Coxsackievirus A6 Recombinant Subclades D3/A and D3/H Were Predominant in Hand-Foot-And-Mouth Disease Outbreaks in the Paediatric Population, France, 2010–2018

Abstract

Coxsackievirus A6 (CVA6) emerged as the most common enterovirus of seasonal outbreaks of hand-foot-and-mouth disease (HFMD). We investigated CVA6 genetic diversity among the clinical phenotypes reported in the paediatric population during sentinel surveillance in France between 2010 and 2018. CVA6 infection was confirmed in 981 children (mean age 1.52 years [IQR 1.17–2.72]) of whom 564 (58%) were males. Atypical HFMD was reported in 705 (72%) children, followed by typical HFMD in 214 (22%) and herpangina in 57 (6%) children. Throat specimens of 245 children were processed with a target-enrichment new-generation sequencing approach, which generated 213 complete CVA6 genomes. The genomes grouped within the D1 and D3 clades (phylogeny inferred with the P1 genomic region). In total, 201 genomes were classified among the recombinant forms (RFs) A, B, F, G, H, and N, and 12 genomes were assigned to 5 previously unreported RFs (R–V). The most frequent RFs were A (58%), H (19%), G (6.1%), and F (5.2%). The yearly number of RFs ranged between 1 (in 2012 and 2013) and 6 (2018). The worldwide CVA6 epidemic transmission began between 2005 and 2007, which coincided with the global spread of the recombinant subclade D3/RF-A.

Evolutionary and Genetic Recombination Analyses of Coxsackievirus A6 Variants Associated with Hand, Foot, and Mouth Disease Outbreaks in Thailand between 2019 and 2022

“…Phylogenetic analysis revealed that the nt sequences from the 3Dpol region belonged to 23 bootstrap-supported clades (recombinant forms (RFs); A–X) in agreement with previous reports ( Figure 2 B) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 43 , 44 , 45 , 46 , 47 ]. Most of the CV-A6/TH strains (84%, 147/174) in this study belonged to the previously described RF-A, while only ~6% (11/174) of the strains were assigned to RF-N (6%), and one strain was classified as RF-H (0.6%).…”

“…Over the past decade, an increase in the number of CV-A6 recombinant mutants has been reported [ 40 , 41 ]. To find evidence of recombination within the CV-A6 variants characterized in Thailand (CV-A6/TH strains) and the previously defined strains, 174 samples were analyzed using sequencing of their VP1 and 3Dpol regions.…”

“…A previous study of CV-A6 epidemiology revealed that the shift from CV-A6 clade D2 to D3 occurred in China and France [ 40 , 41 ]. Moreover, since 2010, CV-A6/D3 strains have caused large HFMD outbreaks in several countries, including Brazil [ 7 ], China [ 8 ], India [ 11 ], Japan [ 12 ], and Vietnam [ 15 ].…”

‘Tomato flu’ a new epidemic in India: Virology, epidemiology, and clinical features

“…The study also determined risk factors for adult HFMD which included a family size of 4 or more, having a child under 5 years of age, and having a child recently diagnosed with HFMD. These results support the human-to-human transmission of and why children may be affected more than adults [ 28 ].…”

“…These include fever, anorexia, rashes, and joint pain. The difference in the clinical picture of this recent outbreak to other outbreaks of HFMD was the appearance of red blisters on skin, and can be due to a new variant of CV-A16 [ 28 ].…”