West Nile virus (WNV) and Zika virus (ZIKV) are mosquito-borne viruses in the family Flaviviridae. Residents in, and travelers to, areas where the viruses are circulating are at risk for
infection, and both viruses can cause an acute febrile illness. Given known cross-reactivity in flavivirus serologic assays, it is possible a patient with acute
WNV infection could be misdiagnosed as having
ZIKV infection if appropriate testing is not conducted. To understand how frequently persons with
WNV infection have detectable cross-reactive ZIKV
immunoglobulin M (
IgM) antibody, we used archived serum samples from patients in the United States with recent
WNV infection confirmed by a
microsphere-based immunoassay test for
IgM antibody and
neutralizing antibody testing. Samples were tested for ZIKV
IgM antibody with the Centers for Disease Control and Prevention (CDC) ZIKV
IgM antibody capture
enzyme-linked
immunosorbent assay. Among 153 sera from patients with acute
WNV infection, the ZIKV
IgM antibody result was positive in 56 (37%; 95% confidence interval [CI] 29-44%) and equivocal in 28 (18%; 95% CI 13-25%). With 55% of samples having cross-reactive
antibodies, it is important for health care providers to request appropriate testing based on the most likely cause of a patient's possible arboviral
infection considering their clinical symptoms and signs, travel history, and place of residence. For cases where the epidemiology does not support the preliminary
IgM findings, confirmatory
neutralizing antibody testing should be performed. These measures will avoid an incorrect diagnosis of
ZIKV infection, based on cross-reactive
antibodies, in a person truly infected with WNV.