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Tuberculosis

Last updated: February 25, 2021

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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. 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. Patients with suspected LTBI should be tested using the tuberculin skin test (TST) or interferon-γ release assay (IGRA) and then 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. 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 empirical treatment includes combination therapy with rifampin, isoniazid, ethambutol, and pyrazinamide for two months, followed by rifampin and isoniazid for an additional four months. The incidence of multidrug-resistant TB is steadily increasing.

Types of tuberculosis
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]
  • 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]
  • Symptomatic
  • Contagious
Diagnostics
Treatment
  • Drug-resistant tuberculosis [5]
    • Definition: a form of TB that is resistant to one or more antitubercular agents
    • Types
    • 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 [6]
    • 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.
  • Worldwide [7]
    • 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. [8]
    • 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]

Features of Mycobacterium tuberculosis

Risk factors for tuberculosis

Risk factors for TB exposure [15]

  • Working in the health care industry
  • Migration from countries with a high TB incidence (≥ 100 cases per 100,000 population) [16]
  • 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

Risk factors for reactivation of latent TB [17]

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).

Tuberculosis case definitions and management [31][32]
Class Classification Description Notifiable Treatment
0 No TB exposure, not infected
  • No history of exposure
  • Negative TST
  • No
  • None
1 TB exposure, no evidence of infection
  • History of exposure
  • Negative TST
  • No
  • For patients with HIV and children < 15 years of age with significant exposure in the last 3 months, start treatment for latent TB and follow up with TST results after 10 weeks of exposure to decide further continuation of therapy.
  • For other individuals with significant exposure within 3 months, treatment is initiated based on TST results after 10 weeks of exposure.
2 Latent TB infection, no disease
  • Yes
  • Consider chemoprophylaxis in certain patients in this group (see “Latent TB infection” under “Treatment”).
3

Clinically active TB
  • Positive TST
  • Clinical, bacteriological, or radiographic evidence of active TB disease
  • Yes
  • Yes (see “Treatment” below)
4 TB, not clinically active
  • No clinical or radiological evidence of current disease in individuals with:
    • Previous history of TB
    • Abnormal but stable radiological changes (in patients with a positive TST and negative bacteriological studies)
  • Treatment status (one of the following):
    • Never received treatment
    • Currently receiving treatment for latent TB
    • Completed course of treatment
  • No
  • Complete treatment and monitor the course of disease.
  • If an individual has never received treatment and active TB has not been ruled out, reclassify as class 5.
5

TB is suspected (diagnosis pending)
  • Clinical suspicion of TB
  • Diagnostic tests have not been completed
  • Patients should not remain in this classification for longer than 3 months.
  • Yes
  • Initiated based on the results of diagnostic tests

Primary tuberculosis [1][33][34]

Innate immune response

Cellular immune response

Secondary tuberculosis [34]

Pulmonary tuberculosis

Clinical features

Patients with primary TB are typically asymptomatic. Symptomatic patients present with the following features: [40]

Clinical examination findings

Findings are nonspecific.

  • General
  • Chest examination
    • Percussion
      • Dullness over areas of consolidation
      • Hyperresonance over areas of cavitation
    • Auscultation

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.

Complications [42]

Extrapulmonary tuberculosis

TB lymphadenitis [43]

Tuberculous hilar lymphadenopathy [1][45]

Tuberculous pleurisy [46]

Miliary TB [40]

Tuberculous meningitis

Pericardial TB [49][50]

Adrenal TB [51]

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

Cutaneous TB [40][52]

  • 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 TB [53][54]

  • 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

Genitourinary TB [40][55]

Renal and urologic TB

Male genital tract TB

Female genital tract TB [56]

Pott disease [40]

Active TB [40][57]

Individuals with a history and physical examination findings that suggest TB must undergo bacteriological and/or radiological testing to confirm active TB infection.

Diagnosis of active TB
Test Characteristics Advantages Disadvantages
Bacteriological confirmation
Acid-fast bacilli smear microscopy
  • Rapid detection
  • Inexpensive
PCR
  • High sensitivity
  • Rapid diagnosis [57]
  • Rapid detection of drug-resistant strains [57]
  • Species identification
  • Expensive
  • Cannot be used in resource-limited settings.
Culture
  • Gold standard diagnostic test
  • Used for drug susceptibility testing
  • High sensitivity
  • Species identification
  • Identification of drug resistance
  • Long time for positive cultures to develop [57]
  • Delays the initiation of treatment, especially drug-resistant TB
Radiological confirmation
Chest x-ray [58]
  • Inexpensive
  • Low specificity
  • Variability in interpretation
  • Indications for drug susceptibility testing [57]
    • Previous history of treated tuberculosis
    • Patient has had contact with individuals with MDR-TB
    • HIV infection
    • Patients born or living (for at least one year) in countries with high TB burden (≥ 20 cases per 100,000 population) or high prevalence of primary MDR-TB (≥ 2%) [57]
  • Testing in HIV infection: Urine lipoarabinomannan assay can be used in patients with a CD4 count < 100 cells/mm3. [59]

Latent TB [57][60]

  • Testing objective: to identify individuals who will benefit from treatment
  • Indications
    • High risk of TB exposure
      • Close contact with individuals who have TB
      • Individuals born in or who frequently travel to countries with a high TB burden (> 20 cases per 100,000 population) [57]
      • Individuals living or working in high-risk settings (e.g., homeless shelters, prisons)
      • Health care workers who come into contact with individuals who have TB
    • High risk of TB reactivation
      • HIV infection
      • Children < 5 years of age
      • Recent TB infection (within 2 years of treatment)
      • Intravenous drug users
      • Diabetes mellitus
      • CKD
      • Individuals taking immunosuppressant drugs
      • Silicosis
      • Individuals with cancer of the head and neck
      • Individuals with gastrectomy or jejunoileal bypass
  • Tests: See “Diagnosis of latent TB.”
Diagnosis of latent TB
Tuberculin skin test (purified protein derivative test, Mantoux test) Interferon-γ release assay (IGRA)
Mechanism
Procedure
  • Step 1: 0.1 mL (or 5 units) of PPD injected intradermally on the volar surface of forearm resulting in wheal formation
  • Step 2: transverse diameter of palpable induration checked 48–72 hours later
Interpretation
  • Positive TST indicates active TB or latent TB
  • ≥ 5 mm is considered positive in:
    • Close contacts of patients with TB
    • HIV infection
    • Individuals with clinical or radiographic evidence of active or prior TB
    • Individuals with organ transplants or receiving immunosuppressive therapy
  • ≥ 10 mm is considered positive in:
    • Individuals who have moved within the last 5 years from a high TB burden country (> 20 cases per 100,000 population) [57]
    • Individuals living or working in high-risk settings (e.g., homeless shelters, prisons)
    • Intravenous drug users
    • 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
  • ≥ 15 mm is considered positive in all other individuals.
Benefits
  • Inexpensive
  • Preferred test in children < 5 years of age
  • Only requires a single office visit
  • Preferred test in individuals with prior BCG vaccination
  • Results are available within 24 hours. [60]
Limitations
  • No differentiation between active and latent TB
  • Expensive
  • Requires phlebotomy
  • Errors in collecting and transporting blood can decrease accuracy.
  • Approach
    • Selection of test: based on cost, availability, and history of BCG vaccination
    • Positive IGRA or TST
    • Negative IGRA or TST
      • Consider a second test (TST or IGRA) to increase sensitivity.
      • Two-step TST: baseline test for individuals who are tested periodically (except when IGRA is the baseline test) [60]
        • If repeat TST after 1–3 weeks is negative, no further management is required.
        • If repeat TST after 1–3 weeks is positive, it is a boosted reaction and no treatment is needed.
      • Health care workers with a prior negative TST or IGRA must be retested immediately and again after 8–10 weeks of last known TB exposure. [61]

A healthy individual without any risk factors for TB infection who has an induration smaller than 15 mm is considered negative for TB.

Gross pathology [33]

Histopathology [33]

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 [62]
    • 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").

The differential diagnoses listed here are not exhaustive.

Active TB [63]

General measures

First-line drugs [40][65]

First-line drugs for tuberculosis
Duration of treatment Common side effects
Rifampin
  • 6 months
Isoniazid
  • 6 months
Pyrazinamide
  • 2 months
Ethambutol
  • 2 months

"RIPE": Rifampin, Isoniazid, Pyrazinamide, and EthambutolRifampin and isoniazid alter the efficacy of drugs metabolized by cytochrome P450 (especially protease inhibitors, NNRTIs, OCPs, warfarin, sulfonylureas).

Second-line drugs

These drugs are typically indicated in drug-resistant TB.

Latent TB infection [68]

  • Case notification: mandatory reporting to local health department [32]
  • Indication: positive IGRA or TST
  • Pretreatment evaluation
    • No clinical or radiological evidence of TB
    • Comorbid conditions and medication history
  • Therapy monitoring
Treatment of latent TB
Drug(s) Frequency Duration of therapy
Preferred regimens

Isoniazid PLUS rifapentine
  • Once weekly
  • 3 months
Rifampin (OR rifabutin)
  • Daily
  • 4 months
Isoniazid PLUS rifampin
  • Daily
  • 3 months
Alternative regimen
Isoniazid
  • Daily or twice weekly
  • 6 months
  • 9 months

Bacillus Calmette-Guérin vaccine (BCG) [69]

Postexposure management [72]

  • Risk assessment
    • Individuals with the following characteristics are highly contagious:
      • Pulmonary or laryngeal TB
      • Positive sputum smear microscopy
      • Cavitary lesions on chest x-ray
      • Untreated or inadequately treated TB
    • Type of exposure: frequency and duration
    • People with the following characteristics and who have had contact with individuals with TB have a high risk of developing severe disease:
  • Clinical assessment
  • Baseline test: All individuals should be offered HIV testing if HIV status is unknown.
  • Treatment
    • Positive TST or IGRA: See “Latent TB infection” under “Treatment” above.
    • Negative TST or IGRA
      • If HIV positive and < 5 years of age: Start treatment for latent TB until TST or IGRA is repeated 8–10 weeks following exposure.
      • Other patients: no treatment
  • Follow up test: TST or IGRA repeated 8–10 weeks following exposure
    • Positive TST or IGRA: See “Latent TB infection” under “Treatment” above.
    • Negative TST or IGRA
      • Children < 5 years and patients with HIV infection: Discontinue treatment for latent TB.
      • Other patients: no treatment

Disinfectants active against M. tuberculosis [73]

One-Minute Telegram 4-2020-3/3: Rifampin vs. isoniazid for latent TB infection: better care at a lower cost

Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.

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