What causes extrapulmonary tuberculosis (TB) in immunocompromised individuals, such as those with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)?

Cause of Extrapulmonary Tuberculosis

Extrapulmonary tuberculosis results from lymphohematogenous dissemination of Mycobacterium tuberculosis from the initial pulmonary infection to other organ systems, with immunocompromised states—particularly advanced HIV/AIDS—dramatically increasing both the frequency and severity of extrapulmonary manifestations. 1

Primary Pathophysiologic Mechanism

• Extrapulmonary TB develops through hematogenous spread of tubercle bacilli during or after the initial pulmonary infection, allowing the organism to seed virtually any organ system in the body 2, 3
• The bacilli disseminate via blood and lymphatic channels, establishing foci in distant sites including lymph nodes, pleura, meninges, bones, joints, genitourinary tract, and other organs 2, 3

Critical Role of Immunosuppression

• Advanced HIV disease is the single most important risk factor for extrapulmonary TB, with EPTB occurring in more than 50% of HIV-positive individuals compared to only 15-20% of immunocompetent patients 2, 3
• Most extrapulmonary forms (TB meningitis, tuberculous lymphadenitis, pericardial TB, pleural TB, disseminated or miliary TB) are significantly more common among persons with advanced-stage HIV disease than among patients with asymptomatic HIV infection 1
• The declining CD4+ T-cell count in HIV infection progressively impairs cell-mediated immunity, which is essential for containing M. tuberculosis infection 1

Specific Immunologic Mechanisms

• Progressive immunodeficiency associated with HIV infection allows reactivation of latent tuberculous foci that were previously contained by intact cellular immunity 1
• HIV-infected individuals experience development of cutaneous anergy to tuberculin protein as immunodeficiency progresses, reflecting the profound impairment of T-cell function 1
• The risk of progression from latent M. tuberculosis infection to active disease—including extrapulmonary manifestations—is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB 1

Clinical Patterns and Site Predilection

• Lymph nodes are the most common site of extrapulmonary involvement, followed by pleural effusion, though virtually every organ system can be affected 2
• TB meningitis represents the most severe form of extrapulmonary tuberculosis and constitutes a medical emergency requiring immediate recognition and treatment 4
• Bone and joint tuberculosis, genitourinary TB, pericardial TB, and disseminated/miliary TB represent other major extrapulmonary manifestations 1, 2

Important Clinical Pitfalls

• Extrapulmonary TB often presents with atypical, nonspecific, and insidious clinical manifestations, leading to diagnostic delays that can extend for years in some cases 3
• Patients with TB pleural effusions may have concurrent unsuspected pulmonary or laryngeal TB disease and should be considered infectious until pulmonary disease is excluded 1
• Patients with suspected extrapulmonary TB should also be evaluated for concomitant pulmonary TB, as extrapulmonary disease can occur in isolation or alongside a pulmonary focus in disseminated tuberculosis 1, 2
• Mixed mycobacterial infections (either simultaneous or sequential) may occur and obscure recognition of M. tuberculosis clinically and in the laboratory 1

Genetic and Strain Considerations

• Some evidence suggests that genetic variations in M. tuberculosis strains might contribute to disease presentation in extrapulmonary sites, though more research is needed to definitively establish these associations 5
• Whole genome sequencing has identified genetic diversity among MTB isolates from extrapulmonary sites, including mutations conferring drug resistance 5