What is the initial workup for a patient suspected of having mononucleosis?

Initial Workup for Suspected Mononucleosis

The initial workup for suspected mononucleosis should include a complete blood count with differential looking for >40% lymphocytes and >10% atypical lymphocytes, followed by a rapid heterophile antibody test (Monospot), which serves as the most cost-effective first-line diagnostic approach. 1

Clinical Presentation to Assess

Look specifically for the classic triad: fever, tonsillar pharyngitis, and posterior cervical or auricular lymphadenopathy. 2, 3 Additional highly suggestive features include:

• Palatal petechiae 3
• Periorbital or palpebral edema (bilateral, occurs in one-third of patients) 2
• Marked posterior cervical adenopathy or inguinal adenopathy 3
• Splenomegaly (approximately 50% of cases) and hepatomegaly (approximately 10%) 2
• Profound fatigue that may persist for months 2, 3

Laboratory Testing Algorithm

First-Line Testing

Complete Blood Count with Differential: 1

• Lymphocytosis ≥50% of total white blood cell count strongly supports the diagnosis 4
• Atypical lymphocytes >10% of total lymphocyte count is characteristic 4, 2
• The combination of ≥20% atypical lymphocytes OR ≥10% atypical lymphocytes plus ≥50% total lymphocytosis strongly supports infectious mononucleosis 3

Rapid Heterophile Antibody Test (Monospot): 1

• Sensitivity 87%, specificity 91% 1
• Most cost-effective initial test 1
• Becomes detectable between days 6-10 after symptom onset 4

Critical Pitfall: False-Negative Heterophile Testing

False-negative heterophile tests occur in approximately 10% of patients with infectious mononucleosis and are especially common in two populations: 4, 5

1. Children younger than 10 years 4, 1
2. Adults tested during the first week of illness 1, 5

When Heterophile Test is Negative

If clinical suspicion remains high with negative heterophile antibody, proceed to EBV-specific antibody testing: 4, 5

• VCA IgM and IgG (viral capsid antigen) 4
• EBNA (Epstein-Barr nuclear antigen) 4

Interpretation pattern for acute infection: 4

• VCA IgM present (with or without VCA IgG) + EBNA antibodies absent = recent primary EBV infection
• EBNA antibodies present = infection occurred >6 weeks ago, unlikely to be causing current symptoms 4

Additional Laboratory Considerations

Liver function tests are frequently abnormal but routine assessment is not required in immunocompetent patients: 6

• 57-62% have elevated transaminases 6
• Derangement typically resolves within 8 weeks (range 6-12 weeks) 6
• Serial monitoring is unnecessary in asymptomatic patients 6

Abdominal ultrasound is not routinely indicated for evaluation of deranged liver function tests in infectious mononucleosis. 6

Alternative Diagnoses to Consider with Negative Testing

When both heterophile and EBV serologies are negative, consider testing for mononucleosis-like illnesses: 4, 3

• Cytomegalovirus (CMV) 4
• Toxoplasma gondii 4, 3
• HIV (acute infection) 3
• Adenovirus 4
• Streptococcal pharyngitis (can coexist) 3

Key Diagnostic Pitfalls to Avoid

Do not rely solely on heterophile testing in children <10 years or in the first week of illness - proceed directly to EBV-specific serology if clinical suspicion is high. 4, 1, 5

False-positive heterophile tests can occur with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection. 4

Timing matters: A patient with classic clinical features but negative heterophile test in the first week should have repeat testing at 7-10 days or proceed to EBV serology. 4, 5