193.1 🎓 醫學生版

193.1.0.1 📌 一頁重點

• 菌: Mycobacterium tuberculosis — slow-growing acid-fast bacillus (AFB), aerobic, intracellular
• 流行病學:
  • 全球: 10.6M new cases, 1.3M deaths /年 (2023 WHO)
  • High burden: India, Indonesia, China, Philippines, Pakistan, Nigeria, Bangladesh
  • Taiwan: 5000+ cases/yr, 主要 elderly + reactivation; declining but persistent
• Transmission: airborne (droplet nuclei), prolonged close contact, indoor crowded
• Pathogenesis: 4 stages
  1. Inhalation → alveoli → macrophage uptake
  2. Initial replication → “Ghon focus” lung lesion
  3. Dissemination → granuloma formation (containment in immunocompetent)
  4. Reactivation (in 5-10% lifetime; 50%+ in HIV co-infection)
• Latent TB infection (LTBI): dormant, asymptomatic, IGRA / TST + only
  • Lifetime reactivation 5-10%
  • Higher: HIV, DM, CKD, anti-TNF, transplant, malnutrition, silicosis, < 5 yr or > 65 yr
• Active TB Forms:
  • Pulmonary:
    • Primary (immunologically naive — often missed): mild flu-like, may resolve
    • Reactivation/Post-primary: upper lobe cavitary, fibronodular, productive cough, hemoptysis, night sweats, weight loss
    • Miliary: hematogenous spread, “millet seed” diffuse small nodules
  • Extrapulmonary (15% in non-HIV, 40%+ in HIV):
    • Lymph node (cervical “scrofula” most common)
    • Pleural (effusion, exudative lymphocytic, ADA elevated)
    • GU (kidney, epididymis, salpingitis)
    • Spinal (Pott disease) — vertebral, cold abscess, kyphosis
    • Bone / joint
    • CNS: TB meningitis (basal, CN palsy), tuberculoma
    • Pericardial
    • GI / peritoneum (ascites, abdominal pain, “doughy” abdomen)
    • Skin (lupus vulgaris, scrofuloderma)
    • Adrenal — TB Addison’s disease historic cause
• Dx:
  • Active: AFB smear + culture + GeneXpert MTB/RIF PCR (1-2 hr, rifampin R)
  • LTBI: IGRA (QuantiFERON Gold, T-SPOT) preferred over TST (no BCG cross-reaction, less reader variability)
  • CXR, CT, biopsy for extrapulmonary
• Treatment:
  • Drug-sensitive: 2HRZE / 4HR (standard 6-month) OR 2024 WHO 4-month regimen (rifapentine + moxifloxacin + INH + PZA → rifapentine + moxi + INH)
  • MDR / Pre-XDR / XDR: BPaL / BPaLM × 6 mo (game changer)
  • LTBI: 3HP (weekly INH + rifapentine × 12 doses), 4R (rifampin × 4 mo), 6H/9H (INH × 6-9 mo)
• Vaccines:
  • BCG: live attenuated; ~ 50% efficacy for child TB meningitis + miliary; no proven efficacy adult pulmonary; given at birth in TB-endemic
  • M72/AS01E — Phase 3 ongoing (Gates Foundation) — promising vaccine candidate
• 2024 trends: AI-guided diagnostics, urine LAM (HIV with low CD4), molecular AST, BPaL universal availability

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193.1.0.2 1️⃣ 細菌學

• Mycobacterium tuberculosis — slow-growing rod (generation 18-24 hr vs 30 min E. coli)
• Acid-fast (mycolic acid in cell wall) — Ziehl-Neelsen / auramine stain
• Aerobic, intracellular (macrophage)
• Generation time + spore-like dormancy = explains long treatment courses
• Genome ~ 4.4 Mb
• Closely related species: M. bovis (cattle TB, also human via raw milk), M. africanum, M. canettii

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193.1.0.3 2️⃣ Transmission + Pathogenesis

193.1.0.3.1 Transmission

• Airborne droplet nuclei (1-5 µm)
• Prolonged close contact (hours of exposure typically)
• Crowded indoor settings (homeless shelter, prison, healthcare, schools, family)
• 1 untreated active patient = 10-15 transmissions/yr

193.1.0.3.2 Pathogenesis (Granuloma)

• Inhalation → alveolar macrophage uptake → intracellular replication
• Inflammation + cell-mediated immunity → granuloma (Th1 + macrophage + lymphocyte + central caseous necrosis)
• Ghon focus: primary lung lesion (subpleural lower / mid lobe)
• Ranke complex: Ghon focus + hilar LAP (primary TB complex)
• Caseous granuloma → liquefaction → cavity formation in reactivation TB (high O2 favors growth)

193.1.0.3.3 LTBI

• Successful immune containment but no eradication
• Bacilli dormant in macrophage, granuloma
• Lifetime reactivation 5-10% in healthy; 50%+ in HIV + co-infection
• Risk factors: HIV, DM, CKD/dialysis, immunosuppression (anti-TNF, steroid, transplant), malnutrition, silicosis, age extremes, post-gastrectomy, ileal bypass, head-neck cancer, leukemia

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193.1.0.4 3️⃣ Active TB — Clinical

193.1.0.4.1 A. Primary Pulmonary

• Often subclinical
• Mild flu-like, transient
• CXR: hilar LAP, mid-lower lobe consolidation
• Self-resolves in immunocompetent
• May progress: pleural effusion, miliary, dissemination in young / immunocompromised
• Children + HIV +: often progressive

193.1.0.4.2 B. Reactivation (Post-Primary) Pulmonary

• Upper lobe predominant (apical posterior or apical anterior segments)
• Cavitation common
• Fibronodular opacities
• Productive cough > 3 wk
• Hemoptysis (cavity erosion of vessel)
• Night sweats, weight loss, anorexia, low-grade fever — “B symptoms” mnemonic
• Progressive over weeks-months

193.1.0.4.3 C. Miliary TB

• Hematogenous dissemination
• CXR: bilateral diffuse small (1-3 mm) nodules (“millet seed”)
• Severe systemic: high fever, multi-organ
• Mortality high if untreated
• Common in HIV, elderly, immunosuppressed

193.1.0.4.4 D. Extrapulmonary

193.1.0.4.4.1 Lymphadenitis (“Scrofula”)

• Cervical (anterior + posterior cervical chain) most common
• Firm matted painless nodes ± draining sinus
• Children: more common
• Biopsy: caseating granuloma + AFB
• Treatment: standard regimen (don’t drain — excision can cause sinus tract)

193.1.0.4.4.2 Pleural

• Hypersensitivity reaction in primary infection (often without active pulmonary)
• Exudative, lymphocytic predominance, glucose normal/low, ADA > 40 suggestive
• Pleural biopsy higher yield than fluid AFB (paucibacillary)

193.1.0.4.4.3 Genitourinary

• 4-15% of EPTB
• “Sterile pyuria” — WBC in urine but neg routine culture
• Renal, bladder, epididymal, prostatic, salpingitis → infertility, ectopic
• Voided morning urine × 3 for AFB / PCR / culture

193.1.0.4.4.4 Skeletal (Pott Disease)

• Spine #1 (thoracolumbar) — vertebral destruction
• Cold abscess (psoas, paraspinal)
• Progressive kyphosis (“gibbus”)
• Neurologic compromise possible
• MRI spine + biopsy
• Treatment: TB regimen + sometimes surgery

193.1.0.4.4.5 CNS TB

• TB Meningitis: basal meninges, CN palsies (esp. CN VI), hydrocephalus, vasculitis (stroke)
• Subacute course (weeks)
• CSF: lymphocytic pleocytosis, high protein, low glucose, ADA elevated
• Mortality high without prompt Tx + steroid
• Steroid (dexamethasone) reduces mortality + morbidity (Cochrane meta-analysis)
• Tuberculoma: granulomatous mass; mimic tumor

193.1.0.4.4.6 Pericardial

• Pericardial effusion / tamponade
• Constrictive pericarditis sequela
• Steroid adjunct may reduce constrictive complication
• Pericardiocentesis + biopsy

193.1.0.4.4.7 Abdominal / Peritoneal

• “Doughy abdomen”, ascites
• Lymphadenitis, ileocecal involvement (mimic Crohn’s)
• Laparoscopy biopsy
• Stricture risk

193.1.0.4.4.8 Skin

• Lupus vulgaris (chronic), scrofuloderma (cervical extension), miliary tuberculides

193.1.0.4.4.9 Adrenal

• TB Addison’s disease historic cause
• Bilateral adrenal calcification on imaging

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193.1.0.5 4️⃣ 診斷

193.1.0.5.1 A. Sputum AFB Smear + Culture

• 3 specimens (different days) — increases sensitivity
• Smear: low sensitivity (50-60% in HIV-positive less)
• Culture: gold standard, 2-6 wk; AST takes another 1-2 wk
• Liquid culture (MGIT) faster than solid

193.1.0.5.2 B. GeneXpert MTB/RIF

• Rapid (1-2 hr) PCR-based
• Detects TB DNA + rifampin resistance simultaneously
• Sensitivity ~ 70-90% smear-positive; lower in smear-negative
• WHO first-line replacing smear in many settings
• Xpert MTB/XDR: extended R panel (INH, FQ, aminoglycoside, ethionamide)

193.1.0.5.3 C. Urine LAM (Lipoarabinomannan)

• POC dipstick test
• WHO recommended for HIV + low CD4 (< 200)
• High sensitivity in advanced HIV + disseminated TB
• Useful in resource-limited settings

193.1.0.5.4 D. LTBI Tests

• IGRA (Interferon-Gamma Release Assay) — QuantiFERON Gold, T-SPOT.TB
  • Preferred over TST in most situations
  • No BCG cross-reactivity
  • Single visit
• TST (Mantoux) — purified protein derivative (PPD)
  • 0.1 mL intradermal; read at 48-72 hr
  • Induration > 5 / 10 / 15 mm cutoffs based on risk
  • Boosting + booster effect in older patients
• Two-step TST for healthcare workers baseline (rule out booster)

193.1.0.5.5 E. Imaging

• CXR: cavity, upper-lobe, fibronodular, miliary
• CT: greater detail
• MRI: spine, brain
• PET-CT: extrapulmonary disease

193.1.0.5.6 F. Biopsy / Tissue

• Affected site (LN, pleura, peritoneum, bone, brain)
• Histology: caseating granuloma + AFB on Ziehl-Neelsen
• Send tissue for culture + GeneXpert + PCR

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193.1.0.6 5️⃣ Treatment

193.1.0.6.1 A. Drug-Sensitive Pulmonary TB

193.1.0.6.1.1 Standard 6-Month Regimen (Old Standard)

• Intensive phase (8 weeks): HRZE — Isoniazid + Rifampin + Pyrazinamide + Ethambutol daily
• Continuation phase (16 weeks): HR — Isoniazid + Rifampin daily or 3×/wk
• Total 6 months

193.1.0.6.1.2 2024 WHO 4-Month Regimen (Drug-Sensitive Non-Cavitary Smear-Neg)

• Intensive (8 wk): Rifapentine + Moxifloxacin + INH + PZA daily
• Continuation (9 wk): Rifapentine + Moxifloxacin + INH daily
• Total ~ 17 wk (4 months)
• Equivalent outcome to standard 6-month
• Adherence improvement

193.1.0.6.1.3 Cavitary Disease

• Standard 6-month
• Some advocate 9 months if smear-positive at 2 months

193.1.0.6.2 B. MDR-TB

• MDR: R to INH + Rifampin
• Pre-XDR: MDR + FQ R
• XDR: MDR + FQ R + bedaquiline/linezolid R (2021 update)

193.1.0.6.2.1 Old Regimens (Pre-2019)

• 18-24 months
• Multi-drug toxic
• ~ 50% cure

193.1.0.6.2.2 BPaL / BPaLM (2024 WHO First-Line for MDR/Pre-XDR/XDR)

• BPaL: Bedaquiline + Pretomanid + Linezolid × 6 months
• BPaLM: BPaL + Moxifloxacin (for some MDR retaining FQ susceptibility)
• 90% cure in XDR-TB (Nix-TB trial)
• Shorter, less toxic
• Outpatient feasible
• Game changer

193.1.0.6.3 C. CNS / TB Meningitis

• 9-12 month regimen (longer)
• Add steroid (dexamethasone): reduces mortality + morbidity
• Higher INH + rifampin doses considered
• Linezolid + moxifloxacin good penetration

193.1.0.6.4 D. Pericardial TB

• Standard regimen + steroid (reduces constrictive complications)

193.1.0.6.5 E. Pregnancy

• Standard regimen — RIPE all OK (some US caution PZA but WHO endorses)
• Streptomycin contraindicated
• Pyridoxine for INH

193.1.0.6.6 F. HIV + TB Co-infection

• ART critical
• TB treatment first if not on ART
• Start ART:
  • CD4 < 50: 2 wk after TB Tx (early ART)
  • CD4 ≥ 50: within 8 wk (intermediate)
  • CNS TB: caution — 4-8 wk (IRIS risk)
• Drug interactions: rifampin + ART → use rifabutin if needed; DTG-based ART compatible with rifampin

193.1.0.6.7 G. LTBI Treatment

• 3HP: INH + rifapentine weekly × 12 doses (preferred — best completion rate)
• 4R: rifampin daily × 4 months
• 9H: INH daily × 9 months (longer, less preferred)
• 6H: INH daily × 6 months (alt if 9H not tolerated)
• Choice based on:
  • HIV / ART
  • Pregnancy (3HP preferred)
  • Age (rifampin caution in elderly)
  • Drug interactions

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193.1.0.7 6️⃣ Prevention

193.1.0.7.1 BCG Vaccine

• Live attenuated M. bovis
• ~ 50% efficacy for child TB meningitis + miliary
• No proven efficacy adult pulmonary
• Given at birth in TB-endemic (Taiwan, etc.)
• USA: not routine
• IGRA preferred over TST in BCG-vaccinated

193.1.0.7.2 Infection Control (Healthcare)

• Negative-pressure isolation
• N95 respirators
• UV light
• Annual TST/IGRA for HCW
• Mask cough patients

193.1.0.7.3 Active Case Finding

• Symptom screen (cough > 2 wk, weight loss, night sweats)
• CXR + GeneXpert in high-risk populations
• HIV + + DM + + dialysis + contacts

193.1.0.7.4 LTBI Screening Programs

• High-risk groups: HIV, contacts of active cases, immigrants from high-burden, healthcare workers, immunosuppressed, transplant candidates, anti-TNF candidates
• Annual IGRA / TST + Tx if +

193.1.0.7.5 M72/AS01E + Other Vaccines

• M72/AS01E — Phase 3 (Gates Foundation) — promising
• BCG revaccination some evidence in adolescent
• mRNA vaccine candidates in trials

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