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(See also Infections in Neonates: Perinatal Tuberculosis (TB).)
Tuberculosis
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 by sputum culture and smear. Treatment is with multiple antimicrobial
agents.
Tuberculosis (TB) is the leading infectious cause of morbidity and mortality in adults worldwide, killing about 2 million people every year.
Etiology
TB properly refers only to disease caused by Mycobacterium
tuberculosis. Similar disease occasionally results from M. bovis
, M. africanum, and M. microti.
TB occurs almost exclusively from inhalation of droplet nuclei containing M. tuberculosis. They disperse primarily through coughing, singing, and other forced respiratory maneuvers by a person with active pulmonary TB 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 float on room-air currents for several hours, increasing the chance of spread. About 1⁄4 of household contacts acquire infection. Health care practitioners in the US who have close contact with active cases have increased risk. Transmission is enhanced by overcrowding; thus, people living in poverty or in institutions are at particular risk. Once effective treatment begins, however, cough rapidly decreases, and within weeks, TB is no longer contagious.
Less commonly, spread occurs from aerosolization of organisms after irrigation of infected wounds, in mycobacteriology laboratories, and in autopsy rooms. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints was once commonly caused by ingestion of milk infected with M. bovis, but such infection has been largely eradicated in developed countries by slaughtering cows that test positive on a tuberculin skin test. Fomites do not appear to facilitate spread.
Epidemiology
About 1.6 billion are infected worldwide. Of these, perhaps only 15 million have active disease at any given time. Case rates vary widely by country, age, race, sex, and socioeconomic status. In the US, the case rate has declined 10-fold since 1953. There are now about 15,000 cases/yr; > 50% occur in patients born outside the US in high-prevalence areas (eg, Asia, Africa, Latin America). In the southeastern US and inner cities throughout the US, poor US-born blacks, the homeless, those in jails and prisons, and other disenfranchised minorities contribute disproportionately to the case rate.
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, corticosteroids) are risks but less so 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 prevalence is no longer as large, probably because the incidence of infectious cases (and hence lifetime risk of significant exposure) has declined.
A resurgence of TB occurred in parts of the US and other developed countries between 1985 and 1992, associated with several factors, including HIV, homelessness, a deteriorated public health infrastructure, and the appearance of multidrug-resistant–TB (MDR-TB—see Mycobacteria: Drug resistance). Although substantially controlled in the US by public health and institutional infection control measures, the problem of MDR-TB appears to be growing around the world, fueled by poor treatment supervision, weak retreatment regimens, HIV coinfection, institutional transmission, and inadequate resources. Control efforts, including prolonged (eg, > 18 mo) use of 2nd-line antibiotics, treatment of drug adverse effects, community-based supervision, and social and emotional support, are raising hopes for better global control of MDR-TB.
Pathophysiology
Tubercle bacilli initially produce a primary infection, followed by a latent (dormant) phase and, in some cases, by active disease. Infection is not transmissible in the primary and latent phases.
Primary infection:
Airborne droplet nuclei lodge in subpleural terminal airspaces, predominantly in the lower lung, usually in only one site. Tubercle bacilli replicate inside macrophages, ultimately killing them; inflammatory cells are attracted to the area, causing a tubercle and sometimes pneumonitis. In the early weeks of infection, some infected macrophages are borne to regional lymph nodes (eg, hilar, mediastinal). Hematogenous spread to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges, may occur. 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 host's resistance determining whether the infection ultimately resolves without treatment, remains dormant, or becomes active. Foci may leave nodular 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) is positive.
Rarely, 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. Primary extrapulmonary TB at any site can sometimes present 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 patients overall, 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 1st 2 yr, but it can occur decades later. Any organ initially seeded may be a site of reactivation, but reactivation occurs most often in the lung apices, where O2 tension is highest. Ghon foci and affected hilar lymph nodes are much less likely to be sites of reactivation. Extrapulmonary TB is discussed in Mycobacteria: Extrapulmonary Tuberculosis (TB).
Conditions that facilitate activation include impaired immunity (particularly HIV infection), certain immunosuppressant drugs (eg, corticosteroids, infliximab and other tumor necrosis factor blockers), gastrectomy, jejunoileal bypass surgery, silicosis, renal insufficiency, stress, diabetes, head or neck cancer, adolescence, and advanced (particularly > 70 yr) age.
TB damages tissues through delayed hypersensitivity (see Allergic and Other Hypersensitivity Disorders: Introduction), typically producing granulomatous necrosis with a caseous histologic appearance. Lung lesions are cavitary. Pleural effusion is less common than in progressive primary TB but may occur from direct extension or hematogenous spread. Rupture of a large tuberculous lesion into the pleural space may produce empyema with or without bronchopleural fistula; it sometimes causes pneumothorax. In the prechemotherapy era, TB empyema sometimes complicated medically induced pneumothorax therapy and was usually rapidly fatal.
The course varies greatly, depending on the virulence of the organism and the state of host defenses. The course may be rapid among blacks and American Indians who have not had as many centuries of selective pressure to develop innate or natural immunity.
Acute respiratory distress syndrome, 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, the patient may have no symptoms except “not feeling well” or 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. Drenching night sweats are a classic symptom but are neither common in nor specific for TB. Dyspnea may result from lung parenchymal involvement, spontaneous pneumothorax, or pleural TB with effusion. Hemoptysis occurs only with cavitary TB.
Diagnosis
PulmonaryTB is often suspected on the basis of 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). In adults, a multinodular infiltrate above or behind the clavicle (the most characteristic location, most visible in an apical lordotic view) 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.
Initial tests are chest x-ray, sputum examination (stain and culture), and tuberculin skin testing. If the chest x-ray is highly characteristic (upper lobe lung cavitation) in a person with TB risk factors, sputum examination is still required, but skin testing is often not done. 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 a positive rapid molecular test. Culture results may take ≥ 3 wk, but examination by molecular methods usually takes only days. Rapid molecular tests can also detect a genetic mutation associated with resistance to rifampin , a key feature of MDR-TB. Positive cultures are routinely tested for resistance to isoniazid , rifampin , and ethambutol , but results take up to 8 wk by conventional bacteriologic methods.
Patients who cannot produce sputum spontaneously can have it induced by aerosolized hypertonic saline. If not, bronchial washings, which are particularly sensitive, can be obtained by fiberoptic bronchoscopy. Transbronchial biopsies should be performed on infiltrative lesions and submitted for culture, histologic evaluation, and molecular testing. Gastric washings are often positive but are no longer commonly used except in small children, who usually cannot produce a good sputum specimen. 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.
Skin
testing:
The tuberculin skin test (TST; Mantoux or PPD—purified protein derivative) is usually performed, although it is a test of infection, latent or active, and is not diagnostic of active disease. The standard dose of 5 units 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. The diameter of induration (not erythema) is measured 48 to 72 h after injection. Induration of ≥ 10 mm generally indicates infection with M.
tuberculosis but does not indicate activity of the infection. Different cutoffs, intended to improve sensitivity and specificity, are sometimes appropriate; induration ≥ 5 mm is considered positive in patients with HIV infection or chest x-ray evidence of past TB and close contacts of patients with TB, whereas for patients with no known risk factors, the test is not considered positive unless induration is > 15 mm. Results can be falsely negative, most often in the febrile, elderly, HIV-infected (especially if CD4+ cell count is < 200 cells/μL), and the very ill, many of whom show no reaction to any skin test (anergy). Anergy probably occurs because of inhibiting antibodies or because so many T cells have been mobilized to the disease site that too few remain to produce a significant skin reaction. Multiple-puncture devices (the tine test) are no longer recommended for general use.
Blood tests based on the production of gamma interferon by lymphocytes exposed in vitro to TB-specific antigens are now available and will likely soon replace the tuberculin skin test for routine testing for TB infection.
Prognosis
and Treatment
In immunocompetent patients with drug-susceptible pulmonary TB, even severe disease and large cavities usually heal if appropriate therapy is instituted and completed. Still, TB causes or contributes to death in about 10% of cases, often in those 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 properly and aggressively treated, may be fatal in as little as 2 mo from its initial symptom. This is especially true of MDR-TB, in which mortality can approach 90%.
Most patients with uncomplicated TB and all with complicating illness (eg, AIDS, hepatitis, diabetes), adverse drug reactions, and 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 can be treated at home with instructions on how to avoid spreading disease; these measures include staying at home, avoiding visitors (previously exposed family members may stay), and covering coughs with a tissue or hand. Surgical face masks for TB patients are stigmatizing and are generally not recommended for cooperative patients. Precautions must be continued for several weeks in or outside the hospital. The main indications for hospitalization are serious concomitant illness, need for diagnostic procedures, social issues (eg, homelessness), and need for respiratory isolation, such as people living in congregate settings where previously unexposed people would be regularly encountered.
All hospitalized patients initially 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 that has been appropriately fitted and that meets The National Institute for Occupational Safety and Health guidelines to filter 1-micron particles.
Public
health considerations:
To limit transmission and development of drug-resistant strains, treatment is monitored by public health programs to ensure adherence, even if the patient is 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.
Frequently, case management includes supervision of the ingestion of every dose of medication by public health personnel, 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 for children and adolescents; for those with HIV infection, psychiatric illness, or substance abuse; and after treatment failure, relapse, or development of drug resistance.
Public health departments usually perform a home visit to evaluate potential barriers to treatment (eg, extreme poverty, unstable housing, alcoholism, or mental illness) and seek other active cases and close contacts. Close contacts are people who share the same breathing space for prolonged periods, typically household residents, but often includes people at work, school, and places of recreation. The precise duration and degree of contact that constitutes risk varies because TB patients vary greatly in infectiousness. For a patient who is highly infectious, as evidenced by multiple family members with disease or positive skin tests, even relatively casual contacts (eg, passengers on the bus he rides) should be referred for skin testing and evaluation for latent infection (see Mycobacteria: Screening and Prevention), whereas a patient who does not infect any household contacts is less likely to infect casual contacts.
First-line
drugs:
The 1st-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 Antituberculosis Drugs* ).
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Table 1
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Dosing of First-Line Antituberculosis
Drugs*
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Drug
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Adults/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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|
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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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|
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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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|
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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)
40–55 kg
56–75 kg
≥ 76 kg§
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1 g
1.5 g
2 g
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N/A
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2 g
3 g
4 g
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1.5 g
2.5 g
3 g
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Children (maximum)
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20–40 mg/kg (2 g)
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N/A
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15–50 mg/kg (2 g)
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N/A
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Ethambutol
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Adults (whole tablets)
40–55 kg
56–75 kg
≥ 76 kg§
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800 mg
1200 mg
1600 mg
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N/A
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2000 mg
2800 mg
4000 mg
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1200 mg
2000 mg
2400 mg
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|
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Children (maximum)
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15–25 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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All dosing < 7 days/wk must be given as directly observed therapy.
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*Specific regimens are discussed in text.
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†Considered either 5 or 7 days/wk.
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‡Continuation phase only.
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§Maximum dose.
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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, decades of uncontrolled use (often as a single agent) 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% and symptomatic (usually reversible) hepatitis in about 1/1000 (more often in people > 35 yr, alcoholics, and patients with chronic liver disease). Monthly liver function testing is not recommended, but patients with unexplained fatigue, anorexia, nausea, vomiting, or jaundice may have hepatic toxicity; treatment is suspended and liver function tests obtained. Those with symptoms and any significant aminotransferase elevation (or asymptomatic elevation > 5 times normal) probably have hepatic toxicity, and INH is stopped. After recovery from mild aminotransferase elevations and symptoms, the patient can be safely challenged with a half-dose for 2 to 3 days. If this dose is tolerated (typically in about 1⁄2 of patients), the full dose may be restarted with close monitoring for symptoms and liver function deterioration. If the patient is receiving both INH and RIF, both drugs must be stopped, and the challenge performed with each drug separately. INH, rather than RIF, is more likely the cause of hepatotoxicity. Peripheral neuropathy can occur due to INH-induced pyridoxine (vitamin B6) deficiency, most likely in pregnant or undernourished patients, alcoholics, patients with cancer or uremia, and the elderly. A daily dose of 25 to 50 mg of pyridoxine can prevent this complication, although it 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. RIF is safe during pregnancy. Newer rifamycins, rifabutin and rifapentine , are available for special situations. Rifabutin is used for patients taking drugs (particularly antiretroviral agents) that have unacceptable interactions with RIF. Its action is similar to RIF, but it has been associated with uveitis when used with clarithromycin or fluconazole . Rifapentine is used in certain once/wk regimens (see Table 1: Mycobacteria: Dosing of First-Line Antituberculosis Drugs*) but is not used in children or patients with HIV or extrapulmonary TB.
PZA, an oral bactericidal drug, when used during the intensive initial 2 mo of treatment, prevents development of resistance to RIF and shortens therapy to 6 mo. 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.
EMB is given orally and is the best tolerated of the 1st-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 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. EMB is generally 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. It can be used safely in pregnancy. Resistance to EMB is uncommon.
Second-line
drugs:
Other antibiotics are active against TB and are used primarily for MDR-TB. The 2 most important classes are the aminoglycosides 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 (usually 1 g for adults, reduced to 0.5 g for those > 60 yr, < 45 kg, or who have any degree of renal insufficiency). In patients > 60 yr with renal insufficiency, the dose is 0.25 g. To limit dose-related adverse effects, one dose is given only 5 days/wk for > 2 mo. Then it may be given twice/wk for another 2 mo if necessary. Patients should be monitored with appropriate testing of balance, hearing, and serum creatinine levels. Allergic reactions include rash, fever, agranulocytosis, and serum sickness. Flushing and tingling around the mouth commonly accompany injection but subside quickly. Streptomycin is contraindicated in 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 parenteral bactericidal drug, has dosage, effectiveness, and adverse effects similar to those of streptomycin . It is an important drug for MDR-TB because isolates resistant to streptomycin are often susceptible to capreomycin , and it seems somewhat better tolerated than the aminoglycosides when prolonged administration is required.
Some of the fluoroquinolones— levofloxacin , moxifloxacin , and gatifloxacin —are the most active and safe TB drugs after INH and RIF. The newer fluoroquinolones, moxifloxacin and gatifloxacin , appear almost as active with RIF as INH. Unfortunately, resistance to one fluoroquinolone usually means resistance to the others.
Other 2nd-line drugs include ethionamide , cycloserine , and para-aminosalicylic acid (PAS). These are less effective and more toxic than the 1st-line drugs but useful in treatment of MDR-TB.
Drug resistance:
Treatment with any single antibiotic always results in survival of a few resistant mutant organisms. For most infections, survival of a few organisms is not a problem because immune defenses eliminate these remaining bacteria. However, resistance is a significant problem with TB because very few organisms (< 100) are required to perpetuate disease as susceptible organisms are suppressed. Thus, multiple drugs are used simultaneously; because drug resistance mutations occur separately, the possibility is remote that a given bacterium would have spontaneous mutations causing resistance to several drugs. However, once a resistant strain has developed and proliferated, it may acquire resistance to additional drugs through the same process; thus MDR-TB can occur.
Treatment
regimens:
All patients with new, previously untreated TB should receive a 2-mo initial phase of treatment followed by a 4- or 7-mo continuation phase.
Initial-phase therapy is with 4 antibiotics for the first 2 mo: INH, RIF, PZA, and EMB (see Table 1: Mycobacteria: Dosing of First-Line Antituberculosis Drugs* for dosing). These can be given daily throughout (for all regimens, 5 days/wk is considered equivalent to daily), or daily for 2 wk followed by doses 2 or 3 times/wk for 6 wk. Intermittent dosing is possible without diminished effectiveness because of the growth characteristics of tubercle bacilli. However, regimens involving less than daily dosing must be carried out as DOT.
At 2 mo, PZA is stopped, and cultures and smears are obtained; continuation-phase treatment depends on their results and presence or absence of a cavitary lesion on the initial chest x-ray. If both culture and smear are negative, regardless of the chest x-ray, or 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 culture shows no resistance to any drug. Continuation-phase drugs can be given daily, twice weekly, or 3 times weekly. Patients with negative culture and smears and no cavitation on chest x-ray who are HIV-negative may receive once-weekly INH plus rifapentine .
For both initial and continuation phases, the total number of doses (calculated by doses/week times number of weeks) must be administered; thus if any doses are missed, treatment is extended and not stopped at the end of the time period.
Management of resistant TB varies by the pattern of drug resistance. Generally, MDR-TB requires prolonged (eg, 18 to 24 mo) treatment with the remaining active 1st-line drugs (including PZA, if susceptible) with addition of one or more 2nd-line drugs (typically a fluoroquinolone and an aminoglycoside or capreomycin ). MDR-TB should always be treated by a TB specialist.
Other treatment:
Surgical resection of a persistent TB cavity may occasionally be necessary. The main indication for resection is persistent, culture-positive MDR-TB in a patient with a destroyed lung region into which antibiotics cannot penetrate.
Corticosteroids are indicated in patients with acute respiratory distress syndrome, meningitis, or pericarditis. Dexamethasone 12 mg po or IV q 6 h is given to adults and children > 25 kg; children < 25 kg receive 8 mg. Treatment is continued for 2 to 3 wk. Corticosteroids that are needed for other indications pose no danger in a patient with active TB who is receiving an effective TB regimen.
Screening
and Prevention
Screening is with TST. Indications for TST include close contact with people who have active pulmonary TB; chest x-ray evidence of past TB infection; risk factors for exposure to TB (eg, immigration within 5 yr from high-risk areas, indigent patients, IV drug users, selected US health care practitioners, such as respiratory therapists); and risk factors for development of active TB, particularly those with HIV infection but also others with impaired immunity, and patients with gastrectomy, jejunoileal bypass surgery, silicosis, renal insufficiency, diabetes, or head or neck cancer, and advanced age (eg, > 70 yr). In the US, most children and others without specific TB risk factors should not be skin tested to avoid false-positive reactions.
A positive result (see Mycobacteria: Skin testing for criteria) suggests latent TB infection (LTBI). Patients with positive skin test 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 on the Centers for Disease Control and Prevention (CDC) web site (www.cdc.gov).
Some patients with remote TB exposure have a negative TST; however, the test itself may serve as an immune booster so that a subsequent test as little as 1 wk or as much as several years later will be positive (booster reaction). Thus, in a person who is 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). In circumstances in which recurrent TST is indicated, a 2nd TST should be done 1 to 4 wk after the 1st to identify a booster reaction (because it is highly unlikely that a person would convert in that brief interval). Subsequent TST is performed and interpreted normally.
Treatment of LTBI is indicated principally in people whose TST converted from negative to positive within the previous 2 yr and in those with x-ray changes consistent with old TB and no evidence of active TB. Another indication for preventive treatment is people who, if infected, are at high risk for developing active TB (eg, HIV-infected people). Treatment is also strongly indicated for any child < 4 yr who is a close contact of a person with smear-positive TB, regardless of whether there was TST conversion.
Treatment generally consists of INH unless resistance is suspected (eg, in exposure to a known 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 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.
The BCG vaccine, made from an attenuated strain of M. bovis, is administered 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 possibly unavoidable exposure to an infectious TB case that cannot be effectively treated, that is, highly resistant MDR-TB. 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 should rarely be > 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 of the risk of serious complications of untreated latent infection. The new in vitro blood tests for TB infection based on gamma interferon production are not influenced by BCG vaccination.
Special
Populations
Children:
Primary TB in children often spreads to the vertebrae (Pott's disease) or the highly vascular epiphyses of long bones. Children ≤ 4 yr may also develop serious TB rapidly, possibly miliary TB, TB meningitis, or cavitary disease, before the TST becomes positive. However, in most children, there are few symptoms other than a brassy cough. The most common sign is hilar lymphadenopathy, but segmental atelectasis is possible. Adenopathy may progress, even after chemotherapy is started, and may produce lobar atelectasis, which usually clears during treatment. If hilar adenopathy is present, treatment with INH, RIF, and PZA is recommended for 6 mo (see Table 1: Mycobacteria: Dosing of First-Line Antituberculosis Drugs*).
The elderly:
Reactivated disease can involve any organ, but particularly lungs, brain, kidneys, long bones, vertebrae, or lymph nodes. Reactivation may produce few symptoms and can be overlooked for weeks or months, delaying appropriate evaluation. Outbreaks in nursing homes may produce apical, middle, or lower lobe pneumonia as well as pleural effusion in previously tuberculin-negative residents. The pneumonia may not be recognized as TB and may persist and spread to others despite broad-spectrum antibiotic treatment. In the US, miliary TB and TB meningitis, commonly thought to afflict mainly young children, are more common in the elderly.
Patients > 60 yr with reactivated infection and no previous therapy usually respond well to RIF plus INH because they acquired the infection decades earlier, long before availability of modern drugs, and INH resistance is rare. INH, however, is hepatotoxic in up to 4 to 5% of patients > 65 yr (compared with 1 to 2% of patients < 65 yr). In the elderly, chemoprophylaxis is indicated only if the TST increases ≥ 15 mm from a previously negative reaction. In these converters, INH decreases active TB by 98.5%.
TST sensitivity can be poor in the elderly. Close contacts of an active case and others at high risk with negative TST should receive preventive treatment unless contraindicated.
HIV-infected
patients:
TST sensitivity is generally poor in immunocompromised patients (who may be anergic). In HIV-infected patients with LTBI, active TB develops in about 5 to 10%/yr, whereas it develops in about the same percentage over a lifetime in people who are not immunocompromised. A decade ago, 1⁄2 of HIV-infected TB patients who were untreated or infected with a resistant strain died, with median survival of only 60 days. Outcomes are somewhat better now due to earlier TB diagnosis and antiretroviral therapy, but TB in HIV patients remains a serious concern. 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 patient's chest x-ray may show a nonspecific pneumonia, or even be normal, even though acid-fast bacilli are present in sufficient numbers to appear on a sputum smear.
TB may develop early in AIDS and may be its presenting manifestation. Hematogenous dissemination of TB in people with HIV infection produces a serious, often baffling illness with symptoms of both infections. A mycobacterial illness in an AIDS patient that develops while the CD4+ T cell 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.
TB in HIV-infected people generally responds well to usual regimens when in vitro study shows sensitivity. For multidrug-resistant strains, however, 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 that there are few infecting 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 should receive chemoprophylaxis. (See also the Centers for Disease Control and Prevention's Division of Tuberculosis Elimination's Updated
Guidelines for the Use of Rifamycins for the Treatment of Tuberculosis Among
HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside
Reverse Transcriptase Inhibitors.)
Extrapulmonary
Tuberculosis (TB)
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 in 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 produce anemia, thrombocytopenia, or a leukemoid reaction.
Genitourinary
TB:
Infection of the kidney may present 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 from 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 (1) clear sensorium with abnormal CSF, (2) drowsiness or stupor with focal neurologic signs, and (3) coma. Stroke may develop due to 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 in alcoholics with cirrhosis.
Symptoms may be mild, with fatigue, abdominal pain, and tenderness, or severe enough to mimic acute abdomen. The “doughy abdomen” referred to in old textbooks is rarely present.
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.
Symptoms may begin with a pericardial friction rub, pleuritic and positional chest pain, or fever. Pericardial tamponade may occur, producing dyspnea, neck vein distention, paradoxical pulse, muffled heart sounds, and possibly hypotension.
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