Risk factors for TB:
- Immunosuppressant drugs
- TNFα inhibitors.
- Diabetes mellitus, end-stage renal disease.
- Previous lung disease (silicosis).
- Drug abuse, alcoholism.
- Malnutrition, poverty.
- Certain living conditions (prisons, homeless shelters).
- Occupational (hospitals).
- Mycolic acid glycolipids.
- Trehalose dimycolate ('cord factor').
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.
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.
- Fever: usually gradual onset and low-grade.
- Night sweats: maybe drenching.
- Weight loss, anorexia, and malaise are also common.
- 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.
- 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).
- 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).
- Primary: hilar lymphadenopathy, effusion, pulmonary infiltrates, calcification.
- Reactivation: upper lobe cavitary lesion.
- 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.
- Nontuberculous mycobacterial infections:
- 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.
- Similarities: cough, dyspnoea.
- Differences: rarely forms cavities, negative sputum culture, non-caseating granulomas.
- 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.
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.
- 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.
- 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.
- 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.
- 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.
- Need for mechanical ventilation.
Screening and prevention
- Individuals with recent exposure (contacts).
- Health care workers.
- Homeless shelters and prisons.
- Individuals with increased risk of reactivation: HIV.
- Travellers from high-incidence countries.
- TST test or IGRA.
- If any positive or active TB suspected:
- Chest x-ray
- Sputum stain and culture
- 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.