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

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Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World International Journal of Molecular Sciences Review 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 and Tsuguto Fujimoto 6,* 1 Division of Bioinformatics, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; [email protected] 2 National Advanced Computing Collaboratory, National Center for High Technology, San Jose 1174-1200, Costa Rica 3 National Virus Reference Laboratory, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland; [email protected] 4 Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 001-0020, Japan 5 Kobayashi Pediatric Clinic, Fujieda 426-0067, Japan; [email protected] 6 Division 4, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; [email protected] * Correspondence: [email protected] Received: 26 August 2019; Accepted: 18 October 2019; Published: 20 October 2019 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: hand-foot and mouth disease; central nervous system complications; encephalitis; molecular characterization; enterovirus A71 1. Introduction Multiple, highly contagious Enterovirus A types are the etiological agents of infectious disease outbreaks affecting pediatric populations worldwide [1,2]. Among these types, enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6) and coxsackievirus A16 (CV-A16), are most frequently associated with hand-foot-and-mouth disease (HFMD), aseptic meningitis (AM) and encephalitis [2,3]. Despite the vast majority of enterovirus infections being sub-clinical and self-resolving in nature, large outbreaks Int. J. Mol. Sci. 2019, 20, 5201; doi:10.3390/ijms20205201 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 15 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 15 A71, CV-A6, and CV-A16 have been reported in Asia since 1997 with severe cases developing complicationsA71, CV-A6, affectingand CV-A16 the central have nervous been reported system (C inNS) Asia with since persisting 1997 sequelaewith severe and fatalitiescases developing [4–6]. complicationsAnnual HFMD affecting data the are central recorded nervous by system the National (CNS) with Epidemiological persisting sequelae Surveillance and fatalities of Infectious [4–6]. Int.Diseases J. Mol.Annual Sci.(NESID)2019 HFMD, 20 ,in 5201 Japandata are [7] recordedwith 60% byof the caNationalses occurring Epidemiological between weeks Surveillance 27 to 37 of during Infectious2 ofthe 16 summerDiseases season (NESID) (July in andJapan September [7] with 60%in Figure of the 1). ca HFMDses occurring patients between are typically weeks children 27 to 37 up during to three the yearssummer of age season and represent(July and 76%September of the total in Figure number 1). ofHFMD annual patients cases (Figure are typically 2). Among children these up cases, to three the caused by EV-A71, CV-A6, and CV-A16 have been reported in Asia since 1997 with severe cases severeyears ofinfections age and representcomprised 76% brainstem of the total encephalitis number of and annual deaths cases from (Figure central 2). pulmonary Among these edema cases, and the developing complications affecting the central nervous system (CNS) with persisting sequelae and heartsevere failure infections [8]. Ascomprised a consequence, brainstem HFMD encephalitis outbreaks and deathsare of fromgreat centralpublic pulmonaryhealth importance edema andas fatalities [4–6]. enterovirusesheart failure (EVs)[8]. As can a easilyconsequence, spread by HFMD droplet outbreaks transmission are andof great via fomites public among health children importance in day as Annual HFMD data are recorded by the National Epidemiological Surveillance of Infectious nurseriesenteroviruses or kindergartens (EVs) can easily [9]. spread by droplet transmission and via fomites among children in day Diseases (NESID) in Japan [7] with 60% of the cases occurring between weeks 27 to 37 during the nurseriesThe present or kindergartens study details [9]. the current research related to the incidence, diagnosis, treatment and summer season (July and September in Figure1). HFMD patients are typically children up to three clinicalThe management present study of HFMD,details the AM current and encephalitis research rela, arisingted to from the incidence, laboratory-confirmed diagnosis, treatment enterovirus and years of age and represent 76% of the total number of annual cases (Figure2). Among these cases, Aclinical types managementEV-A71, CV-A6, of HFMD, and CV-A16. AM and Viral, encephalitis epidemiological, arising from and laboratory-confirmed clinical factors are analyzed enterovirus to the severe infections comprised brainstem encephalitis and deaths from central pulmonary edema provideA types aEV-A71, comprehensive CV-A6, andassessment CV-A16. of Viral, the patholepidemiologicalogy associated and clinicalwith EV factors infections are analyzed and what to and heart failure [8]. As a consequence, HFMD outbreaks are of great public health importance as parametersprovide a contributecomprehensive to prevention assessment and ofcountermea the patholsuresogy toassociated mitigate diseasewith EV chains infections of transmission. and what enteroviruses (EVs) can easily spread by droplet transmission and via fomites among children in day parameters contribute to prevention and countermeasures to mitigate disease chains of transmission. nurseries or kindergartens [9]. Figure 1. Distribution of the number of hand-foot and mouth disease (HFMD) cases per week in each yearFigureFigure between 1.1. DistributionDistribution July 2012 of ofand thethe August numbernumber 2019 ofof hand-foot hand-footin Japan. The andand horizontal mouthmouth diseasedisease and vertical (HFMD)(HFMD) axes casescases represent perper weekweek the inin week eacheach yearofyear the between between year and July July the 2012 2012 number and and August Augustof cases 2019 2019 in Japan in in Japan.Japan. for each TheThe horizontalhorizontalweek, respectively. andand verticalvertical Months axesaxes representrepresent corresponding thethe weekweek to of the year and the number of cases in Japan for each week, respectively. Months corresponding to theof theweek year number and the are number colored of by cases Japanese in Japan season for eachas spring week, (pink), respectively. summer Months (orange), corresponding autumn (light to the week number are colored by Japanese season as spring (pink), summer (orange), autumn (light brown)the week and number winter are(light colored blue). byColors Japanese and marks season for as each spring yearly (pink), series summer are pr esented(orange), in autumnthe legend (light at brown) and winter (light blue). Colors and marks for each yearly series are presented in the legend at thebrown) bottom and of winter the panel. (light blue). Colors and marks for each yearly series are presented in the legend at the bottom of the panel. the bottom of the panel. 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). Int. J. Mol. Sci. 2019, 20, 5201 3 of 16 The present study details the current research related to the incidence, diagnosis, treatment and clinical management of HFMD, AM and encephalitis, arising from laboratory-confirmed enterovirus A types EV-A71, CV-A6, and CV-A16. Viral, epidemiological and clinical factors are analyzed to provide a comprehensive assessment of the pathology associated with EV infections and what parameters contribute to prevention and countermeasures to mitigate disease chains of transmission. 2. Enterovirus A Species Enterovirus A are classified within the genus Enterovirus, one of the more than 30 genera in the family Picornaviridae, which also includes the related human viral pathogens within the Hepatovirus,
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