Mycobacteria: TB Pathogenesis, NTM, Leprosy & Drugs

Mycobacterial structure and virulence

The acid-fast wall. Mycobacteria are obligately aerobic rods whose cell wall is rich in long-chain mycolic acids layered on arabinogalactan. This waxy envelope retains carbolfuchsin after an acid-alcohol wash, so the organisms are acid-fast on Ziehl-Neelsen or Kinyoun staining while staining poorly with Gram stain. It also resists drying and many disinfectants and slows growth: M. tuberculosis divides roughly once a day, so culture on Löwenstein-Jensen medium takes weeks (liquid media are faster).

Cord factor. Trehalose dimycolate makes virulent strains grow in parallel serpentine cords. It inhibits macrophage maturation and stimulates TNF-α release, which drives granuloma formation.

Sulfatides. These sulfated glycolipids block fusion of the phagosome with the lysosome, so ingested bacilli survive and multiply inside resting macrophages.

The immune response and the granuloma

Th1 axis. Alveolar macrophages ingest the bacilli, present antigen on MHC class II, and secrete IL-12, which drives naive CD4+ T cells toward Th1. Th1 cells release IFN-γ, activating macrophages to fuse phagosomes with lysosomes and generate nitric oxide. Activated macrophages become epithelioid histiocytes, some fuse into Langhans giant cells with nuclei arranged in a horseshoe at the periphery, and together with lymphocytes they wall off a center of caseous necrosis. TNF-α from macrophages recruits monocytes and keeps the granuloma intact.

When the axis fails. Inherited defects of the IL-12 receptor or the IFN-γ receptor cause disseminated infection with weakly virulent mycobacteria, including nontuberculous species and the BCG vaccine strain. TNF-α inhibitors (infliximab, adalimumab, etanercept and others) dissolve granulomas and reactivate latent TB, often as extrapulmonary or disseminated disease.

Before a TNF-α inhibitor is started, screen for latent TB with an interferon-γ release assay or tuberculin skin test and treat latent infection first.

Primary, reactivation, and extrapulmonary TB

Primary infection. Inhaled droplet nuclei reach the well-ventilated mid-lung zone (lower upper lobe or upper lower lobe) and form a subpleural caseating granuloma, the Ghon focus. Bacilli carried to the hilar lymph nodes complete the Ghon complex. In most people cell-mediated immunity contains the infection, the lesions fibrose and calcify (a Ranke complex), and viable bacilli persist as latent infection, with a lifetime reactivation risk of about 5–10% in immunocompetent hosts.

Progressive primary and miliary TB. Infants, young children, and people with HIV may fail to contain primary infection, producing progressive pneumonia, miliary TB (innumerable millet-seed nodules from hematogenous spread through the lungs, liver, spleen, marrow, and other organs), and TB meningitis. BCG, a live attenuated M. bovis vaccine used in high-burden countries, mainly protects young children against these severe forms.

Reactivation (secondary) TB. Reactivation favors the apical and posterior segments of the upper lobes, where oxygen tension is highest. Caseous necrosis erodes into bronchi, producing cavities that shed large numbers of bacilli, so cavitary patients are the most contagious. Symptoms are chronic cough, hemoptysis, fever, night sweats, and weight loss. Risk rises with HIV, TNF-α inhibitors, glucocorticoids, diabetes, silicosis, end-stage kidney disease, and malnutrition.

Extrapulmonary TB.

• Meningitis: thick basilar exudate causing cranial nerve palsies and hydrocephalus; CSF shows lymphocytes, high protein, and low glucose.
• Pott disease: vertebral osteomyelitis, usually thoracolumbar, destroying adjacent vertebral bodies and disc with gibbus deformity and psoas abscess.
• Scrofula: cervical lymphadenitis that may drain through the skin.
• Adrenal TB: bilateral destruction causing primary adrenal insufficiency (Addison disease).
• Others: renal TB with sterile pyuria, pericarditis, and GI disease.

Antituberculous drugs

Isoniazid details. Pyridoxine is given with isoniazid to prevent neuropathy; B6 is also the cofactor for ALA synthase, which explains the sideroblastic anemia. Hepatitis risk rises with age and alcohol use. Slow NAT2 acetylators reach higher drug levels and more toxicity. Because isoniazid inhibits CYP450 it raises levels of drugs such as phenytoin and warfarin. Overdose causes refractory seizures and anion-gap metabolic acidosis, treated with IV pyridoxine.

Rifampin details. By inducing CYP450, rifampin lowers levels of warfarin, oral contraceptives, azoles, and HIV protease inhibitors; rifabutin, a weaker inducer, is substituted in patients on protease inhibitors. Its orange secretions can stain soft contact lenses. Beyond TB it is used for meningococcal and Hib prophylaxis and in leprosy, but never alone for active infection.

Pyrazinamide and ethambutol. Pyrazinamide kills semidormant bacilli in acidic phagolysosomes and competes with urate for renal excretion. Ethambutol toxicity is dose-related, so visual acuity and color vision are checked at baseline and during therapy, and the dose is lowered in renal failure.

Why combinations. Large cavity populations contain spontaneous mutants resistant to any single drug, so several drugs are combined to prevent selection of resistance.

Nontuberculous mycobacteria

General features. Nontuberculous mycobacteria live in water and soil, spread by inhalation, ingestion, or inoculation rather than from person to person, and are often resistant to standard TB drugs.

Leprosy (Hansen disease)

Organism. M. leprae is an acid-fast bacillus that has never been grown in culture; it is propagated experimentally in mouse footpads and armadillos. It prefers temperatures below core body temperature, so it targets skin, peripheral nerves, nasal mucosa, earlobes, and testes. Transmission is by respiratory droplets during prolonged close contact with untreated patients, incubation lasts years, and in the southern United States nine-banded armadillos are a reservoir. Diagnosis rests on skin or nerve biopsy showing acid-fast bacilli.

Consequences and treatment. Loss of sensation leads to repeated painless injuries, ulcers, and deformity such as claw hand from ulnar nerve damage. Multidrug therapy combines dapsone and rifampin, adding clofazimine for multibacillary (lepromatous) disease; current WHO guidance uses all three drugs for every form. Dapsone can cause hemolysis in G6PD deficiency and methemoglobinemia, and clofazimine discolors the skin.