• Clinical science

Tuberculosis

Abstract

Tuberculosis (TB) is a common infectious cause of morbidity and mortality worldwide that is caused by Mycobacterium tuberculosis and typically affects the lungs. Primary infection, which is transmitted via airborne droplets, is often initially asymptomatic. Typically, M. tuberculosis remains dormant as the host's immune system keeps it in check (latent tuberculosis). However, if the immune system becomes compromised, reactivation disease may occur. Patients with active disease classically 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. However, disseminated disease is rare, unless the patient is severely immunocompromised. Patients with possible latent TB infection (LTBI) should be tested using the purified protein derivative (PPD) skin test or γ-interferon release assay (IGRAs) and be treated accordingly. Treatment of LTBI reduces the risk of active infection in up to 90% of cases, and therefore plays a crucial role in active TB prevention. Any suspicion of active TB infection should be followed by imaging and an attempt to identify M. tuberculosis using microscopy, cultures, and/or polymerase chain reaction (PCR). The treatment of tuberculosis is a lengthy process due to the slow growth of M. tuberculosis, its concealment in macrophages, and the fact that drugs cannot easily penetrate its cell wall. The standard empirical treatment includes combination therapy with rifampin, isoniazid, ethambutol, and pyrazinamide for 2 months, followed by rifampin and isoniazid for an additional 4 months. Despite combination therapy, the incidence of multidrug-resistant tuberculosis is steadily increasing.

Epidemiology

  • Sex: > (2:1)
  • United States
    • The incidence of TB infection in the US has been slowly declining.
    • Foreign-born individuals (especially Asians and Hispanics) account for two-thirds of new TB cases.
  • Globally
    • A leading infectious cause of death worldwide
    • Despite ∼ 1 in 3 individuals being infected with TB worldwide, the overall incidence and prevalence have been declining.
    • Countries with the highest incidence of TB: India, Indonesia, China, Nigeria, Pakistan, and South Africa

The incidence of multidrug-resistant tuberculosis is steadily rising.

References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Mycobacteria

  • General features
    • Nonmotile, aerobic, gram-positive, acid-fast bacilli with a rich lipid cell wall
    • Resistance: survives in aerosols, even over long distances
    • Acid-fast: able to survive in gastric secretions
      • Difficult to decolorize
    • Complex waxy, resistant cell walls increase the resistance to antimicrobial medication → Antibiotics only have an effect if used in combination over a long period of time.
  • Species
    • Mycobacterium tuberculosis complex
      • Mycobacterium tuberculosis
        • Main pathogen causing tuberculosis: 95% of cases
        • First described by Robert Koch in 1882
        • Transmission: mostly spread via droplet infection
        • Pathogen host: predominantly humans
      • Mycobacterium bovis:
        • Common pathogen causing gastrointestinal tuberculosis
        • Mechanism of infection: predominantly via ingestion of contaminated cow's milk
        • Pathogen reservoir: predominantly cattle

References:[4][5]

Etiology

Risk factors

TB and AIDS each work to exacerbate the disease progression of the other!

References:[4][2][6]

Classification

Tuberculosis case definitions

Classification Description Notifiable Treatment?
No TB exposure; not infected
  • No
No
TB exposure; no evidence of infection
  • No
TB infection; no active disease
  • No
Consider chemoprophylaxis in certain patients in this group

TB infection; active disease, clinical evidence

  • Yes
Yes
TB not clinically active
  • History of episodes of TB OR
  • Abnormal but stable radiological changes; positive tuberculin skin test; negative M. tuberculosis culture
  • AND no clinical or radiological evidence of current disease
  • No
May have completed chemoprophylaxis therapy; may never have received therapy before or may be completing chemoprophylaxis currently.

TB suspected

  • Diagnosis is pending
  • Patients should not be in this classification for longer than 3 months
  • Yes

TB treatment may or may not have commenced.

Primary tuberculosis (primary infection)

  • Latent tuberculosis infection (LTBI)
    • Definition: primary infection without any pathological findings on radiological imaging; ; however, screening tests indicating previous infection with M. tuberculosis are positive.
    • The lifetime risk of reactivation TB for a person with LTBI is about 5–10%.
  • Active primary tuberculosis (only 1–5% of cases): primary infection with radiological-pathological findings of tuberculosis (see “Diagnostics” below)

Reactivation tuberculosis (secondary infection)

  • Definition: following a latent primary TB infection; 80% of secondary infections begin in the lungs (many months or years may pass between the onset of primary and secondary infection).
  • Endogenous reactivation (very common)
  • Exogenous reinfection (rare)

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)!

Drug-resistant tuberculosis

  • Variations
    • Single drug-resistant tuberculosis (SDR-TB)
    • Multidrug-resistant tuberculosis (MDR-TB)
    • Extensively drug-resistant tuberculosis (XDR-TB)
  • Causes: inadequate combination therapy or drug concentration
  • Commonly affects multiple organs; relapse is common.
  • Prognosis: Chances of recovery are about half that of non-resistant pathogens.

References:[7][8][9]

Pathophysiology

  • Alveolar macrophages phagocytose the TB bacteria but cannot eliminate them.
  • The infection is usually contained in the lung by formation of caseating granulomas (see “Pathology” below) that limit damage to the lungs and bacterial dissemination.
    • The bacteria may remain dormant in the granulomas for many years without any active clinical disease manifesting (latent TB).
    • Immunosuppression (compromised T cell function) → dormant bacteria become active, replicate in the macrophages and spread into the lungs and other organs (active TB).
  • IFN-γ deficiency: impaired phagocytosis and impaired granuloma formation → disseminated TB

References:[4][10][11]

Clinical features

  • Latent infection
    • Asymptomatic
    • The patient is not contagious.
  • Active infection (either primary or reactivated)
    • Constitutional symptoms: fever, weight loss, night sweats, fatigue, lymphadenopathy
    • Pulmonary symptoms: dyspnea, productive cough (possibly hemoptysis) lasting > 3 weeks
    • The patient is contagious
    • 80% pulmonary tuberculosis
    • 20% extrapulmonary tuberculosis

Always consider TB as a differential diagnosis in a young patient with hemoptysis! Depending on the degree of immunosuppression, TB in HIV-positive patients may progress atypically or more rapidly!

References:[4][12]

Subtypes and variants

Extrapulmonary TB

The most common sites of extrapulmonary TB include the bones, pleura, lymphatic system, and liver. TB may also affect the central nervous system (CNS), heart, urogenital and gastrointestinal tracts, and the skin.

Urogenital tuberculosis

  • Clinical features
  • Diagnosis
    • Urinary tract
      • Sterile leukocytosis in the first urine culture
      • Imaging: calcifications, strictures, and cavities
    • Adnexal involvement
      • Direct identification of M. tuberculosis in the menstrual blood
      • Imaging: pyosalpinx
  • Management
    • Normal TB therapy
    • Surgical intervention to remove adhesions () and urethral strictures

Adrenal tuberculosis

Miliary tuberculosis

  • Definition: massive lymphohematogenous spread of Mycobacterium tuberculosis bacilli from a pulmonary or extrapulmonary focus with multiple organ involvement and very small granuloma lesions (1–2 mm)
  • Epidemiology: accounts for ∼ 20% of all extrapulmonary TB cases
  • Etiology: may present 2–5 months after initial infection or years after
  • Pulmonary involvement (most common)
    • Chest x-ray: multiple, small, nodular densities of equal size, scattered throughout the lungs; (often described as having a "millet seed" appearance)
  • Other commonly affected organs: central nervous system, choroid, skin, liver/spleen (hepatosplenomegaly), kidneys, adrenal glands
  • Management
    • Normal TB therapy
    • Surgical interventions depending on the affected sites and scope of disease

Dermatological tuberculosis

Other areas

References:[4][13][14][15][16][17][18]

Diagnostics

Active TB

  • Assess risk of active TB through history and physical examination
    • Moderate to high risk: chest x-ray → if suggestive of pulmonary TB, collect three sputum samples for culture, PCR; , and microscopy → initiate treatment if tuberculous mycobacteria are confirmed (through culture) and also if PCR and microscopy are positive for tuberculous mycobacteria (while culture is pending)
    • Low risk: : consider testing for latent tuberculosis (see below)
  • Chest x-ray findings in tuberculosis
  • Sputum microscopy with acid-fast stain (Ziehl-Neelsen stain)
    • Rapid results but lacks sensitivity
    • Collect species over a course of three days: sputum for pulmonary or airway disease; blood, gastric juices, urine, liquor, or tissue for extrapulmonary disease
    • No differentiation between M. tuberculosis or nontuberculous mycobacteria possible
  • Culture (gold standard)
    • Used for species identification, sensitivity testing, and to identify possibly resistances
    • Culturing can take up to six weeks (not useful for initial therapy planning)
    • E.g., Löwenstein–Jensen agar

Latent tuberculosis (LTBI)

  • Test patients at risk for reactivation or new LTBI who would benefit from treatment of LTBI.
    • Asymptomatic individuals in whom new infection is suspected; (e.g., close contacts of patient with active TB, health care workers)
    • People at risk for reactivation (e.g., immunocompromised patients)
  • If patients would benefit from treatment → TST or IGRA
    • Positive test → Evaluate for active TB (see “active TB” above) to decide whether treatment for active or latent TB is indicated.
    • Negative test
      • Repeat test after 8 weeks in patients who are close contacts of patients with active TB or annually in patients with ongoing exposure (e.g., healthcare workers).
      • If none of the above applies, no repeat testing is necessary and the patient is considered negative for LTBI.
  • Both TST and IGRA are adequate, with the following exceptions:
  • Interferon-γ release assay (IGRA)
    • ELISA test that measures the level of interferon-γ expressed by T cells after coming into contact with synthetic TB-specific peptides
    • Results available within 24 hours
    • Higher costs
    • Errors in collecting and transporting blood can decrease accuracy
  • Tuberculin skin test (TST) or purified protein derivative (PPD) test
    • 5 units (= 0.1 mL) of purified protein derivative tuberculin is injected intradermally into the ventral surface of the lower arm. The diameter of the induration at the injection site is measured after 48–72 hours.
    • The test only becomes positive 6–8 weeks after infection
    • Limited specificity and sensitivity (∼ 70%)
Interpretation of the PPD test
Diameter of the induration Considered positive in the following groups

5 mm, positive

  • HIV-positive patients
  • Recent contact with a TB-infected person
  • Signs of TB on chest x-ray

10 mm

  • Patients with high risk of reactivation
    • IV drug use
    • Homelessness
    • Immigration from endemic country
    • Chronic illness (e.g., diabetes, kidney or lung disease, malignancy)
    • Occupation (health care or prison workers)
15 mm, highly positive, may have partial blistering
  • Always considered positive, even without risk factors

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

References:[4][6][12][19][20][21][22][23][24]

Pathology

Gross pathology

Histopathology

Tuberculous granuloma

Caseous tuberculous granulomas are a sign of a functioning immune system in TB infection. However, they do not necessarily demonstrate TB infection. Other mycobacteria (including tuberculoid leprosy) and tertiary syphilis may present similarly!

Other histological types

  • Acinar nodular tuberculosis: merging of multiple epithelioid granulomas into macroscopically visible areas of necrosis
  • Miliary tuberculosis: single, small, nodular foci; mostly without central necrosis
  • Urogenital tuberculosis
    • Step-like progression with initial singular foci of tuberculosis; gradually increasing destruction of the renal calyces
    • During the end-stage, the kidney appears to have homogenous sac-like collections of calcified caseous material on plain abdominal x-ray ("putty kidney").

References:[7]

Differential diagnoses

The differential diagnoses listed here are not exhaustive.

Treatment

General

  • Isolation: Every patient diagnosed with active TB must be isolated until sputum, gastric juices, and urine are negative!
  • Therapy monitoring
    • Monthly sputum samples for microscopy and culture
    • Monitor drug side effects: renal retention parameters, ophthalmological check-up , ENT, and liver function tests
    • Non-compliance: possibly directly observed therapy (DOT)
  • For treatment of extrapulmonary TB manifestations, see “Subtypes and variants” above.

Active disease

First-line treatment

Active agent Time Important side effects
Isoniazid 6 months

Rifampin

6 months
  • Hepatotoxic
  • CYP-inducer (especially CYP3A4, CYP2C9)
  • Red or orange body fluids (e.g., urine, tears)
Pyrazinamide 2 months
Ethambutol 2 months

"RIPE" is the acronym for four drugs used in first-line treatment: Rifampin, Isoniazid, Pyrazinamide, and Ethambutol.

The efficacy of drugs metabolized by cytochrome P450 may be reduced because of hepatic enzyme induction by tuberculostatic drugs (especially oral diabetic treatments, calcium antagonists, statins, and oral contraceptives)!

Latent tuberculosis infection

Postexposure management

  • Recent contact with a person who has active TB
    • Perform PPD test or IGRAs and a chest x-ray
    • Positive results and/or clinical symptoms of active TB → sputum stain and culture
      • Sputum stain and/or culture positive: immediate initiation of treatment for active TB disease (see ”Treatment of active disease” above)
      • Sputum stain and/or culture negative but interferon-γ and/or PPD test positive: start treatment for LTBI (see ”Treatment of LTBI” above)
      • All tests negative: LTBI treatment for infants, children, and HIV-positive patients

References:[4][25][26][27][28][29]

Prevention

  • BCG-vaccination
    • Children with a negative TST and continued high-risk exposure (e.g., drug-resistant TB)
    • Health-care workers on an individual basis
  • Population groups with tuberculosis infection risk below 0.1% (e.g., Europe) should not impose a generalized BCG vaccination regulation.
  • Notification: Any health care worker that knows of a case of suspected or confirmed tuberculosis in a patient should notify the TB program in their department within 24 hours, after which time the local board of health will be notified (within the following 24 hours). This includes patients who refuse treatment or do not adhere to treatment.
  • Postexposure management: after recent contact with a person who has active TB
    • Perform PPD test or IGRAs and a chest x-ray
    • Positive results and/or clinical symptoms of active TB → sputum stain and culture
      • Sputum stain and/or culture positive: start treatment for active TB (see ”Treatment of active disease” above)
      • Sputum stain and/or culture negative but interferon-γ and/or PPD test positive: start treatment for LTBI (see “Treatment of LTBI” above)
    • If tests are negative in infants, children, and HIV-positive or other severely immunocompromised patients → LTBI treatment

References:[4][30]