases and deaths. The increasing threats of HIV-related tuberculosis and drug-resistant tuberculosis receive particular attention. There is a brief review of the extent of implementation of effective tuberculosis control using the DOTS strategy. The article ends with a summary of the approaches needed to accelerate progress in global tuberculosis control.

Review of the global tuberculosis epidemic As part of the description of the global tuberculosis epidemic, the size of the burden of tuberculosis indicates progress in tuberculosis control and draws attention to the scale of the problem, thereby helping to mobilize resources for tuberculosis control.

* Corresponding author. E-mail address: [email protected] (M. Raviglione).

The size of the burden of tuberculosis Tuberculosis case notifications and reported deaths Tuberculosis notification data are important and are routinely reported by WHO [6]. At the country level, a system of recording and reporting tuberculosis cases and their treatment outcomes (including death) is an intrinsic part of the DOTS strategy (Box 1). Therefore as the number of countries implementing the DOTS strategy increases, routine national tuberculosis program (NTP) data on tuberculosis cases and deaths are becoming more widely available [6]. Notification data reflect health service coverage and the efficiency of case-finding and reporting activities of NTPs. Thus, in the developing countries where tuberculosis incidence is generally high, where access to health services may be limited, and where NTP performance may be suboptimal, notification data often represent only a fraction of the true incident cases. In addition, because case definitions vary among countries (eg, when some countries’ notification data include all cases, both new and re-treatment cases), comparisons of case notification data from different countries are difficult. In industrialized countries, however, where tuberculosis incidence is generally low, where health service coverage is generally universal, and where NTPs are effective, notifications of cases often closely approximate to the true incidence of tuberculosis. In any country, under stable program conditions, case notifications may provide useful data on the trend of incidence and a means for obtaining rates by age, sex, and risk group. Despite the limitations of tuberculosis case notifications, WHO has since 1997 published worldwide data provided by its member states, most recently referring to the 4.1 million cases reported in 2002 [6].



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Box 1. The five elements of the directly observed treatment, short-course strategy for tuberculosis control Sustained government commitment

to tuberculosis control Diagnosis based on quality-assured

sputum-smear microscopy mainly among symptomatic patients presenting to health services Standardized short-course chemotherapy for all cases of tuberculosis, under proper casemanagement conditions including direct observation of treatment Uninterrupted supply of qualityassured drugs A standard recording and reporting system enabling program monitoring by systematic assessment of treatment outcomes of all patients registered Data from Refs. [2,3].

Table 1 shows tuberculosis case notifications and rates by WHO region. Three regions dominate the worldwide distribution of notified cases: the SouthEast Asian Region (36% of cases), the African Region (24% of cases), and the Western Pacific Region (20% of cases). The three other regions have much smaller proportions of the cases notified worldwide: the Region of the Americas (9%), the Eastern Mediterranean Region (6%), and the European Region (5%). Fig. 1 shows tuberculosis case notification rates by country in 2002 [6]. In industrialized countries, case notifications generally approximate the true incidence of tuberculosis more closely than in developing countries. Tuberculosis case notifications steadily declined throughout most of the twentieth century in industrialized countries, beginning before the introduction of antituberculosis chemotherapy, largely because of socioeconomic improvements and possibly also because of the isolation of infectious cases in sanatoria. The effective application of chemotherapy in the latter half of the twentieth century further accelerated the decline. From the mid-1980s onwards, however, several countries saw a failure of the expected continued decline, and others saw the trend reversed, with case notifications increasing for the first time in many years. For example, in the United States, after

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30 years of previous steady decline, tuberculosis incidence increased regularly between 1985 and 1992 [7]. Factors responsible for the reversal of the previous trend included increased poverty among marginalized groups in inner city areas, immigration from countries with high tuberculosis prevalence, the impact of HIV, and, most importantly, the failure to maintain the necessary public health infrastructure under the mistaken belief that tuberculosis was a problem of the past. Many countries in Europe, including Denmark, the Netherlands, Sweden, and the United Kingdom, also reported a failure of the expected continued decline or even a steady rise in tuberculosis cases [8]. The high proportion of cases in the foreign-born (eg, 24% in France, 51% in the Netherlands, 54% in Sweden, 68% in Switzerland) indicated immigration as the main cause of this change in trend [9]. Annual case rates in foreign-born populations often exceed 50 per 100,000 and may even exceed 100 per 100,000 (eg, in the Netherlands), in contrast to annual case rates usually below 15 per 100,000 in indigenous populations [9]. In Western Europe, the impact of HIV on tuberculosis has been largely limited to certain countries (eg, Spain, Portugal) and cities (eg, Paris, Amsterdam) [10]. In most countries in Western Europe, the proportion of AIDS cases diagnosed with tuberculosis is low; two notable exceptions are Spain and Portugal [11], where the overlap between the population infected with HIV and the population infected with Mycobacterium tuberculosis is greater than in the other countries of Western Europe. Tuberculosis incidence rates in Japan are still high, at about 40 per 100,000, but

Table 1 Tuberculosis case notifications and rates by World Health Organization region in 2002

WHO region

No. of Proportion Rate cases notified of global (per 100,000 (all forms) total (%) population)

African 992,054 Americas 233,648 Eastern 188,458 Mediterranean European 373,497 Southeast Asia 1,487,985 Western Pacific 806,112 Global 4,081,754

24 9 6

148 27 37

5 36 20 —

43 94 47 66

Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 21.

global epidemiology of tuberculosis

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Fig. 1. Tuberculosis case notification rates by country in 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 218, fig. 4; with permission.]

are declining [12]. In other industrialized countries, including Australia, New Zealand, and Canada, rates have leveled off during the past few years below 10 per 100,000. The proportion of cases in the foreign-born is about 70% in Australia and about 50% in Canada [12]. The implication of the high proportion of cases in the foreign-born in most industrialized countries is that tuberculosis control in these settings depends on tuberculosis control globally. Tuberculosis case notification rates are still high in the countries of the former Soviet Union [6]. In many countries the previous continued decline in case notifications stopped or reversed from the early 1990s onwards. For example, annual notification rates doubled in Russia from 1990 to 2002, with an increased proportion of cases in young adults [6]. Dramatic social changes following the end of the Soviet Union engendered a combination of factors responsible for the reversal of the previous trend, probably through increased susceptibility to infection and increased breakdown to disease after infection. These factors include increased poverty and poor

living conditions (resulting in malnutrition, crowding, and stress) and in some cases civil conflicts and wars, deteriorating health services, and lack of drugs, resulting in decreased rates of cure of tuberculosis patients and continued transmission in the community. The spread of HIV in some countries, particularly the Russian Federation and Ukraine, has the potential, if unchecked, to fuel the tuberculosis epidemic further. Data on tuberculosis deaths are reported through national vital registration systems and through the routine standard NTP recording and reporting system. Few developing countries have comprehensive vital registration systems for the accurate reporting of deaths. Routine NTP data on tuberculosis deaths are becoming more widely available in developing countries [6]. NTPs report these tuberculosis-cohort deaths (the number and proportion of tuberculosis patients dying during treatment) without specifying cause, because the cause of death can rarely be determined in countries where income is low and the prevalence of tuberculosis is high [13]. Inaccurate

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routine NTP reporting of cohort deaths and incomplete NTP coverage of all incident cases in many countries limit the extent to which tuberculosis cohort deaths reflect tuberculosis mortality.

Estimated tuberculosis cases and deaths Because of the limitations of tuberculosis notifications and the difficulties in directly measuring the numbers of cases and deaths, the size of the tuberculosis disease burden must be estimated. WHO estimates of tuberculosis incidence and deaths are based on a variety of inputs, including surveys of prevalence of tuberculosis infection and disease, vital registration data, and independent assessments of quality of surveillance systems [14,15]. In 2002 there were an estimated 8.8 million new cases of tuberculosis worldwide, with an incidence rate of 141 per 100,000 population [6]. The global incidence rate of tuberculosis is growing at approximately 1.1% per year, although this overall global trend is fueled by and hides much faster increases in sub-Saharan Africa and in countries of the former Soviet Union

[6]. Table 2 summarizes tuberculosis incidence and mortality estimates in 2002 by WHO regions [6,14]. Fig. 2 shows estimated tuberculosis incidence by country for 2002 [6]. The ranking of countries by number of tuberculosis cases draws attention to the 22 countries that account for roughly 80% of the world’s tuberculosis burden (Table 3). Developing countries suffer the brunt of the tuberculosis epidemic. Overall, it is estimated that 95% of the world’s tuberculosis cases and 98% of the tuberculosis deaths occur in the developing world [12], and that tuberculosis causes more than 25% of avoidable adult deaths in the developing world [16]. The importance of the tuberculosis problem for individual countries is expressed as the annual incidence (absolute number of cases occurring yearly) and as the incidence rate (cases per 100,000 population). Fig. 3 shows estimated tuberculosis incidence rates by country in 2002 [6]. Tuberculosis incidence rates are generally much lower in industrialized countries than in developing countries. Among the 15 countries with the highest estimated tuberculosis incidence rates, 13 are in subSaharan Africa, and in most of these countries the

Table 2 Summary of tuberculosis estimates by World Health Organization region in 2002 WHO region AFRa Population (millions) New cases of TB (all forms) No. of incident cases (thousands) Incidence rate (per 100,000) Change in incidence rate 1997 – 2000 (%/y) HIV prevalence in new adult cases (%) Attributable to HIV (thousands) Attributable to HIV (% of adult cases) New SS+ cases of TB No. of incident cases (thousands) Prevalence rate of SS+ TB (per 100,000) Prevalent SS+ cases HIV+ (%) Deaths from TB No. of deaths from TB (thousands) Deaths from TB (per 100,000) Deaths from TB in HIV-positive adults (thousands) Adult AIDS deaths caused by TB (%) TB deaths attributable to HIV (%)

AMR

EMR

EUR

SEAR

WPR

Global

857

507

877

1591

1718

6222

2354 350 5.9 37.0 506.0 31.0

370 43 3.6 5.5 11.0 5.0

622 123 0.7 2.8 9.8 2.5

472 54 1.9 3.6 10.0 3.3

2890 182 2.1 3.5 56.0 2.9

2090 122 0.2 1.2 14.0 1.1

8798 141 1.1 12.0 656.0 11.0

1000 224 6.9

165 25 1.0

279 102 0.4

211 34 0.7

1294 166 0.5

939 104 0.2

3888 112 1.8

556 83.0 208.0 15.0 34.0

53 6.2 3.7 5.4 6.5

143 28.0 4.8 20.0 3.2

73 8.3 3.0 13.0 3.9

625 39.0 26.0 7.6 3.8

373 22.0 5.5 14.0 1.4

1823 29.0 251.0 13.0 13.0

672

Abbreviations: adult, 15 – 49 years old; AFR, African; AMR, Americas; EMR, Eastern Mediterranean; EUR, European; SEAR, Southeast Asia; SS+, sputum smear-positive; TB, tuberculosis; WPR, Western Pacific. a WHO African region comprises sub-Saharan Africa and Algeria. The remaining North African countries are included in the WHO Eastern Mediterranean region. Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004; and Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009 – 21.


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Fig. 2. Estimated tuberculosis incidence by country in 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004; with permission.]

prevalence of HIV infection among tuberculosis patients is high [6]. In conclusion, worldwide notification data and estimates suggest a steady decline in the tuberculosis burden in many regions except in sub-Saharan Africa and the former Soviet Union. The reasons for the persisting global tuberculosis burden include (1) poverty and the widening gap between rich and poor in various populations (eg, developing countries, inner city populations in developed countries); (2) previous neglect of tuberculosis control (inadequate case detection, diagnosis, and cure); (3) changing demography (increasing world population and changing age structure); and (4) the impact of the HIV pandemic [17].

HIV-related tuberculosis Through potent immunocompromise of infected hosts, HIV has emerged as the most important risk

factor for progression of dormant M. tuberculosis infection to clinical tuberculosis disease [18]. A short overview of HIV epidemiology is useful because HIV is such an important force driving the tuberculosis epidemic in sub-Saharan Africa and has the potential to drive the tuberculosis epidemic in other regions wherever HIV transmission spreads unchecked. HIV surveillance systems in most countries with generalized epidemics rely on tracking HIV prevalence among pregnant women attending antenatal clinics. These antenatal clinic data, supplemented by data from other sources such as blood donors and sex workers, are used to obtain national estimates of HIV prevalence among men and women and to assess trends. By the end of 2003, an estimated 38 million adults and children worldwide had HIV infection or AIDS [19]. Of these, 25 million (66%) were in subSaharan Africa, and 6.5 million (17%) were in South and South-East Asia. In 2003, 4.8 million adults and children were newly infected with HIV. An estimated 2.9 million adults and children died from HIV/AIDS

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Table 3 Ranking of countries by estimated number of tuberculosis cases Number estimated All cases

Rank

Country

1 2 3 4 5 6 7 8 9 10

Smear-positive cases

Population (thousands)

No. (thousands)

Rate (per 100,000 population)

1,049,549 1,294,867 217,131 120,911 143,809 149,911 68,961 78,580 44,759 51,201

1761 1459 557 368 318 272 255 251 250 196

168 113 256 304 221 181 370 320 558 383

787 656 250 159 143 122 110 113 102 85

75 51 115 132 99 81 159 144 227 167

20 37 43 47 51 54 57 60 62 65

No. (thousands)

Rate (per 100,000 population)

Cumulative incidence (%)

India China Indonesia Nigeria Bangladesh Pakistan Ethiopia Philippines South Africa Democratic Republic of the Congo 11 Russian Federation 12 Kenya 13 Vietnam 14 United Republic of Tanzania 15 Brazil 16 Uganda 17 Zimbabwe 18 Mozambique 19 Thailand 20 Afghanistan 21 Cambodia 22 Myanmar High-burden countries

144,082 31,540 80,278 36,276

182 170 155 132

126 540 192 363

81 70 69 56

56 223 86 155

67 69 70 72

176,257 25,004 12,835 18,537 62,193 22,930 13,810 48,852 3,892,274

110 94 88 81 80 76 76 75 7005

62 377 683 436 128 333 549 154 180

49 41 35 34 35 34 33 33 3100

28 164 271 182 57 150 242 68 80

73 74 75 76 77 78 79 80 80

Global total

6,219,011

8797

141

3887

63

100

The top 22 countries account for roughly 80% of the world’s tuberculosis burden. Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 22.

during 2003. Roughly 2.2 million (76%) of these deaths occurred in sub-Saharan Africa. Sub-Saharan Africa is the region with the highest overall HIV prevalence rate in the general adult (15 – 49 years) population, 7.5% at the end of 2003. Of 20 countries in the world with an adult HIV prevalence rate in 2003 above 5%, 19 are in subSaharan Africa (the other is Haiti). In seven countries in southern Africa, adult HIV prevalence is 15% or above. Although the countries that have the highest rates of HIV infection are in Africa, certain countries in South-East Asia and Latin America are also badly affected, with an adult HIV prevalence of 1% to 5%. Although the rise in HIV prevalence seems now to be decelerating or even decreasing in parts of Eastern and Southern Africa, it is still increasing rapidly in

some other large populations, for example in the Russian Federation.

Tuberculosis cases The HIV pandemic has dramatically fuelled tuberculosis in populations where there is overlap between those infected with M. tuberculosis and those infected with HIV. Table 4 shows the number of M. tuberculosis- and HIV-coinfected adults (15 – 49 years) in WHO regions and globally by the end of 2000 [14]. Of the 11.4 million adults coinfected with M. tuberculosis and HIV worldwide by the end of 2000, 70% were in sub-Saharan Africa (Table 4) [14]. The estimated national HIV prevalence in tuberculosis patients reflects the extent of the overlap


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Fig. 3. Estimated tuberculosis incidence rates by country in 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 215, fig. 1; with permission.]

Table 4 Number and global percentage of Mycobacterium tuberculosis- and HIV-coinfected adults (15 – 49 years) in World Health Organization regions by the end of 2000

WHO region African Americas Eastern Mediterranean European Southeast Asia Western Pacific Total

No. of people coinfected with M. tuberculosis and HIV (thousands)

Proportion of global total (%)

7979 468 163 133 2269 427

70 4 1 1 20 4

11,440

100

Data from Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163: 1009 – 21.

between the population infected with M. tuberculosis and the population infected with HIV in that country. Fig. 4 shows the estimated HIV prevalence in tuberculosis patients by country in 2002. The estimated HIV prevalence in tuberculosis patients is greater than 20% in nearly all of the countries of subSaharan Africa and is greater than 50% in most of the countries of the southern cone. Haiti is the only country outside sub-Saharan Africa where the estimated HIV prevalence in tuberculosis patients is greater than 20%. The largest share of the global burden of HIV-related tuberculosis falls on subSaharan Africa, where 31% of new cases of tuberculosis (all forms) and 34% of tuberculosis deaths are attributable to HIV, and where HIV is now the most important single predictor of tuberculosis incidence (Fig. 5) [14]. The increasing spread of HIV, especially in Eastern and Southern Africa, resulting in an increased population of M. tuberculosis- and HIV-coinfected

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Fig. 4. Estimated HIV prevalence in tuberculosis cases by country in 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/ HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 216, fig. 2; with permission.]

Estimated TB incidence (per 100,000 population)

1000 800 600 400 200 0

0

10

20

30

40

Estimated HIV prevalence, adults 15-49 yrs (%)

Fig. 5. Estimated tuberculosis incidence in relation to estimated HIV prevalence for 42 countries in the WHO African Region. (From Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1018; with permission.)

people, has driven the incidence of tuberculosis upwards in sub-Saharan Africa [6]. From 1997 to 2002, the tuberculosis incidence rate in the WHO African region grew at approximately 4% per year, and at 6% per year in Eastern and Southern Africa, faster than on any other continent and considerably faster than the 1% per year global increase. In several African countries, including those with well-organized control programs [20,21], annual tuberculosis case notification rates have risen more than fivefold since the mid 1980s, reaching more than 400 cases per 100,000 population [6]. Because HIV infection rates are higher in women than men, more tuberculosis cases are also being reported among women, especially those aged 15 to 24 years. Although tuberculosis case notifications typically show a male gender predominance, in several African countries with high rates of HIV infection, the majority of notified tuberculosis cases are now women [6].


Tuberculosis deaths The aims of tuberculosis control are to reduce tuberculosis mortality, morbidity, and disease transmission while preventing the development of drug resistance [13]. Tuberculosis deaths are not related to the public health objective of cutting the cycle of disease transmission, but, as an adverse outcome for tuberculosis patients and their families, they are an important indicator of NTP performance and of progress toward reaching the global health targets agreed as part of the United Nations Millennium Development Goals (MDGs) [22]. These considerations are particularly important in countries with high HIV prevalence where the advent of the HIV epidemic has dramatically increased both the incidence of tuberculosis and tuberculosis deaths. It is useful to consider briefly tuberculosis case fatality (the proportion of tuberculosis cases that die within a specified time) in the pre-HIV era (before and after the introduction of effective antituberculosis chemotherapy) before turning to the HIV era (ie, from the 1980s onwards). Tuberculosis case fatality was high before the introduction of effective antituberculosis chemotherapy. For example, survival analysis of confirmed pulmonary tuberculosis patients diagnosed between 1925 and 1934 in a large town in Denmark showed that the probability of dying ranged between 17% and 29%, 32% and 43%, and 42% and 55% 1 year, 3 years, and 5 years after tuberculosis diagnosis, respectively [23]. In an observational study of sputum-positive tuberculosis patients diagnosed between 1928 and 1938 in the United Kingdom, 40% of patients died in the first year after they were diagnosed with tuberculosis [24]. A reduction in tuberculosis deaths usually quickly followed the introduction of antituberculosis chemotherapy. Data on tuberculosis case fatality in the prechemotherapy era in sub-Saharan Africa are lacking, but data from clinical trials of combination chemotherapy in Eastern Africa in the 1970s showed a low case fatality [25]. HIV has dramatically increased tuberculosis case fatality as measured in clinical trials and as reflected by tuberculosis cohort deaths reported by NTPs. Risk of death during and after tuberculosis treatment is higher among HIV-positive than among HIV-negative patients who have smear-positive pulmonary tuberculosis and is higher still among HIV-positive patients who have smear-negative tuberculosis (probably reflecting their greater degree of immunosuppression) [26]. In sub-Saharan Africa, up to 30% of HIV-infected tuberculosis patients die within 12 months of starting treatment [27]. Even with treatment regimens that are highly effective in HIV-

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negative pulmonary tuberculosis patients, cohort deaths for HIV-positive pulmonary tuberculosis patients in some sub-Saharan African countries are now as high as 20% for sputum smear – positive cases and 50% for sputum smear – negative cases [26]. Tuberculosis cohort deaths are linked closely to HIV prevalence, both within countries (ie, in many countries tuberculosis cohort deaths have increased as adult HIV seroprevalence has increased) and in wider areas (tuberculosis cohort deaths and national HIV seroprevalence in sub-Saharan Africa are strongly correlated) [26]. The increase in tuberculosis deaths in populations with high HIV prevalence in subSaharan Africa may change the popular perception of tuberculosis as a curable disease and threaten the reputation of NTPs. This experience may have an adverse influence on the willingness of tuberculosis suspects to come forward for diagnosis and on the ability of the NTPs to ensure that tuberculosis patients complete treatment. Measures to prevent tuberculosis deaths in countries with high HIV prevalence include [27] 1. Antiretroviral therapy (likely to have the greatest impact) 2. Tuberculosis treatment regimens of proven effectiveness 3. Preventive therapy for HIV-related diseases other than tuberculosis (eg, co-trimoxazole to prevent common bacterial infections) 4. Improved tuberculosis and HIV control services 5. Improved general health services with better diagnosis and treatment of HIV-related diseases Implementing these measures will need increased financial and human resources for the general health services and for tuberculosis and HIV programs and more effective collaboration between tuberculosis and HIV/AIDS programs [4].

Drug-resistant tuberculosis Drug resistance and eventually MDR (ie, resistance to at least isoniazid and rifampicin) are expected to occur wherever there is inadequate application of antituberculosis chemotherapy [28]. An assessment of the number and distribution of drug-resistant tuberculosis cases is important for planning tuberculosis control, because the treatment of resistant cases is more costly and more complex when second-line drugs are used, with more frequent failures and deaths. The distinction between resistance among new cases (previously known as

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primary resistance) and resistance among previously treated cases (previously known as acquired resistance) is important because of their different implications for NTPs. Three rounds of surveys coordinated by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) between 1996 and 2002 have yielded data on antituberculosis drug resistance among new and previously treated cases. The third round of surveys included new data from 77 settings or countries collected between 1999 and 2002 and gave the following results for resistance among new and previously treated cases [29]. New cases Data on new cases were available for 75 settings. In total, 55,779 patients were surveyed. The prevalence of resistance to at least one antituberculosis drug (any resistance) ranged from 0% in some Western European countries to 57.1% in Kazakhstan (median, 10.2%). Median prevalences of resistance to specific drugs were as follows: streptomycin, 6.3%; isoniazid, 5.9%; rifampicin, 1.4%; and ethambutol,

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0.8%. Prevalence of MDR ranged from 0% in eight countries to 14.2% in Kazakhstan (51/359) and Israel (36/253) (median, 1.1%). Fig. 6 shows by participating country the prevalence of MDR-tuberculosis among new tuberculosis cases. Other high prevalences of MDR were observed in Tomsk Oblast (Russian Federation) (13.7%), Karakalpakstan (Uzbekistan) (13.2%), Estonia (12.2%), Liaoning Province (China) (10.4%), Lithuania (9.4%), Latvia (9.3%), Henan Province (China) (7.8%), and Ecuador (6.6% on preliminary data). Trends in drug resistance in new cases were determined in 46 settings (20 with two data points and 26 with at least three). Significant increases in prevalence of any resistance were found in Peru, Botswana, New Zealand, Poland, and Tomsk Oblast, (Russian Federation). Cuba, Hong Kong SAR, and Thailand reported significant decreases over time. Tomsk Oblast (Russian Federation) and Poland showed significantly increased prevalences of MDR. Decreasing trends in MDR were observed in Hong Kong SAR, Thailand, and the USA.

Fig. 6. Prevalence of MDR-tuberculosis among new tuberculosis cases, 1994 – 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dashed lines represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Anti-tuberculosis drug resistance in the world. Report no. 3. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999 – 2002. Document WHO/HTM/TB/2004.343. Geneva (Switzerland): World Health Organization; 2004. p. 47; with permission.]


Previously treated cases Data on previously treated cases were available for 66 settings. In total, 8405 patients were surveyed. The median prevalence of resistance to at least one drug (any resistance) was 18.4%, with the highest prevalence, 82.1%, in Kazakhstan (262/319). Median prevalences of resistance to specific drugs were as follows: isoniazid, 14.4%; streptomycin, 11.4%; rifampicin, 8.7%; and ethambutol, 3.5%. The median prevalence of MDR was 7.0%. Fig. 7 shows by participating country the prevalence of MDR tuberculosis among previously treated tuberculosis cases. The highest prevalences of MDR were reported in Oman (58.3%; 7/12) and Kazakhstan (56.4%; 180/ 319). Among countries of the former Soviet Union, the median prevalence of resistance to the four drugs was 30%, compared with a median of 1.3% in all other settings. Given the small number of subjects tested in some settings, prevalence of resistance among previously treated cases should be interpreted with caution. Drug-resistance trends in previously treated cases were determined in 43 settings (19 with two data

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points and 24 with at least three data points). A significant increase in the prevalence of any resistance was observed in Botswana. Cuba, Switzerland, and the United States showed significant decreases. The prevalence of MDR significantly increased in Estonia, Lithuania, and Tomsk Oblast (Russian Federation). Decreasing trends were significant in Slovakia and the United States. More representative geographic coverage of global antituberculosis drug resistance surveillance, with further data from longitudinal studies, will enable more accurate and comprehensive monitoring of global trends in the spread of MDR tuberculosis. Increases in prevalence of resistance can be caused by poor or worsening tuberculosis control, immigration of patients from areas of higher resistance, outbreaks of drug-resistant disease, and variations in surveillance methodologies. In conclusion, although drug-resistant tuberculosis is present in all settings surveyed, the prevalence of MDR is high only in certain settings. Because good tuberculosis control practices are generally associated with lower or decreasing levels of resistance, the findings of the WHO/IUATLD Global Project

Fig. 7. Prevalence of MDR-tuberculosis among previously treated tuberculosis cases, 1994 – 2002. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dashed lines represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Anti-tuberculosis drug resistance in the world. Report no. 3. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999 – 2002. Document WHO/HTM/TB/2004.343. Geneva (Switzerland): World Health Organization; 2004. p. 53; with permission.]

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emphasize the vital importance of strengthening tuberculosis control worldwide, by expanding and improving the quality of implementation of the DOTS strategy, to prevent the emergence of further drug resistance. National programs need to manage MDR tuberculosis cases, regardless of prevalence, through application of the DOTS-Plus strategy [30].

Status of global tuberculosis control The scale of the tuberculosis epidemic, as described previously, and the human rights approach to tuberculosis demand effective and urgent action [31]. WHO has promoted the DOTS strategy to control tuberculosis primarily by the interruption of transmission through the rapid identification and cure of infectious cases. By 2002, the number of countries and territories implementing the DOTS strategy was 180 (of 210), with an estimated 69% of the world’s population living in administrative areas of countries where the DOTS strategy was being implemented [6]. In practice, however, the proportion of the population with access to the DOTS strategy is less than this administrative figure because of several possible barriers to access, including geographic, financial, and cultural impediments, within the administrative area. Relying on currently available methods of diagnosis and treatment, the DOTS strategy is effective, affordable, and adaptable in different settings (eg, as part of a strategy of expanded scope where HIV prevalence is high [4], as DOTS-Plus in areas where the prevalence of MDR tuberculosis is high [5], and as public-private mix [PPM] DOTS where the majority of tuberculosis suspects consult private practitioners) [32]. WHO coordinates a global tuberculosis monitoring and evaluation project in which countries report annual progress in implementation of the DOTS strategy [33]. The World Health Assembly (WHA) has set global targets for tuberculosis control through the implementation of the DOTS strategy [34]. The choice of these global targets reflected the need to achieve a significant epidemiologic impact by reaching targets that field experience had demonstrated were feasible in countries with a high incidence of tuberculosis. These targets are to detect at least 70% of all new infectious cases and to cure at least 85% of those detected by 2005 [35]. A 70% case detection rate and an 85% cure rate eventually would reduce both the prevalence of infectious tuberculosis cases and the number of infected contacts by about 40% [36] and would lead to an expected decline in annual

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tuberculosis incidence rate of 6% to 7% per year [37]. The epidemiologic impact on the global tuberculosis epidemic of sustained achievement of these targets is expressed in the MDG relevant to tuberculosis (Goal 6, Target 8), ‘‘to have halted and begun to reverse incidence by 2015’’ [22]. The epidemiologic interpretation of this goal set by politicians is to decrease tuberculosis prevalence and deaths by half by 2015. The following section summarizes the most recent assessment of progress in implementation of the DOTS strategy toward achieving the cure rate and case detection targets as set out in the 2004 WHO Report, which reports on the cases detected in 2002 and the outcomes of treatment of patients detected in 2001 [6]. Cases detected and notified Through the global tuberculosis monitoring and evaluation project coordinated by WHO, countries report annually the number and type of tuberculosis cases detected, reported, and treated under DOTS and non-DOTS programs [6]. In 2002, approximately 3 million patients who were newly diagnosed with tuberculosis, 1.4 million of whom were smearpositive, were reported in DOTS programs. A total of 13.3 million tuberculosis patients and 6.8 million smear-positive patients were treated in DOTS programs between 1995 and 2002. Regarding new cases of sputum smear – positive pulmonary tuberculosis, for the calculation of case detection rate in each country, the numerator is the number of annual cases detected and reported under the DOTS strategy, and the denominator is the estimated annual incidence of cases in that country. The numerator is derived annually from country reports of registered cases (ie, cases detected and reported under the DOTS strategy). The denominator is an estimate based on a variety of inputs, as outlined earlier. One of the challenges in improving the accuracy of measurement of the case detection rate is ensuring that all cases detected by different care providers (eg, private practitioners) and treated in line with the DOTS strategy are reported through the NTP. The 1.4 million smear-positive cases reported globally by DOTS programs in 2002 represent 37% of the estimated incidence, a little more than half of the 70% target. Treatment success The cure rate is reported by each country through cohort analysis of standard treatment outcomes of registered patients (Table 5) [13]. Because practice varies considerably among countries in documenting

global epidemiology of tuberculosis Table 5 Standard treatment outcomes in patients who have sputum smear-positive pulmonary tuberculosis Outcome

Patient characteristics

Cure

Patient who is sputum smear-negative in the last month of treatment and at least on one previous occasion Patient who has completed treatment but who does not meet the criteria to be classified as a cure or a failure Patient who is sputum smear-positive at 5 months or later during treatmentb Patient who dies for any reason during the course of treatment Patient whose treatment was interrupted for 2 consecutive months or more Patient who has been transferred to another recording and reporting unit and for whom the treatment outcome is not known

Treatment completeda Treatment failure Died Default Transfer out

a Treatment success is defined as the sum of patients cured and those who have completed treatment. b Also a patient who was initially smear-negative before starting treatment and became smear-positive after completing the initial phase of treatment. Data from World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 3rd edition. Document WHO/CDS/TB/2003.313. Geneva (Switzerland): World Health Organization; 2003. p. 55.

negative sputum smears on completion of treatment, for practical purposes the treatment success rate (cure plus treatment completion) is used as a proxy for cure rate. Treatment success under DOTS for the 2001 cohort was 82% on average. As in previous years, treatment success was substantially below average in the WHO African Region (71%) and in the former Soviet Union (70%). Low treatment success in these two regions is attributable, in part, to NTPs failing to cope with the increased caseload fuelled by HIV and the problem of drug resistance, respectively. All indicators of treatment outcome were much worse in non-DOTS areas, although the true outcome of treatment is unknown for a high proportion of patients in non-DOTS areas because of the lack of use of standardized definitions and lack of systematic reporting when programs are weak. Fatal outcomes were most common in Africa (7.2%), where a higher percentage of cases is HIV-positive, and in Europe (5.9%), where a higher percentage of cases occurs among the elderly. Treatment interruption (default) was most frequent in the WHO African Region (10.3%), Eastern Mediterranean Region (7.2%), and South-East Asia Region (6.7%). Transfer without follow-up was also especially high in Africa (6.6%).

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Treatment failure was conspicuously high in the European region (8.1%), mainly because of high failure rates in the former Soviet Union, most likely resulting from the high prevalence of MDR tuberculosis. In summary, the global case detection rate for patients who had sputum smear – positive tuberculosis was 37% in 2002, half of the 70% target, whereas treatment success under the DOTS strategy for the 2001 cohort was 82% on average, close to the 85% target. Although this progress toward the WHA 2005 targets of 70% case detection and 85% treatment success represents a considerable gain, making an impact on the global tuberculosis burden as expressed in the 2015 MDGs will require speeding progress toward meeting and then sustaining the 2005 WHA targets.

Approaches needed to accelerate progress in global tuberculosis control A global alliance named the Stop TB Partnership provides the means for international partners and the governments of countries with high tuberculosis incidence to intensify efforts to accelerate progress in global tuberculosis control [38]. The development of new tools for tuberculosis control (eg, a more effective vaccine [39], better diagnostic tests [40], and improved preventive [41] and therapeutic [42] approaches) holds out the prospect of rapid progress in tuberculosis control in the future. In the meantime, the challenge in maximizing the impact of currently available methods of diagnosis and treatment lies in implementing the DOTS strategy and its adaptations as effectively and as widely as possible. In coordination with a global network of partners known as the DOTS Expansion Working Group (DEWG), WHO is committed to implementing the DOTS strategy as effectively and as widely as possible [43]. WHO published the Global DOTS Expansion Plan (GDEP) in 2001 [44]. The GDEP is based on two pillars: the preparation in each country of a mid-term (at least 5-year) DOTS expansion plan, and the establishment of a mechanism for interagency coordination ensuring that all relevant partners contribute to the implementation of the national plan. Effective development and implementation of the national plan depends on the engagement of the full range of health providers under NTP stewardship: government services, whether Ministry of Health (nationally and locally administrated services) or not (eg, social security schemes, prisons, military), and nongovernment services (eg, NGOs, community

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groups [45], private practitioners [32], and employers [46]). In practice, all health providers should refer patients to public health facilities delivering tuberculosis care under the DOTS strategy or deliver tuberculosis care consistent with the DOTS strategy in collaboration with the NTP. The failure of providers to deliver care consistent with the DOTS strategy compromises the achievements of NTPs and the chances of successful tuberculosis control. Governments should consider reform of legislative and regulatory frameworks to engage the full range of health providers and will need to invest in developing human resource capacity (for strengthened NTP stewardship and service delivery) [47]. Three of the main adaptations of the DOTS strategy are as part of a strategy of expanded scope where HIV prevalence is high [4], as DOTS-Plus in areas where the prevalence of MDR tuberculosis is high [5], and as PPM DOTS where the majority of tuberculosis suspects consult private practitioners [32]. Until recently, the efforts to control tuberculosis among HIV-infected people have focused mainly on identifying and curing infectious tuberculosis cases among patients presenting to general health services. This approach targets the final step in the sequence of events by which HIV fuels tuberculosis, namely the transmission of M. tuberculosis infection by infectious tuberculosis cases. The strategy of expanded scope for tuberculosis control in populations with high HIV prevalence comprises interventions against tuberculosis (the DOTS strategy and tuberculosis preventive treatment) and interventions against HIV (and therefore indirectly against tuberculosis) (eg, condoms, treatment of sexually transmitted infections, safe injecting drug use, and highly active antiretroviral treatment) [4]. DOTS-Plus is the programmatic approach to the diagnosis and treatment of MDR tuberculosis within the context of DOTS programs. Management involves the diagnosis of MDR tuberculosis through quality-assured culture and drug-susceptibility testing and treatment with second-line drugs under proper case management conditions. In response to the seriousness of MDR tuberculosis as a global public health problem, the DOTS-Plus Working Group was established in 1999 to promote improved management of MDR tuberculosis in resource-limited countries. The Working Group aims to assess the feasibility and cost effectiveness of the use of secondline antituberculosis drugs in DOTS-Plus projects. Since 2000, the Working Group’s Green Light Committee has successfully negotiated with the pharmaceutical industry to obtain substantial concessionary prices for second-line drugs that otherwise

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were unaffordable in poor settings. As a result, prices of the most expensive regimens have dropped by 95%. PPM-DOTS is the means of engaging private practitioners in collaboration with the NTP in the delivery of tuberculosis care consistent with the DOTS strategy. This approach is necessary where large numbers of tuberculosis suspects seek care from private practitioners rather than from public health services. Recent studies indicate the success of the PPM approach in achieving high rates of case detection, notification, and cure [48]. A global subgroup of the DEWG concerned with PPM-DOTS is promoting the scaling up of this approach, accompanied by the necessary strengthening of the NTP stewardship and leadership roles. Lessons learned from PPM-DOTS are applicable to engaging the contributions of a wide range of public providers who in many countries are providing tuberculosis care independently of the NTP (eg, in prisons and social security programs). Accelerating progress in global tuberculosis control depends on developments in the specific field of tuberculosis control and on strengthening health systems. In 2003, the Stop TB Partnership convened a second ad hoc committee on the tuberculosis epidemic to seek solutions to the health system constraints to more rapid progress in global tuberculosis control and to make recommendations to overcome those constraints [49,50]. The committee made recommendations under seven headings (many of which cut across the different aspects of tuberculosis control) [49]: 1. Consolidate, sustain, and advance achievements 2. Enhance political commitment (and its translation into policy and action) 3. Address the health workforce crisis 4. Strengthen health care systems, particularly primary care delivery 5. Accelerate the response to the TB/HIV emergency 6. Mobilize communities and the corporate sector 7. Invest in research and development to shape the future. Implementation of these recommendations depends on coordination between the health care sector and other sectors to deliver effective tuberculosis control covering all populations in need.

Summary In 2002 there were an estimated 8.8 million new cases of tuberculosis worldwide, and the global


incidence rate was growing at approximately 1.1% per year. The scale of the global tuberculosis epidemic indicates the huge challenge for tuberculosis control, which is complicated by the impact of HIV and drug-resistant tuberculosis. Global efforts to implement the DOTS strategy widely and effectively have resulted in a global case detection rate of 37% in 2002, more than half of the target of 70%, and treatment success for the 2001 cohort of 82%, on average, close to the target of 85%. Faster progress toward global targets depends on future development of new drugs, diagnostics, and vaccines, meanwhile overcoming health system constraints to intensified implementation of the DOTS strategy and to its adaptations in areas with high prevalence of HIV or MDR tuberculosis or where not all care providers deliver the internationally recommended standard of care.

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[9] Rieder HL, Zellwegger J-P, Raviglione MC, et al. Tuberculosis control in Europe and international migration. Report of European Task Force. Eur Respir J 1994;7:1545 – 53. [10] Raviglione MC, Sudre P, Esteves K, et al. Tuberculosis – Western Europe, 1974 – 1991. MMWR Morb Mortal Wkly Rep 1993;42:628 – 31. [11] European Centre for the Epidemiological Monitoring of AIDS. HIV/AIDS surveillance in Europe: quarterly report no. 46, 30 June 1995. [12] Raviglione MC, Snider D, Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 1995;273(3):220 – 6. [13] World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 3rd edition. Document WHO/CDS/TB/2003.313. Geneva (Switzerland)7 World Health Organization; 2003. [14] Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163: 1009 – 21. [15] Dye C, Scheele S, Dolin P, et al for the WHO Global Surveillance and Monitoring Project. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country. JAMA 1999;282:677 – 86. [16] Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990;65:6 – 24. [17] Raviglione MC, Luelmo F. Update on the global epidemiology of tuberculosis. Curr Issues Public Health 1996;2:192 – 7. [18] Rieder HL, Cauthen GM, Comstock GW, et al. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79 – 98. [19] Joint United Nations Programme on HIV/AIDS (UNAIDS). 2004 report on the global AIDS epidemic. Geneva (Switzerland)7 UNAIDS; 2004. [20] Kenyon TA, Mwasekaga MJ, Huebner R, et al. Low levels of drug-resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus coepidemics in Botswana. Int J Tuberc Lung Dis 1999;3: 4 – 11. [21] Harries AD, Nyong’Onya Mbewe L, Salaniponi FM, et al. Tuberculosis programme changes and treatment outcomes in patients with smear-positive pulmonary tuberculosis in Blantyre, Malawi. Lancet 1996;347: 807 – 9. [22] United Nations Statistics Division. Millennium Indicators Database. Available at: http://unstats.un.org/ unsd/mi/mi_goals.asp. Accessed August 4, 2004. [23] Buhl K, Nyboe J. Epidemiological basis of tuberculosis eradication. Changes in the mortality of Danish tuberculosis patients since 1925. Bull World Health Organ 1967;37:907 – 25. [24] Thompson BC. Survival rates in pulmonary tuberculosis. BMJ 1943;2:721. [25] Second East African/British Medical Research Council Kenya Tuberculosis Survey follow-up 1979. Tuberculosis in Kenya: follow-up of the second (1974)

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maher national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. An East African and British Medical Research Council co-operative investigation. Tubercle 1979;60: 125 – 49. Mukadi YD, Maher D, Harries AD. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001;15:143 – 52. Harries AD, Hargreaves NJ, Kemp J, et al. Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1. Lancet 2001;357:1519 – 23. Crofton J, Chaulet P, Maher D. Guidelines for the management of drug-resistant tuberculosis. Document WHO/TB/1996.210. Geneva (Switzerland)7 World Health Organization; 1997. World Health Organization. Anti-tuberculosis drug resistance in the world. Report number 3. The WHO/ IUATLD Global project on anti-tuberculosis drug resistance surveillance 1999 – 2002. Geneva (Switzerland)7 World Health Organization; 2004. World Health Organization. Guidelines for establishing DOTS-plus pilot projects for the management of multidrug-resistant tuberculosis. Document WHO/ CDS/TB/2000.278. Geneva (Switzerland)7 World Health Organization; 2000. World Health Organization. Guidelines for social mobilization: a human rights approach to tuberculosis. Document WHO/CDS/TB/2001.9. Geneva (Switzerland)7 World Health Organization; 2001. Murthy KJR, Frieden TR, Yazdani A, et al. Publicprivate partnership in tuberculosis control: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001;5: 354 – 9. Raviglione MC, Dye C, Schmidt S, et al. Assessment of worldwide tuberculosis control. Lancet 1997;350: 624 – 9. World Health Organization. Forty-fourth World Health Assembly. Resolutions and decisions. Resolution WHA 44.8. WHA44/1991/REC/1. Geneva (Switzerland)7 World Health Organization; 1991. World Health Organization. Fifty-third World Health Assembly. Resolutions and decisions. Resolution WHA 53.1. Geneva (Switzerland)7 World Health Organization; 2000. Styblo K., Bumgarner J.R. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance Research Unit Progress Report (The Hague, The Netherlands) 1991;2:60 – 72. Dye C, Williams BG. Criteria for the control of drugresistant tuberculosis. Proc Natl Acad Sci USA 2000; 97:8180 – 5.

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raviglione [38] Stop TB Partnership. Annual Report 2001. Document WHO/CDS/STB/2002.17. Geneva (Switzerland)7 World Health Organization; 2001. [39] Young DB. Current tuberculosis vaccine development. Clin Infect Dis 2000;30(Suppl 3):S254 – 6. [40] Perkins MD. New diagnostics for tuberculosis. Int J Tuberc Lung Dis 2000;4(12):S182 – 8. [41] Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47(No. RR-20):1 – 58. [42] Barry III CE, Slayden RA, Sampson AE, et al. Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs. Biochem Pharmacol 2000;59:221 – 31. [43] World Health Organization. Report on DOTS Expansion Working Group meeting, Montreal, Canada, in October 2002 [internal document]. Geneva (Switzerland)7 World Health Organization; 2002. [44] World Health Organization. Global DOTS expansion plan—progress in TB control in high-burden countries 2001, 1 year after the Amsterdam Ministerial Conference. Document WHO/CDS/TB/2003.312. Geneva (Switzerland)7 World Health Organization; 2001. [45] World Health Organization. Community contribution to TB care: practice and policy. Document WHO/CDS/ TB/2003.312. Geneva (Switzerland)7 World Health Organization; 2003. [46] World Health Organization and International Labour Office. Guidelines for workplace TB control activities. Document WHO/CDS/TB/2003.323. Geneva (Switzerland)7 World Health Organization; 2003. [47] World Health Organization. Good practice in legislation and regulations for TB control: an indicator of political will. Document WHO/CDS/TB/2001.290. Geneva (Switzerland)7 World Health Organization; 2001. [48] Lo¨nnroth K, Uplekar M, Arora VK, et al. Publicprivate mix for improved TB control—what makes it work? Bull World Health Organ 2004;82(8):580 – 6. [49] World Health Organization. Report on the meeting of the second ad hoc committee on the TB epidemic. Montreux, Switzerland, 18 – 19, 2003. Recommendations to Stop TB partners. Document WHO/HTM/ STB/2004.28. Geneva (Switzerland)7 World Health Organization; 2004. [50] World Health Organization. Background document prepared for the meeting of the second ad hoc committee on the TB epidemic. Document WHO/HTM/ STB/2004.27. Geneva (Switzerland)7 World Health Organization; 2004.

Clin Chest Med 26 (2005) 283 – 294

Issues in the Management of HIV-Related Tuberculosis William J. Burman, MDa,b,* a

Division of Infectious Diseases, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA b Infectious Diseases Clinic, Denver Department of Public Health, 605 Bannock Street, Denver, CO 80204, USA

The HIV pandemic poses major problems for the tuberculosis control program and for the individual clinician treating HIV-related tuberculosis. HIVrelated immunosuppression is the single most potent risk factor for progression from latent tuberculosis infection to active tuberculosis [1]. As a result, HIV is major factor driving the global resurgence of tuberculosis; incidence rates of tuberculosis in countries with high prevalence of HIV infection have increased up to fivefold [2]. Severe immunosuppression also results in marked changes in the clinical, radiographic, and histopathologic presentation of tuberculosis [3]. This article does not review all aspects of HIV-related tuberculosis; the dramatic effects of HIV on the epidemiology, presentation, and diagnosis of tuberculosis have been reviewed elsewhere recently [2,3]. This article focuses on the ways in which HIV infection and the associated immunodeficiency affect the management of active tuberculosis. Controversial topics are highlighted, followed by a suggested strategy for management while awaiting additional data. There are a number of unique challenges in the treatment of HIV-related tuberculosis, but the basic principles of tuberculosis treatment developed over the past 50 years are applicable to HIV-related tuberculosis. Drug-susceptible tuberculosis is treated most efficiently with regimens including an initial intensive phase—2 months of isoniazid, rifampin or

This work was supported in part by the Tuberculosis Trials Consortium, Centers for Disease Control and Prevention, Atlanta, GA. The author has had research contracts with Roche Laboratories, Merck, Glaxo-Smith Kline, and Bristol Myers-Squibb. * 605 Bannock Street, Denver, CO 80204. E-mail address: [email protected]

rifabutin, pyrazinamide, and ethambutol—followed by a 4-month continuation phase of isoniazid and rifampin or rifabutin. A remaining challenge for the treatment of active tuberculosis among HIV-infected and uninfected persons is finding efficient and programmatically relevant ways to identify patients at increased risk for relapse and targeting them for prolonged or otherwise altered treatment [4,5]. Adherence to multidrug therapy is difficult, particularly when it must be sustained for at least 6 months. Directly observed therapy, the most effective way of promoting adherence to tuberculosis treatment [6], is all the more important in the management of HIVrelated tuberculosis [7]. There is little margin for error in the treatment of tuberculosis in a severely immunocompromised person.

Issues in the treatment of HIV-related tuberculosis When these basic principles are observed, the outcomes of treatment of active tuberculosis among persons with HIV infection are similar to those of HIV-negative patients with tuberculosis [5,8 – 14]. The rates of treatment failure (a positive culture at or beyond 4 months of treatment) and relapse are low. Whether the rates of treatment failure and relapse are somewhat higher among patients with HIV coinfection and how the rate of treatment failure should affect the management of HIV-related tuberculosis remain subjects of controversy. One key difference is that the risk of death during tuberculosis treatment is much higher among persons with HIV-related tuberculosis. For example, in a study from South Africa the risk of death during tuberculosis treatment was 13.7% among HIV-infected miners versus 0.5%



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among HIV-negative miners [11]. After the first few weeks of tuberculosis treatment, nearly all the excess mortality is related to complications of AIDS other than tuberculosis [10,15]. Combination antiretroviral therapy markedly reduces new opportunistic infections and death among persons with AIDS [16] and seems to do so among persons with HIV-related tuberculosis [17 – 19]. The use of combination antiretroviral therapy in persons being treated with tuberculosis poses a number of challenges for the patient and clinician, however. To summarize, the controversies in the management of HIV-related tuberculosis can be grouped into issues about tuberculosis treatment itself and issues posed by the use of combination antiretroviral therapy. The issues related to tuberculosis treatment are the uncertainties about the optimal duration of therapy and the adequacy of intermittent dosing of tuberculosis therapy (dosing less frequently than daily). Use of combination antiretroviral therapy during tuberculosis treatment is complicated by (1) the adherence challenge of polypharmacy, (2) overlapping side-effect profiles of the antituberculosis drugs, antiretroviral therapy, and drugs used to prevent or treat other opportunistic infections, (3) drug – drug interactions, and (4) the occurrence of immune reconstitution inflammatory syndromes following the institution of effective antiretroviral therapy. These four issues lead to uncertainties about the optimal timing of antiretroviral therapy during tuberculosis treatment.

Issues related to tuberculosis treatment Optimal duration of therapy Early in the HIV pandemic, it became clear that some opportunistic infections required prolonged, if not lifelong, treatment in persons with advanced HIV disease. For example, cryptococcal meningitis can be cured in a high percentage of immunocompetent patients with 6 weeks of treatment [20], but

patients with advanced HIV disease (in the era before combination antiretroviral therapy) required lifelong therapy to prevent recurrent meningitis [21]. Such experience suggested that treatment of tuberculosis might also have to be longer among patients with advanced HIV disease. Despite the importance of the question, there have been no definitive studies of the optimal duration of treatment for HIV-related tuberculosis. A large study performed in Zaire randomly assigned patients to 6 or 12 months of therapy and found a higher rate of recurrent tuberculosis among patients treated with 6 months of therapy [22]. High losses to follow-up and the inability to distinguish infection with a new strain of Mycobacterium tuberculosis (re-infection) from relapse of the initial infecting strain make this study difficult to interpret. In an area with high tuberculosis case rates, re-infection can be a common cause of recurrent tuberculosis, particularly among HIV-infected persons [23,24]. A trial in the United States comparing 6 versus 9 months of therapy showed low relapse rates in both arms (

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