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Tuberculosis (TB)

By

Edward A. Nardell

, MD, Harvard Medical School

Last full review/revision Jul 2022| Content last modified Jul 2022
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Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include productive cough, fever, weight loss, and malaise. Diagnosis is most often by sputum smear and culture and, when available, by nucleic acid amplification tests. Treatment is with multiple antimicrobial drugs given for at least 4 months.

Mycobacteria are small, slow-growing, aerobic bacilli. They are distinguished by a complex, lipid-rich cell envelope that makes them acid-fast (ie, resistant to decolorization by acid after staining with carbolfuchsin) and relatively resistant to Gram stain. The most common mycobacterial infection is tuberculosis; others include leprosy Leprosy Leprosy is a chronic infection usually caused by the acid-fast bacilli Mycobacterium leprae or the closely related organism M. lepromatosis. These organisms have a unique tropism... read more Leprosy and various environmental nontuberculous mycobacterial infections Nontuberculous Mycobacterial Infections There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more , such as those caused by Mycobacterium avium complex.

Tuberculosis (TB) is a leading infectious cause of death in adults worldwide, killing about 1.5 million people in 2020, most of them in low- and middle-income countries ( 1 General reference Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more General reference ). HIV/AIDS is the most important factor predisposing to TB infection and mortality in parts of the world where both infections are prevalent.

General reference

Etiology of TB

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. These three bacteria, together with M. tuberculosis and other less common mycobacteria, are known as the Mycobacterium tuberculosis complex.

TB results almost exclusively from inhalation of airborne particles (droplet nuclei) containing M. tuberculosis. They disperse primarily through coughing, singing, and other forced respiratory maneuvers by people who have active pulmonary or laryngeal TB and whose sputum contains a large number of organisms (about 10,000 organisms/mL, the limit of detection by fluorescent microscopy). People with pulmonary cavitary lesions are especially contagious because of the large number of bacteria contained within a lesion.

Droplet nuclei (particles < 5 micrometers 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, personal respirators) do not appear to facilitate spread.

Untreated active pulmonary TB is highly variable in contagiousness. Certain strains of M. tuberculosis are more contagious, and patients with positive sputum smears Sputum examination, culture, and testing Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Sputum examination, culture, and testing 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. Respiratory secretions with lower viscosity are more easily aerosolized, and the effectiveness of cough and other respiratory maneuvers in generating aerosol varies greatly.

Environmental factors also are important. Transmission is enhanced by frequent or prolonged exposure to untreated patients who are generating 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, but the World Health Organization (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; cough decreases, and organisms are noninfectious even if they persist in sputum. Epidemiologic studies of household contacts suggest that transmission ends within 2 weeks of patients starting effective treatment, but more precise human-to-animal studies suggest that transmission ends within a few days of starting treatment.

Much less commonly, contagion results from aerosolization of organisms after irrigation of infected wounds, in mycobacteriology laboratories, or by aerosol or direct puncture 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 countries where milk is pasteurized and cows that have a positive tuberculin skin test result are slaughtered. Tuberculosis due to M. bovis still occurs in countries where bovine tuberculosis is endemic (eg, some Latin American countries) and in immigrants from those 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). Bovine and human TB can be transmitted to other species such as badgers, deer, primates, and zoo animals. Slaughterhouses have been associated with zoonotic TB transmission.

Epidemiology of TB

Based on tuberculin skin testing surveys, it is estimated that about one fourth of the world’s population is infected. Of those infected, perhaps 15 million have active disease at any given time.

In 2020, an estimated 9.9 million (127/100,000) new tuberculosis cases occurred worldwide. Most new cases occurred in Southeast Asia (43%), Africa (25%), and the Western Pacific (18%) ( 1) Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references .

Case rates vary widely by country, age, race, sex, and socioeconomic status. In 2020, two thirds of new cases occurred in 8 countries; most occurred in India (26%), followed by Indonesia (8.4%), China (8.5%), the Philippines (6.0%), Pakistan (5.8%), Nigeria (4.6%), Bangladesh (3.6%), and South Africa (3.3%) ( 1 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ). A few countries, including North Korea, Lesotho, Mozambique, the Philippines, and South Africa, had incidence rates above 500/100,000 ( 1 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ).

Globally, drug-susceptible TB incidence and mortality are slowly decreasing. The cumulative reduction from 2015 to 2019 was 9% (from 142 to 130 new cases per 100,000), including a reduction of 2.3% between 2018 and 2019. 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. However, the 2020 to 2021 global COVID-19 pandemic disrupted other public health programs, including TB control, and although it is too soon to quantify, the WHO predicts a stalling or reversal of these decreasing global trends ( 1 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ).

In the US in 2021, 7860 new cases of TB were reported to the CDC for a case rate of 2.4/100,000 ( 2 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ). During the COVID-19 pandemic in 2020, there was a 20% decrease from 2019 rates ( 3 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ). The breadth and magnitude of this 20% decrease compared to the usual 2 to 3% per year decrease suggest there was under-reporting of TB during the COVID-19 pandemic and/or delayed diagnosis of a substantial number of cases. During 2020, 71% of US TB cases occurred in patients born outside the US in high-prevalence areas. The TB rate among non–US-born people (11.5/100,000) was much higher than the rate among US-born people (0.7/100,000 [ 3 Epidemiology references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Epidemiology references ]). Risk of TB 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 TB occurred in parts of the US and other economically advanced 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, defined as resistance to at least isoniazid and rifampin). MDR-TB and rifampin-resistant TB (MDR/RR-TB) have been substantially controlled in the US by effective public health and institutional infection control measures, but until recently, infection caused by these organisms had been increasing around the world. However, the incidence appears to be slowly decreasing worldwide. Decreasing TB incidence and improved (molecular) diagnostics, treatment, and case management of drug-sensitive and drug-resistant TB are the likely explanations. Although MDR/RR-TB cases make up less than 4% of incident cases, the diagnosis and treatment of these cases consume a disproportionate fraction of TB control resources. MDR/RR-TB results in a disproportionate share of human suffering, death, and economic consequences for impacted people and their families.

Still, in many parts of the world, MDR/RR-TB cannot be rapidly diagnosed and promptly treated with effective regimens, including effective management of adverse effects of second-line drugs. This situation results in ongoing transmission, low cure rates, and amplified resistance. Treatment of highly drug-resistant TB cases has had even less favorable outcomes, including high mortality rates, especially in patients coinfected with HIV, even when they are being treated with antiretroviral drugs. Newer, shorter, more effective (noninjectable) treatment regimens combined with adverse effect management, community outreach, and social support have resulted in more favorable downward epidemiologic trends for drug-resistant TB globally, especially in a few areas (eg, Peru, the Tomsk region of Russia). India and China are implementing countrywide MDR-TB programs, and the future of MDR-TB may be greatly influenced by the success or failure of these programs.

Epidemiology references

Pathophysiology of TB

Tuberculosis may occur in 3 stages:

  • Primary infection

  • Latent infection

  • Active infection

M. tuberculosis bacilli initially cause a primary infection, a small percentage of which eventually progress to clinical disease of variable severity. However, most (about 95%) primary infections are asymptomatic. An unknown percentage of primary infections resolve spontaneously, but the majority are followed by a latent (dormant) phase. A variable percentage (5 to 10%) of latent infections subsequently reactivate with symptoms and signs of disease.

Infection is usually not transmissible in the primary stage and is never contagious in the latent stage.

Primary TB infection

Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lungs, 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 TB infection occurs after most primary infections. In about 95% of cases, after about 3 weeks 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 Skin testing Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Skin testing and interferon-gamma release blood assays ( IGRA IGRA (interferon-gamma release assay) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more IGRA (interferon-gamma release assay) ) become positive during the latent stage of infection. Sites of latent infection are dynamic processes and are not entirely dormant as was 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 Extrapulmonary Tuberculosis (TB) Tuberculosis outside the lung usually results from hematogenous dissemination. Sometimes infection directly extends from an adjacent organ. Symptoms vary by site but generally include fever... read more Extrapulmonary Tuberculosis (TB) at any site can sometimes manifest without evidence of lung involvement. TB lymphadenopathy is the most common extrapulmonary manifestation; however, meningitis is the most feared because of its high mortality in the very young and very old.

Active TB disease

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 years, but it can also reactivate 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 Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.

Other risk factors that facilitate reactivation, but to a lesser extent than HIV infection, include

Patients who require immunosuppression after solid organ transplantation are at the highest risk, but other immunosuppressants such as corticosteroids and tumor necrosis factor (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 Type IV (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.

Symptoms and Signs of TB

Primary infection is almost always asymptomatic, but when symptoms occur, they typically are nonspecific and include low-grade fever and fatigue without a prominent cough.

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 delayed hypersensitivity is impaired; patients are more likely to have symptoms of extrapulmonary or disseminated disease.

Diagnosis of TB

  • Chest x-ray

  • Acid-fast stain and culture

  • Tuberculin skin test (TST) or interferon-gamma release assay (IGRA)

  • When available, nucleic acid amplification test (NAAT)

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 weeks, night sweats, weight loss, and/or lymphadenopathy and in patients with possible TB exposure (eg, via infectious 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, but these are tests for infection not active disease. NAATs (eg, polymerase chain reaction [PCR]–based) are rapid and can be diagnostic.

Chest x-ray

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 younger) 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 Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those... read more Histoplasmosis in areas where histoplasmosis is endemic (eg, the Ohio River Valley).

Sputum examination, culture, and testing

Sputum testing is the mainstay for diagnosis of pulmonary tuberculosis. A nonsputum-based diagnostic test has long been sought because sputum is often difficult to collect; breath and urine tests are available, and the urine tests have proved useful in diagnosing TB disease in people with HIV infection. 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 in sputum examination 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 the more sensitive 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 in the presence of TB risk factors, in other settings environmental mycobacteria may be more likely, and definitive diagnosis requires a positive mycobacterial culture or NAAT.

Culture is also required to isolate bacteria for conventional drug susceptibility testing and genotyping. However, molecular drug susceptibility testing is increasingly replacing culture-based methods. 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 months for final confirmation of culture results. Liquid media are more sensitive and faster that solid media, with results available in 2 to 3 weeks. 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

  • Line probe assay

Xpert MTB/RIF is an automated rapid NAAT that can simultaneously identify M. tuberculosis DNA in a sputum sample and detect resistance to rifampin (rifampicin) in as little as 2 hours. The Xpert MTB/RIF NAAT is more sensitive than sputum smear microscopy and about as sensitive as culture for diagnosing TB. Newer versions of Xpert MTB/RIF Ultra (Xpert Ultra) can detect resistance mutations to both first-line drugs First-line drugs for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more First-line drugs for TB and many second-line drugs Second-line drugs for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Second-line drugs for 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. Probes for several second-line drugs are available.

There are a variety of diagnostic algorithms that differ based on the tests available.

If an Xpert MTB/RIF or Xpert Ultra test on a sputum sample is positive, the diagnosis of pulmonary TB is considered confirmed. In such cases, treatment can be started based on local drug susceptibility patterns.

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

Drug susceptibility tests 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 months of treatment or if cultures become positive after a period of negative cultures. TB disease can be caused by more than one strain, each with different drug resistance patterns, especially in settings of high transmission.

Results of susceptibility tests may take up to 8 weeks if conventional bacteriologic methods are used, but as noted above, several molecular DSTs can rapidly (within hours) detect drug resistance to rifampin and other first- and second-line drugs.

Tests of other specimens

Transbronchial biopsies can be done on infiltrative lesions, and samples are submitted for culture, histologic evaluation, and molecular testing.

Gastric washings, which are culture-positive in a minority of samples, are no longer commonly used except in small children, who usually cannot produce a good sputum specimen. However, sputum induction is being used in young children who are able to cooperate.

Ideally, biopsy samples of other tissue should be cultured fresh. Culture of fresh specimens remains the gold standard for the detection of M. tuberculosis in tissue because fixation can inhibit PCR, and PCR does not distinguish viable from dead organisms. However, NAAT can be used for fixed tissues when necessary (eg, for biopsied lymph node if histologic examination unexpectedly detects granulomatous changes). This use of NAAT has not been approved, but it can be extremely useful, although positive and negative predictive values have not been established.

Skin testing

Multiple-puncture devices (tine test) are no longer recommended.

The tuberculin skin test (TST—Mantoux intradermal method) using purified protein derivative (PPD) is usually done. The TST measures the immunologic response to M. tuberculosis and thus should be positive in both latent and active infection and so 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 upon injection indicates a properly placed injection. The diameter of induration (not erythema) transverse to the long axis of the arm is measured 48 to 72 hours after injection. Use of a pen to demarcate the boundaries of induration on the skin can help produce more precise measurements, but reading skin tests is inherently variable and subject to a number of errors, including terminal digit preference, that is, a tendency to favor recording 5-, 10-, 15- and 20-mm results. In research studies, measurements done with a caliper or ruler where measurement numbers were not immediately visible to the reader produced less biased readings.

Given the difficulty of demarcating and accurately measuring the induration, it is ill-advised to attach clinical significance to minor differences. For example, a 9-mm reading should probably not be interpreted as different from an 11-mm reading (ie, treating the 11-mm reading as latent infection while dismissing the 9-mm reading as uninfected). Among household contacts, and in other settings where recent transmission is considered certain, TST results average about 17 mm in induration. Clinically, it is useful to remember that recently infected people are at greatest risk of reactivation and that, if they are immunocompetent, they usually have a vigorous immune response, manifested by a large TST or interferon gamma release test ( IGRA IGRA (interferon-gamma release assay) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more IGRA (interferon-gamma release assay) ) result.

Pearls & Pitfalls

  • With the tuberculin skin test, it is the diameter of induration, not erythema, that is measured.

TST responses tend to decrease over time, commonly long outlasting the presence of viable M. tuberculosis organisms capable of reactivation. Although late reactivation is well documented, most reactivation of latent infection occurs within a year to 18 months of initial infection. Treating latent TB many years after infection likely occurred may be advisable when immunosuppression is contemplated, but residual infection that is likely to reactivate may no longer be present. Reversion of skin tests that occurs in the absence of treatment or anergy (no reaction to any skin test) is often missed because follow-up testing is not done. Spontaneous cure is the likely reason. In settings of high transmission, disease often results from recent rather than remote infection, although both can occur.

Repeated administration of TSTs can cause the immune system to recall previous hypersensitivity that has waned over time, so-called boosting. Unrecognized, boosting can result in unnecessary treatment of contacts, for example, in the context of an outbreak investigation. To avoid misinterpreting boosting as recent infection in settings where serial testing is indicated, two-step baseline testing is recommended. The idea is to retest people with a negative TST result within a 1 to 4 weeks to see whether there is recall of previous hypersensitivity. If not, that result is a true negative. However, a positive TST result on retesting 1 to 4 weeks after the first test is assumed to indicate pre-existing latent infection and patients are treated or not treated based on clinical criteria. Boosting is not a problem with repeated IGRA testing because no antigens are injected.

Recommended cutoff points for a positive TST 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 month), 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)

False-negative TST results can occur, most often in patients who are febrile, older, HIV-infected (especially if CD4 count is < 200 cells/mcL [0.2 x 109/L]), 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 TST results may occur if patients have nontuberculous mycobacterial infections Nontuberculous Mycobacterial Infections There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more or have received the bacille Calmette-Guérin (BCG) vaccine. However, the effect of BCG vaccination on TST usually wanes after several years; after this time, a positive test is likely to be due to TB infection. Infection after BCG vaccination occurs in high-transmission settings. People arriving in the US from high-burden areas often cite BCG as the reason for their positive TST, rather than get stigmatized by a diagnosis of TB, and resist treatment for latent infection even when it is clearly indicated. Authorities suggest that BCG vaccination status should be ignored and infection assumed, but this leads to overdiagnosis of latent TB infection, unnecessary concern and treatment, and potential drug adverse effects. The use of IGRAs to diagnose TB infection, although not also without interpretation problems, has largely solved the BCG/latent TB infection controversy.

IGRA (interferon-gamma release assay)

Two commercial IGRAs with different testing platforms exist, but many comparative studies reveal very similar performance. The choice of IGRA is often dictated by availability in a given clinical setting.

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. Unlike the TST, prior BCG vaccination does not cause a false-positive test result on IGRA, but repeat TST testing itself can cause low-level positive IGRA results. Like the TST, IGRAs do not distinguish active from latent TB and although lymphocyte hypersensitivity occurs in both conditions, because in vitro lymphocyte stimulation with TB antigens is brief, IGRAs are thought more likely to reflect recent (sensitized circulating lymphocytes) rather than remote (sensitized memory lymphocytes) TB infection. Therefore, IGRAs are thought to better correlate with a risk of reactivation compared to the TST.

In low-TB burden areas where more resources are available to focus on latent infection, IGRAs have largely replaced the TST because they have less operator-related variability, lack BCG interference, lack boosting Booster reaction Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Booster reaction , and people do not have to return for a reading. However, in low-TB burden areas like the US, fewer and fewer people are at sufficient risk to warrant even one-time much less serial TB testing.

Use of IGRA is limited in low-resource settings because of its relatively high cost. However, the WHO is emphasizing the treatment of latent infection in high-TB burden as a necessary component of TB elimination globally. Because of BCG interference with the TST, IGRAs are clearly more specific for latent TB.

Prognosis for TB

In immunocompetent patients with drug-susceptible pulmonary tuberculosis, even severe disease with large cavities, appropriate, drug susceptibility test–directed therapy is usually curative if it is instituted promptly 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. In addition, there is substantial morbidity resulting from residual tissue damage (lungs especially, but any organ) remaining after bacteriological cure. Tissue damage often results from the immune response to infection, most dramatically in the immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Immune reconstitution inflammatory syndrome (IRIS) (IRIS), but is increasingly recognized in advanced cases of TB, where TB-induced inflammation can lead to, for example, chronic respiratory insufficiency, upper airway stenosis, constrictive pericarditis, and skeletal deformities.

Although immune-induced tissue damage is a major problem, the lack of an immune response is an even greater problem. TB progresses more rapidly and more extensively in immunocompromised patients and, if not appropriately and aggressively treated, can be fatal in as little as 2 months from a patient's initial presentation, especially with multidrug-resistant TB (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 have occurred in patients with extensively drug-resistant TB because of less effective treatment, but this is rapidly changing as new regimens address highly drug-resistant TB.

Treatment of TB

  • Measures to prevent transmission, sometimes including respiratory isolation

  • Antibiotics

Depending on the degree of illness and social circumstances, most patients with TB can be treated as outpatients. Instructions on how to prevent transmission usually include

  • Staying at home

  • Avoiding visitors (except for previously exposed family members)

  • Covering coughs with a tissue

Surgical face masks for patients with TB are effective at limiting transmission but can be stigmatizing and are typically not recommended for cooperative patients except, for example, those who need pretreatment in a hospital or clinic. Longstanding expert advice has been to maintain transmission control precautions for at least 2 weeks after initiation of treatment that the patient is responding to (as noted by decreased cough, fever, and fatigue). However, there is strong evidence indicating that effective treatment stops transmission much more quickly, within hours or days of initiation through sublethal effects on organisms, which is long before sputum conversion by sputum smear or culture (usually takes 2 months). This finding appears to be true even in most drug-resistant cases (when effectively treated). However, accurately predicting the likelihood that treatment will be effective requires drug susceptibility test (DST) data on the patient's TB isolate, and ideally enough time to judge a good clinical response. Also, drugs must match the DST profile, must be reliably ingested, and achieve therapeutic blood levels. Thus, although effective drugs may stop transmission within hours, a few days of observing the patient undergoing treatment may be needed to ensure a good clinical response. For highly drug-resistant TB, the consequences of transmission are greater and the response to treatment may be slower, so greater caution is used before transmission control precautions are removed.

Hospitalization

The main indications for hospitalization for active TB are

  • Serious concomitant illness

  • Need for diagnostic procedures

  • Social issues (eg, homelessness)

  • Need for respiratory isolation, as for people living in congregate settings where previously unexposed people would be regularly encountered (important primarily if effective treatment cannot be ensured)

Because the consequences of drug-resistant TB are so great, hospitalization with respiratory isolation for treatment initiation is warranted at least until a clinical response to treatment is certain. Ideally, all hospitalized patients should be in a negative-pressure room with 6 to 12 air changes/hour. Healthcare personnel 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 consequences of infecting other vulnerable 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. Two negative sputum NAATs can be used to rule out TB for isolation purposes in patients under evaluation based on symptoms or signs but cannot be used in patients with known TB because M. tuberculosis DNA may be detected by NAATs long after treatment renders patients noninfectious. However, discharging patients directly home from isolation rooms regardless of sputum smear status often makes good sense because household members (who have been previously exposed) are likely at less risk than hospital patients whose illnesses render them more vulnerable.

A frequent question is how long patients require hospitalization for TB. Given that most patients with TB, regardless of sputum smear status, can be diagnosed and treated entirely on an ambulatory basis while living at home, there should be no required amount of hospitalization before discharge nor should discharge be based on sputum smear or culture status. As noted, the start of effective treatment rapidly reduces transmission. In the US, patients with TB are often first encountered in the hospital emergency department, admitted for diagnosis, and started on treatment while the health department is notified of the case and arrangements are made for contact investigations and supervised treatment. Because this sequence of admission and respiratory isolation occurs often, the false impression exists that hospitalization and respiratory isolation are required until a person is deemed not contagious based on sputum tests. This requirement is incorrect, and clinicians should focus on clinically responsible early discharge.

Pearls & Pitfalls

  • In hospitals and clinics, the highest risk of TB transmission is from patients who have undiagnosed TB or unidentified drug resistance and are receiving inadequate treatment, not from known TB patients who are receiving effective treatment.

Public health considerations

To improve treatment adherence, ensure cure, and limit transmission and the development of drug-resistant strains, public health programs closely monitor treatment, even if patients are being treated by a private physician. In most US 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 part of optimal patient case management; DOT involves supervision by public health personnel (ideally not family members) of the ingestion of every dose of drug. DOT increases the likelihood from 61% to 86% that the full treatment course will be completed. Enhanced DOT, in which incentives and enablers such as transportation vouchers, child care, outreach workers, and meals are provided, increases the likelihood to 91%.

DOT is particularly important

  • For children and adolescents

  • For patients with HIV infection, psychiatric illness, or substance abuse

  • After treatment failure, relapse, or development of drug resistance

In some programs, selective self-administered treatment (SAT) is an option for patients who are judged 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:

  • Evaluate potential barriers to treatment (eg, extreme poverty, unstable housing, child care problems, alcohol use disorder, mental illness)

  • Check for other active cases

  • Assess close contacts

Close contacts are people who share the same breathing space for prolonged periods, typically household residents, but often include people at work, school, and places of recreation. The precise duration and degree of contact that constitute risk vary because patients with TB 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 Screening for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Screening for TB and preventive treatment Treatment of LTBI Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment of LTBI if needed. Patients who do not infect any household contacts are less likely to infect casual contacts.

First-line drugs for TB

The first-line drugs isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) are used together in initial treatment. There are a several different TB treatment regimens Treatment regimens Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment regimens , chosen based on numerous factors. Dosing of first-line drugs Dosing of Oral First-Line Anti-TB Drugs* Dosing of Oral First-Line Anti-TB Drugs* can be done at different intervals.

Isoniazid (INH) is given orally once/day, has good tissue penetration (including cerebrospinal fluid), 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 years old, patients with alcohol use disorder, postpartum women, and patients with chronic liver disease. Monthly liver 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 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, patients with alcohol use disorder, patients with cancer or uremia, and older patients. 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 alcohol use disorder. INH is safe during pregnancy.

Rifampin (RIF), given orally, is bactericidal, is well-absorbed, penetrates well into cells and cerebrospinal fluid, 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:

In 2020, nitrosamine impurities were found in samples of RIF and rifapentine. Some of these impurities have been implicated as possible carcinogens in long-term animal studies, with toxicity largely related to cumulative exposure. However, for treatment of TB disease, the Centers for Disease Control and Prevention (CDC) favors continued use of RIF, if acceptable to the patient, because exposure is time-limited and the risks of not taking RIF likely outweigh any potential risks of nitrosamine impurities.

Pyrazinamide (PZA) is an oral bactericidal drug. When used during the intensive initial 2 months of treatment, it shortens the duration of therapy to 6 months and prevents development of resistance to RIF.

The major adverse effects of PZA are gastrointestinal 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 months or at doses higher than those listed in the 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 to the other first-line drugs.

Table

Second-line drugs for TB

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. Until 2016, the 2 most important classes were the aminoglycosides and the closely related polypeptide drug, capreomycin (injectable only), and the fluoroquinolones.

Streptomycin, the first and once the most commonly used injectable, is now uncommonly used and is increasingly difficult to obtain because of its replacement by newer injectable and oral second-line drugs. It 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 years. To limit dose-related adverse effects, clinicians give the drug only 5 days/week for up to 2 months. Then it may be given twice/week for another 2 months if necessary. In patients with renal insufficiency, dosing frequency should be reduced (eg, 12 to 15 mg/kg/dose 2 or 3 times/week). 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 has been a widely used injectable for MDR-TB, but amikacin is rapidly replacing it in the increasingly uncommon situations in which injectables are needed.

Capreomycin, a related nonaminoglycoside parenteral bactericidal drug, has dosage, effectiveness, and adverse effects similar to those of aminoglycosides. It was 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. Like all injectables, it is painful to administer and less well tolerated than the newer, oral, drug-resistant regimens, which are now typically preferred.

Some fluoroquinolones (levofloxacin, moxifloxacin) are the most active and safest TB drugs after isoniazid and rifampin; however, until the introduction of the new 4-month regimen containing moxifloxacin, fluoroquinolones were not first-line drugs for TB susceptible to isoniazid and rifampin. Moxifloxacin appears to be as active as isoniazid when used with rifampin or rifapentine.

Other second-line drugs include ethionamide, cycloserine, and para-aminosalicylic acid (PAS). These drugs are less effective and more toxic than other anti-TB drugs but were essential until the advent of all-oral regimens ( see below Drug resistance Drug resistance ).

Newer anti-TB drugs include bedaquiline, delamanid, pretomanid, and sutezolid. These had been reserved for highly resistant TB or for patients who cannot tolerate other second-line drugs but are increasingly being used in the all-oral drug-resistant regimens.

Drug resistance

Drug resistance is a major concern. It develops through spontaneous genetic mutation. Incomplete, erratic, or single drug therapy and poor adherence select for these resistant organisms. Once a drug-resistant strain has developed and proliferated, it may acquire resistance to additional drugs through subsequent mutations. In this way, the organism can become resistant to multiple antibiotics in steps, a process that can occur rapidly even though plasmid transfer among mycobacteria does not play a role.

However, in any given patient, the most common reason for drug-resistant TB (DR-TB) is acquisition by person-to-person transmission, often from unsuspected, undiagnosed, or inadequately treated people with DR-TB. Globally, only one third of people with MDR-TB have access to effective treatment. In areas where resistance testing is inadequate or unavailable, many patients who do not respond to first-line therapy probably have unrecognized MDR-TB and are contagious to others, including reinfection of people with drug-susceptible TB. The use of rapid molecular testing for TB and rifampin resistance has been shown to reduce the propagation of DR-TB.

Drug-resistance categories are defined based on the antibiotics to which an organism is resistant. In January 2021, the WHO revised its definition of XDR-TB and formally defined pre-XDR-TB ( 4 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references ). In the US in January 2022, the CDC recommended hybrid definitions, allowing use of the WHO definitions or alternatives appropriate in the US:

  • Multidrug-resistant TB (MDR-TB): Resistance to isoniazid and rifampin, the two most effective first-line drugs, with or without resistance to other drugs

  • Pre-XDR-TB: Resistance to isoniazid and rifampin and also any fluoroquinolone; CDC alternative definition: Resistance to isoniazid, rifampin, and a second-line injectable (amikacin, capreomycin, and kanamycin)

  • Extensively drug-resistant tuberculosis (XDR-TB): Resistance to isoniazid, rifampicin, any fluoroquinolone, and at least one additional group A drug (The group A drugs are levofloxacin, moxifloxacin, bedaquiline, and linezolid. They are the most potent of the second-line drugs used for drug-resistant TB and require longer treatment regimens.); CDC alternative definition: Resistance to isoniazid, rifampin, any fluoroquinolone, and either bedaquiline or linezolid (or both)

The diagnosis of MDR-TB and consequent need to use second-line drugs has great significance in terms of length, cost, and success of treatment. However, the new, shorter, all-oral DR-TB regimens have made treatment less difficult and rendered those issues less of a dividing line between clinical success and failure.

Numerous outbreaks of MDR-TB have been reported, and the global burden remains high, in part because of diagnostic and treatment limitations; in 2020, about 71% of bacteriologically proven cases had access to testing for rifampin resistance (a surrogate for identifying MDR-TB), an improvement from the 61% reported in 2019. In 2020, the WHO reported 157,903 new cases of MDR-TB worldwide, but this was only 38% of the estimated total number of cases ( 3 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references ). The WHO estimates that only about 1 in 3 people who develop MDR/RR-TB each year are enrolled in treatment ( 3 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references ).

The new anti-TB drugs bedaquiline, delamanid, and pretomanid and the fluoroquinolone moxifloxacin are oral drugs highly active against drug-resistant strains using shorter treatment duration than other regimens. They rapidly stop transmission and have higher rates of completion and cure and thus are likely to help control the epidemic of DR-TB. However, success will continue to depend on strong global commitments to provide access to molecular diagnostics and effective treatment as well as full treatment supervision. In 2020, 65 countries were using shorter, oral regimens for DR-TB.

The cost to patients of DR-TB and its treatment is estimated to be catastrophic in as high as 49% of cases.

Treatment regimens

Until the introduction of the new, 4-month regimen, treatment of all patients with new, previously untreated TB had consisted of the following:

  • 2-month initial intensive phase

  • 4- to 7-month continuation phase

Initial intensive–phase therapy is with 4 antibiotics (see table Dosing of Oral First-Line Anti-TB Drugs* Dosing of Oral First-Line Anti-TB Drugs* for dosing):

  • Isoniazid (INH)

  • Rifampin (RIF)

  • Pyrazinamide (PZA)

  • Ethambutol (EMB)

These drugs can be given daily throughout this 2-month phase or daily for 2 weeks, followed by doses 2 or 3 times/week for 6 weeks. 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 directly observed therapy (DOT) because each dose becomes more important.

After 2 months of intensive 4-drug treatment, PZA and usually EMB are stopped, depending on the drug susceptibility pattern of the original isolate.

Continuation-phase treatment depends on

  • Results of drug susceptibility testing of initial isolates (where available)

  • The presence or absence of a cavitary lesion on the initial chest x-ray

  • Results of cultures and smears taken at 2 months

If positive, 2-month 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 months (6 months total).

If the x-ray showed cavitation and the culture or smear is positive, INH and RIF are continued for 7 more months (9 months 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/week. Patients who have negative culture and smears at 2 months and no cavitation on chest x-ray and who are HIV-negative may receive INH plus rifapentine once/week.

Patients who have positive cultures after 2 months 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/week 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.

A new 4-month regimen was described in a clinical trial published in 2021, which reported that a 4-month TB treatment regimen that included rifapentine 1200 mg orally once/day and moxifloxacin 400 mg orally once/day ( 1 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references , 2 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references ) was noninferior to the standard 6-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol. There were no differences in serious adverse reactions between the 4- and 6-month regimens.

Considerations before using the shorter rifapentinemoxifloxacin regimen include the following:

  • Testing should show susceptibility to fluoroquinolones, isoniazid, and rifampin.

  • High-fat foods increase gut absorption of rifapentine.

  • The rifapentinemoxifloxacin regimen may be more expensive in the short term than the standard 6-month regimen.

Because of the cost of the 4-month regimen, it is likely that many public health programs will continue to use the standard 6-month regimen for most cases and reserve the 4-month regimen option for uncomplicated cases where adherence to the 6-month regimen is problematic (eg, when a patient must travel before the 6 months can be completed).

Management of drug-resistant TB (DR-TB) had until recently varied with the pattern of drug resistance, was long (18 to 24 months) and arduous for patients because of prolonged injections and severe adverse effects, and was expensive to administer, especially when prolonged hospitalization was required. More so than drug-susceptible TB, DR-TB requires management by specialists in treatment centers with adequate support systems in place. However, the results of recent trials of all-oral regimens for DR-TB using novel drugs is changing the success rate, tolerability, and cost of treating DR-TB. A three-drug regimen consisting of bedaquiline, pretomanid, and linezolid (known as the BPaL regimen) had favorable outcomes in an uncontrolled clinical trial of 109 people with extensively drug-resistant TB (XDR-TB) as well as treatment-intolerant or nonresponsive multidrug-resistant TB. In this trial, 90% of patients had a favorable outcome, whereas outcomes for patients with XDR-TB were historically less than 50% favorable, and often much worse when comorbidities were present ( 6 Treatment references Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Treatment references ). Drug toxicity of linezolid was the major limitation of the trial, but subsequent trials are testing lower doses of linezolid and other variations of all-oral regimens for highly DR-TB. The evolution of all-oral, shorter, better tolerated regimens for highly DR-TB is a landmark in global TB control, but a major commitment from countries to diagnose and effectively treat such cases and prevent their spread is still required.

Other treatments

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.

Surgery is not widely available in high-burden areas. But with increasing access to rapid molecular testing for drug resistance and shorter, better-tolerated drug resistance treatment, the numbers of chronic drug-resistant patients with lung destruction requiring surgery is likely to eventually decrease. In the meantime, access to surgeons skilled in TB surgery often means the difference between treatment success and failure in patients who have advanced cases with severe lung destruction. Even with bacteriologic cure, the long-term adverse effects of surgery on cardiorespiratory function require further research.

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 orally or IV every 6 hours is given to adults and children > 25 kg; children < 25 kg are given 8 mg. Treatment is continued for 2 to 3 weeks. Corticosteroids that are needed for other indications pose no danger to patients who have active TB and who are receiving an effective TB regimen.

Treatment references

Screening for TB

  • 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 years from high-risk areas, indigent patients, IV drug users, selected 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 years)

  • Therapeutic immunosuppression with corticosteroids, tumor necrosis factor (TNF) inhibitors, or cancer chemotherapy

In the US, most children and other people without specific TB risk factors should not be tested to minimize the number of false-positive results.

A positive TST or IGRA result (see Skin testing Skin testing Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Skin testing for criteria) suggests latent TB infection (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 Diagnosis Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Diagnosis , including sputum examination by microscopy and culture.

Updated guidelines for testing of LTBI are available from the CDC.

Booster reaction

Some patients with remote TB exposure, BCG vaccination, or infection with nontuberculous mycobacteria may have a negative TST or IGRA result; however, the TST itself may serve as an immune booster so that a subsequent test done as little as 1 week or as much as several years later may be positive (booster reaction). Thus, in people who are tested regularly (eg, health care workers), the second 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 second TST should be done (on the opposite forearm) 1 to 4 weeks after the first to identify a booster reaction (because conversion due to infection during that brief interval is highly unlikely). Subsequent TST is done and interpreted normally.

The new IGRAs for LTBI do not involve injection of antigens and thus do not cause boosting. They also are not influenced by preexisting hypersensitivity from BCG vaccination or infection with environmental mycobacteria other than M. kansasii, M. szulgai, and M. marinum.

Treatment of LTBI

Treatment of latent tuberculosis infection is indicated principally for

  • People whose TST converted from negative to positive within the previous 2 years

  • People with x-ray changes consistent with old TB but no evidence of active TB

Other indications for preventive treatment include

  • People who, if infected, are at high risk of developing active TB (eg, people with HIV infection, people with drug-induced immunosuppression)

  • Any child < 5 years old who is a close contact of a person with smear-positive TB, regardless of whether there was TST conversion

Other people with an incidentally positive TST or IGRA result 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 isoniazid (INH) unless resistance is suspected (eg, in exposure to a known INH-resistant case). The dose is 300 mg once/day for 9 months for most adults and 10 mg/kg for 9 months for children. An alternative for patients resistant to or intolerant of INH is rifampin (RIF) 600 mg once/day for 4 months. INH plus rifapentine taken once/week for 3 months is also effective.

Current guidelines for treatment of LTBI are available from the CDC.

The main limitations of treatment of LTBI are

  • Hepatotoxicity

  • Poor adherence

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 have 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-month course of INH. Adherence is better with 4 months of RIF. Monthly visits to monitor symptoms and to encourage treatment completion are standard good clinical and public health practice.

Prevention of TB

Vaccination

The BCG vaccine, made from an attenuated strain of M. bovis is given to > 80% of the world’s children, primarily in high-burden countries. Overall average efficacy is probably only 50%, but 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 Drug resistance Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Drug resistance or XDR-TB Drug resistance Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Drug resistance ) and possibly previously uninfected health care workers exposed to MDR-TB Drug resistance Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Drug resistance 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 years 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.

Special Populations

Children

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 Tuberculosis of bones and joints Tuberculosis of bones and joints ), the highly vascular epiphyses of long bones, or the central nervous system 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:

  • Gastric aspiration

  • Sputum induction

  • A more invasive procedure such as bronchoalveolar lavage

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 ).

Older people

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 previously had a negative TST 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 older people.

Risks and benefits of preventive treatment should be carefully assessed before older people are treated. INH causes hepatotoxicity in up to 4 to 5% of patients > 65 years old (compared with < 1% of patients < 65 years old). As a result, chemoprophylaxis is usually given to older people 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 result should also be considered for preventive treatment unless contraindicated.

Patients with HIV infection

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 Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection and latent tuberculosis infection (LTBI), active TB develops in about 10%/year, whereas in people who are not immunocompromised, it develops in about the same percentage over a lifetime. In the early 1990s, half of patients coinfected with TB and HIV who were untreated or infected with a multidrug-resistant strain died, with median survival of only 60 days. Now, outcomes are somewhat better in countries where there is better testing and treatment because of earlier TB diagnosis and antiretroviral therapy, but TB in patients with HIV remains a serious concern. In countries with limited access to drugs and testing for TB and HIV infection, mortality continues to be high among patients coinfected with HIV and multidrug-resistant TB or extensively drug-resistant 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 central nervous system 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 patients with AIDS, a mycobacterial illness that develops while the CD4 count is 200/mcL (0.2 × 109/L) is almost always TB. By contrast, depending on the probability of TB exposure, a mycobacterial infection that develops while the CD4 count is < 50/mcL (0.05 × 109/L) is usually due to Mycobacterium avium complex ( MAC Nontuberculous Mycobacterial Infections There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more ). Infection with MAC is not contagious and, in patients with HIV infection, affects primarily the blood and bone marrow, not the lungs.

Patients with HIV infection who were not diagnosed before presenting with TB should receive 2 weeks of antimycobacterial treatment before starting antiretroviral therapy to decrease the risk of developing the immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Immune reconstitution inflammatory syndrome (IRIS) (IRIS). TB in patients with HIV infection generally responds well to usual regimens when in vitro testing shows drug susceptibility. However, for multidrug-resistant 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 months after sputum cultures convert to negative but may be shortened to 6 months 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 months of therapy, treatment is prolonged to 9 months.

Patients with HIV infection whose tuberculin reactions are 5 mm (or with a positive IGRA result) should receive chemoprophylaxis.

Current CDC TB treatment guidelines should be consulted.

Key Points

  • 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.

More Information

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

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