What is the pathophysiology and treatment of tuberculosis?

Pathophysiology and Treatment of Tuberculosis

Tuberculosis is characterized by granuloma formation, which is the hallmark pathological feature where host immune cells surround Mycobacterium tuberculosis bacteria, serving as both a containment mechanism and potential site for bacterial persistence and dissemination. 1

Pathophysiology of Tuberculosis

Initial Infection and Bacterial Populations

• M. tuberculosis is transmitted via aerosol droplets that reach the alveoli of the lungs 1
• Within the host, three separate subpopulations of M. tuberculosis exist, defined by their growth characteristics and location:
  • Rapidly growing extracellular bacilli residing mainly in cavities (largest population)
  • Slow-growing bacilli in acidic environments
  • Dormant bacilli in hypoxic environments 2
• The frequency of spontaneous mutations conferring drug resistance varies by drug: approximately 10^-6 for isoniazid and streptomycin, 10^-8 for rifampin, and 10^-5 for ethambutol 2

Granuloma Formation and Function

• Granulomas are organized structures formed by host immune cells surrounding the infecting M. tuberculosis bacteria 1
• Key cellular components include macrophages, CD4+ and CD8+ T cells, with chemokines and cytokines serving as immune effectors 3
• Critical factors in granuloma formation include:
  • Chemokine diffusion
  • Prevention of macrophage overcrowding
  • Arrival time, location, and number of T cells
  • Host ability to activate macrophages 3
• Granulomas have a dual role:
  • Protective: containing bacterial spread
  • Pathogenic: providing a survival niche for bacteria 1, 4

Dissemination Mechanisms

• M. tuberculosis can breach the alveolar epithelium through several bacterial factors:
  • Heparin binding haemagglutinin adhesin (HBHA) enables binding to epithelial cells
  • ESAT-6 and CFP-10 (products of RD1 gene locus) contribute to cell lysis and invasion of alveolar epithelium 5
• Bacteria can spread from the lungs to regional lymph nodes and other organs through:
  • Direct invasion of epithelial barriers
  • Transport within infected macrophages 5
• Hypoxic conditions within granulomas contribute to disease progression as bacilli adapt to oxygen and nutrient scarcity 6

Extrapulmonary Tuberculosis

• M. tuberculosis can affect virtually any organ or tissue in the body 2
• Extrapulmonary sites are more common among children and immunocompromised individuals 2
• Common extrapulmonary sites include lymph nodes, bone and joints, pleura, pericardium, central nervous system, genitourinary tract, and peritoneum 2

Treatment of Tuberculosis

Principles of Treatment

• The primary goals of antituberculosis therapy are to:
  • Rapidly reduce actively growing bacilli to decrease disease severity and halt transmission
  • Eradicate persisting bacilli to achieve durable cure
  • Prevent acquisition of drug resistance 2
• Multiple drugs must be used simultaneously to prevent emergence of drug-resistant populations 2

Standard Treatment Regimens

Pulmonary Tuberculosis in Adults

• The recommended standard regimen for drug-susceptible pulmonary TB is a 6-month course consisting of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by INH and RIF for 4 months. 2
• Each drug plays a specific role:
  • INH has the most potent early bactericidal activity, rapidly decreasing infectiousness 2
  • RIF has strong sterilizing activity against persisting bacilli 7, 8
  • PZA is active against bacilli in acidic environments 2
  • EMB helps prevent emergence of resistance to other drugs 2

Extrapulmonary Tuberculosis

• The basic principles of pulmonary TB treatment apply to extrapulmonary forms 2
• A 6-9 month regimen is recommended for most forms of extrapulmonary TB 2
• Exceptions requiring longer treatment (9-12 months):
  • Tuberculous meningitis
  • Disseminated (miliary) tuberculosis
  • Bone/joint tuberculosis in children 2, 7
• Adjunctive corticosteroid therapy is strongly recommended for:
  • Tuberculous meningitis (dexamethasone 8-12 mg/day initially, tapered over 6 weeks) 2
  • Tuberculous pericarditis 2

Tuberculosis in Children

• Children most commonly develop primary tuberculosis characterized by:
  • Intrathoracic adenopathy
  • Mid and lower lung zone infiltrates
  • Absence of cavitation 2
• Treatment regimen for children:
  • Initial phase: INH, RIF, and PZA (with EMB added if drug resistance is suspected)
  • Continuation phase: INH and RIF 2
• Total duration: 6 months for pulmonary TB; 9-12 months for disseminated TB and TB meningitis 2

HIV Co-infection

• HIV infection enhances HIV replication and might accelerate HIV disease progression 2
• Treatment duration for HIV-infected patients with TB should be at least 9 months 2
• Directly observed therapy (DOT) is especially important for HIV-infected patients 7
• Paradoxical reactions (temporary worsening of symptoms after starting treatment) are more common in HIV-infected patients and may require corticosteroid therapy 2

Drug Resistance Considerations

• Multi-drug resistant tuberculosis (MDR-TB) is defined as resistance to at least isoniazid and rifampin 7
• Treatment must be individualized based on susceptibility testing 7
• Risk factors for drug resistance include:
  • Previous TB treatment
  • Contact with known drug-resistant TB case
  • HIV infection in some settings 2

Treatment Administration

• Directly observed therapy (DOT) is recommended for all patients to ensure compliance 7
• DOT involves observation of the patient by a healthcare provider or other responsible person as the patient ingests anti-tuberculosis medications 7
• Special considerations for specific populations:
  • Pregnant women: Avoid streptomycin; pyrazinamide use is controversial; use INH, RIF, and EMB 7
  • Renal insufficiency: Dose adjustments needed for certain drugs 2
  • Liver disease: Close monitoring required due to hepatotoxicity risk of INH, RIF, and PZA 2

Common Pitfalls and Caveats

• Failure to use multiple drugs simultaneously can lead to emergence of drug resistance 2
• Inadequate treatment duration increases risk of relapse 7
• Extrapulmonary TB may be difficult to diagnose due to limited access to specimens and lower bacterial loads 2
• Response to treatment in extrapulmonary TB often must be judged on clinical and radiographic findings rather than bacteriological evaluation 2
• Non-adherence to treatment is a major cause of drug-resistant tuberculosis 7
• Rifampin has significant drug interactions due to enzyme induction properties 8