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

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.

Molecular epidemiology of enteroviruses associated with severe hand, foot and mouth disease in Shenzhen, China, 2014-2018

“…The most frequent complication was myoclonic jerk (61.9%, 306/494), and other common severe complications included aseptic encephalitis (47.0%, 232/494), tachypnea (29.8%, 147/494), vomiting (28.1%, 139/494), tachycardia (24.5%, 121/494), and lethargy (17.0%, 84/494). Gonzalez et al reported that myoclonic jerk is a significant indicator of central nervous system complications in EV-A71-infected HFMD patients [ 17 ], and this was also found in our study. Furthermore, our study showed that myoclonic jerk is also the most frequent complication in severe CVA6 and CVA16-associated HFMD.…”

“…Other EV-A types, including CVA2, CVA4, CVA5, CVA6, CVA8, CVA10, CVA14 and CVA16, can also cause severe HFMD [ 3 – 10 ]. Some members of the species Enterovirus B , such as CVA9, CVB1-5, echovirus 3 (E3), E6, E7 E9, E11, E14, E16, E18, E20, E30 and E33, are also frequently associated with severe complications, especially encephalitis and aseptic meningitis [ 11 – 17 ].…”

Leading Enterovirus Genotypes Causing Hand, Foot, and Mouth Disease in Guangzhou, China: Relationship with Climate and Vaccination against EV71

“…Hand, foot, and mouth disease (HFMD) is a common and potentially fatal infectious disease in children under 5 years of age [ 1 ]. Deaths from HFMD occur infrequently [ 2 ], with an annual average of 191 deaths over the past five years in China [ 3 ]. In China, HFMD has caused substantial disease burden, and has remained at the top of the list for Group C infectious diseases in terms of morbidity and mortality since the May 2008 outbreak in Anhui [ 3 ].…”

Enterovirus genomic load and disease severity among children hospitalised with hand, foot and mouth disease

“…Surviving cases can suffer long term sequelae [1] . HFMD is caused by human enteroviruses, which are positive-sense single stranded RNA viruses of about 27–30 nm in size [2] . The HFMD etiological agents primarily belong to species of Enterovirus (EV) A, including commonly detected serotypes of EV-A71, coxsackie virus (CV) A16, CV-A6 and CV-A10, as well as other relatively rare serotypes including CV-A4, CV-A2 and CV-A8.…”

“…Of these, EV-A71 accounts for the largest proportion of cases with unfavorable clinical outcomes, but the frequency of severe disease caused by other serotypes has been increasing recently [3 , 4] . There are frequent HFMD epidemics in the Asia Pacific region, posing a significant threat to public health [ 2 , 3 , 5 ].…”