Background
Hand, foot and mouth disease (HFMD), a common viral disease that usually affects children, caused by a group of viruses including enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16). Most HFMD cases are mild self-limiting, characterized by fever, and flat spots or bumps on the hands, feet and mouth; severe cases could develop into cardiopulmonary failure and death [
1].
HFMD outbreaks have been frequently reported in Asia-Pacific in the past two decades, posing great threats to the public health, including Taiwan (1998), Singapore (2000), South Korea (2000), Vietnam (2005), Hong Kong (2010), Cambodia (2012) and China (2007, 2008) [
2‐
9]. After two severe outbreaks in Linyi City in 2007 and Fuyang City in 2008, HFMD has been classified as a Class III notifiable communicable disease by the Chinese government [
8,
9]. But vaccines and antiviral drugs against EV-A71 or CV-A16 are still on the way to limit the spread of HFMD [
10,
11].
Many studies have proved that meteorological factors contribute to the epidemic of HFMD, including temperature, relative humidity, rainfall, wind speed and sunshine [
12‐
15]. Meteorological effects on the HFMD differ from place to place. For example, a positive effect of temperature at lag of 5 days, a negative effect of relative humidity at lag of 1 day and a positive effect of relative humidity at lag of 5–7 days were observed on adolescent HFMD in an eastern city of China [
12]. However, another study in a southern city of China has shown that temperature was negatively correlated with HFMD following a lag of 1–3 days, turned to be positive at lag of 5–9 days; a positive effect was also observed at lag of 3–10 days [
13]. In another study in East Asia reported that the average temperature was not significantly associated with HFMD [
15]. Moreover, few studies have fully explored the interacting effects of weather factors on HFMD in different climate regions remain to be evaluated. Thus, in this study, three areas located with different climate features were chosen to determine the linear and non-linear interacting relationship between weather factors and HFMD in children in three different climate areas in Gansu, China, and gain further traction as an early warning signal based on weather variability for HFMD transmission.
Discussion
This study quantified different responses of HFMD to weather factors in three specifically-chosen, geographical separated and climate different sites in Gansu Province, China. It can be concluded that HFMD responded differently on different weather factors, and the effect also was a non-linear, and interacted association.
Different seasonal patterns of HFMD infection in three study areas were observed. Other than Jiuquan and Lanzhou, Tianshui had no secondary peaks in seasonal components time series. And the primary peaks in Lanzhou came 2 weeks earlier that other two study areas. As previously reported, Kobe (Japan, 2010), Fukuoka (Japan, from 2000 to 2010), Henan (mainland China, from 2008 to 2013), Suzhou (Jiangsu, mainland China), Shandong (mainland China, from 2008 to 2012) also showed similar pattern in the original HFMD infection, but most parts of the mainland China (Zhejiang, from 2008 to 2012; Huainan, Anhui, from 2009 to 2014; Sichuan, from 2010 to 2014; Guangzhou, Guangdong, from 2009 to 2013; Zhejiang, from 2008 to 2012; Jiangsu, from 2009 to 2013), Taiwan (from 1998 to 2005), Korea (EV71, from 2007 to 2012) and Hong Kong (from 2001 to 2009) had secondary peaks in HFMD infection [
14,
21‐
32]. And the secondary peaks occurred mainly in October and November, which was consistent with the current study in Jiuquan and Lanzhou. One plausible reason was that substantial asymptomatic infected children transmitted the disease to their younger siblings or neighbors during summer holiday, which gave the second rise in September and peaked in November [
33]. Another potential reasons and causes of this phenomenon could be that the primary weather drivers of HFMD of two peaks could be different.
With a linear view, different weather could have different effect on HFMD epidemics in different sites. Our study showed temperature, including AT, MaxT and MinT, has positive association with HFMD after taking control of seasonal components. Similar findings have been reported in mainland China, Hong Kong and Japan [
14,
29,
34,
35]. Additionally, temperature effect on HFMD in each study areas were different, increasing from Jiuquan to Tianshui. That could possible due to different temperature ranges of three areas that increased from Jiuquan to Tianshui, which had consistent trend with temperature effect in three study areas. We also observed that TD’s association with HFMD were positive in Jiuquan and negative in Lanzhou and Tianshui. Liao found that TD had inverse “V” shaped association with HFMD, which decreasing when TD blew 17 °C, and increasing when TD beyond 17 °C [
36]. In our study, TD in Jiuquan was greater than Lanzhou and Tianshui, which indicated that TD could be a key weather factors led to difference response of effect of weather on HFMD in three study areas. The present research also demonstrated that RH had similar role like TD in response of weather effect on HFMD. Zhang reported non-linear, “S” shaped association with thresholds of 45% and 85% between RH and HFMD [
37]. In our study, Jiuquan with in low range of RH showed no association with HFMD, RH of Lanzhou may lie in the middle range and presented positive association with HFMD. While Tianshui with higher RH modeled the head of “S” cure, which could be a relatively horizontal line. From a locally aspects, RH showed no statistical association with HFMD. Our study also showed that RF was correlated with HFMD negatively, which was consistent with previous study [
36,
38]. RH could protect the susceptible children from social gathering activity or contact in public.
From a nonlinear and interacting view, CART provides more clear information on non-linear interaction among weather factors on HFMD. Considering seasonal components had significant influence on tree building and splitting, seasonal components were not including in the CART model. In the present research, we found that AT and RH were the first two important determinants, but the threshold values for three study areas were slightly different. AT threshold values decreased from northwestern Jiuquan to southeastern Tianshui, which was on the contrary to the actual AT trend. One reason for this phenomenon could be attributed to different enteroviruses molecular types composition in three study areas, since subtype of enteroviruses could have different responses facing different environmental temperature. Models variance and adoption could also induce this difference, longer study period range in the future could help to explore more information on this. With the condition of AT ≥ 20 °C and RH(MA = 10) < 38%, MaxT can still statistically increase the HFMD incidence in Jiuquan, which indicated MaxT also play an important role in Jiuquan. CART tree in Lanzhou also indicated that with the condition of AT ≥ 17 °C, lower RH could increase HFMD occurrence, but it better if RH was higher than 39%.
This study provides novel insights into the different response of impact of weather on HFMD in three study areas. Firstly, study areas were specifically designated, geographical separated and climate different study areas, which made it easy to observe the different response under different weather environment through horizontal comparison. Secondly, we compared and the association between weather factors and HFMD among three study areas. Finally, the association was both measured through linear and nonlinear ways.
Some limitations of this study should also be acknowledged. Firstly, this study designed and collected weekly weather factors of each study areas, so it’s possible that the representativeness of the weather factors varies among study areas. Fortunately, weather stations and population distributed similarly in the whole study areas and gathered more like in urban and suburb, which can narrow this limitation into a more considerable situation. Secondly, measurement and information bias are possible in this ecological study. For example, Jiuquan has more areas than other two study areas, integrated weekly weather factors can only partially represent the whole region. HFMD cases with mild symptoms may be underreported in the surveillance system. Finally, other potential confounding variables such as social factors, enterovirus type, behavioral information and other possible weather factors were not available for the current study.
Conclusions
Main peaks of HFMD in Lanzhou came 2 weeks earlier than that in Jiuquan and Tianshu. Tianshui had no clear secondary peak in seasonal patterns, which should be further studied. Impact of weather on HFMD in three areas is similar but their thresholds are different. Average temperature is the primary weather factor in three areas, more sensitive in southeast Tianshui, compared with northwest Jiuquan. Relative humidity also plays a non-linear interacting relationship with average temperature on HFMD.
Although many studies have investigated the association between weather and HFMD, our study indicated that the suitable environment for HFMD transmission varies from place to place. Warning models should be built based on local environment. Weather thresholds from CART model can provide a clue to develop HFMD management strategies and public health interventions.