---

Tuberculosis (TB) — Full Pathology Exam Notes (MBBS Level)

---

1. DEFINITION

---

2. ETIOLOGY AND BACTERIOLOGY

• Causative organism: Mycobacterium tuberculosis (human type); rarely M. bovis (from unpasteurized milk — bovine TB, now rare in developed countries).
• Characteristics: Slender, slightly curved, aerobic, acid-fast bacilli (AFB); rod-shaped with a waxy lipid-rich cell wall containing mycolic acids.
• Acid-fastness: Due to mycolic acids in the cell wall — the organism retains carbol-fuchsin dye after acid-alcohol decolorization (Ziehl-Neelsen stain).
• Growth: Slow-growing; culture on solid agar (Löwenstein-Jensen medium) shows visible colonies in 3–6 weeks; liquid media (BACTEC) gives results within 2 weeks.
• Virulence factors:
  • Cord factor (trehalose dimycolate) — inhibits leukocyte migration, mitochondrial damage.
  • Wax-D (cell wall component) — adjuvant-like effect, promotes granuloma formation.
  • Sulfatides — inhibit phagolysosome fusion.
  • Lipoarabinomannan (LAM) — inhibits macrophage activation, suppresses IFN-γ.

---

3. EPIDEMIOLOGY

• WHO (2022): ~10.6 million new cases worldwide; 1.3 million deaths (167,000 in HIV-infected persons).
• Leading infectious cause of death by a single pathogen globally.
• In the US: ~8,300 cases reported; 73% in foreign-born individuals.
• Risk factors for TB:
  • HIV/AIDS (dominant risk factor — loss of CD4⁺ Th1 cells)
  • Silicosis, diabetes mellitus, Hodgkin lymphoma
  • Chronic renal failure, malnutrition, alcohol use disorder
  • Glucocorticoids, TNF inhibitors, immunosuppression (transplants)
  • Poverty, crowding, homelessness, incarceration
  • Rare: inherited mutations in IL-12 receptor β1 → severe TB + atypical mycobacteria

---

4. PATHOGENESIS

Step 1 — Entry and Ingestion

• Organisms inhaled as droplet nuclei (1–5 μm particles) — settle in alveoli of lower lobe (better ventilated middle and lower zones).
• Alveolar macrophages phagocytose bacilli via mannose-binding lectin and complement receptor 3 (CR3).
• Dendritic cells also engulf and carry bacilli to draining lymph nodes.

Step 2 — Replication in Macrophages

• M. tuberculosis blocks phagolysosome formation by recruiting host protein coronin to the phagosome membrane → coronin activates calcineurin → inhibits phagosome-lysosome fusion.
• Bacteria replicate freely inside macrophages.
• During the first <3 weeks (pre-immune phase): unchecked proliferation → bacteremia and seeding of multiple sites (most people are asymptomatic or mildly flu-like at this stage).

Step 3 — Innate Immunity

• PAMPs on M. tuberculosis activate toll-like receptors:
  • Lipoarabinomannan → TLR2
  • Unmethylated CpG nucleotides → TLR9
• Enhance innate and adaptive immune responses.
• M. tuberculosis also infects neutrophils, resists killing, and after replicating induces death of infected cells.

Step 4 — Th1 Adaptive Immune Response (~3 weeks post-infection)

• Dendritic cells migrate to draining lymph nodes and present mycobacterial antigens to T cells.
• IL-12 and IL-18 (from APCs) drive differentiation of Th1 cells.
• Th1 cells produce IFN-γ, the critical cytokine that:
  1. Stimulates production of nitric oxide and reactive oxygen species (ROS) in phagolysosome → bactericidal.
  2. Mobilizes antimicrobial peptides (defensins, cathelicidin).
  3. Stimulates autophagy → destroys intracellular bacilli.

Step 5 — Granuloma Formation and Tissue Damage

• IFN-γ-activated macrophages differentiate into epithelioid histiocytes → aggregate into granulomas.
• Some epithelioid cells fuse → Langhans giant cells (nuclei arranged in horseshoe/peripheral pattern).
• TNF (from activated macrophages) is essential for granuloma maintenance → patients on TNF inhibitors have significantly increased risk of TB reactivation.
• In most individuals: granulomas contain infection with caseous necrosis (cheese-like centre).
• In advanced/immunosuppressed disease: ongoing inflammation → caseous necrosis ± cavitation — without granuloma formation.

Key concept — Infection vs. Disease

---

5. TUBERCULIN TEST (PPD / MANTOUX) AND IGRAs

Tuberculin Skin Test (TST / Mantoux)

• Intradermal injection of purified protein derivative (PPD) of M. tuberculosis.
• Read at 48–72 hours — measures visible, palpable induration.
• Positive = Type IV delayed hypersensitivity (DTH) reaction.
• Significance: Indicates T-cell sensitisation to mycobacterial antigens; does NOT differentiate infection from active disease.

IGRA (Interferon-Gamma Release Assay)

• In vitro test: patient's lymphocytes stimulated with M. tuberculosis antigens → IFN-γ production measured.
• More specific than TST (not affected by BCG vaccination).

False Negatives (Anergy) in both tests:

• Viral infections (measles, HIV)
• Sarcoidosis, Hodgkin lymphoma
• Malnutrition, immunosuppression
• Overwhelming active TB itself (anergy from excessive T-cell depletion)

False Positives:

• Atypical mycobacteria (TST only)
• Prior BCG vaccination (TST only; IGRAs less affected)

---

6. PRIMARY TUBERCULOSIS

Definition

• Disease occurring in a previously unexposed, unsensitised individual.
• Source of infection: exogenous (inhaled airborne droplet nuclei from an active case).

Sequence of Events

1. Droplet nuclei inhaled → lodge in subpleural zone, lower part of upper lobe or upper part of lower lobe (most aerated regions).
2. Initial exudative reaction (non-specific pneumonic patch) within days.
3. After ~3 weeks, immune response develops → lesion organises into a granuloma with caseous necrosis.
4. A 1–1.5 cm area of grey-white consolidation with caseous necrosis forms = Ghon focus (Ghon lesion).
5. Bacilli drain via lymphatics to regional hilar/mediastinal lymph nodes → caseating lymphadenopathy.
6. Ghon focus + regional caseating lymph node = Ghon complex.
7. Ghon complex undergoes progressive fibrosis and calcification → Ranke complex (visible on CXR as calcified parenchymal nodule + calcified hilar node).

Outcomes of Primary TB

• Infection is contained; Ghon complex calcifies.
• Organisms remain latent (dormant) for decades.
• No clinical disease; patient becomes tuberculin positive.

• Progressive primary TB: lesion enlarges, caseates, spreads → pneumonia, pleural effusion, hematogenous dissemination.
• Particularly in infants, elderly, HIV-positive individuals.

Morphology of Primary TB (Microscopy)

• Granulomas (tubercles): central caseous necrosis surrounded by epithelioid macrophages, Langhans giant cells, lymphocytes, fibroblasts.
• Caseating granulomas = hallmark of TB.
• Sites of hematogenous seeding may show granulomas in liver, spleen, kidneys, bone marrow, meninges, adrenals, bone — but in most immunocompetent people these remain dormant.

---

7. SECONDARY (POST-PRIMARY / REACTIVATION) TUBERCULOSIS

Definition

• TB occurring in a previously sensitised host.
• May follow shortly after primary TB or, more commonly, months to years later (reactivation of dormant organisms — latent TB reactivation).
• May also result from exogenous reinfection with a new strain.

Characteristics distinguishing it from Primary TB

Location

• Apex of one or both upper lobes (Simon foci — small apical seedlings from primary hematogenous spread that later reactivate).
• Reason: high O₂ tension, poor lymphatic drainage, less surfactant activity.

Morphology — Sequence

1. Fibrocaseous nodule at lung apex: 1–2 cm focus, central caseous necrosis, surrounded by fibrosis.
2. Cavity formation: caseous material liquefies and drains into airways → erosion into bronchus → tuberculous cavity (irregular, ragged walls lined by grey-white caseous material).
3. Erosion of cavities into bronchi → aerogenous spread to other lung areas → tuberculous bronchopneumonia.
4. Erosion into blood vessels → haemoptysis (and potentially dissemination).

Gross Pathology — Secondary TB

• Fibrocaseous lesions — soft caseous centre + surrounding fibrosis.
• Apical cavities with caseous grey walls; may be up to several cm.
• Satellite nodules around main cavity.
• Old healed lesions: dense fibrous scars ± calcification at apex.

Microscopy

• Caseating granulomas (as above) but more numerous and destructive.
• Areas of coagulative necrosis (caseous) — acellular, granular, eosinophilic.
• Langhans giant cells — multinucleated, peripheral arrangement of nuclei.
• Epithelioid macrophages (elongated, eosinophilic cytoplasm, "footprint" nuclei).
• Surrounding lymphocytes and peripheral fibrosis.
• In cavities: AFB may be numerous in caseous material.

---

8. DISSEMINATION AND COMPLICATIONS OF TB

A. Miliary Tuberculosis

• Definition: Haematogenous dissemination of M. tuberculosis → seeding of multiple organs with tiny (1–2 mm) granulomas resembling millet seeds.
• Occurs when: primary TB in immunocompromised, erosion of caseous focus into a vessel (pulmonary vein → systemic), or during secondary TB.
• Organs involved: Lungs, liver, spleen, bone marrow, kidneys, adrenals, meninges, eyes.
• Gross: Innumerable small yellow-white nodules throughout parenchyma.
• Micro: Non-caseating or caseating granulomas at multiple sites.
• CXR: Diffuse bilateral 1–3 mm nodules in a "snow-storm/millet seed" pattern.

B. Tuberculous Pleuritis / Pleural Effusion

• Extension of subpleural Ghon focus into pleural space.
• Exudative effusion (lymphocyte-predominant, high protein, low glucose, positive ADA).
• Parietal pleural biopsy shows caseating granulomas.

C. Tuberculous Lymphadenitis (Scrofula)

• Most common extrapulmonary TB manifestation.
• Cervical lymph nodes most commonly involved (especially posterior triangle).
• Nodes: caseous necrosis → matting → collar-stud abscess → sinus tract to skin.
• Histology: Caseating granulomas in lymph node parenchyma.

D. Tuberculous Meningitis

• Haematogenous seeding of leptomeninges.
• Exudate at base of brain (basal exudative meningitis) → obstructs CSF flow → hydrocephalus.
• Endarteritis → infarcts.
• CSF: Clear/turbid; lymphocytosis; elevated protein; very low glucose; acid-fast smear often negative (culture positive).
• Histology: Tubercles on meninges; endarteritis of small vessels.

E. Pott's Disease (Tuberculous Spondylitis)

• Haematogenous spread to vertebral bodies (lower thoracic / lumbar most common).
• Caseous necrosis destroys disc space → vertebral collapse → kyphosis/gibbus deformity.
• Psoas abscess: Cold abscess tracking along psoas sheath → inguinal region.
• Spinal cord compression → paraplegia (Pott's paraplegia).

F. Renal Tuberculosis

• Haematogenous seeding of renal cortex (high O₂) → caseating granulomas → papillary necrosis → cavitation → "putty kidney" (dystrophic calcification throughout).
• Bacteria shed in urine → ureteric stricture → sterile pyuria (WBCs in urine, no ordinary bacteria on culture).
• "Sterile pyuria" is a classic clue for renal TB.

G. Adrenal Tuberculosis

• Historically a cause of Addison's disease (adrenal insufficiency).
• Bilateral caseating granulomas → adrenal destruction.

H. GI / Peritoneal Tuberculosis

• Primary: ingestion of M. bovis (rare).
• Secondary: swallowed infected sputum.
• Ileocaecal region most commonly involved.
• Macroscopy: Transverse ulcers (perpendicular to long axis of bowel — vs. Crohn's longitudinal fissuring ulcers).
• Peritoneal TB: Ascites (lymphocyte-exudate, high ADA) + "dough-belly" (omentum matted, caseous).

---

9. SPECIAL PATTERNS

TB in HIV/AIDS

• Most common AIDS-defining infection worldwide.
• CD4⁺ count determines pattern:
  • CD4 >350/μL: typical secondary TB (upper lobe cavitary disease).
  • CD4 200–350/μL: atypical pattern, lower lobe involvement, less cavitation.
  • CD4 <200/μL: Miliary TB, diffuse infiltrates, extrapulmonary TB dominant; non-caseating granulomas (poor granuloma formation due to lack of T cells).
• Co-infection with HIV dramatically worsens prognosis.
• Paradoxical reactions (Immune Reconstitution Inflammatory Syndrome — IRIS) occur when ART is started and immune function is restored.

Drug-Resistant TB

• MDR-TB: Resistant to isoniazid + rifampicin (two key first-line drugs).
• XDR-TB: MDR-TB + resistance to any fluoroquinolone AND at least one injectable second-line drug (amikacin, kanamycin, capreomycin).
• New WHO definitions (2021): Pre-XDR-TB = MDR-TB + fluoroquinolone resistance.
• Rising globally, particularly in Eastern Europe and South/Southeast Asia.

---

10. DIAGNOSIS

---

11. HISTOLOGICAL HALLMARKS — SUMMARY TABLE

---

12. CLINICAL FEATURES — PULMONARY TB

• Systemic: Fever (low-grade, afternoon), night sweats, malaise, anorexia, weight loss ("consumption").
• Respiratory: Persistent productive cough (>3 weeks), purulent sputum, haemoptysis (~50% of cases), pleuritic chest pain.
• Examination: Dullness at apex, bronchial breathing, amphoric breath sounds (over cavity), post-tussive suction sounds.
• CXR: Upper lobe infiltrates, cavitation, fibrosis, calcification, hilar lymphadenopathy (primary TB), miliary pattern.

---

13. TREATMENT (Overview — for context)

• First-line regimen (RIPE/DOTS): Rifampicin (R), Isoniazid (I), Pyrazinamide (P), Ethambutol (E).
• Phases: 2 months intensive (RIPE) + 4 months continuation (RI).
• BCG vaccine: Attenuated M. bovis; protects against severe childhood forms (miliary, meningeal TB); less effective against pulmonary TB in adults.

---

14. KEY HIGH-YIELD EXAM POINTS

1. Ghon focus = primary parenchymal lesion (subpleural, lower upper lobe).
2. Ghon complex = Ghon focus + ipsilateral caseating hilar lymph node.
3. Ranke complex = calcified Ghon complex (healed, visible on CXR).
4. Secondary TB site = apex of upper lobe (Simon foci).
5. Caseous necrosis = cheese-like, acellular, eosinophilic — pathognomonic of TB.
6. Langhans giant cells = peripheral/horseshoe nuclei (different from foreign-body type).
7. IFN-γ = critical cytokine for granuloma formation and macrophage activation.
8. TNF = essential for granuloma maintenance; TNF inhibitors → TB reactivation risk.
9. Sterile pyuria = classic sign of renal TB.
10. Pott's disease = vertebral TB → gibbus deformity + cold psoas abscess.
11. Miliary TB = haematogenous dissemination; 1–2 mm nodules; resembles millet seeds.
12. Scrofula = TB cervical lymphadenitis; collar-stud abscess.
13. MDR-TB = resistant to rifampicin + isoniazid.
14. In HIV with very low CD4: non-caseating granulomas (poor T-cell function).
15. Tuberculin test positivity = delayed hypersensitivity (Type IV); does NOT mean active disease.

---

---

TUBERCULOSIS — PATHOLOGY

Long Answer | MBBS University Examination Standard

---

DEFINITION

---

ETIOLOGY AND BACTERIOLOGY

• Slender, slightly curved, aerobic, non-spore-forming bacillus
• Acid-fast — owing to high mycolic acid content in the cell wall; retains carbol-fuchsin dye after acid-alcohol decolorization (Ziehl-Neelsen stain)
• Obligate aerobe — explains predilection for well-oxygenated areas (lung apex, renal cortex)
• Slow-growing: colonies appear in 3–6 weeks on Löwenstein-Jensen solid medium; 2 weeks in BACTEC liquid medium

---

EPIDEMIOLOGY

• WHO (2022): ~10.6 million new cases; 1.3 million deaths worldwide.
• Called the "White Plague" or "consumption" historically.
• TB flourishes in settings of poverty, overcrowding, and chronic debilitating illness.
• In the US: 73% of cases are foreign-born; predominantly affects older adults, immigrants, the homeless, prisoners, and HIV-positive individuals.

---

PATHOGENESIS

Concept: Infection vs. Disease

Infection = organisms present in the body (may be latent — no symptoms, not infectious). Active Disease = organisms proliferating with tissue destruction and clinical symptoms (infectious).

Step-by-Step Mechanism

• TB is transmitted by airborne droplet nuclei (1–5 μm) — produced by coughing, sneezing, or speaking by a patient with active pulmonary TB.
• Droplet nuclei reach the alveoli (lower lobe or middle lobe — better ventilated).
• Alveolar macrophages phagocytose the bacilli via:
  • Mannose-binding lectin receptors
  • Complement receptor 3 (CR3 / CD11b/CD18)
• M. tuberculosis blocks phagolysosome formation: it recruits the host protein coronin to the phagosomal membrane → coronin activates calcineurin → inhibits phagosome-lysosome fusion.
• Bacteria replicate freely within macrophages. Infected macrophages migrate to the lung interstitium.
• Bacteraemia occurs within the first 3 weeks → haematogenous seeding of multiple organs (liver, spleen, kidney, meninges, bone, adrenals).
• At this stage: most patients are asymptomatic or have a mild flu-like illness.

• PAMPs on M. tuberculosis activate pattern recognition receptors:
  • Lipoarabinomannan → TLR2
  • Unmethylated CpG DNA → TLR9
• These interactions prime the innate and adaptive immune responses.
• M. tuberculosis also infects neutrophils → resists killing → replicates → induces neutrophil death.

• Dendritic cells process mycobacterial antigens and migrate to regional draining lymph nodes → present antigens to naïve CD4⁺ T cells.
• IL-12 and IL-18 (from antigen-presenting cells) drive Th1 cell differentiation.
• Th1 cells produce IFN-γ — the central cytokine of TB immunity.

1. Activates macrophages → produce nitric oxide (NO) and reactive oxygen species (ROS) within phagolysosome → bactericidal
2. Mobilises antimicrobial peptides (defensins, cathelicidin)
3. Stimulates autophagy → destroys intracellular bacteria

• IFN-γ-activated macrophages transform into epithelioid histiocytes (elongated, abundant pale-pink cytoplasm, oblong "footprint" nucleus).
• Epithelioid cells aggregate → granuloma (the hallmark of TB).
• Some epithelioid cells fuse → Langhans giant cells (nuclei arranged in a horseshoe/peripheral pattern — distinguishing them from foreign-body giant cells with random nuclei).
• TNF (from activated macrophages) is essential for granuloma maintenance and integrity.
• Granuloma centre undergoes caseous necrosis: the bacteria and macrophages die → cheese-like (acellular, granular, eosinophilic) necrotic material.
• In most people: granulomas contain the infection. In immunocompromised: ongoing inflammation → tissue destruction without granuloma formation.

⚠️ Patients on TNF inhibitors (e.g., anti-rheumatic drugs) have a markedly elevated risk of TB reactivation because TNF is required to maintain granuloma integrity.

Tuberculin Test Basis

---

PRIMARY TUBERCULOSIS

Definition

Sequence of Events and Morphology

1. Inhaled bacilli → settle in subpleural zone, lower lobe or lower part of upper lobe (zones of maximal ventilation).
2. Initial non-specific pneumonic patch (exudative reaction) develops within days.
3. After ~3 weeks, cell-mediated immunity activates → exudative lesion organises into granuloma.
4. A 1–1.5 cm area of grey-white pulmonary consolidation with central caseous necrosis = GHON FOCUS (also called Ghon lesion).
5. Bacilli drain via lymphatics to regional hilar/paratracheal lymph nodes → caseating lymphadenopathy (prominent in children).
6. GHON COMPLEX = Ghon focus + ipsilateral caseating hilar lymph nodes.
7. In most cases (~95%), cell-mediated immunity contains the infection → both components undergo progressive fibrosis and dystrophic calcification → RANKE COMPLEX (visible on CXR as calcified peripheral nodule + calcified hilar node).

Microscopy of Primary TB Granuloma

• Central caseous necrosis: acellular, eosinophilic, granular — structureless (unlike coagulative necrosis which preserves outlines)
• Epithelioid histiocytes: surrounding the necrotic core; elongated pink cytoplasm, oblong nucleus
• Langhans giant cells: horseshoe/peripheral arrangement of nuclei; multinucleated
• Lymphocytic cuff: surrounding the epithelioid cells
• Outer fibrous rim: encircling the entire granuloma

Outcomes of Primary TB

---

SECONDARY (POST-PRIMARY / REACTIVATION) TUBERCULOSIS

Definition

Comparison with Primary TB

Why the Apex?

• Simon foci — tiny apical seedlings deposited during initial primary bacteraemia
• High oxygen tension (M. tuberculosis is an obligate aerobe)
• Poor lymphatic drainage
• Reduced lymphatic clearance at the apex

Morphological Progression in Secondary TB

• Small (1–2 cm) focus at apex with caseating granuloma + surrounding fibrosis.
• Central caseous material may remain solid for a time.

• Caseous material liquefies → drains into an adjacent bronchus → tuberculous cavity forms.
• Cavity walls: ragged, grey-white caseous lining; poorly vascularised.
• Positive AFB sputum smear (bacteria shed into sputum from cavity).

• Erosion of cavity into bronchi → aerogenous (bronchogenic) spread → cough-spreads infection to other lung segments → tuberculous bronchopneumonia (patchy consolidation throughout lung).
• Spread via:
  • Airways → same/opposite lung
  • Lymphatics → hilar nodes, pleura
  • Blood vessels → haematogenous miliary spread

Gross Pathology — Secondary TB Lung

• Fibrocaseous lesions with soft grey-yellow caseous centres and grey-white fibrotic walls
• Apical cavities — variable size, ragged walls
• Satellite nodules around main cavity
• Old healed lesions: dense apical scars, calcification, pleural adhesions
• In progressive disease: entire lobe can be replaced by caseous material

Microscopy — Secondary TB

• Caseating granulomas — more numerous and destructive than primary
• Caseous necrosis: acellular, granular, eosinophilic — no cellular detail
• Epithelioid macrophages — classical "footprint" nucleus
• Langhans giant cells — horseshoe/peripheral nuclei
• Lymphocytic infiltrate peripheral
• AFB on ZN stain — slender red rods in caseous material (may be scanty)
• Progressive disease: large areas of coagulative-caseous necrosis replacing normal architecture

---

COMPLICATIONS AND SPREAD — DISSEMINATION

A. Miliary Tuberculosis

• Erosion of a caseous focus into a pulmonary vein or lymphovascular channel → bacteraemia → systemic spread.
• May occur during primary (especially in immunocompromised) or secondary TB.

---

B. Tuberculous Pleuritis / Pleural Effusion

• Extension of a subpleural Ghon focus or secondary TB lesion into the pleural space.
• Exudative effusion: lymphocyte-predominant, high protein, low glucose, raised ADA (adenosine deaminase >40 IU/L).
• Parietal pleural biopsy shows caseating granulomas.
• May organise → empyema necessitans → pleural fibrosis / trapped lung.

---

C. Tuberculous Lymphadenitis (Scrofula)

• Most common extrapulmonary form of TB.
• Cervical lymph nodes (posterior triangle) most commonly involved.
• Nodes undergo caseating necrosis → matting together → collar-stud (shirt-stud) abscess: caseous material perforates the deep fascia → subcutaneous fluctuant swelling connected to deep node by a narrow neck.
• Sinus tracts to skin surface may develop.
• Microscopy: Caseating granulomas in lymph node parenchyma; Langhans giant cells.

---

D. Tuberculous Meningitis

• Haematogenous seeding of leptomeninges (pia-arachnoid).
• Base of brain predominantly affected — thick gelatinous exudate (basal exudative meningitis).
• Complications: hydrocephalus (obstructed CSF flow), endarteritis → cerebral infarcts, cranial nerve palsies.
• CSF findings: Clear/slightly turbid; lymphocytic pleocytosis (cells 100–500/mm³); elevated protein; very low glucose (≤45 mg/dL or CSF/serum glucose <0.5); AFB smear often negative; culture gold standard.
• Histology: Granulomas on meninges; fibrinous exudate; endarteritis of small vessels.

---

E. Pott's Disease (Tuberculous Spondylitis)

• Haematogenous spread to vertebral bodies (most common site of skeletal TB).
• Predilection: lower thoracic and upper lumbar vertebrae (T10–L2).
• Mechanism: Caseous necrosis destroys intervertebral disc → spreads to adjacent vertebral bodies → vertebral collapse → angular kyphosis (gibbus deformity).
• Cold (Pott's) abscess: Caseous pus tracks along the psoas sheath → presents as a fluctuant swelling in the inguinal region; "cold" = no warmth/redness (unlike pyogenic).
• Complications: Pott's paraplegia (spinal cord compression by caseous mass or collapsed vertebra).
• Histology: Caseating granulomas in bone, disc space, paravertebral soft tissue.

---

F. Renal Tuberculosis

• Haematogenous seeding of renal cortex (high oxygen tension).
• Sequence: Cortical granuloma → caseation → papillary necrosis → cortical cavity → "putty kidney" (entire kidney replaced by dystrophic calcification).
• Bacilli shed in urine → ureteric stricture → obstructive uropathy.
• Classic finding: Sterile pyuria — WBCs in urine with no growth on routine bacterial culture ("sterile pyuria with acid urine" = TB until proven otherwise).

---

G. Adrenal Tuberculosis

• Bilateral caseating granulomas → adrenocortical destruction → historically a leading cause of Addison's disease (primary adrenocortical insufficiency).

---

H. Intestinal / Peritoneal Tuberculosis

• Either from ingestion of M. bovis (unpasteurised milk) or swallowed infected sputum.
• Ileocaecal region most commonly involved.
• Macroscopy: Transverse (circumferential) ulcers — perpendicular to the long axis of the bowel (vs. longitudinal fissuring ulcers of Crohn's disease).
• Lymph node caseation → peritoneal seeding → ascites (lymphocytic exudate, elevated ADA) + "dough-belly" (matted omentum with caseous nodules).

---

TUBERCULOSIS AND HIV/AIDS

• Non-caseating granulomas in HIV occur because the Th1 response is insufficient to form proper granulomas.
• Immune Reconstitution Inflammatory Syndrome (IRIS): Paradoxical worsening of TB on starting ART as the immune system recovers.

---

DRUG-RESISTANT TUBERCULOSIS

---

DIAGNOSIS

• Basis: Type IV delayed hypersensitivity (DTH) reaction to mycobacterial PPD.
• Positive: Induration ≥10 mm at 48–72 hours (not redness/erythema).
• Positive test = sensitisation only (does not differentiate active disease from latent infection).

• HIV/AIDS (CD4 <200), viral infections (measles), sarcoidosis
• Hodgkin lymphoma, malnutrition, overwhelming active TB itself

• BCG vaccination (TST, not IGRA)
• Infection with atypical (non-tuberculous) mycobacteria

---

CLINICAL FEATURES

• Constitutional (systemic): Low-grade fever (afternoon remittent), night sweats, malaise, anorexia, progressive weight loss ("consumption," "wasting disease")
• Respiratory: Productive cough (>3 weeks), purulent sputum, haemoptysis (in ~50%), pleuritic chest pain, dyspnoea
• Examination: Dullness at apex, bronchial breathing, post-tussive suction sounds (open cavities), amphoric breathing

• Primary TB: mid/lower zone opacity + hilar adenopathy (Ghon complex); calcified lesions (Ranke complex)
• Secondary TB: upper lobe infiltrates, cavitation, fibrosis, calcification, pleural effusion
• Miliary TB: diffuse bilateral 1–3 mm nodules ("millet seed" / "snowstorm" pattern)

---

TREATMENT (DOTS — Directly Observed Treatment, Short Course)

• Intensive phase (2 months): Rifampicin (R) + Isoniazid (H/I) + Pyrazinamide (Z) + Ethambutol (E) — RIPE / HRZE
• Continuation phase (4 months): Rifampicin + Isoniazid — HR/RH
• Total duration: 6 months for drug-sensitive pulmonary TB
• TB meningitis: 9–12 months + adjunct corticosteroids

---

HISTOLOGICAL HALLMARKS — QUICK SUMMARY TABLE

---

HIGH-YIELD EXAM POINTS (MBBS)

1. TB is caused by M. tuberculosis — acid-fast, aerobic bacillus, identified by Ziehl-Neelsen stain.
2. Mode of spread: airborne droplet nuclei (1–5 μm); NOT fomites or droplets.
3. M. tuberculosis survives in macrophages by blocking phagolysosome formation via coronin-calcineurin pathway.
4. Key immune effector: IFN-γ (from Th1 cells) — activates macrophages; drives granuloma formation.
5. TNF maintains granuloma integrity — TNF inhibitors → reactivation of latent TB.
6. Ghon focus = primary lung lesion; Ghon complex = lesion + hilar node; Ranke complex = calcified healed complex.
7. Primary TB → lower/middle zone; Secondary TB → apex of upper lobe (Simon foci).
8. Caseous necrosis = cheese-like, acellular, granular on H&E — characteristic of TB (other organisms cause liquefactive, coagulative, etc.).
9. Langhans giant cell = peripheral horseshoe nuclei (NOT foreign-body giant cell = randomly arranged nuclei).
10. Miliary TB = haematogenous dissemination → 1–2 mm millet-seed nodules in multiple organs.
11. Scrofula = tuberculous cervical lymphadenitis → collar-stud abscess → sinus tract to skin.
12. Pott's disease = vertebral TB → gibbus deformity + cold psoas abscess + paraplegia.
13. Sterile pyuria (WBCs in urine, no bacterial growth on routine culture) = renal TB until proven otherwise.
14. Mantoux test = Type IV DTH reaction; read at 48–72 hrs; induration (not erythema) assessed.
15. MDR-TB = resistant to Rifampicin + Isoniazid; XDR-TB = MDR + fluoroquinolone + injectable resistance.
16. In HIV with CD4 <200: TB presents with non-caseating granulomas (poor T-cell response) or no granulomas.
17. Gold standard for diagnosis = culture; fastest confirmatory test = GeneXpert PCR.
18. Standard treatment = HRZE × 2 months + HR × 4 months (6 months total — DOTS).

---