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Tuberculosis - BHMS 3rd Year

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1. Definition

• Robbins & Kumar Basic Pathology

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2. Causative Organism

• Medical Microbiology 9e

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3. Epidemiology

• One of the leading infectious causes of death globally; WHO estimated 10 million new cases and 1.3 million deaths in 2021
• One-third of the global population is asymptomatically infected; only 5-10% develop clinical disease during their lifetime
• An infectious TB patient can infect 10-15 persons per year
• High burden countries: India, Pakistan, sub-Saharan Africa, South Africa, China, Eastern Europe
• MDR-TB: 3.3% of new cases; 18% of previously treated cases had MDR/RR-TB
• Risk factors: poverty, overcrowding, malnutrition, HIV/AIDS, diabetes, silicosis, chronic renal failure, Hodgkin lymphoma, alcohol use disorder, immunosuppression
• Park's Textbook of Preventive and Social Medicine; Robbins & Kumar Basic Pathology

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4. Pathogenesis

Key Concept: Infection vs. Disease

• Infection = seeding of a focus with organisms (may not cause disease)
• Disease = clinically significant tissue damage

Sequence of Events (see diagram below):

1. Mycobacteria inhaled → enter alveolar macrophages via mannose receptors and complement receptors (CR3)
2. Organisms inhibit phagolysosome fusion → prevent acidification and killing → proliferate unchecked in macrophages
3. Bacteremia occurs → organisms seed multiple body sites
4. Patient is usually asymptomatic or has mild flu-like illness

1. Macrophages present mycobacterial antigens to CD4+ T cells via MHC Class II
2. Under macrophage-secreted IL-12, CD4+ T cells differentiate into Th1 cells
3. Th1 cells secrete IFN-γ → activates macrophages
4. Activated macrophages produce: nitric oxide, reactive oxygen species → kill mycobacteria
5. TNF secreted → recruits more monocytes
6. Macrophages differentiate into epithelioid histiocytes → form granulomas
7. Some epithelioid cells fuse → Langhans giant cells
8. Outcome: granuloma formation + caseous necrosis + tuberculin skin test positivity

Important: Immunity and hypersensitivity are two sides of the same coin - the same Th1 cells that mediate protection also cause tissue destruction (caseation).

• Robbins & Kumar Basic Pathology, p. 475-476

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5. Primary Tuberculosis

• Occurs in a previously unexposed, unsensitized host
• ~5% of newly infected individuals develop significant disease

Ghon Complex (Morphology):

• Bacilli implant in distal air spaces of lower upper lobe or upper lower lobe, close to pleura
• A 1-1.5 cm gray-white area of consolidation forms = Ghon focus (often with central caseous necrosis)
• Bacilli travel via lymphatics to regional hilar lymph nodes (also caseate)
• Ghon complex = Ghon focus + affected regional lymph nodes (parenchymal + nodal lesion)
• Hematogenous dissemination occurs in first few weeks
• In ~95% of cases, cell-mediated immunity controls the infection → Ghon complex undergoes progressive fibro-calcification

Progressive Primary TB:

• Occurs in immunocompromised (especially HIV+ with CD4 < 200 cells/µL), severely malnourished
• No granuloma formation (cannot mount CD4+ T cell response)

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6. Secondary (Reactivation) Tuberculosis

• Arises in a previously sensitized host
• May follow primary TB (reactivation of dormant lesions, even decades later) or reinfection
• Only < 5% of primary disease progresses to secondary TB

Key Features:

Morphology of Secondary TB:

• Initial lesion: small (<2 cm) consolidation, 1-2 cm from apical pleura
• Sharply circumscribed, firm, gray-yellow areas with central caseation + peripheral fibrosis
• Active lesions: coalescent granulomas with central caseation (histologically)
• Resolution leaves fibrocalcific scars

Histological appearances of TB:

• A: Low-power - central caseating necrosis surrounded by granulomatous inflammation
• B: Fibrous wall with caseous necrosis
• C: High-power - epithelioid histiocytes + Langhans giant cell
• D: Acid-fast bacilli (red rods on ZN stain)

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7. Complications / Forms of Progressive TB

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8. Diagnosis

• Medical Microbiology 9e; Robbins & Kumar Basic Pathology, p. 476

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9. Treatment

Standard Regimen (RNTCP/NTEP - India):

Drug Mnemonics:

• RIPE = Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (first-line drugs)
• SHREK = Streptomycin, isoniazid (H), Rifampicin, Ethambutol, piraZinamide (second-line and reserve)

Key Side Effects:

Drug-Resistant TB:

• MDR-TB: resistant to at least Isoniazid + Rifampicin (the two most effective drugs)
• XDR-TB: MDR-TB + resistance to any fluoroquinolone + at least one of bedaquiline/linezolid
• Treatment: 18-20 months with second-line agents
• Medical Microbiology 9e; Sherris & Ryan's Medical Microbiology

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10. Prevention and Control

BCG Vaccine:

• Bacillus Calmette-Guérin (BCG) - live attenuated M. bovis
• Given at birth (part of UIP in India)
• Protective efficacy: 28-60% (mainly prevents disseminated/miliary TB and TB meningitis in children)
• Does not prevent adult pulmonary TB reliably

DOTS (Directly Observed Treatment Short-course):

• 5 components of DOTS strategy:
  1. Political commitment
  2. Case detection by sputum smear microscopy
  3. Standardized short-course chemotherapy under direct observation
  4. Regular, uninterrupted drug supply
  5. Standardized recording and reporting system

RNTCP / NTEP (India):

• India's National TB Elimination Programme (NTEP) aims to eliminate TB by 2025 (5 years ahead of the global target of 2030)
• Nikshay portal for TB case notification
• Ni-kshay Poshan Yojana - nutritional support Rs 500/month to TB patients

Chemoprophylaxis:

• Isoniazid preventive therapy (IPT) for 6-9 months for high-risk contacts (household contacts of smear-positive cases, HIV-positive patients)
• Park's Textbook of Preventive and Social Medicine

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11. Extrapulmonary TB - Key Points for Exams

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12. Quick Revision Points (High-yield for BHMS Exams)

• Causative organism: M. tuberculosis - acid-fast bacillus
• Stain: Ziehl-Neelsen (ZN stain) - red on blue background
• Ghon complex = Ghon focus + hilar lymph node involvement (primary TB)
• Secondary TB: apex of upper lobe, cavitation, high infectivity
• Granuloma components: Epithelioid histiocytes + Langhans giant cells + caseous necrosis + lymphocytes
• Immunity: Th1 / CD4+ T cells (cell-mediated immunity); IFN-γ is the key cytokine
• Tuberculin test: delayed hypersensitivity (Type IV) - read at 48-72 hours
• Treatment: 2 HRZE + 4 HR (6 months total for new cases)
• Most common site of extrapulmonary TB: lymph nodes (cervical)
• Most common site of skeletal TB: vertebral column (Pott's disease)
• MDR-TB = resistant to INH + Rifampicin
• BCG: live attenuated M. bovis
• Key side effect to remember: Ethambutol → optic neuritis; INH → peripheral neuropathy; Rifampicin → orange urine

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