Epidemiological, Clinical, and Virological Characterizations of Yezo Virus Infections, an Emerging Tick-borne Orthonairovirus Disease in Japan

BACKGROUND: Febrile disease caused by infection with Yezo virus (YEZV), a tick-borne orthonairovirus, was first reported in Japan in 2021 and subsequently identified in China. While recent studies suggest a broader endemic area of the emerging YEZV infections, its clinical and epidemiological characteristics remain poorly elucidated due to the limited number of reported cases. METHODS: We conducted retrospective and prospective surveillance of patients with suspected tick-borne febrile illnesses in Hokkaido, Japan, between 2013 and 2024. Serum samples were analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR), IgM/IgG enzyme-linked immunosorbent assay (ELISA), and neutralization assay. Viral genomes of isolates were sequenced and phylogenetically analyzed with publicly available YEZV genomes. RESULTS: A total of 22 patients with YEZV infections, including 10 newly identified patients, were analyzed. Most infections occurred between May and July, coinciding with the peak activity of Ixodes ticks in the study area. The first case from southern Hokkaido was identified. Fever, leukocytopenia, thrombocytopenia, elevated levels of liver enzymes, and ferritin were determined as common features observed in patients with YEZV infections. Viral RNA was typically detectable in the serum within 7 days after disease onset. Serum antibodies became positive later and might persist up to at least 600 days. Phylogenetic analysis incorporating 5 new isolates showed the circulations of 2 genetic groups of YEZVs in Japan. CONCLUSIONS: Our results revealed characteristics of YEZV infections in patients and highlighted the importance of a combination of molecular and serological diagnostics. The proposed case definitions and diagnostic framework may contribute to future surveillance.