Tuberculosis

Last updated: August 25, 2022

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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 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.

Types of tuberculosis
Characteristics Primary tuberculosis (primary infection) Reactivation tuberculosis (secondary infection) [1]
Latent tuberculosis infection (LTBI) [2] Active primary tuberculosis [3]
Definition
Features
  • Asymptomatic
  • Not contagious
  • The risk of reactivation is 5–10% during the course of a lifetime. [4]
  • Can be symptomatic
  • Contagious
  • Progressive primary tuberculosis is a severe form of disease seen in individuals with impaired immune systems (e.g., HIV, malnutrition) or immature immune systems (e.g., young children). [1]
Diagnostics
Treatment

  • United States [12]
    • 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% [13]
  • Worldwide [14]
    • 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. [15]
    • 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:

Features of Mycobacterium tuberculosis

Risk factors for tuberculosis exposure [22]

Primary tuberculosis [1][24][25]

Innate immune response

Cellular immune response

Secondary tuberculosis [25]

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

Pulmonary tuberculosis [1]

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.

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]

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.

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:

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]

Because sputum induction carries a high risk of transmission to health care workers, the procedure must be performed under strict infection control precautions. [37]

Microbiological tests for active TB [7][38]
Test Description Advantages Disadvantages
Acid-fast bacilli smear microscopy
  • Rapid detection
  • Inexpensive
Nucleic acid amplification test
  • For initial testing (along with AFB smear microscopy and culture) if clinical suspicion is high
  • Used for confirmation of AFB positive smears [7]
  • High specificity and sensitivity (lower sensitivity in individuals with a negative AFB smear) [38]
  • Rapid diagnosis
  • Rapid detection of drug-resistant strains [38]
  • Low cross-reactivity with nontuberculous mycobacteria [38]
  • Requires laboratory equipment and trained staff, which may make use in resource-limited settings more difficult
  • Both viable and nonviable mycobacteria are detectable. [37]
Culture
  • High sensitivity [38]
  • Species identification
  • Identification of drug resistance
  • Takes 2 to 6 weeks for positive cultures to develop [38]
  • Delays the initiation of treatment, especially drug-resistant TB

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]

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

Imaging [7][8][41]

  • 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.
Chest imaging findings in active TB [33][41]
Primary TB (middle/lower lobes) Postprimary (reactivation) TB
Chest x-ray
  • Consolidation (patchy or confluent)
  • Fibrocaseous cavitary lesions in upper lobes
  • Calcifications

CT chest

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. [33]

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][32][41]

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. [32][37]

  • Advanced testing in patients with HIV (not widely available) [37]
  • In resource-limited settings: a lower threshold for defining smear positivity and consideration of empiric treatment may be necessary [37]

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. [37]

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

General principles [1][9]

Indications for treatment [9]

  • Confirmed active TB
  • 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]

Antituberculosis therapy

Standard antituberculosis therapy [9]

Standard first-line therapy consists of 6 months with isoniazid and rifampin plus ethambutol and pyrazinamide 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]

Treatment of drug-resistant TB disease [10]

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

Treatment of extrapulmonary TB [9]

Treatment of extrapulmonary TB is usually guided by experts, and the choice of agents and duration of treatment are dependent on the site of manifestation.

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.

Specific side effects of antituberculosis drugs [9]

Isoniazid

Rifampin
Pyrazinamide
Ethambutol

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

Monitoring [9][45]

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

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. [45]

Description

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 [13]

  • 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][45]

Screening for LTBI [7][13][54]

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

All patients with HIV should be screened for LTBI, regardless of additional risk factors. [45]

All individuals due to start immunosuppressive therapy should be screened for LTBI. [55]

Selection of screening test [7]

Screening tests for LTBI [7]
Tuberculin skin test (purified protein derivative test, Mantoux test) [62] Interferon-γ release assay (IGRA) [63]
Mechanism
Procedure
  • Step 1: 0.1 mL (or 5 units) of purified protein derivative (PPD) injected intradermally on the volar surface of the forearm resulting in wheal formation
  • Step 2: transverse diameter of palpable induration checked 48–72 hours later
  • QuantFERON-TB Gold In-Tube (QFT) assay: Whole blood is drawn into three test tubes in the following order: [64]
    1. Negative control tube
    2. TB antigen test tube
    3. Positive control tube containing mitogen
  • T-SPOT.TB assay: One sample of whole blood is required. [63]
Benefits
  • Inexpensive
  • Preferred test in children < 5 years of age [7]
  • Only requires a single office visit
  • Preferred test in individuals with prior BCG vaccination
  • Results are available within 24 hours. [45]
Limitations
  • No differentiation between active and latent TB
  • Expensive [45]
  • Errors in collecting and transporting blood can decrease accuracy. [13]

Interpretation of results [7][45]

  • IGRA
    • Positive: TB infection is likely
    • Negative: TB infection is unlikely, but cannot be excluded
    • Indeterminate: can occur in immunosuppressed states, and a repeat IGRA or TST can be useful [66]
  • TST: Depending on patient characteristics, a 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.
Positive TST according to induration diameter [45]
> 5 mm
  • Individuals exposed to AFB smear-positive case
  • Individuals with HIV
  • Individuals with clinical or radiographic evidence of active or prior TB
  • Individuals with organ transplants or receiving immunosuppressive therapy
> 10 mm
  • Individuals who have moved within the last 5 years from a country with a high TB burden (> 20 cases per 100,000 population) [7]
  • Individuals living or working in high-risk settings (e.g., homeless shelters, prisons)
  • Individuals who inject drugs
  • Mycobacteriology laboratory workers
  • Individuals with illnesses such as diabetes and CKD
  • Children < 5 years of age
  • Children who have had contact with adults in high-risk categories
  • Individuals with low BMI
> 15 mm
  • All otherwise healthy individuals with no known risk factors [67]

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. [13]

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. [13]

Further evaluation

Management of individuals screened for TB [68]
Initial management Further management
Positive IGRA or TST
IGRA or TST negative If < 8–10 weeks since exposure
  • Immunocompetent individuals and children ≥ 5 years of age: no treatment; repeat screening test 8–10 weeks following exposure.
  • Immunocompromised individuals and children < 5 years of age: Start treatment for LTBI until TST or IGRA is repeated 8–10 weeks following exposure.
If > 8–10 weeks since exposure
  • No further evaluation is required.

If health care workers are exposed to an individual with active TB without adequate personal protective equipment, IGRA or TST must be performed immediately and repeated after 8–10 weeks if the initial test is negative. [69]

Special situations [45]

  • HIV infection: Screen for LTBI at the time of diagnosis and repeat annually in patients at risk of exposure.
  • BCG vaccine: may cause false-positive results in TST; if available, IGRA is preferred.
  • Screening prior to starting immunosuppressive therapy: Follow the usual screening algorithm, but consider a second test if the initial screening test is negative. [70]
  • Individuals who are periodically tested with 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. [71]
        • 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 [45]

  • 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.
  • 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. [72]
  • 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 [45]

  • Pharmacological therapy: indicated for patients with positive IGRA or TST after active TB has been excluded
  • Select a regimen based on the length of treatment, drug tolerance, pharmacological interactions, and HIV status.
Drug regimens for treatment of LTBI [45]
Detailed regimen Indications
Short regimens
  • Most patients > 2 years of age
  • Select patients with HIV/AIDS
  • Once-daily rifampin for 4 months (abbreviation: 4R) [45]
  • HIV-negative patients of any age who:
    • Are unable to tolerate INH
    • OR have been exposed to INH-resistant TB
Long regimens
  • Most patients with HIV
  • Patients of any age with contraindications for rifamycins [73]

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 [74]

Tuberculous hilar lymphadenopathy [1][76]

Tuberculous pleurisy [77]

Miliary tuberculosis [79]

Tuberculous meningitis

Pericardial tuberculosis [81][82]

Adrenal tuberculosis [83]

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

Cutaneous tuberculosis [79][84]

  • Classification: based on pathogenesis, morphology of the lesion, and histopathological features
Types of cutaneous TB
Type Pathophysiology Clinical features Histopathology features
Exogenous source of TB
Primary inoculation TB (tuberculous chancre)
Postprimary inoculation TB (tuberculosis verrucosa cutis)
Endogenous source of TB
Scrofuloderma
  • Firm nodule or swelling that ulcerates to form a discharging sinus tract
Autoinoculation
Hematogenous source of TB
Lupus vulgaris
  • Individuals previously sensitized to TB with a high degree of sensitivity
  • Nonspecific features
Tuberculosis miliaris cutis disseminata
  • Site: trunk, thighs, buttocks, genitalia
  • Widespread papules and crusted vesicles
Tuberculous gumma (metastatic tuberculous abscess)
  • Multiple skin nodules that may ulcerate to form discharging sinus tract
Tuberculid
Variable forms
  • Unknown
  • Papules or nodules with ulceration and scarring

Gastrointestinal tuberculosis [85][86]

  • 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.
Types of gastrointestinal TB
Site of involvement Clinical features Diagnostics Differential diagnosis
Peritoneum
Esophagus
Stomach

Jejunum and ileocecal region

Colorectal
  • Abdominal pain
  • Weight loss
  • Loss of appetite
  • Altered bowel habits

Urogenital tuberculosis [79][87]

Renal and urologic TB

Male genital tract TB

Female genital tract TB [88]

Pott disease [79]

Gross pathology [24]

Histopathology [24]

Caseating tuberculous granulomas are pathognomonic of reactivation (secondary) tuberculosis.

Although caseating tuberculous granulomas are a sign of a functioning immune system in TB infection, they do not necessarily indicate TB infection because other mycobacteria (including tuberculoid leprosy) and tertiary syphilis manifest similarly.

Histopathology of other types of tuberculosis

  • Acinar nodular tuberculosis: merging of multiple epithelioid granulomas into macroscopically visible areas of necrosis
  • Miliary tuberculosis: single, small, and nodular foci without central necrosis
  • Urogenital tuberculosis [89]
    • 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").

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

Bacillus Calmette-Guérin vaccine (BCG) [90]

The BCG vaccine is not widely used in the US and is only given to very select people in consultation with a TB expert. [93]

Disinfectants active against M. tuberculosis [94]

Contact tracing and postexposure management [68]

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. [68][95]

  • 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
    • Type of exposure: intensity, frequency, duration of exposure
  • Management of contacts

Offer HIV testing to all contacts if HIV status is unknown. [68]

Contact tracing is recommended if the index case has pulmonary or laryngeal TB or has a positive AFB smear. [68]

Postexposure management in health care settings [69]

  • 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][45][96]

General [45][96]

Latent TB [45][96]

  • 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.
Drug regimens for treatment of LTBI in pregnant women [45]
Detailed regimen
Short regimens
  • Rifampin once daily for 4 months (abbreviation: 4R)
Long regimens
  • Isoniazid once daily for 6 months (abbreviation: 6H) or 9 months (abbreviation: 9H) PLUS pyridoxine

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. [45]

Active TB [9][96]

Active TB [9][96]

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][96][97]

  • 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 [97]

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