Background
Hand, foot and mouth disease (HFMD) is a worldwide infectious disease [
1]. It is mainly caused by Coxsackie virus A16 (CV-A16) or enterovirus 71 (EV71) [
2‐
4]. This disease is characterized by flu-like clinical symptoms including fever, mouth ulcers, poor appetite, vomiting, diarrhea, and rashes on the hands, feet, and buttocks [
2,
4]. It is believed to be transmitted mainly through direct contact with contaminated discharges, contaminated objects, and fluid from blisters or stool from infected persons, with an average incubation period of three to 7 days [
5,
6]. This disease continues to be a serious public health threat, especially to children, as there is no definitive treatment for HFMD, currently.
During the past decades, HFMD outbreak has occurred in numerous areas, especially in the Asia-Pacific region, such as Thailand [
7], Taiwan [
8], Singapore [
9], Hong Kong [
10], Vietnam [
11], Malaysia [
12], Japan [
13] and parts of mainland China [
14,
15]. In 2007 and early 2008, mainland China experienced several serious outbreaks of HFMD and established a national enhanced surveillance system to respond those outbreaks [
15]. In May 2008, HFMD was defined as a Class C infectious disease that requires reporting of every case [
16]. A considerable threat still exists, because HFMD especially affects areas of high economic level, possesses distinctive seasonality, and can result in death in severe cases.
Some studies have determined that HFMD risk has temporal variations. It is well accepted that meteorological factors play an important role in the transmission of HFMD. For example, in Finland and Japan, a single season peak of HFMD has been observed during the summer and early autumn months, separately [
13,
17]. Meanwhile, an annual peaks in the warmer months (May to July) and a smaller winter peak (October to December) have been detected in subtropical and tropical regions, including Hong Kong, Malaysia, and parts of mainland China [
6,
10,
12,
18,
19]. Furthermore, the annual peak of incidence seasonality has varied from April in the southern area to July in the northern area of China [
15]. In recent years, there has been increased interest in exploring the impact of meteorological factors on HFMD, such as temperature [
20‐
23], relative humidity [
20,
23], precipitation [
15,
20,
22], wind speed [
15,
20], hours of sunlight [
15], and air pressure [
15,
21].
Meanwhile, the risk of HFMD also presents obvious spatial heterogeneity. Some studies indicated that it was closely correlated to socio-economic variables: demographics, local geographic environment, socio-economic status, health conditions, and infrastructure. For example, Yan et al. showed that HFMD incidence was higher in urban areas compared with rural areas and demonstrated that the distance to the nearest freeway and per capital GDP are risk factors associated with HFMD incidence [
24]. Hu et al. indicated that the population density of children can explain 56% of the variance in the cumulative monthly HFMD incidences in 2912 counties in China [
23]. Likewise, rural-to-urban migrant-worker parents were found to be a major risk factor associated with HFMD in children [
25], which implies that socio-economic factors also play an essential role in the transmission and spread of HFMD.
To our knowledge, few studies have quantified spatiotemporal heterogeneity of HFMD and detected spatiotemporal interactive effect of potential driving factors on this disease in the study region. The aims of this study are to 1) reveal the county-level spatiotemporal heterogeneity of HFMD risk, 2) detect the hot/cold spots, and 3) quantify the relationships between meteorological, socio-economic factors and HFMD incidence.
Discussion
HFMD remains a serious threat to childhood health and has become one of the leading causes of childhood mortality in mainland China [
15,
23,
36,
37]. In recent decades, Henan province, as one of the largest population provinces in China, has experienced several serious outbreaks of HFMD [
38,
39]. The present study, from spatiotemporal perspective, explored the epidemiological characteristics of the disease, and quantified the impacts of meteorological factors and socio-economic variations on childhood HFMD incidence in Henan. The results revealed that the highest risk was mainly gathered in areas with high urbanization levels, meanwhile, meteorological factors were found have significant effects on the transmission of HFMD.
The relative risk of HFMD was linked to an obvious seasonal variation, with the highest risk appearing in late spring and early summer (April to June), and the lowest risk in autumn (August to October). It is widely accepted that meteorological factors play a decisive role in the seasonal changes of HFMD incidence, which are regarded as crucial environmental factors that influence the spread and survival of viruses causing HFMD [
36,
37,
40]. The association between meteorological factors and the seasonal evolution of HFMD incidence has captured particular interests from many researchers, and some studies have reported that temperature and relative humidity played an extraordinary important role in the seasonal variation of HFMD [
40‐
43].
The study found that average temperature was strongly positively association with monthly HFMD incidence, which is consistent with previous studies in month time scale. For example, a rise in average temperature may have led to an increase in the number of HFMD cases in Vietnam [
44]. And a study showed that an increase in average temperature was associated with a rise of the number of HFMD cases [
45]. The potential mechanism could be that temperature affects the behavioral patterns of people, and warmer weather can lead to increased contact, especially among young children, accordingly facilitating the spread of HFMD infection [
46].
Similarly, there was a positive relationship between relative humidity and the incidence of HFMD, which is same as other studies [
23,
47]. That maybe because during humid days the virus could easily attach to articles in the air, facilitating the spread of the disease [
48]. However, a previous study found that relative humidity is not related to the prevalence of this disease, which was different from the present research [
46].
Another important driving meteorological factor that influence the transmission of HFMD are air pressure, also presenting positive correlation with HFMD incidence, which was consistent with other study [
49]. The potential mechanism may be that air pressure affects the immune system and increases the risk of disease.
Additionally, precipitation presented negative correlation with HFMD incidence, which was also consistent with other studies. Some studies demonstrated that heavy downpours could break down the survival environment of viruses [
44,
50]. The potential reasons may be that precipitation would reduce social contact, thus affect the spread of the disease [
51].
Furthermore, wind speed and sun hour were found to have no statistic significant association with HFMD in the study. This was consistent with some of previous studies, however, some studies have drawn opposite conclusions. For example, Liao et al. found that wind speed and sun hour has no significant association with HFMD incidence [
6]. Whereas, Xiao et al. demonstrated that the weaker association presented between the sun hour and HFMD incidence [
52]. Meanwhile, Wang et al. denoted that the wind speed and sun hour were found to be positively associated with HFMD [
53].The potential reasons may be that these meteorological factors have different relationships with the HFMD in different regions.
These results denoted that meteorological factors play different roles in contributing to the transmission of enteric infectious diseases by affecting the ecological environment of pathogens, exposure probability, and host susceptibility, thus resulting in the occurrence of the disease.
In the study, in order to analysis the spatial heterogeneity of the influence of meteorological factors on HFMD, the relationships between HFMD and meteorological factors was further calculated in three strata classified by the BSTHM in hot spots, cold spots and neither hot nor cold spots, respectively. The results indicated that there presented distinctive local relationships in each stratum compared with those in global model (Table
1, Additional file
1: Tables S2, S3 and S4). In the global model, average temperature and relative humidity were found to be key factors affecting HFMD risk, however it indicated no statistically significant influence of average temperature on HFMD risk in the cold spots (Additional file
1: Table S3), and the effect of relative humidity was also not found statistically significant relationship with HFMD risk in each stratum (Additional file
1: Tables S2, S3 and S4). The potential reasons for these difference between global and local models may be that there existed different HFMD transmission mechanisms in different regions, and small size of samples in each stratum also affected the statistically significant level of estimated parameters.
In addition, the study indicated that the distribution of HFMD risk presented apparently spatial heterogeneity. High risk of HFMD (hot spots) was mainly concentrated in the areas where the level of economic and urbanization was high, while low risk of HFMD (cold spots) was mainly distributed in the undeveloped counties having lower economic level and incomplete infrastructure [
35], which was consistent with previous studies. For example, one previous study found that the proportion of tertiary industry was positively correlated to the incidence of HFMD [
36]. One previous study found that incidence in economically developed areas, for example Beijing, Tianjin, Shanghai, and Zhejiang, are higher than in less developed areas [
19]. Furthermore, a study found that population density and tertiary industry presented the most significant impact on this disease, explaining 42% of the HFMD transmission [
54]. The potential mechanism may be that, due to the rapid economic development and urbanization in recent years, there exists increased floating population in the more developed regions compared with cold spots, however, there is limited living and work room, which providing more opportunities for contact between each other, thus accelerating the spread of the virus.
In the study, three models, GeoDetector, BSTHM and SLM, were used, in which the BSTHM is linear models used to detect the spatiotemporal heterogeneity of the HFMD risk. However, HFMD transmission in reality has a fundamentally non-linear nature, and a linear method was a first-order approximation for reality. This introduces some uncertainty to the results of the study. Fortunately, in a linear model, the physical mechanism of parameters is clear, and the calculation is easy to implement and repeat.