What is the diagnostic approach for mononucleosis infection?

Diagnosing Mononucleosis Infection

The diagnosis of mononucleosis should be established through a combination of clinical presentation and laboratory testing, with EBV antibody testing (VCA IgM, VCA IgG, and EBNA IgG) being the gold standard for definitive diagnosis. 1

Clinical Presentation

• Classic triad: fever, tonsillar pharyngitis, and cervical lymphadenopathy 2
• Additional common findings:
  • Fatigue (may persist up to 3 months)
  • Periorbital/palpebral edema (in approximately one-third of patients)
  • Splenomegaly (50% of cases)
  • Hepatomegaly (10% of cases)
  • Maculopapular rash (10-45% of cases), especially in patients given ampicillin

Initial Laboratory Testing

1. Complete blood count with differential

   • Look for lymphocytosis (lymphocytes >40% of white blood cells)
   • Atypical lymphocytes >10% of total lymphocyte count 3

2. Heterophile antibody test (Monospot test)

   • First-line test due to rapid results and cost-effectiveness
   • Sensitivity: 87%, Specificity: 91% 3
   • Important caveat: May be falsely negative in:
     • Children under 5 years
     • First week of illness
     • 10-15% of cases overall 3

3. Liver function tests

   • Elevated liver enzymes increase clinical suspicion when heterophile test is negative 3

Definitive Diagnostic Testing

When confirmation is needed (especially with negative heterophile test but high clinical suspicion):

EBV Antibody Panel

• Viral Capsid Antigen (VCA) IgM
• Viral Capsid Antigen (VCA) IgG
• Epstein-Barr Nuclear Antigen (EBNA) IgG 1

Interpretation of Serological Patterns

• Acute primary infection (within 6 weeks): VCA IgM (+), VCA IgG (+), EBNA IgG (-)
• Past infection (>6 weeks): VCA IgM (-), VCA IgG (+), EBNA IgG (+)
• No previous EBV infection: VCA IgM (-), VCA IgG (-), EBNA IgG (-) 1

Diagnostic Pitfalls to Avoid

1. Relying solely on a single antibody test at symptom onset

   • Collect acute sample at symptom onset and convalescent sample 10-14 days later for optimal accuracy 1

2. Waiting too long (>4 weeks) for convalescent sample

   • May miss the diagnostic window for VCA IgM 1

3. Failing to consider heterophile antibody testing as a complementary tool 1

4. Not accounting for atypical antibody responses in immunocompromised patients 1

5. Overlooking other causes of mononucleosis-like syndrome

   • Cytomegalovirus (CMV)
   • HIV
   • Toxoplasmosis
   • Hepatitis viruses

Advanced Testing When Needed

• PCR-based viral panels can confirm active viral replication
• Quantitative EBV viral load by PCR in peripheral blood
• IgG avidity testing to distinguish between recent and past infection 1

Special Considerations

• In children under 5 years: Heterophile antibody tests are often negative; EBV-specific antibody testing is preferred
• In immunocompromised patients: Higher risk for severe disease and atypical presentations; consider PCR testing and close monitoring for complications 1, 3