What is the appropriate treatment and management for a patient with a suspected Epstein-Barr virus (EBV) infection, particularly those with a history of cancer or autoimmune disease?

Management of Epstein-Barr Virus Infection

Immunocompetent Patients: Supportive Care Only

For immunocompetent patients with primary EBV infection or infectious mononucleosis, provide supportive care only—no antiviral medications, no antibiotics, and no specific pharmacologic interventions are indicated. 1

• The infection is self-limited and typically resolves over weeks to months without intervention 1
• Antiviral medications (acyclovir, valacyclovir, ganciclovir) are completely ineffective against EBV and should never be prescribed for primary infection or uncomplicated infectious mononucleosis 1, 2
• These antivirals show no efficacy because latently infected B cells do not express the EBV thymidine kinase enzyme required for drug activation 3
• Management focuses on symptom relief, adequate hydration, and rest 2
• Corticosteroids may hasten resolution of upper airway obstruction and possibly immune-mediated anemia/thrombocytopenia, but should be used judiciously 4
• Do not order EBV DNA viral load testing in immunocompetent patients—this is not indicated and leads to unnecessary interventions 1

High-Risk Immunocompromised Patients: Intensive Monitoring Required

Post-Allogeneic HSCT Patients

All allogeneic HSCT patients require prospective EBV DNA monitoring by quantitative PCR beginning no later than 4 weeks post-transplant, with weekly testing for at least 4 months. 3, 1

Pre-transplant screening:

• Test all allo-HSCT patients and donors for EBV antibodies before transplantation 3, 2
• For EBV-seronegative recipients, prefer an EBV-seronegative donor 3
• For EBV-seropositive recipients, an EBV-seropositive donor might be beneficial due to presence of EBV-positive CTLs 3

Monitoring protocol:

• Use whole blood, plasma, or serum for quantitative PCR 3
• Test weekly in high-risk EBV PCR-negative patients 3
• Extend monitoring beyond 4 months in patients with poor T-cell reconstitution: those on treatment for severe acute/chronic GvHD, after haplo-HSCT, with T-cell depletion, after ATG/alemtuzumab conditioning, or with early EBV reactivation 3, 1
• More frequent sampling should be considered in patients with rising EBV DNA-emia 3

Low-risk exception:

• HLA-identical family transplant recipients not receiving T-cell depletion and without GvHD have low risk—no routine EBV screening recommended 3

Auto-HSCT and Conventional Chemotherapy Patients

• Routine EBV monitoring is not recommended for auto-HSCT patients before and after transplant 3
• Routine EBV monitoring is not recommended for conventional chemotherapy patients 3

Preemptive Therapy for Significant EBV DNA-emia

For significant EBV DNA-emia without clinical symptoms in high-risk patients, administer rituximab 375 mg/m² once weekly (1-4 doses) until EBV DNA-emia negativity. 1, 2

• A rate of increase in EBV copy number is clinically significant and warrants intervention 1
• Combine rituximab with reduction of immunosuppression when possible, except in patients with uncontrolled severe acute or chronic GvHD 1
• Response is indicated by at least 1 log10 decrease in EBV DNA-emia within the first week 1
• The goal is to obtain negative EBV PCR or EBV DNA-emia below the initial threshold without relapse 3
• EBV-specific cytotoxic T lymphocytes (CTLs) should be considered as first-line prophylaxis when available 2

Critical pitfall: Reduction of immunosuppression alone is rarely successful for PTLD following HSCT and increases GvHD risk 2

Treatment of Established EBV-PTLD

Start rituximab 375 mg/m² once weekly immediately if proven or probable EBV-PTLD develops, due to the risk of rapidly growing high-grade lymphoid tumor. 1

Diagnosis requirements:

• Biopsy with histological examination and EBV detection by in situ hybridization for EBER transcripts or viral antigen detection is mandatory for proven diagnosis 3, 1
• Non-invasive methods include quantitative EBV DNA-emia and PET-CT/CT (PET-CT preferred for extranodal disease) 3
• Clinical staging includes nodal vs. extranodal, limited (unifocal) vs. advanced (multifocal) disease 3

Treatment approach:

• Rituximab monotherapy achieves positive outcomes in approximately 70% of patients 1, 2
• Always combine with reduction of immunosuppression when possible 1, 2
• Cellular therapy with donor or third-party EBV-specific CTLs should be considered if available 2
• Additional doses beyond 4 doses might result in down-regulation of CD20 expression and decreased efficacy 2

CNS EBV-PTLD Special Considerations

• CNS localization requires special consideration due to risk of neurocognitive dysfunction 2
• Options include rituximab ± chemotherapy based on primary CNS lymphoma protocols, systemic or intrathecal rituximab monotherapy, T-cell therapy with EBV-specific CTLs, or radiotherapy 2

Chronic Active EBV Disease (CAEBV)

For CAEBV, hematopoietic stem cell transplantation is the only curative option. 1, 5

• Diagnosis requires persistent symptoms for >3 months, EBV DNA load ≥10,000 IU/mL in whole blood, and confirmation of EBV-infected T or NK cells 5
• Chemotherapy can be administered to control disease activity before HSCT 5
• Do not confuse past infection with CAEBV, which requires persistent symptoms and high viral loads 6

Special Population: Multiple Myeloma on Bispecific Antibodies

• Consider monitoring EBV DNA copies in relapsed/refractory multiple myeloma patients receiving bispecific antibody therapy, particularly with persistent fever and fatigue 1
• Rituximab may be used as prophylaxis against EBV reactivation in this setting 1

Management of Past EBV Infection

No specific treatment or monitoring is recommended for asymptomatic patients with past EBV infection (positive VCA IgG and EBNA IgG, negative VCA IgM). 6

• In immunocompromised patients, regular monitoring of EBV DNA-emia may be warranted 6
• Antiviral medications have no efficacy against latent EBV 6
• Avoid unnecessary antiviral therapy and routine monitoring in immunocompetent individuals, as this leads to unnecessary interventions 6