When should patients be tested for infectious mononucleosis (mono)?

When to Test for Infectious Mononucleosis

Test for infectious mononucleosis when patients aged 10-30 years present with sore throat and significant fatigue, especially if accompanied by posterior cervical or auricular lymphadenopathy, palatal petechiae, or marked adenopathy. 1

Clinical Indications for Testing

High-Suspicion Clinical Features

Test when patients present with the classic triad of:

• Fever, tonsillar pharyngitis, and lymphadenopathy 2, 3
• Significant fatigue that is disproportionate to other symptoms 1
• Posterior cervical or auricular adenopathy (more specific than anterior cervical nodes) 1
• Palatal petechiae 1
• Periorbital or palpebral edema (occurs in one-third of patients) 2

Age-Specific Considerations

• Primary target age: 15-24 years (most commonly affected) 2, 3
• Broader testing range: 10-30 years when clinical features are present 1
• Be aware that heterophile antibody tests have higher false-negative rates in children younger than 5 years 3

Initial Laboratory Testing Approach

First-Line Testing

Order a complete blood count with differential and rapid heterophile antibody test (Monospot) as the initial cost-effective approach 3:

• CBC findings supporting diagnosis:

  • Lymphocytosis ≥50% of white blood cell differential 4
  • Atypical lymphocytosis ≥10% of total lymphocyte count 4, 2
  • An atypical lymphocytosis ≥20% OR atypical lymphocytosis ≥10% plus lymphocytosis ≥50% strongly supports the diagnosis 1

• Heterophile antibody test characteristics:

  • Sensitivity: 87%, Specificity: 91% 3
  • Usually becomes positive between the sixth and tenth day after symptom onset 4, 5
  • False-negative results are common early in the course of infection (first week) 4, 3

Common Pitfalls with Heterophile Testing

False-positive heterophile results may occur in patients with:

• Leukemia 4, 5
• Pancreatic carcinoma 4, 5
• Viral hepatitis 4, 5
• CMV infection 4, 5

False-negative heterophile results are common in:

• Children younger than 10 years (approximately 10% false-negative rate overall) 4
• Early infection (first week of symptoms) 1, 3

When to Proceed with EBV-Specific Serologic Testing

Order EBV serologic testing when clinical suspicion remains high despite a negative heterophile test 6, 5:

EBV Antibody Panel to Order

Test for the following three antibodies 4, 5:

1. IgM antibodies to viral capsid antigen (VCA)
2. IgG antibodies to VCA
3. Antibodies to Epstein-Barr nuclear antigen (EBNA)

Interpretation of EBV Serology

• Recent primary EBV infection: VCA IgM present (with or without VCA IgG) AND EBNA antibodies absent 4, 5
• Past infection (>6 weeks): EBNA antibodies present, indicating infection is not recent 4, 5
• EBNA antibodies develop 1-2 months after primary infection and persist for life 4
• Note: 5-10% of EBV-infected patients fail to develop EBNA antibodies 4, 5

Additional Laboratory Findings

Elevated liver enzymes increase clinical suspicion for infectious mononucleosis when the heterophile test is negative 3

Differential Diagnosis Requiring Alternative Testing

When heterophile and EBV testing are negative, consider testing for other causes of mononucleosis-like illness 4, 5:

• Cytomegalovirus (CMV) infection 4, 5, 7
• HIV infection (perform opportunistic screening) 5, 7
• Toxoplasma gondii infection 4, 7
• Adenovirus infection 4, 5
• Streptococcal pharyngitis 7

Special Populations Requiring Testing

Immunocompromised Patients

Test immunocompromised patients more aggressively as they have increased risk of:

• Severe disease 6
• Lymphoproliferative disorders 5
• Hemophagocytic syndrome 4

Consider EBV viral load testing by nucleic acid amplification in immunocompromised patients, particularly organ transplant recipients 4

Patients on Immunosuppressive Therapy

Screen for EBV status before initiating thiopurine therapy, particularly in pediatric IBD patients who are at higher risk from primary EBV infection 4

Testing NOT Recommended

Do not routinely perform EBV-specific antibody testing when:

• The heterophile test is positive and clinical presentation is typical 8
• The diagnosis is straightforward and illness is not severe 8