How is Epstein Barr virus (EBV) managed?

Management of Epstein-Barr Virus Infection

Management of EBV depends entirely on the clinical context: immunocompetent patients with primary infection require only supportive care, while immunocompromised patients—particularly post-transplant—require aggressive monitoring and rituximab-based interventions for EBV DNA-emia and post-transplant lymphoproliferative disorders (PTLD). 1

Immunocompetent Patients with Primary EBV Infection

Supportive care is the only treatment needed for uncomplicated infectious mononucleosis. 1, 2 This includes:

• Symptom relief with analgesics and antipyretics 1
• Adequate hydration and rest until the self-limiting infection resolves 1
• Antiviral drugs (acyclovir, ganciclovir, foscarnet, cidofovir) are NOT effective and should NOT be used 3, 1, 4

The evidence is clear that while antivirals may suppress oropharyngeal viral shedding, they provide minimal clinical benefit because EBV exists in a latent state in B-cells where these drugs cannot reach the virus 3. Even combination therapy with acyclovir and corticosteroids showed only transient effects 5.

High-Risk Immunocompromised Patients

Pre-Transplant Assessment and Prophylaxis

All allogeneic hematopoietic stem cell transplant (HSCT) patients and donors must be tested for EBV antibodies before transplantation. 1, 2

For high-risk patients (T-cell depleted grafts, anti-thymocyte globulin recipients, or those with GvHD):

• Prospective monitoring of EBV DNA-emia by quantitative PCR is required 1, 2
• EBV-specific cytotoxic T lymphocytes (CTLs) should be considered as first-line prophylaxis when available 3, 1
• Prophylactic rituximab may reduce the risk of EBV DNA-emia 3, 1
• Antiviral drugs are NOT recommended for prophylaxis 3

Preemptive Therapy for Asymptomatic EBV DNA-emia

When significant EBV DNA-emia is detected without clinical symptoms, initiate preemptive therapy immediately with rituximab. 3, 1, 2

Rituximab Dosing Protocol

• Rituximab 375 mg/m² once weekly for 1-4 doses until EBV DNA-emia negativity 3, 1, 2
• Combine with reduction of immunosuppression whenever possible 3
• Monitor EBV viral load to guide number of doses 3

Critical caveat: No universal threshold for EBV DNA-emia exists to trigger intervention. Centers use varying thresholds (1,000 to 40,000 copies/mL in blood or 1,000 copies per 10⁵ PBMC), and PTLD can occur even below these thresholds 3. The rate of increase in EBV copy number is likely more clinically significant than absolute values 3.

Treatment of Established EBV-PTLD

Rituximab monotherapy is the first-line treatment for proven or probable EBV-PTLD, achieving positive outcomes in approximately 70% of patients. 3, 1, 2

First-Line Therapy Algorithm

1. Rituximab 375 mg/m² once weekly (typically 1-4 doses) 3, 1, 2
2. Reduction of immunosuppressive therapy combined with rituximab whenever possible 3, 1, 2
   • Exception: Do NOT reduce immunosuppression in patients with uncontrolled severe acute or chronic GvHD 3
3. Cellular therapy with donor or third-party EBV-specific CTLs if available 3, 1

Important pitfall: Reduction of immunosuppression alone is rarely successful for PTLD following HSCT and may increase the risk of rejection or GvHD 3, 1. Always combine with rituximab 3, 1.

Another critical caveat: Additional rituximab doses beyond 4 may cause down-regulation of CD20 expression, potentially decreasing efficacy 3, 1.

Second-Line Therapy (After Rituximab Failure)

1. Cellular therapy (EBV-specific CTLs or donor lymphocyte infusion) 3
2. Chemotherapy ± rituximab 3
3. Surgery, IVIG, interferon, and antiviral agents are NOT recommended 3

Warning: Unselected donor lymphocyte infusions carry severe GvHD risk; previous GvHD is usually a contraindication 1.

CNS EBV-PTLD

CNS involvement requires special consideration due to neurocognitive dysfunction risk. 1

Therapeutic options include:

• Rituximab ± chemotherapy (based on primary CNS lymphoma protocols) 3, 1
• Systemic or intrathecal rituximab monotherapy 3, 1
• EBV-specific CTL therapy 3, 1
• Radiotherapy 3, 1

Chronic Active EBV Disease (CAEBV)

Hematopoietic stem cell transplantation is the only curative treatment for severe CAEBV. 6

Diagnosis requires:

• Persistent or recurrent symptoms (fever, lymphadenopathy, hepatosplenomegaly) for >3 months 6
• Elevated EBV antibody titers (VCA-IgG ≥1:640 and EA-IgG ≥1:160) 6

Management includes:

• Reduction of immunosuppression when possible 6
• Rituximab 375 mg/m² weekly for 1-4 doses for significant EBV DNA-emia 6

Special Populations

Patients on Immunosuppressive Therapy

Patients on thiopurines have increased risk of EBV-associated lymphoproliferative disorders. 6

• Consider temporary discontinuation of immunomodulators during acute primary EBV infection 6
• Discontinuation of immunosuppression may result in spontaneous regression of EBV-associated lymphoproliferative disease in some cases 6

Late-Onset PTLD

EBV-negative B-PTLD presenting >5 years post-transplant should be treated as malignant lymphoma with appropriate chemotherapy protocols, not as PTLD. 1