The Global Emergence of Coxsackievirus-A6 as a Major Causative Agent of Hand, Foot, and Mouth Disease

Abstract

BACKGROUND: Hand, Foot, and Mouth Disease (HFMD) is a common childhood infectious disease. Following the near complete eradication of polio, non-polio enteroviruses have become responsible for large outbreaks of HFMD and less frequently, severe and often fatal neurological complications. The predominant serotypes responsible for HFMD are Enterovirus-71 (EV-71) and Coxsackievirus-A16 (CV-A16), but Coxsackievirus-A6 (CV-A6) has increasingly been reported as a causative agent in a series of HFMD outbreaks worldwide since 2008. The rise of CV-A6-associated HFMD incidence has presented new challenges in the control and prevention of the disease not only because CV-A6-associated HFMD has different clinical features from classic HFMD caused by EV-71 and CV-A16, but also since its severe cases have been associated with fatal neurological and cardiovascular complications. Clarifying and understanding the changing epidemiology of CV-A6 is thus key to successful management of future HFMD outbreaks.METHODS: This thesis documents and elucidates the rise of CV-A6 as a significant etiological agent of HFMD through a combination of systematic review, epidemiological data analysis, and mathematical modeling. The systematic review focuses on studies and surveillance reports on CV-A6 incidence. To clarify the global burden, spread, and genetic evolution of CV-A6, descriptive and statistical analyses have been conducted on epidemiological data acquired and aggregated from various published studies and records from disease surveillance systems. Finally, this thesis simulates the disease dynamics of Coxsackievirus-A6 in Japan by adapting a previously published Time Series Susceptible-Infected-Recovered (TSIR) model.RESULTS: Over the past ten years, CV-A6 has emerged as a major causative agent of HFMD outbreaks in many countries in different regions of the world: China, Cuba, Finland, France, India, Israel, Italy, Japan, Malaysia, the Netherlands, New Zealand, Singapore, Spain, Switzerland, Taiwan, Thailand, the United Kingdom, and the United States. The average age of CV-A6-associated HFMD infection is significantly lower in Asia than in Europe, North America, Central America, and Oceania. The results of the systematic review indicate that the CV-A6 strain responsible for the series of outbreaks across the globe is a new, more virulent genetic variant that likely originated from the CV-A6-associated HFMD outbreak in Finland in 2008. A review of the phylogenetic studies on the CV-A6 strains circulating in China revealed that the CV-A6 strain has further mutated and undergone genetic recombination since then. Finally, the results of the TSIR model simulations demonstrate that increasing CV-A6’s initially low transmission rate produces cycles that qualitatively resemble HFMD’s biennial episodic patterns in Japan.DISCUSSION: CV-A6 has emerged as a major causative agent of HFMD in different countries worldwide in the span of a five-year period, 2008-2013. This global pattern of emergence suggests that CV-A6 evolved to partially escape from cross-protective immunity from other circulating enterovirus serotypes. As CV-A6 “escaped” from this cross-protective effect, individuals immunologically naïve to this strain accumulated until there were enough susceptibles for a series of CV-A6-associated HFMD outbreaks to occur. CV-A6’s increased incidence and presentation as HFMD poses a risk to public health and presents new challenges in the management of HFMD. Thus, to more effectively control HFMD, we must improve CV-A6-associated HFMD detection and surveillance.