What is the diagnosis and treatment for Epstein-Barr Virus (EBV) infection?

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

Diagnostic Approach

For acute primary EBV infection (infectious mononucleosis), diagnosis relies on serologic testing with VCA-IgM and VCA-IgG positive with negative EBNA1 IgG, while heterophile antibody tests (Monospot) should be avoided due to suboptimal accuracy. 1

Initial Diagnostic Testing

• Avoid Paul-Bunnell and Monospot tests as they are suboptimal for diagnosis with a 25% false-negative rate in the first week of illness 1, 2
• Order EBV-specific serology detecting IgM and IgG directed against viral capsid antigen (VCA) with negative EBNA1 IgG to confirm primary infection 1
• EBNA1 IgG typically appears weeks to months after primary infection, so its absence with positive VCA antibodies confirms acute infection 1
• Lymphocyte count less than 4,000/mm³ makes infectious mononucleosis unlikely 2

Clinical Presentation to Recognize

• Classic triad: fever, tonsillar enlargement with pharyngeal inflammation, and cervical lymphadenopathy 2
• Additional findings include fatigue, palatal petechiae, hepatosplenomegaly, and sore throat 1, 2
• Peak incidence occurs between ages 15-24 years 2

Treatment Strategy

Infectious mononucleosis in immunocompetent patients requires only symptomatic management, as acyclovir and other antivirals do not ameliorate the clinical course and should not be used. 1, 3

Immunocompetent Patients

• Provide symptomatic relief only with anti-emetics and antidiarrheals (e.g., loperamide) for gastrointestinal symptoms 3
• Do not prescribe antiviral agents (acyclovir, ganciclovir, foscarnet) as they have no proven efficacy in reducing illness duration or severity 1, 3, 2
• Corticosteroids are indicated only for specific complications such as airway obstruction, not for routine management 1, 2
• Restrict physical activity and contact sports for the first 3 weeks to reduce risk of splenic rupture 2

Immunocompromised Patients

• Immediately reduce or discontinue immunosuppression if EBV-associated post-transplant lymphoproliferative disorder (PTLD) is suspected or confirmed 3
• Initiate rituximab 375 mg/m² once weekly as first-line therapy for proven or probable EBV-PTLD 3
• Perform urgent endoscopy with tissue biopsy for histological examination including EBER in situ hybridization to diagnose PTLD 1, 3
• Obtain quantitative EBV DNA PCR from whole blood, plasma, or serum 3
• Monitor EBV DNA-emia weekly during treatment and for at least 4 months post-transplant 3

Chronic Active EBV Infection (CAEBV)

CAEBV diagnosis requires three mandatory criteria: persistent/recurrent IM-like symptoms, elevated anti-VCA and anti-EA antibodies (VCA-IgG ≥1:640, EA-IgG ≥1:160) and/or increased EBV DNA in peripheral blood (>10^2.5 copies/mg DNA), and exclusion of other disease processes. 1

Diagnostic Criteria for CAEBV

• Persistent or recurrent symptoms including fever, lymphadenopathy, hepatosplenomegaly, and debilitating fatigue 1
• Unusual antibody pattern with markedly elevated VCA-IgG (≥1:640) and EA-IgG (≥1:160); positive IgA antibodies to VCA/EA often present 1
• Quantitative PCR showing >10^2.5 copies/mg DNA in peripheral blood mononuclear cells 1
• EBER in situ hybridization on affected tissues to confirm EBV presence 1

Critical Complications to Monitor

• Watch for hemophagocytic lymphohistiocytosis and T-cell or NK-cell lymphoproliferative disorders/lymphomas that may develop during illness course 1
• Cardiovascular complications including coronary aneurysms and valvular disease require particular attention 1
• Cutaneous manifestations such as hypersensitivity to mosquito bites may indicate underlying lymphoproliferative disorder 1

Special Populations

Inflammatory Bowel Disease Patients

• Consider EBV IgG screening before initiating immunomodulator therapy, particularly thiopurines 1
• In EBV-seronegative patients, anti-TNF monotherapy may be preferred over thiopurines at clinician's discretion 1
• Primary EBV infection during thiopurine therapy carries increased risk of fatal infectious mononucleosis and EBV-associated lymphoproliferative disorders 1

Pediatric Considerations

• Children face highest risk of airway obstruction, the most common cause of hospitalization from infectious mononucleosis 2
• Monitor closely for respiratory compromise requiring corticosteroid intervention 2

Common Pitfalls to Avoid

• Never rely on heterophile antibody tests alone due to poor sensitivity, especially in the first week of illness 1, 2
• Do not prescribe antivirals for uncomplicated infectious mononucleosis as they provide no clinical benefit 1, 3, 2
• Avoid premature return to contact sports before 3 weeks to prevent splenic rupture 2
• Do not use immunohistochemistry alone for EBV detection in tissue; EBER in situ hybridization is mandatory as viral proteins (e.g., LMP-1) are often not expressed 1
• Recognize that immunosuppressed patients are at higher risk for fulminant EBV infection requiring aggressive intervention 2