What is the management plan for a patient with a positive Epstein-Barr Virus (EBV) result, potentially indicating infectious mononucleosis, considering various demographics and past medical histories?

Management of Positive EBV Result

For immunocompetent patients with positive EBV testing consistent with infectious mononucleosis, provide supportive care only—antivirals are not effective and corticosteroids should be reserved for specific complications like airway obstruction. 1, 2

Initial Assessment and Risk Stratification

Determine immune status immediately, as this fundamentally changes management:

• Immunocompetent patients: Expect self-limited disease with supportive care 1, 3, 2
• Immunocompromised patients (transplant recipients, patients on thiopurines, HIV): High risk for EBV-associated lymphoproliferative disorders requiring aggressive monitoring and potential intervention 4, 1, 5
• Patients on immunosuppressive therapy: Reduce or discontinue immunomodulators if possible 1, 5

Confirm Diagnosis and Timing of Infection

Interpret EBV serology to determine acute vs. past infection:

• Recent primary infection: VCA IgM positive (with or without VCA IgG) AND EBNA negative 1, 5
• Past infection (>6 weeks ago): VCA IgG positive, EBNA positive, VCA IgM negative 1, 5
• Important caveat: 5-10% of EBV-infected patients never develop EBNA antibodies, complicating interpretation 1, 5

If heterophile antibody (Monospot) was used initially, recognize its limitations: 87% sensitivity, 91% specificity, with false-negatives common in children under 10 years and during the first week of illness 1, 2

Management by Patient Population

Immunocompetent Adolescents and Adults (15-24 years)

Supportive care is the only proven effective treatment:

• Activity restriction: Avoid contact sports and strenuous exercise for 8 weeks from symptom onset or while splenomegaly persists 3, 2
• Rest as tolerated with gradual return to activity using shared decision-making 2
• Monitor for splenic rupture (occurs in 0.1-0.5% of cases)—the most feared complication 3
• Do not use acyclovir, ganciclovir, or other antivirals—they have no proven benefit in immunocompetent patients 1, 6
• Reserve corticosteroids only for: upper airway obstruction, severe immune-mediated anemia, or thrombocytopenia 1, 6

Immunocompromised Patients (Critical Population)

This population requires aggressive intervention:

• Immediately reduce or discontinue immunosuppressive therapy if clinically feasible 1, 5
• Monitor EBV viral load via nucleic acid amplification testing (NAAT), not just serology 5
• Consider antiviral therapy with ganciclovir or foscarnet in severe cases, despite limited supporting evidence 1, 5
• Seek specialist consultation immediately for suspected lymphoproliferative disease 1
• Special concern for patients on thiopurines: Fatal infectious mononucleosis-associated lymphoproliferative disorders and hemophagocytic lymphohistiocytosis (HLH) have been reported 1, 5

Post-Transplant Patients (Allogeneic HSCT)

Rituximab is first-line therapy for EBV-PTLD:

• Administer rituximab once weekly for up to 4 doses while monitoring EBV viral load 4
• Expect positive response in approximately 70% of patients 4
• Combine with reduction of immunosuppression (reduction alone is rarely successful) 4
• Second-line options if rituximab fails: EBV-specific cytotoxic T lymphocytes (CTLs) preferred, or chemotherapy ± rituximab 4
• Do not use antiviral drugs—they are not effective against EBV in this setting 4

Elderly Patients

Systematically exclude lymphoproliferative disorders and underlying immunosuppression:

• Screen for HIV, occult malignancy, and review all medications for immunosuppressive agents 5
• Lymphoma is particularly concerning with prolonged symptoms in this age group 5
• If severe primary EBV infection confirmed in immunocompromised elderly: consider ganciclovir or foscarnet 5

Children Under 10 Years

• Heterophile antibody testing has high false-negative rate—proceed directly to EBV-specific serology if clinical suspicion is high 1, 2
• Otherwise, management is supportive as in adolescents 3

Common Pitfalls to Avoid

• Do not diagnose "recurrent mononucleosis": True EBV reinfection causing clinical mono is extremely rare in immunocompetent patients due to lifelong immunity 5
• When "recurrent mono" is suspected, systematically exclude: CMV infection, acute HIV, toxoplasmosis, adenovirus 1, 5
• Do not routinely use antivirals or corticosteroids in uncomplicated cases—no proven benefit and potential harm 1, 2, 6
• False-positive heterophile tests can occur with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 1
• Over 90% of adults are EBV-seropositive from past infection—positive VCA IgG and EBNA alone do not indicate acute infection 5

Monitoring and Follow-up

• Fatigue typically resolves within 3 months but can persist longer 3
• Repeat clinical assessment if symptoms persist beyond expected timeframe to exclude complications or alternative diagnoses 3
• In immunocompromised patients, monitor EBV viral load to assess treatment response—expect at least 1 log10 decrease in EBV DNA within first week of rituximab therapy 4