Cross-Reactive Antibodies in Tick-Borne Encephalitis: Case Report and Literature Review

Abstract

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.

Tick-Borne Encephalitis in a 6-Year-Old Patient: A Case Report

“…The surface envelope glycoprotein (E-protein) is the main target for the antibody response to flaviviruses, which may result in the production of cross-reactive, non-neutralizing antibodies, particularly within the same serocomplex, owing to the protein structure containing virus-specific and cross-reactive epitopes. 9-12 In particular, the classic biphasic course 7 with an initial myositis (unaccompanied by hyperpyrexia in our patient) and an encephalitic manifestation occurred approximately 15 days later. Montvydaite et al 7 found that the presence of myositis predicted a severe disease course.…”

Tick-borne zoonotic flaviviruses and Borrelia infections in wildlife hosts: What have field studies contributed?

“…Cross-reactivity in wide-range immunoassays may also hamper data interpretation [ 84 ]. For instance, anti-MEAV antibodies were surprisingly detected in Cervidae [ 36 ], whilst MEAV belongs to the seabird group in TBFV phylogeny [ 85 ].…”

An Overview of Tick-Borne Encephalitis Epidemiology in Endemic Regions of Continental Croatia, 2017–2023

“…The TBEV IgG avidity index (AI) was interpreted as follows: <40% low (acute/recent infection); 40–60% borderline; and >60% high (past infection). Samples with cross-reactive flavivirus antibodies were confirmed using a virus neutralization test in cell culture (VNT) [ 25 , 26 ].…”