20.3 Tuberculosis: Pathogenesis & Clinical Manifestations

Tuberculosis (TB), caused by the acid-fast intracellular pathogen Mycobacterium tuberculosis, remains one of the most critical global infectious diseases. For MRCP(UK) Part 1, candidates must master the immunological pathogenesis of primary versus reactivation infection, distinguish between the protean manifestations of pulmonary and extrapulmonary disease, correctly interpret diagnostic modalities (including the clinical superiority of IGRAs over tuberculin skin testing in BCG-vaccinated cohorts), and demonstrate thorough knowledge of the mechanisms, toxicities, and drug interactions of first-line anti-tuberculous pharmacotherapy.

1. Pathogenesis of Mycobacterium tuberculosis

M. tuberculosis is an obligate aerobe with an exceptionally lipid-rich, waxy cell wall composed of peptidoglycan, arabinogalactan, and mycolic acids, conferring resistance to complement lysis, desiccation, and standard Gram staining.

Inhalation, Phagocytosis & The Primary Complex

• Transmission: Spread exclusively via aerosolized droplet nuclei ($1\text{–}5\ \mu\text{m}$) expelled by individuals with active, infectious pulmonary or laryngeal tuberculosis during coughing, sneezing, or speaking.
• Alveolar Inoculation: Droplets bypass upper airway mucociliary clearance and deposit in the well-ventilated mid-to-lower subpleural alveoli. Non-activated alveolar macrophages engulf bacilli via mannose receptors and complement receptors.
• Inhibition of Phagolysosomal Fusion: Pathogenic M. tuberculosis prevents phagosome maturation into an acidic phagolysosome by secreting cell-wall glycolipids (cord factor / trehalose 6,6'-dimycolate) and protein tyrosine phosphatase PtpA. Unrestrained intracellular mycobacterial replication occurs within macrophages, leading to cellular lysis.
• The Ghon Complex: Mycobacteria drain via lymphatic channels to regional bronchopulmonary and hilar lymph nodes. The combination of the initial peripheral parenchymal lesion (Ghon focus) and the draining calcified regional hilar lymph node is termed the Ghon complex (or Ranke complex once fully fibrocalcified).

Cell-Mediated Immunity & Granuloma Architecture

Between 2 and 6 weeks post-inoculation, dendritic cells present mycobacterial antigens to naive CD4+ T-lymphocytes, priming a robust Type 1 helper T-cell (Th1) adaptive immune response:

• Cytokine Orchestration: Th1 cells secrete interferon-gamma (IFN-$\gamma$), which powerfully activates macrophages, stimulating nitric oxide synthase (iNOS) and reactive oxygen species generation to destroy intracellular mycobacteria. Macrophages and T-cells simultaneously secrete tumour necrosis factor-alpha (TNF-$\alpha$), which is essential for recruiting monocytes, organizing granuloma structure, and maintaining vascular integrity around the lesion. Therapeutic inhibition of TNF-$\alpha$ (e.g., with infliximab, adalimumab, or etanercept) causes catastrophic breakdown of granuloma architecture and rapid, disseminated reactivation of latent TB.
• Caseous Granuloma Formation: The hallmark histopathological lesion consists of central caseous necrosis (hypoxic, acidic, cheese-like acellular debris) surrounded by transformed epithelioid histiocytes, multinucleated Langhans giant cells (horseshoe arrangement of nuclei), and an outer rim of CD4+ and CD8+ T-lymphocytes and fibroblasts.

Latent TB Infection (LTBI) vs. Post-Primary Reactivation

• Latent TB Infection (LTBI): In approximately $90%$ of immunocompetent individuals, the immune response successfully seals off viable mycobacteria within calcified granulomas. The host remains asymptomatic, non-infectious, and displays a normal chest radiograph, but demonstrates persistent immunological memory via a positive tuberculin skin test or IGRA.
• Post-Primary / Reactivation TB: In $5\text{–}10%$ of infected individuals, lifetime reactivation occurs due to waning cell-mediated immunity (aging, malnutrition, HIV infection, end-stage renal disease, anti-TNF therapy, systemic corticosteroids). Reactivation characteristically localizes to the apical and posterior segments of the upper lobes (and superior segments of the lower lobes). These anatomic regions feature the highest ventilation-perfusion ($V/Q$) ratios in the lung, producing the highest local alveolar partial pressures of oxygen ($\text{PaO}_2$), which uniquely favours the replication of this strict aerobe. Extensive tissue liquefaction, cavity formation, and bronchial erosion lead to infectious aerosol production.

2. Clinical Manifestations: Pulmonary & Extrapulmonary Tuberculosis

Pulmonary Tuberculosis

• Cardinal Symptoms: Insidious onset of chronic productive cough lasting $> 3\text{ weeks}$, intermittent haemoptysis, low-grade swinging pyrexia (frequently with late-afternoon spikes), drenching nocturnal diaphoresis, progressive anorexia, and unexplained cachexia/weight loss.
• Radiological Findings: Upper lobe fibro-cavitary consolidation, volume loss, apical pleural thickening, and traction bronchiectasis. In immunocompromised patients or primary progressive disease, cavitation may be absent, presenting instead with lower lobe consolidation or pleural effusions.
• Miliary Tuberculosis: Arises from massive haematogenous dissemination when a caseating focus erodes directly into a pulmonary vein or lymphatic duct. Produces diffuse, non-reactive multiorgan involvement. High-resolution chest radiography or CT demonstrates a pathognomonic diffuse 1–2 mm micronodular 'millet-seed' pattern distributed uniformly throughout both lung fields. Associated with hepatosplenomegaly, bone marrow suppression (pancytopenia), and choroidal tubercles on fundoscopy.

Extrapulmonary Tuberculosis (EPTB)

Extrapulmonary tuberculosis accounts for $15\text{–}20%$ of cases in immunocompetent patients and $> 50%$ of cases in HIV-coinfected individuals.

• Tuberculous Lymphadenitis (Scrofula): The most frequent form of extrapulmonary TB. Typically involves the anterior cervical or supraclavicular lymph node chains. Presents as firm, discrete, painless lymphadenopathy that gradually becomes fluctuant, matting together to form a subcutaneous cold abscess (lacking erythema and calor) that may break through the skin to create a chronically draining sinus tract.
• Tuberculous Meningitis: The most lethal manifestation. Arises from rupture of a subependymal or subpial caseating tubercle (Rich focus) into the subarachnoid space. Pathologically characterized by a thick, gelatinous basal meningeal exudate encasing the circle of Willis and cranial nerves.
  • Clinical Presentation: Subacute prodrome (2–3 weeks of headache, malaise, low-grade fever) evolving into signs of raised intracranial pressure, confusion, and isolated cranial nerve palsies (cranial nerve VI [abducens] is most commonly affected due to its long intracranial course, followed by cranial nerve III).
  • Complications: Tuberculous vasculitis causing middle cerebral artery territory ischemic stroke (tubercular arteritis), communicating hydrocephalus, and coma.
• Tuberculous Spondylitis (Pott's Disease): Infection begins in the anterior subchondral bone of the vertebral body and spreads via the anterior longitudinal ligament across the intervertebral disc into adjacent vertebrae (unlike metastatic spinal malignancy, which characteristically destroys the posterior pedicles and spares the intervertebral disc). Most commonly involves the lower thoracic and upper lumbar spine. Progressive anterior vertebral body collapse causes acute kyphotic angulation (gibbus deformity). Mycobacterial pus dissects along the psoas muscle sheath to present as a painless, fluctuant psoas cold abscess in the groin or femoral triangle.
• Pleural Tuberculosis: Presents as an acute or subacute unilateral exudative pleural effusion. Pleural fluid biochemistry confirms an exudate (protein $> 30\text{ g/L}$), marked lymphocytic predominance ($> 80%$), low glucose, and significantly elevated Adenosine Deaminase (ADA $> 40\text{ U/L}$). Direct microscopy is rarely positive ($< 20%$); closed pleural biopsy (Abrams needle) or thoracoscopic pleural biopsy demonstrates non-caseating/caseating granulomas in $> 85%$.
• Gastrointestinal Tuberculosis: Acquired via swallowing infected sputum or ingestion of unpasteurized milk (Mycobacterium bovis). Predominantly strikes the ileocaecal region due to the abundance of lymphoid tissue (Peyer's patches). Presents with right iliac fossa pain, palpable abdominal mass, fever, bowel obstruction, and mucosal ulcerations, closely mimicking Crohn's disease on endoscopy and CT imaging.
• Renal & Urogenital Tuberculosis: Characterized by insidious, destructive papillary necrosis, ureteric strictures, and bladder contracture. The classic laboratory hallmark is sterile pyuria (persistent white blood cells in urine with negative routine bacterial cultures on blood and MacConkey agar; requires 3 early morning urine samples for mycobacterial culture).