Characterization of genome sequences and clinical features of coxsackievirus A6 strains collected in Hyogo, Japan in 1999‐2013

Abstract

Coxsackievirus A6 (CV-A6) is an enterovirus, which is known to cause herpangina. However, since 2009 it has frequently been isolated from children with hand, foot, and mouth disease (HFMD). In Japan, CV-A6 has been linked to HFMD outbreaks in 2011 and 2013. In this study, the full-length genome sequencing of CV-A6 strains were analyzed to identify the association with clinical manifestations. Five thousand six hundred and twelve children with suspected enterovirus infection (0-17 years old) between 1999 and 2013 in Hyogo Prefecture, Japan, were enrolled. Enterovirus infection was confirmed with reverse transcriptase-PCR in 753 children (791 samples), 127 of whom (133 samples) were positive for CV-A6 based on the direct sequencing of the VP4 region. The complete genomes of CV-A6 from 22 positive patients with different clinical manifestations were investigated. A phylogenetic analysis divided these 22 strains into two clusters based on the VP1 region; cluster I contained strains collected in 1999-2009 and mostly related to herpangina, and cluster II contained strains collected in 2011-2013 and related to HFMD outbreak. Based on the full-length polyprotein analysis, the amino acid differences between the strains in cluster I and II were 97.7 ± 0.28%. Amino acid differences were detected in 17 positions within the polyprotein. Strains collected in 1999-2009 and those in 2011-2013 were separately clustered by phylogenetic analysis based on 5'UTR and 3Dpol region, as well as VP1 region. In conclusion, HFMD outbreaks by CV-A6 were recently frequent in Japan and the accumulation of genomic change might be associated with the clinical course.

Impact of Coxsackievirus A6 emergence on hand, foot, and mouth disease epidemic in Osaka City, Japan

“…Phylogenetic analysis revealed that the majority of circulating CV‐A6 strains detected from 2011 to 2015 in Osaka City and CV‐A6 strains detected from 1999 to 2009 in Japan classified into different clades. Another report describes a similar trend, and so the clade to which an infecting virus belongs to might be a one of the determinants as to whether HFMD or herpangina occurs . In cases of EV‐A71, it is reported that amino acid substitutions in VP1 are responsible for increased virulence, adaptation to the host, and tissue dissemination .…”

“…Another report describes a similar trend, and so the clade to which an infecting virus belongs to might be a one of the determinants as to whether HFMD or herpangina occurs. 32 In cases of EV-A71, it is reported that amino acid substitutions in VP1 are responsible for increased virulence, adaptation to the host, and tissue 33,34 However, it is likely that changes in other region may be involved in determining pathogenicity, because only the VP1 region was analysed in this study.…”

A review and meta‐analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand‐foot‐mouth disease in China and global implications

“…53 A study of severe HFMD cases showed that EV-A71 was the dominant pathogen (79.3%, 2783/3510). 55 CV-A6 usually caused mild HFMD, whose common symptom is some form of generalized (whole-body) rash, 56,57 but it was the most prevalent genotype of other EVs (42.9%, 21/49). 55 In order to study the severity of CV-A6, 57 articles describing severe CV-A6 HFMD patients were included in the meta-analysis.…”

Emerging Coxsackievirus A6 Causing Hand, Foot and Mouth Disease, Vietnam

“…Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) have been regarded as the major causes of HFMD ( 3 ). CV-A6 was isolated in the United States in 1949 ( 4 ) and has steadily become one of the main viruses causing HFMD outbreaks in Europe, America, and Asia, including China, Japan, Taiwan, and Thailand ( 3 , 5 – 10 ). Unlike EV-A71, for which the (sub)genogroup designation has been well established ( 11 ), but similar to other coxsackieviruses (CV-A16 and CV-A10), CV-A6 is arbitrarily divided into several phylogenetic clusters or lineages, from cluster A to F ( 12 ) or lineage A to E (E1 and E2) ( 3 ).…”