Circulation of Coxsackievirus A10 and A6 in Hand-Foot-Mouth Disease in China, 2009–2011

Qing-Bin Lu,Ying Wo,Xiu-Jun Li,Li-Juan Liu,Xian-Jun Wang,Hong Yang,Cui He,Hong-Mei Xu,Ting-Yu Li,Wei Liu,Shu-Jun Ding,Wu-Chun Cao,Hao Li,Xiao-Dan Chen,Xiao-Ai Zhang,Chiyu Zhang

doi:10.1371/journal.pone.0052073

Abstract

Coxsackieviruses A10 (CV-A10) and A6 (CV-A6) have been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events globally. However, our understanding of epidemiological and genetic characteristics of these new agents remains far from complete. This study was to explore the circulation of CV-A10 and CV-A6 in HFMD and their genetic characteristics in China. A hospital based surveillance was performed in three heavily inflicted regions with HFMD from March 2009 to August 2011. Feces samples were collected from children with clinical diagnosis of HFMD. The detection and genotyping of enteroviruses was performed by real-time PCR and sequencing of 5′UTR/VP1 regions. Phylogenetic analysis and selection pressure were performed based on the VP1 sequences. Logistic regression model was used to identify the effect of predominant enterovirus serotypes in causing severe HFMD. The results showed 92.0% of 1748 feces samples were detected positive for enterovirus, with the most frequently presented serotypes as EV-71 (944, 54.0%) and CV-A16 (451, 25.8%). CV-A10 and CV-A6 were detected as a sole pathogen in 82 (4.7%) and 44 (2.5%) cases, respectively. Infection with CV-A10 and EV-71 were independently associated with high risk of severe HFMD (OR = 2.66, 95% CI: 1.40–5.06; OR = 4.81, 95% CI: 3.07–7.53), when adjusted for age and sex. Phylogenetic analysis revealed that distinct geographic and temporal origins correlated with the gene clusters based on VP1 sequences. An overall ω value of the VP1 was 0.046 for CV-A10 and 0.047 for CV-A6, and no positively selected site was detected in VP1 of both CV-A10 and CV-A6, indicating that purifying selection shaped the evolution of CV-A10 and CV-A6. Our study demonstrates variety of enterovirus genotypes as viral pathogens in causing HFMD in China. CV-A10 and CV-A6 were co-circulating together with EV-71 and CV-A16 in recent years. CV-A10 infection might also be independently associated with severe HFMD.

Highlights

Hand-foot-mouth disease (HFMD) is a common disease characterized with fever, sore throat, general malaise and vesicular eruptions on hand, feet, oral mucosa and tongue
Outbreaks of HFMD were mainly caused by two types of enterovirus A species, enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16), with differing ratios
92.0% of the 1748 feces samples were detected to be positive for HEV, with the most frequently presented serotypes as EV-71 (944, 54.0%) and CV-A16 (451, 25.8%)

Summary

Introduction

Hand-foot-mouth disease (HFMD) is a common disease characterized with fever, sore throat, general malaise and vesicular eruptions on hand, feet, oral mucosa and tongue. Large outbreaks of HFMD were reported to be caused by the cocirculating of CV-A10 and CV-A6 in Finland [11]. During 2008, an outbreak of HFMD with onychomadesis as a common feature occurred in Finland was identified to be caused by CV-A6 [2]. CV-A6, as the main serotype, caused outbreaks of HFMD in Taiwan, 2010 [8] and in Japan, 2010 [9]. All of these previous studies provided strong evidence of CV-A6 and CV-A10 infections as new and important causes of HFMD, highlighting the necessity of comprehensive surveillance of all HEVs circulation in HFMD epidemics

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Results

Conclusion