Abstract Background Previously healthy adults hospitalized with an acute undifferentiated illness who test positive for cytomegalovirus (CMV) immunoglobulin M (IgM) in their serum may have a primary CMV infection, CMV reactivation/reinfection, or a false-positive result. We aimed to understand how clinicians interpret and incorporate positive CMV IgM test results into their diagnostic and management decisions. Methods A retrospective case series study of 13 previously healthy, immunocompetent adults hospitalized with an acute illness in a 12-hospital system from January 1, 2017, to January 1, 2020, who tested positive for CMV IgM within 3 days of hospitalization. Twelve of 13 had CMV IgG. Results Among these 13 adults (median age, 36), elevated liver enzymes (100%), fever (85%), hepatosplenomegaly (54%), and headache (38%) were common. Lymphocytosis was observed in five patients, reactive lymphocytes in three, and one patient died from hemophagocytic lymphohistocytosis. Dual positivity for CMV and EBV IgM was frequent, yet only one patient was tested for both CMV and EBV DNA in blood or for CMV IgG avidity index, which indicated a primary CMV infection. Of the six patients with CMV DNA in blood, four received anti-CMV treatment. Uncertainty regarding CMV’s role in the illness was common, and final assessments varying even among cases with similar clinical presentations and serologic patterns. Conclusions Interpreting positive CMV IgM results in immunocompetent adults hospitalized with acute illness is challenging and ambiguous due to test limitations and confounders. Supplemental CMV IgG avidity testing can help determine whether primary CMV infection caused the illness, thereby refining the diagnosis and potentially influencing clinical decision-making.
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