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(See also Perinatal Tuberculosis on See also Infections in Neonates: Perinatal Tuberculosis (TB).)
Tuberculosis (TB) is a chronic, progressive infection with a period of latency following initial infection. It occurs most commonly in the lungs. Pulmonary symptoms include productive cough, chest pain, and dyspnea. Diagnosis is most often by sputum culture and smear. Treatment is with multiple antimicrobial drugs.
TB is a leading infectious cause of morbidity and mortality in adults worldwide, killing about 1.5 million people every year. HIV/AIDS is an increasingly prominent factor predisposing to TB infection and mortality in parts of the world where both infections are prevalent.
Etiology
TB properly refers only to disease caused by Mycobacterium tuberculosis. Similar disease occasionally results from the closely related mycobacteria, M. bovis, M. africanum, and M. microti.
TB results almost exclusively from inhalation of airborne particles (droplet nuclei) containing M. tuberculosis. They disperse primarily through coughing, singing, and other forced respiratory maneuvers by people who have active pulmonary TB and whose sputum contains a significant number of organisms (typically enough to render the smear positive). People with pulmonary cavitary lesions are especially infectious. Droplet nuclei containing tubercle bacilli may remain suspended in room air currents for several hours, increasing the chance of spread. However, once these droplets land on a surface, it is difficult to resuspend the organisms (eg, by sweeping the floor, shaking out bed linens) as respirable particles. Although such actions can resuspend dust particles containing tubercle bacilli, these particles are far too large to reach the alveolar surfaces necessary to initiate infection. Fomites (eg, contaminated surfaces, food, and personal respirators) do not appear to facilitate spread.
Although there is wide variability, patients with pulmonary TB infect about 7 close contacts, on average, but most of those infected do not develop active disease. Transmission is enhanced by frequent or prolonged exposure to a patient who is dispersing large numbers of tubercle bacilli in overcrowded, enclosed, poorly ventilated spaces; thus, people living in poverty or in institutions are at particular risk. Health care practitioners who have close contact with active cases have increased risk. However, once effective treatment begins, cough rapidly decreases, organisms are inactivated, and within weeks, TB is no longer contagious.
Much less commonly, spread results from aerosolization of organisms after irrigation of infected wounds, in mycobacteriology laboratories, or in autopsy rooms. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints was once commonly caused by ingestion of milk or milk products (eg, cheese) contaminated with M. bovis, but this transmission route has been largely eradicated in developed countries by slaughter of cows that test positive on a tuberculin skin test and by pasteurization of milk. Tuberculosis due to M. bovis still occurs in developing countries and in immigrants from developing countries where bovine tuberculosis is endemic (eg, some Latin American countries).
Risk factors
HIV infection is the greatest single medical risk factor because cell-mediated immunity, which is impaired by HIV, is essential for defense against TB; other immunosuppressive illnesses (eg, diabetes) or therapies (eg, tumor necrosis factor [TNF] inhibitors, corticosteroids) increase risk but less than HIV.
Age has traditionally been considered an independent risk factor because the elderly have more years of potential exposure and are more likely to have impaired immunity. However, in the US, the difference in the age-specific case rate is no longer as large, probably because the incidence of infectious cases (and hence lifetime risk of significant exposure) has declined.
Epidemiology
About one third of the world's population is infected. Of these, perhaps only 15 million have active disease at any given time. In 2006, an estimated 9.2 million new TB cases occurred worldwide (139/100,000). Of these, Africa and Southeast Asia each accounted for about 3 million cases, and the Western Pacific region for about 2 million. Case rates vary very widely by country, age, race, sex, and socioeconomic status. India and China reported the largest numbers of new cases, but South Africa has the largest case rate: 940/100,000.
In the US, the case rate has declined 10-fold since 1953. In 2007, 13,299 cases were reported to the CDC for a case rate of 4.4/100,000 (ranging from 0.4 in Wyoming to 10.2 in Washington DC). Over half of these cases occurred in patients born outside the US in high-prevalence areas. The TB rate among foreign-born people (20.7/100,000) was nearly 10 times the rate among US-born people (2.1/100,000). Blacks accounted for 45% of cases among the US-born. In the southeastern US and inner cities throughout the US, poor US-born blacks, the homeless, people in jails and prisons, and other disenfranchised minorities contribute disproportionately to the case rate. In such high-risk populations, case rates can approach those in high-burden parts of the world.
A resurgence of TB occurred in parts of the US and other developed countries between 1985 and 1992; it was associated with several factors, including HIV coinfection, homelessness, a deteriorated public health infrastructure, and the appearance of multidrug-resistant TB (MDR-TB). Although substantially controlled in the US by public health and institutional infection control measures, the problem of MDR-TB, including extensively drug-resistant TB (XDR-TB), appears to be growing around the world, fueled by poor treatment supervision, weak retreatment regimens, inadequate drug supplies, HIV coinfection, institutional transmission, and inadequate diagnostic laboratory facilities. Control efforts, including prolonged (eg, > 18 mo) use of 2nd-line antibiotics, treatment of adverse drug reactions, community-based supervision, social and emotional support, and improved institutional transmission control are raising hopes for better global control of MDR-TB. Treatment of XDR-TB has less favorable outcomes, and the mortality rate is extremely high in patients coinfected with HIV despite concomitant antiretroviral therapy.
Pathophysiology
Tubercle bacilli initially cause a primary infection, which only rarely causes acute illness. Most (about 95%) primary infections are asymptomatic and followed by a latent (dormant) phase. However, a variable percentage of latent infections subsequently reactivate with symptoms and signs of disease. Infection is usually not transmissible in the primary stage and is never contagious in the latent stage.
Primary infection
Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lung, usually in the subpleural airspaces of the lower lung. Large droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single initial focus.
To initiate infection, tubercle bacilli must be ingested by alveolar macrophages. Tubercle bacilli that are not killed by the macrophages actually replicate inside them, ultimately killing the host macrophage (with the help of CD8 lymphocytes); inflammatory cells are attracted to the area, causing a focal pneumonitis that evolves into the characteristic tubercles seen histologically. In the early weeks of infection, some infected macrophages migrate to regional lymph nodes (eg, hilar, mediastinal), where they access the bloodstream. Organisms may then spread hematogenously to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges.
In 95% of cases, after about 3 wk of uninhibited growth, the immune system suppresses bacillary replication before symptoms or signs develop. Foci of infection in the lung or other sites resolve into epithelioid cell granulomas, which may have caseous and necrotic centers. Tubercle bacilli can survive in this material for years; the balance between the host's resistance and microbial virulence determines whether the infection ultimately resolves without treatment, remains dormant, or becomes active. Infectious foci may leave fibronodular scars in the apices of one or both lungs (Simon foci), calcified scars from the primary infection (Ghon foci), or calcified hilar lymph nodes. The tuberculin skin test (see Mycobacteria: Skin testing) and the newer interferon-γ release assay become positive.
Less often, the primary focus immediately progresses, causing acute illness with pneumonia (sometimes cavitary), pleural effusion, and marked mediastinal or hilar lymph node enlargement (which, in children, may compress bronchi). Small pleural effusions are predominantly lymphocytic, typically contain few organisms, and clear within a few weeks. This sequence may be more common among young children and recently infected or reinfected immunosuppressed patients. Extrapulmonary TB at any site can sometimes manifest without evidence of lung involvement. TB lymphadenopathy is the most common extrapulmonary presentation; however, meningitis is the most feared because of its high mortality in the very young and very old.
Active disease
In about 10% of immunocompetent patients, latent infection develops into active disease, although the percentage varies significantly by age and other risk factors. In 50 to 80% of those who develop active disease, TB reactivates within the first 2 yr, but it can occur decades later. Any organ initially seeded may become a site of reactivation, but reactivation occurs most often in the lung apices, presumably because of favorable local conditions such as high O2 tension. Ghon foci and affected hilar lymph nodes are much less likely to be sites of reactivation.
Conditions that facilitate activation include impaired immunity (particularly HIV infection), certain immunosuppressants (eg, corticosteroids, infliximab, other TNF inhibitors), gastrectomy, jejunoileal bypass surgery, silicosis, renal insufficiency, stress, diabetes, head or neck cancer, significant weight loss, adolescence, and advanced age (particularly > 70 yr).
TB damages tissues through delayed-type hypersensitivity (DTH—see Allergic, Autoimmune, and Other Hypersensitivity Disorders: Type IV), typically producing granulomatous necrosis with a caseous histologic appearance. Lung lesions are characteristically but not invariably cavitary, especially in immunosuppressed patients with impaired DTH. Pleural effusion is less common than in progressive primary TB but may result from direct extension or hematogenous spread. Rupture of a large tuberculous lesion into the pleural space may cause empyema with or without bronchopleural fistula and sometimes causes pneumothorax. In the prechemotherapy era, TB empyema sometimes complicated medically induced pneumothorax therapy and was usually rapidly fatal, as was sudden massive hemoptysis due to erosion of a pulmonary artery by an enlarging cavity.
The course varies greatly, depending on the virulence of the organism and the state of host defenses. The course may be rapid among blacks, American Indians, and other populations who have not had as many centuries of selective pressure to develop innate or natural immunity as descendents of the European and American TB epidemics have had. The course is often more indolent in the latter populations.
Acute respiratory distress syndrome (ARDS), which appears to be due to hypersensitivity to TB antigens, develops rarely after diffuse hematogenous spread or rupture of a large cavity with spillage into the lungs.
Symptoms and Signs
In active pulmonary TB, even moderate or severe disease, patients may have no symptoms, except “not feeling well,” anorexia, fatigue, and weight loss, which develop gradually over several weeks, or they may have more specific symptoms. Cough is most common. At first, it may be minimally productive of yellow or green sputum, usually on rising, but cough may become more productive as the disease progresses. Hemoptysis occurs only with cavitary TB (sometimes due to fungal growth in a cavity). Low-grade fever is common but not invariable. Drenching night sweats are a classic symptom but are neither common in nor specific for TB. Dyspnea may result from lung parenchymal damage, spontaneous pneumothorax, or pleural TB with effusion.
With HIV coinfection, the clinical presentation is often atypical because DTH is impaired; patients are more likely to have symptoms of extrapulmonary or disseminated disease.
Diagnosis
Pulmonary TB is often suspected based on chest x-rays taken while evaluating respiratory symptoms (cough > 3 wk, hemoptysis, chest pain, dyspnea), an unexplained illness, FUO, or a positive tuberculin skin test (see Mycobacteria: Skin testing).
Initial tests are chest x-ray, sputum examination, and tuberculin skin testing. If the chest x-ray is highly characteristic (upper lobe lung cavitation) in patients with TB risk factors, sputum examination is still required, but skin testing is often not done.
Chest x-ray
In adults, a multinodular infiltrate above or behind the clavicle (the most characteristic location, most visible in an apical-lordotic view or with CT) suggests reactivation of TB. Middle and lower lung infiltrates are nonspecific but should prompt suspicion of primary TB in patients (usually young) whose symptoms or exposure history suggests recent infection, particularly if there is pleural effusion. Calcified hilar nodes may be present; they may result from primary TB infection but also may result from histoplasmosis in areas where histoplasmosis is endemic (eg, the Ohio River Valley).
Sputum examination
Sputum is tested for the presence of acid-fast bacilli (AFB). Tubercle bacilli are nominally gram-positive but take up Gram stain inconsistently; samples are best prepared with Ziehl-Neelsen or Kinyoun stains for conventional light microscopy or fluorochrome stains for fluorescent microscopy.
If patients cannot produce sputum spontaneously, aerosolized hypertonic saline can be used to induce it. If induction is unsuccessful, bronchial washings, which are particularly sensitive, can be obtained by fiberoptic bronchoscopy. Because induction of sputum and bronchoscopy entail some risk of infection for medical staff, these procedures should be done as a last resort in selected cases when MDR-TB is not likely. Appropriate precautions (eg, negative-pressure room, N-95 or other fitted respirators) should be used.
In addition to acid-fast staining, sputum can be tested using nucleic acid amplification techniques (NAAT) for TB; this test can shorten the time needed to diagnose TB from 1 to 2 wk to 1 to 2 days. However, in low-prevalence situations, this test is usually done only on smear-positive specimens. It is approved for smear-negative specimens and is indicated when suspicion is high and a rapid diagnosis is essential for medical or public health reasons.
If NAAT and AFB smear results are positive, patients are presumed to have TB and treatment can be started. If the NAAT result is positive and the AFB smear result is negative, an additional specimen is tested using NAAT; patients can be presumed to have TB if ≥ 2 specimens are NAAT-positive. If NAAT and AFB smear results are negative, clinical judgment is used to determine whether to begin anti-TB treatment while awaiting results of culture.
The finding of acid-fast bacilli in a sputum smear is strong presumptive evidence of TB, but definitive diagnosis requires a positive sputum culture or NAAT. Culture is also required for isolating bacteria for drug-susceptibility testing and genotyping.
Drug susceptibility tests (DSTs) should be done on initial isolates from all patients to identify an effective anti-TB regimen. These tests should be repeated if patients continue to produce culture-positive sputum after 3 mo of treatment or if cultures become positive after a period of negative cultures. Results of DSTs may take up to 8 wk if conventional bacteriologic methods are used. However, several new molecular DSTs can detect drug resistance in a sputum sample within hours.
Tests of other specimens
Transbronchial biopsies can be done on infiltrative lesions, and samples are submitted for culture, histologic evaluation, and molecular testing. Gastric washings, which are culture-positive in a minority of samples, are no longer commonly used except in small children, who usually cannot produce a good sputum specimen. Ideally, biopsied samples of other tissue should be cultured fresh, but NAAT can be used for fixed tissues (eg, for biopsied lymph node if histologic examination unexpectedly detects granulomatous changes). The latter use of NAAT has not been approved but can be extremely useful, although positive and negative predictive values have not been established.
Skin testing
Multiple-puncture devices (tine test) are no longer recommended. The tuberculin skin test (TST; Mantoux or PPD—purified protein derivative) is usually done, although it is a test of infection, latent or active, and is not diagnostic of active disease. The standard dose in the US of 5 tuberculin units (TU) of PPD in 0.1 mL of solution is injected on the volar forearm. It is critical to give the injection intradermally, not subcutaneously. A well-demarcated bleb or wheal should result immediately. The diameter of induration (not erythema) transverse to the long axis of the arm is measured 48 to 72 h after injection. Recommended cutoff points for a positive reaction depend on the clinical setting:
Results can be falsely negative, most often in patients who are febrile, elderly, HIV-infected (especially if CD4+ count is < 200 cells/μL), or very ill, many of whom show no reaction to any skin test (anergy). Anergy probably occurs because inhibiting antibodies are present or because so many T cells have been mobilized to the disease site that too few remain to produce a significant skin reaction.
Other tests
New blood tests based on the release of interferon-γ by lymphocytes exposed in vitro to TB-specific antigens are now available and are likely to soon replace the TST for routine testing for TB infection. Although results of interferon-γ release assays (IGRAs) are not always concordant with TST, these tests appear to be as sensitive as and more specific than TST in contact investigations. Importantly, they are often negative in patients with remote TB infection. Long-term studies are being done to see whether TST-positive, IGRA-negative patients (particularly those with immunosuppression) are at low risk of reactivation.
Prognosis
In immunocompetent patients with drug-susceptible pulmonary TB, even severe disease and large cavities usually resolve if appropriate therapy is instituted and completed. Still, TB causes or contributes to death in about 10% of cases, often in patients who are debilitated for other reasons. Disseminated TB and TB meningitis may be fatal in up to 25% of cases despite optimal treatment.
TB is much more aggressive in immunocompromised patients and, if not appropriately and aggressively treated, may be fatal in as little as 2 mo from its initial symptom, especially with MDR-TB, in which mortality can approach 90%. With effective antiretroviral therapy (and appropriate anti-TB treatment), the prognosis for immunocompromised patients, even with MDR-TB, may approach that of immunocompetent patients. However, poorer outcomes should be expected for patients with XDR-TB because there are so few effective drugs.
Treatment
Most patients with uncomplicated TB and all patients with complicating illnesses (eg, AIDS, hepatitis, diabetes), adverse drug reactions, or drug resistance should be referred to a TB specialist. (See also the Joint Statement from the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America: Treatment of Tuberculosis.) However, most TB can be fully treated at home with instructions on how to avoid spreading disease; these measures include
Surgical face masks for TB patients are stigmatizing and are generally not recommended for cooperative patients. For drug-susceptible TB that is being treated effectively, precautions must be continued for at least 2 wk in or outside the hospital. For patients with MDR-TB and XDR-TB, response to treatment may be slower, and the consequences of transmission greater; thus, precautions are continued longer, until there is clear evidence of treatment response.
Hospitalization
The main indications for hospitalization are
Initially, all hospitalized patients should be in respiratory isolation, ideally in a negative-pressure room with 6 to 12 air changes/h. Anyone entering the room should wear a respirator (not a surgical mask) that has been appropriately fitted and that meets National Institute for Occupational Safety and Health certification (N-95 or greater). Because risk of exposing other hospitalized patients is high, release from respiratory isolation usually requires 3 negative sputum smears over 2 days, including at least one early-morning negative specimen.
Public health considerations
To improve treatment adherence, ensure cure, and limit transmission and the development of drug-resistant strains, public health programs closely monitor treatment, even if patients are being treated by a private physician. In most states, TB care (including skin testing, chest x-rays, and drugs) is available free through public health clinics to reduce barriers to treatment.
Increasingly, optimal patient case management includes supervision by public health personnel of the ingestion of every dose of drug, a strategy known as directly observed therapy (DOT). DOT increases the likelihood that the full treatment course will be completed from 61% to 86% (91% with enhanced DOT, in which incentives and enablers such as transportation vouchers, child care, outreach workers, and meals are provided). DOT is particularly important
In some programs, selective self-administered treatment (SAT) is an option for patients who are committed to treatment; ideally, fixed-dose combination drug preparations are used to avoid the possibility of monotherapy, which can lead to drug resistance. Mechanical drug monitors have been advocated to improve adherence with SAT.
Public health departments usually visit homes to evaluate potential barriers to treatment (eg, extreme poverty, unstable housing, child care problems, alcoholism, mental illness) and to check for other active cases and close contacts. Close contacts are people who share the same breathing space for prolonged periods, typically household residents, but often include people at work, school, and places of recreation. The precise duration and degree of contact that constitutes risk vary because TB patients vary greatly in infectiousness. For patients who are highly infectious as evidenced by multiple family members with disease or positive skin tests, even relatively casual contacts (eg, passengers on the bus they ride) should be referred for skin testing and evaluation for latent infection (see Mycobacteria: Screening); patients who do not infect any household contacts are less likely to infect casual contacts.
First-line drugs
The first-line drugs isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) are used together in initial treatment (for regimens and doses, see Mycobacteria: Treatment regimens and Table 1: Mycobacteria: Dosing of First-Line Anti-TB Drugs* ).
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Table 1
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| Dosing of First-Line Anti-TB Drugs* |
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Drug
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Adults or Children
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Daily†
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Once/wk
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2 Times/wk
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3 Times/wk
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Isoniazid
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Adults (maximum)
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5 mg/kg (300 mg)
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15 mg/kg (900 mg)
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15 mg/kg (900 mg)
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15 mg/kg (900 mg)
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Children (maximum)
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10–15 mg/kg (300 mg)
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N/A
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20–30 mg/kg (900 mg)
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N/A
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Rifampin
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Adults (maximum)
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10 mg/kg (600 mg)
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N/A
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10 mg/kg (600 mg)
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10 mg/kg (600 mg)
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Children (maximum)
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10–20 mg/kg (600 mg)
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N/A
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10–20 mg/kg (600 mg)
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N/A
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Rifabutin
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Adults (maximum)
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5 mg/kg (300 mg)
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N/A
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5 mg/kg (300 mg)
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5 mg/kg (300 mg)
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Children
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Dosing unknown
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N/A
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N/A
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N/A
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Rifapentine‡
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Adults
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N/A
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10 mg/kg (600 mg)
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N/A
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N/A
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Children
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N/A
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N/A
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N/A
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N/A
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Pyrazinamide
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Adults (whole tablets):
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40–55 kg
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1 g
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N/A
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2 g
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1.5 g
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56–75 kg
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1.5 g
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N/A
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3 g
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2.5 g
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≥ 76 kg§
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2 g
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N/A
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4 g
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3 g
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Children (maximum)
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15–30 mg/kg (2 g)
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N/A
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50 mg/kg (2 g)
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N/A
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Ethambutol
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Adults (whole tablets):
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40–55 kg
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800 mg
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N/A
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2000 mg
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1200 mg
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56–75 kg
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1200 mg
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N/A
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2800 mg
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2000 mg
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≥ 76 kg§
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1600 mg
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N/A
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4000 mg
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2400 mg
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Children (maximum)
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15–20 mg/kg (1 g)
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N/A
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50 mg/kg (2.5 g)
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N/A
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*Specific regimens are discussed in text.
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†Daily is considered either 5 or 7 days/wk. All dosing < 7 days/wk must be given as directly observed therapy.
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‡Continuation phase only.
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§Maximum dose.
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N/A = not applicable.
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INH is given orally once/day, has good tissue penetration (including CSF), and is highly bactericidal. It remains the single most useful and least expensive drug for TB treatment. However, inconsistent drug levels and decades of uncontrolled use (often as monotherapy) in many countries (especially in East Asia) have greatly increased the percentage of resistant strains. In the US, about 10% of isolates are INH-resistant. INH is safe during pregnancy.
Adverse reactions include rash, fever, and, rarely, anemia and agranulocytosis. INH causes harmless, transient aminotransferase elevations in up to 20% of patients and symptomatic (usually reversible) hepatitis in about 1/1000 (more often in patients > 35 yr, alcoholics, postpartum women, and patients with chronic liver disease). Monthly liver function testing is not recommended unless patients have risk factors for liver disease. Patients with unexplained fatigue, anorexia, nausea, vomiting, or jaundice may have hepatic toxicity; treatment is suspended and liver function tests are obtained. Those with symptoms and any significant aminotransferase elevation (or asymptomatic elevation > 5 times normal) by definition have hepatic toxicity, and INH is stopped. After recovery from mild aminotransferase elevations and symptoms, patients can be safely challenged with a half-dose for 2 to 3 days. If this dose is tolerated (typically in about half of patients), the full dose may be restarted with close monitoring for symptoms and liver function deterioration. If patients are receiving INH, RIF, and PZA, all drugs must be stopped, and the challenge done with each drug separately. INH or PZA, rather than RIF, is the more likely cause of hepatotoxicity. Peripheral neuropathy can result from INH-induced pyridoxine (vitamin B6) deficiency, most likely in pregnant or breastfeeding women, undernourished patients, patients with diabetes mellitus or HIV infection, alcoholics, patients with cancer or uremia, and the elderly. A daily dose of pyridoxine 25 to 50 mg can prevent this complication, although pyridoxine is usually not needed in children and healthy young adults. INH delays hepatic metabolism of phenytoin, requiring dose reduction. INH can also cause a violent reaction to disulfiram, a drug occasionally used for alcoholism.
RIF, given orally, is bactericidal, is well absorbed, penetrates well into cells and CSF, and acts rapidly. It also eliminates dormant organisms in macrophages or caseous lesions that can cause late relapse. Thus, RIF should be used throughout the course of therapy. Adverse effects include cholestatic jaundice (rare), fever, thrombocytopenia, and renal failure. RIF adds only slightly to the hepatotoxicity of INH. RIF has many significant drug interactions. It accelerates metabolism of anticoagulants, oral contraceptives, corticosteroids, digitoxin, oral antihyperglycemic drugs, methadone, and many other drugs. The interactions of rifamycins and many antiretroviral drugs is particularly complex; combined use requires specialized expertise. RIF is safe during pregnancy.
The following newer rifamycins are available for special situations:
PZA is an oral bactericidal drug. When used during the intensive initial 2 mo of treatment, it shortens therapy to 6 mo and prevents development of resistance to RIF.
Its major adverse effects are GI upset and hepatitis. It often causes hyperuricemia, which is generally mild and only rarely induces gout. It is contraindicated in pregnancy. PZA plus rifampin is no longer recommended as a 2-mo regimen for latent TB because excessive hepatotoxicity can occur.
EMB is given orally and is the best tolerated of the first-line drugs. Its main toxicity is optic neuritis, which is more common at higher doses (eg, 25 mg/kg) and in patients with impaired renal function. Patients present initially with an inability to distinguish blue from green, followed by impairment of visual acuity. Because both symptoms are reversible if detected early, patients should have a baseline test of visual acuity and color vision and should be questioned monthly regarding their vision. Caution is warranted if communication is limited by language and cultural barriers. For similar reasons, EMB is usually avoided in young children who cannot read eye charts but can be used if needed because of drug resistance or drug intolerance. Another drug is substituted for EMB if optic neuritis occurs. EMB can be used safely during pregnancy. Resistance to EMB is less common than that to the other first-line drugs.
Second-line drugs
Other antibiotics are active against TB and are used primarily when patients have MDR-TB or do not tolerate one of the first-line drugs. The 2 most important classes are aminoglycosides (and the closely related polypeptide drug, capreomycin) and fluoroquinolones.
Streptomycin, the most commonly used aminoglycoside, is very effective and bactericidal. Resistance is still relatively uncommon in the US but is more common globally. CSF penetration is poor, and intrathecal administration should not be used if other effective drugs are available.
Dose-related adverse effects include renal tubular damage, vestibular damage, and ototoxicity. The dose is about 15 mg/kg IM (maximum: usually 1 g for adults, reduced to 0.75 g [10 mg/kg] for those ≥ 60 yr). To limit dose-related adverse effects, clinicians give one dose only 5 days/wk for > 2 mo. Then it may be given twice/wk for another 2 mo if necessary. In patients with renal insufficiency, dosing frequency should be reduced (eg, 12 to 15 mg/kg/ dose 2 or 3 times/wk). Patients should be monitored with appropriate testing of balance, hearing, and serum creatinine levels. Adverse effects include rash, fever, agranulocytosis, and serum sickness. Flushing and tingling around the mouth commonly accompany injection but subside quickly. Streptomycin is contraindicated during pregnancy because it may damage the 8th cranial nerve in the fetus.
Kanamycin and amikacin may remain effective even if streptomycin resistance has developed. Their renal and neural toxicities are similar to those of streptomycin.
Capreomycin, a related nonaminoglycoside parenteral bactericidal drug, has dosage, effectiveness, and adverse effects similar to those of aminoglycosides. It is an important drug for MDR-TB because isolates resistant to streptomycin are often susceptible to capreomycin, and it is somewhat better tolerated than aminoglycosides when prolonged administration is required.
Some fluoroquinolones (levofloxacin, moxifloxacin) are the most active and safest TB drugs after INH and RIF, but they are not first-line drugs for TB susceptible to INH and RIF. Moxifloxacin appears to be as active as INH when used with RIF.
Other 2nd-line drugs include ethionamide, cycloserine, and para-aminosalicylic acid (PAS). These drugs are less effective and more toxic than the first-line drugs but are essential in treatment of MDR-TB.
Drug resistance
Treatment with any single antibiotic always results in survival of a very few (about 1 in a million) organisms that have acquired spontaneous resistance mutations. Incomplete or erratic therapy selects for these resistant organisms, making treatment adherence particularly important in prevention of resistance. Multiple drugs are used concurrently for TB so that organisms resistant to one drug are killed by the others; simultaneous spontaneous mutations to multiple drugs are unlikely. However, once a strain resistant to a single drug has developed and proliferated, it may acquire resistance to additional drugs through the same process; thus, MDR-TB can occur by stepwise acquired resistance to INH, RIF, and often other drugs. Some resistant strains appear to be less fit (ie, less transmissible and virulent); others have acquired compensatory mutations that restore fitness, allowing disease progression and transmission to occur.
Once a drug-resistant strain develops in a patient, it can spread from person to person (primary drug resistance). Uninhibited transmission of drug-resistant strains in congregate settings, such as hospitals, clinics, prisons, shelters, and refugee camps, is a major barrier to global control.
Several new anti-TB drugs that may be active against resistant strains are in preclinical or clinical development but will not be available for several more years. Furthermore, unless treatment programs are strengthened (eg, by full supervision of each dose), stepwise resistance to new drugs is likely.
MDR-TB is TB resistant in vitro to both isoniazid and rifampin, with or without resistance to other drugs. Numerous outbreaks of MDR-TB have been reported, and the global burden is rising. The Stop TB Partnership estimates that 780,000 new cases of MDR-TB will occur between 2006 and 2015. In parts of the world where resistance testing is inadequate or unavailable, many patients who do not respond to first-line therapy probably have MDR-TB that is undiagnosed. MDR-TB has major negative implications for TB control; alternative treatments require a longer treatment course with less effective, more toxic, and more expensive 2nd-line drugs.
XDR-TB is MDR-TB that is also resistant to fluoroquinolones and injectable drugs (eg, streptomycin, amikacin, kanamycin, capreomycin). TB strains that are resistant to other drug combinations but that do not meet the definitions of MDR or XDR are termed polyresistant. Because the fluoroquinolones and injectables are important for treatment of MDR-TB, XDR-TB has dire therapeutic implications. Although some patients can be cured, mortality is higher and depends on the number of effective drugs remaining and the extent of lung destruction. Surgery to remove localized areas of lung destruction plays an important role in the treatment of advanced cases of MDR-TB or XDR-TB but is not widely available in high-burden regions.
Treatment regimens
Treatment of all patients with new, previously untreated TB should consist of a
Initial intensive–phase therapy is with 4 antibiotics: INH, RIF, PZA, and EMB (see Table 1: Mycobacteria: Dosing of First-Line Anti-TB Drugs* for dosing). These drugs can be given daily throughout this phase or daily for 2 wk, followed by doses 2 or 3 times/wk for 6 wk. Intermittent administration (usually with higher doses) is usually satisfactory because of the slow growth of tubercle bacilli and the residual postantibiotic effect on growth (after antibiotic inhibition, bacterial growth is often delayed well after antibiotics are below the minimal inhibitory concentration). However, daily therapy is recommended for patients with MDR-TB or HIV coinfection. Regimens involving less than daily dosing must be carried out as DOT because each dose becomes more important.
After 2 mo of intensive 4-drug treatment, PZA and usually EMB are stopped, depending on the drug susceptibility pattern of the original isolate.
Continuation-phase treatment depends on results of drug susceptibility testing of initial isolates (where available), the presence or absence of a cavitary lesion on the initial chest x-ray, and results of cultures taken at 2 mo. If positive, 2-mo cultures indicate the need for a longer course of treatment. If both culture and smear are negative, regardless of the chest x-ray, or if the culture or smear is positive but x-ray showed no cavitation, INH and RIF are continued for 4 more mo (6 mo total). If the x-ray showed cavitation and the culture or smear is positive, INH and RIF are continued for 7 more mo (9 mo total). In either regimen, EMB is stopped if the initial culture shows no resistance to any drug. Continuation-phase drugs can be given daily or, if patients are not HIV-positive, 2 or 3 times/wk. Patients who have negative culture and smears at 2 mo and no cavitation on chest x-ray and who are HIV-negative may receive once/wk INH plus rifapentine.
For both initial and continuation phases, the total number of doses (calculated by doses/wk times number of weeks) should be given; thus if any doses are missed, treatment is extended and not stopped at the end of the time period.
Management of drug-resistant TB varies with the pattern of drug resistance. Generally, MDR-TB requires prolonged (eg, 18 to 24 mo) treatment with the remaining active first-line drugs (including PZA, if the strain is susceptible) with addition of an injectable, a fluoroquinolone, and other 2nd-line drugs as needed to build a 4- or 5-drug regimen that the infecting strain is known or likely to be susceptible to (ie, based on testing, a known source-case, prior treatment, or drug susceptibility patterns in the community). Managing the adverse effects of these long, complex regimens is challenging. MDR-TB should always be treated by a TB specialist experienced with these cases. Fully supervised treatment is essential to avoid additional drug resistance through nonadherance.
Other treatments
Surgical resection of a persistent TB cavity is occasionally necessary. The main indication for resection is persistent, culture-positive MDR-TB or XDR-TB in patients with a destroyed lung region into which antibiotics cannot penetrate. Other indications include uncontrollable hemoptysis and bronchial stenosis.
Corticosteroids are sometimes used to treat TB when inflammation is a major cause of morbidity and are indicated for patients with acute respiratory distress syndrome or closed-space infections, such as meningitis and pericarditis. Dexamethasone 12 mg po or IV q 6 h is given to adults and children > 25 kg; children < 25 kg are given 8 mg. Treatment is continued for 2 to 3 wk. Corticosteroids that are needed for other indications pose no danger to patients who have active TB and who are receiving an effective TB regimen.
Screening
Screening for latent TB infection (LTBI) is done with TST or IGRA. Indications for testing include
In the US, most children and other people without specific TB risk factors should not be tested to avoid false-positive reactions.
A positive TST or IGRA test result (see Mycobacteria: Skin testing for criteria) suggests LTBI. Patients with a positive TST or IGRA result are evaluated for other risk factors and have a chest x-ray. Those with x-ray abnormalities suggesting TB require evaluation for active TB as above, including sputum examination and culture. Updated guidelines for testing and treatment of LTBI are available at the Centers for Disease Control and Prevention (CDC) web site (www.cdc.gov).
Booster reaction
Some patients with remote TB exposure, BCG vaccination, or infection with nontuberculous mycobacteria may have a negative TST or IGRA; however, the TST itself may serve as an immune booster so that a subsequent test done as little as 1 wk or as much as several years later may be positive (booster reaction). Thus, in people who are tested regularly (eg, health care workers), the 2nd routine test will be positive, giving the false appearance of recent infection (and hence mandating further testing and treatment). If recurrent testing for LTBI is indicated, a 2nd TST should be done 1 to 4 wk after the first to identify a booster reaction (because conversion in that brief interval is highly unlikely). Subsequent TST is done and interpreted normally.
The new IGRAs for LTBI do not involve injection of antigens and thus do not cause boosting. They also are not influenced by preexisting hypersensitivity from BCG vaccination or infection with environmental mycobacteria other than M. kansasii, M. szulgai, and M. marinum.
Treatment of LTBI
Treatment is indicated principally for
Other indications for preventive treatment include
Other people with an incidental positive TST or IGRA but without these risk factors are often treated for LTBI, but physicians should balance individual risks of drug toxicity against the benefits of treatment.
Treatment generally consists of INH unless resistance is suspected (eg, in exposure to a known INH-resistant case). The dose is 300 mg once/day for 6 to 9 mo for most adults and 10 mg/kg for 9 mo for children. HIV-infected patients and people with abnormal chest x-rays consistent with old TB also require 9 mo of therapy. An alternative for patients resistant to or intolerant of INH is RIF 600 mg once/day for 4 mo.
The main limitations of treatment of LTBI are poor adherence and hepatotoxicity. Used for LTBI, INH causes clinical hepatitis in 1/1000 cases; hepatitis usually reverses if INH is stopped promptly. Patients being treated for LTBI should be instructed to stop the drug if they experience any new symptoms, especially unexplained fatigue, loss of appetite, or nausea. Hepatitis due to RIF is less common than with INH, but drug interactions are frequent. Monthly visits to monitor symptoms and to encourage treatment completion are standard good clinical and public health practice.
Prevention
General preventive measures (eg, staying at home, avoiding visitors, covering coughs with a tissue or hand—see Mycobacteria: Treatment) are followed.
Vaccination
The BCG vaccine, made from an attenuated strain of M. bovis is given to > 80% of the world's children, primarily in high-burden countries. Overall average efficacy is probably only 50%. However, although BCG is not believed to prevent TB infection, it reduces the rate of extrathoracic TB in children, especially TB meningitis, and therefore is considered worthwhile. BCG has few indications in the US, except unavoidable exposure of a child to an infectious TB case that cannot be effectively treated (ie, highly resistant MDR-TB) and possibly previously uninfected health care workers exposed to MDR-TB or XDR-TB on a regular basis. Although BCG vaccination often converts the TST, the reaction is usually smaller than the response to natural TB infection, and it usually wanes more quickly. The TST reaction due to BCG is rarely > 15 mm and rarely > 10 mm 15 yr after BCG administration. CDC recommends that all TST reactions in children who have had BCG be attributed to TB infection (and treated accordingly) because untreated latent infection can have serious complications. IGRAs for LTBI are not influenced by BCG vaccination.
Special Populations
Children
Primary TB in children can spread to the vertebrae (Pott's disease) or the highly vascular epiphyses of long bones. Young children may also rapidly develop serious TB, possibly miliary TB, TB meningitis, or cavitary disease, even before the TST becomes positive. However, most children have few symptoms other than a brassy cough, and the primary focus usually resolves spontaneously with or without treatment. The most common sign is hilar lymphadenopathy, but segmental atelectasis is possible. Adenopathy may progress, even after chemotherapy is started, and may cause lobar atelectasis, which usually clears during treatment. Cavitary disease is less common than in adults, and most children harbor far fewer organisms and are not infectious. Except for dosage adjustments, treatment of children is similar to that of adults (see Table 1: Mycobacteria: Dosing of First-Line Anti-TB Drugs*).
The elderly
Reactivated disease can involve any organ, but particularly the lungs, brain, kidneys, long bones, vertebrae, or lymph nodes. Reactivation may cause few symptoms and can be overlooked for weeks or months, delaying appropriate evaluation. The frequent presence of other disorders in old age further complicates the diagnosis. At any age, recent transmission may cause apical, middle-lobe, or lower-lobe pneumonia as well as pleural effusion in previously tuberculin-negative nursing home residents. The pneumonia may not be recognized as TB and may persist and spread to other people despite broad-spectrum antibiotic treatment. In the US, miliary TB and TB meningitis, commonly thought to affect mainly young children, are more common among the elderly.
INH is hepatotoxic in up to 4 to 5% of patients > 65 yr (compared with < 1% of patients < 65 yr). In the elderly, chemoprophylaxis is indicated only if the TST increases ≥ 15 mm from a previously negative reaction. TST sensitivity can be poor in the elderly. Close contacts of an active case and others at high risk and with a negative TST or IGRA should be considered for preventive treatment unless contraindicated.
HIV-infected patients
TST sensitivity is generally poor in immunocompromised patients (who may be anergic). In some studies, IGRAs appear to perform better than the TST in immunocompromised patients, although this advantage has not yet been established.
In HIV-infected patients with LTBI, active TB develops in about 5 to 10%/yr, whereas in people who are not immunocompromised, it develops in about the same percentage over a lifetime. In the early 1990s, half of HIV-infected TB patients who were untreated or infected with an MDR strain died, with median survival of only 60 days. Now, outcomes are somewhat better in developed countries because of earlier TB diagnosis and antiretroviral therapy, but TB in HIV patients remains a serious concern. In developing countries, mortality continues to be high among patients coinfected with HIV and MDR-TB or XDR-TB.
Dissemination of bacilli during primary infection is usually much more extensive in patients with HIV infection. Consequently, a larger proportion of TB is extrapulmonary. Tuberculomas are more common and more destructive. HIV reduces both inflammatory reaction and cavitation of pulmonary lesions. As a result, a chest x-ray may show a nonspecific pneumonia or even be normal, even though AFB are present in sufficient numbers to appear on a sputum smear. Smear-negative TB is more common when HIV coinfection is present.
TB may develop early in AIDS and may be its presenting manifestation. Hematogenous dissemination of TB in patients with HIV infection causes a serious, often baffling illness with symptoms of both infections. In AIDS patients, a mycobacterial illness that develops while the CD4 count is ≥ 200/μL is almost always TB. By contrast, depending on the probability of TB exposure, a mycobacterial infection that develops while the CD4 count is < 50/μL is usually due to M. avium complex (see Mycobacteria: Other Mycobacterial Infections Resembling Tuberculosis), which is not contagious and is predominantly an infection of the blood and bone marrow, not the lungs.
TB in HIV-infected patients generally responds well to usual regimens when in vitro testing shows sensitivity. However, for MDR-TB strains, outcomes are not as favorable because the drugs are more toxic and less effective. Therapy for susceptible TB should be continued for 6 to 9 mo after conversion of sputum cultures to negative but may be shortened to 6 mo if 3 separate pretreatment sputum smears are negative, suggesting a low burden of organisms. Current recommendations suggest that if the sputum culture is positive after 2 mo of therapy, treatment is prolonged to 9 mo. HIV-infected patients whose tuberculin reactions are ≥ 5 mm (or with a positive IGRA) should receive chemoprophylaxis. Current CDC TB treatment guidelines should be consulted.
Extrapulmonary Tuberculosis
TB outside the lung usually results from hematogenous dissemination. Sometimes infection directly extends from an adjacent organ. Symptoms vary by site but generally include fever, malaise, and weight loss.
Miliary TB
Also known as generalized hematogenous TB, miliary TB occurs when a tuberculous lesion erodes into a blood vessel, disseminating millions of tubercle bacilli into the bloodstream and throughout the body. The lungs and bone marrow are most often affected, but any site may be involved. Miliary TB is most common among children < 4 yr, immunocompromised people, and the elderly.
Symptoms include fever, chills, weakness, malaise, and often progressive dyspnea. Intermittent dissemination of tubercle bacilli may lead to a prolonged FUO. Bone marrow involvement may cause anemia, thrombocytopenia, or a leukemoid reaction.
Genitourinary TB
Infection of the kidneys may manifest as pyelonephritis (eg, fever, back pain, pyuria) without the usual urinary pathogens on routine culture (sterile pyuria). Infection commonly spreads to the bladder and, in men, to the prostate, seminal vesicles, or epididymis, causing an enlarging scrotal mass. Infection may spread to the perinephric space and down the psoas muscle, sometimes causing an abscess on the anterior thigh.
Salpingo-oophoritis can occur after menarche, when the fallopian tubes become vascular. Symptoms include chronic pelvic pain and sterility or ectopic pregnancy due to tubal scarring.
TB meningitis
Meningitis often occurs in the absence of infection at other extrapulmonary sites. In the US, it is most common among the elderly and immunocompromised, but in areas where TB is common among children, TB meningitis usually occurs between birth and 5 yr. At any age, meningitis is the most serious form of TB and has high morbidity and mortality. It is the one form of TB believed to be prevented in childhood by vaccination with BCG.
Symptoms are low-grade fever, unremitting headache, nausea, and drowsiness, which may progress to stupor and coma. Kernig's and Brudzinski's signs may be positive. Stages are
Stroke may result from thrombosis of a major cerebral vessel. Focal neurologic symptoms suggest a tuberculous mass intracranial lesion (tuberculoma).
TB peritonitis
Peritoneal infection represents seeding from abdominal lymph nodes or from salpingo-oophoritis. Peritonitis is particularly common among alcoholics with cirrhosis.
Symptoms may be mild, with fatigue, abdominal pain, and tenderness, or severe enough to mimic acute abdomen.
TB pericarditis
Pericardial infection may develop from foci in mediastinal lymph nodes or from pleural TB. In some high-incidence parts of the world, TB pericarditis is a common cause of heart failure.
Patients may have a pericardial friction rub, pleuritic and positional chest pain, or fever. Pericardial tamponade may occur, causing dyspnea, neck vein distention, paradoxical pulse, muffled heart sounds, and possibly hypotension.
TB lymphadenitis
Usually, the hilar lymph nodes are involved. Other nodes are generally not involved unless the inoculum is large or poorly contained, allowing organisms to reach the thoracic duct, where they disseminate into the bloodstream. Most infected nodes heal, but reactivation commonly occurs. Infection in supraclavicular nodes may inoculate anterior cervical nodes, eventually resulting in scrofula (TB lymphadenitis in the neck).
Affected nodes are swollen and may be mildly tender or drain.
TB of bones and joints
Weight-bearing joints are most commonly involved, but bones of the wrist, hand, and elbow may also be affected, especially after injury.
Pott's disease is spinal infection, which begins in a vertebral body and often spreads to adjacent vertebrae, with narrowing of the disk space between them. Untreated, the vertebrae may collapse, possibly impinging on the spinal cord. Symptoms include progressive or constant pain in involved bones and chronic or subacute arthritis (usually monoarticular). In Pott's disease, spinal cord compression produces neurologic deficits, including paraplegia; paravertebral swelling may result from an abscess.
Gastrointestinal TB
Because the entire GI mucosa resists TB invasion, infection requires prolonged exposure and enormous inocula. It is very unusual in developed countries where bovine TB is rare.
Ulcers of the mouth and oropharynx may develop from eating M. bovis–contaminated dairy products; primary lesions may also occur in the small bowel. Intestinal invasion generally causes hyperplasia and an inflammatory bowel syndrome with pain, diarrhea, obstruction, and hematochezia. It may also mimic appendicitis. Ulceration and fistulas are possible.
TB of the liver
Liver infection is common in patients with advanced pulmonary TB and widely disseminated or miliary TB. However, the liver generally heals without sequelae when the principal infection is treated. TB in the liver occasionally spreads to the gallbladder, leading to obstructive jaundice.
Other sites
Rarely, TB may develop on abraded skin in patients with cavitary pulmonary TB. TB may infect the wall of a blood vessel and has even ruptured the aorta. Adrenal involvement, leading to Addison's disease, formerly was common but now is rare. Tubercle bacilli may spread to tendon sheaths (tuberculous tenosynovitis) by direct extension from adjacent lesions in bone or hematogenously from any infected organ.
Diagnosis
Testing is similar to that for pulmonary TB (see Mycobacteria: Diagnosis), including chest x-ray, tuberculin skin testing (TST), and microscopic analysis (with appropriate staining) and cultures of affected body fluids (CSF, urine, or pleural, pericardial, or joint fluid) and tissue for mycobacteria. However, cultures and smears are often negative because few organisms may be present; in this case, nucleic acid amplification techniques (NAAT) may be helpful. If all tests are negative and miliary TB is still a concern, biopsies of the bone marrow and the liver are done. Blood culture results are positive in about 50% of patients with disseminated TB; such patients are often immunocompromised by HIV infection or another immunosuppressive condition. If TB is highly suspected based on other features (eg, granuloma seen on biopsy, positive TST plus unexplained lymphocytosis in pleural fluid or CSF), treatment should usually proceed despite inability to demonstrate TB organisms.
Chest x-ray may show signs of primary or active TB; in miliary TB, it shows thousands of 2- to 3-mm interstitial nodules evenly distributed through both lungs. TST and IGRA may initially be negative, but a repeat test in a few weeks is likely to be positive. If it is not, the diagnosis of TB should be questioned or causes of anergy sought.
Other imaging studies are done based on clinical findings. Abdominal or GU involvement usually requires CT or ultrasonography; renal lesions are often visible. Bone and joint involvement requires CT or MRI; MRI is preferable for spinal disease.
Body fluids typically show lymphocytosis. The most suggestive CSF constellation also includes a glucose level < 50% of that in the serum and an elevated protein level.
Treatment
Drug treatment is the most important modality and follows standard regimens and principles (see Mycobacteria: First-line drugs). Six to 9 mo of therapy is probably adequate for most sites except the meninges, which require treatment for 9 to 12 mo. Corticosteroids may help in pericarditis and meningitis (for dosing, see Mycobacteria: Other treatments).
Surgery is required for the following:
Surgical debridement is sometimes needed in Pott's disease to correct spinal deformities or to relieve cord compression if there are neurologic deficits or pain persists; fixation of the vertebral column by bone graft is required in only the most advanced cases. Surgery is usually not necessary for TB lymphadenitis except for diagnostic purposes.
Last full review/revision September 2009 by Edward A. Nardell, MD
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