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

* 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.

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.

Extrapulmonary Tuberculosis

As tubercle bacilli spread throughout the body during the initial infection, they can lodge in any organ and produce a focus of disease. Approximately 17% of HIV-uninfected patients with TB have an extrapulmonary form of disease only. An extrapulmonary site of infection is more likely to develop in HIV-infected patients than in HIV-seronegative persons, and the risk of extrapulmonary TB increases as the CD4⁺ lymphocyte count decreases. The two most commonly involved extrapulmonary sites are peripheral lymph nodes and the pleura, but any site or organ can be involved. Other common sites for extrapulmonary TB are within well-vascularized areas such as the kidney, the meninges, the spine, and the growing ends of long bones.

Tuberculous Lymphadenitis (Scrofula)

Lymphadenitis is the most common form of extrapulmonary TB, accounting for approximately 25% of extrapulmonary disease. Lymphadenitis usually manifests as a painless, erythematous, firm mass most commonly involving the anterior and posterior cervical nodes or supraclavicular fossa. In HIV-uninfected people, the mass usually is unilateral, not associated with other sites, and systemic symptoms are absent. However, in HIV-infected patients, tuberculous lymphadenitis often is associated with multifocal disease and systemic symptoms. Without treatment, the mass will enlarge and a fistulous tract may develop.

Diagnosis of tuberculous lymphadenitis usually involves fine needle aspiration or excisional biopsy with histopathologic examination, examination for acid-fast organisms, and culture for mycobacteria. Histopathologic evidence of mycobacterial infection, including caseating granulomas, is seen in nearly all cases, but the smear is positive in only approximately 25% to 50% of cases and the culture in approximately 70% to 80%.

Pleural Tuberculosis

Pleurisy usually is a manifestation of primary TB and results when a subpleural caseous focus ruptures into the pleural space. The resulting delayed-type hypersensitivity reaction produces pleural liquid that has a high protein concentration. Most patients are initially seen with chest pain, fever, and a nonproductive cough. If left untreated, the pleural effusion will resolve spontaneously over 2 to 4 months. The rate of reactivation, however, is approximately 65% within the next 5 years.

Diagnosis of tuberculous pleural disease begins with sampling of the pleural fluid. Early in the course of disease, the fluid may have a polymorphonuclear predominance, but in almost all cases, mononuclear cells become the majority. Cell counts typically are in the 100 to 5000 cells/µL range, and the cells are almost all lymphocytes; the presence of mesothelial cells and/or eosinophils makes the diagnosis of TB unlikely.

Pleural fluid AFB smears are seldom positive, and pleural fluid cultures are positive in only approximately 20% to 40% of cases. M. tuberculosis can be isolated from 30% to 50% of induced sputum specimens from patients with TB pleuritis; such specimens should therefore be obtained in all patients. Pleural biopsy specimens provide the highest diagnostic yield, with positive culture results in up to 80% to 90% of cases when at least three specimens are obtained. Thoracoscopic biopsies are nearly always diagnostic, but the procedure is invasive, costly, and often not available.

Other tests that may be helpful in the diagnosis of pleuritis are adenosine deaminase and interferon-γ (IFN-γ) assays. The enzyme marker adenosine deaminase has been shown to have high sensitivity but variable specificity. A recent metaanalysis suggested that pleural fluid IFN-γ concentration has sensitivity of 89% and specificity of 97% for pleural TB in HIV-uninfected patients. Sensitivity and specificity also are high in HIV-infected patients.

When faced with a lymphocytic exudative pleural effusion in a patient with a positive TST reaction or IGRA result, the clinician should strongly consider TB. Whether to start treatment empirically or proceed with a pleural biopsy will depend on the certainty of the diagnosis and whether or not the patient is at risk for drug-resistant TB. In the latter situation, pleural tissue should be obtained for smear and culture to direct drug susceptibility testing.

Genitourinary Tuberculosis

Genitourinary disease is responsible for approximately 15% of extrapulmonary cases of TB and can affect either the kidneys or genitals. Renal disease may manifest with local symptoms that include dysuria, hematuria, urinary frequency, and flank discomfort. In many cases, however, the patient may be asymptomatic. Urine examination may demonstrate sterile pyuria, hematuria, or both. M. tuberculosis can be isolated from urine in 80% to 95% of patients who provide three morning urine specimens for culture. In patients with pulmonary TB, urine cultures have been reported to be positive in approximately 5% of cases. An intravenous pyelogram may show evidence of destructive changes in the kidney or ureteral abnormalities such as strictures and hydronephrosis. Computed tomography (CT) often demonstrates renal enlargement with abscess formation.

Genital involvement is common in patients with renal TB. Men usually present with a slowly enlarging mass in the seminal vesicles, prostate, or epididymis. TB usually is diagnosed using fine needle aspiration or urine culture. In female patients, the fallopian tube is the primary site of involvement. Women tend to present with pelvic pain, abnormal uterine bleeding, irregular menses, amenorrhea, or infertility. Genital TB is diagnosed using urine culture and endometrial biopsy or curettage. Unfortunately, infertility is common even after successful treatment.

Bone and Joint Tuberculosis

Skeletal involvement is thought to arise from reactivation from foci that were seeded at the time of initial infection. The infection begins in the subchondral region of the bone and then spreads to cartilage, synovium, and joint space. Although weight-bearing bones are the most likely to be affected, any bone or joint may be involved. In most series, TB of the spine, or Pott’s disease, accounts for more than 50% of cases. In children, the upper thoracic spine is the most frequently affected site, whereas in adults, the lower thoracic and upper lumbar vertebrae typically are involved. After the spine, the hips and knees are the most common sites of skeletal TB.

Most patients initially are seen with pain in the involved joint. Systemic symptoms usually are absent, and delays in diagnosis are common. Tuberculous involvement of the joint usually is first suspected after a radiograph shows changes suggestive of the diagnosis. Typical findings include metaphyseal erosion and cysts, loss of cartilage, and narrowing of the joint space. In Pott’s disease, two vertebral bodies and the intervening joint space usually are involved. CT and/or magnetic resonance imaging (MRI) should be obtained to better define the pattern and extent of involvement. Confirmation of the diagnosis requires aspiration of joint fluid or of periarticular abscesses or biopsy of affected bone or synovium. Acid-fast smears are positive in 20% to 25% of joint fluid aspirates, with isolation of mycobacteria in 60% to 80%. Histopathologic evidence of granulomatous inflammation is almost always present in bone and synovial biopsy specimens.

Central Nervous System Tuberculosis

Meningitis is the most common form of central nervous system (CNS) TB, with tuberculomas occurring less commonly. Tuberculous meningitis, although less common than in the past, is still associated with the highest rates of morbidity and mortality for any form of TB, with a mortality rate of approximately 20%. Patients usually are initially seen with some combination of headache, abnormal behavior, confusion, fever, cranial nerve abnormalities, and occasionally seizures.

CT and MRI studies may provide evidence for a basilar meningitis or show hydrocephalus or tuberculous abscesses. To confirm the diagnosis, however, cerebrospinal fluid (CSF) must be sampled for examination and culture. CSF protein is usually elevated, and glucose concentration decreased. Very high protein concentrations are associated with a worse prognosis. White blood cell counts are elevated, with values of 100 to 1000 cells/µL, most of which are lymphocytes. As with pleural effusions, however, a polymorphonuclear predominance may be noted early in the disease. AFB smears of cerebrospinal fluid are positive in only 10% to 25% of cases, and cultures are positive in approximately 55% to 80%. An RD-1 antigen–specific ELISPOT assay in combination with other rapid tests (Gram staining and cryptococcal antigen assay) was reported to be a good “rule-in” test for TB meningitis, with a sensitivity of 82% and specificity of 100%.

Gastrointestinal Tuberculosis

Gastrointestinal disease is an uncommon manifestation of extrapulmonary TB, although it is more common in HIV-infected patients. Classically, ileocecal involvement and tuberculous peritonitis are the most common forms. Patients with ileocecal involvement may present with abdominal pain simulating appendicitis or intestinal obstruction. Diagnosis of ileocecal TB can be difficult and often is made at the time of surgery.

Tuberculous peritonitis often manifests with abdominal pain and swelling. Fever, weight loss, and anorexia are also common. Ascitic fluid usually is high in protein. Ascitic fluid white blood cell count typically is more than 150 cells/mm³ with a lymphocytic predominance. AFB smears are seldom positive, and cultures are positive in approximately 50% to 80% of cases; the higher yield has been reported when 1 L of fluid was cultured. Laparoscopic biopsy usually is required to make the diagnosis of peritoneal TB.

Pericardial Tuberculosis

Tuberculous pericarditis is a relatively uncommon manifestation of extrapulmonary TB. The clinical presentation is quite variable and determined by the stage of disease. Early in the clinical course, fever and chest pain may predominate. Some patients present with large-volume pericardial effusions and signs and symptoms of tamponade. Other patients present with constrictive pericarditis. The pericardial fluid usually is serosanguineous and occasionally grossly bloody. It typically is a lymphocytic exudative fluid with white blood cell counts in the range of 5000 to 7000 cells/µL, although counts up to 50,000 have been reported. AFB smears of the fluid are seldom positive, and cultures are positive in less than a third of cases. Often pericardial biopsy samples show histopathologic evidence consistent with a mycobacterial infection, but in some cases nonspecific inflammatory findings are described.

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.

Tuberculin Skin Test and Interferon-γ Release Assays

The TST (discussed in more detail later on), which uses purified protein derivative (PPD), is the most common way to identify persons with latent tuberculosis infection (LTBI) but should not be used in the diagnosis of active TB. In general, the sensitivity of the TST for detection of active TB ranges from 65% to 94%, but in critically ill patients with disseminated disease, the sensitivity decreases to only 50%. Thus, a negative TST reaction can never exclude a diagnosis of TB.

IGRAs measure the release of IFN-γ in whole blood in response to stimulation by M. tuberculosis antigens. Whole blood is incubated overnight with early secretory antigen target 6 [ESAT-6], culture filtrate protein 10 [CFP10], TB7.7, and control antigens; lymphocytes sensitized by previous exposure to M. tuberculosis release IFN-γ. IGRAs currently available include the QuantiFERON-TB (QFT-TB) Gold and QFT-TB Gold In-Tube (QFT-GIT), which measure IFN-γ in the serum using enzyme-linked immunosorbent assay (ELISA) (Cellestis Limited, Carnegie, Victoria, Australia) and the T-Spot.TB test, which uses enzyme-linked immunospot (ELISPOT) methodology (Oxford Immunotec, Oxford, United Kingdom) to identify IFN-γ–producing cells.

The reported sensitivity of QFT-GIT in patients with active TB has varied, ranging from 62% to 94%, with a pooled sensitivity of 80%, whereas the T-Spot.TB test has a sensitivity of 35% to 100%, with a pooled sensitivity of 81%. By contrast, the TST has a pooled sensitivity of 65% in patients with TB. Although the IGRAs have improved sensitivity compared with the TST, the values are still too low to rule out active TB with confidence, and neither test can differentiate latent from active TB.

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.

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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