Flaviviruses are a heterogeneous group of viruses that may induce broad antigenic cross-reactivity. We present a patient who was admitted to the
infectious disease department with symptoms suggestive of
aseptic meningitis. During the clinical workup, the patient reported a
tick bite two weeks before the disease onset. High titers of
IgM and
IgG antibodies to tick-borne encephalitis virus (TBEV) were found in both serum and cerebrospinal fluid (CSF) samples, indicating acute TBEV
infection. West Nile virus (WNV) and Usutu virus (USUV)
IgM and/or
IgG antibodies were also detected, and a virus neutralization test (VNT) was performed. A high titer of TBEV neutralizing (NT)
antibodies (640) was detected, which confirmed acute TBE. However, NT
antibodies to WNV and USUV were also detected (titer 80 for both viruses). After TBEV and WNV
IgG avidity evaluation, previous
flavivirus infection was highly suspected (avidity index 82% and 89%, respectively). Blood, CSF, and urine samples were negative for respective viruses' RNA. The presented case highlights the challenges in flavivirus serodiagnosis. In the published literature, different degrees of cross-reactivity or cross-neutralization between TBEV and
dengue,
louping ill,
Omsk hemorrhagic fever, Langat, and Powassan virus were also observed. Therefore, the serology results should be interpreted with caution, including the possibility of cross-reactivity. In areas where several flaviviruses co-circulate VNT is recommended for disease confirmation.