What is the diagnosis and treatment for Epstein-Barr virus (EBV) infection?

Epstein-Barr Virus (EBV) Diagnosis and Treatment

Epstein-Barr virus infection is diagnosed through specific serological testing and PCR viral load measurements, with treatment focused on supportive care for uncomplicated cases and targeted therapies for chronic active EBV infection or complications. 1, 2

Diagnosis of EBV Infection

Diagnostic Criteria

• Primary EBV infection (Infectious Mononucleosis)

  • Presence of IgG and IgM antibodies to viral capsid antigen (VCA)
  • Absence of antibodies to EBV nuclear antigens (EBNA)
  • Heterophile antibody testing (Monospot) is positive in ~85% of cases 3
  • Note: Paul-Bunnell and monospot tests are suboptimal; EBV-specific antibody testing is preferred 1

• Chronic Active EBV Infection (CAEBV) - Must fulfill all three criteria:

  1. Persistent or recurrent infectious mononucleosis-like symptoms
  2. Unusual pattern of anti-EBV antibodies (typically VCA-IgG ≥1:640 and EA-IgG ≥1:160) and/or increased EBV genomes in affected tissues
  3. Chronic illness unexplained by other known disease processes 1, 2

Laboratory Testing

• Recommended specific tests:

  • Quantitative PCR for EBV DNA in peripheral blood (>102.5 copies/mg DNA in PBMC indicates active infection)
  • In situ hybridization for EBV-encoded RNAs (EBERs)
  • Immunofluorescence for EBV nuclear antigens (EBNA) and latent membrane protein (LMP)
  • Southern blotting for EBV clonality 1
  • Unfractionated whole blood is the preferred specimen for EBV DNA monitoring 2

• Target cell identification:

  • Double staining to identify which cell types harbor the virus (B cells, T cells, NK cells, or monocytes/macrophages)
  • Important for prognosis, as T-cell infection is associated with poorer outcomes 1

Treatment Approaches

Uncomplicated Primary EBV Infection

• Supportive care:
  • Rest
  • Adequate hydration
  • Antipyretics and analgesics for symptom relief
  • Standard antiviral drugs have limited efficacy against latent EBV 2, 4

Severe or Complicated EBV Infection

• For fulminant infectious mononucleosis:

  • Consider combination of intravenous acyclovir and prednisolone 4
  • Valacyclovir may be considered for persistent fatigue with confirmed EBV reactivation (1.0-1.5g every 6 hours) 2

• For chronic active EBV infection:

  1. First-line therapy:

     • Immunomodulative therapy with prednisolone and cyclosporine A with or without etoposide 2
     • Rituximab 375 mg/m² IV weekly until EBV DNA-emia negativity (80% response rate) 2
     • Reduction of immunosuppression if applicable

  2. Second-line options:

     • Cellular therapy (EBV-specific cytotoxic T lymphocytes)
     • Allogeneic hematopoietic stem cell transplantation (HSCT) for refractory cases
     • Earlier initiation of HSCT is associated with better outcomes (87.3% 3-year survival when disease is controlled before transplant) 2

EBV-Associated Lymphoproliferative Disorders

• Treatment approach:
  • Reduction of immunosuppression when possible
  • Rituximab for CD20+ B-cell proliferations
  • Chemotherapy or radiation for established lymphomas 2, 4
  • PD-1 blockade (Sintilimab) combined with lenalidomide has shown 54.2% overall response rate 2

Monitoring and Follow-up

• Weekly EBV DNA monitoring by quantitative PCR for high-risk patients (transplant recipients, immunosuppressed)
• Regular follow-up every 4-8 weeks to monitor:
  • Clinical symptoms (fever, lymphadenopathy, hepatosplenomegaly)
  • Laboratory findings (EBV viral load)
  • Complications (lymphoproliferative disorders, hemophagocytic syndrome) 2

Special Considerations

• Post-exposure prophylaxis: Not typically indicated for EBV
• Pre-transplant screening: EBV serology recommended for all recipients and donors 2
• Gastrointestinal involvement: More severe in immunocompromised patients with intestinal disease, requiring individualized treatment and vigilant follow-up 5

Common Pitfalls

• Relying solely on heterophile antibody tests (Monospot) which can miss ~15% of cases
• Failure to identify target cells of EBV infection, which impacts prognosis
• Delayed recognition of complications such as hemophagocytic syndrome or lymphoproliferative disorders
• Inappropriate use of antivirals without clear evidence of benefit in uncomplicated cases