199.1 🎓 醫學生版

199.1.0.1 📌 一頁重點

• Virus: dsDNA, Herpesviridae γ-subfamily, lymphotropic (B cells + epithelial cells)
• Universal infection (90-95% adults seropositive worldwide)
• Transmission: saliva (“kissing disease”), sexual, blood/transplant
• Latency in memory B cells (lifelong); also epithelial cells
• Primary infection:
  • Childhood: usually asymptomatic
  • Adolescent/young adult: infectious mononucleosis (IM) classic
• IM Triad: fever + pharyngitis + LAP (posterior cervical + generalized) + splenomegaly (50%)
• Lab clue: atypical lymphocytes (reactive T cells responding to EBV-infected B cells) + heterophile + (Monospot)
• Complications: 脾破 (splenic rupture — rare but emergent), airway obstruction (tonsillar swelling), AIHA, ITP, EBV encephalitis, GBS, hepatitis, HLH
• Diseases / Cancer Associations:
  • Burkitt lymphoma (endemic Africa, jaw mass)
  • Nasopharyngeal carcinoma (Asia, S China)
  • Gastric carcinoma (~ 10% EBV-positive)
  • Hodgkin lymphoma (~ 40% EBV-positive)
  • NK/T-cell lymphoma
  • Post-Transplant LPD (PTLD) — major transplant complication
  • Primary CNS lymphoma in HIV
  • HIV-associated lymphomas (Burkitt-like, DLBCL)
• X-linked LPD (XLP): SH2D1A / SAP mutation → fulminant IM, hemophagocytic syndrome, lymphoma
• 2022 game changer (Bjornevik et al., Science): EBV serology + risk of multiple sclerosis (MS) — strong association suggests EBV may be necessary trigger
• Treatment:
  • IM: supportive (rest, fluids, acetaminophen); contact sports restriction × 3-4 wk (splenic rupture); avoid amoxicillin (causes rash in EBV — pathognomonic!)
  • PTLD: reduce immunosuppression + rituximab + EBV-specific T cells + chemo
  • CNS lymphoma in HIV: ART + methotrexate/whole-brain radiation
  • No effective antiviral for typical EBV (acyclovir minimal effect)

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199.1.0.2 1️⃣ Virology

• dsDNA herpesvirus
• Two clinically distinct latency programs: Latency I, II, III (different gene expression)
• Genome ~ 172 kb, ~ 90 genes
• Key proteins: EBNA-1 (maintains genome), LMP-1 (oncoprotein), LMP-2A/B
• Latency in memory B cells primary; epithelial cells in oropharynx for shedding

199.1.0.2.1 Cell Entry

• B cell: CD21 (CR2 receptor) + gp350 binding → endocytosis → fusion via gp42 + HLA-II
• Epithelial: integrins
• Transformation of B cells → continuous proliferation (essential to disease + cancer)

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199.1.0.3 2️⃣ Primary Infection

199.1.0.3.1 Childhood Acquisition

• Most childhood EBV infection asymptomatic
• 50% seropositive by age 5 in developed countries; nearly universal by adolescence

199.1.0.3.2 Infectious Mononucleosis (IM)

• Classic in adolescent / young adult primary infection (developed countries)
• Triad: fever + pharyngitis + lymphadenopathy
• Posterior + anterior cervical LAP, axillary, inguinal
• Splenomegaly ~ 50%
• Hepatosplenomegaly 10%
• Hepatitis (mild transaminitis common)
• Atypical lymphocytes on smear — reactive T cells responding to EBV-infected B cells (10-50% of lymphocytes)
• Heterophile antibody (Monospot) + 90% in classic IM
• Petechiae on soft palate (clue)
• Rash with amoxicillin (~ 90% develop rash if given amoxicillin during EBV — pathognomonic of EBV; NOT true penicillin allergy)
• 2-4 wk duration; fatigue often longer

199.1.0.3.3 Complications

• Splenic rupture (rare but emergent) — RUQ pain, hypotension, shock; avoid contact sports × 3-4 wk
• Airway obstruction (severe tonsillar swelling) — steroid + airway management
• Autoimmune cytopenia (AIHA, ITP — cold agglutinins)
• Encephalitis (rare, post-infectious)
• Hepatitis (severe rare)
• GBS (post-infectious)
• Hemophagocytic lymphohistiocytosis (HLH) — especially in immunocompromise, XLP

199.1.0.3.4 Diagnosis

• Monospot (heterophile Ab) — 90% sens classic IM; negative in young children
• EBV-specific serology:
  • VCA IgM + EA + → acute
  • VCA IgG + → past or acute
  • EBNA IgG + → past (appears 3-6 mo after primary)
• Atypical lymphocytes on smear
• Lymphocytosis typical
• CBC + LFT + LDH
• PCR for EBV DNA in immunocompromise / transplant monitoring

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199.1.0.4 3️⃣ EBV-Associated Cancers

199.1.0.4.1 Burkitt Lymphoma

• Endemic Burkitt (Africa, sub-Saharan): jaw mass, EBV-associated, t(8;14) c-myc translocation
• Sporadic Burkitt (Europe, USA): abdominal mass, EBV less commonly
• HIV-associated Burkitt
• Children + young adult predominant
• Treatment: intensive chemotherapy (e.g., R-EPOCH); CR rate 80%+

199.1.0.4.2 Nasopharyngeal Carcinoma (NPC)

• S China, SE Asia, N Africa endemic
• Strong EBV association in all cases (regardless of geography)
• Smoking, salted fish (Cantonese), genetic susceptibility
• Cervical mass, nasal obstruction, hearing loss, headache
• Treatment: chemoradiation; cisplatin-based
• Plasma EBV DNA load = prognostic + monitoring biomarker
• Taiwan high-incidence — screening high-risk possible

199.1.0.4.3 Gastric Carcinoma

• ~ 10% gastric cancers EBV-positive
• Distinct molecular subtype (immune cell infiltration)
• Better prognosis

199.1.0.4.4 Hodgkin Lymphoma

• ~ 40% classical Hodgkin EBV-positive (LMP-1 expression in Reed-Sternberg cells)
• Mixed cellularity > nodular sclerosing
• Treatment: ABVD chemotherapy + radiation

199.1.0.4.5 NK/T-cell Lymphoma

• Nasal + extranodal types
• Asia high incidence
• Strong EBV association
• Aggressive course

199.1.0.4.6 Post-Transplant LPD (PTLD)

• Major transplant complication (solid organ + HSCT)
• EBV reactivation in immunocompromise → uncontrolled B cell proliferation → polyclonal → monoclonal lymphoma
• Risk: EBV-naive recipient + EBV-positive donor (esp. pediatric, intestinal/lung transplant)
• Sx: fever + LAP + organ dysfunction + EBV viremia
• Treatment:
  • Reduce immunosuppression
  • Rituximab (anti-CD20)
  • EBV-specific T cells (adoptive transfer)
  • Chemotherapy if monoclonal high-grade
• Surveillance EBV PCR in high-risk transplant

199.1.0.4.7 Primary CNS Lymphoma (PCNSL) in HIV

• AIDS + CD4 < 50
• Single or multi-focal brain lesions
• Strong EBV association
• Treatment: ART + methotrexate or whole-brain radiation
• CSF EBV PCR diagnostic clue
• Differential: toxoplasmosis (multi-ring enhancing — empirical Tx if + serology; if no improvement → biopsy for PCNSL)

199.1.0.4.8 Other Associated Cancers

• Smooth muscle tumors in HIV + transplant
• Leiomyosarcoma
• DLBCL especially in immunocompromise

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199.1.0.5 4️⃣ Special Conditions

199.1.0.5.1 X-Linked Lymphoproliferative Disease (XLP)

• SH2D1A / SAP gene mutation
• Fulminant IM with hemophagocytosis
• High mortality
• Predisposition to lymphoma, dysgammaglobulinemia
• HSCT curative

199.1.0.5.2 Chronic Active EBV (CAEBV)

• Persistent EBV viremia + multi-organ involvement
• Asia predominant (Japan)
• High mortality without HSCT

199.1.0.5.3 Hemophagocytic Lymphohistiocytosis (HLH)

• EBV common trigger (especially in XLP, NK/T-cell dysfunction)
• Treatment: HLH-94 protocol (etoposide + dexamethasone + cyclosporine)

199.1.0.5.4 Multiple Sclerosis Association (2022 Game Changer)

• Bjornevik et al. Science 2022 — large US Military cohort:
  • EBV seroconversion preceded MS in ~ all cases
  • 32-fold increased MS risk after EBV infection
  • Other viruses no such association
• Strongly suggests EBV is necessary (not sufficient) for MS development
• Mechanism: molecular mimicry (EBNA-1 + GlialCAM CNS protein) — Lanz et al. Nature 2022
• Implication: EBV vaccine + therapeutic targeting may prevent MS

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199.1.0.6 5️⃣ Treatment

199.1.0.6.1 IM (Healthy)

• Supportive: rest, fluids, acetaminophen, NSAID
• Contact sports avoidance × 3-4 wk (splenic rupture)
• Avoid amoxicillin (90% develop rash — not allergic but pathognomonic)
• Corticosteroid for severe complications:
  • Airway obstruction (massive tonsillar swelling)
  • Severe autoimmune cytopenia
  • Severe systemic complications
  • Not for uncomplicated IM (no benefit on duration)

199.1.0.6.2 Severe / Complications

• Splenic rupture: emergent surgery + transfusion
• Encephalitis: supportive; acyclovir uncertain benefit
• AIHA / ITP: steroid + IVIG + rituximab if severe
• HLH: HLH-94 protocol
• EBV viremia in immunocompromise: reduce immunosuppression + rituximab + EBV-specific T cells

199.1.0.6.3 PTLD

• Reduce immunosuppression first
• Rituximab (anti-CD20)
• EBV-specific cytotoxic T cells (CTL infusion, adoptive transfer) — game changer for refractory cases
• Chemotherapy for high-grade
• Surveillance EBV PCR

199.1.0.6.4 CNS Lymphoma in HIV

• ART critical
• High-dose methotrexate (mainstay)
• Whole-brain radiation alternative
• Rituximab adjunct
• Prognosis poor historically but improving with ART era

199.1.0.6.5 Acyclovir

• Minimal effect against EBV in vivo
• Not recommended for typical IM
• May reduce viral shedding but no clinical benefit

199.1.0.6.6 Vaccines

• In development
• gp350 subunit, mRNA candidates 2024
• Therapeutic + prophylactic approaches
• Goal: prevent IM, lymphoma, MS

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