Epidemiological and genetic characterizations of hand, foot, and mouth disease and acute respiratory infections due to CV-A6 infection in Henan Province, China between 2021 and 2022

Coxsackievirus (CV) A6 has been widely considered as the main cause of global hand, foot, and mouth disease (HFMD) outbreaks. Despite the serious threat to children's health posed by the emerging CV-A6, our knowledge of the epidemiological features and etiology of HFMD caused by the new CV-A6 strains remains limited. In the present study, we aimed to investigate the epidemiological and genetic characterizations of CV-A6-associated HFMD outbreaks in Henan Province, China between 2021 and 2022. Clinical data and biospecimens of 407 children with mild and severe CV-A6 infection from Henan Children's Hospital (Children's Hospital Affiliated to Zhengzhou University) were collected for this prevalence study. Logistic regression analysis was employed to assess potential risk factors for severe illness. We also sequenced the VP1 gene of 4 CV-A6 strains, and a phylogenetic tree was conducted to characterize the evolutionary features of these CV-A6 strains. The majority of patients were 1 ~ 2 years old (236/407, 62.93%). Rash (364/407, 89.43%) and increase of lung markings in both lungs (224/407, 55.04%) were found to account for the highest percentage of clinical manifestations and clinical examination. Logistic regression analysis showed that boys were more likely to develop critical illness (OR: 1.970; 95% CI: 1.220 ~ 3.180), and that persistent high fever (OR: 2.066; 95% CI: 1.375 ~ 3.105), and elevated procalcitonin (PCT) levels (OR: 2.931; 95% CI: 1.590 ~ 5.405) would increase the risk of developing a critical illness (P < 0.01). The phylogenetic tree indicated that the genotype of CV-A6 strains in Henan Province was the D3 subtype. Collectively, in addition to the rash, acute respiratory infections due to CV-A6 infection are becoming increasingly common. Male sex, persistent high fever, and elevated PCT levels are associated with an increased risk of critical illness in patients infected with the D3 subtype of CV-A6. These findings may provide a scientific basis for guiding the prevention of HFMD and increase clinicians' awareness of CV-A6 infection.