Paragraph: Context: Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). Objective: This study reports a systematic review of the epidemiology of HFMD in Asia. Data Sources: PubMed, Web of Science and Google Scholar were searched up to December 2014. Study Selection: Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. Data Extraction: Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. Results: HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. Limitations: Diversity of study designs complicates attempts to identify features of HFMD epidemiology. Conclusions: Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps. Key Words: hand, foot and mouth disease, EV-A71, CV-A16, epidemiology (Pediatr Infect Dis J 2016;35:e285-e300) H and, foot and mouth disease (HFMD) has become an endemic childhood disease in East and Southeast Asia. Its main etiologic agents are human enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16). Although usually mild-with symptoms limited to >38°C fever, malaise, rashes on the volar regions of the hands and feet, herpangina and difficulty eating and drinking-more rarely, infection can lead to complications of the nervous or cardiopulmonary systems. Such cases can result in long-term sequelae such as cognitive and motor disorders 1,2 or death, usually from pulmonary edema or brainstem encephalitis. 3 Although complications are rare, the number of children being infected in high-incidence countries such as China (≈2.7 M cases in 2014 3 ) means the death toll can be substantial (384 deaths in China in 2014 3 ). The EV-A71 virus seems to be responsible for more severe outcomes, while CV-A16 and other Coxsackieviruses, such as CV-A2, CV-A6 and CV-A10, usually present milder symptoms that resolve within a few weeks. [4] [5] [6] There are nearly 25 years of literature from Asia that describes the epidemiology of HFMD, drawing on pediatric cohorts, national surveillance systems, outbreak investigations and clinical data, and from disparate countries that span stages of economic development and with climates that range from tropical to temperate. This diversity complicates attempts to identify general features of HFMD epidemiology and conceals gaps in the body of knowledge of this important pediatric disease. The objective of this paper is to provide a robust systematic review of the epidemiology of HFMD that informs public health policy making about HFMD epidemics. The review covers 3 major areas: (1) history and seasonality of HFMD, and the efforts in predictive modeling; (2) risk factors for infection, to guide control and (3) global epidemiologic parameters, such as the incubation period and basic reproduction number, which may determine the effectiveness of control policies. 
 Title: Original StudieS
Output: True