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

Abstract

Hand, foot and mouth disease (HFMD) is a major public health issue in Asia and has global pandemic potential. Coxsackievirus A6 (CV-A6) was detected in 514/2,230 (23%) of HFMD patients admitted to 3 major hospitals in southern Vietnam during 2011-2015. Of these patients, 93 (18%) had severe HFMD. Phylogenetic analysis of 98 genome sequences revealed they belonged to cluster A and had been circulating in Vietnam for 2 years before emergence. CV-A6 movement among localities within Vietnam occurred frequently, whereas viral movement across international borders appeared rare. Skyline plots identified fluctuations in the relative genetic diversity of CV-A6 corresponding to large CV-A6-associated HFMD outbreaks worldwide. These data show that CV-A6 is an emerging pathogen and emphasize the necessity of active surveillance and understanding the mechanisms that shape the pathogen evolution and emergence, which is essential for development and implementation of intervention strategies.

Keywords: Asia; Hand foot and mouth disease; Vietnam; coxsackievirus A6; deep sequencing; enteroviruses; phylogeny; viruses.

Figure 1

Temporal distribution of PCR-positive hand, foot and mouth disease cases and detection rates of CV-A6 during 2011–2015, Vietnam. CV, coxsackievirus.

Figure 2

Maximum-likelihood tree of viral capsid protein 1 sequences of coxsackievirus A6 strains from Vietnam and worldwide. Branches are colored by cluster; cluster A, which includes the Vietnam strains, is indicated. Scale bar indicates nucleotide substitutions per site.

Figure 3

Maximum clade credibility trees illustrating the phylogeography of coxsackievirus A6. A) Complete coding sequence–based tree of Vietnam strains; B) viral capsid protein 1–based tree of global strains. Branches are color-coded according to location of sampling. Posterior probabilities >85% and state probabilities >75% (black circles) are indicated at all nodes. Map in panel A obtained from https://mapchart.net.

Figure 4

Skyline plots depicting the relative genetic diversity of CV-A6 over time. A) Result obtained from the analysis of viral capsid protein 1 sequences of global strains; B) result obtained from the analysis of complete coding sequences of Vietnam strains. Blue shading indicates 95% highest posterior density interval. Arrows in panel A indicate worldwide CV-A6 outbreaks and associated fluctuations in relative genetic diversity ; map (obtained from https://mapchart.net) illustrates the countries in which CV-A6–associated HFMD outbreaks have been recorded to date (3). No sequences from Cuba, Singapore, or the United States fulfilled the selection criteria for the skyline plot and phylogenetic analyses (see Methods section). CV, coxsackievirus.