How can Epstein-Barr Virus (EBV) acquisition be prevented and managed?

EBV Acquisition Prevention and Management

Primary Prevention

No vaccine is currently available for EBV prevention, and since the virus is transmitted primarily through saliva (kissing, sharing drinks), avoiding exposure is nearly impossible in real-world settings. 1, 2

Transmission Routes

• Saliva is the primary mode of transmission among adolescents and young adults through intimate oral contact 3, 4
• Blood and droplet transmission can also occur 5
• The mechanism of transmission in preadolescents remains unclear 3

High-Risk Populations Requiring Screening

EBV IgG screening should be performed before initiating immunomodulator therapy, particularly thiopurines, to identify seronegative patients at risk for primary infection. 1

• In EBV-seronegative IBD patients, consider anti-TNF monotherapy instead of thiopurines at the clinician's discretion 1
• Pre-transplant EBV IgG testing identifies susceptible patients who require post-transplant EBV DNA surveillance for early recognition of primary infection 1

Management of Primary EBV Infection

In Immunocompetent Patients

Treatment is entirely supportive, as antiviral agents (aciclovir, ganciclovir, foscarnet) do not ameliorate the course of infectious mononucleosis in otherwise healthy individuals. 1, 6

• Recommend activity reduction and bed rest as tolerated 2
• Advise avoidance of contact sports or strenuous exercise for 8 weeks or while splenomegaly persists to prevent splenic rupture (occurs in 0.1-0.5% of cases) 2
• Corticosteroids should be reserved only for specific complications such as airway obstruction 1, 6

In Immunocompromised Patients

Immunomodulator therapy should be reduced or discontinued immediately when primary EBV infection is suspected, as this population faces significantly increased risk of fatal lymphoproliferative disorders. 1, 6

Diagnostic Workup

• Perform complete blood count with blood film, liver function tests, and EBV serology 1
• Primary EBV infection is diagnosed by VCA IgM (with or without VCA IgG) in the absence of EBNA antibodies 6
• Do not rely on Paul-Bunnell or monospot tests alone, as they are suboptimal for diagnosis 1

Treatment Algorithm

• In severe primary EBV infection, consider antiviral therapy with ganciclovir or foscarnet despite lack of supporting evidence, as these agents are more potent than aciclovir for replicative EBV infection (though more toxic) 1, 6
• Seek specialist advice for investigation and management of suspected lymphoproliferative disease/lymphoma 1, 6

Management of EBV Reactivation and PTLD

Post-Transplant Monitoring

Post-transplant EBV DNA surveillance in high-risk patients (seronegative recipients, HSCT patients) facilitates early recognition of reactivation and allows prompt reduction of immunosuppression. 1

Preemptive Therapy for Significant EBV DNA-emia

Rituximab 375 mg/m² once weekly for 1-4 doses is the primary method for preemptive therapy when significant EBV DNA-emia is detected without clinical PTLD symptoms. 1

• Combine rituximab with reduction of immunosuppression whenever possible (except in patients with uncontrolled severe acute or chronic GvHD) 1
• Continue treatment until EBV DNA-emia negativity 1
• No specific threshold of EBV DNA-emia can be universally recommended; local experience should guide center-specific cut-off values 1
• Antiviral drugs are NOT recommended for preemptive therapy or prophylaxis, as they have no proven impact on EBV-PTLD development 1

Treatment of Established EBV-PTLD

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

First-Line Therapy

• Rituximab 375 mg/m² once weekly for up to 4 doses while monitoring EBV viral load 1
• Always combine with reduction of immunosuppressive therapy when possible 1
• Consider EBV-specific cytotoxic T lymphocytes (CTLs) if available 1

Second-Line Therapy

• Cellular therapy (EBV-specific CTLs or donor lymphocyte infusion) 1
• Chemotherapy ± rituximab after failure of other methods 1
• Surgery, IVIG, interferon, and antiviral agents are NOT recommended for PTLD therapy 1

CNS EBV-PTLD

• Therapeutic options include rituximab ± chemotherapy, rituximab systemic or intrathecal monotherapy, anti-EBV T-cell therapy, or radiotherapy 1

Critical Pitfalls to Avoid

• Never use prophylactic antivirals (aciclovir, ganciclovir) in IBD patients, as the risk of lymphoma is too low to justify this approach despite its reported benefit in renal transplant recipients 1
• Discontinuation of immunosuppressive therapy alone may result in spontaneous regression of EBV-associated lymphoproliferative disease in some cases 1, 7
• Primary EBV infection during thiopurine therapy poses particular threat: in the CESAME cohort, two males under 50 years had fatal infectious mononucleosis-associated lymphoproliferative disorders 1
• The overall risk of lymphoma on thiopurines remains small (one additional lymphoma per 300-1400 years of treatment), but 12 of 15 lymphomas in thiopurine-treated patients were PTLD-like and EBV-associated 1