Tuberculosis

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis, which typically affects the lungs. It is a common infectious cause of morbidity and mortality worldwide. Primary infection, transmitted via airborne aerosol droplet nuclei, is often initially asymptomatic. M. tuberculosis infection is typically dormant (latent TB infection; LTBI) because of intact innate and cellular immune responses. If the immune system is compromised, however, reactivation of the infection may occur and lead to active TB. Patients with active disease characteristically present with fever, weight loss, night sweats, and a productive cough (with or without hemoptysis) that does not respond to conventional antibiotic therapy. The infection may spread hematologically to any organ, causing extrapulmonary TB. However, disseminated disease is rare, occurring in severely immunocompromised individuals. If active TB infection is suspected, imaging should be obtained as well as microscopy, cultures, and/or polymerase chain reaction (PCR) to identify M. tuberculosis. The treatment of tuberculosis is prolonged due to the slow growth of M. tuberculosis, its concealment in macrophages, and the inability of drugs to easily penetrate its cell wall. Standard treatment includes combination therapy with rifampin, isoniazid, ethambutol, and pyrazinamide for two months, followed by rifampin and isoniazid for an additional four months. Patients with suspected LTBI should be tested using the purified protein derivative (PPD) tuberculin skin test (TST) or interferon-γ release assay (IGRA) and treated accordingly. Treatment of LTBI reduces the risk of active infection in up to 90% of cases and, therefore, plays a crucial role in the prevention of active TB.

• Active tuberculosis
  • Definition: any TB infection with symptoms and signs of disease, including primary TB and reactivation of latent TB [1][6][7]
  • Features [1]
    • Pulmonary TB: the most common form of active TB
    • Extrapulmonary TB: The most common forms are TB lymphadenitis and pleural tuberculosis.
  • Diagnostics: confirmed if bacilli are present in respiratory secretions or other tissues, and subsequent microbiological testing and imaging results are consistent with active TB [7][8]
  • Treatment
    • Combination of antibiotics, most commonly given for 6 months [9]
    • Occasionally, invasive procedures (e.g., drainage for pleural TB) or surgery (e.g., lobectomy for drug-resistant TB) may be necessary. [9][10]
• Drug-resistant tuberculosis [11]
  • Definition: a form of TB that is resistant to one or more antitubercular agents
  • Types
    • Rifampin-resistant tuberculosis (RR-TB): resistance to rifampin with or without resistance to other antitubercular drugs
    • Monoresistant TB: resistance to one of the first-line antitubercular drugs
    • Multidrug-resistant tuberculosis (MDR-TB): resistance to both isoniazid and rifampin
    • Pre-extensively drug-resistant TB (Pre-XDR-TB): resistance to isoniazid, rifampin, and either any fluoroquinolone or a second-line injectable agent (e.g., amikacin, kanamycin, or capreomycin) [12]
    • Extensively drug-resistant tuberculosis (XDR-TB): resistance to isoniazid, rifampin, any fluoroquinolone, and either one of the second-line injectable drugs (e.g., amikacin, kanamycin, or capreomycin) or bedaquiline or linezolid [12]
  • Causes
    • Incorrect drug combination therapy
    • Inadequate duration or dosage of drug therapy
    • Poor treatment adherence
    • Poor quality of drugs
    • Close contact with an individual with drug-resistant TB

• United States [13]
  • The incidence of TB infection in the US has been slowly declining.
  • The incidence rate for 2018 was 2.8 cases per 100,000 population.
  • Two-thirds of new TB cases reported in the US in 2019 were in individuals born outside the US.
  • The prevalence of LTBI in the United States is estimated to be 5% [14]
• Worldwide [15]
  • A leading cause of death from a single infectious agent
  • The overall incidence and prevalence have been declining.
  • The incidence rate for 2018 was 132 cases per 100,000 population.
  • One-fourth of the world's population has latent TB.
  • The sex ratio varies across countries and communities and largely depends on social and cultural factors. [16]
  • Countries with the highest incidence of TB: India, Indonesia, China, the Philippines, Bangladesh, Nigeria, Pakistan, and South Africa
  • The incidence of multidrug-resistant TB is steadily rising.

Epidemiological data refers to the US, unless otherwise specified.

Mycobacteria

Species

Mycobacterium species that cause tuberculosis are collectively known as the Mycobacterium tuberculosis complex, which includes:

• Mycobacterium tuberculosis
  • Mode of transmission: spread via aerosol droplet nuclei
  • Reservoir: predominantly humans
  • Disease: all forms of tuberculosis
• Mycobacterium bovis
  • Mode of transmission: predominantly via ingestion of contaminated cow's milk
  • Reservoir: predominantly cattle
  • Disease: gastrointestinal tuberculosis in humans
• Mycobacterium africanum: common cause of tuberculosis in West, Central, and East Africa [1]
• Mycobacterium microti

Features of Mycobacterium tuberculosis

• Type: facultative intracellular rod-shaped bacteria
• Gram stain: does not stain well [17][18]
• Special stains
  • Ziehl-Neelsen stain: acid-fast bacilli appear pink [19]
  • Auramine-rhodamine stain [20]
    • Acid-fast bacilli appear reddish-yellow on fluorescence microscopy.
    • Used as a screening tool because of high sensitivity and low cost
• Culture mediums for growth
  • Löwenstein Jensen medium
  • Middlebrook medium
  • Rapid automated broth culture
• Mechanism of resistance
  • Remains viable in airborne droplet nuclei and soil [21]
  • Able to survive in acidic conditions [22]
• Virulence factors: See “Pathophysiology” below.

Risk factors for tuberculosis exposure [23]

• Working in the health care industry
• Migration from countries with a high TB incidence (≥ 100 cases per 100,000 population) [2]
• Frequent travel to countries with a high TB burden
• Close contact with a patient with active TB infection
• Crowded living conditions (e.g., prisons)
• Homelessness

Primary tuberculosis [1][3][24]

Innate immune response

• Exposure to M. tuberculosis
  • Individuals with M. tuberculosis infection disperse droplet nuclei that contain bacilli via sneezing or coughing.
  • Inhaled droplet nuclei reach the terminal alveoli and are taken up by the alveolar macrophages.
• Entry into macrophages
  • Mycobacterial cell wall contains pathogen-associated molecular patterns (PAMPs) such as lipoarabinomannan and lipomannan.
  • Alveolar macrophages recognize M. tuberculosis PAMPs via toll-like receptors (TLRs)
  • Activation of TLRs leads to the production of proinflammatory cytokines (e.g., IL-1, IL-12, TNF-α) and phagocytosis of mycobacteria.
• Replication within macrophages
  • Typically, phagocytosed organisms reside within a phagosome to undergo intracellular killing via the following steps:
    • Phagosome maturation: acidification using a proton pump system [25]
    • Fusion of phagosome and lysosome: mediated by increased intracellular calcium levels [26]
    • Killing of bacteria by reactive oxygen species (ROS), reactive nitrogen intermediates (RNI), and lysosomal enzymes
  • M. tuberculosis survives within macrophages because of the inhibition of both phagosome maturation and phagolysosome fusion
  • Virulence factors involved include: [18]
    • Cord factor (trehalose-6,6'-dimycolate): a surface glycolipid that causes serpentine cord-like growth, inhibits neutrophil migration, and induces TNF-α release to stimulate activated macrophages to form granulomas [27][28]
    • Sulfatides: surface glycolipids that inhibit phagolysosome fusion [29]
    • Lipoarabinomannan: a lipoglycan that induces TNF-α release from macrophages and scavenges ROS
    • Catalase-peroxidase: an enzyme that catalyzes the destruction of ROS and H₂O₂
• Macrophage lysis and release of bacteria
  • Following replication in the alveolar macrophages, the released bacteria attack uninfected macrophages to spread infection.
  • Dendritic cells migrate to the site of infection and process mycobacterial antigens.
  • Some bacteria enter the bloodstream, causing bacteremia and seeding multiple organs.

Cellular immune response

• Th1 cell activation
  • Dendritic cells present mycobacterial antigens complexed with MHC 2 to naive T cells
  • Activated CD4+ T cells migrate to the focus of infection (type IV HSR).
• Macrophage activation and bacterial killing
  • Activated CD4+ T cells release IFN-γ
  • IFN-γ acts on macrophages to enable bacterial killing via the following mechanisms:
    • Promotion of phagosome maturation
    • Enhanced RNI production
    • Autophagy
• Granulomatous inflammation and tissue destruction
  • IFN-γ-activated macrophages secrete TNF-α.
  • TNF-α promotes the aggregation of macrophages and T cells to form granulomas, affecting the lungs and regional lymph nodes
  • Destruction of M. tuberculosis-infected macrophages causes central caseous necrosis and tissue damage.
  • Granuloma limits the spread of infection.
  • Ghon focus: a granuloma typically located in the middle/lower lung lobes.
  • Ghon complex: formed by the Ghon focus, regional lymph node, and the linking lymphatic vessels
• Disease progression
  • Sufficient immune response
    • Most of the bacteria are killed.
    • Some bacteria may persist, causing LTBI.
    • The granulomas in the Ghon complex undergo fibrosis and calcification to form the Ranke complex.
  • Deficient immune response (e.g., HIV, malnutrition)
    • Failure of granulomas to limit infection
    • Progressive primary TB causing progressive lung disease, bacteremia, and miliary TB

Secondary tuberculosis [24]

• Latent TB: Dynamic equilibrium is maintained between the host immune response and M. tuberculosis.
• Reactivation of disease: due to weakening of immune response (e.g., resulting from HIV, TNF-α inhibitor therapy)
• Disease progression
  • Caseating granulomas with central necrosis and Langhans giant cells are characteristic features.
  • Usually affects the upper lobes of the lungs because of higher oxygen tension
  • Can also affect other organs (due to seeding of organs in primary tuberculosis)
  • Prior sensitization to mycobacterial antigens results in a stronger inflammatory response, causing extensive tissue destruction, cavitation, and scarring.

Latent tuberculosis infection does not typically manifest with symptoms. Patients with primary TB are commonly asymptomatic.

Pulmonary tuberculosis [1]

• Systemic
  • Low-grade fever with night sweats
  • Weight loss (often severe), anorexia
  • Decreased appetite
  • Malaise, weakness
• Pulmonary
  • Non-productive cough
  • Symptoms of progression: productive cough with purulent sputum, hemoptysis
  • Shortness of breath
  • Pleuritic chest pain [30]
• Clinical examination: Findings are nonspecific.
  • General: pallor, clubbing (advanced disease), generalized wasting
  • Chest examination: Findings vary depending on the type and degree of pulmonary involvement.
    • Consolidation: dullness on percussion, crackles, diminished breath sounds
    • Cavitation: hyperresonance on percussion, amphoric breath sounds
    • Bronchial obstruction: rhonchi
    • Pleural effusion and/or empyema: dullness on percussion, diminished breath sounds
  • Other possible findings: erythema nodosum, phlyctenular conjunctivitis

Depending on the degree of immunosuppression, TB in HIV-positive individuals may progress atypically or more rapidly.

Always consider TB as a differential diagnosis in a young individual with hemoptysis and if treatment for other pulmonary conditions (e.g., pneumonia) does not improve symptoms.

Extrapulmonary tuberculosis

See “Extrapulmonary tuberculosis” for respective clinical features.

This section reviews the diagnosis of active tuberculosis infection. For screening and diagnosis of latent TB, see the section “Latent tuberculosis.”

Approach [7]

• Initial workup in all patients
  • Focused patient history (e.g., exposure to individuals with TB, history of visiting or living in countries with a high TB burden)
  • Microbiological studies
    • Initial tests: microscopy examination for acid-fast bacilli (AFB), nucleic acid amplification test (NAAT)
    • Confirmatory test: mycobacterial culture (gold standard)
    • Drug susceptibility testing: indicated in certain circumstances to identify resistant mycobacteria
  • Consider CT chest or CXR
• Suspicion for extrapulmonary TB: Additional invasive procedures (e.g., lymph node biopsy, thoracocentesis) may be required for bacteriological confirmation (see “Extrapulmonary TB”). [31]

Lung cancer is an important differential diagnosis of pulmonary TB. Start investigations for malignancy in any patient with systemic symptoms (e.g., weight loss, persistent fevers, anorexia) and abnormal imaging.

PPD TST and IGRA are screening tests for latent TB and do not aid in the diagnostics of active TB. [7]

Laboratory studies [1]

Laboratory findings are mostly unspecific but can provide important information during initial diagnostic stages. Possible findings include:

• CBC: mild leukocytosis (common) , anemia (in advanced disease)
• BMP: mild hyponatremia
• Liver chemistries: ↑ in concomitant liver disease; useful as a baseline prior to treatment [32]
• Other nonspecific findings: ↑ ESR, pyuria in renal disease [32]

Microbiological studies [7]

Confirmation of the presence of tuberculosis bacilli in different samples is done by direct visualization, positive culture, or by detecting genetic material. Samples used for testing include: [7]

• Sputum samples (most common): Obtain ≥ 3 samples separated by 8 to 24-hour intervals (should include at least one early morning sample). [7][33][34]
• Induced sputum [34]
• Gastric lavage [35]
• Bronchoalveolar lavage
• Extrapulmonary TB suspected: Fluid specimens or tissue samples should be sent for cell count, chemistries, AFB smear microscopy, and NAAT. [7]

Because sputum induction carries a high risk of transmission to health care workers, the procedure must be performed under strict infection control precautions. [36]

Request AFB and cultures of every sample obtained; request NAAT for the initial respiratory sample along with microscopy and culture if clinical suspicion is high. [7]

Drug susceptibility testing [7]

• Standard culture: used to assess for drug susceptibility in most patients; results are available after several weeks.
• Rapid molecular testing : for select patients at high risk of resistant tuberculosis [7]
  • History of previously treated tuberculosis
  • Contact with individuals with MDR-TB
  • HIV infection
  • Patients born or having lived for ≥ 1 year in a country with moderate to high TB incidence or high MDR-TB prevalence [7]

A negative AFB smear microscopy result does not rule out pulmonary TB and a confirmatory culture should be obtained. [7]

Imaging [7][8][40]

• Indications: often performed as part of the diagnostic workup of patients with respiratory symptoms
• Modalities: x-ray or CT chest
• Findings
  • Highly variable and nonspecific, but can help narrow the differential diagnosis
  • In primary TB, chest x-ray is often normal.

Extensive cavitation can lead to areas of bronchiectasis and damaged lung areas can be colonized with Aspergillus spp., leading to aspergillomas, sometimes referred to as fungus balls. [32]

Normal imaging does not rule out TB. Although radiographic changes are common in immunocompetent patients, individuals who are immunocompromised can have normal imaging findings. [8][31][40]

HIV and TB coinfection

Diagnosing TB in patients with HIV coinfection is challenging because these individuals often have a negative AFB smear and commonly have atypical imaging findings resulting from paucibacillary disease due to a reduced immune response. Different measures can be used to increase diagnostic sensitivity. [31][36]

• Advanced testing in patients with HIV (not widely available) [36]
  • For most patients: fluorescent AFB smear microscopy , specialized culture mediums
  • For patients with severe disease and those with a CD4 count < 100/mm³: lateral flow urine lipoarabinomannan assay [41][42][43]
• In resource-limited settings: a lower threshold for defining smear positivity and consideration of empiric treatment may be necessary [36]

In patients with HIV, the sensitivity of routine initial microbiological studies may be low; additional investigations may be required.

Obtain HIV tests in all patients with suspected (rather than confirmed) TB, as this can help to interpret test results. [36]

Pulmonary TB

• Typical pneumonia
• Atypical pneumonia
• COVID-19 pneumonia
• Lung cancer
• Lung abscess
• Interstitial lung disease
• See “Differential diagnosis of granulomatous disease.”
  • Sarcoidosis
  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma
  • Pneumoconiosis
  • Granulomatosis with polyangiitis
  • Histoplasmosis
• See “Nontuberculous mycobacterial infections” and “Mycobacterium avium complex infection.”
• Brucellosis
• Tularemia

Extrapulmonary TB

• Leprosy
• Syphilis
• Erythema nodosum
• Lymphoma
• Multiple myeloma
• Rheumatoid arthritis
• Systemic lupus erythematosus

The differential diagnoses listed here are not exhaustive.

This section reviews the treatment of active tuberculosis. For the treatment of latent TB, see the section “Latent tuberculosis.”

General principles [1][9]

• Goals
  • Reduction of disease severity and risk of transmission
  • Eradication of all bacilli to achieve sustained cure without relapse following completion of treatment
  • Prevention of drug resistance during therapy
• Infection control measures
  • Case notification: mandatory reporting to local health department [44]
  • Airborne precautions: should include a surgical mask for the patient and adequate personal protective equipment (including respirators) for medical staff and caregivers [45]
  • Contact tracing: See “Prevention” section for testing indications.
• Antituberculosis therapy
  • All patients should undergo a pretreatment evaluation.
  • Choice of pharmacologic therapy is based on the site of infection and drug susceptibility.

Indications for treatment [9]

• Confirmed active TB
  • Positive culture for M. tuberculosis
  • Positive NAAT (with positive or negative AFB smear microscopy)
• Suspected active TB: Consider empiric treatment in all patients pending test results.
  • Factors favoring empiric treatment: high risk of disease progression and/or dissemination , imaging consistent with active TB, positive screening , critically ill patients, high transmission risk
  • Factors favoring delayed therapy: no known TB exposure, high risk of therapy side effects, negative NAAT (with positive or negative AFB smear microscopy)

Empiric treatment with standard antituberculosis therapy is indicated in most cases in which active infection is suspected. [9]

Pretreatment evaluation [9]

• Clinical assessment
  • Weight
  • Nutritional assessment
  • Symptom review
  • Eye exam: visual acuity and color discrimination
• Microbiology: sputum smear microscopy and culture, drug susceptibility testing
• Imaging: chest x-ray or other chest imaging
• Laboratory studies
  • All patients: liver chemistries; , platelet count, BMP, HIV screening
  • Depending on risk: hepatitis B and hepatitis C screening, diabetes screen, β-HCG in individuals who can become pregnant

Antituberculosis therapy

Consultation with infectious disease experts is advised.

RIPE TB regimen [9][46]

• Intensive phase: : 8 weeks (∼ 2 months) of rifampin PLUS isoniazid , pyrazinamide , and ethambutol [9]
• Continuation phase: : 18 weeks (∼ 4 months) of rifampin PLUS isoniazid [9]
• Adjuvant treatment: : pyridoxine to prevent vitamin B₆ deficiency resulting from isoniazid (promotes pyridoxine excretion) for all individuals at risk of neuropathy [9]
• Additional considerations
  • Self-administered and daily dosages are preferred
  • Directly observed therapy (DOT; standard practice): Health care personnel observe the patient taking the medication.
  • Restart full treatment if there is an interruption of ≥ 14 days during the intensive phase.

RIPE TB regimen consists of 6 months of rifampin and isoniazid plus pyrazinamide and ethambutol during the first 2 months.

"RIPE": Rifampin, Isoniazid, Pyrazinamide, and Ethambutol

The long duration of treatment for active TB requires patient-centered coordination with primary care and specialist services and directly observed therapy (DOT) to ensure adherence. [47]

4-month regimen for TB [46][48][49]

This regimen may be considered for patients with drug-susceptible pulmonary TB who are age ≥ 12 years, ≥ 40 kg, and without contraindications (e.g., drug-drug interactions, prolonged QT syndrome, pregnancy).

• Intensive phase: 8 weeks of rifapentine , isoniazid , pyrazinamide , and moxifloxacin
• Continuation phase: 9 weeks of rifapentine , isoniazid , and moxifloxacin
• Adjuvant treatment: Pyridoxine to prevent vitamin B₆ deficiency resulting from isoniazid
• Additional considerations: DOT should be implemented during the treatment period.

Treatment of drug-resistant TB disease [10][49]

This includes MDR-TB and XDR-TB. Consultation with infectious disease experts is required.

• Agents
  • Oral: later-generation fluoroquinolone (e.g., moxifloxacin), bedaquiline, linezolid, clofazimine, cycloserine, pretomanid [50]
  • IV: amikacin, streptomycin, and carbapenem with amoxicillin-clavulanic acid
• Phases of treatment: combine at least 3–5 agents for the intensive and continuation phases
• Role of surgery: Elective partial lung surgery can be beneficial.

An all-oral regimen (i.e., bedaquilline, pretomanid, and linezolid ± moxifloxacin) may be considered for drug-resistant TB based on drug susceptibility. [49]

Treatment of extrapulmonary TB [9]

Choose antimicrobials under specialist guidance and tailor choice and duration of therapy to the infection site, severity, and response.

• Standard antituberculosis therapy (e.g., 6-month RIPE TB regimen): used for lymph node, pleural, miliary, pericardial, adrenal, gastrointestinal, and genitourinary TB
• Extended regimens
  • TB meningoencephalitis (9–12 months of therapy)
    • 2 months of 4-drug intensive phase, followed by 7–10 months of continuation phase with isoniazid and rifampin
    • See RIPE TB regimen for daily dosages.
    • Adjunctive glucocorticoid treatment with dexamethasone or prednisolone for 6–8 weeks
  • Pott disease and other bone and joint TB
    • Typically 6–9 months of therapy
    • May be extended up to 12 months
    • Surgery in select patients

Consultation with a specialist is always advised in all patients with extrapulmonary TB, especially for miliary disease.

Side effects of antituberculosis agents [9]

Mild side effects can usually be managed with symptomatic treatment, while more severe side effects (e.g., significant hepatotoxicity, optic neuritis) usually require one or more drugs to be discontinued and replaced in consultation with a specialist.

• General side effects: may be caused by any of the drugs commonly used in standard antituberculosis therapy
  • Hepatotoxicity (most common serious side effect)
  • Rash, pruritus
  • GI symptoms
  • Allergic and nonallergic hypersensitivity reactions

Rifampin and isoniazid alter the efficacy of drugs metabolized by cytochrome P450 (especially protease inhibitors, NNRTIs, OCPs, warfarin, sulfonylureas).

Monitoring [9][44]

Monthly follow-ups are recommended in all patients receiving antituberculosis treatment for active TB or LTBI.

• All patients
  • Assess adherence to therapy.
  • Perform a symptom review and screen for clinical features of active TB.
  • Monitor for side effects.
• Patients with active TB
  • Sputum smear microscopy and culture
  • Weight and vision assessment
  • Laboratory studies: If indicated, obtain liver chemistries, platelet count, and creatinine.

Advise patients to self-monitor for features that suggest hepatitis (e.g., jaundice, fatigue, anorexia, abdominal pain) and seek prompt medical attention if any of them arise. [44]

Description

• A state of constant immune response stimulation due to M. tuberculosis antigens, with no signs of active TB infection
• Individuals with latent TB are asymptomatic and not contagious.

M. tuberculosis remains dormant within the host and may be reactivated once the immune system becomes compromised (e.g., by high doses of glucocorticoids or chemotherapeutic agents, HIV infection).

Epidemiology [14]

• The prevalence of LTBI in the United States is estimated to be 5%.
• 5–10% of untreated cases progress to active TB if left untreated.

Diagnosis [7][44]

Screening for LTBI [7][57][58]

The decision of whether to test an individual should be carefully considered based on the likelihood of someone having LTBI, the likelihood of progression of LTBI to active TB, and the potential benefit of therapy.

• Individuals with a high likelihood of LTBI (i.e., high risk of TB exposure; see also “Risk factors for tuberculosis”) [7][44]
  • Known contact with AFB smear-positive individual
  • Individuals born in or former residents of countries with a high TB burden (> 20 cases per 100,000 population) [58]
  • People who live or work in high-risk settings (e.g., correctional facilities, long-term care facilities or nursing homes, homeless shelters)
  • Health-care workers who care for patients at increased risk for TB disease
  • Children (< 18 years of age) exposed to adults at increased risk for tuberculosis infection
• Individuals with a high likelihood of progression from LTBI to active TB [7][44]
  • High risk factors:
    • HIV infection
    • Immunosuppressive therapy, including: [59]
      • Corticosteroid therapy [60][61]
      • TNF-α inhibitor therapy (e.g., infliximab) [62]
      • Others: methotrexate, cyclosporine; drugs used for organ transplant and stem cell transplant recipients
    • Silicosis
    • Age < 5 years
    • Prior TB infection
  • Intermediate risk factors: diabetes, chronic kidney disease, IV drug use
  • Other risk factors:
    • Smoking [63]
    • Heavy alcohol consumption [64]
    • Malnutrition, low body mass index
    • Advanced age [65]
    • Malignancy
    • Gastrectomy or jejunoileal bypass

All patients with HIV should be screened for LTBI, regardless of additional risk factors. [44]

All individuals due to start immunosuppressive therapy should be screened for LTBI. [59]

Selection of screening test [7]

• Most patients: IGRA (preferred in those who have had the BCG vaccine) or PPD TST [44]
• Patients with HIV, children aged < 5 years, immunocompromised patients
  • PPD TST and chest x-ray
  • OR IGRA and chest x-ray

Interpretation of results [7][44]

• IGRA
  • Positive: TB infection is likely
  • Negative: TB infection is unlikely, but cannot be excluded
  • Indeterminate: can occur in inflammation or infection; and/or immunosuppressed states (e.g., due to immunomodulatory medications and/or HIV infection), and a repeat IGRA or PPD TST can be useful [71]
• PPD TST: Depending on patient characteristics, a PPD TST can be positive with an induration ≥ 5 mm, ≥ 10 mm, or ≥ 15 mm.
  • For healthy individuals with no risk factors, an induration < 15 mm is considered negative for TB.
  • For patients with BCG vaccination history, interpret a positive PPD TST according to induration diameter and relevant risk factors. [69]

The diagnosis of LTBI is based on a positive screening result in patients with a medical history and physical examination consistent with latent disease, once active TB has been excluded. [14]

If screening for LTBI is positive, it is still necessary to exclude active TB prior to starting treatment for LTBI because neither screening test can differentiate between active and latent infection. [14]

Further evaluation

If health care workers are exposed to an individual with active TB without adequate personal protective equipment, IGRA or PPD TST must be performed immediately and repeated after 8–10 weeks if the initial test is negative. [75]

Special situations [44]

• HIV infection: Screen for LTBI at the time of diagnosis and repeat annually in patients at risk of exposure.
• BCG vaccination: IGRA is preferred to PPD TST. [69]
• Screening prior to starting immunosuppressive therapy: Follow the usual screening algorithm, but consider a second test if the initial screening test is negative. [76]
• Individuals who are periodically tested with PPD TST
  • TST results may be affected by booster phenomenon
  • Consider two-step TST in select cases to avoid misinterpretation; two-step testing is not required if IGRA is used as a baseline test.
    • Method: initial baseline TST and a second TST 1–3 weeks later
    • Interpretation: Repeat TST is considered positive if TST conversion occurs. [77]
      • Negative repeat TST: LTBI is unlikely and no further management is required.
      • Positive repeat TST: A boosted reaction has occurred and LTBI is likely and requires further management.

Treatment

The primary goal of the treatment of latent TB is to prevent reactivation to active TB.

Pretreatment considerations [44]

• Medical and drug history
• Baseline liver chemistries (for all individuals at risk of liver injury)
• Exclusion of active TB: Patients should have no clinical or radiological evidence of TB.
  • Most patients: Obtain AFB smear microscopy ONLY if symptoms or radiological features are identified.
  • Patients with HIV: Consider AFB smear microscopy regardless of symptoms or radiological features.
• Case notification: Reporting to the local health department is advised and may be mandatory in some locations.
• Infection control: Airborne precautions are not required once active pulmonary TB has been excluded. [78]
• Patient education: Provide information about treatment and its side effects, methods available to support adherence to therapy, and instructions to seek medical attention if side effects occur.

Pharmacotherapy of LTBI [44]

• Pharmacological therapy: indicated for patients with positive IGRA or PPD TST after active TB has been excluded
• Rifamycin-based short regimens are preferred.
• Long regimens may be considered based on drug tolerance, pharmacological interactions, and HIV status.

Rifampin and rifapentine are not interchangeable and clinicians and pharmacists should be careful to prescribe and administer the correct drug.

This section provides an overview of the most common types of extrapulmonary tuberculosis.

Tuberculous lymphadenitis [80]

• Pathophysiology
  • Hematogenous dissemination following primary TB
  • Local extension of infection from the affected organ
• Sites of lymph node involvement
  • Cervical
  • Inguinal
  • Axillary
• Clinical features
  • Constitutional symptoms
  • Lymphadenopathy: Findings vary depending on the stage of lymphadenitis. [81]
    • Lymphadenitis: firm, mobile, and discrete lymph nodes
    • Periadenitis: rubbery and fixed lymph nodes
    • Cold abscess: soft and fluctuant lymph nodes
    • Draining sinus tract
• Diagnostics [80]
  • Ultrasound or CT: matted lymph nodes with a necrotic center
  • FNAC or excisional biopsy
    • Acid-fast bacilli
    • Granulomatous inflammation
• Treatment: See “Treatment of extrapulmonary TB.”

Tuberculous hilar lymphadenopathy [1][82]

• Pathophysiology
  • Lymphatic spread of M. tuberculosis from the lung during primary TB infection
  • Bronchus compression
    • Total: causes distal airway collapse
    • Partial: causes ball-valve effect and hyperinflation
• Clinical features
  • Commonly seen in children
  • Wheezing
  • Mostly asymptomatic
• Diagnostics: chest x-ray or CT
  • Unilateral or bilateral enlarged hilar lymph nodes
  • Lung atelectasis
  • Hyperinflation
• Treatment: See “Treatment of extrapulmonary TB.”

Tuberculous pleurisy [83]

• Pathophysiology
  • Direct spread of infection from the lungs
  • Hematogenous spread
  • Delayed hypersensitivity reaction in the pleural space due to mycobacterial antigen
• Clinical features
  • Constitutional symptoms
  • Nonproductive cough
  • Intensive (pleuritic) chest pain
  • Dyspnea
• Diagnostics
  • Imaging
    • Chest x-ray: unilateral pleural effusion
    • Chest ultrasound or CT: loculated effusion with septations; pleural thickening
  • Thoracentesis: pleural fluid analysis [84]
    • Exudative type (Light criteria)
    • pH: < 7.4
    • Glucose: < 60 mg/dL
    • ↑ Adenosine deaminase
    • Rich in lymphocytes
    • Microbiology: acid-fast staining, PCR, and culture
  • Sputum smear examination: acid-fast staining
• Treatment
  • Therapeutic thoracentesis for symptom relief
  • See “Treatment of extrapulmonary TB.”

Miliary tuberculosis [85]

• Definition: a form of TB with multiorgan involvement that manifests with granulomatous lesions (resembling millets) as a result of lymphohematogenous dissemination of bacilli from a pulmonary or extrapulmonary source
• Epidemiology: ∼ 20% of extrapulmonary TB cases [86]
• Pathophysiology: primary infection or reactivation
• Common sites of involvement: lungs, spleen, liver, lymph nodes, adrenals, meninges, vertebrae (Pott disease), joints and long bones, and choroid
• Clinical features: mostly nonspecific
  • Cough and dyspnea
  • Constitutional symptoms
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Tuberculosis miliaria cutis disseminata
• Diagnostics: requires a high index of clinical suspicion
  • Fundoscopy: choroid tubercles
  • Microbiology: sputum, body fluids, and tissue
    • Acid-fast staining
    • PCR
    • Culture
  • Blood
    • ↑ ESR and CRP
    • CBC: anemia, leukopenia
    • LFT: elevated transaminases and bilirubin
    • Electrolytes: hyponatremia, hypercalcemia
  • PPD TST: negative
  • Imaging
    • Chest x-ray: multiple small nodules (< 2 mm) with an appearance resembling millet seeds [86]
    • Ultrasound: pleural effusion, ascites, hepatic or splenic lesions
    • CT: lung nodules, enlarged hilar lymph nodes
    • Brain MRI: meningeal and/or basal cistern enhancement, hydrocephalus, tuberculoma
    • Echocardiography: pericardial effusion
• Treatment: See “Treatment of extrapulmonary TB.”

Tuberculous meningoencephalitis

• Pathogen: : Mycobacterium tuberculosis
• Incubation period: approximately 2–8 weeks
• Risk factors: immunocompromise (e.g., HIV infection)
• Clinical course
  • Subacute course over several weeks or months
  • Gradual manifestation with intermittent fever
• Clinical features
  • Typical symptoms of meningitis, including fever, headache, neck stiffness, and altered mental status (see “Clinical features” section above for details)
  • Focal neurological deficits (e.g., hemiparesis) due to hematogenous dissemination of cranial arteritis
  • Cranial nerve deficits; are most commonly seen in basal meningitis and predominantly involve the abducens nerve [87]
• Diagnostics
  • CSF studies
    • CSF analysis [88]
      • Clear appearance with a spiderweb clot
      • Variable cell count (30–300/mm³) [88]
      • Pleocytosis (predominantly lymphocytes but also granulocytes and mononuclear cells)
      • High lactate, protein, and opening pressure
      • Low glucose
      • See “CSF analysis in meningitis due to atypical pathogens” for comparison with other organisms.
    • Presence of acid-fast bacilli on CSF acid-fast staining [88][89]
    • Culture is the gold standard for diagnosis, but results may take weeks. [89]
    • Analysis of adenosine deaminase (ADA) activity
      • ↑↑ Activity in CSF of individuals with tuberculous meningitis compared to CSF of individuals with other types of meningitis (e.g., cryptococcal or bacterial meningitis)
      • For the differentiation of tuberculous from other types of meningitis, combining serum and CSF ADA activity can increase sensitivity and specificity. [90]
      • However, reported sensitivity and specificity vary greatly in the literature; confounding factors include the CSF ADA cut-offs, assay types, and comorbidities (especially HIV). [91]
  • CT/MRI: possible hydrocephalus, basilar meningeal thickening, tuberculomas, edema, infarcts [88]
• Complications
  • Communicating (malabsorptive) hydrocephalus
  • Pituitary gland insufficiency
• Treatment
  • Antibiotics: See “Treatment of extrapulmonary TB.”
  • Adjunctive glucocorticoid therapy with dexamethasone or prednisolone tapered over 6–8 weeks [92]

Pericardial tuberculosis [93][94]

• Pathophysiology
  • Hematogenous spread from the site of primary infection
  • Retrograde lymphatic spread from hilar lymph nodes
• Stages
  • Stage 1: fibrinous exudate containing neutrophils and mycobacteria
  • Stage 2: serosanguineous effusion with lymphocytes
  • Stage 3: absorption of effusion and caseating granulomas
  • Stage 4: scarring with calcification
• Types
  • Pericardial effusion (rarely, cardiac tamponade)
  • Constrictive pericarditis
  • Effusive-constrictive pericarditis
• Clinical features
  • Constitutional symptoms
  • Chest pain
  • Cough
  • Dyspnea
• Physical examination findings: See “Clinical features” in “Pericardial effusion and cardiac tamponade” and “Pericarditis.”
• Diagnostics
  • ECG: nonspecific ST-T changes
  • Imaging
    • Chest x-ray: enlarged cardiac silhouette or calcification
    • Echocardiography: effusion or diminished wall motility
  • Pericardiocentesis
    • Analysis: exudative, blood-stained
    • Microbiology: acid-fast staining, PCR, and culture
    • ↑ Adenosine deaminase
• Treatment
  • See “Treatment of extrapulmonary TB.”
  • Consider adjunctive steroids only in select patients under specialist guidance (not routinely recommended). [9]
  • Therapeutic pericardiocentesis

Adrenal tuberculosis [95]

• Clinical features: See “Adrenal insufficiency.”
• Diagnostics
  • CT/MRI: bilateral enlargement or calcification of adrenal glands
  • See “Diagnostics” below.
• Management
  • Corticosteroid replacement
  • See “Treatment of extrapulmonary TB.”

Rifampin can precipitate an acute adrenal crisis in patients with undetected adrenal insufficiency due to tuberculosis.

Cutaneous tuberculosis [85][96]

• Classification: based on pathogenesis, morphology of the lesion, and histopathological features

• Diagnostics: skin biopsy for histopathology, acid-fast staining, and culture
• Treatment: See “Treatment of extrapulmonary TB.”

Gastrointestinal tuberculosis [97][98]

• Pathophysiology
  • Ingestion of infected milk or sputum
  • Hematogenous spread resulting from primary pulmonary TB
  • Contiguous spread via affected lymph nodes
• Sites of involvement: See “Types of gastrointestinal TB” below.

• Treatment
  • Surgical: for intestinal obstruction, perforation, fistula, abscess
  • Medical: See “Treatment of extrapulmonary TB.”

Urogenital tuberculosis [85][99]

Renal and urologic TB

• Pathophysiology
  • Hematogenous spread of infection to the kidneys as a result of primary pulmonary TB that is reactivated in immunosuppressed states
  • Ureters and bladder are infected when bacteria are excreted in urine.
• Common sites of involvement
  • Kidneys
  • Ureters
  • Bladder
• Clinical features
  • Constitutional symptoms
  • Flank pain
  • Hematuria
  • Storage symptoms
    • Increased frequency of voiding
    • Nocturia
    • Urgency
  • Hypertension
  • Recurrent UTIs unresponsive to antibiotic therapy
• Diagnostics
  • Urine examination
    • Analysis: hematuria, sterile pyuria, proteinuria
    • Microbiology: acid-fast staining, PCR, and culture
  • Imaging: CT or IV urography
    • Renal scarring
    • Hydroureteronephrosis
    • Calcification involving the entire urinary tract
    • Multiple ureteral strictures
    • Bladder wall thickening and fibrosis
  • Cystoscopy
    • Ulceration
    • Granuloma
    • Fibrosis
• Treatment
  • Medical: See “Treatment of extrapulmonary TB.”
  • Ureteral stenting for strictures
  • Surgery
    • Total or partial nephrectomy
    • Bladder augmentation

Male genital tract TB

• Pathophysiology
  • Hematogenous spread of infection to the epididymis and prostate
  • Extension of infection from the epididymis to the testis, vas deferens, seminal vesicles, and ejaculatory ducts
• Common sites of involvement
  • Epididymis
  • Testis
  • Prostate
  • Vas deferens, seminal vesicles, and ejaculatory duct
• Clinical features
  • Scrotal mass (can be painful or painless)
  • Scrotal sinus tract with watery discharge
  • Infertility
  • Increased urinary frequency, nocturia, and hematospermia
  • Recurrent prostatitis or epididymitis unresponsive to antibiotic therapy
• Diagnostics
  • Urine examination
    • Analysis: hematuria, sterile pyuria
    • Microbiology: acid-fast staining, PCR, and culture
  • Scrotal ultrasound
    • Calcification
    • Hydrocele
    • Diffuse or nodular enlargement of the epididymis
  • Transrectal ultrasound: calcification in prostate and seminal vesicles
• Treatment: See "Treatment of extrapulmonary TB.”

Female genital tract TB [100]

• Pathophysiology: hematogenous spread of infection as a result of primary pulmonary TB that is reactivated in immunosuppressed states
• Common sites of involvement
  • Ovaries
  • Fallopian tubes
  • Endometrium
• Clinical features
  • Constitutional symptoms
  • Menstrual irregularities
  • Abdominal pain
  • Infertility
  • Adnexal mass on pelvic examination
• Diagnostics
  • Menstrual fluid or endometrial curettage sample: acid-fast staining, PCR, and culture
  • Imaging
    • Ultrasound/CT: tuboovarian abscess
    • Hysterosalpingography: occluded fallopian tubes, hydrosalpinx, calcification
    • Hysteroscopy: adhesions and obliterated uterine cavity
• Treatment
  • Medical: See “Treatment of extrapulmonary TB.”
  • Surgery: drainage of tuboovarian abscess

Pott disease [85]

• Pathophysiology
  • Hematogenous dissemination of infection to vertebral bodies following primary TB
  • Infection from vertebral bodies spreads to the intervertebral disk, causing destruction and collapse of the disk
• Common sites of involvement: thoracic and lumbar vertebrae
• Clinical features
  • Constitutional symptoms
  • Back pain
  • Spinal tenderness
  • Kyphosis
  • Gibbus deformity
  • Neurological deficit (e.g., paraplegia)
• Diagnostics
  • Imaging: x-ray, CT, or MRI of the spine
    • Involvement of multiple vertebrae
    • Osteoporosis of vertebral endplate
    • Disk space narrowing
    • Lytic lesions in the anterior vertebral body
    • Collapse of the vertebral body
    • Enlarged psoas muscle shadow (psoas abscess)
    • Spinal cord compression (seen on MRI)
  • See “Diagnostics of active TB.”
• Treatment
  • Surgical: abscess drainage and/or spinal stabilization are indicated in patients with worsening or severe neurological deficits and spinal instability.
  • Medical: See “Treatment of extrapulmonary TB.”

Gross pathology [3]

• Multiple granulomas coalesce as grayish-white areas with necrotic centers that have a cheese-like appearance.
• Calcification and fibrosis are visible in healed lesions.
• Ghon complex
  • Lung parenchyma: gray-white areas of consolidation
  • Hilar lymph nodes: caseous necrosis

Histopathology [3]

Caseating tuberculous granulomas are a characteristic finding of tuberculosis, most commonly reactivation (secondary) tuberculosis.

• Center: area of necrosis
• Periphery: epithelioid histiocytes and Langhans giant cells

Caseating granulomas are strongly associated with tuberculosis but can also occur in infections such as histoplasmosis or those caused by non-tuberculous mycobacteria like Mycobacterium avium.

Histopathology of other types of tuberculosis

• Acinar nodular tuberculosis: merging of multiple epithelioid granulomas into macroscopically visible areas of necrosis
• Miliary tuberculosis: numerous, small, nodular foci with or without central necrosis
• Urogenital tuberculosis [101]
  • Step-like progression with an initial singular focus of tuberculosis
  • Gradually increasing destruction of the renal calyces
  • During the end stage, the kidney appears to have homogeneous, sac-like collections of calcified caseous material on plain abdominal x-ray (known as “putty kidney").

• Rasmussen aneurysm: inflammatory pseudoaneurysm of a branch of the pulmonary artery lying adjacent to a tuberculous cavity and manifesting with hemoptysis
• Massive hemoptysis: due to erosion of blood vessels overlying a lung cavity, Rasmussen aneurysm, or aspergilloma
• Lung cavitation
• Lung fibrosis
• Aspergilloma
• Pneumothorax
• Bronchiectasis
• Fibrosing mediastinitis
• Venous thromboembolism

We list the most important complications. The selection is not exhaustive.

Bacillus Calmette-Guérin vaccine (BCG) [102]

• Composition: live attenuated strain of M. bovis
• Administration: 0.05–0.3 mL of reconstituted vaccine using multiple puncture device over the deltoid region [103]
• Indications
  • Countries with a high TB burden: all newborns at birth [104]
  • Countries with a low TB burden [104]
    • Children with a negative PPD TST and who have come into contact with adults with untreated/inadequately treated TB or drug-resistant TB (if the child cannot take long-term medication for infection)
    • Health care workers continually exposed to individuals with drug-resistant TB
• Other uses: intravesical chemotherapy in superficial bladder cancer
• Benefits: protects against tuberculous meningitis and miliary TB in children [105]
• Adverse effects
  • Localized lymphadenitis and abscess
  • Disseminated TB disease
• Contraindications
  • Immunocompromised individuals
  • Pregnancy

The BCG vaccine is not widely used in the US and is only given to very select people in consultation with a TB expert. [106]

Disinfectants active against M. tuberculosis [107]

• Hydrogen peroxide
• Phenol
• Iodophor
• Chlorine-based solutions
• Glutaraldehyde

Contact tracing and postexposure management [73]

Contact tracing is standard practice in resource-rich countries. Contact tracing and treatment are usually prioritized in cases involving patients with highly infectious TB, vulnerable contacts, or high-risk exposures. [73][108]

• Exposure risk assessment
  • Factors that increase contagiousness of the index case
    • Pulmonary or laryngeal TB
    • Positive sputum smear microscopy
    • Cavitary lesions on chest x-ray
    • Untreated or inadequately treated TB
  • Factors that increase contacts' vulnerability to infection
    • Age < 5 years
    • Immune status: HIV infection, corticosteroid use
    • Comorbid conditions
  • Type of exposure: intensity, frequency, duration of exposure
• Management of contacts
  • Symptomatic contacts: Obtain sputum smear microscopy and chest x-ray and manage according to results.
  • Asymptomatic contacts: Screening tests are indicated, see “Latent tuberculosis” for recommendations on test selection and next steps.

Offer HIV testing to all contacts if HIV status is unknown. [73]

Contact tracing is recommended if the index case has pulmonary or laryngeal TB or has a positive AFB smear. [73]

Postexposure management in health care settings [75]

• All US health care workers are screened for LTBI at the beginning of their employment.
• Health care workers with previous documented LTBI or active TB do not need a screening test after exposure and should be evaluated if features of active TB develop.

Management of TB in pregnant individuals [9][44][109]

General [44][109]

• The diagnostic workup is the same as for nonpregnant individuals.
• Indications for TB testing include:
  • Symptoms of TB
  • Risk factors for TB
  • A high likelihood of progression from LTBI to active TB (see “Screening for LTBI”)
• Abdominal shielding should be used to protect the fetus when performing chest x-rays.
• Liver transaminases should be monitored in patients receiving isoniazid due to an increased risk of isoniazid-induced hepatotoxicity during pregnancy and the postpartum period.

Latent TB [44][109]

• Active TB must to be ruled out by symptom review and chest x-ray before initiating treatment for LTBI.
• Treatment can be delayed until 2–3 months postpartum for women who are not at increased risk of developing active TB.
• Treatment should not be delayed in patients at high risk of developing active TB.

The 3HP regimen (once-weekly isoniazid and once-weekly rifapentine) is not recommended for pregnant women or women planning to become pregnant during the treatment period due to lack of data on safety during pregnancy. [44]

Active TB [9][109]

• Standard first-line regimen
  • Intensive phase: daily rifampin, isoniazid, and ethambutol for 2 months
  • Continuation phase: daily rifampin and isoniazid for 7 months
• Adjuvant treatment: pyridoxine to prevent vitamin B₆ deficiency
• Extrapulmonary or drug-resistant TB: Seek specialist advice. [10]
• Special considerations on pyrazinamide
  • While the WHO recommends pyrazinamide as part of the standard treatment regimen for pregnant women, the CDC and FDA does not recommend its routine use in pregnant women due to a lack of studies in animals as well as humans. [9][109]
  • If pyrazinamide is not used, pregnant patients with drug-susceptible pulmonary TB should be treated for at least 9 months.

Standard first-line therapy for pregnant patients consists of 9 months with isoniazid and rifampin plus ethambutol during the first 2 months.

Streptomycin, kanamycin, amikacin, capreomycin, and fluoroquinolones are contraindicated during pregnancy.

Management during the postpartum period [9][109][110]

• Isolation: Mothers do not need to isolate themselves from their babies after birth but should wear a surgical mask.
• Breastfeeding recommendations
  • Breastfeeding should be encouraged in women receiving treatment with standard first-line agents.
  • Mothers should be informed that rifampin can cause harmless orange discoloration of breastmilk.
  • Exclusively breastfed infants should also receive prophylactic pyridoxine if the mother is taking isoniazid.

Complications of TB during pregnancy [110]

• Maternal
  • Preeclampsia
  • Eclampsia
  • Antepartum hemorrhage
  • Miscarriage
• Fetal
  • Intrauterine growth restriction
  • Preterm birth
  • Low birth weight
  • Increased risk of vertical HIV transmission [111]
  • Congenital TB (rare) [110]
  • Perinatal death

• One-Minute Telegram 115-2025-3/3: Sharing isn’t always caring: preventing TB transmission with levofloxacin
• One-Minute Telegram 75-2023-2/3: Continue screening at-risk individuals for LTBI
• One-Minute Telegram 71-2023-1/3: TRUNCATE-TB: Sometimes less isn’t less
• One-Minute Telegram 4-2020-3/3: Rifampin vs. isoniazid for latent TB infection: better care at a lower cost

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