201.1 🎓 醫孞生版

201.1.0.1 📌 䞀頁重點

201.1.0.1.1 HHV-6 + HHV-7 (β-subfamily)
  • Universal infection in early childhood (90%+ by age 3)
  • HHV-6A + HHV-6B (distinct species since 2012); HHV-6B causes most disease
  • Primary infection (roseola):
    • “Exanthem subitum” / “sixth disease” (HHV-6B mostly)
    • 6-15 mo old, 3-5 days high fever 39-40°C → defervescence → maculopapular rash on trunk appears as fever resolves
    • Self-limited; most common cause of febrile seizures in this age
  • Reactivation in immunocompromise (HSCT especially):
    • HHV-6 encephalitis post-HSCT — limbic encephalitis, amnesia, seizures, hyponatremia (SIADH)
    • Cytopenia, fever, pneumonitis, hepatitis
  • Treatment: ganciclovir or foscarnet (in vitro active); no FDA-approved indication; off-label HSCT context
  • HHV-7: similar to HHV-6, mostly mild
  • Inherited Chromosomally Integrated HHV-6 (ciHHV-6): 1% population — integrated into germline, persistent high blood PCR but not active infection — important not to misinterpret PCR as active disease
201.1.0.1.2 HHV-8 (Kaposi’s Sarcoma-Associated Herpesvirus, KSHV) (γ-subfamily)
  • Endemic in sub-Saharan Africa, Mediterranean, Middle East; sporadic elsewhere
  • Sexually transmitted in MSM; also vertical, blood, transplant
  • Associated diseases:
    • Kaposi’s Sarcoma (KS) — 4 forms:
      • Classic KS: elderly Mediterranean/Jewish men; lower extremity nodules; indolent
      • Endemic (African) KS: African children + adults; aggressive in children
      • Iatrogenic KS: transplant immunosuppression
      • AIDS-related KS: HIV CD4 < 200; aggressive multifocal
    • Primary Effusion Lymphoma (PEL): HIV + KS context; body cavity effusions (pleural, pericardial, peritoneal); aggressive
    • Multicentric Castleman Disease (MCD): HIV + or HIV -; fever + LAP + cytopenia + organomegaly; lethal flares
    • KSHV Inflammatory Cytokine Syndrome (KICS): severe ICU presentation
  • Treatment:
    • KS in HIV: ART + chemotherapy (PEGylated liposomal doxorubicin, paclitaxel) for advanced
    • PEL: aggressive chemo (CHOP-based + rituximab); poor prognosis
    • MCD: rituximab (anti-CD20) — primary
    • KICS: supportive + treatment of KS/MCD + immune therapies

201.1.0.2 1⃣ HHV-6 + HHV-7

201.1.0.2.1 Microbiology
  • β-subfamily herpesviruses
  • HHV-6A + HHV-6B (since 2012 distinct species)
  • HHV-6B causes most disease
  • HHV-7 closely related
  • Lymphotropic (T cells, monocytes)
  • Universal seroprevalence
201.1.0.2.2 Transmission
  • Saliva primary (universal exposure childhood)
  • Vertical (intrauterine, intrapartum)
  • Transplant via grafted tissue
  • Inherited chromosomally integrated form (ciHHV-6): 1% population — chromosomal integration into germline, transmitted Mendelian
201.1.0.2.3 Primary Infection (Roseola Infantum / Exanthem Subitum)
  • HHV-6B most cases
  • 6-15 mo old typical
  • 3-5 days high fever 39-40°C
  • No source of fever found on exam (rules out UTI, pneumonia, etc.)
  • Fever defervesces → maculopapular blanching rash on trunk appears 1-2 days later
  • Self-limited
  • Most common cause of febrile seizures in this age group (10% of HHV-6 primary infections have seizures)
  • 5th-6th disease confusion:
    • 5th disease = parvovirus B19 (slapped cheek)
    • 6th disease = HHV-6 (roseola)
201.1.0.2.4 Reactivation in Immunocompromise
  • HSCT particularly (50%+ reactivate in first months)
  • HHV-6 encephalitis post-HSCT:
    • 1-2% post-transplant
    • 30-60 days post-transplant typically
    • Limbic encephalitis: amnesia, seizures, hyponatremia (SIADH from limbic)
    • MRI: medial temporal T2 hyperintensity
    • CSF PCR + (BUT can also be from ciHHV-6 reactivation — interpret with caution)
    • Mortality high if untreated
    • Treatment: foscarnet or ganciclovir
201.1.0.2.5 Other Reactivation Syndromes
  • Pneumonitis: similar to CMV
  • Cytopenia (marrow suppression)
  • Hepatitis
  • DRESS / DIHS (Drug Reaction with Eosinophilia and Systemic Symptoms): HHV-6 reactivation triggered by drug; allopurinol, anticonvulsants common precipitants
  • HHV-6 + Multiple Sclerosis — proposed but unclear
201.1.0.2.6 Inherited Chromosomally Integrated HHV-6 (ciHHV-6)
  • 1% of population
  • HHV-6 genome integrated into telomeres → transmitted Mendelian
  • Persistent high blood viral load (10,000+ copies/mL whole blood)
  • Not active infection — but easily misinterpreted as active
  • Difficult to distinguish from active reactivation
  • Tissue / CSF PCR better than blood for diagnosing active disease in ciHHV-6 patients
  • Implications: don’t reflexively treat high HHV-6 viral load — confirm clinical disease
201.1.0.2.7 Diagnosis
  • Quantitative PCR of blood / CSF / tissue
  • IgM (acute primary)
  • Cell culture rarely used
  • Distinguish ciHHV-6 with cell-specific or hair follicle PCR (germline carriage)
201.1.0.2.8 Treatment
  • Ganciclovir / Valganciclovir — in vitro active
  • Foscarnet — alternative
  • Cidofovir — alternative
  • No FDA-approved indication for HHV-6 specifically
  • Off-label HSCT encephalitis treatment

201.1.0.3 2⃣ HHV-7

  • Closely related to HHV-6
  • Universal infection (90%+ by age 3)
  • Mostly subclinical
  • Sometimes exanthem subitum-like illness
  • Reactivation in immunocompromise possible but less clinical significance
  • Treatment: ganciclovir / foscarnet if needed

201.1.0.4 3⃣ HHV-8 (KSHV, Kaposi’s Sarcoma-Associated Herpesvirus)

201.1.0.4.1 Microbiology
  • γ-subfamily (like EBV)
  • B-cell + endothelial cell tropism
  • Latency in B cells
201.1.0.4.2 Epidemiology
  • Endemic regions: sub-Saharan Africa, Mediterranean, Middle East
  • Sexual transmission in MSM (saliva primarily)
  • Vertical
  • Blood / transplant
  • HIV + 50-60% seropositive in some MSM cohorts vs 1-5% general
201.1.0.4.3 Associated Diseases
201.1.0.4.3.1 Kaposi’s Sarcoma (KS) — 4 Forms
201.1.0.4.3.2 Classic KS
  • Elderly Mediterranean / Jewish men
  • Lower extremity nodules / plaques
  • Indolent — slow progression
  • Local Tx: cryotherapy, intralesional vinblastine, radiation
201.1.0.4.3.3 Endemic (African) KS
  • Sub-Saharan Africa endemic prior to HIV
  • 4 patterns: nodular (indolent), florid, infiltrative, lymphadenopathic (children — aggressive)
201.1.0.4.3.4 Iatrogenic KS
  • Transplant immunosuppression
  • 50-100× ↑ risk
  • Often regress with immunosuppression reduction
  • Switching to mTOR inhibitors (sirolimus, everolimus) has anti-KS effect
201.1.0.4.3.6 KS Lesion Types
  • Patch: pink-purple flat
  • Plaque: raised, mature
  • Nodular: erythematous-violaceous
201.1.0.4.3.7 Treatment Options
  • ART (HIV-related)
  • Reduce immunosuppression + mTOR inhibitor switch (transplant-related)
  • Intralesional vinblastine for limited
  • Cryotherapy, laser, radiation for localized
  • Systemic chemo: PEGylated liposomal doxorubicin, paclitaxel (advanced visceral)
  • Imatinib: limited efficacy
  • Bevacizumab, pomalidomide: emerging
  • Anti-PD-1 ICI: some response especially with cabozantinib
201.1.0.4.3.8 Primary Effusion Lymphoma (PEL)
  • Body cavity B-cell lymphoma
  • Pleural, pericardial, peritoneal effusions
  • HHV-8 + + EBV + often (co-infection)
  • HIV + KS context
  • Aggressive — median survival 6 months even with treatment
  • Treatment: CHOP-based + rituximab (despite CD20 absent on many cells); ART
  • Cidofovir adjunct?
201.1.0.4.3.9 Multicentric Castleman Disease (MCD)
  • HIV + or HIV -
  • Plasmablastic variant = HHV-8 driven
  • Fever + LAP + cytopenia + organomegaly + ascites
  • Episodic flares
  • Often life-threatening in flares
  • Treatment: Rituximab (primary); siltuximab (anti-IL-6); chemotherapy
201.1.0.4.3.10 KICS (KSHV Inflammatory Cytokine Syndrome)
  • ICU presentation in HIV / immunocompromise
  • Fever + cytopenia + cytokine storm
  • 鑑別 sepsis + HLH + MCD
  • Treat KSHV-MCD + supportive

201.1.0.5 4⃣ Diagnosis

201.1.0.5.1 HHV-8
  • Tissue / blood KSHV PCR
  • IHC for LANA-1 nuclear antigen (KS biopsy)
  • Anti-LANA serology (research)
201.1.0.5.2 KS Biopsy
  • Spindle cells + slit-like vascular channels
  • LANA-1 nuclear staining (HHV-8 IHC) diagnostic

201.1.0.6 5⃣ Treatment Summary

Disease Treatment
HHV-6 roseola Supportive
HHV-6 HSCT encephalitis Foscarnet or ganciclovir
HHV-6 DRESS Supportive + remove offending drug
ciHHV-6 incidental finding No treatment unless clinical disease
Classic KS Local therapy + observation
AIDS KS ART + chemo if advanced (PEG-liposomal doxorubicin, paclitaxel)
Transplant KS Reduce immunosuppression + switch to mTOR inhibitor
PEL Aggressive chemo + ART
MCD Rituximab + siltuximab
KICS Supportive + treatment KS/MCD