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🫁 TUBERCULOSIS (TB) - Complete Exam Notes

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DEFINITION

• Formation of granulomas
• Development of cell-mediated hypersensitivity

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ORGANS AFFECTED BY TB

1. Lungs (most common - Pulmonary TB)
2. Lymph nodes
3. Pleura
4. CNS (brain and meninges)
5. Bones and joints (especially spine)
6. Genitourinary tract (kidneys, bladder, reproductive organs)
7. Gastrointestinal tract and peritoneum
8. Pericardium
9. Skin, Eyes, Liver, Adrenal glands
10. Disseminated/Miliary TB - involves multiple organs at once

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CLINICAL FEATURES

Pulmonary TB - Symptoms:

• Chronic cough, often with haemoptysis (coughing blood)
• Pyrexia (fever of unknown origin)
• Unresolved pneumonia
• Exudative pleural effusion
• Weight loss
• General debility (weakness)
• Spontaneous pneumothorax
• May be asymptomatic - found on chest X-ray

Miliary (Disseminated) TB - Symptoms:

• 2-3 weeks of fever
• Night sweats
• Anorexia (loss of appetite)
• Weight loss, dry cough
• Hepatosplenomegaly may develop
• Headache (may suggest tuberculous meningitis)
• Auscultation: usually normal, but crackles in advanced disease
• Fundoscopy: choroidal tubercles (seen in eye)
• Chest X-ray: 1-2 mm millet seed lesions distributed throughout lung fields
• Anaemia and leucopenia (reflect bone marrow involvement)

Post-Primary Pulmonary TB:

• Occurs from exogenous or endogenous re-infection in a previously sensitized person
• Systemic symptoms: fever, night sweats, malaise, loss of appetite and weight
• Progressive pulmonary symptoms
• Radiological changes:
  • Ill-defined opacification in one or both upper lobes
  • As it progresses: consolidation → collapse → cavitation
  • Extensive disease can displace trachea and mediastinum
  • Caseous lymph nodes may drain into bronchus → tuberculous pneumonia

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INVESTIGATIONS

Why investigate?

• Confirm the diagnosis and exclude other conditions
• Know extent and severity of lesion
• Detect dissemination of lesions
• Detect development of complications
• Evaluate response to treatment

Step 1 - Direct Microscopy of Sputum Smear (MOST IMPORTANT first step):

• Need at least 2 sputum samples (one early morning)
• From spontaneously produced deep cough, or induced sputum
• In selected cases: bronchoscopy and lavage, or lymph node aspiration by EBUS

Stains used:

• LED fluorescent microscopy with Auramine staining - increasingly replacing the traditional
• Ziehl-Neelsen stain (classic acid-fast stain)
• Mercury vapour fluorescent microscopy

Positive smear = Presumptive diagnosis of TB. Definitive diagnosis requires culture. Even negative smear should be cultured (only 10-100 viable organisms needed for culture to be positive)

Culture:

• Slow growth on solid media (Lowenstein-Jensen, Middlebrook) - 4-6 weeks
• Automated/semi-automated liquid media (MGIT) - around 2 weeks
• NAATs (Nucleic Acid Amplification Tests): e.g., Xpert MTB/RIF - detects MTB in less than 2 hours

Drug Sensitivity Testing:

• Gold standard: Culture
• MODS (Microscopically Observed Drug Susceptibility)
• Colorimetric Redox Indicator (CRI)
• Nitrate reductase assay
• Xpert MTB/RIF for rapid identification of rifampicin resistance (important because rifampicin forms the cornerstone of 6-month chemotherapy)
• Line probe assays (LPAs): use PCR to detect resistance to rifampicin, isoniazid, pyrazinamide, ethambutol, and second-line agents

Other tests:

• Adenosine deaminase (ADA): elevated in pleural, pericardial, CSF and ascitic fluid - due to T cell stimulation by mycobacterial antigens
• HIV + TB: lateral flow urinary lipoarabinomannan assay (LF-LAM) in severely ill patients
• Tuberculin skin test (TST/Mantoux): low sensitivity/specificity; useful in primary or deep-seated infection; can be false +ve in BCG vaccinated people
• IGRAs (Interferon Gamma Release Assays): detect IFN-γ released by sensitized T cells in response to MTB-specific antigens (ESAT-6, CFP-10). Two types:
  • T-SPOT.TB test (uses purified T lymphocytes + ELISPOT)
  • QuantiFERON-TB Gold test (uses whole blood + ELISA)
  • More specific and convenient than TST

Specimens needed:

Baseline blood tests:

• Full blood count, CRP, ESR, urea and electrolytes, liver function tests

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DIAGNOSIS (Summary Box 17.51)

Trigger for investigation: Unexplained cough for more than 2-3 weeks (especially in TB-prevalent regions), OR typical chest X-ray/CT changes.

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MANAGEMENT

Principle:

1. Intensive phase - rapidly reduces bacterial population
2. Continuation phase - destroys remaining bacteria

Standard Treatment (WHO Recommendations - Box 17.52):

If isoniazid resistance is high: continuation phase uses HRE (4 months)

• Fixed dose tablets combining 2-3 drugs are preferred
• Treatment should be started immediately in any patient who is smear +ve, or smear -ve but with typical chest X-ray changes and no response to standard antibiotics

Special Situations:

• Meningeal TB: 12 months
• Spinal TB with cord involvement: ethambutol may be replaced by streptomycin
• Pyridoxine should be given to pregnant women and malnourished patients (to reduce risk of peripheral neuropathy from isoniazid)

Setting of Treatment:

• Most patients can be treated at home
• Hospital admission needed if: uncertain diagnosis, medication intolerance, poor adherence, adverse social conditions, risk of MDR-TB

Non-infectious after:

• 2 weeks of appropriate therapy (if no drug resistance)

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ADVERSE DRUG REACTIONS (Box 17.53)

• Rifampicin turns urine, tears, and secretions orange/red - warn patients
• Women on oral contraceptives must use alternative contraception (rifampicin reduces efficacy)
• Ethambutol and streptomycin: use with caution in renal impairment
• Adverse reactions occur in about 10% of patients (more common with HIV co-infection)
• Hepatotoxicity: significant in only 2-5%, but baseline LFTs and regular monitoring needed
• If hepatotoxicity occurs: stop treatment, let LFTs recover, then reintroduce drugs one by one. Switch to less hepatotoxic regimen (streptomycin, ethambutol, fluoroquinolones)

Glucocorticoids (Steroids):

• Pericardial disease
• Meningeal TB
• Endobronchial disease (in children)
• TB of ureter
• Pleural effusions
• Extensive pulmonary disease

Surgery:

• Massive haemoptysis
• Loculated empyema
• Constrictive pericarditis
• Lymph node suppuration
• Spinal disease with cord compression

Monitoring Response:

• Sputum smear at 2 months and 5 months
• Failure = positive smear OR multidrug resistant strain

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CONTROL AND PREVENTION

1. Detection of Latent TB:

• Most people exposed to MTB harbour bacteria in a dormant state - non-infectious but at risk
• Lifetime risk of TB in latent infection: 5-15% (majority within first 5 years)
• Detected by: TST (can be false +ve with BCG) or IGRAs (more specific)
• Asymptomatic contact who tests +ve with normal chest X-ray → chemoprophylaxis:
  • Adults up to 65 years
  • HIV-infected close contacts of smear-positive patients
  • Regimen: Rifampicin + Isoniazid for 3 months OR Isoniazid alone for 6 months
• Close contacts should receive BCG vaccination or chemotherapy
  • 10-20% of close contacts of smear +ve pulmonary TB patients have TB infection
  • 2-5% of contacts of smear -ve, culture +ve cases have evidence of infection

2. Directly Observed Therapy (DOT):

• Major factors in prolonged illness: poor adherence, risk of relapse, emergence of drug resistance
• DOT = supervised administration of therapy 3 times a week to improve adherence

3. TB and HIV/AIDS:

• Mortality is high; TB is a leading cause of death in HIV patients
• All TB patients should be tested for HIV

4. Drug-Resistant TB:

• Drug-resistant TB: resistance to any first-line agent
• MDR-TB (Multidrug Resistant): resistance to at least rifampicin + isoniazid ± other drugs
• XDR-TB (Extensively Drug Resistant): resistance to rifampicin + isoniazid + any quinolone + at least one injectable second-line agent
• More common in: prior history of TB, inadequate treatment, HIV infection
• Requires prolonged treatment with less effective, more toxic and more expensive drugs

5. BCG Vaccine:

• Live attenuated vaccine derived from M. bovis
• Given by intradermal injection
• Highly immunogenic
• Effective in preventing disseminated disease and tuberculous meningitis in children
• Efficacy in adults is inconsistent
• Should NOT be given to: immunocompromised patients, pregnant women

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QUICK EXAM MNEMONICS

• Isoniazid → Neuropathy (peripheral)
• Rifampicin → Red urine + Reduced OCP efficacy
• Pyrazinamide → Gout (hyperuricaemia)
• Ethambutol → Eye damage (retrobulbar neuritis)
• Streptomycin → Sound loss (8th nerve damage)

• MDR = Resistant to R + H
• XDR = Resistant to R + H + Quinolone + 1 injectable

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🧠 TB Made Super Easy - Memory Edition

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1. WHAT IS TB? (The Simple Story)

🧠 Memory trick: "TB = Tiny Bacteria that builds Jail Cells (granulomas)"

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2. CLINICAL FEATURES - The "COWPS" Story 🐄

🧠 Mnemonic: "COWPS" - A sick cow with tuberculosis!

• Fever for 2-3 weeks
• Night sweats + anorexia
• Hepatosplenomegaly (liver and spleen swell)
• Headache (TB got into the brain!)
• Chest X-ray: millet seeds (tiny 1-2mm spots everywhere) - that's WHY it's called miliary (millet = tiny grain)

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3. INVESTIGATIONS - The "SDC-NI" Ladder 🪜

STEP 1 (Bottom) → Sputum Smear (ZN stain / Auramine) - quickest
STEP 2          → Culture (gold standard, takes 2-6 weeks)
STEP 3          → NAAT / Xpert MTB/RIF (fastest, < 2 hours!)
STEP 4 (Top)    → Drug Sensitivity Testing

🧠 Memory trick: "Spit on the Culture, then NAAT it" (Smear → Culture → NAAT)

• Smear +ve = you can presume TB, but you need culture to confirm
• Xpert MTB/RIF = detects TB AND rifampicin resistance in under 2 hours
• Ziehl-Neelsen (ZN) stain = the classic acid-fast stain for TB

• Mantoux / Tuberculin skin test = old method, not very reliable (BCG causes false +ve)
• IGRA (QuantiFERON / T-SPOT) = modern, more accurate blood test. Measures IFN-gamma released when your T cells see TB antigens

🧠 Memory trick: "IGRA = Immune Guards Recognise Antigen"

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4. THE DRUGS - The "RIPE" Framework 🍎

🧠 Mnemonic: "RIPE fruit cures TB" - Rifampicin, Isoniazid, Pyrazinamide, Ethambutol

START OF RACE (2 months) = All 4 drugs: R + I + P + E  (intensive)
FINISH LINE (4 months)   = Only 2 drugs: R + I         (continuation)
TOTAL RACE = 6 months

🧠 Story: "You need all 4 players at the START of the race, but by the end only 2 are left running"

• Meningeal TB = 12 months (brain needs longer)
• Streptomycin replaces Ethambutol in spinal TB

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5. SIDE EFFECTS - The "RIPES" Table with Stories 🏥

🧠 Use the phrase: "Rifampicin Ruins Liver, Isoniazid Injures Nerves, Pyrazinamide Pinches Joints, Ethambutol Erases Eyesight, Streptomycin Steals Sound"

⚠️ 3 drugs cause Hepatitis: Rifampicin, Isoniazid, Pyrazinamide (remember: RIP your liver 💀)

🧠 Rifampicin special warning: Reduces the pill (OCP) efficacy - tell female patients!

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6. STEROIDS - When to Add Them? "PUMP ME"

🧠 Mnemonic: "PUMP ME with steroids"

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7. MDR vs XDR - The "More Dangerous, eXtremely Dangerous" Rule

🧠 Think of it as levels of a video game boss:

• MDR = Level 1 Boss (resists R + I)
• XDR = Final Boss (resists R + I + quinolone + injectable)

• Prior history of TB
• Inadequate/incomplete treatment
• HIV infection

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8. PREVENTION - "BCG + DOT + IGRA"

🧠 All TB patients must be tested for HIV (they are deadly partners)

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9. THE MASTER CHEAT SHEET 📋

TB = MTB bacteria → granulomas → CMI hypersensitivity

SYMPTOMS (COWPS): Cough, unresOlved pneumOnia, Weight loss, Pyrexia, Spontaneous pneumothorax

INVESTIGATIONS: Smear → Culture → NAAT (Xpert < 2 hrs)

TREATMENT:
  2 months: RIPE (Rifampicin + Isoniazid + Pyrazinamide + Ethambutol)
  4 months: RI
  TOTAL: 6 months

SIDE EFFECTS:
  R = Red urine, Rifampicin ruptures liver
  I = Isoniazid Injures nerves (give B6!)
  P = Pyrazinamide = Painful gout
  E = Ethambutol = Eyes
  S = Streptomycin = Sound (deaf)
  RIP liver = Rifampicin + Isoniazid + Pyrazinamide all cause hepatitis

MDR = Resists R + I
XDR = MDR + Quinolone + Injectable

BCG = Live vaccine, works in children
DOT = 3x/week supervised
Test ALL TB for HIV

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🔁 Quick Recall Test (cover the answers and try!)

1. What bacteria causes TB? → M. tuberculosis
2. What is miliary TB? → Disseminated TB, millet seed X-ray pattern
3. First step in investigation? → Sputum smear (ZN stain)
4. Definitive diagnosis? → Culture
5. Fastest test? → Xpert MTB/RIF (< 2 hours)
6. Treatment duration? → 6 months (2 RIPE + 4 RI)
7. Which drug turns urine red? → Rifampicin
8. Which drug damages eyes? → Ethambutol
9. Which drug causes deafness? → Streptomycin
10. 3 drugs causing hepatitis? → RIP - Rifampicin, Isoniazid, Pyrazinamide
11. MDR-TB = resistant to? → Rifampicin + Isoniazid
12. When to use steroids? → PUMP ME (Pericardial, Ureter, Meningeal, Pleural, Massive pulmonary, Endobronchial)

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🦠 Causes & Pathophysiology of Pulmonary Tuberculosis

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PART 1: CAUSES (What causes TB?)

The Bacteria

• M. bovis (causes TB in cattle, used for BCG vaccine)
• M. africanum (found in West Africa)

🧠 Easy memory: "MTB wears a fatty armour coat that the immune system struggles to break through"

How does it spread?

• Airborne transmission - via droplet nuclei (tiny particles < 5 microns)
• Released when an infected person coughs, sneezes, or speaks
• These tiny droplets stay suspended in the air for hours
• Only a few bacilli are needed to cause infection
• Humans are the only significant reservoir - no animal reservoir for M. tuberculosis

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PART 2: PATHOPHYSIOLOGY (What happens step by step in the body?)

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🎬 ACT 1 - ENTRY (Inhalation)

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🎬 ACT 2 - THE BATTLE INSIDE THE MACROPHAGE

1. MTB prevents the phagosome from fusing with the lysosome (blocks acidification)
2. So the bacteria sit inside the macrophage in a "safe bubble" - un-digested and alive
3. MTB then multiplies freely inside the macrophage
4. Eventually the macrophage bursts and releases more bacteria

🧠 Easy analogy: "Imagine swallowing a bad guy who builds a bulletproof room inside your stomach so he can live there and multiply"

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🎬 ACT 3 - THE IMMUNE RESPONSE (Th1 response + Delayed-Type Hypersensitivity)

• Macrophages and dendritic cells digest TB proteins and present them to naïve T cells
• They release IL-12 and IFN-γ (interferon-gamma) as alarm signals

• CD4+ T cells are recruited and mount the Th1 immune response
• IFN-γ is the key cytokine that activates macrophages to become better killers
• CD8+ cytotoxic T cells also arrive and destroy MTB-infected macrophages

• MTB proteins trigger a DTH response - this is your body's "inflammation" component
• DTH causes fluid accumulation and release of digestive enzymes at infection sites
• This is the only source of tissue damage in TB - your own immune system damages your lungs
• The DTH response is also what makes the Mantoux/TST test positive

🧠 Key concept: In TB, the damage comes from your own immune system fighting the bacteria, not directly from the bacteria itself!

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🎬 ACT 4 - GRANULOMA FORMATION (The "Jail Wall")

        CENTER
    ┌───────────────────────────────┐
    │   CASEOUS NECROSIS            │  ← cheesy dead material
    │   (caseation = "cheese")      │
    ├───────────────────────────────┤
    │   Epithelioid cells           │  ← activated macrophages
    │   + Multinucleated Giant      │  ← fused macrophages
    │     Cells (Langhans cells)    │
    ├───────────────────────────────┤
    │   Lymphocytes (CD4 T cells)   │  ← immune border
    ├───────────────────────────────┤
    │   Fibroblasts (outer wall)    │  ← scar tissue ring
    └───────────────────────────────┘
        OUTSIDE

🧠 Easy memory: "Granuloma = the body building a prison wall around TB. If the wall holds = latent TB. If the wall breaks = active TB"

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🎬 ACT 5 - PRIMARY COMPLEX & WHAT HAPPENS NEXT

1. Ghon focus - the original site of infection in the lung parenchyma
2. Lymphangitis - inflammation of the lymphatic vessel draining from it
3. Hilar lymphadenopathy - enlarged lymph node at the lung root

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PART 3: REACTIVATION TB (Post-Primary)

• The upper lobes have higher oxygen tension (more O₂)
• MTB is an aerobe - it loves oxygen
• Upper lobes also have less lymphatic drainage so immune cells don't arrive as quickly

Reactivation
     ↓
Upper lobe infiltrate / opacity
     ↓
Consolidation (area of lung filled with pus/cells)
     ↓
Caseation (central part becomes cheesy)
     ↓
Liquefaction (cheesy material softens)
     ↓
CAVITATION (wall breaks, cavity forms in lung)
     ↓
Bacteria spill into airways
     ↓
Patient coughs → spreads to others (infectious)
     ↓
Can spread to other parts of same lung (bronchopneumonia)

• Miliary TB - bacteria flood the bloodstream, create tiny (1-2mm) granulomas in EVERY organ (looks like millet seeds on X-ray)
• TB meningitis, TB spine (Pott's disease), TB kidney, TB pericarditis etc.

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SUMMARY FLOW CHART (The whole story)

Inhale MTB droplets
        ↓
Land in alveoli (middle/lower zones)
        ↓
Alveolar macrophage phagocytoses MTB
        ↓
MTB BLOCKS phagolysosome → survives and multiplies inside macrophage
        ↓
Bacteria spread to hilar lymph nodes → bloodstream → whole body (silent)
        ↓
3-9 weeks: Th1 immune response (IFN-γ, CD4+ T cells) + DTH response
        ↓
GRANULOMA FORMS (macrophages, epithelioid cells, giant cells, lymphocytes, caseous centre)
        ↓
      ╔══════════╗           ╔══════════╗
      ║ SUCCESS  ║           ║ FAILURE  ║
      ║ Ghon     ║           ║ Cavitation║
      ║ complex  ║           ║ Active TB ║
      ║ calcifies║           ║ Cough +   ║
      ║ Latent TB║           ║ infective ║
      ╚══════════╝           ╚══════════╝
           ↓                      ↓
    Reactivation later       Miliary TB / spread
    (if immunity drops)      to other organs

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QUICK EXAM MEMORY TRICKS 🧠

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