Tuberculosis

Epidemiology, Risk Factors, and Pathogenesis

Epidemiology

The World Health Organization (WHO) estimates that 30% of adults worldwide are infected with organisms in the M. tuberculosis complex. From this large reservoir of infected people, an estimated 9 million new cases of TB occurred in 2009, leading to approximately 1.3 million deaths. In 2008, TB was estimated to be the seventh leading cause of death worldwide, and it is the number one killer of HIV-infected patients.

The burden of TB varies significantly throughout the world, with more than 90% of cases occurring among people residing in developing countries (Figure 31-1). The highest incidence rates for TB are in sub-Saharan Africa, particularly in the southern region of the continent. Not surprisingly, the highest prevalence of HIV co-infection also is in this region. Worldwide, approximately 23% of all persons with TB have underlying HIV co-infection; however, in sub-Saharan Africa, an estimated 50% of persons with TB have HIV/AIDS.

Figure 31-1 Tuberculosis (TB) notification rates, 2009. The legend depicts the number of notified TB cases, which includes both new and relapse cases per 100,000 population.

(From Global tuberculosis control 2010, Geneva, World Health Organization, 2010.)

Recent reports of outbreaks of multidrug-resistant TB (MDR TB) and extensively resistant TB (XDR TB) have highlighted the importance of providing effective antituberculosis therapy to patients. MDR TB refers to disease caused by isolates of M. tuberculosis that are resistant to at least isoniazid (INH) and rifampin, whereas XDR TB refers to that due to MDR TB isolates that also are resistant to fluoroquinolones and at least one second-line injectable agent (amikacin, capreomycin, or kanamycin). Surveys have documented that approximately 4.6% of TB cases worldwide are MDR TB, and 5.4% of these cases are XDR TB. More cases of drug-resistant TB exist today than in all of recorded history, and this trend is likely to continue unless more effective TB control measures are implemented globally.

In the United States, the TB case rate declined by 3% to 5% per year from 1953 to 1984. Between 1986 and 1992, the numbers of TB cases increased by approximately 20%. This increase in the number of cases was the result of at least three major factors: (1) inadequate public health measures, (2) immigration from countries where TB is prevalent, and (3) co-infection with HIV. Fortunately, case numbers have declined since 1992 and are now at a historic low. In 2010, a total of 11,181 cases of TB were reported in the United States, for an incidence of 3.6 per 100,000 population. TB case rates declined an average of 4.5% each year during 2000 to 2010. TB rates were 11 times higher among foreign-born persons than among U.S.-born people. Among U.S.-born persons, blacks were 7 times more likely to have TB than whites. Approximately 1% of new cases in the country had MDR TB, approximately 90% of whom were foreign-born. Of these MDR TB cases, approximately 1% to 2% were XDR TB.

Risk Factors

Certain people are at higher risk for development of TB simply because they are more likely to be exposed to and thus infected with M. tuberculosis (Table 31-1). For example, approximately 60% of reported TB cases in the United States occur among foreign-born people who come from areas where the disease is endemic. Other populations with an increased prevalence of TB infection include certain racial and ethnic groups, low-income populations, the homeless, and injection drug users.

Table 31-1 Criteria for a Positive Reaction on Tuberculin Skin Testing

Induration Size	Risk Groups
≥5 mm	HIV-infected persons Close contact with an infectious tuberculosis case Abnormal-appearing chest radiograph* consistent with previous tuberculosis Immunosuppressed patients receiving the equivalent of ≥15 mg/day of prednisone for at least 1 month

≥10 mm

Foreign-born persons recently arrived (<5 years) from high-prevalence countries

Medical conditions† that increase the risk of tuberculosis

Injection drug users

Medically underserved, low-income populations (e.g., homeless persons)

Residents and staff of long-term care facilities (e.g., nursing homes, correctional institutions, homeless shelters)

Health care workers

Children <4 years of age

Tuberculin skin test converters (increase of ≥10 mm induration within a 2-year period)

≥15 mm

All others; these persons should not be screened in the absence of indication

* The predominant chest radiographic finding consistent with previous tuberculosis is presence of fibrotic lesions; other changes such as pleural thickening or isolated calcified granulomas are not related.

† Medical conditions and factors associated with increased risk for development of active disease in a patient with latent tuberculosis infection include silicosis, end-stage renal disease, malnutrition, diabetes mellitus, carcinoma of the head or neck and lung, immunosuppressive therapy, lymphoma, leukemia, weight loss of more than 10% ideal body weight, gastrectomy, and jejunoileal bypass.

Anyone infected with M. tuberculosis can develop TB disease, but certain groups are at higher-than-normal risk for progression to active disease (see Table 31-1). Patients who have been recently infected with M. tuberculosis and those with medical conditions associated with significant immunosuppression are at particularly high risk for development of TB. HIV co-infection is the strongest known risk factor for the development of TB and is estimated to increase the risk of progression to TB by 50- to 100-fold. Inhibitors of tumor necrosis factor-α (TNF-α) may increase the risk for development of TB by up to 10-fold, and patients taking TNF-α blockers frequently present with disseminated disease. This association appears to be stronger for infliximab and adalimumab than for etanercept. Other medical conditions are associated with a more modest increase in risk for development of disease.

Pathogenesis

TB is spread from person to person almost exclusively through the air by droplet nuclei, which are particles 1 to 5 µm in diameter that contain viable tubercle bacilli. Droplet nuclei are expelled into the air when patients with infectious TB create an aerosol by talking, coughing, or singing. Three factors determine the likelihood of transmitting TB: the number of bacilli expelled into the air, the concentration of organisms in the air, and the duration of contact with (i.e., breathing of) the infected air. Whether an inhaled tubercle bacillus establishes an infection in the exposed person’s lung depends on both bacterial virulence and host immune defenses.

The tubercle bacillus grows slowly, dividing approximately every 18 to 24 hours. Tubercle bacilli spread through the lymphatics to the hilar lymph nodes or through the bloodstream. Small numbers of bacilli are deposited in other organs, which may then become sites of extrapulmonary disease. An adaptive immune response occurs after 2 to 8 weeks.

Once cell-mediated immunity develops, collections of activated T cells and macrophages form granulomas that wall off the mycobacterial organisms (Figure 31-2). For most persons with normal immune function, infection with M. tuberculosis seems to be arrested once cell-mediated immunity develops, even though small numbers of viable bacilli remain within the granuloma. Although a primary complex can sometimes be seen on chest radiograph, most TB infections are asymptomatic and can be detected only indirectly with a tuberculin skin test (TST) or interferon-γ release assay (IGRA). Persons with “walled-off” TB infection who do not have active disease are not infectious and thus cannot spread the disease to others.

Figure 31-2 Caseating granuloma in lung tissue. This lung biopsy specimen contains a caseating granuloma. The large arrow highlights the caseous center. The smaller arrows point out giant cells, typical of granulomatous inflammation.

If cell-mediated immunity does not contain the tubercle bacilli, the initial infection progresses to active disease. Without treatment, infected persons have approximately a 5% chance of developing TB in the first 1 to 2 years after infection and an additional 5% chance of developing TB during the remainder of their lifetime (Figure 31-3). By contrast, persons who are co-infected with HIV have a 5% to 10% annual risk of active disease developing. When active TB develops soon after infection, the disease is referred to as primary TB. By contrast, when TB develops years or even decades after the initial infection, the disease is referred to as postprimary or reactivation disease. Exogenous reinfection, involving acquisition of a second strain of M. tuberculosis, also can lead to disease and seems to be more common in HIV-infected patients.

Figure 31-3 Pathogenesis of tuberculosis. After exposure to an infectious case of tuberculosis, approximately 30% of close contacts become infected with Mycobacterium tuberculosis. Of the contacts who become infected, approximately 5% will develop active tuberculosis in the first year after infection and an additional 5% will develop active tuberculosis over the course of their lifetime. Therefore, approximately 90% of infected people will not develop tuberculosis. When tuberculosis is introduced into an HIV-infected population, its pathogenesis is altered. Although susceptibility is difficult to establish conclusively, HIV-infected people appear to be more susceptible to initial infection than HIV-negative contacts. In outbreak settings, approximately 40% of HIV-infected contacts develop tuberculosis within the first year of exposure. After tuberculosis infection, HIV-infected people develop active tuberculosis at a rate of 5% to 10% per year. HIV, human immunodeficiency virus.

Genetics

Both susceptibility and resistance to developing TB have long been thought to have a genetic component. Epidemiologic and genetic studies, including those in animal and human models, support this hypothesis. Recent investigations of specific candidate genes and genome-wide scans have identified people at increased risk for TB. Although polymorphisms in more than 10 genes have been associated with active TB, only polymorphisms in the human leukocyte antigen (HLA)-DR molecules and in the genes for the vitamin D₃ receptor, SCL11A-1, IFN-γ promoter, and mannose-binding lectin all have been associated with increased susceptibility to M. tuberculosis. Because each association has been relatively modest at the individual level, the genetic susceptibility is likely to be polygenic in nature. Ultimately, whether an individual with TB infection progresses to disease will depend on the interplay among host, infecting organism, and environment.

Clinical Features

The clinical manifestations of TB are protean. Patterns of disease vary depending on whether the disease is primary or reactivation in nature, the host’s immune status, and possibly the strain of M. tuberculosis. Of note, the clinical features of active TB are the result of a balance between host defenses and bacterial virulence; therefore, a continuum of disease is likely, and the clinical presentation of disease may be altered in severely immunocompromised patients. Most patients initially are seen with pulmonary disease, which is classically divided into primary disease and postprimary disease.

Pulmonary Tuberculosis

The initial infection in the lung, referred to as primary infection, causes formation of an inflammatory infiltrate, which may be seen on a chest radiograph, often in the middle or lower lung zones. The draining lymph nodes may enlarge and compress adjacent bronchi, particularly in infants and children. Parenchymal disease usually clears as cell-mediated immunity develops, and it tends to clear more rapidly than nodal involvement. If the parenchymal disease persists beyond the development of cell-mediated immunity, cavitation may occur, although this finding is uncommon. Pleural effusions are a common manifestation of primary TB and presumably result when a peripheral, caseous focus ruptures into the pleural space (Figure 31-4). Pleuritis caused by TB may manifest as an acute illness characterized by cough, fever, and pleuritic chest pain.

Figure 31-4 Primary tuberculosis in a young adult. The chest radiograph demonstrates a large, left-sided pleural effusion (arrows).

During most initial infections with M. tuberculosis, small numbers of organisms are disseminated hematogenously, and some become seeded in the apices of the lung. The organisms seem to grow preferentially in this well-oxygenated environment, with progression to active disease occurring months or years after the initial infection. This accounts for the characteristic radiographic location of reactivation disease, which in most cases occurs in the apical or posterior segments of the upper lobes (Figure 31-5). In areas of chronic infection or areas of caseation, fibrosis may occur. Fibrocaseous lesions may contain live mycobacteria for many years, and these are the lesions that may reactivate years later.

Figure 31-5 Postprimary tuberculosis. The chest radiograph shows upper lobe air space opacities with cavitation. Bronchial spread of the infection is evident in the lower lung zones.

Miliary Tuberculosis

Miliary or disseminated TB occurs when tubercle bacilli spread throughout the body, through the bloodstream, resulting in small (approximately 1 to 2 mm) granulomatous lesions. Miliary TB is seen more commonly in infants, children less than 4 years old, and in immunocompromised people. Disease can result from early dissemination after infection or later after reactivation and dissemination. Disseminated TB usually develops insidiously with systemic symptoms such as fever, weakness, weight loss, fatigue, and anorexia. Cough and dyspnea also may be prominent symptoms. The mean duration of symptoms approaches 16 weeks, but some patients may go undiagnosed for more than 2 years. The chest radiograph typically shows the classic “miliary” pattern of diffuse small nodules (Figure 31-6). Sputum AFB smears are positive in 20% to 25% of cases, and sputum is culture-positive for M. tuberculosis in up to 65% of cases. Bronchoscopy should be considered in patients who are unable to produce sputum or who have produced negative sputum smears. Other potential sources include urine, which is culture-positive in up to 25% of patients, and liver and bone marrow, which are culture-positive in up to 25% to 40%.

Figure 31-6 Miliary tuberculosis in an older child. The chest radiograph demonstrates diffuse small nodules 2 to 3 mm in diameter. The patient was diagnosed with disseminated tuberculosis with meningitis.

Diagnosis

To diagnose TB, the disease must first be suspected. TB should be suspected in certain high-risk groups reviewed previously (see Table 31-1) and when the clinical and/or radiographic presentation is consistent with TB. The medical history should elicit whether or not the person suspected of having TB has been exposed to M. tuberculosis or has a previous history of TB infection or disease. Symptoms at presentation will vary depending on the sites(s) of involvement and extent of disease as described previously. Guidelines suggest that all persons with an unexplained cough lasting 2 to 3 weeks or more be evaluated for TB. Of note, up to 20% of patients with pulmonary disease are asymptomatic. Findings at physical examination are rather nonspecific and will vary, depending on the site of involvement. Among HIV-infected patients, TB should be considered when any respiratory infection or fever of unknown origin occurs, because the risk for TB in this group is substantially elevated, and signs and symptoms of TB often are atypical.

Radiographic Examinations

Plain chest radiography is a sensitive but nonspecific test to detect pulmonary TB. Radiographic manifestations of TB vary, depending on whether the patient has primary or postprimary TB and whether co-infection with HIV is present. Patients who have primary pulmonary TB at initial evaluation may demonstrate radiographic opacities in the lower lung zones and an associated pleural effusion (see Figure 31-4). TB caused by reactivation typically involves the apical and posterior segments of the upper lobes or superior segment of the lower lobe (see Figure 31-5). Cavitation and volume loss are common in reactivation disease but unusual in primary disease. Findings on the chest radiograph in patients co-infected with HIV depend on the severity of immunosuppression. Early in the course of HIV disease, the radiograph may show a typical reactivation pattern with cavitation (Figure 31-7), but as the CD4⁺ cell count declines, the radiographic appearance is more like the pattern seen in primary TB (Figure 31-8). Patients co-infected with HIV may sometimes have a normal-appearing chest radiograph despite being sputum AFB smear–positive.

Figure 31-7 Tuberculosis in a human immunodeficiency virus (HIV)-infected patient. The chest radiograph demonstrates a left upper lobe cavitary process (large arrow). In addition, bilateral hilar adenopathy and aortopulmonary window adenopathy (small arrows) are evident.

Figure 31-8 Primary-type presentation of tuberculosis in a human immunodeficiency virus (HIV)-infected patient. The chest radiograph demonstrates right lower lobe and right middle lobe air space consolidation with likely right hilar and paratracheal adenopathy.

Bacteriologic Examination

Sputum Microscopy

Diagnosis of pulmonary TB begins with obtaining two or three spontaneously expectorated sputum samples collected at 8- to 24-hour intervals, with at least one collected in early morning. Two methods are commonly used for acid-fast staining: the carbolfuchsin methods (Ziehl-Neelsen and Kinyoun methods) and a fluorochrome procedure that uses auramine O or auramine-rhodamine dyes (Figure 31-9).

Figure 31-9 Acid-fast stain in tissue showing Mycobacterium tuberculosis. (Ziehl-Neelsen stain.)

Approximately 5,000 to 10,000 bacilli/mL are necessary to allow detection of these organisms in stained smears. The sensitivity of sputum AFB smears ranges from 50% to 80%, depending on the extent of disease; patients with cavitary disease are more likely than those without cavities to expectorate tubercle bacilli. Light-emitting diode (LED)–based fluorescence microscopy allows for more rapid evaluation of specimens and may increase the sensitivity slightly over that for conventional light microscopy. If patients are unable to produce sputum or have negative sputum smears, additional diagnostic tests may be indicated. In such circumstances, either sputum induction or biopsy using fiberoptic bronchoscopy (FOB) may provide adequate specimens. Studies suggest that sputum induction with hypertonic saline and FOB with bronchoalveolar lavage produce similar yields in smear-negative cases. The primary role of FOB is in smear-negative HIV-infected TB suspects, in whom this technique also can help identify alternative causes of the illness.

Mycobacterial Cultures and Identification

Culture of M. tuberculosis remains the “gold standard” modality for diagnosis of TB, and isolation of the organism is necessary for drug susceptibility testing and genotyping. Thus, all clinical specimens suspected of containing mycobacteria should be inoculated onto culture media. There are three different types of traditional culture media: egg-based (Lowenstein-Jensen or Ogawa), agar-based (Middlebrook 7H10 or 7H11), and liquid (Middlebrook 7H12) media. Growth in the liquid media is faster than that in solid media, and automated commercial broth systems allow for growth detection within 1 to 3 weeks compared with solid media, for which growth takes 3 to 8 weeks. However, solid media allow for observation of colony morphology and the detection of mixed infections. Because only 10 to 100 organisms are required to detect M. tuberculosis, cultures are more sensitive than smears, with reported sensitivity ranging from 80% to 93%. The tubercle bacilli can be identified from cultures and distinguished from NTM species by chemical means or with molecular methods.

Molecular Assays

Nucleic acid amplification assays (NAAs) amplify and detect M. tuberculosis–specific nucleic acid sequences in clinical specimens within 24 to 48 hours. Two U.S. Food and Drug Administration (FDA)-approved NAAs are available in the United States: the AMPLICOR M. tuberculosis

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