Tuberculosis

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis bacteria. Tuberculosis (TB) is one of the most common infections worldwide (>2 billion people may have latent TB infection). In the United States, the rate of TB cases has been declining since 1992 as a result of the establishment of tuberculosis control programs, implementation of screening programs for patients at high risk for the disease, and advancement of diagnostic techniques that allow rapid diagnosis. In this section, we cover the diagnosis and management of:

• Active Tuberculosis Infection

• Latent Tuberculosis Infection

Active Tuberculosis Infection

Active tuberculosis is characterized by infection with Mycobacterium tuberculosis and associated signs and symptoms of disease. Primary infection occurs when airborne M. tuberculosis is inhaled and travels through the respiratory tract until it reaches the alveoli. In most individuals, the immune system can control this infection without treatment (see Latent Tuberculosis Infection below). In some patients, particularly those with compromised immune systems (e.g., HIV infection), the primary infection can progress to pneumonia and can even disseminate to cause extrapulmonary tuberculosis (in 10%-40% of cases). TB is a great imitator: it can affect any organ in the body (e.g., brain, heart, kidney, eye, lymph node, skin), has varied clinical manifestations, and requires a high index of suspicion.

Presentation

The typical presentation of active pulmonary TB includes pulmonary symptoms and constitutional symptoms:

• chronic cough (>2 weeks)

• sputum production

• hemoptysis

• chest pain

• dyspnea

• appetite loss

• weight loss

• fever

• night sweats

If TB is suspected, the patient should be placed in a negative-pressure isolation room. Airborne precautions should be undertaken by those in contact with the patient to avoid transmission. Contact tracing of confirmed cases should be performed by the public health department.

Diagnosis

The following table indicates some patient groups that warrant an evaluation of pulmonary TB:

(Source: Controlling Tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recommendations and Reports 2005).

Testing recommendations and considerations:

• Obtain three induced sputum samples for acid-fast bacilli (AFB) smear microscopy. A single AFB smear has lower sensitivity for ruling out pulmonary disease.

• Consider bronchoscopy in patients who cannot provide induced sputum. The advantage of bronchoscopy is that a biopsy can be obtained.

• Culture for M. tuberculosis is the gold-standard microbiologic test with the highest sensitivity but can take several days to weeks to grow.

• Perform a diagnostic nucleic acid amplification test (NAAT) on an initial respiratory specimen. A negative NAAT can help rule out a false-positive AFB smear. NAAT has higher sensitivity than AFB smear in some situations (e.g., concurrent HIV infection, where the disease can be paucibacillary and has higher chance of negative AFB smear). TB tests on the market are the Cepheid Xpert MTB/RIF test (can also detect rifampin resistance) and the Hologic Amplified Mycobacteria Tuberculosis Direct (MTD) test.

• Interferon-gamma release assay (IGRA) test and tuberculin skin tests can be negative in acute disease and in immunocompromised patients.

• Elevated adenosine deaminase levels can be seen in TB-infected body fluids, such as pleural effusion, cerebrospinal fluid, ascites, or pericardial effusion.

• Chest imaging typically shows upper-lobe cavitary disease.

• Histopathological examination of biopsies shows necrotizing granulomas. Culture, AFB smear, and NAAT can be performed on extrapulmonary specimens for diagnosis.

Treatment

M. tuberculosis during treatment exhibits a biphasic decline, during which actively replicating bacilli are killed initially while a nonreplicating subpopulation persists and requires longer treatment. Some bacilli may be sequestered by the immune system and inaccessible to antibiotics. Consequently, treatment is split into the intensive phase (~2 months), followed by a continuation phase (~4 months) to maximally eradicate bacilli. Treatment regimens will vary depending on whether infection is with drug-susceptible or drug-resistant TB. Drug-resistant TB is defined as resistance to at least one of the first-line antimycobacterial drugs.

Panel A shows the time course of decline of viable Mycobacterium tuberculosis in a sputum sample from a patient being treated for tuberculosis. The number of bacteria declines at a rapid rate during the early phase of therapy (blue curve), with a less rapid rate of decline during the later phase (red curve). The biphasic pattern that is observed (black dashed curve) suggests that there are bacterial subpopulations that differ in their drug susceptibility. CFU denotes colony-forming units. (Source: Treatment of Tuberculosis. N Engl J Med 2015.)

CDC recommendations for drug-susceptible TB regimens are shown below. The traditional 6 months of RIPE-based therapy is still a first-line option for most patients; however, the CDC issued interim guidance in 2022 to also include a 4-month rifapentine-moxifloxacin regimen as a first-line option for certain populations. Please see the CDC website for more information on drug-resistant TB.

The 6- to 9-month RIPE TB treatment regimens consist of rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB).

(Source: Treatment for TB Disease. Centers for Disease Control and Prevention Last Reviewed: March 22, 2023.)

Treatment of extrapulmonary TB is similar to that of pulmonary TB, but the duration of therapy is usually longer than 6 months. Patients with TB meningitis, and sometimes TB pericarditis, require glucocorticoids as an adjunct to antimicrobial therapy.

Fluoroquinolones are active against TB and should be avoided in cases of pneumonia when TB is suspected. The following figure illustrates the various mechanisms of anti-TB drugs.

Shown are the known targets of various agents that have been used clinically in tuberculosis treatment. Many antituberculosis agents target the M. tuberculosis cell envelope. The box is a high-resolution representation showing the agents that act on each of the three component polymers of the macromolecular outer-cell envelope. Drugs such as aminosalicylic acid act like antimetabolites; they are incorporated into folate metabolism as substrates and inhibit downstream folate-dependent processes. The mode of action of pyrazinamide remains enigmatic, and the drug appears to act at least partially by acidifying the cytoplasm of the cell. (Source: Treatment of Tuberculosis. N Engl J Med 2015.)

Latent Tuberculosis Infection

Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active disease. After initial exposure to M. tuberculosis, some people develop an active infection while others’ immune systems contain the bacilli within macrophages, granuloma, and lymph nodes, leading to LTBI. LTBI is usually asymptomatic. An estimated 5%-15% of immunocompetent individuals with LTBI develop active infection during their lifetimes, and the risk increases in patients with compromised immune systems, either because of age or concomitant illnesses.

Diagnosis

Most cases of TB resulting from reactivated LTBI can be prevented with antibiotics. Therefore, it is important to screen for infections in populations at high risk for either acquiring LTBI or reactivation or both.

Risk factors for LTBI include:

• close contact with someone with infectious TB

• born in a TB-endemic country

• homelessness

• injection-drug use

• immunosuppression (e.g., HIV infection, tumor necrosis factor [TNF]-alpha inhibitors, organ transplantation)

• end-stage kidney disease on hemodialysis

• incarceration

• health care workers

(Source: Latent Mycobacterium tuberculosis Infection. N Engl J Med 2015.)

Diagnostic tests: One of the following tests can be used for diagnosis in a patient who does not have symptoms of active TB and who has no signs of active TB on chest radiograph. These tests may be negative in active TB and should not be used to rule out active TB. They also poorly predict progression to active TB.

• tuberculin skin test (TST)

  • TST is inexpensive but has poor specificity in populations vaccinated with bacille Calmette-Guérin (BCG) and poor sensitivity in immunocompromised hosts. Be aware of booster phenomenon (positive result on retesting).

  • Interpretation of TST at 2-3 days after administration depends on risk of infection, risk of progression, and benefit of treatment (see figure below for interpretation in various populations).

• interferon-gamma release assay (IGRA) test

  • Currently available IGRAs include the QuantiFERON-TB Gold (QFT, Qiagen) in-tube assay and the T-SPOT.TB assay (Oxford Immunotec).

  • IGRA is more specific than the tuberculin skin test (because it is not affected by prior BCG vaccination) but is more expensive and may not be widely available. IGRAs can be indeterminant in patients with poor immune response.

Paradigm for evaluation of those with latent tuberculosis infection (LTBI) based on risk of infection, risk of progression to tuberculosis, and benefit of therapy Abbreviations: CXR, chest radiograph; HIV, human immunodeficiency virus; LTBI, latent tuberculosis infection; Mtb, Mycobacterium tuberculosis; RR, relative risk; TB, tuberculosis; TST, tuberculin skin test. (Source: Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infec Dis 2017.)

The Infectious Diseases Society of America (IDSA) recommends IGRA rather than TST for LTBI testing in individuals aged 5 years and older who are likely to be infected with M. tuberculosis, have low or intermediate risk of disease progression, and either have a history of BCG vaccination or are unlikely to follow up for TST reading.

Treatment

Although patients with LTBI typically are asymptomatic and not contagious, the potential for reactivation places them at risk of becoming sick and is a public health concern. Thus, treatment of LTBI is essential for controlling and eliminating TB. The CDC’s recommended treatment regimens for latent TB are shown in the following table. Shorter rifamycin-based regimens are preferable to longer isoniazid monotherapy. Note, these recommendations must be modified if the patient has been in contact with an individual with drug-resistant TB. Rule out active TB before starting these regimens.