What are the diagnostic criteria and management options for mononucleosis?

Mononucleosis Diagnosis

Diagnose infectious mononucleosis in adolescents and young adults (15-24 years) with the classic triad of fever, pharyngitis, and posterior cervical lymphadenopathy, confirmed by a complete blood count showing >50% lymphocytes with >10% atypical lymphocytes and a positive heterophile antibody (Monospot) test. 1, 2, 3

Clinical Presentation

The diagnosis begins with recognizing the characteristic clinical features:

• Classic triad: Fever (can reach 40°C), tonsillar pharyngitis, and cervical lymphadenopathy 1, 4, 3
• Posterior cervical adenopathy is particularly suggestive (specificity 87%, positive LR 3.1) 5
• Palatine petechiae are highly specific (specificity 95%, positive LR 5.3) 5
• Splenomegaly occurs in approximately 50% of cases (specificity range 71-99%, positive LR 1.9-6.6) 1, 4, 5
• Hepatomegaly is present in about 10% of cases 1, 4
• Periorbital or palpebral edema (typically bilateral) occurs in one-third of patients 4
• Maculopapular rash develops in 10-45% of cases, especially after antibiotic administration 1, 4

Key clinical pitfall: The absence of any lymphadenopathy makes mononucleosis unlikely (sensitivity 91%, negative LR 0.23-0.44) 5

Initial Laboratory Testing

First-Line Testing

Order a complete blood count with differential and rapid heterophile antibody test as your initial diagnostic workup. 2, 3

• CBC findings: Look for >50% lymphocytes AND >10% atypical lymphocytes (specificity 99%, positive LR 54) 2, 3, 5
• Atypical lymphocytosis thresholds:
  • ≥10% atypical lymphocytes: positive LR 11.4 5
  • ≥20% atypical lymphocytes: positive LR 26 5
  • ≥40% atypical lymphocytes: positive LR 50 5
• Heterophile antibody (Monospot) test: Sensitivity 87%, specificity 91% 3

When Heterophile Testing is Inadequate

Order EBV-specific antibody testing when the heterophile test is negative but clinical suspicion remains high, particularly in children <10 years old, patients in the first week of illness, or those with atypical presentations. 2, 3

The recommended EBV serologic panel includes:

• Viral Capsid Antigen (VCA) IgM and IgG 2, 6
• Epstein-Barr Nuclear Antigen (EBNA) antibodies 2, 6
• Early Antigen (EA) antibodies 2

Interpretation of EBV serology:

• Acute primary infection: VCA IgM present (with or without VCA IgG) AND EBNA antibodies absent 1, 2, 6
• Past infection: VCA IgG present AND EBNA antibodies present 2

Critical pitfall: False-negative heterophile results occur commonly in children under 10 years and during the first week of illness 2, 7, 3. False-positives can occur with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 2

Alternative Diagnoses to Consider

When heterophile testing is negative with mononucleosis-like symptoms, test for Cytomegalovirus (CMV), HIV, Toxoplasma gondii, and Adenovirus. 2, 7

Consider streptococcal pharyngitis testing as well, since concurrent infection can occur 7

Special Populations

Immunocompromised Patients

In immunocompromised patients, order EBV viral load by quantitative PCR in addition to standard serologic testing. 2

• Quantitative PCR showing >10^2.5 copies/mg DNA in peripheral blood mononuclear cells suggests chronic active EBV 2
• Consider testing for EBV-associated lymphoproliferative disease 2

Children Under 10 Years

Use EBV-specific antibody testing as the primary diagnostic method in children younger than 10 years, as heterophile antibody tests are unreliable in this age group. 2, 3

Supportive Laboratory Findings

• Liver function tests: Mild elevations are common and increase clinical suspicion when heterophile testing is negative 1, 3
• Peripheral blood leukocytosis: Present in most patients, with lymphocytes comprising at least 50% of the differential 4

Management Approach

Provide supportive care with adequate hydration, analgesics, antipyretics, and activity modification guided by the patient's energy level rather than enforced bed rest. 7, 3

• Activity restriction: Withdraw patients from contact or collision sports for at least 3-4 weeks from symptom onset (some guidelines recommend up to 8 weeks or until splenomegaly resolves) 7, 4, 3
• Avoid routine corticosteroids, antivirals, and antihistamines 7, 3
• Consider corticosteroids only for respiratory compromise or severe pharyngeal edema 7

Critical complication: Spontaneous splenic rupture occurs in 0.1-0.5% of cases and is potentially life-threatening 4, 6. This is the most feared complication and justifies the prolonged activity restriction 4, 6