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American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States

	CONTENTS

TOP CONTENTS SUMMARY INTRODUCTION SCIENTIFIC BASIS OF TB... PRINCIPLES AND PRACTICE OF... RECOMMENDED ROLES AND... ESSENTIAL COMPONENTS OF TB... CONTROL OF TB AMONG... CONTROL OF TB IN... RESEARCH NEEDS TO ENHANCE... GRADED RECOMMENDATIONS FOR THE... REFERENCES

Progress toward TB Elimination1170

Challenges to Progress toward TB Elimination1171

Meeting the Challenges to TB Elimination1172

Basic Principles of TB Control in the United States1172

Structure of this Statement1173 Scientific Basis of TB Control1174

Transmission of TB1174

Epidemiology of TB in the United States1176

Contributions of Genotyping of M. tuberculosis1178 Principles and Practice of TB Control1179

Basic Principles of TB Control1179

Deficiencies in TB Control1180

Importance of TB Training and Education1181

Laboratory Services for Optimal TB Control1182 Recommended Roles and Responsibilities

for TB Control1183

Public Health Sector1183

Clinicians1187

Civil Surgeons1188

Community Health Centers1188

Hospitals1189

Academic Institutions1189

Medical Professional Organizations1190

Community-based Organizations1190

Correctional Facilities1191

Pharmaceutical and Biotechnology Industries1191 Essential Components of TB Control in the

United States1191

Case Detection and Management1191

Contact Investigation and Outbreak Control1193

Targeted Testing and Treatment of LTBI1193 Control of TB among Populations at Risk1199

Control of TB among Children and Adolescents1200

Control of TB among Foreign-born Persons1201

Control of TB among Persons with HIV Infection1205

Control of TB among Homeless Persons1206

Control of TB among Detainees and Prisoners1208 Control of TB in Health Care Facilities and Other

High-Risk Environments1209

Control of Transmission of M. tuberculosis in Other

High-Risk Settings1210 Research Needs to Enhance TB Control1211 Graded Recommendations for the Control and

Prevention of TB1212

Recommendations for TB Laboratory Services1212

Recommendations for TB Case Detection1212

Recommendations for Contact Investigations and

for Outbreak Prevention and Response1213

Recommendations for the Public Health Aspects

of Targeted Testing and Treatment of LTBI1213

Recommendations for TB Control among Children

and Adolescents1213

Recommendations for TB Control among

Foreign-born Persons1214

Recommendations for TB Control among

HIV-infected Persons1215

Recommendations for TB Control among

Homeless Persons1216

Recommendations for TB Control among Detainees

and Prisoners1217

Recommendations for TB Control in Health Care

Facilities and Other High-Risk Settings1217

Recommendations on Research for Progress toward

Elimination of TB1218

	SUMMARY

TOP CONTENTS SUMMARY INTRODUCTION SCIENTIFIC BASIS OF TB... PRINCIPLES AND PRACTICE OF... RECOMMENDED ROLES AND... ESSENTIAL COMPONENTS OF TB... CONTROL OF TB AMONG... CONTROL OF TB IN... RESEARCH NEEDS TO ENHANCE... GRADED RECOMMENDATIONS FOR THE... REFERENCES

 
During 1993–2003, incidence of tuberculosis (TB) in the United States decreased 44% and is now occurring at a historic low level (14,874 cases in 2003). The Advisory Council for the Elimination of Tuberculosis has called for a renewed commitment to eliminating TB in the United States, and the Institute of Medicine has published a detailed plan for achieving that goal. In this statement, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) propose recommendations to improve the control and prevention of TB in the United States and to progress toward its elimination.

This statement is one in a series issued periodically by the sponsoring organizations to guide the diagnosis, treatment, control, and prevention of TB. This statement supersedes the previous statement by ATS and CDC, which was also supported by IDSA and the American Academy of Pediatrics (AAP). This statement was drafted, after an evidence-based review of the subject, by a panel of representatives of the three sponsoring organizations. AAP, the National Tuberculosis Controllers Association, and the Canadian Thoracic Society were also represented on the panel.

This statement integrates recent scientific advances with current epidemiologic data, other recent guidelines from this series, and other sources into a coherent and practical approach to the control of TB in the United States. Although drafted to apply to TB-control activities in the United States, this statement might be of use in other countries in which persons with TB generally have access to medical and public health services and resources necessary to make a precise diagnosis of the disease; achieve curative medical treatment; and otherwise provide substantial science-based protection of the population against TB.

This statement is aimed at all persons who advocate, plan, and work at controlling and preventing TB in the United States, including persons who formulate public health policy and make decisions about allocation of resources for disease control and health maintenance and directors and staff members of state, county, and local public health agencies throughout the United States charged with control of TB. The audience also includes the full range of medical practitioners, organizations, and institutions involved in the health care of persons in the United States who are at risk for TB.

	INTRODUCTION

TOP CONTENTS SUMMARY INTRODUCTION SCIENTIFIC BASIS OF TB... PRINCIPLES AND PRACTICE OF... RECOMMENDED ROLES AND... ESSENTIAL COMPONENTS OF TB... CONTROL OF TB AMONG... CONTROL OF TB IN... RESEARCH NEEDS TO ENHANCE... GRADED RECOMMENDATIONS FOR THE... REFERENCES

 
During 1993–2003, incidence of tuberculosis (TB) in the United States decreased 44% and is now occurring at a historic low level (14,874 cases in 2003). The Advisory Council for the Elimination of Tuberculosis (ACET) (1) has called for a renewed commitment to eliminating TB in the United States, and the Institute of Medicine (IOM) (2) has published a detailed plan for achieving that goal. In this statement, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) propose recommendations to improve the control and prevention of TB in the United States and to progress toward its elimination.

This statement is one in a series issued periodically by the sponsoring organizations to guide the diagnosis, treatment, control, and prevention of TB (3–5). This statement supersedes one published in 1992 by ATS and CDC, which also was supported by IDSA and the American Academy of Pediatrics (AAP) (6). This statement was drafted, after an evidence-based review of the subject, by a panel of representatives of the three sponsoring organizations. AAP, the National Tuberculosis Controllers Association (NTCA), and the Canadian Thoracic Society were also represented on the panel. The recommendations contained in this statement (see GRADED RECOMMENDATIONS FOR THE CONTROL AND PREVENTION OF TB) were rated for their strength by use of a letter grade and for the quality of the evidence on which they were based by use of a Roman numeral (Table 1) (7). No rating was assigned to recommendations that are considered to be standard practice (i.e., medical or administrative practices conducted routinely by qualified persons who are experienced in their fields).

This statement is aimed at all persons who advocate, plan, and work at controlling and preventing TB in the United States, including persons who formulate public health policy and make decisions about allocation of resources for disease control and health maintenance and directors and staff members of state, county, and local public health agencies throughout the United States charged with control of TB. The audience also includes the full range of medical practitioners, organizations, and institutions involved in the health care of persons in the United States who are at risk for TB.

Throughout this document, the terms latent TB infection (LTBI), TB, TB disease, and infectious TB disease are used. LTBI is used to designate a condition in which an individual is infected with Mycobacterium tuberculosis but does not currently have active disease. Such patients are at risk for progressing to TB disease. Treatment of LTBI (previously called preventive therapy or chemoprophylaxis) is indicated for those at increased risk for progression as described in the text. Persons with LTBI are asymptomatic and have a negative chest radiograph. TB, TB disease, and infectious TB indicate that the disease caused by M. tuberculosis is clinically active; patients with TB are generally symptomatic for disease. Positive culture results for M. tuberculosis complex are an indication of TB disease. Infectious TB refers to TB disease of the lungs or larynx; persons with infectious TB have the potential to transmit M. tuberculosis to other persons.

Progress toward TB Elimination
A strategic plan for the elimination of TB in the United States was published in 1989 (11), when the United States was experiencing a resurgence of TB (Figure 1). The TB resurgence was attributable to the expansion of HIV infection, nosocomial transmission of M. tuberculosis, multidrug-resistant TB, and increasing immigration from counties with a high incidence of TB. Decision makers also realized that the U.S. infrastructure for TB control had deteriorated (12); this problem was corrected by a substantial infusion of resources at the national, state, and local levels (13). As a result, the increasing incidence of TB was arrested; during 1993–2003, an uninterrupted 44% decline in incidence occurred, and in 2003, TB incidence reached a historic low level. This success in responding to the first resurgence of TB in decades indicates that a coherent national strategy; coordination of local, state, and federal action; and availability of adequate resources can result in dramatic declines in TB incidence. This success also raised again the possible elimination of TB, and in 1999, ACET reaffirmed the goal of TB elimination in the United States (1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Number of reported cases of tuberculosis, by year or diagnosis—United States, 1982–2003.

As noted, the 44% decrease in incidence of TB in the United States during 1993–2003 (14, 15) has been attributed to the development of effective interventions enabled by increased resources at the national, state, and local levels (1, 2, 16). Whereas institutional resources targeted specific problems such as transmission of TB in health care facilities, public resources were earmarked largely for public health agencies, which used them to rebuild the TB-control infrastructure (13, 17). A primary objective of these efforts was to increase the rate of completion of therapy among persons with TB, which was achieved by innovative case-management strategies, including greater use of directly observed therapy (DOT). During 1993–2000, the percentage of persons with reported TB who received DOT alone or in combination with self-supervised treatment increased from 38 to 78%, and the proportion of persons who completed therapy in less than 1 year after receiving a diagnosis increased from 63 to 80% (14). Continued progress in the control of TB in the United States will require consolidation of the gains made through improved cure rates and implementation of new strategies to further reduce incidence of TB.

Challenges to Progress toward TB Elimination
The development of optimal strategies to guide continuing efforts in TB control depends on understanding the challenges confronting the effort. The five most important challenges to successful control of TB in the United States are as follows: (1) prevalence of TB among foreign-born persons residing in the United States, (2) delays in detecting and reporting cases of pulmonary TB, (3) deficiencies in protecting contacts of persons with infectious TB and in preventing and responding to TB outbreaks, (4) persistence of a substantial population of persons living in the United States with LTBI who are at risk for progression to TB disease, and (5) maintaining clinical and public health expertise in an era of declining TB incidence. These five concerns (Box 1) serve as the focal point for the recommendations made in this statement to control and prevent TB in the United States.

BOX 1. MAJOR CHALLENGES TO SUCCESSFUL CONTROL OF TB TB among foreign-born persons residing in the United States Delays in detection and reporting of cases of pulmonary TB Deficiencies in protecting contacts of persons with infectious cases of TB and in preventing and responding to TB outbreaks Presence of a large reservoir of persons living in the United States with latent TB infection who are at risk for progression to TB disease Maintaining clinical and public health expertise in an era of declining TB incidence

 

Prevalence of TB among Foreign-born Persons Residing in the United States.
Once a disease that predominately affected U.S.-born persons, TB now affects a comparable number of foreign-born persons who reside in the United States permanently or temporarily, although such persons make up only 11% of the U.S. population (14). During 1993–2003, as TB incidence in the United States declined sharply, incidence among foreign-born persons changed little (14). Lack of access to medical services because of cultural, linguistic, financial, or legal barriers results in delays in diagnosis and treatment of TB among foreign-born persons and in ongoing transmission of the disease (18–21). Successful control of TB in the United States and progress toward its elimination depend on the development of effective strategies to control and prevent the disease among foreign-born persons.

Delays in Detection and Reporting of Cases of Pulmonary TB.
New cases of infectious TB should be diagnosed and reported as early as possible in the course of the illness so curative treatment can be initiated, transmission interrupted, and public health responses (e.g., contact investigation and case-management services) promptly arranged. However, delays in case detection and reporting continue to occur; these delays are attributed to medical errors (22–26) and to patient factors (e.g., lack of understanding about TB, fear of the authorities, and lack of access to medical services) (18–20). In addition, genotyping studies have revealed evidence of persistent transmission of M. tuberculosis in communities that have implemented highly successful control measures (27–29), suggesting that such transmission occurred before a diagnosis was received. Improvements in the detection of TB cases, leading to earlier diagnosis and treatment, would bring substantial benefits to affected patients and their contacts, decrease TB among children, and prevent outbreaks.

Deficiencies in Protecting Contacts of Person with Infectious TB and in Preventing and Responding to TB Outbreaks.
Although following up contacts is among the highest public health priorities in responding to a case of TB, problems in conducting contact investigations have been reported (30–32). Approaches to contact investigations vary widely from program to program, and traditional investigative methods are not well adapted to certain populations at high risk. Only half of at-risk contacts complete a course of treatment for LTBI (32). Reducing the risk of TB among contacts through the development of better methods of identification, evaluation, and management would lead to substantial personal and public health benefits and facilitate progress toward eliminating TB in the United States.

Delayed detection of TB cases and suboptimal contact investigation can lead to TB outbreaks, which are increasingly reported (26, 33–38). Persistent social problems, such as crowding in homeless shelters and detention facilities, are contributing factors to the upsurge in TB outbreaks. The majority of jurisdictions lack the expertise and resources needed to conduct surveillance for TB outbreaks and to respond effectively when they occur. Outbreaks have become an important element in the epidemiology of TB, and measures to detect, manage, and prevent them are needed.

Persistence of a Substantial Population of Persons Living in the United States with LTBI Who Are at Risk for Progression to TB Disease.
An estimated 9.6 to 14.9 million persons residing in the United States have LTBI (39). This pool of persons with latent infection is continually supplemented by immigration from areas of the world with a high incidence of TB and by ongoing person-to-person transmission among certain populations at high risk. For TB disease to be prevented among persons with LTBI, those at highest risk must be identified and receive curative treatment (4). Progress toward the elimination of TB in the United States requires the development of new cost-effective strategies for targeted testing and treatment of persons with LTBI (17, 40).

Maintaining Clinical and Public Health Expertise in an Era of Declining TB Incidence.
Detecting a TB case, curing a person with TB, and protecting contacts of such persons require that clinicians and the staff members of public health agencies responsible for TB have specific expertise. However, as TB becomes less common, maintaining such expertise throughout the loosely coordinated TB-control system is challenging. As noted previously, medical errors associated with the detection of TB cases are common, and deficiencies exist in important public health responsibilities, such as contact investigations and outbreak response. Errors in the treatment and management of patients with TB continue to occur (41, 42). Innovative approaches to education of medical practitioners, new models for organizing TB services (2), and a clear understanding and acceptance of roles and responsibilities by an expanded group of participants in TB control will be needed to ensure that the clinical and public health expertise necessary to progress toward the elimination of TB are maintained.

Meeting the Challenges to TB Elimination
Further improvements in the control and prevention of TB in the United States will require a continued strong public health infrastructure and involvement of a range of health professionals outside the public health sector. The traditional model of TB control in the United States, in which planning and execution reside almost exclusively with the public health sector (17), is no longer the optimal approach during a sustained drive toward the elimination of TB. This statement emphasizes that success in controlling TB and progressing toward its elimination in the United States will depend on the integrated activities of professionals from different fields in the health sciences. This statement proposes specific measures to enhance TB control so as to meet the most important challenges; affirms the essential role of the public health sector in planning, coordinating, and evaluating the effort (43); proposes roles and responsibilities for the full range of participants; and introduces new approaches to the detection of TB cases, contact investigations, and targeted testing and treatment of persons with LTBI.

The plan to reduce the incidence of TB in the United States must be viewed in the larger context of the global effort to control TB. The global TB burden is substantial and increasing. In 2000, an estimated 8.3 million (7.9–9.2 million) new cases of TB occurred, and 1.84 million (1.59–2.22 million) persons died of TB; during 1997–2000, the worldwide TB case rate increased 1.8%/year (44). TB is increasing worldwide as a result of inadequate local resources and the global epidemic of HIV infection. In sub-Saharan Africa, the rate of TB cases is increasing 6.4%/year (44). ACET (1), IOM (2), and other public health authorities (45, 46) have acknowledged that TB will not be eliminated in the United States until the global epidemic is brought under control, and they have called for greater U.S. involvement in global control efforts. In response, CDC and ATS have become active participants in a multinational partnership (Stop TB Partnership) that was formed to guide the global efforts against TB. U.S. public and private entities also have provided assistance to countries with a high burden of TB and funding for research to develop new, improved tools for diagnosis, treatment, and prevention, including an effective vaccine.

Despite the global TB epidemic, substantial gains can be made toward elimination of TB in the United States by focusing on improvements in existing clinical and public health practices (47–49). However, the drive toward TB elimination in the United States will be resource-intensive (1, 12). Public health agencies that plan and coordinate TB-control efforts in states and communities need sufficient strength in terms of personnel, facilities, and training to discharge their responsibilities successfully, and the growing number of nonpublic health contributors to TB control, all pursuing diverse individual and institutional goals, should receive value for their contributions. Continued progress toward TB elimination in the United States will require strengthening the nation's public health infrastructure rather than reducing it (1, 50).

Basic Principles of TB Control in the United States
Four prioritized strategies exist to prevent and control TB in the United States (17), as follows:

• The first strategy is to promptly detect and report persons who have contracted TB. Because the majority of persons with TB receive a diagnosis when they seek medical care for symptoms caused by progression of the disease, health care providers, particularly those providing primary health care to populations at high risk, are key contributors to the detection of TB cases and to case reporting to the jurisdictional public health agency for surveillance purposes and for facilitating a treatment plan and case-management services.
  
• The second strategy is to protect close contacts of patients with contagious TB from contracting TB infection and disease. Contact evaluation not only identifies persons in the early stages of LTBI, when the risk for disease is greatest (30–32), but is also an important tool to detect further cases of TB disease.
  
• The third strategy is to take concerted action to prevent TB among the substantial population of U.S. residents with LTBI. This is accomplished by identifying those at highest risk for progression from latent infection to active TB through targeted testing and administration of a curative course of treatment (4). Two approaches exist for increasing targeted testing and treatment of LTBI. The first approach is to encourage clinic-based testing of persons who are under a clinician's care for a medical condition, such as HIV infection or diabetes mellitus, who are at risk for progressing from LTBI to active TB (4). The second approach is to establish specific programs to reach persons who have an increased prevalence of LTBI, an increased risk for developing active disease if LTBI is present, or both (51).
  
• The fourth strategy is to reduce the rising burden of TB from recent transmission of M. tuberculosis by identifying settings at high risk for transmission and applying effective infection-control measures to reduce the risk. This strategy was used during the 1985–1992 TB resurgence, when disease attributable to recent transmission was an important component of the increase in TB incidence (52–54). TB morbidity attributable to recent spread of M. tuberculosis continues to be a prominent part of the epidemiology of the disease in the United States. Data collected by CDC's National Tuberculosis Genotyping and Surveillance Network at seven sentinel surveillance sites indicate that 44% of M. tuberculosis isolates from persons with newly diagnosed cases of TB were clustered with at least one other intrasite isolate, often representing TB disease associated with recent spread of M. tuberculosis (55). TB outbreaks are also being reported with greater frequency in correctional facilities (37), homeless shelters (33), bars (27), and newly recognized social settings (e.g., among persons in an East Coast network of gay, transvestite, and transsexual HIV-infected men [34]; persons frequenting an abandoned junkyard building used for illicit drug use and prostitution [26]; and dancers in adult entertainment clubs and their contacts, including children [38]). Institutional infection-control measures developed in the 1990s in response to the 1985–1992 resurgence in transmission of M. tuberculosis in the United States (10) have been highly successful in health care facilities (56). However, newly recognized high-risk environments (26, 27, 33, 34, 37, 38) present challenges to the implementation of effective infection-control measures. Further attention is required to control the transmission of M. tuberculosis in these environments.
  

Structure of this Statement
This statement provides comprehensive guidelines for the full spectrum of activities involved in controlling and preventing TB in the United States. The remainder of this statement is structured in eight sections, as follows:

• Scientific Basis of TB Control. This section reviews the base of knowledge of how TB is transmitted and how the disease is distributed in the U.S. population, including new information based on genotyping studies. It provides basic background information as a review for current workers in the field and orients health care professionals who become new participants in TB-control efforts.
  
• Principles and Practice of TB Control. This section makes the transition from the scientific knowledge base to clinical and public health practice by discussing the goal of TB control in the United States, which is to reduce the morbidity and mortality caused by TB by preventing transmission of M. tuberculosis from persons with contagious forms of the disease to uninfected persons and preventing progression from LTBI to TB disease among persons who have contracted M. tuberculosis infection. This section also provides basic background information as a review for current workers in the field and serves as an orientation for health care professionals who become new participants in TB-control efforts.
  
• Recommended Roles and Responsibilities for TB Control. This section outlines roles and responsibilities for the spectrum of participants in the diverse clinical and public health activities that lead to the control and prevention of TB. The paramount role of the public health sector is reviewed, followed by proposed responsibilities for nine prominent nonpublic health partners in TB control: medical practitioners, civil surgeons, community health centers, hospitals, academic institutions, medical professional organizations, community-based organizations, correctional facilities, and the pharmaceutical and biotechnology industries. Because responsibilities for the nonpublic health sector have not been specified previously, this information also should be useful to policy makers and advocates for strengthened TB control.
  
• Essential Components of TB Control in the United States. This section gives detailed recommendations for enhancing the core elements of TB control: case detection and management, contact investigations, and targeted testing and treatment of LTBI. Recommendations are provided for targeted public education to neutralize the stigma of TB and facilitate earlier care-seeking behavior among patients and for education of health care professionals from whom patients with TB seek care. A set of five clinical scenarios is presented in which a diagnosis of TB should be undertaken in primary medical practice, and guidelines are presented for activities among certain populations to detect TB among persons who have not sought medical care. Guidelines are provided for a conducting a systematic, step-by-step contact investigation. All jurisdictional TB-control programs are urged to develop written policies and procedures on the basis of these guidelines. Recommended procedures are also outlined for conducting surveillance for TB outbreaks and for developing an outbreak response plan. In addition, a framework is presented for identifying and prioritizing subpopulations and settings within a community that are at high risk for TB and that should receive targeted testing and treatment for LTBI. Priorities for high-risk populations should be established on the basis of the expected impact and efficacy of the intervention. Persons who are readily accessible and have preexisting access to health care services (e.g., prisoners, patients receiving ongoing clinic-based care for HIV infection, and immigrants and refugees with abnormalities on preimmigration chest radiographs) should receive the highest priority. An approach is also presented to reach members of new immigrant and refugee communities, who often exist on the margin of U.S. society.
  
• Control of TB among Populations at High Risk. On the basis of the epidemiology of TB in the United States, this section provides specific recommendations for controlling and preventing TB among five populations: (1) children, (2) foreign-born persons, (3) HIV-infected persons, (4) homeless persons, and (5) detainees and prisoners in correctional facilities. Each population is readily identifiable and has been demonstrated to be at risk for TB exposure or progression from exposure to disease, or both. Surveillance and surveys from throughout the United States indicate that certain epidemiologic patterns of TB are consistently observed among these populations, suggesting that the recommended control measures are generalizable.
  
• Control of TB in Health Care Facilities and Other High-Risk Environments. This section recommends infection-control measures to prevent the transmission of M. tuberculosis in high-risk settings. The approach to control of TB that was developed for health care facilities continues to be the most successful model and is discussed in detail. The recommendations in this section have been updated with respect to the assessment of institutional risk for TB. Three levels of risk (low, medium, and potential ongoing transmission) are outlined on the basis of community and institutional experience with TB. An associated recommendation is that the frequency of testing of employees for LTBI should be based on the institution's risk category. Recommendations also are provided for control of transmission of M. tuberculosis in correctional facilities, homeless shelters, and other newly identified high-risk environments.
  
• Research Needs to Enhance TB Control. This section defines gaps in knowledge and deficiencies in technology that limit current efforts to control and prevent TB. Additional research is needed in these areas to produce the evidence base and the tools for optimal diagnosis, treatment, and prevention of TB. This section should be useful to persons who formulate U.S. public health policy and research priorities and members of academic professions interested in contributing to enhanced TB control, both in the United States and throughout the world.
  
• Graded Recommendations for Control and Prevention of TB. This section groups detailed graded recommendations for each area discussed in this report.
  

	SCIENTIFIC BASIS OF TB CONTROL

TOP CONTENTS SUMMARY INTRODUCTION SCIENTIFIC BASIS OF TB... PRINCIPLES AND PRACTICE OF... RECOMMENDED ROLES AND... ESSENTIAL COMPONENTS OF TB... CONTROL OF TB AMONG... CONTROL OF TB IN... RESEARCH NEEDS TO ENHANCE... GRADED RECOMMENDATIONS FOR THE... REFERENCES

 
Transmission of TB
M. tuberculosis is nearly always transmitted through an airborne route, with the infecting organisms being carried in droplets of secretions (droplet nuclei) that are expelled into the surrounding air when a person with pulmonary TB coughs, talks, sings, or sneezes. Person-to-person transmission of M. tuberculosis is determined by certain characteristics of the source-case and of the person exposed to the source-person and by the environment in which the exposure takes place (Box 2). The virulence of the infecting strain of M. tuberculosis might also be a determining factor for transmission.

BOX 2. FACTORS DETERMINING TRANSMISSION OF M. TUBERCULOSIS Characteristics of the source-case Concentration of organisms in sputum Presence of cavitary disease on chest radiograph Frequency and strength of cough Characteristics of the exposed person Previous M. tuberculosis infection Innate resistance to M. tuberculosis infection Genetic susceptibility to M. tuberculosis infection or disease or both Characteristics of the exposure Frequency and duration of exposure Dilution effect (i.e., the volume of air containing infectious droplet nuclei) Ventilation (i.e., the turnover of air in a space) Exposure to ultraviolet light, including sunlight Virulence of the infecting strain of M. tuberculosis

 

Characteristics of the Source-Case.
By the time persons with pulmonary TB come to medical attention, 30 to 40% of persons identified as their close personal contacts have evidence of LTBI (30). The highest rate of infection among contacts follows intense exposure to patients whose sputum smears are positive for acid-fast bacilli (AFB; Figure 2) (31, 57–59). Because patients with cavitary pulmonary TB are more likely than those without pulmonary cavities to be sputum AFB smear–positive (60), patients with cavitary pulmonary disease have greater potential to transmit TB. Such persons also have a greater frequency of cough, so the triad of cavitary pulmonary disease, sputum AFB smear positivity, and frequency of cough are likely related causal factors for infectivity. AFB smear–negative patients with TB also transmit TB, but with lower potential than smear-positive patients. Patients with sputum AFB smear–negative pulmonary TB account for approximately 17% of TB transmission (61).

View larger version (9K): [in this window] [in a new window]   Figure 2. Percentage of persons infected with Mycobacterium tuberculosis, by bacteriologic status of and proximity to the source case—British Columbia and Saskatchewan, 1966–1971. Source: Reference 57.

The classic means of protecting persons exposed to infectious diseases is vaccination. Because of its proven efficacy in protecting infants and young children from meningeal and miliary TB (66), vaccination against TB with Mycobacterium bovis bacillus Calmette-Guérin (BCG) is used worldwide (although not in the U.S.). This protective effect against the disseminated forms of TB in infants and children is likely based on the ability of BCG to prevent progression of the primary infection when administered at that stage of life (67). Epidemiologic evidence suggests that BCG immunization does not protect against the development of infection with M. tuberculosis on exposure (68) and use of BCG has not had an impact on the global epidemiology of tuberculosis. One recent retrospective study found that BCG protective efficacy can persist for 50 to 60 years, indicating that a single dose might have a long duration of effect (69). A meta-analysis indicated that, overall, BCG reduced the risk for TB 50% (66); however, another meta-analysis that examined protection over time demonstrated a decrease in efficacy of 5 to 14% in seven randomized controlled trials and an increase of 18% in three others (70). An effective vaccine against M. tuberculosis is needed for global TB control to be achieved.

Because only 30 to 40% of persons with close exposure to a patient with pulmonary TB become infected (30, 31), innate immunity might protect certain persons from infection (71). The innate mechanisms that protect against the development of infection are largely uncharacterized (71). Although immunocompromised persons (e.g., those with HIV infection) are at increased risk for progression to TB disease after infection with M. tuberculosis, no definitive evidence exists that immunocompromised persons, including those with HIV infection, have increased susceptibility to infection on exposure.

Observational studies suggest that population-based variability in susceptibility to TB might be related to the length of time a population has lived in the presence of M. tuberculosis and has thus developed resistance to infection through natural selection (72–74). However, the genetic basis for susceptibility or resistance to TB is not well understood (72, 75).

Characteristics of the Exposure.
Studies that have stratified contacts of persons with pulmonary TB according to time spent with the infected person indicate that the risk for becoming infected with M. tuberculosis is in part determined by the frequency and duration of exposure (60). In a given environment shared by a patient with pulmonary TB and a contact, the risk for transmitting the infection varies with the density of infectious droplet nuclei in the air and how long the air is inhaled. Indoors, tubercle bacilli are expelled into a finite volume of air, and, unless effective ventilation exists, droplet nuclei containing M. tuberculosis might remain suspended in ambient air (76). Exposures in confined air systems with little or no ventilation pose a major risk for transmission of TB; this has been demonstrated in homes, ships, trains, office buildings, and health care institutions (77–80). When contact occurs outdoors, TB bacilli expelled from the respiratory tract of an infectious person are rapidly dispersed and are quickly rendered nonviable by sunlight (77). The risk for transmission during such encounters is very limited.

Considerable attention has been given to transmission of M. tuberculosis during air travel. Investigations have demonstrated that the risk for transmission from an infectious person to others on an airplane is greater on long flights (> 8 hours) and that the risk for contracting M. tuberculosis infection is highest for passengers and flight crew members sitting or working near an infectious person (81, 82). However, the overall public health importance of such events is negligible (77, 81).

Virulence of the Infecting Strain of _{M. TUBERCULOSIS.}
Although much is known about factors that contribute to the risk for transmission of M. tuberculosis from person to person, the role of the organism itself is only beginning to be understood (83). Genetic variability is believed to affect the capability of M. tuberculosis strains to be transmitted or to cause disease once transmitted, or both. The M. tuberculosis W-strain family, a member of the globally spread Beijing family (84), is a group of clonally related multidrug-resistant organisms of M. tuberculosis that caused nosocomial outbreaks involving HIV-infected persons in New York City during 1991–1994 (85, 86). W-family organisms, which have also been associated with TB outbreaks worldwide, are believed to have evolved from a single strain of M. tuberculosis that developed resistance-conferring mutations in multiple genes. The growth of W-family organisms in human macrophages is four- to eightfold higher than that of strains that cause few or no secondary cases of TB; this enhanced ability to replicate in human macrophages might contribute to the organism's potential for enhanced transmission (87).

Whether M. tuberculosis loses pathogenicity as it acquires resistance to drugs is not known. Isoniazid-resistant M. tuberculosis strains are less virulent than drug-susceptible isolates in guinea pigs (88), and genotyping studies from San Francisco, California, and from the Netherlands indicated that isoniazid-resistant strains are much less likely to be associated with clusters of TB cases than drug-susceptible strains (89, 90). Nevertheless, because person-to-person spread has been demonstrated repeatedly, persons with TB with drug-resistant isolates should receive the same public health attention at the programmatic level as those with drug-susceptible isolates (91, 92).

Effect of Chemotherapy on Infectiousness.
Patients with drug-susceptible pulmonary and other forms of infectious TB rapidly become noninfectious after institution of effective multiple-drug chemotherapy. This principle has been established by studies demonstrating that household contacts of persons with infectious pulmonary TB who were treated at home after a brief period of hospitalization for institution of therapy developed LTBI at a frequency no greater than that of persons with pulmonary TB who were hospitalized for 1 year (93) or until sputum cultures became negative (94). This potent effect of chemotherapy on infectiousness is likely attributable, at least in part, to the rapid elimination of viable M. tuberculosis from sputum (95) and to reduction in cough frequency (96). The ability of chemotherapy to eliminate infectivity is one reason why detecting infectious cases and promptly instituting multiple-drug therapy is the primary means of interrupting the spread of TB in the United States.

The effect of chemotherapy to eliminate infectiousness was once believed to occur rapidly, and patients on chemotherapy were believed not to be infectious (97, 98). However, no ideal test exists to assess the infective potential of a patient with TB on treatment, and infectivity is unlikely to disappear immediately after multidrug therapy is started. Quantitative bacteriologic studies indicate that the concentration of viable M. tuberculosis in sputum of persons with cavitary sputum AFB smear–positive pulmonary TB at the time of diagnosis, which averaged 10⁶–10⁷ organisms/ml, decreased by more than 90% (10-fold) during the first 2 days of treatment, an effect attributable primarily to administration of isoniazid (99), and by more than 99% (100-fold) by Days 14–21, an effect attributable primarily to administration of rifampin and pyrazinamide (100). Thus, if no factor other than the elimination of viable M. tuberculosis from sputum were to account for the loss of infectivity during treatment, the majority of patients (at least those with infection attributable to isolates susceptible to isoniazid) who have received treatment for as few as 2 days with the standard regimen (i.e., isoniazid, rifampin, ethambutol, and pyrazinamide) could be assumed to have an infective potential that averages 10% of that at the time of diagnosis. After 14 to 21 days of treatment, infectiousness averages less than 1% of the pretreatment level.

This statement presents general guidelines on elimination of infectivity with treatment (Box 3). However, decisions about infectiousness of a person on treatment for TB should always be individualized on the basis of the following: (1) the extent of illness, (2) the presence of cavitary pulmonary disease, (3) the degree of positivity of sputum AFB smear results, (4) the frequency and strength of cough, (5) the likelihood of infection with multidrug-resistant organisms, and (6) the nature and circumstances of the contact between the infected person and exposed contacts (101). Patients who remain in hospitals or reside either temporarily or permanently in congregate settings (e.g., shelters and correctional facilities) are subject to different criteria for infectiousness. In such congregate settings, identification and protection of close contacts are not possible during the early phase of treatment, and more stringent criteria for determining absence of infectivity (i.e., three consecutive AFB-negative sputum smears) should be followed (10). All patients with suspected or proven multidrug-resistant TB should be subjected to these more stringent criteria for absence of infectivity (10).

BOX 3. CRITERIA FOR DETERMINING WHEN DURING THERAPY A PATIENT WITH PULMONARY TB HAS BECOME NONINFECTIOUS* Patient has negligible likelihood of multidrug-resistant TB (no known exposure to multidrug-resistant TB and no history of prior episodes of TB with poor compliance during treatment). Patient has received standard multidrug anti-TB therapy for 2–3 weeks. (For patients with sputum AFB smear results that are negative or rarely positive, threshold for treatment is 5–7 days.) Patient has demonstrated complete adherence to treatment (e.g., is receiving directly observed therapy). Patient has demonstrated evidence of clinical improvement (e.g., reduction in the frequency of cough or reduction of the grade of the sputum AFB smear result). All close contacts of patient have been identified, evaluated, advised, and, if indicated, started on treatment for latent TB infection. This criterion is critical, especially for close contacts who are children younger than 4 years and those of any age with immunocompromising health conditions (e.g., HIV infection). While in hospital for any reason, patients with pulmonary TB should remain in airborne-infection isolation until they (1) are receiving standard multidrug anti-TB therapy; (2) have demonstrated clinical improvement; and (3) have had three consecutive AFB-negative smear results of sputum specimens collected 8–24 hours apart, with at least one being an early-morning specimen. Hospitalized patients returning to a congregate setting (e.g., a homeless shelter or detention facility) should have three consecutive AFB-negative smear results of sputum specimens collected more than 8 hours apart before being considered noninfectious. *These six criteria for absence of infectivity with treatment should be considered general guidelines. Decisions about infectivity of a person on treatment for TB should depend on the extent of illness and the specific nature and circumstances of the contact between the patient and exposed persons.

 

Progression from LTBI to TB Disease.
Although the human immune response is highly effective in controlling primary infection resulting from exposure to M. tuberculosis among the majority of immunocompetent persons, all viable organisms might not be eliminated. M. tuberculosis is thus able to establish latency, a period during which the infected person is asymptomatic but harbors M. tuberculosis organisms that might cause disease later (4, 71). The mechanisms involved in latency and persistence are not completely understood (71, 72).

For the majority of persons, the only evidence of LTBI is an immune response against mycobacterial antigens, which is demonstrated by a positive test result: either a tuberculin skin test (3) or, in certain circumstances, a whole blood antigen–stimulated IFN- release assay result (e.g., QuantiFERON-TB Gold test [QFT-G]; Cellestis Limited, Carnegie, Victoria, Australia). The tuberculin skin test measures delayed-type hypersensitivity; QFT-G, an ex vivo test for detecting latent M. tuberculosis infection, measures a component of cell-mediated immune response (102). QFT-G is approved by the U.S. Food and Drug Administration, and CDC will publish guidelines on its use. CDC had previously published guidelines for use of QuantiFERON-TB, an earlier version of the test that is no longer available (103). T SPOT-TB, an enzyme-linked immunospot assay for IFN-, is marketed in Europe along with QFT-G but is not FDA-approved for use in the U.S. Although approved by the Food and Drug Administration, the Tine test is not recommended for the diagnosis of M. tuberculosis infection. Tests available in other countries to diagnose M. tuberculosis infection (e.g., T SPOT-TB and Heaf test) are not recommended for clinical use in the United States.

Once a person has contracted LTBI, the risk for progression to TB disease varies. The greatest risk for progression to disease occurs within the first 2 years after infection, when approximately half of the 5 to 10% lifetime risk occurs (4, 104). Multiple clinical conditions also are associated with increased risk for progression from LTBI to TB disease. HIV infection is the strongest known risk factor (4). Other key risk factors because of their prevalence in the U.S. population are diabetes mellitus (105), acquisition of LTBI in infancy or early childhood, and apical fibronodular changes on chest radiograph (106).

A recent addition to the known risk factors for progression from LTBI to TB disease is the use of therapeutic agents that antagonize the effect of cytokine tumor necrosis factor (TNF-) and have been proven to be highly effective treating autoimmune-related conditions (e.g., Crohn's disease and rheumatoid arthritis) (107). Cases of TB have been reported among patients receiving all three licensed TNF- antagonists (i.e., infliximab, etanercept, and adalimimab) (108). CDC has published interim guidelines for preventing TB when these agents are used (109).

Epidemiology of TB in the United States
Surveillance (i.e., the systematic collection, analysis, and dissemination of data) is a critical component of successful TB control, providing essential information needed to (1) determine patterns and trends of the disease, (2) identify populations and settings at high risk, and (3) establish priorities for control and prevention activities. Surveillance is also essential for quality-assurance purposes, program evaluation, and measurement of progress toward TB elimination. In addition to providing the epidemiologic profile of TB in a given jurisdiction, state and local surveillance are essential to national TB surveillance.

CDC's national TB surveillance system publishes epidemiologic analyses of reported TB cases in the United States (110). Data for the national TB surveillance system are reported by state health departments in accordance with standard TB case-definition and case-report formats (110, 111). The system tracked the reversal of the declining trend in TB incidence in the United States in the mid-1980s, the peak of the resurgence in 1992 (with a 20% increase in cases reported during 1985–1992), and the subsequent 44% decline to an all-time low number (14,871) and rate (5.1 cases/100,000 population) of TB cases in 2003 (Figure 1) (14, 15).

Geographic Distribution of TB.
Wide disparities exist in the geographic distribution of TB cases in the United States. In 2003, six states (California, Florida, Georgia, Illinois, New York, and Texas) each reported 500 or more cases and accounted for 57% of the national total (14). These states along with New Jersey accounted for approximately 75% of the overall decrease in cases since 1992. The highest rates and numbers of TB cases are reported from urban areas: more than 75% of cases reported in 2003 were from areas with a population of 500,000 or greater (14). In 2003, 24 states (48%) had an incidence of 3.5 or fewer cases of TB/100,000 population, the rate established as the Year 2000 interim target for the United States in the 1989 strategic plan for eliminating TB (11).

Demographic Distribution of TB.
In 2003, adults aged 15 to 64 years accounted for 73.6% of reported TB cases. Incidence of TB was highest (8.4 cases/100,000 population) among adults older than 65 years, who accounted for 20.2% of cases. Children younger than 14 years accounted for 6.2% of reported cases and had the lowest incidence of TB; 61.3% of reported cases occurred among men, and case rates among men were at least double those of women in mid- and older-adult age groups. In 2003, the white, non-Hispanic population accounted for only 19% of reported cases of TB, and TB incidence among the four other racial/ethnic populations for which data were available was 5.7 to 21.0 times that of non-Hispanic whites (Table 2). Foreign-born persons accounted for 94% of TB cases among Asians and 74% of cases among Hispanics, whereas 74% of cases among non-Hispanic blacks occurred among persons born in the United States (15).

OCCUPATION.
Increased incidence of TB among persons with certain occupations is attributable to exposure in the work environment and to an increased likelihood that workers will have other risk factors unrelated to occupation, such as foreign birth. A 29-state study of patients with clinically active TB reported during 1984–1985 indicated that increased incidence was independent of occupation. An association between general SES groupings of occupations and risk for TB also was demonstrated in that study (113). Chronically unemployed persons had high incidence of TB; this finding is consistent with surveillance data indicating that more than 50% of patients with TB were unemployed during the 2 years before diagnosis (14).

TB AMONG HEALTH CARE WORKERS.
Because transmission of M. tuberculosis in health care institutions was a contributing factor to the resurgence of TB during 1985–1992, recommendations were developed to prevent transmission in these settings (10). In 2003, persons reported to have been health care workers (HCWs) in the 2 years before receiving their diagnoses accounted for 3.1% of reported TB cases nationwide (14). However, the elevated risk among HCWs might be attributable to other factors (e.g., birth in a country with a high incidence of TB) (114). A multistate occupational survey indicated that the majority of HCWs did not have a higher risk for TB than the general population; respiratory therapists, however, did appear to be at greater risk (113).

Identification of Populations at High Risk for TB.
CONTACTS OF INFECTIOUS PERSONS.
A high prevalence of TB disease and LTBI has been documented among close contacts of persons with infectious pulmonary TB (31). A study of approximately 1,000 persons from urban sites with pulmonary AFB sputum smear–positive TB indicated that more than one-third of their contacts had positive tuberculin skin tests and that 2% of all close contacts had active TB. Contacts identified with TB disease were more likely to be household members or children younger than 6 years (31).

FOREIGN-BORN PERSONS.
The proportion of TB cases in the United States occurring among foreign-born persons increased progressively during the 1990s; in 2003, persons born outside the United States accounted for 53% of reported cases (Figure 3) (14). Although foreign-born persons who received a diagnosis of TB in 2002 were born in more than 150 countries worldwide, as in each of the previous 6 years, five countries of origin accounted for the greatest number of foreign-born persons with TB: China (5%), India (8%), Mexico (26%), the Philippines (12%), and Vietnam (8%). During 1992–2003, the number of states in which 50% or more of the total reported cases occurred among foreign-born persons increased from four (8%) in 1992 to 24 (48%) in 2003 (15). Among states and cities, however, this profile can change rapidly, reflecting changes in patterns of immigration and refugee settlement (21).

View larger version (19K): [in this window] [in a new window]   Figure 3. Number and percentage of cases of tuberculosis among foreign-born persons, by year of diagnosis—United States, 1986–2003.

HIV-INFECTED PERSONS.
Because reporting of HIV infection among persons with TB is not complete, the exact prevalence of HIV infection among such persons is unknown. During 1993–2001, the prevalence of reported HIV infection occurring among persons also reported with TB decreased from 15 to 8% (14); this decrease has been attributed, in part, to reduced transmission of TB among HIV-infected persons (16). According to a recent worldwide epidemiologic assessment, however, 26% of adult TB cases in the United States are attributable to HIV infection (44).

HOMELESS PERSONS.
In 2003, persons known to have been homeless in the year before receiving a diagnosis accounted for 6.3% of cases of TB nationwide. On the basis of available population estimates (117), incidence of TB among homeless persons is approximately 30–40/100,000 population, more than five times the national case rate. However, a prospective study of a cohort of approximately 3,000 homeless persons in San Francisco documented an annual incidence of more than 250 cases/100,000 population (118). In addition, outbreaks of TB linked to overnight shelters continue to occur among homeless persons and likely contribute to the increased incidence of TB among that population (119, 120).

OTHER POPULATIONS AT HIGH RISK.
In 2003, persons known to have injected drugs in the year before receiving a diagnosis accounted for 2.2% of reported cases of TB, and noninjection drug use was reported by 7.3% of persons with TB. In certain U.S. communities, injection drug use is sufficiently prevalent so as to constitute a high risk for epidemiologic importance rather than simply an individual risk factor, especially when overlap exists between injection drug use and HIV infection (121, 122).

TB among Detainees and Prisoners in Correctional Facilities.
The proportion of cases of TB occurring among inmates of prisons and jails has remained stable at approximately 3 to 4% since data began to be collected in 1993; it was 3.2% in 2003 (14). Inmates also have high incidence of TB, with rates often more than 200/100,000 population (123), and they have a disproportionately greater number of risk factors for TB (e.g., low SES, HIV infection, and substance abuse) compared with the general population (124, 125). TB transmission in correctional facilities contributes to the greater risk among those populations, presumably because of the difficulties in detecting cases of infectious TB and in identifying, evaluating, and treating contacts in these settings (37, 126).

TB outbreaks occur in both prison and jail settings. Dedicated housing units for prison inmates with HIV infection were sites of transmission in California in 1995 (126) and in South Carolina in 1999 (37). In the South Carolina outbreak, delayed diagnosis and isolation of an inmate who apparently had active TB after entering the facility led to more than 15 outbreak cases. Transmission leading to TB infection in the community also was documented in an outbreak that occurred in a jail in Tennessee during 1995–1997 (127, 128) that involved approximately 40 inmates; contact investigations were incomplete because of brief jail terms and frequent movement of inmates. During the same period, 43% of patients with TB in the surrounding community had previously been incarcerated in that jail (127), and, after 2 years, the jail outbreak strain was more prevalent in the community than it was during the jail outbreak. Genotyping studies indicated that the outbreak strain accounted for approximately 25% of TB cases in the community, including those among patients with no history of incarceration (128).

Contributions of Genotyping of M. tuberculosis
M. tuberculosis genotyping refers to procedures developed to identify M. tuberculosis isolates that are identical in specific parts of the genome (83). To date, M. tuberculosis genotyping has been based on polymorphisms in the number and genomic location of mycobacterial repetitive elements. The most widely used genotyping test for M. tuberculosis is restriction fragment length polymorphism (RFLP) analysis of the distribution of the insertion sequence IS6110 (129). However, genotyping tests based on polymorphisms in three additional mycobacterial repetitive elements (i.e., polymorphic guanine cytosine–rich repetitive sequences, direct repeats [spoligotyping], and mycobacterial interspersed repetitive units [MIRU]) have also been developed (83). M. tuberculosis isolates with identical DNA patterns in an established genotyping test often have been linked through recent transmission among the persons from whom they were isolated.

When coupled with traditional epidemiologic investigations, analyses of the genotype of M. tuberculosis strains have confirmed suspected transmission and identified unsuspected transmission of M. tuberculosis. These analyses have also identified risk factors for recent infection with rapid progression to disease, demonstrated exogenous reinfection with different strains, identified weaknesses in conventional contact investigations, and documented the existence of laboratory cross-contamination. Genotyping has become an increasingly useful tool for studying the pathogenesis, epidemiology, and transmission of TB.

Epidemiology of TB among Contacts in Outbreak Settings.
Conventional contact investigations have used the concentric circles approach to collect information and screen household contacts, coworkers, and increasingly distant contacts for TB infection and disease (17). The concentric circles model has been described previously (130). However, this method might not always be adequate in out-of-household settings. In community-based studies from San Francisco (131), Zurich (132), and Amsterdam (133), only 5 to 10% of persons with clustered IS6110-based genotyping patterns were identified as contacts by the source-person in the cluster. This finding indicates that either (1) transmission of M. tuberculosis might occur more commonly than suspected and is not easily detected by conventional contact tracing investigations or (2) genotype clustering does not necessarily represent recent transmission (55). Because genotyping studies discover only missed or mismanaged contacts (i.e., those that subsequently receive a diagnosis of TB), such studies cannot explain the successes of the process or the number of cases that were prevented.

Certain populations (e.g., the urban homeless) present specific challenges to conducting conventional contact investigations. Genotyping studies have provided information about chains of transmission in these populations (118, 119). In a prospective study of TB transmission in Los Angeles, the degree of homelessness and use of daytime services at three shelters were factors that were independently associated with genotype clustering (119). Additional studies support the idea that specific locations can be associated with recent or ongoing transmission of M. tuberculosis among homeless persons. Two studies among predominantly HIV-infected men have demonstrated evidence of transmission at specific bars in the community (134, 135).

Genotyping techniques have confirmed TB transmission in HIV residential facilities (136), crack houses (i.e., settings in which crack cocaine is sold or used) (137), hospitals and clinics (54), and prisons (138, 139). TB transmission also has been demonstrated among church choirs (140) and renal transplant patients (141) and in association with processing of contaminated medical waste (142) and with bronchoscopy (143, 144).

Communitywide Epidemiology of TB.
TB might arise because of rapid progression from a recently acquired M. tuberculosis infection, from progression of LTBI to TB disease, or occasionally from exogenous reinfection (145). The majority of genotyping studies have assumed that clustered isolates in a population-based survey reflect recent transmission of M. tuberculosis. Certain studies have identified epidemiologic links between clustered TB cases, inferring that the clustered cases are part of a chain of transmission from a single common source or from multiple common sources (131, 146).

The number and proportion of population-based cases of TB that occur in clusters representing recent or ongoing transmission of M. tuberculosis have varied from study to study; frequency of clustering has varied from 17 to 18% (in Vancouver, Canada) to 30 to 40% (in U.S. urban areas) (131, 147, 148). Youth, being a member of a racial or ethnic minority population, homelessness, substance abuse, and HIV infection have been associated with clustering (131, 133, 148, 149).

The increasing incidence of TB among foreign-born persons underscores the need to understand transmission dynamics among this population. In San Francisco, two parallel TB epidemics have been described (150, 151): one among foreign-born persons, which was characterized by a low rate of genotype clustering, and the other among U.S.-born persons, which was characterized by a high rate of genotype clustering. In a recent study from New York City, being born outside the United States, being aged 60 years or older, and receiving a diagnosis after 1993 were factors independently associated with being infected with a strain not matched with any other, whereas homelessness was associated with genotype clustering and recent transmission (152). Among foreign-born persons, clustered strains were more likely to be found among patients with HIV infection (152).

Other Contributions of Genotyping.
Genotyping can determine whether a patient with a recurrent episode of TB has relapsed with the original strain of M. tuberculosis or has developed exogenous reinfection with a new strain (64, 153). In Cape Town, South Africa, where incidence of TB is high and considerable ongoing transmission exists, 16 (2.3%) of 698 patients had more than one episode of TB disease. In 12 (75%) of the 16 recurrent cases, the pairs of M. tuberculosis isolates had different IS6110-based genotyping patterns, indicating exogenous reinfection (154). However, in areas with a low incidence of TB, episodes of exogenous reinfection are uncommon (153). Because TB incidence in the majority of areas of the United States is low and decreasing, reinfection is unlikely to be a major cause of TB recurrence.

Genotyping has greatly facilitated the identification of false-positive cultures for M. tuberculosis resulting from laboratory cross-contamination of specimens. Previously, false-positive cultures (which might lead to unnecessary treatment for patients, unnecessary work for public health programs in investigating cases and pseudo-outbreaks, and unnecessary costs to the health care system) were difficult to substantiate (155). Because of its capability to determine clonality among M. tuberculosis strains, genotyping has been applied extensively to verify suspected false-positive cultures (156–158) and to study the causes and prevalence of laboratory cross-contamination (159, 160).

The Role of Genotyping of _{M. TUBERCULOSIS IN TB-CONTROL PROGRAMS.}
In 2004, CDC established the Tuberculosis Genotyping Program to enable rapid genotyping of isolates from every patient in the United States with culture-positive TB (161). State TB programs may submit one M. tuberculosis isolate from each culture-positive case within their jurisdictions to a contracted genotyping laboratory. A detailed manual describing this program, including information on how to interpret genotyping test results and how to integrate genotyping into TB-control activities, has been published (162).

Genotyping information is essential to optimal TB control in two settings. First, genotyping is integral to the detection and control of TB outbreaks, including ruling a suspected outbreak in or out and pinpointing involved cases and the site or sites of transmission (54, 136–144). Second, genotyping is essential to detect errors in handling and processing of M. tuberculosis isolates (including laboratory cross-contamination) that lead to reports of false-positive cultures for M. tuberculosis (156, 158–160, 163).

More extensive use of M. tuberculosis genotyping for TB control depends on the availability of sufficient program resources to compare results with information from traditional epidemiologic investigative techniques. Time-framed genotyping surveys and good fieldwork can unravel uncertainties in the epidemiology of TB in problematic populations at high risk (150–152, 164). Genotyping surveys and epidemiologic investigations also can be used as a program monitoring tool to determine the adequacy of contact investigations (29, 119, 132–134, 164–166) and evaluate the success of control measures designed to interrupt transmission of M. tuberculosis among certain populations or settings (167).

Programs that use genotyping for surveillance of all of the jurisdiction's M. tuberculosis isolates should work closely on an ongoing basis with the genotyping laboratory and commit sufficient resources to compare genotyping results with those of traditional epidemiologic investigations. Information from both sources is needed for optimum interpretation of the complex epidemiologic patterns of TB in the United States (84, 168).

	PRINCIPLES AND PRACTICE OF TB CONTROL

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Basic Principles of TB Control
The goal of TB control in the United States is to reduce morbidity and mortality caused by TB by (1) preventing transmission of M. tuberculosis from persons with contagious forms of the disease to uninfected persons and (2) preventing progression from LTBI to TB disease among persons who have contracted M. tuberculosis infection. Four fundamental strategies are used to achieve this goal (Box 4) (17, 169), as follows:

• Early and accurate detection, diagnosis, and reporting of TB cases leading to initiation and completion of treatment. Detecting and reporting suspected cases of TB is the key step in stopping transmission of M. tuberculosis because it leads to prompt initiation of effective multiple-drug treatment, which rapidly reduces infectiousness (see Box 3). Completion of a full course of standard therapy is essential to prevent treatment failure, relapse, and the acquisition of drug resistance (5). TB is commonly diagnosed when a person seeks medical attention for symptoms caused by the disease or a concomitant medical condition. Thus, health care providers, particularly those providing primary health care to populations at high risk, are key contributors to TB case detection. A suspected or confirmed case of TB should be reported immediately to the jurisdictional public health agency. Reporting of new cases is essential to initiate public health responses, including institution of a treatment plan, case-management services, and evaluation of contacts, and for surveillance purposes. This statement contains detailed recommendations for improving detection of TB cases. Treatment of TB is the subject of another statement in this series from ATS, CDC, and IDSA (5).
  
• Identification of contacts of patients with infectious TB and treatment of those at risk with an effective drug regimen. The evaluation of contacts of cases of infectious TB is one of the most productive methods of identifying adults and children with LTBI at high risk for progression to TB disease and persons in the early stages of TB disease (30, 31). Contact investigations therefore serve as an important means of detecting TB cases and at the same time identify persons in the early stage of LTBI, when the risk for progression to TB disease is high and the benefit of treatment is greatest (4).
  
• Identification of other persons with LTBI at risk for progression to TB disease and treatment of those persons with an effective drug regimen. Targeted testing is intended to identify persons other than TB contacts who have an increased risk for acquiring TB and to offer such persons diagnostic testing for M. tuberculosis infection and treatment, if indicated, to prevent subsequent progression to TB disease (4). This approach is critical to the eventual elimination of TB in the United States, because it is the only means of preventing TB in the substantial pool of persons with LTBI at high risk for progression to TB disease. Targeted testing and treatment of LTBI is also a primary means of controlling TB among foreign-born persons at high risk residing in the United States because genotyping surveys have consistently demonstrated that the majority of TB cases in that population are attributable to progression from LTBI (150–152). Targeted testing and treatment of LTBI is best accomplished through cost-effec