Tuberculosis (TB)

Definition and Etiology

• Gram-stain neutral, but acid-fast - the hallmark characteristic. High mycolic acid content in the cell wall prevents decolorization by acid-alcohol after carbol fuchsin staining
• Extremely slow growth: doubles every 18-24 hours; cultures may take up to 10 weeks
• The complex, waxy cell envelope (mycolic acids, arabinogalactan, peptidoglycan, unique lipids like phthioceral dimycocerosate and trehalose dimycolates) creates a formidable barrier to antibiotic penetration
• Facultative anaerobe that can replicate intracellularly within macrophages

• M. africanum - causes TB in West/Central/East Africa
• M. bovis - transmitted via unpasteurized dairy; intrinsically pyrazinamide-resistant
• M. caprae, M. pinnipedii, M. microti - zoonotic members

Epidemiology and Risk Factors

• HIV/AIDS patients (dominant risk factor in HIV-endemic regions; CD4 <200/μL carries greatest risk)
• The urban poor, elderly, foreign-born
• Patients with diabetes, Hodgkin lymphoma, silicosis, CRF, malnutrition, alcohol use disorder, immunosuppression
• Approximately 13 million people have latent TB in the United States (2019)
• ~80% of populations in some Asian and African countries are tuberculin-positive

Pathogenesis and Immunity

1. Bacilli inhaled, reach alveolar spaces - phagocytosed by alveolar macrophages
2. Mycobacteria evade phagolysosomal killing (via lipoarabinomannan inhibiting phagosome maturation)
3. Local replication triggers cytokine release (TNF, IL-1, IL-12); Th1 CD4+ T-cell response develops
4. Cell-mediated immunity (CMI) develops over 2-8 weeks, controlled by IFN-γ-activated macrophages
5. Characteristic caseating granulomas form - epithelioid macrophages, Langhans giant cells, central caseous necrosis, surrounded by lymphocytes and fibroblasts
6. In ~95% of immunocompetent individuals, the primary infection is controlled and becomes latent

Primary vs. Secondary (Reactivation) TB

Primary TB

• Develops in the previously unexposed, unsensitized host
• About 5% of newly infected immunocompetent individuals develop significant disease
• Lesion typically forms in the lower part of the upper lobe or upper part of the lower lobe (areas receiving the most inspired air)
• Forms a Ghon focus: 1-1.5 cm gray-white area of consolidation with central caseous necrosis
• Regional lymph node involvement (caseous) + Ghon focus = Ghon complex
• On healing, fibrosis and calcification form the Ranke complex (visible on X-ray)
• Lymphatic/hematogenous dissemination occurs in early weeks, seeding distant organs

Secondary (Reactivation) TB

• Arises in a previously sensitized host - either from reactivation of dormant foci (decades later) or reinfection
• Less than 5% of patients with primary TB develop secondary TB
• Classically localizes to the apex of one or both upper lobes (possibly due to high oxygen tension)
• Prompt tissue response walls off the focus; regional lymph nodes are less prominently involved
• Cavitation is common: central caseous material liquefies and drains into bronchi, forming cavities (which are a major source of infectivity)
• Hallmark: productive chronic cough, hemoptysis, fever, night sweats, weight loss

Clinical Manifestations

Pulmonary TB (most common)

Extrapulmonary TB

Diagnosis

Tests for TB Infection (Latent TB)

1. Tuberculin Skin Test (TST / Mantoux / PPD)
   • Intradermal injection of purified protein derivative
   • Induration read at 48-72 hours
   • Positive if ≥10 mm (≥5 mm in HIV+ patients/close contacts/immunosuppressed)
   • Limitations: false-negative with anergy (HIV, malnutrition, overwhelming TB, sarcoidosis, Hodgkin's); false-positive from BCG vaccination and atypical mycobacteria
2. Interferon-Gamma Release Assays (IGRAs) (QuantiFERON-TB Gold, T-SPOT.TB)
   • In vitro: patient T cells stimulated with M. tuberculosis antigens; IFN-γ production measured
   • More specific than TST; not affected by BCG vaccination
   • Both TST and IGRA cannot differentiate infection from active disease

Tests for Active TB

Treatment

Drug-Susceptible TB - Standard Regimen

• H - Isoniazid (INH)
• R - Rifampicin (Rifampin)
• Z - Pyrazinamide
• E - Ethambutol

• Isoniazid + Rifampicin (+/- Ethambutol)
• Total duration: 6 months for most drug-susceptible pulmonary TB
• Extension by 12-24 weeks for CNS TB, skeletal TB, and disseminated TB

Key Drug Properties and Side Effects

Monitoring During Treatment

• Baseline: LFTs (ALT, bilirubin), creatinine, platelets, hepatitis serology
• Monthly: assessment for hepatotoxicity symptoms (nausea, vomiting, jaundice)
• Stop hepatotoxic drugs if ALT >5x ULN (or >3x ULN with symptoms)
• Monthly sputum cultures until clearance confirmed
• Monthly dispensing allows essential clinical monitoring

Latent TB Infection (LTBI) Treatment

• 9H: 9 months of daily isoniazid (most widely used)
• 4R: 4 months of daily rifampicin
• 3HP: 3 months of weekly isoniazid + rifapentine (directly observed)
• 1HP: 1 month of daily isoniazid + rifapentine (newer regimen)

Drug-Resistant TB

• MDR-TB: Resistance to at least isoniazid AND rifampicin - the two most potent first-line drugs
• XDR-TB: MDR-TB + resistance to fluoroquinolones AND at least one injectable agent (bedaquiline, linezolid)
• WHO estimated 465,000 MDR-TB cases in 2019 (~3% of new cases, ~20% of previously treated cases)
• Epicenter: Eastern Europe, Russia, parts of Africa and Asia
• MDR-TB treatment requires 18-24+ months with second-line drugs (bedaquiline, delamanid, linezolid, fluoroquinolones); treatment is more toxic and less effective

Prevention and Control

1. BCG vaccination: Effective against miliary TB and TB meningitis in children; provides variable protection against pulmonary TB in adults
2. LTBI treatment: Prevents progression from infection to active disease
3. Infection control: Airborne isolation of active cases; N95 respirators for healthcare workers; negative-pressure rooms; UV germicidal irradiation
4. Contact tracing and DOT: Systematic identification and treatment of close contacts
5. HIV treatment: ART markedly reduces TB risk in HIV-infected individuals

Prognosis

• Drug-susceptible TB properly treated: >95% cure rate
• Untreated active TB: fatal in >70% of cases
• MDR-TB: significantly worse outcomes, prolonged treatment, higher toxicity
• HIV co-infection: substantially increases morbidity and mortality