(See also Perinatal Tuberculosis.)
Mycobacteria are small, slow-growing, aerobic bacilli. They are distinguished by a complex, lipid-rich cell envelope responsible for their characterization as acid-fast (ie, resistant to decolorization by acid after staining with carbolfuchsin) and their relative resistance to Gram stain. The most common mycobacterial infection is tuberculosis; others include leprosy and various mycobacterial infections that resemble tuberculosis, such as those caused by Mycobacterium avium complex.
Tuberculosis is a leading infectious cause of morbidity and mortality in adults worldwide, killing about 1.7 million people in 2016, most of them in low- and middle-income countries. HIV/AIDS is the most important factor predisposing to TB infection and mortality in parts of the world where both infections are prevalent.
Tuberculosis properly refers only to disease caused by Mycobacterium tuberculosis (for which humans are the main reservoir). Similar disease occasionally results from the closely related mycobacteria, M. bovis, M. africanum, and M. microti—which together with M. tuberculosis are known as the Mycobacterium tuberculosis complex.
Tuberculosis 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 or laryngeal 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 because of the high number of bacteria contained within a lesion.
Droplet nuclei (particles < 5 μ in diameter) 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. Contact with fomites (eg, contaminated surfaces, food, and personal respirators) do not appear to facilitate spread.
How contagious patients with untreated active pulmonary TB are varies widely. Certain strains of M. tuberculosis are more contagious, and patients with positive sputum smears are more contagious than those with positive results only on culture. Patients with cavitary disease (which is closely associated with mycobacterial burden in sputum) are more contagious than those without.
Environmental factors also are important. Transmission is enhanced by frequent or prolonged exposure to untreated patients who are dispersing large numbers of tubercle bacilli in overcrowded, poorly ventilated enclosed spaces; consequently, people living in poverty or in institutions are at particular risk. Health care practitioners who have close contact with active cases have increased risk.
Thus, estimates of contagiousness vary widely; some studies suggest that only 1 in 3 patients with untreated pulmonary TB infect any close contacts; the WHO estimates that each untreated patient may infect 10 to 15 people per year. However, most of those who are infected do not develop active disease.
Contagiousness decreases rapidly once effective treatment begins; organisms are less infectious even if they persist in sputum, and cough decreases. Studies of household contacts indicate that transmissibility ends within 2 wk of patients starting effective treatment.
Much less commonly, contagion 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). The increasing popularity of cheese made from unpasteurized milk raises new concerns if the cheeses come from countries with a bovine TB problem (eg, Mexico, the United Kingdom).
About one fourth of the world’s population is infected (based on tuberculin skin testing surveys). Of those infected, perhaps 15 million have active disease at any given time.
In 2016, an estimated 10.4 million (140.5/100,000) new tuberculosis cases occurred worldwide. Most new cases occurred in Southeast Asia (45%), Africa (25%), and the Western Pacific(17% ).
Case rates vary widely by country, age, race, sex, and socioeconomic status. In 2016, 64% of new cases occurred in 7 countries; most occurred in India, followed by Indonesia, China, the Philippines, Pakistan, Nigeria, and South Africa (2). A few countries, including North Korea, Lesotho, Mozambique, the Philippines, and South Africa, had incidence rates above 500/100,000 (1).
Rate of infection (for drug-susceptible TB) and mortality are decreasing. New cases declined 1.5% between 2014 and 2015, extending a trend that has been occurring for a number of years. These trends are likely due in part to global TB control efforts that have provided more people with access to drugs for TB and HIV infections.
In the US, the case rate declined from 1994 to 2014. In 2016, 9287 new cases were reported to the CDC for a case rate of 2.9/100,000, which was a slight decrease from 2015. Over half of these cases occurred in patients born outside the US in high-prevalence areas. The TB rate among foreign-born people (14.6/100,000) was much higher than the rate among US-born people (1.1/100,000 ). Risk of being infected is increased for people who live in group facilities, such as shelters, long-term care facilities, or correctional facilities, and for those who have been homeless in the past year. In such high-risk populations, case rates can approach those in high-burden parts of the world.
A resurgence of tuberculosis 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 effective 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 inadequate resources, including diagnostic and treatment delivery systems.
In most parts of the world, drug-resistant TB cannot be rapidly diagnosed and promptly treated with effective regimens, including effective management of adverse effects of 2nd-line drugs. This situation results in ongoing transmission, low cure rates, and amplified resistance. Treatment of XDR-TB has even less favorable outcomes; the mortality rate is extremely high in patients coinfected with HIV, even when they are being treated with antiretroviral drugs. Effective treatment and adverse effect management, community outreach, and social support have resulted in more favorable downward epidemiologic trends for drug-resistant TB in a few areas (eg, Peru, the Tomsk region of Russia). India and China are just beginning to implement countrywide MDR-TB programs, and the future of MDR-TB may be greatly influenced by the success or failure of these programs.
Tuberculosis may occur in 3 stages:
M. tuberculosis bacilli initially cause a primary infection, which uncommonly causes acute illness. Most (about 95%) primary infections are asymptomatic and followed by a latent (dormant) phase. 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.
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 middle or lower lobes. Larger droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single droplet nucleus, which typically carries few organisms. Perhaps only a single organism may suffice to cause infection in susceptible people, but less susceptible people may require repeated exposure to develop infection.
To initiate infection, M. tuberculosis bacilli must be ingested by alveolar macrophages. 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 coalesces 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. Hematogenous dissemination is less likely in patients with partial immunity due to vaccination or to prior natural infection with M. tuberculosis or environmental mycobacteria.
Latent infection occurs after most primary infections. In about 95% of cases, after about 3 wk of uninhibited growth, the immune system suppresses bacillary replication, usually before symptoms or signs develop. Foci of bacilli 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, which usually result from hematogenous seeding from another site of infection) or small areas of consolidation (Ghon foci). A Ghon focus with lymph node involvement is a Ghon complex, which, if calcified, is called a Ranke complex. The tuberculin skin test and interferon-gamma release blood assays (IGRA) become positive during the latent stage of infection. Sites of latent infection are dynamic processes, not entirely dormant as once believed.
Less often, the primary focus progresses immediately, 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.
Healthy people who are infected with tuberculosis have about a 5 to 10% lifetime risk of developing 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 also 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 oxygen tension. Ghon foci and affected hilar lymph nodes are much less likely to be sites of reactivation.
Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate ART have about a 10% annual risk of developing active disease.
Other conditions that facilitate reactivation, but to a lesser extent than HIV infection, include
Jejunoileal bypass surgery
Dialysis-dependent chronic kidney disease
Significant weight loss
Drugs that suppress the immune system
Patients who require immunosuppression after solid organ transplantation are at the highest risk, but other immunosuppressants such as corticosteroids and TNF inhibitors also commonly cause reactivation. Tobacco use also is a risk factor.
In some patients, active disease develops when they are reinfected rather than when latent disease reactivates. Reinfection is more likely to be the mechanism in areas where TB is prevalent and patients are exposed to a large inoculum of bacilli. Reactivation of latent infection predominates in low-prevalence areas. In a given patient, it is difficult to determine whether active disease resulted from reinfection or reactivation.
TB damages tissues through delayed-type hypersensitivity (DTH), 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 of TB varies greatly, depending on the virulence of the organism and the state of host defenses. The course may be rapid in members of isolated populations (eg, Native Americans) who, unlike many Europeans and their American descendents, have not experienced centuries of selective pressure to develop innate or natural immunity to the disease . The course is often more indolent in these European and American 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.
In active pulmonary tuberculosis, even moderate or severe disease, patients may have no symptoms, except “not feeling well,” along with 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 when awakening in the morning, but cough may become more productive as the disease progresses. Hemoptysis occurs only with cavitary TB (due to granulomatous damage to vessels but 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.
Extrapulmonary TB causes various systemic and localized manifestations depending on the affected organs.
Pulmonary tuberculosis is often suspected based on one of the following:
Suspicion for TB is higher in patients who have fever, cough lasting > 2 to 3 wk, night sweats, weight loss, and/or lymphadenopathy and in patients with possible TB exposure (eg, via infected family members, friends, or other contacts; institutional exposure; or travel to TB-endemic areas).
Initial tests are chest x-ray and sputum examination and culture. If the diagnosis of active TB is still unclear after chest imaging and sputum examination, TST or IGRA may be done. Nucleic acid–based tests (eg, PCR) can be diagnostic.
Once TB is diagnosed, patients should be tested for HIV infection, and those with risk factors for hepatitis B or C should be tested for those viruses. Baseline tests of hepatic and renal function should typically be done.
In adults, a multinodular infiltrate above or behind the clavicle is most characteristic of active TB; it suggests reactivation of disease. It is best visualized in an apical-lordotic view or with chest CT.
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 may also result from histoplasmosis in areas where histoplasmosis is endemic (eg, the Ohio River Valley).
Sputum testing is the mainstay for diagnosis of pulmonary tuberculosis. 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. Appropriate precautions (eg, negative-pressure room, N-95 or other fitted respirators) should be used.
The first step is typically microscopic examination to check for 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. Smear microscopy can detect about 10,000 bacilli/mL of sputum, making it insensitive when fewer bacilli are present, as occurs in early reactivation or in patients with HIV coinfection.
Although finding AFB in a sputum smear is strong presumptive evidence of TB, definitive diagnosis requires a positive mycobacterial culture or nucleic acid amplification test (NAAT).
Culture is also required to isolate bacteria for drug-susceptibility testing and genotyping. Culture can detect as few as 10 bacilli/mL of sputum and can be done using solid or liquid media. However, it can take up to 3 mo for final confirmation of culture results. Liquid media are more sensitive and faster that solid media, with results available in 2 to 3 wk. Rapid antigen testing to detect the MPB64 antigen can confirm that organisms growing on mycobacterial culture are M. tuberculosis.
Two types of NAAT are available for TB diagnosis:
Xpert MTB/RIF is an automated rapid nucleic acid amplification test (NAAT) that can simultaneously identify M. tuberculosis DNA in a sputum sample and detect resistance to rifampin (rifampicin) in as little as 2 h. The Xpert MTB/RIF is more sensitive than sputum smear microscopy and about as sensitive as culture for diagnosing TB.
The line probe assay can identify the presence of M. tuberculosis and resistance to rifampin and isoniazid. However, sensitivity is lower than that of Xpert MTB/RIF. This test is usually done only on smear-positive specimens.
There are a variety of diagnostic algorithms that differ based on the tests available.
If an Xpert MTB/RIF test on a sputum sample is positive, the diagnosis of pulmonary TB is considered confirmed. In such cases, treatment can be started based on rifampin susceptibility.
If NAAT and AFB smear results are negative or if AFB smear results are positive and NAAT results are negative, clinical judgment is used to determine whether to begin anti-TB treatment while awaiting results of culture.
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, but several new molecular DSTs can detect drug resistance to rifampin or to rifampin and isoniazid in a sputum sample within hours.
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. However, sputum induction is being used in young children who are able to cooperate.
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.
Multiple-puncture devices (tine test) are no longer recommended.
The TST (Mantoux or PPD—purified protein derivative) is usually done. It is positive in both latent and active infection and thus cannot distinguish between the two. 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:
5 mm: Patients at high risk of developing active TB if infected, such as those who have chest x-ray evidence of past TB, who are immunosuppressed because of HIV infection or drugs (eg, TNF-alpha inhibitors, corticosteroid use equivalent to prednisone 15 mg/day for > 1 mo), or who are close contacts of patients with infectious TB
10 mm: Patients with some risk factors, such as injection drug users, recent immigrants from high-prevalence areas, residents of high-risk settings (eg, prisons, homeless shelters), patients with certain disorders (eg, silicosis, renal insufficiency, diabetes, head or neck cancer), and those who have had gastrectomy or jejunoileal bypass surgery
15 mm: Patients with no risk factors (who typically should not be tested)
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.
False-positive results may occur if patients have nontuberculous mycobacterial infections or have received the BCG vaccine. However, the effect of BCG vaccination on TST wanes after several years; after this time, a positive test is likely to be due to TB infection.
The IGRA is a blood test based on the release of interferon-gamma by lymphocytes exposed in vitro to TB-specific antigens. Although results of 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. Prior BCG vaccination does not cause a false-positive test result on IGRA, unlike on TST.
Long-term studies are being done to see whether TST-positive, IGRA-negative patients (particularly those with immunosuppression) are at low risk of reactivation.
Use of IGRA is limited in low-resource settings because of its relatively high cost.
In immunocompetent patients with drug-susceptible pulmonary tuberculosis, even severe disease with large cavities, appropriate therapy is usually curative if it 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 a patient's initial presentation, especially with MDR-TB. However, with effective antiretroviral therapy (and appropriate anti-TB treatment), the prognosis for patients with HIV infection, even those with MDR-TB, may approach that of immunocompetent patients. Poorer outcomes should be expected for patients with XDR-TB because there are so few effective drugs.
Most patients with uncomplicated tuberculosis 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 Official American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America: Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.
Most patients with TB can be treated as outpatients, with instructions on how to prevent transmission usually including
Surgical face masks for TB patients are stigmatizing and are typically not recommended for cooperative patients. Precautions are needed until drug treatment has made patients sufficiently noncontagious. For patients with proven drug-susceptible or MDR-TB, precautions are maintained until there is a clinical response to therapy (typically, 1 to 2 wk). However, for XDR-TB, response to treatment may be slower, and the consequences of transmission even greater; thus, a more convincing response to therapy (eg, smear or culture conversion) is required to end precautions.
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, even though patients receiving effective treatment become noncontagious before sputum smears become negative, release from respiratory isolation usually requires 3 negative sputum smears over 2 days, including at least one early-morning negative specimen.
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, directly observed therapy (DOT) is becoming part of optimal patient case management; DOT involves supervision by public health personnel of the ingestion of every dose of drug. 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 monitoring devices have been advocated to improve adherence with SAT.
Public health departments usually visit homes to do the following:
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 contagiousness. For patients who are highly contagious 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; patients who do not infect any household contacts are less likely to infect casual contacts.
The first-line drugs isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) are used together in initial treatment (for regimens and doses, see Tuberculosis (TB) : Treatment regimens and see Table: Dosing of Oral First-Line Anti-TB Drugs*).
Dosing of Oral First-Line Anti-TB Drugs*
Isoniazid (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. 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.
Adverse effects of isoniazid include rash, fever, and, rarely, anemia and agranulocytosis. INH causes asymptomatic, transient aminotransferase elevations in up to 20% of patients and clinical (usually reversible) hepatitis in about 1/1000. Clinical hepatitis occurs 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 done. 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 recurrence of symptoms and deterioration of liver function. 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. It can also cause a violent reaction to disulfiram, a drug occasionally used for alcoholism. INH is safe during pregnancy.
Rifampin (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 of rifampin include cholestatic jaundice (rare), fever, thrombocytopenia, and renal failure. RIF has a lower rate of hepatotoxicity than INH. Drug interactions must be considered when using RIF. 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 are particularly complex; combined use requires specialized expertise. RIF is safe during pregnancy.
The following newer rifamycins are available for special situations:
Rifabutin is used for patients taking drugs (particularly antiretroviral drugs) that have unacceptable interactions with RIF. Its action is similar to RIF, but it affects the metabolism of other drugs less. When used with clarithromycin or fluconazole, rifabutin has been associated with uveitis.
Rifapentine is used in one dose/wk regimens (see Table: Dosing of Oral First-Line Anti-TB Drugs*) but is not used in children or patients with HIV (because of unacceptable treatment failure rates) or extrapulmonary TB. It is also used in a 12-dose, once/wk DOT regimen with INH for TB prophylaxis. This prophylactic combination is not recommended for children < 2 yr, HIV-infected patients receiving antiretroviral treatment, pregnant women, or women expecting to become pregnant during treatment because safety in these groups is unknown.
Pyrazinamide (PZA) is an oral bactericidal drug. When used during the intensive initial 2 mo of treatment, it shortens the duration of therapy to 6 mo and prevents development of resistance to RIF.
The major adverse effects of pyrazinamide are GI upset and hepatitis. It often causes hyperuricemia, which is generally mild and only rarely induces gout. PZA is commonly used during pregnancy, but its safety has not been confirmed.
Ethambutol (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 with optic neuritis 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. Patients taking EMB for > 2 mo or at doses higher than those listed in the table above should have monthly visual acuity and color vision testing. 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. Ethambutol can be used safely during pregnancy. Resistance to EMB is less common than that to the other first-line drugs.
Other antibiotics are active against TB and are used primarily when patients have drug-resistant TB (DR-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; aminoglycosides are available only for parenteral use.
Streptomycin, once 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 of streptomycin include renal tubular damage, vestibular damage, and ototoxicity. The dose is about 15 mg/kg IM. The maximum is 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 the drug only 5 days/wk for up to 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 of streptomycin 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 cause vestibular toxicity and ototoxicity 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. Kanamycin is the most widely used injectable for MDR-TB.
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 isoniazid and rifampin, but they are not first-line drugs for TB susceptible to isoniazid and rifampin. Moxifloxacin appears to be as active as isoniazid when used with rifampin.
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.
Bedaquiline, delamanid, and sutezolid are new anti-TB drugs that are typically reserved for highly resistant TB (precise indications are not yet fully defined) or for patients who cannot tolerate other 2nd-line drugs.
Drug resistance develops through spontaneous genetic mutation. Incomplete, erratic, or single-drug therapy selects for these resistant organisms. Once a drug-resistant strain has developed and proliferates, it may acquire resistance to additional drugs through the same process. In this way, the organism can become resistant to multiple antibiotics in steps.
MDR-TB is resistant to isoniazid and rifampin, with or without resistance to other drugs. Numerous outbreaks of MDR-TB have been reported, and the global burden is increasing. The WHO estimates that 220,000 to 490,000 new cases occurred worldwide in 2016. In parts of the world where resistance testing is inadequate or unavailable, many patients who do not respond to first-line therapy probably have unrecognized MDR-TB. Multidrug resistance 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.
Pre-XDR-TB is MDR-TB plus resistance to either a fluoroquinolone or an injectable drug but not both.
XDR-TB extends the resistance profile of MDR-TB to include fluoroquinolones and at least one injectable drug (eg, streptomycin, amikacin, kanamycin, capreomycin). This additional resistance has dire therapeutic implications. Although some patients with XDR-TB can be cured, mortality is higher, and the outcome depends on the number of effective drugs that remain as well as the extent of lung destruction caused by the bacilli.
Surgery to remove localized areas of necrotic lung tissue is important in the treatment of advanced cases of MDR-TB or XDR-TB but is not widely available in high-burden areas.
Resistant strains can be transmitted from person to person. A person who is infected with a drug-resistant strain from another person is said to have primary drug resistance. Slightly more than half of all MDR-TB cases have not previously been treated, probably because of transmission of (often reinfection with) MDR or XDR strains. 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 and improved access to culture and susceptibility testing), stepwise resistance to new drugs is likely.
Successful treatment of drug-resistant TB depends on the use of multiple active drugs simultaneously, so that any resistance to one drug is countered by the killing effects of a 2nd, 3rd or 4th drug. Furthermore, all drugs in the regimen must be taken scrupulously for an extended period. Any lapses in adherence may lead to further drug resistance and/or treatment failure.
The new anti-TB drugs bedaquiline, delamanid, and sutezolid are active against resistant strains and may help control the epidemic of drug-resistant TB. However, success will continue to depend on strong global efforts to diagnose TB early, give patients appropriate therapy, and provide supervision of ingestion of each dose (DOT).
Treatment of all patients with new, previously untreated TB should consist of a
Initial intensive–phase therapy is with 4 antibiotics:
Ethambutol (EMB—see Table: Dosing of Oral 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/week 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 (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
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 usually 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.
Patients who have positive cultures after 2 mo of treatment should be evaluated to determine the cause. Evaluation for MDR-TB, a common cause, should be thorough. Clinicians should also check for other common causes (eg, nonadherence, extensive cavitary disease, drug resistance, malabsorption of drugs).
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 treatment for 18 to 24 mo using a regimen that contains 4 or 5 active drugs. Presumed activity is based on drug susceptibility test results, a known source case, prior exposure to anti-TB drugs, or drug susceptibility patterns in the community. The regimen should include all remaining active first-line drugs (including PZA, if the strain is susceptible) plus a 2nd-line injectable, a fluoroquinolone, and other 2nd-line drugs as needed to build a 4- or 5-drug regimen. Designing a treatment regimen for XDR-TB becomes even more challenging, often requiring the use of unproven and highly toxic drugs such as clofazimine and linezolid.
Managing adverse effects of these long, complex regimens is challenging. A TB specialist experienced with drug-resistant TB should be consulted for assistance in managing these cases. DOT is essential to avoid development of additional drug resistance through nonadherance.
Surgical resection of a persistent TB cavity or a region of necrotic lung tissue is occasionally necessary. The main indication for resection is persistent, culture-positive MDR-TB or XDR-TB in patients with a region of necrotic lung tissue 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.
Close contact with a person who has active pulmonary TB
Chest x-ray evidence of past TB infection
Risk factors for exposure to TB (eg, people who have immigrated within 5 yr from high-risk areas, indigent patients, IV drug users, selected US health care practitioners such as respiratory therapists and practitioners working with high-risk populations)
Risk factors for development of active TB (eg, HIV infection or other impaired immunity, gastrectomy, jejunoileal bypass surgery, silicosis, renal insufficiency, diabetes, head or neck cancer, age > 70 yr)
Therapeutic immunosuppression with corticosteroids, TNF inhibitors, or cancer chemotherapy
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 result (see Tuberculosis (TB) : Skin testing for criteria) suggests LTBI. Patients with a positive TST or IGRA result are evaluated for other clinical and epidemiologic 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 by microscopy and culture.
Updated guidelines for testing and treatment of LTBI are available at the CDC web site (www.cdc.gov).
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 (on the opposite forearm) 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 latent tuberculosis infection 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 9 mo for most adults and 10 mg/kg for 9 mo for children. An alternative for patients resistant to or intolerant of INH is RIF 600 mg once/day for 4 mo. DOT with INH plus rifapentine taken once/wk for 3 mo is also effective.
The main limitations of treatment of LTBI are
When 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.
Only about 50% of patients complete the recommended 9-mo course of INH. Adherence is better with 4 mo of RIF. Monthly visits to monitor symptoms and to encourage treatment completion are standard good clinical and public health practice.
General preventive measures (eg, staying at home, avoiding visitors, covering coughs with a tissue or hand) are followed.
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%. BCG clearly reduces the rate of extrathoracic TB in children, especially TB meningitis, and may prevent TB infection. Thus, it is considered worthwhile in high-burden regions. Immunization with BCG has few indications in the US, except unavoidable exposure of a child to an infectious TB case that cannot be effectively treated (ie, pre-XDR or XDR-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 15 yr after BCG administration, it is rarely > 10 mm. The 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 are not influenced by BCG vaccination and should ideally be used in patients who have received BCG to be sure that the TST response is due to infection with M. tuberculosis.
Children infected with tuberculosis are more likely than adults to develop active disease, which commonly manifests as extrapulmonary disease. Lymphadenitis (scrofula) is the most common extrapulmonary manifestation, but TB may also affect the vertebrae (Pott disease), the highly vascular epiphyses of long bones, or the CNS and meninges.
Clinical presentation of active TB in children varies, making the diagnosis challenging. Most children have few symptoms other than a brassy cough.
Obtaining a sample for culture often requires one of the following:
The most common sign on chest x-ray 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 contagious.
Treatment strategies are similar to those for adults except that drugs must be dosed strictly based on the child's weight (see Table: Dosing of Oral First-Line Anti-TB Drugs*).
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.
Regardless of their age, nursing home residents who were previously TST negative are at risk of disease due to recent transmission, which may cause apical, middle-lobe, or lower-lobe pneumonia as well as pleural effusion. The pneumonia may not be recognized as TB and may persist and spread to other people while it is being erroneously treated with ineffective broad-spectrum antibiotics.
In the US, miliary TB and TB meningitis, commonly thought to affect mainly young children, are more common among the elderly.
Risks and benefits of preventive treatment should be carefully assessed before the elderly are treated. INH causes hepatotoxicity in up to 4 to 5% of patients > 65 yr (compared with < 1% of patients < 65 yr). As a result, chemoprophylaxis is usually given to the elderly only if the induration after TST increases ≥ 15 mm from a previously negative reaction. Close contacts of an active case and others at high risk and with a negative TST or IGRA should also be considered for preventive treatment unless contraindicated.
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 patients with untreated HIV infection and 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 (mass lesions in the lungs or CNS due to TB) are more common and more destructive. HIV infection 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.
Smear-negative TB is more common when HIV coinfection is present. Because smear-negative TB is common, HIV-TB coinfection is often considered a paucibacillary disease state.
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. aviumcomplex (MAC). Infection with MAC is not contagious and, in HIV-infected patients, affects primarily the blood and bone marrow, not the lungs.
HIV-infected patients who were not diagnosed before presenting with TB should receive 2 wk of antimycobacterial treatment before starting antiretroviral therapy to decrease the risk of developing the immune reconstitution inflammatory syndrome(IRIS). TB in HIV-infected patients generally responds well to usual regimens when in vitro testing shows drug susceptibility. 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.
Tuberculosis causes a primary, often asymptomatic infection followed by latent infection and, in a few patients, an active disease phase.
About one fourth of the world's population is infected with tuberculosis, and about 15 million have active disease at a given time.
Active disease is much more likely in patients with impaired immunity, particularly those with HIV infection.
Suspect the diagnosis based on symptoms, risk factors, tuberculin skin testing, and interferon-gamma release assays; confirm by sputum testing (microscopic examination and culture) and/or nucleic acid amplification tests.
Treat with multiple drugs for several months.
Drug resistance is a major concern and is increased by poor adherence, use of inappropriate drug regimens, and inadequate susceptibility testing.