What is the appropriate work‑up and management for a 13‑year‑old girl presenting with fever, sore throat, posterior cervical lymphadenopathy, fatigue and possible hepatosplenomegaly suggestive of infectious mononucleosis?

Evaluation for Possible Infectious Mononucleosis in a 13-Year-Old Female

Initial Laboratory Testing

Begin with a complete blood count with differential and a rapid heterophile antibody test (Monospot) as the most cost-effective initial approach. 1, 2

Complete Blood Count Findings

• Look for lymphocytosis ≥50% of the white blood cell differential and atypical lymphocytosis ≥10% of total lymphocyte count, which strongly support the diagnosis 1, 2
• Absolute lymphocytosis with atypical lymphocytes is present in most cases 3, 4
• Elevated liver enzymes (AST, ALT) occur in approximately 90% of patients and increase clinical suspicion even when heterophile testing is negative 2, 5

Heterophile Antibody Testing

• The Monospot test has 87% sensitivity and 91% specificity and is the most widely used initial diagnostic test 1, 2
• Critical timing consideration: The test usually becomes positive between the sixth and tenth day after symptom onset, so false-negatives are common in the first week of illness 3, 1
• False-negative results occur in approximately 10% of patients overall and are especially common in children younger than 10 years 3, 1

When Heterophile Testing is Negative

If clinical suspicion remains high despite a negative Monospot test, proceed immediately to EBV-specific serologic testing. 3, 1

EBV Serologic Panel

Order the following three antibody tests together 3, 1:

• IgM antibodies to viral capsid antigen (VCA)
• IgG antibodies to VCA
• Antibodies to Epstein-Barr nuclear antigen (EBNA)

Interpretation of EBV Serology

• Acute primary EBV infection: VCA IgM present (with or without VCA IgG) AND EBNA antibodies absent 3, 1, 6
• Past infection (>6 weeks): EBNA antibodies present, which essentially rules out acute mononucleosis as the cause of current symptoms 3, 1
• EBNA antibodies develop 1-2 months after primary infection and persist for life 3

Physical Examination Findings to Document

Focus on these specific clinical features that differentiate EBV mononucleosis 6, 2, 7:

• Posterior cervical lymphadenopathy (highly characteristic of EBV-IM)
• Tonsillar pharyngitis with white exudate or coating
• Periorbital or palpebral edema (occurs in one-third of patients, typically bilateral) 4
• Splenomegaly (present in approximately 50% of cases) 4
• Hepatomegaly (present in approximately 10% of cases) 4
• Temperature elevation (can reach 40°C) 6

Differential Diagnosis Testing

If both heterophile and EBV serologies are negative or equivocal, consider testing for other causes of mononucleosis-like illness 3, 1:

• Cytomegalovirus (CMV) - typically presents with older age, longer symptom duration before presentation, less prominent lymphadenopathy, and less tonsillar involvement 7
• HIV infection - particularly important to consider in adolescents
• Toxoplasma gondii infection
• Adenovirus infection
• Streptococcal pharyngitis (can coexist with EBV-IM)

Critical Pitfalls to Avoid

False-Positive Heterophile Results

Be aware that false-positives can occur in 3:

• Leukemia
• Pancreatic carcinoma
• Viral hepatitis
• CMV infection

Age-Related Testing Considerations

• At 13 years old, this patient is in the typical age range for classic EBV-IM presentation (15-24 years most common, but adolescents 13-14 frequently affected) 2, 4
• Heterophile antibody testing is more reliable in this age group than in younger children 3

Timing of Testing

• Do not rule out mononucleosis based on a single negative heterophile test obtained in the first week of illness 1, 2
• If clinical suspicion is high and initial testing is negative, repeat heterophile testing after 7-10 days or proceed directly to EBV serology 3

Additional Supportive Laboratory Tests

Consider ordering 2, 4:

• Liver function tests (AST, ALT, bilirubin) - elevated in 90% of cases and support diagnosis when heterophile is negative
• Abdominal ultrasound if splenomegaly is suspected clinically - helps assess splenic size for activity restriction counseling and differentiates EBV-IM from CMV-IM 7

Special Considerations for This Age Group

• Adolescent females have no increased risk compared to males for severe complications 4
• Screen for complications if symptoms are severe, including neurologic symptoms, severe thrombocytopenia, or respiratory compromise 6, 4
• Counsel regarding activity restriction for 3-8 weeks to prevent splenic rupture, which occurs in 0.1-0.5% of cases and is the most feared complication 2, 4