The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis

Abstract

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.

FIGURE 1.

Temporal patterns of HFMD outbreaks in Asia, by latitude. Left: Plot Digitizer is used to convert charts into numbers. White boxes are the months where HFMD cases fall below the year’s median. The remaining cells are then shaded into 4 darker shades by octiles. The regions of China were based on Wang et al’s classification(C standing for central). The regions are arranged by latitude. South China, Hong Kong and Taiwan have subtropical climates. Areas further north are temperate, while the Southeast Asian regions are tropical. Right: The coefficient of variation is the ratio of the standard deviation to its mean, and the proportion of cases in top 3 months is the proportion of cases of the 3 months with highest incidence to the annual incidence. Points represent 1 year per region. The lines are obtained from ordinary least squares regression with latitude as the independent variable and show how clearly defined epidemics become the further north from the equator.

FIGURE 2.

Temporal incidence of HFMD or enterovirus and climatic factors for 4 Asian cities spanning temperate, subtropical and tropical latitudes. Top: incidence, temperature, absolute and relative humidity. Top panels indicate incidence (data in gray, mean and 95% interval in black) for the time period Jan 2001 to Mar 2012 (Tokyo), Jan 2001 to Dec 2009 (Hong Kong, Peoples Republic of China), Jan 2001 to Dec 2011 (Taiwan, Republic of China) and Jan 2001 to Jan 2012 (Singapore). Middle and bottom panels show mean daily temperature, absolute and relative humidity at Tokyo Narita, Hong Kong International, Taipei Taoyuan International and Singapore Changi airports, downloaded from the Weather Underground. Bottom: Coefficients of meteorological variables at 0–2 week time lags in autoregressive models of Z-scored HFMD case counts to facilitate comparison between locations. Each city is analyzed separately using a model in which HFMD incidence in week t is (auto)regressed on incidence in weeks t-1 up to t-3 (using the Akaike information criterion to select the order of the autoregression component) and, independently, on each meteorological variable. Weather parameters are not regressed together in a single model because of collinearity. The effect of weather on HFMD incidence can be seen by coefficient mean (points) and 95% confidence intervals (lines), colored red if statistically significant at the 5% level.

FIGURE 3.

Historical establishment of HFMD in Asia. Dots represent a reported outbreak in that year, with the main causal agent written below. Boxes with right arrow indicate endemicity of HFMD, evidenced by repeated reporting of HFMD. Boxes with left arrow indicate seroepidemiologic evidence that the pathogen is already in existence, even if no significant outbreaks were documented previously. Triangles indicate the point where data on HFMD started to be collected systematically, for example, through government surveillance. The length of the left arrows are arbitrary as there is no way to know how long has HFMD been circulating before the tests.

FIGURE 4.

Excerpts from studies on risk factors. Ruan et al case-control study in Qiaosi, China, was conducted by taking 273 diagnosed HFMD/herpangina as cases (6 years of age or younger) and 273 stratified random sample as controls. Park et al case-control study uses hospital cases of enteroviral aseptic meningitis (n = 205) and HFMD (n = 116), and nonenteroviral disease controls (n = 170). Their case-crossover design uses only cases. 1–7 days before admission was set as the hazard period, and 22–28 days prior to admission was set as the nonhazard period. Both studies gather data via questionnaires. White points indicate nonadjusted ORs, black points indicate adjusted OR. For the effect of sex (bottom right), confidence intervals are omitted from complete case notifications, and colored gray and white alternately for visual distinction.

FIGURE 5.

HFMD cases by age and estimates of incubation period. Left: Each line indicates a unique data set (total 79 lines). Distributions within age ranges were assumed to be constant. The black dots are average proportion for that age (with 95% CI). Right: Reported incubation periods for HFMD, by year of publication and provision of evidence to support claimed period. Lines indicate that the incubation period “is X days.” Gray bars indicate that the incubation period is “usually” or “typically” X days. Gray bars with lines shows an extended interval “can be up to X days.” The point indicates a median. Notes: (1) provides information within the paper, which is inconsistent in this estimate; (2) uses generation interval distribution as a proxy for incubation period; (3) cites a US CDC factsheet on aseptic meningitis, which in turn provides no supporting evidence and (4) cites Goh et al. CI indicates confidence interval.