How is EBV (Epstein-Barr Virus) serology interpreted and what are the management options for a patient with a current infection?

EBV Serology Interpretation and Management

Serological Interpretation

For diagnosing EBV infection status, use a three-marker approach: VCA-IgM, VCA-IgG, and EBNA-1 IgG, which allows interpretation of >95% of cases and provides clear differentiation between acute, recent, and past infection. 1, 2

Primary Acute Infection (Recent, <6 weeks)

• VCA-IgM positive (with or without VCA-IgG) + EBNA-1 IgG negative indicates acute primary infection 1, 3
• Heterophile antibodies (Monospot) can be used as initial screening but have ~10% false negative rate, particularly in children under 10 years 1
• EBNA-1 antibodies typically appear 1-2 months after primary infection and their absence confirms recent infection 1, 3

Past Infection (>6 weeks)

• VCA-IgM negative + VCA-IgG positive + EBNA-1 IgG positive indicates past infection 1, 3
• This pattern represents >90% of the adult population in most regions 4

Atypical Serological Patterns (~11-15% of cases)

When encountering atypical patterns, additional testing is required:

Isolated VCA-IgG positive (most common atypical pattern at 7.9%):

• Perform IgG avidity testing to distinguish acute from past infection 3, 5
• Low avidity = acute/recent infection; High avidity = past infection or secondary anti-EBNA-1-negative state 5
• Consider immunocompromised status, as 5-10% of immunocompromised patients never develop EBNA-1 antibodies despite infection 1, 4

All three markers positive (VCA-IgM + VCA-IgG + EBNA-1 IgG):

• May indicate recent infection (EBNA-1 appearing early) or reactivation 3
• Clinical correlation and follow-up serology in 2-4 weeks recommended 4

Isolated EBNA-1 IgG positive:

• Rare pattern requiring immunoblotting confirmation and clinical correlation 3, 4

Management of Current EBV Infection

Immunocompetent Patients

Acyclovir and other antivirals have no proven benefit for infectious mononucleosis in immunocompetent hosts and are not recommended. 6

• Supportive care is the mainstay of treatment 6
• Corticosteroids may be indicated specifically for airway obstruction 6
• Monitor for complications including hepatosplenomegaly, neurological manifestations, and hematological abnormalities 6

Immunocompromised Patients (Post-Transplant, IBD on Immunosuppression)

In high-risk immunocompromised patients, prospective EBV DNA monitoring by quantitative PCR should be performed weekly starting within the first month and continuing for at least 4 months, with pre-emptive rituximab therapy for rising viral loads. 6

Risk Stratification for PTLD

High-risk features include: 6

• T-cell depletion therapy
• EBV donor/recipient mismatch (especially seronegative recipient)
• Cord blood transplantation
• Steroid-refractory GVHD
• EBV DNA >10^2.5 copies/mg DNA in peripheral blood mononuclear cells 6, 1

Monitoring Strategy

• Use quantitative PCR on whole blood, plasma, or serum (all acceptable) 6
• Frequency: At least weekly, with EBV doubling time as short as 56 hours requiring more frequent monitoring if levels rising 6
• Threshold for intervention: Rising viral loads warrant pre-emptive therapy before clinical disease develops 6

Pre-emptive and Treatment Approaches

• Rituximab is the primary intervention for rising EBV DNA-emia or proven PTLD 6
• Reduction of immunosuppression when feasible 6
• For proven PTLD: tissue diagnosis via biopsy with EBER in situ hybridization (high sensitivity/specificity) is preferred over immunohistochemistry 6
• PET-CT staging using Lugano classification for extent of disease 6

Special Populations

For IBD patients on immunomodulators: Consider EBV IgG screening before initiating thiopurines, with preference for anti-TNF monotherapy in seronegative patients to reduce lymphoma risk. 6

Key Diagnostic Pitfalls

• False positives: VCA-IgM can be falsely positive in leukemia, pancreatic carcinoma, CMV infection, and other viral hepatitis 1
• False negatives: Heterophile antibodies have poor sensitivity in children <10 years; use specific EBV antibodies instead 1
• Immunocompromised patients: May never develop EBNA-1 antibodies (5-10% of cases), making isolated VCA-IgG pattern common 1, 5
• EBV DNA detection alone: Blood PCR positivity without clinical correlation is insufficient for PTLD diagnosis; tissue confirmation required 6