Introduction

Tuberculosis (TB) is a disease that is caused by Mycobacterium tuberculosis. It typically affects the lungs. According to the World Health Organisation (WHO), every year, around ten million people fall ill with TB and 1.5 million people die from TB, making it the leading infectious cause of death. It is transmitted via airborne droplets. Primary infection is mostly asymptomatic. The infection may remain dormant or reactivate later when the immune system is compromised. Sputum analysis and imaging are required for diagnosis. Treatment includes combination therapy for a long duration.

Epidemiology

  • Incidence: 9.00 cases per 100,000 person-years
  • Peak incidence: 50-60 years
  • Sex ratio: 1:1
Condition Relative
incidence
Lung cancer8.56
Bronchiectasis1.67
Tuberculosis1
Sarcoidosis0.78
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

Mycobacterium tuberculosis is an aerobic, acid-fast bacilli . It mostly spreads via droplet infection.

Risk factors for TB:
  • Immunosuppression:
    • HIV.
    • Immunosuppressant drugs
    • TNFα inhibitors.
  • Diabetes mellitus, end-stage renal disease.
  • Previous lung disease (silicosis).
  • Smoking.
  • Drug abuse, alcoholism.
  • Malnutrition, poverty.
  • Certain living conditions (prisons, homeless shelters).
  • Occupational (hospitals).

Pathophysiology

Virulence factors resist host response and elicit granuloma formation.
  • Mycolic acid glycolipids.
  • Trehalose dimycolate ('cord factor').
  • Catalase-peroxidase.
  • Lipoarabinomannan.

Inhalation of Mycobacterium tuberculosis via droplet → deposition in the lungs (alveoli) → engulfed by alveolar macrophages → proliferates in macrophages → release → immune response.
  • Immediate clearance of the organism: the majority of individuals never develop the clinical disease.
  • Primary disease: rapid progression to active disease if the immune response is inadequate.
  • Latent infection (with or without subsequent reactivation disease): TH1 response → caseating granuloma formation (caseous centre with necrotic material, surrounded by lymphocytes and macrophages) → successful containment.
  • Reactivation disease:
    • Occurs when the immune response is suppressed.
    • Onset of the active disease years after latent infection.

Clinical features

After infection with Mycobacterium tuberculosis, most individuals with intact immunity control further replication, which may be cleared or enter a “latent” phase. Some individuals, specifically those with low immunity or risk factors for TB, develop progressive “primary” disease. Individuals with latent TB have bacilli that can “reactivate” and progress to symptomatic disease later in life. There is around 10% lifetime risk of reactivation of TB.

Latent infection of TB is asymptomatic and non-contagious. The active infection due to primary or reactivated TB leads to various symptoms and is contagious.

Constitutional symptoms:

Pulmonary tuberculosis:
  • Most common.
  • Dyspnoea, cough (+/- haemoptysis) , chest pain.
  • Cough: over 2 to 3 weeks; initially dry, later productive.
  • Chest examination: crackles, bronchial breath sounds, or maybe normal.

Extrapulmonary tuberculosis:
  • Less common.
  • Pleura, bones, lymphatic system, liver, central nervous system, urogenital tract, gastrointestinal tract, and the skin.
  • Symptoms based on the organ-involvement (enlarged lymph node, pleuritic chest pain, skeletal pain, urinary symptoms, abdominal swelling, abdominal pain, headache).

Investigations

Investigations for latent infection in a person exposed to M tuberculosis but without signs of active TB are based on the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Both tests evaluate cell-mediated immunity. An IGRA is preferred in individuals with a history of BCG vaccination. These tests should not be used alone to exclude a diagnosis of active TB as false-negative results occur in around 25% of patients.
  • TST: purified protein derivative tuberculin is injected intradermally in the lower arm. The diameter of the induration is measured after 48–72 hours.
  • IGRA: blood test that measures the level of interferon-γ. Two major IGRAs are: QuantiFERON-TB assay and T-SPOT TB assay.

The possibility of TB should be considered in any person with risk factors for TB, who has suggestive symptoms. Primary investigations for active pulmonary infection include chest x-ray, three sputum samples obtained for microscopy, culture, and nucleic acid amplification testing (NAAT).

Chest x-ray:
  • Primary: hilar lymphadenopathy, effusion, pulmonary infiltrates, calcification.
  • Reactivation: upper lobe cavitary lesion.

Sputum analysis:
  • Sputum microscopy: typically, three samples are required. Acid-fast stain (Ziehl-Neelsen stain) identifies the bacilli. Sensitivity is around 55%.
  • Culture (gold standard): most sensitive and specific test (about 80 and 98 percent, respectively). It can take up to six weeks with conventional solid media (eg. Löwenstein–Jensen agar). Culture techniques using liquid media give rapid results within one to three weeks. Mycobacteria growth indicator tube and microscopic observation drug susceptibility assay are commonly used.
  • NAAT: probe-based tests that amplifies a specific nucleic acid sequence that can be detected via a nucleic acid probe; some NAATs can detect genes encoding drug resistance. It facilitates rapid diagnosis in smear-negative disease (sensitivity: 67% and specificity: 98%).
    • Xpert MTB/RIF assay: detects M tuberculosis and rifampin-resistance mutations.
    • Amplified Mycobacterium tuberculosis direct test: detects TB but not drug resistance.

Bronchoalveolar lavage sample, pleural fluid, or gastric aspirate may be used in patients unable to provide an adequate sputum sample. Pleural biopsy or lung biopsy may be used if other testing is not diagnostic.

The diagnosis of extra-pulmonary TB can be established by identification of M tuberculosis from a bodily secretion or tissue biopsy depending on the organ involvement.

Differential diagnosis

TB should be differentiated from other pulmonary conditions with similar presentations. Possible differential diagnoses are:
  • Nontuberculous mycobacterial infections:
    • Similarities: fatigue, dyspnoea, occasional haemoptysis.
    • Differences: fever and weight loss occur less frequently than in patients with TB, distinguished from TB by culture results or molecular diagnostic testing.
  • Pneumonia:
    • Similarities: fever, dyspnoea, chest pain, cough.
    • Differences: shorter duration of symptoms and responds to typical antibiotics.
  • Lung cancer:
    • Similarities: fever, cough, haemoptysis, chest pain, dyspnoea.
    • Differences: sputum cytology, CT of the chest and tissue biopsy maybe needed.
  • Sarcoidosis:
    • Similarities: cough, dyspnoea.
    • Differences: rarely forms cavities, negative sputum culture, non-caseating granulomas.
  • Lymphoma:
    • Similarities: fever, night sweats, weight loss.
    • Differences: rapidly growing mass, absence of cough and dyspnoea, distinguished from TB by histopathology.
  • Lung abscess:
    • Similarities: cough with sputum production, chest pain.
    • Differences: high grade fever, chest imaging usually shows infiltrates with a cavity, other organisms in culture results.

Management

Treatment for latent TB infection: isoniazid for nine months or rifampin for four months are commonly prescribed. Before the initiation of treatment for latent TB, active infection must be ruled out to prevent the development of resistance.

Treatment for active TB infection:
  • Initiated when TB is confirmed or strongly suspected.
  • TB mostly requires a long duration of treatment (mostly 6 months) consisting of an initial intensive phase and a subsequent continuation phase.
  • Isolation is needed while infectious.
  • Combination of drugs and directly observed therapy is recommended to minimize the likelihood of development of resistance.
  • The recommended regimen for drug-susceptible individuals is:
    • Intensive phase: two months of isoniazid + rifampin + pyrazinamide + ethambutol.
    • Continuation phase: four months of isoniazid + rifampin.

Monitoring:
  • Sputum samples (microscopy and culture) should be obtained for acid-fast bacilli smear and culture at monthly intervals until two consecutive cultures are negative.
  • Drug-related side effects are common.
    • Hepatotoxicity is an important adverse effect of isoniazid, rifampin, and pyrazinamide.
    • Pyridoxine is always given with isoniazid to prevent peripheral neuropathy.

Additional considerations:
  • Interruption of the treatment is managed by either extending the duration of treatment or restarting the treatment from the beginning.
  • If treatment failure (positive cultures after four months of therapy) or relapse (recurrent TB at any time after completion of therapy) is confirmed or suspected, the drug susceptibility testing should be done.

Multidrug-resistant tuberculosis:
  • TB resistant to at least both isoniazid and rifampin.
  • A longer, individualised regimen vs a shortened, standardised regimen.
  • Different regimens of combination of second-line drugs are used for a duration of 9 to 18 months.
  • Management of drug-resistant TB requires expert consultation.
  • Levofloxacin (or moxifloxacin) + bedaquiline + linezolid is a commonly used regimen.

Extensively drug-resistant TB:
  • Resistant to at least isoniazid, rifampin, and fluoroquinolones as well as either aminoglycoside (amikacin, kanamycin) or capreomycin or both.
  • Treatment consists of an intensive and continuation phase for prolonged duration.
  • The regimen consists of at least five drugs: comprised of susceptible first-line drugs if any, a fluoroquinolone, bedaquiline, linezolid, and additional oral agents (clofazimine, cycloserine, or terizidone).
  • A new alternative regimen for treatment of XDR-TB consists of a 26-week regimen including bedaquiline, pretomanid, and linezolid.

Complications

More common with reactivation disease.
  • Pulmonary:
    • Haemoptysis
    • Pneumothorax
    • Bronchiectasis
    • Pulmonary destruction
    • Fistula
    • Tracheobronchial stenosis
    • Malignancy
    • Chronic pulmonary aspergillosis.
  • Tuberculous effusions and empyema.
  • Miliary TB : massive spread with multiple organ involvement.
  • Septic shock.

Prognosis

Generally, patients do well with treatment.
  • Worldwide, the case-fatality rate is 3.8% in smear-positive pulmonary TB patients on treatment.
  • Risk factors for death:
    • Older age
    • Delay in diagnosis of TB.
    • Significant co-morbidities.
    • Immunosuppression.
    • Need for mechanical ventilation.

Screening and prevention

Screening for latent TB infection is done for:
  • Individuals with recent exposure (contacts).
  • Health care workers.
  • Homeless shelters and prisons.
  • Individuals with increased risk of reactivation: HIV.
  • Travellers from high-incidence countries.

Screening tests:
  • TST test or IGRA.
  • If any positive or active TB suspected:
    • Chest x-ray
    • Sputum stain and culture

Prevention:
  • Bacille Calmette-Guérin (BCG) vaccination: children in high-risk region, health-care workers, and other individuals based on exposure status; should not be administered to individuals with decreased immunity.
  • Isolate patient (short-term, until two weeks after initiating treatment), avoid new encounters, identify and treat the contacts.
  • Reportable condition to the local health authorities.