What is the interpretation of a positive Epstein‑Barr virus viral capsid antigen IgG with negative Epstein‑Barr nuclear antigen IgG?

Interpretation of Positive VCA IgG with Negative EBNA IgG

A positive VCA IgG with negative EBNA IgG indicates either acute/recent primary EBV infection (within the past 1-2 months) or, less commonly, a secondary EBNA-negative state in immunocompromised patients. 1, 2

Primary Diagnostic Interpretation

The serologic pattern of VCA IgG-positive/EBNA-negative represents one of two distinct clinical scenarios:

Acute Primary EBV Infection (Most Common)

• Primary acute EBV infection is definitively diagnosed when VCA IgM is positive alongside VCA IgG-positive and EBNA-negative antibodies. 3, 1, 2
• EBNA antibodies typically develop 1-2 months (4-8 weeks) after primary infection onset and persist for life. 1, 2
• The absence of EBNA antibodies indicates the infection occurred within the past 6 weeks, making EBV a likely cause of current symptoms. 1
• VCA IgG appears early during acute infection and rises rapidly during the acute phase. 2

Secondary EBNA-Negative State (Immunocompromised Patients)

• Approximately 5-10% of EBV-infected individuals fail to develop EBNA antibodies even after acute infection has resolved. 4, 2
• Immunocompromised patients (transplant recipients, HIV-infected individuals, tumor patients) may lose EBNA antibodies despite past infection, creating a "secondary EBNA-negative" pattern. 5
• In one study, 45% of VCA IgG-positive/EBNA-negative cases were secondary (reactivation or past infection with antibody loss) rather than primary infection. 5

Critical Next Step: VCA IgM Testing

You must immediately check VCA IgM status to distinguish between these two scenarios:

• VCA IgM positive = acute primary infection 1, 2
• VCA IgM negative = likely secondary EBNA-negative state or very late primary infection 5

Advanced Diagnostic Approach: IgG Avidity Testing

When the clinical picture remains unclear (particularly if VCA IgM is equivocal or the patient is immunocompromised), IgG avidity testing provides definitive differentiation:

• Low-avidity VCA IgG = acute primary infection (within past 3-4 months) 6, 5, 7
• High-avidity VCA IgG = past infection or reactivation (>3-4 months ago) 6, 5, 7
• The combination of negative EBNA and low-avidity VCA IgG has 100% sensitivity and specificity for primary infection. 6
• Avidity rises from mean 54% at 6 weeks to 82% by 28 weeks after symptom onset. 6
• High-avidity IgG antibodies in EBNA-negative patients indicate secondary EBNA-negative status rather than acute infection. 5

Special Population Considerations

Immunocompromised Patients

• For transplant recipients, HIV-infected individuals, or those with congenital immunodeficiencies, quantitative EBV viral load testing by nucleic acid amplification (NAAT) is preferred over serology alone. 1, 4, 2
• EBV DNA levels >10^2.5 copies/mg DNA in peripheral blood mononuclear cells indicate active infection. 3, 1
• These patients require viral load monitoring due to risk of EBV-associated lymphoproliferative disease. 3, 1

Chronic Active EBV Infection (CAEBV)

• Markedly elevated VCA IgG titers (≥1:640) combined with elevated early antigen (EA) IgG (≥1:160) may suggest CAEBV, particularly with persistent infectious mononucleosis-like symptoms. 3, 1
• CAEBV diagnosis requires persistent symptoms, unusual antibody patterns, and exclusion of other disease processes. 3, 2
• Positive IgA antibodies to VCA and/or EA are often demonstrated in CAEBV. 3

Common Pitfalls to Avoid

• Do not assume VCA IgG-positive/EBNA-negative always means acute infection—check VCA IgM and consider avidity testing. 5, 8
• Do not overlook immunocompromised status—these patients may have lost EBNA antibodies from past infection. 5
• Do not rely on heterophile (Monospot) testing alone in children <10 years, as false-negative rates are markedly higher. 4, 2
• Do not obtain EBV testing from throat swabs—EBV persists in the oropharynx for weeks to months and does not confirm acute infection. 4, 2

Practical Clinical Algorithm

1. Confirm VCA IgM status immediately 1, 2
2. If VCA IgM positive: Diagnose acute primary EBV infection 1, 2
3. If VCA IgM negative or equivocal: Order IgG avidity testing 6, 5, 7
   • Low avidity = acute primary infection 6, 5
   • High avidity = past infection with secondary EBNA-negative state 5
4. If immunocompromised: Add quantitative EBV viral load (NAAT) regardless of serology 1, 4, 2
5. If persistent symptoms >10 days with fever, lymphadenopathy, hepatosplenomegaly: Evaluate for CAEBV with EA IgG and quantitative viral load 3, 1