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Review
. 2019 Oct 20;20(20):5201.
doi: 10.3390/ijms20205201.

Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World

Gabriel Gonzalez  1   2 , Michael J Carr  3   4 , Masaaki Kobayashi  5 , Nozomu Hanaoka  6 , Tsuguto Fujimoto  7
Affiliations
Review

Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World

Gabriel Gonzalez et al. Int J Mol Sci. .

Abstract

Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is predominantly attributable to EV-A types, including the major pathogen EV-A71, and coxsackieviruses, particularly CV-A6, CV-A16, and CV-A10. There have been multiple EV-A71 outbreaks associated with a profound burden of neurological disease and fatal outcomes in Asia since the early 1980s. Efficacious vaccines against EV-A71 have been developed in China but widespread pediatric vaccination programs have not been introduced in other countries. Encephalitis, as a consequence of complications arising from HFMD infection, leads to damage to the thalamus and medulla oblongata. Studies in Vietnam suggest that myoclonus is a significant indicator of central nervous system (CNS) complications in EV-A71-associated HFMD cases. Rapid response in HFMD cases in children is imperative to prevent the progression to a CNS infection; however, prophylactic and therapeutic agents have not been well established internationally, therefore surveillance and functional studies including development of antivirals and multivalent vaccines is critically important to reduce disease burden in pediatric populations.

Keywords: central nervous system complications; encephalitis; enterovirus A71; hand-foot and mouth disease; molecular characterization.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Distribution of the number of hand-foot and mouth disease (HFMD) cases per week in each year between July 2012 and August 2019 in Japan. The horizontal and vertical axes represent the week of the year and the number of cases in Japan for each week, respectively. Months corresponding to the week number are colored by Japanese season as spring (pink), summer (orange), autumn (light brown) and winter (light blue). Colors and marks for each yearly series are presented in the legend at the bottom of the panel.
Figure 2
Figure 2
Distribution of HFMD cases by age between 2009 and 2018. The counts of patients were normalized as the percentages of the yearly total number of cases (vertical axis) and then stratified by age (horizontal axis).
Figure 3
Figure 3
Photographs of a patient with the HFMD caused by CV-A6. Day 0 and 2 after the onset of the disease in hands, feet, and mouth. After one month, onycholysis was observed for both hands (foot and mouth lesions healed after one month). Pictures were taken with the informed consent of patients.
Figure 4
Figure 4
Phylogenetic tree of nucleotide sequences encoding the VP1 in EV-A71 genogroups, CV-A6, CV-A10, and CV-A16. The phylogenetic tree was inferred with MrBayes v3.5 [78] with the general time reversible substitution model allowing for heterogeneity modeled by a gamma distribution and allowing for invariable sites (GTR + G + I) with 5 × 106 chain length. The sequences are publicly available in GenBank with the accession number between parentheses. Tips are colored according to the genogroup A, B, C, D, E, F, and CV genotypes (CV-A6, -A10 and -A16), as black, red, blue, green, orange, purple and gray, respectively. Posterior probability supporting the topology is shown next to the branches.
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