Diagnostic Approach for Mononucleosis

Initial Testing and Interpretation

The Infectious Diseases Society of America recommends EBV-specific antibody testing for patients with negative heterophile antibody tests but persistent clinical suspicion, as well as for children younger than 10 years and patients in the first week of illness 1, 2
EBV-specific serologic testing is indicated for patients with atypical or severe presentations requiring confirmation, and the recommended panel includes Viral Capsid Antigen (VCA) antibodies, Epstein-Barr Nuclear Antigen (EBNA) antibodies, and Early Antigen (EA) antibodies 1, 2
Acute primary EBV infection is indicated by the presence of VCA IgM (with or without VCA IgG) and absence of EBNA antibodies, while past infection is indicated by the presence of VCA IgG and EBNA antibodies 1, 2

For patients with negative heterophile tests but mononucleosis-like symptoms, consider testing for other causes, including Cytomegalovirus (CMV), Adenovirus, HIV, and Toxoplasma gondii 1, 2
In immunocompromised patients, consider more extensive testing, including EBV viral load by nucleic acid amplification testing (NAAT) and testing for EBV-associated lymphoproliferative disease 1, 2

False-negative heterophile antibody results can occur in children under 10 years of age and early disease, while false-positive results may occur in leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 1, 2

For immunocompromised patients, quantitative PCR showing more than 10^2.5 copies/mg DNA in peripheral blood mononuclear cells suggests chronic active EBV 3