What is the management approach for a patient with Epstein-Barr Virus (EBV) positive serology?

Management of EBV Positive Serology

For immunocompetent patients with EBV positive serology indicating past infection, no treatment or monitoring is required. 1

Interpretation of Serological Results

The specific serological pattern determines the clinical approach:

• Past infection (VCA IgG positive, EBNA IgG positive, VCA IgM negative): No intervention needed in asymptomatic immunocompetent individuals 1
• Recent past infection (VCA IgG positive, EBNA IgG negative, VCA IgM negative): Still represents resolved infection; EBNA may remain negative for 3-6 months or indefinitely in some individuals 2
• Acute infection (VCA IgM positive): Requires symptomatic management only in immunocompetent hosts 3

Management Algorithm by Patient Population

Immunocompetent Patients

No treatment is indicated for asymptomatic patients with positive EBV serology. 1

• Antiviral medications (acyclovir, valacyclovir, ganciclovir) are completely ineffective against latent EBV and should not be prescribed 4, 1, 2
• Routine monitoring of EBV DNA levels is not recommended and leads to unnecessary interventions 1, 2
• Throat PCR results (even if positive) have no clinical significance in asymptomatic individuals and should not guide management 2

High-Risk Immunocompromised Patients

For allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, prospective EBV DNA monitoring by quantitative PCR is mandatory. 4

Pre-transplant Assessment

• Test all allo-HSCT patients and donors for EBV antibodies before transplant 4
• For EBV-seronegative recipients, prefer an EBV-seronegative donor 4

Post-transplant Monitoring Protocol

• Begin screening within the first month after allo-HSCT (though PTLD incidence is <0.2% in first month) 4
• Monitor weekly for at least 4 months post-transplant using whole blood, plasma, or serum 4
• Use quantitative PCR for EBV DNA-emia (high sensitivity and specificity) 4
• Extend monitoring beyond 4 months for patients with poor T-cell reconstitution, including those with severe acute/chronic GvHD, haplo-HSCT, T-cell depletion, ATG/alemtuzumab conditioning, or early EBV reactivation 4

Risk Stratification

Pre-transplant risk factors: 4

• T-cell depletion (in vivo or ex vivo) - the principal risk factor
• EBV serology donor/recipient mismatch
• Cord blood transplantation
• HLA mismatch
• Splenectomy
• Second HSCT

Post-transplant risk factors: 4

• Severe acute or chronic GvHD requiring intensive immunosuppression
• High or rising EBV viral load
• Treatment with mesenchymal stem cells

Treatment Strategies

Preemptive Therapy (Asymptomatic EBV DNA-emia)

Rituximab 375 mg/m² once weekly for 1-4 doses is indicated for significant EBV DNA-emia without clinical symptoms in high-risk patients. 4, 1

• No specific threshold can be universally recommended; centers use 1,000-40,000 copies/mL based on local experience 4
• The rate of increase in EBV DNA is clinically significant (doubling time can be as short as 56 hours) 4
• Combine rituximab with reduction of immunosuppression when possible 4
• Consider EBV-specific cytotoxic T lymphocytes (CTLs) if available 4
• Monitor for response: expect ≥1 log10 decrease in EBV DNA-emia within the first week 4

Treatment of Proven/Probable EBV-PTLD

Rituximab monotherapy is first-line treatment for EBV-PTLD, achieving positive outcomes in approximately 70% of patients. 4, 1

Diagnostic Criteria

• Probable PTLD: Significant lymphadenopathy, hepatosplenomegaly, or end-organ manifestations with significant EBV DNA-emia (without tissue biopsy, excluding other causes) 4
• Proven PTLD: Detection of EBV nucleic acids or proteins in tissue specimen with symptoms/signs from affected organ 4

Diagnostic Workup

• Physical examination for fever, tonsillitis, adenopathy, organomegaly 4
• PET-CT/CT imaging (PET-CT preferred for extranodal disease) 4
• Tissue biopsy with EBER in situ hybridization (high sensitivity and specificity) 4
• Peripheral blood EBV viral load by PCR 4
• Endoscopy if gastrointestinal symptoms present 4, 3

First-Line Treatment

• Rituximab 375 mg/m² once weekly for up to 4 doses 4, 1
• Reduce immunosuppression when possible (except in uncontrolled severe acute/chronic GvHD) 4
• Consider EBV-specific CTLs if available 4

Second-Line Treatment (After Rituximab Failure)

• Cellular therapy (EBV-specific CTLs or donor lymphocyte infusion) 4
• Chemotherapy ± rituximab 4

CNS EBV-PTLD

• Rituximab ± chemotherapy (high-dose methotrexate and/or cytarabine) 4
• Consider systemic or intrathecal rituximab monotherapy 4
• EBV-specific CTL therapy if available 4
• Radiotherapy as alternative option 4

Critical Pitfalls to Avoid

Never prescribe antiviral drugs for EBV-related conditions. Acyclovir, ganciclovir, foscarnet, and cidofovir are completely ineffective against latent EBV because latently infected B cells do not express EBV thymidine kinase 4, 1, 2, 3

• Do not use throat PCR for clinical decision-making; blood EBV DNA quantification is the appropriate test for high-risk populations 2
• Do not monitor EBV DNA serially in immunocompetent patients 1, 2
• Do not confuse asymptomatic viral shedding with active disease 2
• Do not use reduction of immunosuppression alone for PTLD (rarely successful and increases GvHD risk) 4, 1
• Do not confuse past infection with chronic active EBV infection (requires persistent symptoms >3 months) 1
• Avoid prophylactic rituximab except in highest-risk patients due to risk of hypogammaglobulinemia and infectious mortality 4

Special Populations

Low-Risk Transplant Recipients

• HLA-identical family transplant recipients without T-cell depletion and without GvHD do not require routine EBV screening 4

Autologous HSCT and Conventional Chemotherapy Patients

• Routine EBV monitoring is not recommended 4

Solid Organ Transplant Recipients

• Regular EBV DNA-emia monitoring may be warranted 1
• Preemptive rituximab therapy indicated for significant viremia 2