Hand, 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 disorders1,2 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 20143) means the death toll can be substantial (384 deaths in China in 20143). 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.4–6
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.
Search Strategy and Selection Criteria
Using a combination of search terms, including “Hand foot and mouth disease,” “Hand foot and mouth,” “HFMD,” “Enterovirus,” “Enterovirus 71,” “EV-A71,” “Coxsackie A16,” “CV-A16,” “CVA16,” we searched PubMed, Thomson Reuters Web of Science and Google Scholar to identify 1305, 1255 and 100 articles, respectively.
Eligibility criteria were articles that: (1) were published in peer-reviewed journals from January 1957 to December 2014; (2) were studies with epidemiologic and/or serologic information (quantitative/qualitative) about incidence and prevalence of HFMD; and/or (3) contained information about factors associated with prevalence and incidence and/or (4) employed statistical models to derive the above. Articles not in English, not related to HFMD, or HFMD articles that did not cover epidemiologic or clinical factors were excluded.
Two independent readers examined each of the 407 abstracts to determine if specific research questions were answered. The 8 specific research questions were as follows: (1) What time of the year do HFMD outbreaks occur, and with what seasonal factors are outbreaks associated? (2) How long have EV-A71 and CV-A16 been circulating in Asia? (3) What age groups are at higher risk of infection? (4) What risk factors are associated with infection and severe outcomes? (5) Where do infections predominantly occur (home or school)? (6) What is the incubation period? (7) What proportion of infections are symptomatic? and (8) What is the basic reproduction number for HFMD by virus? An article was retained as long as both readers indicated that it answered at least 1 specific research question and was discarded if both readers agreed that no questions were answered. A third independent reader arbitrated when there was a disparity between the original readers.
The 2 original readers each read the full text of half of the articles to identify answers to the questions. A second pair of independent readers read the articles again. Finally, the first author compiled all answers to the specific questions and compared the extracted answers to the original text. Relevant references from these papers were included in the analysis, in particular to identify non-English and early references. In total, information from 242 papers was compiled and 108 papers were used in data synthesis.
Hourly weather data were downloaded from the Weather Underground and aggregated at a weekly scale. Incidence data from Tokyo, Hong Kong, Taiwan and Singapore were extracted from routine surveillance data published by government agencies (the National Institute of Infectious Diseases, Japan7; the Department of Health, Hong Kong8; the Taiwan National Infectious Disease Statistics System9 and the Ministry of Health, Singapore).
Nontabular data were extracted from figures using Plot Digitizer.10 Data on weather and incidence were analyzed using a time series model. Symptomatic proportions were pooled by aggregating denominators and numerators. Other analyses used standard statistical methods and were conducted using R.11
Timing and Seasonality of HFMD Outbreaks
Outbreaks of HFMD do not occur uniformly throughout the year across Asia. In Fukuoka, Japan, for example, weekly numbers of HFMD cases have been found to increase with average temperature and humidity, especially among younger children.12 By digitizing the incidence data from publications on Japan5,12–14 and North China15–20 (Fig. 1), we observe that May through July are the months with highest incidence in temperate regions of Asia. However, this relationship is less clear for tropical and subtropical Asia. The extracted data on Southwest China,15,21 South China,2,15,22,23 Hong Kong24,25 and Taiwan26–28 show that outbreaks typically happen in late spring and fall. No distinct pattern is obvious for tropical regions as seen from data in Thailand,29–31 Vietnam,32,33 Malaysia34 and Singapore,35–38 where outbreaks occur sporadically throughout the year, although models have been developed for Singapore (≈1° north) that show a positive statistical relationship between maximum daily temperature above 32°C with HFMD incidence in the subsequent 1–2 weeks.37
To assess how general the relationship between climate and transmissibility of HFMD was, we took incidence data from Tokyo, Hong Kong, Taiwan and Singapore (Fig. 2, Appendix 1), that is, spanning temperate, subtropical and tropical latitudes, and fitted time series models to them. After controlling for contagion via autoregression terms, the effect of meteorologic factors was weak: a small positive increase in transmissibility with rising absolute humidity/temperature during the current week in Tokyo and Singapore. There was no evidence for temperature and humidity in having the same effect in Hong Kong or Taiwan, although rising relative humidity seems to decrease transmissibility in Singapore.
The earliest recorded cases of HFMD in Asia are from Japan (1967),30 Singapore (1970),31 Taiwan (1980)32 and Shanghai, China (1981).33 Since then, outbreaks have been reported in many parts of Asia, including mainland China,12–14,33–52 Korea,53–55 Japan,56–70 Taiwan,6,69,71–74 Hong Kong,17,18,75 India,76–81 Thailand,21,23,82 Vietnam,24 Malaysia,26,69,83–87 Singapore4,88 and Brunei,89 as summarized in Figure 3. These reported outbreaks are unlikely to reflect the true first outbreaks of HFMD, as serologic studies provide evidence that by the time surveillance systems were established, EV-A71 and CV-A16 were already endemic in many of these countries. Early serologic tests conducted in Japan in 1970 show evidence of EV-A71 and CV-A16 circulation.90 Serum taken in the late 1990s in Singapore, before the start of surveillance in 2000, shows that around 50% children and 44% cord blood, indicating maternal infection, had already seroconverted to EV-A71.91 Blood samples from Taiwan (1989–1997) show 3%–11% EV-A71 incidence per year, and up to 68% of children92 had serologic evidence of EV-A71 infection before the large HFMD outbreak of 1997. Similarly, although China has reported millions of HFMD cases since the beginning of the HFMD surveillance program in 2008, evidence from Anhui47 shows high seroprevalence of up to 74.6% in older children before the 2008 outbreaks. Retrospective seroepidemiologic tests from blood serum collected in 200593 also show that China had positive rates of 32.0% to EV-A71 and 43.4% to CV-A16, indicating that outbreaks happened earlier but were simply not reported in the literature.
Risk factors for infection are depicted in Figure 4 (Appendix 2) and summarized below.
Evidence from Qiaosi, China,94 indicates the importance of hygiene for protection against HFMD infection. Children who always wash their hands before meals are about 50 times less likely to contract HFMD, while those whose caregivers wash their hands before feeding are about 25 times less likely. Additional protective habits include washing of hands after play, washing of hands more than 4 times per day, using soap, and not sucking fingers.
A study in Korea95 revealed that drinking unboiled water [odds ratio (OR): 3.34 (1.59–6.99)], a change in water quality such as color, taste, smell, presence of precipitation or floating materials [OR: 6.93 (2.17–22.15)], using communal toilets/toilets outside the house [OR: 2.77 (1.14–6.74)] and eating outside the home [OR: 37.0 (5.1–269.5)] were risk factors for HFMD.
Rural Versus Urban Areas
All papers51,96–98 that compared urban with rural areas agreed that the latter conferred a higher risk for HFMD. However, this might be confounded by socioeconomic status and hygiene practices.
Although most papers show that being male is a risk factor for both mild4,14,16,23,27,34,37,51,82,98–101 and severe52,97,102,103 HFMD (OR ranges between 1.2 and 2), surprisingly, serologic evidence does not support this finding: A study from Singapore104 shows marginal evidence that females are more likely to have seroconverted to EV-A71 [OR: 0.79 (0.61–1.01)], while a Taiwanese96 study shows no statistically significant differences [OR: 0.94 (0.76–1.16)]. Taken together, these suggest that infection rates are comparable, but that boys are more likely to develop symptoms, more involved in propagation of outbreaks or more likely to be brought for medical care than girls.
A case–control study in Xi’an, China,97 found that breastfeeding may lower the risk of developing severe HFMD [adjusted OR: 0.57 (0.33–0.98)], even though breastfeeding does not apparently lower the chance of being infected by EV-A71 [OR: 1.1 (0.93–1.3)].96 It further found that patients with a history of Epstein–Barr virus are at greater risk of contracting severe, rather than mild, HFMD [adjusted OR: 2.6 (1.5–4.4)]. A spatial-temporal model of Guangdong14 showed that sunshine could be protective against HFMD. This is agreed by a matched case-control study of preschoolers in Beijing,41 which showed that UV radiation in classrooms is associated with lower HFMD attack rate (P value of 0.027), and recommended installing UV lamps to sterilize unoccupied classrooms. These findings are, however, inconsistent with the seasonal nature of HFMD, where outbreaks in temperate countries tend to occur in summer, when sunlight and UV exposure are strongest.
Age Distribution of HFMD Cases
The age distribution of HFMD cases in Asia, compiled from a variety of sources including surveillance and cohort data, is summarized in Figure 5. Data from China12–14,34,49–52,94,100–103,105–107 and Taiwan5,6,73,108–111 are particularly abundant. Other sources include Hong Kong,17,18 India,76,80 Japan,56,112 Korea,54,95 Malaysia,84,113 Singapore,4,27,88 Thailand22,23 and Vietnam.24
The symptomatic HFMD incidence rate varies widely even within the narrow 0- to 6-year age-band. The greatest proportion of cases occur at ages 1 [18.8% (17.4%–20.2%)] and 2 [17.9% (16.6%–19.2%)]. By the age of formal schooling, from 6 years in most Asian countries, the proportion is substantially lower [8.7% (7.9%–9.5%)]. Overall, 82.6% (82.2%–82.9%) of all cases occur before age 6. The lower rate during the first year of life could be because of lack of contact with other children or to presence of maternal antibodies.91
Community Versus School as Medium for Infection
The literature is ambiguous about the importance of locations for transmission. Four studies showed that contact with a case, particularly a household member, is as or more significant a risk factor than preschool attendance.21,88,96,108 An early study in Singapore observed 60 families with secondary cases and found the secondary attack rate amongst children below 12 years old to be 77%.88 Similarly, in a large seroepidemiologic study of EV-A71 in Taiwanese children,96 multivariate analysis showed attendance at a preschool imparted a similar magnitude of risk as contact with a case [adjusted ORs: 1.6 (1.2–2.1) and 1.8 (1.3–2.5), respectively], as well as a strong concordance (84%) between seropositivity in younger and older siblings.
Also, a number of studies showed that a higher percentage of diagnoses occurred among children who did not attend a nursery or preschool.37,51 Liu et al49 note that about half of symptomatic cases in Nanchang, China, are among children under 3 years, the age at which preschooling starts in China.
Conversely, some studies suggest that preschool attendance is a key risk factor.4,114 For example, a seroepidemiologic study in 1996 to 1997 in Singapore showed that seropositivity to EV-A71 increases rapidly from age 2 to 5,91 when attendance at childcare or preschool is the norm. Also, a case-control study in Japan114 showed that preschool attendance was associated with increased risk of severe disease.
Other studies suggest that both locations are important. In Shanghai, China,103 there was a marked shift from 2007 to 2008 in the proportion of cases among children in preschools (from 59% to 37%) with a concurrent shift from local to migrant children, suggesting that the importance of routes of transmission can vary over time within the same locale. A case-control study from Zhejiang94 showed that although attending preschool is a risk factor (OR: 2.1), other factors such as contact with neighbors (OR: 11), going to hospital (OR: 20) and going to parties (OR: 31) impart greater risk. Yet, a Korean case-control study95 found no significant relationship between infection and school attendance or household size.
Overall, the evidence points to both home and school environments contributing to transmission, but the relative importance of these venues remains murky.
Several papers describe the incubation period (Fig. 5, Appendix 3) though it is striking that the majority do not provide a source to justify the claimed period. These unsupported claims vary substantially from paper to paper, from the incubation period “is” 3–6 days115 or 3–7 days,76 “is usually 3–4 days, but can be ... 10 days or more,”32 or “is usually 3–5 days (range, 2–12 days),”111 is “typically” 3–7 days116 or 3–5 days,49 ranges from 5 to 7 days42,98 or 3 to 7 days113 and the “usual period” is 3–5 days “with longest period of 7 days.”117 Only a few provide evidence to justify the claim: one reports95 that the incubation period is usually 3–7 days, citing a US Centers for Disease Control and Prevention (CDC) factsheet on aseptic meningitis. Another cites118 an early study from Singapore,88 which presented the median and range for the serial interval (3 days [1–7]), not the incubation period. Another early study119 states that the incubation period is “said to be” 3–5 days, but notes that this is inconsistent with the serial interval observed in the study. It appears that there is no empirical support whatsoever for any distribution of incubation periods.
Although several studies report that the asymptomatic rate of EV-A71 infection is high, few studies report data (Table 1). Two studies, from Taiwan and Shanghai, tested sera for evidence of EV-A71 infection and asked patients or their families to recall past HFMD infection, deriving estimates of 29%120 and 10%106 of symptomatic infection, respectively. Some HFMD cases may have been caused by other enteroviruses, biasing these estimates upwards, while some may have been diagnosed as another viral illness or forgotten, biasing them downwards.
Two additional studies in Taiwan found much higher symptomatic infection rates. The first108 study recruited symptomatic cases suspected of having EV-A71 infection, and took throat and rectal swabs or stool samples, of cases and their household members. Signs and symptoms of the entire household were monitored with follow-up telephone interviews. Excluding the 94 symptomatic index cases, 68% of confirmed infections in the household were symptomatic (88% of infected children and 47% of infected adults). A second study121 prospectively followed a cohort of neonates over 3 years, taking repeat sera, requesting that parents report suspected HFMD and giving reminders during HFMD epidemics. This study found that 71% of serologically confirmed infections were symptomatic, though the sample size is only 28.
The discrepancy between these 2 pairs of papers is substantial, undoubtedly because of differences in methodology. An overall estimate, combining the 4 studies, is 36% (33%–39%), but given the large discrepancy between studies, this estimate does not appear reliable. The latter pair of studies is prospective, thereby circumventing recall bias, and thus appear to provide a more accurate description of the epidemiology of enterovirus infection.
Basic Reproduction Number for HFMD by Virus
Only 3 papers have sought to estimate the reproduction number for HFMD or the viruses that cause it. One paper101 estimates what they call the “local effective reproduction number” in China—meaning using the average number of secondary cases from a randomly selected index to estimate the cases that would be caused in a fully susceptible population (note, this is substantially different from the effective reproduction number122 in a partially susceptible population)—using a sophisticated Poisson regression model that incorporated infection from the environment, the prefecture and neighboring prefectures. This model did not, however, account for the accumulation of herd immunity and required arbitrary assignment of the infectious period, so the estimated local effective reproduction number of 1.1–1.2 during peak periods may be biased.
A second paper117 used a method from Choi and Pak123 to estimate the basic reproduction number to be 5.5 (interquartile range, 4.2–6.5) for EV-A71 and 2.5 (interquartile range, 2.0–3.7) for CV-A16. These estimates are likely inaccurate because the method assumes (i) a known generation time distribution, labeled incubation period in the paper; (ii) a completely immunonaïve population, though applied to groups of individuals for whom past exposure was highly plausible and (iii) an early exponential growth period, despite being applied to complete outbreak data.
The third paper124 attempted to estimate the reproduction number using a SEIQRS (Susceptible, Exposed, Infectious, Quarantined, Recovered) simulation model and obtained an estimate of 1.1 for the years 2009 to 2012 in China. However, the model used 10% of China population as the initial susceptible population, but did not conduct a sensitivity analysis on this vital parameter.
Despite the substantial number of papers on HFMD, this systematic review shows that many fundamental questions about EV-A71 and CV-A16 persist. Both viruses occur year round in tropical Asia, but are epidemic in the summer in Northeast Asia. A role for temperature or humidity therefore seems plausible,14,125–128 although given the relative lack of seasonality in equatorial Asia, it is not clear whether prediction of outbreaks is possible there. In Japan, summer temperatures peak after HFMD incidence does, suggesting correlation but not temporality, and that it may not be possible to provide early warning of impending epidemics. This also differs from other human enteric viruses including poliovirus 1 (also an enterovirus), hepatitis A and adenovirus that have been shown to survive longer on colder surfaces.129
Urashima et al125 claimed that enteroviruses experience a more rapid virus decline during dry seasons than during wet seasons, which could explain the seasonality. This result is supported by Wang et al,130 where they showed that precipitation patterns has the most similar structure as HFMD incidence, more so than other meteorologic variables, albeit with only 11 months of data.
While any causal relationship between climate and HFMD is unknown, speculations include a lower HFMD incidence because of decreased social contact during temperate zones’ winter.118,131 In contrast, increased social contacts during winter have been speculated to facilitate spread of other droplet-borne diseases, such as influenza,132 which are epidemic in winter. Given the unknowns surrounding this issue, further research is clearly required to ascertain whether meteorologic factors or seasonal social contact patterns is an adequate explanation for the seasonality of HFMD.
The next step to analyzing the dynamics of HFMD seasonality is likely to involve social and environmental factors, another under-researched area for this pediatric disease. For instance, the literature is unclear on the relative importance of school versus community transmission, with evidence to support both, yet knowledge of where HFMD most often is transmitted is important as school closure policies are employed to control outbreaks in some countries. Further, the environment of schools in Asia may vary widely, and attributes such as hygiene practices should be characterized and quantified to allow more definitive results and conclusions in future studies.
Even without being able to determine the relative importance of school versus community transmission, the effectiveness of school closure to prevent large-scale HFMD outbreaks is questionable, as the interruption to social networks cannot be enforced while children are out of school. Additionally, although we know little about the infectiousness of asymptomatic cases of HFMD, the proportion of infections that are asymptomatic is substantial, and so even quite modest school closure attack rate thresholds, such as Singapore’s 25%,133 corresponds to a possible majority of students being infected before the trigger for closure being met. Further, EV-A71 can be found in fecal samples for up to 54 days after infection,134 and thus continue to be shed after a school is closed, disinfected and reopened.
Studies on risk factors were rare, and we identified only 3 papers that describe risk factors for hygiene and contact patterns, making a meta-analysis of risk factors unfeasible. These typically were only powered to provide unadjusted effect sizes, and so provide evidence of correlation, not causation. One interesting finding was the apparent protective effect of a caregiver “always washing” their hands. This suggests that adult to child transmission might be important, even if adults are mostly asymptomatic with EV-A71 and CV-A16, but may reflect confounding with general hygiene. Future work may elicit hygiene factors at the preschool level and relate these to attack rates.
A recently developed EV-A71 vaccine has undergone phase 3 trials in China.135–137 To determine the cost-effectiveness of incorporating the vaccine in pediatric vaccination schedules, or of other interventions such as school closure or isolation, would require epidemiologic models that account for the protective effects of herd immunity. However, this review indicates that vital parameters for such models remain unknown. The asymptomatic rate and relative infectiousness of asymptomatic cases are both poorly known, while estimates of the incubation period, although commonly cited as 3–5 days, appear to be based solely on expert opinion. Most importantly, estimates of the basic reproduction number range widely from 1.1 to 5.5. This uncertainty prohibits utilitarian estimation of the necessary vaccine coverage to prevent epidemics of EV-A71.
To reconcile the differences between the disparate estimates, the age distributions of the samples need to be considered. As shown in this review, symptomatic HFMD incidence rate differ greatly even between ages 0 and 6, and thus, studies conducted predominantly on preschoolers may derive higher estimates of R0 compared with studies in older children. Accordingly, future studies on HFMD should use narrower age bands and also state the distribution clearly to allow adjustments or standardization.
Two final omissions from the literature are quantitative estimates of the impact of infection on complications, child and caregiver absenteeism and costings of complications, and qualitative evidence on the impact of infection and enforced isolation on families and schools. Given the promising direct effects of the EV-A71 vaccine and the huge public health impacts of HFMD in East and Southeast Asia, research is urgently needed to fill these gaps.
The research questions in this systematic review were generally answered only by a limited number of papers, with substantial differences in their study design, and thus, most data were not synthesized through meta-analysis. More research to assess risk factors and measure key epidemiologic parameters is needed. We were also unable to trace the earliest cases of HFMD in Asia as our scope only covers published material on outbreaks, which leads us back to 1967 in Japan. Finally, we limited the scope of this study to exclude virologic characteristics or molecular epidemiology, which have been well reviewed elsewhere,116,138–141 and clinical manifestations of EV-A71 and CV-A16.28,116,138,141,142 A recent review of the case-fatality rate has recently been published,143 as has a review of the epidemiology in Taiwan.144
Appendix 1. Timing and Seasonality of HFMD Outbreaks
An autoregressive (AR) model was used to investigate the effect of meteorological variables after correcting for contagion via autoregression.
A lag 2 model can be specified as follows:
The A coefficients are the coefficients for the AR terms, while the B coefficients represent how a change in weather is correlated with changes in HFMD incidence. The number of lag terms is determined by the Akaike information criterion values of the regression models.
This same model was used for 4 countries—Japan (lag 2), Hong Kong (lag 3), Taiwan (lag 3) and Singapore (lag 2)—and for 3 meteorological parameters—temperature, absolute humidity and relative humidity. As this model carries autocorrelated terms, we used generalized least squares for model fitting. Coefficients from the fitted models are presented in Tables A1–A3.
APPENDIX 2. Odds Ratio From Figure 4
APPENDIX 3. Data Source for Figure 5 (Left)
APPENDIX 4. PRISMA 2009 Checklist
APPENDIX 5. PRISMA 2009 Flow Diagram
We thank Alex S. Leow and Vincent J. Pang for screening some of the papers and Zhao Xiahong for processing the meteorologic data.
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hand; foot and mouth disease; EV-A71; CV-A16; epidemiology