Tuberculosis

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. It can affect virtually any organ system but predominantly affects the lungs. It is transmitted via airborne droplet nuclei and remains a leading global cause of infectious death.

The natural history comprises primary infection, a prolonged latent phase in the majority of infected individuals, and reactivation disease. The organism grows slowly and tends to acquire resistance with inadequate therapy, so treatment is prolonged and multidrug.

Pathophysiology

Inhaled bacilli are engulfed by alveolar macrophages. The host immune response contains most infections by forming a granuloma. Viable but dormant organisms can persist within it for decades (latent tuberculosis infection).

Reactivation occurs in a proportion of those infected when host immunity is compromised (HIV infection, immunosuppressive therapy, malnutrition, advancing age, diabetes). It is most common within the first two years after infection.

Pulmonary tuberculosis presents with a chronic, typically productive cough persisting beyond two to three weeks, haemoptysis, fever, night sweats and weight loss. Symptoms develop insidiously over weeks to months.

Extrapulmonary disease can affect:

• Lymph nodes: typically cervical, causing painless, matted lymphadenopathy that may progress to a discharging sinus
• Pleura: exudative effusion
• Bone and joints: particularly the spine (Pott disease), causing back pain and, in advanced cases, neurological deficit
• Central nervous system: tuberculous meningitis and tuberculoma
• Genitourinary tract
• Disseminated disease: miliary tuberculosis, with widespread haematogenous dissemination producing multiorgan involvement and a characteristic fine nodular pattern on chest imaging

Risk factors for progression from latent to active disease include HIV infection, immunosuppressive therapy, diabetes, malnutrition, chronic kidney disease and silicosis. HIV is a particularly powerful risk factor, with a substantially elevated annual reactivation risk compared with the general population.

Sputum microscopy for acid fast bacilli provides rapid, though relatively insensitive, initial evidence of pulmonary disease, with sputum culture (on solid or liquid media) remaining the diagnostic reference standard, albeit requiring several weeks given the slow growth of the organism.

Molecular testing (nucleic acid amplification testing, such as Xpert MTB/RIF) provides rapid diagnosis directly from sputum with simultaneous detection of rifampicin resistance, and is increasingly the preferred initial diagnostic test given the substantial reduction in time to diagnosis and treatment initiation compared with culture alone.

Chest radiography classically shows upper lobe cavitating infiltrates in reactivation disease, though findings vary considerably, and computed tomography provides greater detail where required.

Extrapulmonary disease is diagnosed through sampling of the affected site (lymph node biopsy or aspirate, pleural fluid and biopsy, cerebrospinal fluid, bone or joint aspirate) with the same combination of microscopy, culture and molecular testing applied to the specific specimen obtained.

Latent tuberculosis infection is identified through tuberculin skin testing or interferon gamma release assay blood testing, used for screening of contacts and high risk populations, with a normal chest radiograph and absence of symptoms distinguishing latent from active disease.

HIV testing should be offered to every patient diagnosed with tuberculosis given the strong bidirectional relationship between the two conditions.

Standard treatment for fully sensitive pulmonary tuberculosis is an intensive phase of four drugs for two months, followed by a continuation phase of two drugs for a further four months. Total standard treatment duration is six months.

The intensive phase comprises rifampicin 10 mg per kg (typically 600 mg), isoniazid 5 mg per kg (typically 300 mg), pyrazinamide 25 mg per kg, and ethambutol 15 mg per kg. All are given together once daily, typically as a fixed dose combination tablet to support adherence.

The continuation phase comprises rifampicin and isoniazid at the same doses for a further four months. Extend it:

• To seven months (giving a total of nine months) for cavitary pulmonary disease with a positive sputum culture at completion of the intensive phase
• To a total of nine to twelve months for central nervous system and bone or joint tuberculosis. Drug penetration is harder to achieve at these sites, and treatment failure has more severe consequences

Co administer pyridoxine 10 to 25 mg once daily with isoniazid to prevent peripheral neuropathy. This is particularly important in pregnancy, malnutrition, diabetes, chronic kidney disease and HIV infection.

Baseline and regular monitoring of liver function is essential, given the hepatotoxic potential of rifampicin, isoniazid and pyrazinamide. If significant hepatotoxicity develops, interrupt treatment and reintroduce drugs in stages. It is typically defined as a transaminase rise to five times the upper limit of normal, or three times the upper limit with symptoms.

Directly observed therapy or other structured adherence support is recommended. Treatment completion is critical to prevent relapse and the emergence of drug resistance.

Multidrug resistant tuberculosis (resistant to at least rifampicin and isoniazid) requires specialist management. The regimen is longer and individualised, incorporating second line agents (including bedaquiline, linezolid and fluoroquinolones), typically extending to eighteen to twenty months. A specialist tuberculosis service directs it, given the complexity, toxicity and cost.

Latent tuberculosis infection, once active disease has been excluded, is treated to reduce reactivation risk. Options are:

• Isoniazid 5 mg per kg (maximum 300 mg) once daily for six to nine months
• Rifampicin 10 mg per kg (maximum 600 mg) once daily for four months
• Isoniazid and rifapentine once weekly for twelve weeks

Select according to local availability, drug interaction profile and patient preference.

Complete management of every confirmed case includes contact tracing and screening of close contacts for both active and latent infection. Notify public health authorities, as the disease is mandatorily reportable in most jurisdictions.