Pathogenic Surveillance and Genetic Characteristics of Hand, Foot, and Mouth Disease Pathogens in Xi’an, 2020–2024

Background: Hand, foot, and mouth disease (HFMD) is a common pediatric infectious disease that frequently causes outbreaks in the Asia-Pacific region. The causative pathogens of HFMD are dynamically changing, with a notable genotypic shift observed in coxsackievirus A16 (CVA16) across China. Methods: Epidemiologic data and clinical specimens were collected from reported HFMD cases. Pan-enterovirus, enterovirus A71 (EV-A71), CVA16, coxsackievirus A6 (CVA6), and coxsackievirus A10 (CVA10) were detected by real-time polymerase chain reaction. VP1 regions of CVA6 and CVA16 were amplified, sequenced, and phylogenetically analyzed. Results: Among 2596 specimens, 2148 (82.7%) were enterovirus-positive. The proportions were: CVA6 52.8%, CVA16 23.8%, CVA10 5.0%, EV-A71 0.3%. CVA6 predominated in 2020, 2022 and 2023; CVA16 predominated in 2021 and 2024. Compared with CVA16 infection, CVA6 infection was associated with younger age (3.25 vs. 4.14 years, P < 0.001) and a higher risk of severe disease (OR = 12.93). All CVA6 strains detected in Xi’an were assigned to subgenotype D3a, whereas CVA16 strains were classified as B1a, B1b or B1c, among which B1a was the most prevalent (87.3%). Notably, the B1c lineage, first detected in Xi’an in 2024, accounted for a substantial proportion of cases. Conclusions: CVA6 and CVA16 are the predominant HFMD pathogens in Xi’an with alternating circulation. All identified CVA6 strains belonged to the D3a subtype, whereas the B1a subtype predominated among CVA16 strains. The first emergence of the CVA16 B1c sublineage in 2024 mirrors national trends and warrants intensified surveillance. The lack of cross-protection among serotypes highlights the need for multivalent vaccines.