Tuberculosis - Medical Pathology: Key Points

1. Causative Agent & Transmission

2. Pathogenesis & Immune Response

Fig. 11.34 - Sequence of events in primary pulmonary tuberculosis immunity (Robbins & Kumar Basic Pathology)

Phase A: Before Cell-Mediated Immunity (first ~3 weeks)

• Inhaled bacilli are engulfed by alveolar macrophages
• M. tuberculosis survives within the phagosome by:
  • Arresting phagosome maturation
  • Preventing phagolysosome acidification
  • Blocking reactive nitrogen and oxygen species
• Result: Unchecked bacillary proliferation and bacteremia with seeding of multiple sites (liver, spleen, bone marrow, kidneys, meninges, apices of both lungs)

Phase B: Initiation of Cell-Mediated Immunity (~3 weeks onward)

1. Macrophages present MTb antigens via MHC Class II to CD4+ T cells in draining lymph nodes
2. Macrophage-secreted IL-12 drives differentiation to Th1 CD4+ T cells
3. Th1 cells release IFN-γ → activates macrophages
4. Activated macrophages:
   • Produce TNF (recruits monocytes)
   • Upregulate iNOS (nitric oxide - kills mycobacteria)
   • Produce reactive oxygen species and defensins
5. Macrophages differentiate into epithelioid histiocytes → form granulomas; some fuse to form Langhans-type giant cells

Key concept: Immunity comes at the cost of hypersensitivity and tissue destruction (caseation). Defects in IL-12, IFN-γ, TNF, or NO production result in poorly formed granulomas and disease progression. - Robbins & Kumar Basic Pathology, p. 475

3. Primary Tuberculosis

Fig. 8.27 - Natural history and spectrum of tuberculosis (Robbins, Cotran & Kumar Pathologic Basis of Disease)

Morphology: The Ghon Complex

FIG. 11.35 - Primary pulmonary tuberculosis, Ghon complex (Robbins & Kumar)

• In ~95% of cases, cell-mediated immunity controls the infection
• The Ghon complex undergoes progressive fibrosis and calcification
• Despite hematogenous seeding, no lesions develop in organs if immunity is intact
• Only ~5% of newly infected individuals develop significant disease

Progressive Primary TB

• Occurs in immunocompromised patients (HIV, severe malnutrition, very young/old)
• Resembles acute bacterial pneumonia: lobar consolidation, hilar lymphadenopathy, pleural effusion
• May lead to miliary TB or tuberculous meningitis via lympho-hematogenous spread
• Histologically: sheets of macrophages with numerous bacilli but no granulomas (Panel D in image below)

4. Histological Spectrum of Tuberculosis

FIG. 11.36 - Morphologic spectrum of tuberculosis: A/B = Caseating tubercle; C = non-caseating granuloma; D = Macrophage sheets in HIV/immunocompromised (Robbins & Kumar Basic Pathology)

The Tuberculous Granuloma (MUST-KNOW for exams)

• Central caseous necrosis - "cheese-like," pink, acellular material
• Surrounded by: Epithelioid macrophages (activated, elongated)
• Langhans giant cells - nuclei arranged in horseshoe/peripheral arc pattern
• Peripheral rim of lymphocytes and plasma cells
• Outer layer of fibroblasts (fibrosis in healing)

Note: Non-caseating granulomas can occur even in immunocompetent TB patients; therefore ZN/acid-fast staining is always indicated when TB is suspected, regardless of whether caseation is present. - Robbins & Kumar Basic Pathology, p. 477

Caseation vs. Non-caseation

5. Secondary (Reactivation/Postprimary) Tuberculosis

• Arises in a previously sensitized host - either reactivation of latent disease or re-infection
• Classically involves the apex of upper lobes (high oxygen tension favors aerobic mycobacteria)
• Prompt and marked tissue response due to pre-existing hypersensitivity
• Regional lymph nodes less involved than in primary TB (unlike primary where lymph nodes are prominent)

Morphology of Secondary TB

• Initial focus: <2 cm consolidation within 1-2 cm of apical pleura
• Gray-to-yellow with central caseation and peripheral fibrosis
• Cavitation is a hallmark - cavity erodes into airway → expectorated sputum contains bacilli (source of transmission)
• Healing: fibrous encapsulation → fibrocalcific scars
• Active histology: coalescent nodules with central caseation (classic tubercle)

Systemic Symptoms of Secondary TB

• Constitutional: malaise, anorexia, weight loss, low-grade remittent fever (afternoon fever), night sweats
• Pulmonary: productive cough, purulent sputum, hemoptysis (in ~50%)
• Extension to pleura: pleuritic chest pain

6. Miliary Tuberculosis

• Massive hematogenous dissemination of bacilli
• Millet seed-sized (1-2 mm) granulomas scattered throughout lungs, liver, spleen, bone marrow, kidneys, adrenals
• CXR: diffuse bilateral 1-2 mm nodules ("snowstorm" appearance)
• More common in immunocompromised and young children
• Can cause TB meningitis, TB peritonitis, Addison's disease (adrenal involvement)

7. Extrapulmonary TB - Key Sites

8. TB in HIV/Immunocompromised

• Risk increases at all stages of HIV; falls with ART
• With CD4+ >300: "Usual" secondary TB (apical cavitation)
• With CD4+ <200: Resembles progressive primary TB (lobar consolidation, hilar nodes, no cavitation)
• With severe immunodeficiency: No granulomas - sheets of macrophages, very high bacillary load
• Higher rate of false-negative sputum smears and tuberculin tests ("anergy")
• Extrapulmonary involvement >50% in severe immune compromise
• TNF antagonists (used in RA, IBD) also markedly increase TB reactivation risk

9. Diagnosis - Pathological & Laboratory Methods

10. Summary Covercall Points

• Robbins & Kumar Basic Pathology (Robbins Pathology), Ch. 11 - Lung Pathology, pp. 475-478
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Ch. 8, pp. 352-355
• [Fitzpatrick's Dermatology Vol. 1&2] - Histopathology of tuberculoid granulomas
• [Bailey & Love's Short Practice of Surgery, 28th Ed.] - Surgical pathology of ileocaecal TB

Most Common Site for Pulmonary TB

Secondary (Reactivation) TB - the classic form

"The most frequent sites are the apical and posterior segments of the right upper lobe and the apical-posterior segment of the left upper lobe."

• Murray & Nadel's Textbook of Respiratory Medicine

Why the Apex?

• Poor lymphatic drainage (less immune surveillance)
• Lower blood flow relative to ventilation
• Less macrophage activity compared to lower lobes

Summary by TB Type

Key Exam Point

• Secondary TB = Apex of upper lobe = high O₂ tension
• Cavitation is characteristic at this site - the cavity erodes into airways → infected sputum expectorated → source of transmission
• On CXR: upper lobe fibronodular shadows/cavities are the classic radiological hallmark

Low-Grade vs High-Grade Fever

Definition of Normal Body Temperature

Temperature Classification

Costanzo Physiology: "Fever is an abnormal elevation of body temperature. Pyrogens produce fever by increasing the hypothalamic set-point temperature."

Key Differences at a Glance

Pathophysiology (Common to Both)

1. Pyrogens (bacteria, viruses, immune complexes, tumors, drugs) stimulate phagocytic cells
2. These cells release IL-1, IL-6, TNF-α (endogenous pyrogens)
3. These act on the anterior hypothalamus → increased local prostaglandin E2 synthesis
4. Hypothalamic set-point rises → shivering (heat generation), vasoconstriction (heat conservation)
5. Body temperature rises to match the new set-point

Aspirin/NSAIDs work by inhibiting cyclooxygenase → blocking prostaglandin synthesis → lowering the set-point back to normal. - Costanzo Physiology, 7th Ed.

Clinical Causes by Grade

Low-Grade Fever causes:

• Tuberculosis (classic - afternoon low-grade fever + night sweats)
• Viral infections (EBV, CMV, HIV)
• Autoimmune diseases (SLE, RA, IBD)
• Malignancies (lymphoma - "B symptoms")
• Infective endocarditis (subacute - SBE)
• Brucellosis
• Typhoid (early stages)
• Physiological (ovulation, pregnancy)

High-Grade Fever causes:

• Acute bacterial infections (pneumonia, meningitis, UTI, sepsis)
• Malaria (Plasmodium falciparum - can be very high)
• Dengue fever
• Typhoid (later stages - "stepladder" fever)
• Drug fever
• Septicemia
• Acute appendicitis, peritonitis

Hyperpyrexia (>41°C) causes:

• Gram-negative septicemia/septic shock
• Heat stroke
• Malignant hyperthermia (anesthetic complication)
• Pontine hemorrhage (neurogenic fever)
• Thyroid storm

Fever Patterns - Clinically Important

Exam Pearl: TB Fever Pattern