What is the diagnostic approach for infectious mononucleosis?

Diagnostic Approach for Infectious Mononucleosis

The diagnosis of infectious mononucleosis should be made using a combination of clinical presentation (fever, pharyngitis, and cervical lymphadenopathy), complete blood count with differential (looking for >40% lymphocytes and >10% atypical lymphocytes), and a rapid heterophile antibody test (Monospot). 1

Clinical Presentation

• Classic triad:
  • Fever
  • Pharyngitis
  • Posterior cervical lymphadenopathy 1
• Other common findings:
  • Fatigue (often profound)
  • Periorbital/palpebral edema (in about one-third of patients)
  • Splenomegaly (approximately 50% of cases)
  • Hepatomegaly (approximately 10% of cases)
  • Maculopapular rash (10-45% of cases) 2

Laboratory Diagnostic Algorithm

Step 1: Initial Testing

• Complete blood count (CBC) with differential
  • Look for lymphocytosis (>40% lymphocytes)
  • Presence of atypical lymphocytes (>10%)
• Rapid heterophile antibody test (Monospot)
  • Sensitivity: 87%
  • Specificity: 91% 1

Step 2: If Monospot is Negative but Clinical Suspicion Remains High

• Consider liver function tests
  • Elevated liver enzymes increase clinical suspicion for infectious mononucleosis 1
• Be aware that false-negative heterophile antibody tests are common:
  • In children younger than 5 years
  • During the first week of illness 1

Step 3: Confirmatory Testing (when needed)

• EBV-specific serologic testing:
  • Viral capsid antigen (VCA) antibodies
    • VCA IgM (+), VCA IgG (+), EBNA IgG (-) indicates acute primary infection (within 6 weeks)
    • VCA IgM (-), VCA IgG (+), EBNA IgG (+) indicates past infection (>6 weeks)
    • VCA IgM (-), VCA IgG (-), EBNA IgG (-) indicates no previous EBV infection 3

Important Diagnostic Considerations

Age-Related Differences

• The classic presentation and laboratory findings may vary by age
• False-negative heterophile antibody tests are more common in children under 5 years 1

Differential Diagnosis

Consider other causes of mononucleosis-like illness when heterophile antibody test is negative:

• Cytomegalovirus infection
• Toxoplasmosis
• Streptococcal infection
• Other viral infections 4

When to Consider Chronic Active EBV Infection

Look for:

• Persistent or recurrent infectious mononucleosis-like symptoms
• Unusual pattern of anti-EBV antibodies with raised anti-VCA and anti-EA
• Elevated EBV early antigen (EA) antibodies
• Chronic illness not explained by other known disease processes 3

Common Pitfalls to Avoid

1. Relying solely on the Monospot test - False negatives occur in early disease and in young children
2. Failing to consider differential diagnoses when heterophile antibody tests are negative
3. Missing complications - Monitor for splenic rupture (occurs in 0.1-0.5% of cases), which is potentially life-threatening 2
4. Premature return to contact sports - Patients should avoid contact sports for at least 3-4 weeks from symptom onset 1
5. Unnecessary antibiotic use - Antibiotics should be avoided unless bacterial co-infection is confirmed 3

The most recent evidence emphasizes the cost-effectiveness of initial testing with CBC with differential and heterophile antibody testing, reserving more expensive EBV-specific serologic testing for cases where clinical suspicion remains high despite negative initial testing 1.