18.3 Tuberculosis, Leprosy & Nontuberculous Mycobacteria: Pathogenesis, Diagnosis, NTP Regimens & Prevention

Why this area matters

The Philippines has one of the highest tuberculosis burdens in the world. The Comprehensive Tuberculosis Elimination Plan Act (RA 10767, 2016) makes TB control a national and local government responsibility. The National TB Control Program (NTP) of the DOH sets case-finding, diagnosis and treatment standards.

Board questions test:

• pathology and the stages of infection;
• adverse effects of each first-line drug;
• interpretation of Xpert results;
• drug-resistance categories;
• leprosy classification and treatment.

TB also appears in Pathology (caseating granulomas), Pharmacology (drug toxicity), Pediatrics (childhood TB and BCG) and Preventive Medicine (case-finding and DOTS).

Mycobacterium tuberculosis Pathogenesis & Philippine NTP Framework

Mycobacterium tuberculosis (MTB) is an obligate aerobe, acid-fast bacillus (AFB) characterized by a lipid-rich cell envelope containing mycolic acids, lipoarabinomannan, and cord factor (trehalose 6,6'-dimycolate). Cord factor inhibits phagosome-lysosome fusion and stimulates TNF-alpha release, causing the serpentine cord formation characteristic of virulent strains on culture.

Pathogenesis: Primary vs Secondary Tuberculosis

• Primary Tuberculosis: Inhaled bacilli infect alveolar macrophages. Bacilli multiply intracellularly until cell-mediated immunity develops (weeks 3 to 6). CD4+ Th1 lymphocytes secrete interferon-gamma, activating macrophages to form epithelioid histiocytes and multinucleated Langhans giant cells, walling off organisms inside caseating granulomas.
  • Ghon Focus: A subpleural granulomatous lesion, usually in the lower part of the upper lobe or the upper part of the lower lobe.
  • Ghon Complex: Combination of a Ghon focus and ipsilateral hilar lymph node involvement.
  • Ranke Complex: A healed, calcified Ghon complex visible on chest radiography.
• Secondary (Reactivation) Tuberculosis: Occurs when waning host cell-mediated immunity allows dormant bacilli in old lesions to reactivate. Reactivation characteristically occurs in the apices of the upper lung lobes (apical and posterior segments) where high alveolar ventilation-to-perfusion ratios ($V/Q$) generate high oxygen tensions ($P_{O_2}$). Cavitation and caseous necrosis erode into bronchioles, discharging live bacilli into sputum and causing hemoptysis, night sweats, fevers, and cachexia.

Modern Diagnostics: GeneXpert MTB/RIF

While traditional Ziehl-Neelsen or Kinyoun acid-fast sputum microscopy remains widespread, the Philippine National Tuberculosis Control Program (NTP) mandates GeneXpert MTB/RIF as the primary, frontline diagnostic modality for presumptive TB. GeneXpert is a cartridge-based, automated real-time PCR assay that simultaneously detects M. tuberculosis complex DNA and mutations in the rpoB gene conferring rifampicin resistance within 2 hours, bypassing weeks-long culture delays.

Philippine NTP Treatment Regimens & Pharmacology

For drug-susceptible pulmonary tuberculosis in adults (Regimen 1 in the current NTP Manual of Procedures, which replaced the older Category I label), the standard regimen consists of a 2-month intensive phase followed by a 4-month continuation phase, abbreviated as 2HRZE / 4HR:

$\text{Standard Regimen: } 2 \text{ months of } [\text{HRZE}] \longrightarrow 4 \text{ months of } [\text{HR}]$

Drug-Resistant Tuberculosis Categories

• Multidrug-Resistant Tuberculosis (MDR-TB): Defined strictly as resistance to at least both Isoniazid and Rifampicin, the two most potent first-line agents.
• Pre-XDR-TB: MDR/RR-TB (rifampicin-resistant, with or without isoniazid resistance) that is also resistant to any fluoroquinolone.
• Extensively Drug-Resistant Tuberculosis (XDR-TB): Under the 2021 WHO definitions used by the NTP, MDR/RR-TB that is resistant to any fluoroquinolone (levofloxacin or moxifloxacin) and at least one additional Group A drug (bedaquiline or linezolid). Second-line therapy requires individualized or standardized long-course regimens managed at specialized PMDT (Programmatic Management of Drug-resistant TB) treatment facilities.

Extrapulmonary tuberculosis

Testing for infection and preventive treatment

• Tuberculin skin test (TST): read induration at 48 to 72 hours.
  • 10 mm or more is positive in most people.
  • 5 mm or more is positive in people living with HIV, close contacts of TB patients and the immunosuppressed.
  • BCG and nontuberculous mycobacteria can cause false positives. Malnutrition, HIV, recent viral infection and miliary TB can cause false negatives.
• Interferon-gamma release assays (IGRA) use antigens that BCG lacks, so they are more specific in vaccinated people.
• Neither test separates latent infection from active disease. Active TB must be excluded, by symptoms and chest X-ray, before TB preventive treatment (TPT) is given.
• TPT regimens recognized by WHO:
  • 6 months of isoniazid (6H);
  • 3 months of weekly rifapentine plus isoniazid (3HP);
  • 3 months of daily rifampicin plus isoniazid (3HR), often used in children.
• Priority groups for TPT: people living with HIV, household contacts (especially children under 5) and patients starting anti-TNF therapy or dialysis.
• BCG is given at birth. It protects infants and young children against miliary TB and TB meningitis but gives little protection against adult pulmonary TB.

Leprosy (Hansen disease)

Mycobacterium leprae is an acid-fast bacillus that cannot be cultured in vitro. It grows best at the cooler temperatures of skin, nerves, nose and testes. Transmission is mainly by nasal droplets after prolonged close contact.

• WHO classification: paucibacillary leprosy has 1 to 5 skin lesions and a negative smear. Multibacillary leprosy has more than 5 lesions, nerve involvement or a positive smear.
• WHO multidrug therapy: rifampicin, dapsone and clofazimine for 6 months (PB) or 12 months (MB). Clofazimine causes red-brown skin discoloration, and dapsone can cause hemolysis in G6PD deficiency.
• Reactions:
  • Type 1 (reversal) reaction: acute inflammation of existing lesions and nerves, treated with corticosteroids.
  • Type 2 reaction (erythema nodosum leprosum): fever and tender nodules in multibacillary disease, treated with corticosteroids or clofazimine.
• Nerve damage causes claw hand (ulnar nerve), foot drop (common peroneal nerve) and insensate ulcers. Prevention of disability is part of care.

Nontuberculous mycobacteria (NTM)

• M. avium complex: disseminated disease in advanced HIV (CD4 below 50), and pulmonary disease in older women and in bronchiectasis.
• M. kansasii: a TB-like cavitary lung disease.
• M. marinum: "fish tank granuloma", nodules that spread up the arm along the lymphatics.
• M. ulcerans: Buruli ulcer.
• Rapid growers (M. abscessus, M. fortuitum, M. chelonae): skin and soft-tissue infections after cosmetic procedures, injections or surgery.

NTM are not spread person to person. A single positive sputum culture may be contamination, so diagnosis needs clinical, radiologic and repeated microbiologic evidence.