How is Epstein Barr virus (EBV) infection diagnosed and managed?

Diagnosis and Management of Epstein-Barr Virus (EBV) Infection

Primary EBV infection is diagnosed by detecting IgM and IgG antibodies against the EBV viral capsid antigen (VCA) with negative EBNA1 IgG, while past infection is indicated by positive VCA IgG and EBNA antibodies with negative VCA IgM. 1, 2

Diagnostic Approach

Serological Testing

• The most reliable diagnostic approach includes:

  • EBV-specific antibody panel:
    • VCA IgM: Positive in acute infection
    • VCA IgG: May be positive in acute infection, positive in past infection
    • EBNA IgG: Negative in acute infection, appears weeks to months later, positive in past infection 1, 2

• Avoid relying on:

  • Paul-Bunnell and monospot tests (suboptimal sensitivity) 1
  • Heterophile antibody tests alone (can miss cases, especially in children) 2

Molecular Testing

• Quantitative PCR for EBV DNA in peripheral blood is recommended for:

  • Immunocompromised patients
  • Transplant recipients
  • Patients on immunosuppressive therapy 1, 2

• Monitoring frequency:

  • Start within first month post-transplant
  • Continue weekly for at least 4 months
  • More frequent sampling for rising EBV DNA-emia 1

Tissue Diagnosis

• For suspected lymphoproliferative disorders:
  • Biopsy of enlarged lymph nodes or affected tissues
  • EBER in situ hybridization (high sensitivity and specificity) 1
  • Immunohistochemistry for EBV proteins (e.g., LMP1) has lower sensitivity 1

Management Approach

For Immunocompetent Patients with Acute EBV Infection

1. Supportive care is the mainstay of treatment:

   • Adequate hydration
   • Rest
   • Analgesics/antipyretics for symptom relief 2

2. Antiviral therapy:

   • Not recommended for uncomplicated cases
   • Aciclovir does not ameliorate the course of infectious mononucleosis 1

For Immunocompromised Patients

Risk Assessment

• Pre-transplant:
  • Screen all transplant recipients and donors for EBV serology 1, 2
  • Identify high-risk patients (T-cell depletion, EBV mismatch, cord blood transplant) 1

Monitoring

• Weekly EBV DNA monitoring by quantitative PCR for high-risk patients 1, 2
• Continue for at least 4 months post-transplant 1

Management of EBV Reactivation

1. Reduction of immunosuppression (if possible) 2

2. Preemptive therapy for significant EBV DNA-emia:

   • Rituximab 375 mg/m² IV weekly until EBV DNA-emia negativity 2
   • Typically requires 1-4 doses 2

3. For established EBV-associated lymphoproliferative disease:

   • Rituximab as first-line therapy (response rate ~80%) 2
   • Consider cellular therapy (EBV-specific cytotoxic T lymphocytes) as second-line option 2

Special Considerations

Chronic Active EBV Disease (CAEBV)

• Diagnosis requires:
  • High EBV DNA load (≥10,000 IU/mL in whole blood)
  • Confirmation of EBV-infected T or NK cells 3
• Treatment:
  • Hematopoietic stem cell transplantation is considered the only curative treatment
  • Chemotherapy may be used to control disease activity before transplantation 3

EBV in Inflammatory Bowel Disease

• Screen for EBV IgG before initiating immunomodulator therapy 1
• Consider anti-TNF monotherapy in preference to thiopurines in EBV seronegative patients 1
• Do not initiate immunomodulators during active EBV infection 1

Common Pitfalls to Avoid

• Diagnostic pitfalls:

  • Relying solely on heterophile antibody tests (can be negative, especially in children)
  • Misinterpreting serology in patients who have received IVIG treatment 2
  • Failing to use EBER in situ hybridization for tissue diagnosis (immunohistochemistry alone is insufficient) 1

• Management pitfalls:

  • Using standard antiviral drugs (aciclovir, ganciclovir) for EBV control - these have limited efficacy against latent EBV 2
  • Delaying intervention in high-risk immunocompromised patients with rising EBV DNA levels
  • Overlooking the need for long-term monitoring in high-risk patients

By following these evidence-based approaches to diagnosis and management, clinicians can effectively identify and treat EBV infections while minimizing complications, particularly in high-risk populations.