Mycobacterium Tuberculosis
William R. Jarvis
Tuberculosis (TB) is a major global health problem. Worldwide, an estimated 8 million new cases occur each year and 2 million deaths are attributed to this disease annually (1). TB case rates in the United States have been decreasing since the most recent peak in cases in 1992, but an increasing number of TB outbreaks in institutional settings, including hospitals, have been noted. Of greatest concern are outbreaks due to microorganisms resistant to multiple anti-TB drugs (2).
THE ETIOLOGIC AGENT
Tuberculosis is caused by bacteria of the Mycobacterium tuberculosis complex, which includes M. tuberculosis, M. bovis, M. bovis [bacille Calmette Guérin (BCG)], M. africanum, and M. microti. M. tuberculosis is by far the most frequent and most important pathogen in this complex. It grows slowly and usually is identified by its rough, nonpigmented, corded colonies on oleic acid albumin agar; a positive niacin test; generally weak catalase activity, which is lost completely by heating to 68°C; and a positive nitrate reduction test. M. bovis is indistinguishable from M. tuberculosis except by culture followed by in vitro tests, restriction fragment length polymorphism (RFLP), or phage typing (3,4).
MODE OF TRANSMISSION
M. tuberculosis is carried in airborne droplet nuclei, which are produced when persons with pulmonary or laryngeal TB cough, sneeze, speak, or sing. The nuclei also can be produced by irrigation or manipulation of tuberculous lesions (e.g., wounds) or processing of tissue or secretions in the hospital or laboratory. Droplet nuclei are so small (1-5 µm) and light that ambient air currents can keep them airborne for long periods of time and carry them substantial distances. Persons who breathe air contaminated with infectious M. tuberculosis droplet nuclei may inhale microorganisms into the alveoli of the lungs and become infected. The risk of infection is correlated with the concentration of infectious droplet nuclei in the air and the duration of exposure to the contaminated air. Airborne transmission of M. bovis also can occur.
PATHOGENESIS OF TUBERCULOSIS
Once tubercle bacilli become implanted in a respiratory bronchiole or alveolus, they are engulfed by macrophages, but they can remain viable and even multiply within the cells. Then, tubercle bacilli are spread via the lymphatic channels to regional lymph nodes and via the bloodstream to more distant sites. A specific cell-mediated immune response, which usually develops several weeks after infection, may limit further multiplication of the bacilli; the lesions heal, although the tubercle bacilli may remain viable. This results in a condition known as latent M. tuberculosis infection (LTBI), in which the person is asymptomatic and noncontagious. Bacilli deposited in some sites, for example, upper lung zones, kidneys, bones, or brain, may find an environment favorable for growth before specific immunity develops and limits multiplication. Hypersensitivity to M. tuberculosis components, as demonstrated by the development of a positive reaction to the tuberculin skin test (TST), develops 2 to 10 weeks after the initial infection.
At any point after this first infection, tubercle bacilli that have spread through the body may begin to replicate and produce active disease. In approximately 5% of all M. tuberculosis-infected persons, disease occurs within 1 year of infection. In another 5%, containment of the infection fails at a later time and M. tuberculosis active disease results. The most common site for this reactivation of M. tuberculosis infection is the upper lung zone, but foci anywhere in the body can be the sites of disease. The ability of the host to contain the infection is reduced by certain diseases, especially human immunodeficiency virus (HIV) infection, silicosis, or diabetes mellitus, and by treatment
with corticosteroids or other immunosuppressive drugs. In these circumstances, the likelihood of TB developing can be >10% per year (5). For persons with LTBI, the risk of progressing to active TB is greatly reduced in persons with drug-susceptible strains by LTBI preventive therapy (e.g., isoniazid or rifampin).
with corticosteroids or other immunosuppressive drugs. In these circumstances, the likelihood of TB developing can be >10% per year (5). For persons with LTBI, the risk of progressing to active TB is greatly reduced in persons with drug-susceptible strains by LTBI preventive therapy (e.g., isoniazid or rifampin).
CLINICAL FEATURES
Early symptoms of TB include fatigue, anorexia, weight loss, or low-grade fever. However, a few patients may present with an acute febrile illness. Erythema nodosum may occur with the acute onset of TB.
Pulmonary TB is the most common form of the disease and the most important from the perspective of hospital infection control. In pulmonary TB, there is insidious onset of cough, which usually progresses slowly over weeks to months to become more frequent and associated with the production of mucoid or mucopurulent sputum. Hemoptysis also may occur. Some patients present with the acute onset of productive cough, fever, chills, myalgia, and sweating similar to the signs and symptoms of influenza, acute bronchitis, or pneumonia. Hoarseness or a sore throat may suggest tuberculous laryngitis. Laryngeal involvement usually is associated with extensive pulmonary involvement, a large number of microorganisms in the sputum, and a very high degree of contagiousness. Physical findings of pulmonary TB may include crackles or signs of lung consolidation.
The infectiousness of a TB patient correlates with the number of microorganisms expelled into the air; this correlates with the site of disease (i.e., pulmonary, laryngeal, tracheal, or endobronchial TB being the most infectious), the presence of cough (or performance of cough-inducing procedures), the presence of acid-fast bacilli (AFB) on sputum smears, the presence of cavitation on chest radiograph, the duration of adequate chemotherapy, and the ability or willingness of the patient to cover his/her mouth when coughing.
Other clinical manifestations of the disease include tuberculous pleuritis, hematogenous dissemination (miliary TB), genitourinary tract TB, TB of the lymph nodes, skeletal TB, tuberculous meningitis, tuberculous peritonitis, or tuberculous pericarditis.
In addition to these sites, there are many other potential body sites where TB may occur less commonly. TB in most of these extrapulmonary sites, without pulmonary or laryngeal involvement, usually is not contagious. However, irrigation or other manipulation of tuberculous lesions can produce infectious droplet nuclei and result in transmission of M. tuberculosis, as can laboratory processing of specimens that contain M. tuberculosis. Standard textbooks can be consulted for information on disease at these sites.
DIAGNOSIS
Radiography
In patients who have signs or symptoms suggesting pulmonary or pleural TB, standard anterior-posterior and lateral radiographs of the chest should be obtained. Special imaging techniques, for example, computed tomography or magnetic resonance imaging, may be of value in defining nodules, cavities, cysts, calcifications, contours of large bronchi, or vascular details in lung parenchyma.
The radiographic manifestation of initial infection in the lung, whether in a child or an adult, usually is parenchymal infiltration accompanied by ipsilateral lymph node enlargement. The parenchymal lesion may be detected at any stage of development and in any portion of the lung, or it may be too small to be seen on the radiograph.
In adults with progression from LTBI to active TB disease, the common presentation is lesions in the apical and the posterior segments of the upper lobes or in the superior segments of the lower lobes. However, lesions may appear in any segment. Cavitation is common except in immunocompromised patients. Other findings include atelectasis or fibrotic scarring with retraction of the hilus and deviation of the trachea. Rarely, patients with pulmonary TB may present with normal chest radiographs, particularly patients with HIV infection or other conditions associated with severe cell-mediated immunosuppression.
Hematogenous TB is characterized by diffuse, finely nodular, uniformly distributed lesions on the chest radiograph. The word miliary is applied to this appearance because the nodules are about the size of millet seeds (˜2 mm in diameter). Unilateral or, rarely, bilateral pleural effusion usually is the only radiographic abnormality evident with pleural TB.
Laboratory Procedures
The identification of M. tuberculosis microorganisms is of great importance for diagnosing TB. Therefore, careful attention should be given to the collection and handling of specimens. Specimens should be transported to the laboratory and processed as soon as possible after collection.
Because TB may occur in almost any body site, a variety of specimens may be appropriate to collect, including sputum (natural or induced), bronchial washings or biopsy material, gastric aspirates, urine, cerebrospinal fluid, pleural fluid, pus, endometrial scrapings, bone marrow biopsy, or other biopsy or resected tissue. All of these materials should be stained and examined by microscopy for the presence of AFB and should be cultured for mycobacteria.
The detection of AFB in stained smears is the easiest and quickest procedure that can be performed, and it provides preliminary support for the diagnosis. Also, the smear is of importance in assessing the patient’s degree of infectiousness. The use of fluorescence microscopy allows the smears to be read much more rapidly than does standard microscopy. If necessary for confirmation, smears stained for fluorescence microscopy can be overstained and examined by standard light microscopy under an oil immersion lens.
All specimens from patients suspected of having M. tuberculosis disease should be inoculated (after appropriate digestion and decontamination, if required) onto appropriate culture media, such as Lowenstein-Jensen or Middlebrook 7H10. Nucleic acid amplification (NAA) testing should be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities.
Genotyping, or DNA fingerprinting, of M. tuberculosis is used to determine the clonality of bacterial cultures. Because this technology is useful for studying the molecular epidemiology of M. tuberculosis and investigating outbreaks, the Centers for Disease Control and Prevention (CDC) established a National TB Genotyping and Surveillance Network in the 1990s. This diagnostic technique in conjunction with traditional epidemiologic methods has enhanced TB surveillance and control programs (6) and has been instrumental in the identification of several pseudo-outbreaks of active TB caused by laboratory crosscontamination of sputum samples from patients without clinical signs of TB (7, 8, 9 and 10).
Drug-Susceptibility Testing
The initial isolate from all patients with positive cultures for M. tuberculosis should be tested for susceptibility to anti-TB drugs. Drug-susceptibility tests for M. tuberculosis are important for choosing the most effective treatment regimen. The laboratory should report to the clinician the amount of growth on drug-containing medium as compared with growth on drug-free control medium. By counting the colonies on the drug-containing medium and on the control medium, the proportion of resistant cells in the total population can be calculated and expressed as a percentage. Generally, when ≥1% of a bacillary population become resistant to the critical concentration of a drug, then that agent is not, or soon will not be, useful for continued therapy, because the resistant population will soon predominate. If broth culture is used, results are reported as resistant or susceptible, and no colony percentage is reported.
Newer Diagnostic Techniques
Radiometric Technology Compared with standard culture methods using solid media, radiometric culture methods, which employ a 14C-labeled substrate medium that is almost specific for mycobacteria, provide much more rapid detection of growth and rapid drug-susceptibility testing. These automated broth culture systems using Middlebrook 7H12 media with added material for detection of mycobacteria can detect growth in 1 to 3 weeks, compared to 3 to 8 weeks for solid media. However, at least one container of solid culture media should be used in conjunction with broth culture systems (11). Combining radiometric culture with techniques for rapid species identification (e.g., genetic probes, high-performance liquid chromatography, or monoclonal antibodies) can further shorten the time required for species identification.
Genetic Probes Genetic probes offer tremendous promise for providing rapid identification. One such probe, an NAA test (Gen-Probe, San Diego, CA), has been approved by the U.S. Food and Drug Administration (FDA) for detection of M. tuberculosis in AFB smear-positive or smear-negative respiratory specimens in patients suspected of having TB. Another NAA test (Amplicor, Roche Diagnostic Systems, Branchburg, NJ) is approved by the FDA only for use on AFB smear-positive respiratory specimens. Interpret NAA test results in correlation with the AFB smear results (12). If the NAA result is positive and the AFB smear result is positive, presume the patient has TB and begin anti-TB treatment while awaiting culture results. The positive predictive value of FDA-approved NAA tests for TB is >95% in AFB smear-positive cases. If the NAA result is positive and the AFB smear result is negative, use clinical judgment whether to begin anti-TB treatment while awaiting culture results and determine if additional diagnostic testing is needed. Consider testing an additional specimen using NAA to confirm the NAA result. A patient can be presumed to have TB, pending culture results, if two or more specimens are NAA positive. If the NAA result is negative and the AFB smear result is positive, a test for inhibitors should be performed and an additional specimen should be tested with NAA. Sputum specimens (3-7%) might contain inhibitors that prevent or reduce amplification and cause falsenegative NAA results. If inhibitors are detected, the NAA test is of no diagnostic help for this specimen. Use clinical judgment to determine whether to begin anti-TB treatment while awaiting results of culture and additional diagnostic testing. If inhibitors are not detected, use clinical judgment to determine whether to begin anti-TB treatment while awaiting culture results and determine if additional diagnostic testing is needed. A patient can be presumed to have an infection with nontuberculous mycobacteria if a second specimen is smear positive and NAA negative and has no inhibitors detected. If the NAA result is negative and the AFB smear result is negative, use clinical judgment to determine whether to begin anti-TB treatment while awaiting results of culture and additional diagnostic tests. Currently available NAA tests are not sufficiently sensitive (detecting 50-80% of AFB smear-negative, culture-positive pulmonary TB cases) to exclude the diagnosis of TB in AFB smearnegative patients suspected to have TB. Probes specific for the genus Mycobacterium, the M. tuberculosis complex, and the two species M. avium and M. intracellulare are available.
Diagnosis of Latent Tuberculosis Infection
Tuberculin Skin Test The TST is the standard method available for identifying persons infected with M. tuberculosis (11,13). Currently available TSTs remain substantially <100% sensitive and specific for detection of infection with M. tuberculosis. Some causes of falsenegative reactions are shown in Table 38-1. False-positive reactions can be due to prior infection with other mycobacteria, BCG vaccination, or problems with the antigen. Anecdotal reports also have raised concern that different commercially available reagents produce different degrees of induration (14); however, a large-scale study of the two reagents available in the United States revealed comparable specificity in people at low risk for M. tuberculosis infection (15).
The intradermal administration of 0.1 mL purified protein derivative (PPD) tuberculin into the skin of the volar surface of the forearm (Mantoux technique) is the preferred method of performing the TST. Tests should be read by a trained health professional between 48 and 72 hours after injection. The basis of reading is the presence or the absence of induration, which should be measured transversely to the long axis of the forearm and recorded in millimeters.
The positive predictive value of the TST varies widely in relation to the prevalence of true M. tuberculosis infection in any given population; furthermore, as already noted, the
risk of progression to disease from LTBI varies according to the characteristics of the infected person (11,13). Thus, to increase the likelihood that a positive test represents true infection with M. tuberculosis and to improve the benefit-to-risk ratio of preventive therapy, the cut point used for defining a positive TST is varied in different populations. A reaction ≥5 mm is considered positive in persons with HIV infection or severe immunosuppression, persons with close contacts of infectious TB cases, or persons with abnormal chest radiographs consistent with TB.
risk of progression to disease from LTBI varies according to the characteristics of the infected person (11,13). Thus, to increase the likelihood that a positive test represents true infection with M. tuberculosis and to improve the benefit-to-risk ratio of preventive therapy, the cut point used for defining a positive TST is varied in different populations. A reaction ≥5 mm is considered positive in persons with HIV infection or severe immunosuppression, persons with close contacts of infectious TB cases, or persons with abnormal chest radiographs consistent with TB.
TABLE 38-1 Factors Causing Decreased Ability to Respond to Tuberculin Skin Tests | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A reaction ≥10 mm is classified as positive in persons who do not meet the above criteria but who have other risk factors for TB. These would include (a) recent (≤5 years) immigrants from countries with a high prevalence of TB; (b) intravenous drug users; (c) residents and employees of high-risk congregate settings (e.g., correctional institutions, nursing homes, healthcare facilities, homeless shelters, or mental institutions); (d) persons with medical conditions that have been reported to increase the risk of TB (e.g., silicosis, gastrectomy, jejunoileal bypass, being ≥10% below ideal body weight, chronic renal failure, diabetes mellitus), some hematologic disorders (i.e., leukemias, lymphomas, or carcinomas of the head, neck, or lung); (e) mycobacteriology laboratory personnel; (f) children <4 years of age or infants, children, and adolescents exposed to adults in high-risk categories; and (g) other high-risk populations identified locally as having a relatively high incidence of TB.
A reaction of ≥15 mm is classified as positive in persons with no risk factors for TB.
The TST can be valuable for identifying persons newly infected with M. tuberculosis when repeated periodically in surveillance of tuberculin-negative persons likely to be exposed to TB (e.g., healthcare workers) (13). However, there are special considerations in identifying newly infected persons.
First, there are unavoidable errors in even the most carefully performed tests. For this reason, small increases in reaction size may not be meaningful. For persons whose previous reaction was negative, an increase in reaction size of ≥10 mm in diameter within 2 years should be considered a TST conversion. Healthcare workers with some degree of TST induration as a result of nontuberculous mycobacterial infection or previous BCG vaccination have converted, if induration increases by ≥10 mm over previous tests. For healthcare workers at low risk of exposure with a history of a negative TST, an increase of 15 mm within a 2-year period may be more appropriate for defining a recent conversion. Converters should be considered newly infected with M. tuberculosis and strongly considered for preventive therapy (11,16).
A second problem in identifying newly infected persons is the so-called booster phenomenon (17). Repeated testing of uninfected persons does not sensitize them to tuberculin. However, delayed hypersensitivity to tuberculin, once it has been established by infection with any species of mycobacteria or by BCG vaccination, may gradually wane over the years, resulting in a TST reaction that is negative. The stimulus of this test may recall the immune reaction, which results in an increase in the size of the reaction to a subsequent test, sometimes causing an apparent conversion that is then interpreted as indicating new infection. The booster effect can be seen on a second test done as soon as a week after the initial stimulating test and the booster effect can persist for a year and perhaps longer.
When tuberculin skin testing of adults is to be repeated periodically, the initial use of a two-step testing procedure can reduce the likelihood of interpreting a boosted reaction as representing recent infection (18). In two-step testing, an initial TST is performed. If the reaction to the first test is negative, a second test should be given 1 to 3 weeks later. If the reaction to the second of the initial two tests reaches the appropriate cut point for a positive result in the patient, this probably represents a boosted reaction. On the basis of this second test result, the person should be classified as being previously infected and managed accordingly. If the second test result remains below the appropriate cut point, the person is classified as being uninfected. A positive reaction to a third test (with an appropriate increase) in such a person, within the next
2 years, is likely to represent the occurrence of new infection with M. tuberculosis in the interval.
2 years, is likely to represent the occurrence of new infection with M. tuberculosis in the interval.
Whole-Blood Interferon-γ Release Assays In 2005, a new in vitro test, QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), received final approval from the FDA as an aid in diagnosing M. tuberculosis infection, including both LTBI and TB disease. This enzymelinked immunosorbent assay test detects the release of interferon-gamma (IFN-γ) in fresh heparinized whole blood from sensitized persons when it is incubated with mixtures of synthetic peptides simulating two proteins present in M. tuberculosis: early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10). ESAT-6 and CFP-10 are secreted by all M. tuberculosis and pathogenic M. bovis strains. Because these proteins are absent from all BCG vaccine strains and from commonly encountered nontuberculous mycobacteria except M. kansasii, M. szulgai, and M. marinum, QFT-G is expected to be more specific for M. tuberculosis than tests that use tuberculin PPD as the antigen. QFT-G represents one type of interferon-γ release assay (IGRA). Tests such as QFT-G measure the IFN-γ released by sensitized white blood cells after whole blood is incubated with antigen. Tests such as ELISpot enumerate cells releasing IFN-γ after mononuclear cells recovered from whole blood are incubated with similar antigens. Two IGRAs have been approved by FDA for use in the United States: the original QuantiFERON-TB test (QFT) and the recently approved QFT-G. The two tests use different antigens to stimulate IFN-γ release, different methods of measurement, and different approaches to test interpretation. QFT was approved as an aid for diagnosing LTBI, whereas QFT-G is approved as an aid for diagnosing both LTBI and TB disease. QFT is no longer commercially available.
Each of the three tests (TST, QFT, and QFT-G) relies on a different immune response and differs in its relative measures of sensitivity and specificity. The TST assesses in vivo delayed type hypersensitivity (Type IV), whereas QFT and QFT-G measure in vitro release of IFN-γ. The TST and the QFT measure response to PPD, a polyvalent antigenic mixture, whereas QFT-G measures response to a mixture of synthetic peptides simulating two specific antigenic proteins that are present in PPD. The IGRA is less likely to be concordant with the TST in persons with a history of BCG vaccination and in persons with immune reactivity to nontuberculous mycobacteria (19). The advantages of the IGRA test are that it requires only one patient visit, does not boost immune response like the TST, and is less subject to reader bias and error. Its disadvantages are that it requires phlebotomy, processing within 12 hours, and 16 to 24 hours of incubation.
QFT-G can be used in all circumstances in which the TST is used, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of healthcare workers and others undergoing serial evaluation for M. tuberculosis infection. QFT-G usually can be used in place of (and not in addition to) the TST. A positive QFT-G result should prompt the same public health and medical interventions as a positive TST result. No reason exists to follow a positive QFT-G result with a TST. Persons who have a positive QFT-G result, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed. At a minimum, a chest radiograph should be examined for abnormalities consistent with TB disease. Additional medical evaluation would depend on clinical judgment on the basis of findings from history (including exposure to infectious TB), physical examination, and chest radiography. HIV counseling, testing, and referral is recommended, because HIV infection increases the suspicion for TB and the urgency of treating LTBI. After TB has been excluded, treatment of LTBI should be considered.
The majority of healthy adults who have negative QFT-G results are unlikely to have M. tuberculosis infection and do not require further evaluation. However, for persons with recent contact with persons who have infectious TB, negative QFT-G results should be confirmed with a repeat test performed 8 to 10 weeks after the end of exposure, as is recommended for a negative TST result. The CDC guidelines for use and interpretation of the interferon-γ test are listed in Table 38-2 (20).
GENERAL EPIDEMIOLOGY OF TUBERCULOSIS IN THE UNITED STATES
In the United States, TB affects certain segments of the population disproportionately because the factors that affect the likelihood of exposure to and infection with M. tuberculosis and the likelihood of progression from LTBI to disease are not homogeneously distributed throughout the population.
For 2008, 12,898 episodes of TB were reported to the CDC, reflecting a rate of 4.2 cases per 100,000 population (21). This represents the 16th consecutive year that TB cases declined and the lowest rate recorded since national reporting began in 1953. However, the rate of decline has slowed; an average of 7.3% decline from 1993-2000 to 3.8% during 2000-2008. In 2008, the largest declines occurred in persons ≥65 years and older (from 17.7 per 100,000 in 1993 to 6.4 in 2008), in adults aged 45 to 64 years (from 12.4 to 5.0), in adults aged 25 to 44 years (from 11.5 to 5.1), and in children <15 years of age (from 2.9 to 1.3), each group having decreased more than 50% (22). The rate declined by 32% in those 15 to 24 years of age (from 5.0 to 3.4). Six percent were children <15 years of age, 11% were age 15 to 24, 33% were age 25 to 44, 30% were age 45 to 64, and 19% were ≥65 years old.
The overall national trend reflects the impact of changes within population subgroups. Of the 12,824 incident cases of known origin, 5,283 (41.2%) were U.S. born and 7,541 (58.8%) were foreign born. From 1993 to 2008, there was a 72.6% decline in TB cases among U.S.-born persons of all age groups to a rate of 2.0 per 100,000 population. Among foreign-born persons in the United States, both the number and the rate of TB declined, 3.9% compared to 2007 and 69.7% compared to 1993; the 2008 rate was 20.2 per 100,000 population—a 2.6% decline from 2007 and a 40.6% decline since 1993. In 2008, four countries accounted for approximately half (50.1%) of foreign-born TB cases: Mexico (1,742), the Philippines (855), India (598), and Vietnam (580). U.S.-born non-Hispanic Blacks comprised the largest number of TB cases among US born (42.2%; 2,227/5,283).
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The geographic distribution of TB in the U.S. also is not homogeneous. In 2008, four states (California, Florida, New York, and Texas) reported approximately half (49.2%) of all TB cases and each reported >500 cases each. However, by 2008, 35 states had met the Advisory Council for TB Elimination interim goal of ≤3.5 cases/100,000 population. Cases of TB remained concentrated in urban areas: in 2001, 39% of TB cases were reported from 64 major cities (23).
A total of 125 cases of multidrug-resistant TB (MDR-TB) were reported in 2007, the most recent year with complete drug-susceptibility testing data. Of those with drug-susceptibility results in 2006 and 2007, 97.4 (10,477/10,762) were susceptible to isoniazid and 97.8% (10,190/10,421) to rifampin. The percentage of TB cases that were MDR-TB for 2007 (1.2%; 125/10,190) was similar to that of 2006 (1.2%; 124/10,477). The percentage of MDR-TB cases among persons without a previous history of TB has remained stable at approximately 1.0% since 1997. In 2007, the percentage of MDR-TB cases among persons with a previous history of TB was 3.6%. In 2007, MDR-TB continued to disproportionately affect foreign-born persons, who accounted for 81.6% of MDR-TB cases. Foreign-born persons had a higher percentage of MDR-TB, both among those with (5.2%) and without (1.5%) a previous history of TB. Cases of extensively drug-resistant TB (XDR-TB) have been reported every year in the United States except 2003 since drugsusceptibility reporting began in 1993. Four XDR-TB cases were reported in 2006 and two in 2007. Provisional data indicated that four XDR-TB cases were reported in 2008.
Data on the HIV status of persons with TB reported to the national TB surveillance system at the CDC are limited. Reporting of HIV status has improved slowly since 1993, the year such information was first included on TB case reports submitted to the CDC. In 2001, 3,254/5,630 (58%) TB case reports for persons aged 25 to 44 years included information about HIV status (22). In 2001, 26 states reported HIV test results for at least 75% of cases in persons in this age group. Of these 26 states, the percentage of TB cases in persons aged 25 to 44 years who were coinfected with HIV ranged from 0% (New Hampshire, South Dakota, and Wyoming) to >39% (District of Columbia and Florida). To help estimate the proportion of reported TB cases coinfected with HIV, state health departments have compared TB and acquired immunodeficiency syndrome (AIDS) registries. During 1993 to 1994, 14% of all TB cases (27% of cases in persons aged 25-44 years) had a match in the AIDS registry (24). In 2008, among 7,625 persons with TB with a known HIV test result, 802 (10.5%) were infected with HIV. California, Michigan, and Vermont data were not available for this calculation. In 2007, excluding California and Vermont, among 8,289 persons with TB and an HIV test, 884 (10.7%) were infected with HIV (21).
From 1953, when national reporting of incident TB cases was first fully implemented in the U.S., through 1984, the number of cases reported to the CDC decreased from 84,304 to 22,255. This average annual decline of 5% to 6% was interrupted only by a transient increase in 1980, which was attributed to cases arising from a large influx of refugees from Southeast Asia (25). Between 1984 and 1992, there was a dramatic reversal of the long-standing decline in the number of TB cases.
From 1985 through 1992, reported cases increased 20.1%, from 22,201 to 26,673. Based on an extrapolation of the trend in cases observed from 1980 through 1984, approximately 52,000 excess cases of TB were reported to the CDC from 1985 through 1992 (26).
From 1985 through 1992, reported cases increased 20.1%, from 22,201 to 26,673. Based on an extrapolation of the trend in cases observed from 1980 through 1984, approximately 52,000 excess cases of TB were reported to the CDC from 1985 through 1992 (26).
Increases in the number of cases in the late 1980s were mainly due to the HIV/AIDS epidemic and the emergence of MDR-TB. Other contributing factors include (a) an increase in the number of cases occurring in persons who immigrate to the United States from areas of the world that have a high prevalence of TB; and (b) an increase in active transmission of M. tuberculosis caused largely by adverse social conditions and an inadequate healthcare infrastructure (26).
The decline in the overall number of reported TB cases and in the level of MDR-TB since 1992 has been attributed to stronger TB controls that emphasize prompt identification of persons with TB, initiation of appropriate therapy, and ensuring completion of therapy. The declining TB trend among US-born persons reflects the reduction of community transmission of M. tuberculosis, particularly in areas with a high incidence of HIV (27). In comparison, the relatively stable number of reported cases of TB among foreign-born persons indicates that most cases of active TB disease among foreign-born persons residing in the United States results from infection with M. tuberculosis in the person’s country of birth (28). The CDC, in collaboration with state and local health departments, continues to focus on its comprehensive plan to reduce active TB disease among foreign-born persons residing in the United States. This plan includes strategies to (a) improve case finding and completion of therapy, (b) conduct contact investigations, (c) screen those at high risk for infection, and (d) ensure completion of preventive therapy in eligible candidates (29).
EPIDEMIOLOGY OF HEALTHCARE-ASSOCIATED TUBERCULOSIS IN THE UNITED STATES
Factors Influencing the Epidemiology of Healthcare-Associated Tuberculosis
The factors that influence the epidemiology of healthcareassociated TB are the joint probabilities that exposure to M. tuberculosis will occur, exposure will result in infection, and infection will lead to active TB (Fig. 38-1). In a healthcare facility, the likelihood of exposure to M. tuberculosis may be affected by factors such as the prevalence of infectious TB in the population served by the facility; the degree of crowding in the facility; the effectiveness of the facility’s TB infection control program in rapidly identifying, isolating, and treating persons with infectious TB; and the effectiveness of engineering controls, such as directional airflow and booths for cough-inducing procedures, in preventing the spread of contaminated air throughout the facility.
Factors that may affect the likelihood that exposure to M. tuberculosis will result in infection are largely related to the effectiveness of the facility’s infection control program. These factors include the effectiveness of the program in identifying and successfully treating persons with infectious TB, thereby rendering them noninfectious; the effectiveness of engineering controls, such as ventilation and ultraviolet germicidal irradiation (UVGI), in reducing the concentration of infectious droplet nuclei in the air; and the effectiveness of the respiratory protection program in preventing the inhalation of infectious droplet nuclei. Additionally, although supporting data are lacking, it is possible that medical conditions that cause severe suppression of cell-mediated immunity may increase susceptibility to infection with M. tuberculosis; thus, the prevalence of such conditions, either in patients or healthcare workers, may affect the likelihood that exposure of these persons will result in infection.
 FIGURE 38-1 Schematic illustration of the steps involved in the acquisition of tuberculous infection and the development of active tuberculosis. |
Factors that are likely to influence the risk that infection with M. tuberculosis will result in progression to active TB probably include the prevalence in the facility’s patient and healthcare worker population of medical conditions that increase the likelihood of progression from LTBI to active disease (e.g., HIV infection). In addition, the infection control program’s effectiveness in identifying persons who have been exposed and infected and providing them with appropriate preventive therapy is likely to influence the likelihood of progression to active disease. Events or conditions that alter any of these probabilities (the probability of exposure, infection, or progression to active TB) may result in changes in the epidemiology of TB in a healthcare facility.
Several types of information may be considered in describing the epidemiology of healthcare-associated TB. These include surveillance for active TB in healthcare workers, surveillance for LTBI (i.e., TST conversions or IGRA-positive) in healthcare workers, and reports of episodes of healthcare-associated M. tuberculosis transmission (such as reports of outbreaks).
Surveillance for Active Tuberculosis in Healthcare Workers
There are very few national data on the recent or current risk of active TB in healthcare workers. Information on the occupation of persons with TB was not collected in the national TB surveillance system until 1993, at which time limited variables on occupation were added to the data collection forms. However, without appropriate denominators, it is not possible to calculate incidence rates or relative risks for healthcare workers. In 2001, 50 of the reporting areas in the United States reported information
on occupation for at least 75% of TB cases. There were 414 reported TB cases among healthcare workers in 2001, a slight decline when compared to the 427 cases reported in 2000 (22,30). The percentage of cases occurring among healthcare workers in 2001 ranged from 0% in the District of Columbia, Idaho, Indiana, Nevada, North Dakota, South Dakota, Utah, Vermont, West Virginia, and Wyoming to 6.6% in Massachusetts and 15.8% in New Hampshire.
on occupation for at least 75% of TB cases. There were 414 reported TB cases among healthcare workers in 2001, a slight decline when compared to the 427 cases reported in 2000 (22,30). The percentage of cases occurring among healthcare workers in 2001 ranged from 0% in the District of Columbia, Idaho, Indiana, Nevada, North Dakota, South Dakota, Utah, Vermont, West Virginia, and Wyoming to 6.6% in Massachusetts and 15.8% in New Hampshire.
In a questionnaire survey of medical school-affiliated physicians in California, Barrett-Connor (31) found that 3.5% had been treated for active TB. Seventy-five percent of cases of active disease began when the physicians were within 10 years of beginning medical school; 62% of cases of active disease followed infection acquired after beginning medical school. In the cohort of those who graduated between 1966 and 1975, disease rates after beginning medical school were 0% (0/54) among those who were TST positive at entry; 1.0% (7/669) among those who were TST negative at entry; and 10.0% (7/69) among those who became TST positive after entry.
A questionnaire survey of 1938 to 1981 graduates of the University of Illinois Medical School found that, for most years, the incidence of TB in the cohort of graduates was higher than that in the general population (32). More than two thirds of all cases of TB occurred during medical school or within 6 years of graduation.
Finally, a review of the recorded occupations of persons with TB reported to the North Carolina TB control program found that TB case rates in hospital personnel in 1983 and 1984 were similar to or lower than rates in the general population (33). However, these data were not adjusted for age or race, nor was a definition of the term hospital employee provided.
In summary, data concerning the recent or current risk of active TB in healthcare workers in the United States are very limited. Two questionnaire surveys suggest an increased risk among physicians, whereas a third study suggests that the risk for hospital employees in general is similar to that for the general population. The data from Barrett-Connor’s survey suggest a protective effect of a previous positive TST. The incidence of TB is a relatively insensitive measure of the actual risk posed to healthcare workers by occupational exposure to M. tuberculosis. A more sensitive measure of this risk is the rate of TST conversions or IGRA positives among healthcare workers.
Surveillance for TST Conversions in Healthcare Workers
The annual rate of TST conversions in healthcare workers is the best potential indicator of the risk of becoming infected with M. tuberculosis through occupational exposure in the healthcare setting. However, there is no systematic national surveillance for such conversions in U.S. healthcare workers. In 1995, the CDC, in collaboration with selected state and local health departments, began a prospective TST surveillance project to estimate the incidence of occupational transmission of M. tuberculosis to healthcare workers. Participating sites (Florida, Massachusetts, Mississippi, New Jersey, New York City, San Francisco, and San Diego) were required to implement TST programs consistent with current CDC guidelines and to pilot test a CDC-developed microcomputer software system, staffTrakTB, to assist with collection, tracking, management, and analysis of data (34a,34b). The project areas enrolled 26 facilities: eight hospitals, five health departments, two long-termcare facilities, three correctional facilities, and eight other facilities (including a state laboratory). From 1995 to 1997, a total of 29,004 healthcare workers were enrolled in the project; 9,088 (31.3%) were included in the analysis. TST conversions (i.e., ≥10 mm increase in reaction size on follow-up TST) were documented in 1.1% (104 of 9,088) of healthcare workers (35). Conversion rates varied by project area, ranging from 0% in Florida to 4.2% in New York City, and by facility (correctional, 2.1%; health departments, 1.3%; hospitals, 1.0%; or nursing homes, 0.8%). TST conversion rates also varied by occupation of the healthcare worker (outreach worker, 4.2%; scientist, 2.7%; technician, 2.2%; nurse, 1.2%; housekeeper, 1.2%; clerical worker, 1.0%; administrator, 0.8%; attending physician, 0.6%; and social worker, 0.3%). TST conversion rates among nurses were highest in New York City (4.2%) and San Francisco (2.2%) and lowest in Mississippi (0.1%) and Florida (0%), probably reflecting an elevated risk of M. tuberculosis transmission in areas with high TB incidence such as New York City and San Francisco. Healthcare workers who were outreach workers, nonwhite, non-U.S.-born, or BCG-vaccinated were at a significantly higher risk of conversion. These data suggest that foreign-born status and certain occupations may be associated with an elevated risk of M. tuberculosis transmission, possibly reflecting more exposure to infectious individuals in the healthcare worker’s household or community, and in certain healthcare settings.
There are several reports in the literature of the risk of TST conversion among U.S. healthcare workers (Table 38-3) (18,31,33, 34a, 34b, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50,51,52, 53, 54, 55, 56, 57, 58, 59a and 59b). These reports suggest that, since 1980, the risk of TST conversion among hospital employees in general has been ≤1%.
One prospective study followed workers at an urban hospital in a high TB-incidence area where TST screening was required of all eligible employees every 6 months (59a and 59b). This study found an overall TST conversion rate of 0.38% per year. TST conversion was not associated with the degree of patient contact, but was associated with BCG vaccination, low annual salary, and increasing age. The researchers concluded that, in a hospital with an effective TB infection control program, TST conversion rates were low and that the most important risk factors for TST conversion among workers were not occupational.
At least two other studies have found a higher risk for TST conversion with increasing age of the workers (40,43). A third study that examined age as a risk factor for TST conversion found an association with increasing age when two-step TST was not used to establish the employees’ baseline skin test status; however, when two-step TST was used to eliminate apparent conversions caused by the booster phenomenon, there was no longer any correlation between age and the risk of conversion (18). This finding suggests that the higher rate of apparent conversion sometimes observed in older workers may actually be the result of an increased level of boosting in older persons.
Race has been found to correlate with risk of TST conversion in two studies. One of these reported a higher risk among non-whites compared with whites, and a higher risk among employees in the lowest socioeconomic quintile (40).
The other found a higher risk of TST conversion among black employees than among non-blacks; however, among blacks, the risk was higher among nurses than among persons in other job categories (44). In the one study that examined gender as a potential risk factor, no association was found between gender and the risk of TST conversion (40). A survey that included multiple institutions throughout North Carolina found that the risk of conversion varied according to geographic region within the state (33).
The other found a higher risk of TST conversion among black employees than among non-blacks; however, among blacks, the risk was higher among nurses than among persons in other job categories (44). In the one study that examined gender as a potential risk factor, no association was found between gender and the risk of TST conversion (40). A survey that included multiple institutions throughout North Carolina found that the risk of conversion varied according to geographic region within the state (33).
TABLE 38-3 Tuberculin Skin Test Conversion Rates in Healthcare Workers United States, 1960-1998 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Few reported studies have examined the relationship between job category and risk of TST conversions. One study found a higher risk of conversion among persons
in laundry, housekeeping, and engineering and maintenance departments than among persons in other departments (40). A second study found a higher conversion rate among nurses than among persons in other job categories (44). A third study found higher conversion rates among admissions clerks, phlebotomists, and nurse technicians than among respiratory therapists, environmental services workers, or registered nurses (52). A survey of self-reported TST conversions among medical fellows at multiple institutions found a higher reported rate of conversion among pulmonary fellows than among infectious diseases fellows (50). Finally, a survey of self-reported TST conversions among medical school-affiliated physicians in California found that physicians in the major clinical specialties reported comparable infection rates before and during medical school, but that rates after medical school were highest in medicine, pediatrics, and surgery; intermediate in obstetrics and gynecology and orthopedics; and lowest in radiology and psychiatry (31). In this survey, the cumulative percentage of TST-positive physicians was at least twice the estimated age-specific infection rate for the general U.S. population.
in laundry, housekeeping, and engineering and maintenance departments than among persons in other departments (40). A second study found a higher conversion rate among nurses than among persons in other job categories (44). A third study found higher conversion rates among admissions clerks, phlebotomists, and nurse technicians than among respiratory therapists, environmental services workers, or registered nurses (52). A survey of self-reported TST conversions among medical fellows at multiple institutions found a higher reported rate of conversion among pulmonary fellows than among infectious diseases fellows (50). Finally, a survey of self-reported TST conversions among medical school-affiliated physicians in California found that physicians in the major clinical specialties reported comparable infection rates before and during medical school, but that rates after medical school were highest in medicine, pediatrics, and surgery; intermediate in obstetrics and gynecology and orthopedics; and lowest in radiology and psychiatry (31). In this survey, the cumulative percentage of TST-positive physicians was at least twice the estimated age-specific infection rate for the general U.S. population.
Several studies have found higher conversion rates among workers with a higher likelihood of exposure to patients with TB than among those with a relatively lower likelihood of such exposure (38,39,41,42,57,58). In contrast, in a hospital in Pennsylvania, the reported conversion rates for groups with high or low degrees of exposure to patients with TB were not significantly different (43). Similarly, in a multi-institution survey in Washington, reported conversion rates were not significantly different in hospitals that had admitted no patients with TB compared with hospitals that had admitted patients with AFB smear-negative TB or hospitals that had admitted patients with AFB smearpositive TB (49). In this study, however, postexposure conversions were excluded from analysis, and there was no analysis by risk of exposure within the hospitals that did admit TB patients. A study from Florida reported a higher conversion rate among employees in a psychiatric hospital, in which there was presumably a low risk of exposure, than in a general hospital in which the risk of exposure was presumably higher (51). Again, this study did not examine the risk of TST conversion according to the likelihood of exposure within each hospital. Finally, a prospective study to assess the prevalence of TST positivity among healthcare workers providing service to HIV-infected persons found no association between the amount or the type of contact with HIV-infected individuals and the risk of TB infection (55). Therefore, according to this study, caring for HIV-infected patients was not related to an increased rate of TB infections among healthcare workers in these settings.
These studies, in addition to being few in number, have substantial limitations. With the exception of one study (59a), most are retrospective; the populations being studied often are not well defined; participation rates are not consistently reported but are variable and often quite low; the methods of applying and reading the tests are variable and often rely on employees’ self-reporting of results; twostep TST to establish a baseline is rarely used; the definitions of positive skin tests or of TST conversions are not always specified and are variable; the classification of job categories and the definitions of exposure are inconsistent; there are essentially no data on background risk in the community or on the performance of serial TST in the general population from which to make estimates of attributable risk; the analyses often are insufficiently detailed to allow an estimation of relative risks for different job categories; and problems with the specificity and positive predictive value of the TST rarely are addressed adequately. Furthermore, the antigens used often are not described and appear to vary between, and possibly within, studies. It has been noted that a change in products can result in an increase in the conversion rate or pseudo-outbreak (14). For these reasons, interpretation of the data is difficult, and comparison of data from different studies is problematic. In spite of all these limitations, it is interesting that the overall risk among hospital employees in general seems to be fairly consistent.
In summary, available data suggest that the risk of TST conversion among hospital employees in general is ≤1%. The data, although conflicting, also suggest that there may be substantial variation in risk according to the type of hospital, geographic location, occupational category, and a priori likelihood of exposure. Interpretation of the data is made difficult by methodologic limitations, by the lack of specificity and positive predictive value of the TST, by the difficulty of differentiating occupational risk from exposure in the community, and by an inadequate understanding of serial TSTs reflected in some studies. In international settings or domestic settings with large numbers of healthcare workers who have received BCG, the use of IGRAs may be more useful than TST for monitoring potential occupational exposures to M. tuberculosis (59b).
Healthcare-Associated Outbreaks of Tuberculosis
A healthcare-associated outbreak of TB may be defined as transmission of M. tuberculosis in a healthcare setting, resulting in the acquisition of LTBI or the development of TB among exposed persons. There is no systematic national surveillance for healthcare-associated TB outbreaks; therefore, data on such outbreaks are limited to reports in the literature. Since 1960, at least 41 healthcareassociated outbreaks occurring in the United States have been reported in the literature (Table 38-4) (48,53, 54 and 55,60, 61, 62, 63 and 64,65,66,67,68,69,70,71,72,73,74,75,76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96a and 96b).
The reported outbreaks have occurred in a wide variety of geographic areas. Most have occurred in general medical-surgical hospitals; one occurred in a health department clinic, one in an outpatient methadone treatment program, one in an outpatient hemodialysis unit, one in a pediatric office, one at a children’s hospital, one in two nursing homes and a community hospital, and one involved both a general hospital and a hospice. Outbreak settings within the hospitals have included emergency departments, inpatient medical wards, adult or neonatal intensive care units, a surgical suite, radiology suites, inpatient HIV wards and an outpatient HIV clinic, an inpatient renal transplant unit, an inpatient prison ward, an autopsy suite, a nursery, a maternity ward, and bronchoscopy rooms.
The earlier reports of outbreaks in this series primarily focused on transmission of M. tuberculosis from patients to healthcare workers, with an occasional secondary case
identified in another patient. The apparent infrequency of transmission to other patients in these outbreaks may be artifactual because of the difficulty often encountered in obtaining follow-up information on exposed patients and the natural history of TB. Because the interval from infection to disease is highly variable (ranging from weeks to decades), the occurrence of active TB is not likely to be attributed to a hospitalization in the more remote past. Thus, in the absence of temporal clustering of TB cases or the appearance of strains of M. tuberculosis with distinctive drug resistance or DNA fingerprint patterns, transmission to patients in a hospital may go unrecognized (2). In contrast to the earlier reports, many of the more recently reported outbreaks have occurred in settings where many of the persons exposed were severely immunocompromised patients. These outbreaks have involved rapid propagation of active TB among relatively large numbers of patients.
identified in another patient. The apparent infrequency of transmission to other patients in these outbreaks may be artifactual because of the difficulty often encountered in obtaining follow-up information on exposed patients and the natural history of TB. Because the interval from infection to disease is highly variable (ranging from weeks to decades), the occurrence of active TB is not likely to be attributed to a hospitalization in the more remote past. Thus, in the absence of temporal clustering of TB cases or the appearance of strains of M. tuberculosis with distinctive drug resistance or DNA fingerprint patterns, transmission to patients in a hospital may go unrecognized (2). In contrast to the earlier reports, many of the more recently reported outbreaks have occurred in settings where many of the persons exposed were severely immunocompromised patients. These outbreaks have involved rapid propagation of active TB among relatively large numbers of patients.
A variety of factors have been identified as possibly contributing to the reported healthcare-associated TB outbreaks. In many cases, these factors represent empiric observations, and the actual contribution of any given factor cannot be calculated. In some instances, the analysis presented has allowed an estimate of the relative contribution of a specific factor. In general, potential contributing factors can be categorized into those that increase the likelihood of exposure to M. tuberculosis, those that increase the likelihood of infection occurring among persons who are exposed, and those that increase the likelihood of active disease in persons who become infected.
Factors That Affect the Likelihood of Exposure A major factor increasing the likelihood of exposure to M. tuberculosis has been failure to promptly identify and isolate a potential source of transmission, usually a patient with undiagnosed and untreated, or inadequately treated, TB (Table 38-4). In at least three outbreaks, healthcare workers also have been implicated as sources of transmission (70,88,94); in one, transmission only occurred from healthcare worker to healthcare worker in a setting where routine employee screening did not take place (94). Failure to identify persons with infectious TB (including parents or visitors for pediatric patients) has resulted in these persons not being isolated and appropriately treated, thus increasing the number of persons exposed.
In most instances, transmission has occurred from patients with pulmonary TB. However, in two outbreaks, transmission occurred as a result of irrigation or manipulation of an undiagnosed M. tuberculosis abscess or skin ulcer (64,71). The presence of drug-resistant microorganisms that are inadequately treated also may lead to prolonged infectiousness and an increased likelihood of exposure.
In some outbreaks, there often have been multiple sources, resulting in a web of possible transmissions, rather than a clearly defined single chain of transmission. In at least three recent outbreaks, DNA fingerprinting using RFLP has demonstrated the presence of more than one chain of transmission involving different strains of M. tuberculosis, when epidemiologic evidence seemed to suggest a single chain of transmission (68,72,92).
Inadequate ventilation also has increased the likelihood of exposure to M. tuberculosis. In some instances, the presence of positive air pressure in isolation rooms has allowed potentially contaminated air to escape from the isolation rooms into other areas of the facility. In most situations, the presence of other potentially contributing factors has made it difficult to assess the effect of positive air pressure alone; however, in one outbreak in which other aspects of the infection control program were adequately implemented, the role of positive air pressure was clearly demonstrated (53). In other instances, recirculation of potentially contaminated air from sputum induction or isolation rooms into other areas of the facility has been implicated as a factor in transmission (61,63,66,72).
Lapses in isolation practices have increased the likelihood of exposure in several outbreaks. Such lapses have included not keeping isolation room doors closed, thereby allowing efflux of potentially contaminated air from the room into adjacent areas; not keeping patients with infectious TB confined to their rooms; not enforcing the use of masks by patients with infectious TB when they are out of their rooms; and not maintaining isolation for a period long enough to ensure that the patient is no longer infectious. Additionally, inadequate cleaning, disinfection, or leak testing of bronchoscopes after performing bronchoscopy in pulmonary TB patients led to transmission of infection and active TB disease (86,94) (see also Chapter 62).
Factors That Affect the Likelihood of Infection In general, factors that are likely to produce a relatively high concentration of infectious droplet nuclei in the air also are likely to increase the likelihood that an exposed person will inhale tubercle bacilli and become infected. Thus, patients identified as outbreak sources often have had chest radiographs showing extensive cavitary disease and sputum smears that were positive for AFB—factors suggesting a high bacterial burden. However, in outbreaks among immunocompromised persons, extensive cavitary disease has been relatively infrequent (67,68,72,73,75,77,87,95,96a and 96b). Furthermore, in rare instances, high rates of transmission from persons with sputum smears that were negative for AFB have been documented (48,62).
Inadequate ventilation rates and recirculation of potentially contaminated air within closed environments can lead to increased concentrations of infectious droplet nuclei in the air and have been implicated in several outbreaks (48,61, 62 and 63,66,68,70,72,74,76,77). Patients in rooms in close proximity to a room housing a patient with infectious TB have been shown to be at increased risk when the isolation room is not under appropriate negative pressure (64,73,76).
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