What are the recommended tests and management for infectious mononucleosis?

Diagnostic Testing for Infectious Mononucleosis

The recommended initial diagnostic test for infectious mononucleosis is the heterophile antibody test (Monospot), followed by EBV-specific antibody testing when clinical suspicion remains high despite a negative heterophile test. 1, 2

Initial Diagnostic Approach

• Complete blood count with differential should be obtained to assess for lymphocytosis (>40% lymphocytes) and atypical lymphocytes (>10% of total lymphocytes), which are characteristic findings in EBV-associated mononucleosis 1, 3
• Heterophile antibody test (Monospot) is recommended as the first-line diagnostic test, with sensitivity of 87% and specificity of 91% 2, 3
• Heterophile antibodies typically become detectable between the sixth and tenth day after symptom onset, increase through the second or third week, and may persist for a year or longer 1
• An elevated white blood cell count with increased percentage of atypical lymphocytes is common in EBV-associated mononucleosis 1

When to Perform EBV-Specific Antibody Testing

• EBV-specific antibody testing should be performed when clinical suspicion for infectious mononucleosis remains high despite a negative heterophile test 1, 2
• EBV antibody testing should include IgM and IgG antibodies to viral capsid antigen (VCA) and antibodies to Epstein-Barr nuclear antigen (EBNA) 1, 2
• The presence of VCA IgM (with or without VCA IgG) antibodies in the absence of EBNA antibodies indicates recent primary EBV infection 1
• The presence of EBNA antibodies indicates infection occurring more than 6 weeks prior to testing, making EBV unlikely as the cause of current symptoms 1

Interpretation of EBV Serology Results

• Acute EBV infection: VCA IgM positive, VCA IgG positive or negative, EBNA negative 2, 4
• Past EBV infection: VCA IgM negative, VCA IgG positive, EBNA positive 1, 4
• No prior EBV infection: VCA IgM negative, VCA IgG negative, EBNA negative 2, 4
• Over 90% of normal adults have IgG antibodies to VCA and EBNA antigens, reflecting past infection 1, 2

Important Caveats and Pitfalls

• False-negative heterophile results occur in approximately 10% of patients, especially in children younger than 10 years and during the first week of illness 1, 3, 5
• False-positive heterophile results may occur in patients with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 1, 2
• Approximately 5-10% of patients who have been infected with EBV fail to develop antibodies to EBNA antigen 1, 2
• Elevated liver enzymes increase clinical suspicion for infectious mononucleosis in the setting of a negative heterophile test 3, 6

Differential Diagnosis

• When heterophile tests are negative, consider other causes of mononucleosis-like illness including 1, 2:
  • Cytomegalovirus (CMV) infection 1, 7
  • HIV infection 2, 6
  • Toxoplasma gondii infection 1, 2
  • Adenovirus infection 1, 2

Management Considerations

• Treatment is primarily supportive; routine use of antivirals and corticosteroids is not recommended 2, 3
• Patients should avoid contact sports or strenuous exercise for at least 3-8 weeks from symptom onset or while splenomegaly is present to reduce the risk of splenic rupture (0.1-0.5% of cases) 3, 6
• In immunocompromised patients, consider reducing or discontinuing immunomodulator therapy if possible 1, 2
• In severe cases in immunocompromised patients, antiviral therapy with ganciclovir or foscarnet may be considered, though evidence supporting this approach is limited 1, 2