200.1 🎓 醫學生版

200.1.0.1 📌 一頁重點

• Virus: dsDNA, Herpesviridae β-subfamily (largest herpesvirus genome ~ 235 kb)
• Tropism: epithelial cells + endothelial + fibroblasts + monocytes
• Latency: monocytes/macrophages + CD34+ progenitor cells
• Transmission: saliva, urine, blood, semen, breast milk, organ/tissue transplant, intrauterine (vertical)
• Universal infection (50-90% adults seropositive)
• Primary infection:
  • Healthy: usually asymptomatic; sometimes mononucleosis-like (CMV mono — older + less LAP than EBV IM)
• Congenital CMV:
  • #1 infectious cause of birth defects globally
  • 0.5-2% of all live births
  • 10% symptomatic at birth: hearing loss + microcephaly + chorioretinitis + intracerebral calcifications + hepatosplenomegaly + petechiae + jaundice
  • 90% asymptomatic at birth but 10% develop hearing loss / developmental issues
  • #1 non-genetic cause of sensorineural hearing loss
• Immunocompromised:
  • CMV retinitis — HIV CD4 < 50 (pizza pie fundus); pretreatment ophthalmology screening
  • CMV pneumonia — HSCT + lung transplant (severe, mortality high)
  • CMV colitis — HIV CD4 < 100; severe, can cause perforation
  • CMV esophagitis — endoscopy linear ulcers (vs Candida, HSV)
  • CMV hepatitis
  • CMV encephalitis
  • CMV polyradiculomyelitis — HIV AIDS
• Diagnosis:
  • Quantitative PCR of blood (viral load) — clinical decision-making
  • Tissue biopsy with IHC for organ-specific (colitis, pneumonia) — “owl’s eye” intranuclear inclusions
  • Serology (IgM acute, IgG past) — primary infection diagnosis
  • Antigenemia (pp65) — historical
• Treatment:
  • Ganciclovir / Valganciclovir — most common; myelosuppression
  • Foscarnet — refractory/resistant; nephro + electrolyte toxic
  • Cidofovir — alternative; severe nephrotoxic
  • Letermovir (2017) — terminase inhibitor; NO marrow toxicity; CMV prophylaxis post-HSCT
  • Maribavir (2021) — UL97 kinase inhibitor; refractory/resistant CMV; dysgeusia common
• Prevention:
  • Transplant: prophylaxis or pre-emptive monitoring
  • Pregnancy: hygiene (kids’ saliva); test (controversial)
  • Hyperimmune globulin in congenital prevention (controversial, limited efficacy)

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200.1.0.2 1️⃣ Virology

• dsDNA herpesvirus, β-subfamily (slow growth)
• Largest herpesvirus genome (~ 235 kb, ~ 165 genes)
• Replicates in many cell types (epithelial, endothelial, fibroblast, monocyte)
• Latency in monocytes/macrophages + CD34+ progenitor cells
• Cell-mediated immunity (CD8+ T cells) keeps in check
• Massive immune evasion: 20+ genes targeting MHC I, NK cells, cytokine signaling

200.1.0.2.1 Resistance Mechanisms

• UL97 mutations (kinase) → ganciclovir resistance (M460I, A594V, L595S, C603W common)
• UL54 mutations (polymerase) → cidofovir + foscarnet resistance
• Cross-resistance patterns important

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200.1.0.3 2️⃣ Primary Infection in Healthy Hosts

• Mostly asymptomatic
• CMV mononucleosis (~ 10% of mono-like illness):
  • Older age than EBV IM (20s-40s)
  • Less LAP / pharyngitis than EBV
  • More hepatitis-dominant
  • Monospot negative
  • Mild atypical lymphocytes
  • Fever + malaise weeks-months

200.1.0.3.1 Diagnosis

• CMV IgM + (primary)
• CMV PCR (blood) + (active)
• IgG seroconversion (paired sera)

200.1.0.3.2 Treatment

• Healthy: supportive
• Severe / persistent: ganciclovir / valganciclovir

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200.1.0.4 3️⃣ Congenital CMV

200.1.0.4.1 Epidemiology

• 0.5-2% live births
• Most common congenital viral infection
• #1 infectious cause of birth defects globally
• ~ 10% symptomatic at birth, 90% asymptomatic

200.1.0.4.2 Transmission

• Primary maternal infection during pregnancy → 30-40% transmission to fetus
• Non-primary (reactivation/reinfection) → 1-2% transmission
• Worst outcomes with 1st trimester primary

200.1.0.4.3 Clinical at Birth

• Symptomatic (10%):
  • Intrauterine growth restriction
  • Microcephaly
  • Intracerebral calcifications (periventricular)
  • Hepatosplenomegaly
  • Hyperbilirubinemia
  • Thrombocytopenia, petechiae
  • Sensorineural hearing loss (SNHL)
  • Chorioretinitis
• Asymptomatic at birth but late sequelae (10-15%):
  • Sensorineural hearing loss (delayed onset, progressive) — most common
  • Visual impairment
  • Developmental delay
  • Cognitive deficits

200.1.0.4.4 Diagnosis

• Newborn urine or saliva CMV PCR within 21 days of birth (gold standard)
• After 21 days: difficult to distinguish congenital vs perinatal

200.1.0.4.5 Treatment

• Valganciclovir 16 mg/kg PO bid × 6 months for symptomatic congenital CMV
• Improves hearing + neurodevelopmental outcomes (Kimberlin trial 2015)
• Toxicity: neutropenia → CBC monitoring weekly
• Asymptomatic: no proven treatment benefit; surveillance for delayed hearing loss

200.1.0.4.6 Prevention

• Hygiene for pregnant women in contact with young children (toddler saliva — saliva-saliva is main maternal transmission route)
• Avoid kissing on mouth, sharing utensils/cups, change diaper without handwashing
• Universal congenital CMV screening — controversial (some states implementing — Utah, IL, NY)
• Hyperimmune globulin prevention — mixed trial results

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200.1.0.5 4️⃣ Immunocompromised Hosts

200.1.0.5.1 A. HIV / AIDS

200.1.0.5.1.1 CMV Retinitis

• CD4 < 50 primary risk
• Floaters, blurred vision, visual field defects
• “Pizza pie” fundus: white retinitis lesions + hemorrhage
• Emergent ophthalmology consult
• Early ART + valganciclovir
• Risk of retinal detachment

200.1.0.5.1.2 CMV Colitis

• CD4 < 100
• Bloody diarrhea, abdominal pain, fever
• Endoscopy: linear ulcers
• Biopsy + IHC for CMV inclusions
• Treatment: ganciclovir / valganciclovir + ART

200.1.0.5.1.3 CMV Esophagitis

• Endoscopy: linear ulcers (vs Candida thrush, vs HSV punched-out)
• Biopsy + IHC

200.1.0.5.1.4 CMV Encephalitis / Polyradiculomyelitis

• Rare, late HIV
• CSF PCR
• Ganciclovir + foscarnet combo
• Difficult to treat

200.1.0.5.2 B. Transplant (HSCT + SOT)

200.1.0.5.2.1 Risk Stratification

• HSCT: highest risk first 100 days; reactivation > primary
• SOT: D+/R- highest (CMV-naive recipient + CMV-positive donor)
• Anti-thymocyte globulin / OKT3 = high-risk induction
• Late CMV: 6-12 mo post-transplant

200.1.0.5.2.2 Prophylaxis vs Pre-emptive

• Prophylaxis: ganciclovir/valganciclovir or letermovir × 100 days (HSCT) or 100-200 days (SOT)
• Pre-emptive: serial PCR monitoring; treat if rising titer
• Letermovir = newer option for prophylaxis (no marrow toxicity)

200.1.0.5.2.3 CMV Pneumonia

• HSCT + lung transplant primarily
• Severe — high mortality
• Treatment: ganciclovir + CMV IVIG (Cytogam) — combination
• Lung biopsy + IHC

200.1.0.5.2.4 CMV Disease (Diverse Organs)

• Hepatitis, pancreatitis, esophagitis, colitis, encephalitis, retinitis, marrow suppression
• All in immunocompromise

200.1.0.5.2.5 CMV Syndrome

• Fever + cytopenia + transaminitis + viremia (no organ-specific disease)

200.1.0.5.3 C. CMV in Solid Organ Transplant — D+/R-

• Highest risk for primary CMV disease
• Universal prophylaxis valganciclovir 100-200d
• After prophylaxis: monitor PCR

200.1.0.5.4 D. Letermovir Era (2017+)

• HSCT CMV prophylaxis revolutionized
• 480 mg PO qd × 100 days post-HSCT
• 60% reduction in clinically significant CMV infection (Marty trial)
• NO myelosuppression — major advantage
• Now expanding to SOT prophylaxis

200.1.0.5.5 E. Maribavir for Refractory/Resistant (2021+)

• UL97 kinase inhibitor (different from ganciclovir mechanism)
• Effective against ganciclovir-R CMV
• 400 mg PO bid × 8 weeks
• Dysgeusia prominent side effect
• ID + transplant specialist

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200.1.0.6 5️⃣ Diagnosis

200.1.0.6.1 A. Quantitative PCR

• Blood plasma CMV DNA = gold standard for clinical decision-making
• Sensitivity high
• Quantitative → trends + treatment response
• Threshold for treatment varies by institution (typically 100-1000 IU/mL)

200.1.0.6.2 B. Tissue Biopsy + IHC

• Confirms organ-specific CMV disease
• Owl’s eye intranuclear inclusion in epithelial cells
• IHC stain for CMV antigens
• Required for definitive CMV colitis, pneumonia, etc.

200.1.0.6.3 C. Serology

• IgM (acute primary)
• IgG (past or recent — paired sera)

200.1.0.6.4 D. Antigenemia (pp65)

• Historical; replaced by PCR
• Detects CMV antigen in PBMCs

200.1.0.6.5 E. Viral Culture

• Slow (1-2 wk); rare clinical use now

200.1.0.6.6 F. Resistance Testing

• Genotypic (PCR + sequencing of UL97, UL54)
• Done in suspected resistance (rising titer on treatment)

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200.1.0.7 6️⃣ Treatment Summary

Form	Drug
CMV retinitis (HIV)	Valganciclovir 900 mg PO bid × 21d → 900 qd maintenance (+ ART)
CMV colitis / esophagitis / pneumonia	Ganciclovir/valganciclovir × 21d
CMV encephalitis	Ganciclovir + foscarnet combo
Refractory/resistant	Maribavir or foscarnet or cidofovir
HSCT prophylaxis	Letermovir 480 mg qd × 100d
SOT prophylaxis	Valganciclovir 900 mg qd × 100-200d
Congenital symptomatic	Valganciclovir 16 mg/kg PO bid × 6 mo
Severe / IV	Ganciclovir 5 mg/kg IV q12h × 2 wk → maintenance

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