Introduction
Hand-foot-and-mouth disease (HFMD) is a contagious disease caused by the enterovirus. Most cases of HFMD are mild and self-limited, but a small proportion could further develop to severe complications affecting the central nervous systems [
1,
2]. Due to its rapid progression and the lack of effective antiviral medications [
3‐
5], the prognosis of severe HFMD cases is usually poor [
6,
7]. Patients often suffer due to high medical expenses [
8] and poor quality of life [
9]. Enterovirus A71 (EV-A71) has been shown to be the dominant pathogen causing severe HFMD [
1,
10]. Approximately 80% and 95% of severe and fatal cases test positive for EV-A71, respectively [
1,
11]. However, among the EV-A71 infected cases, only 23.88% and 1.89% develop into severe and fatal cases [
12], implying that there still remain other unidentified risk factors for severe HFMD.
The overwhelming majority of prior studies mainly focused on examining the associations between severe HFMD and individual-level risk factors, such as individual demographic characteristics, early clinical manifestations, and genetic susceptibility. It has been found that younger [
13] and male sex [
14] were more vulnerable to severe HFMD, while breastfeeding and hand washing after playing [
15] were found to be protective. Clinical manifestations including high fever, vomiting, myoclonic twitching, and elevated serum interleukins and interferon-γ levels were found to be early indicators of severe cases [
16]. The presence of the rs4290270 SNP in the TPH2 gene was associated with increased susceptibility to severe HFMD [
17].
Although those above individual-level studies have provided important insights for identifying high-risk individuals from a clinical perspective, there is still an urgent need to clarify the associations between regional-level risk factors and severe HFMD. This would provide a deeper understanding of why severe HFMD cases are more likely to occur in specific regions, and then provide evidences on how to better control severe HFMD from a public health perspectives. To the best of our knowledge, rare studies have paid special attention to the associations between regional-level risk factors and severe HFMD [
18‐
21]. Only a few studies sporadically reported higher population density [
21], rural living [
18], and lower socioeconomic status [
18] would raise the epidemic of severe HFMD. In fact, there were remaining other regional-level factors should be considered when estimating their impact on epidemic of severe HFMD, such as medical resource allocation, meteorological features, GDP, and population scale. Notably, previous studies were mainly limited in a specific province, and a nationwide study covering multidimensional factors is still in lack.
Therefore, to address the above research gap, we conducted this nationwide study including 143 prefectural-level cities and abundant city-level characteristics to identify regional-level risk factors for the severe HFMD.
Discussion
Using nationwide data on severe HFMD, we observed the city-specific characteristics were related to regional differences in the case-severity rate. Our main findings suggest that beyond the type of infected pathogen, attention to social and environmental factors is necessary for controlling epidemics of severe HFMD. In addition, based on the spatial distribution of the case-severity rate and incidence, we found that areas of high HMFD incidence were mainly in the Pearl River Delta and South China, while areas of high case-severity rates were mainly located in Central China.
The city development indicator was negatively associated with the case-severity rate, indicating case-severity rate was higher in areas with lower economic development and insufficient medical resources. This phenomenon might be due to that the rural living [
35,
36], lower socioeconomic status [
21], and insufficient medical capacity [
37] are more common in less developed areas. Poor personal hygiene, insufficient knowledge of disease, and delayed therapy increase the number of severe HFMD cases, thus resulting in a higher case-severity rate. Therefore, we suggest increasing the allocation of local medical resources and improving accessibility, as this might reduce the regional disease burden of severe HFMD.
We found that the meteorological feature indicator representing a warm and humid climate was negatively associated with the case-severity rate. One possible explanation might be that in a warm and humid climate, an increase of probable cases will be more pronounced than the increase of severe cases. At present, most of the researches support the idea that the number of probable cases would increase in a warm and humid climate [
22,
38‐
40]. This is because higher temperatures may increase host activity, resulting in more frequent contact between infected and susceptible individuals. On humid days, enteroviruses can be easily attached to the small articles in the air, resulting in easier transmission of enteroviruses [
40]. In addition, on sunny days, ultraviolet radiation could lead to inactivation of enteroviruses [
39,
41]. However, the increase in severe cases would be less obvious than the increase in probable cases. This is because progression to severe HFMD not is only determined by enteroviral infection, but also depends on individual immunity [
42] and medical treatment [
33]. Therefore, in a warm and humid climate, a faster increase of total HFMD cases would accompanied by a decreased case-severity rate.
Previous studies have shown that both HFMD incidence [
1] and case-severity rate [
21] were positively correlated with the population density, while this relationship is non-significant in severe HFMD incidence [
21]. In the current study, we found that the relationship between population density and the case-severity rate was non-significant. This might for the following reasons: first, we hypothesized that two opposing forces might drive the relationship between population density and case-severity rate. On the one hand, more densely populated areas typically have better socioeconomic status and sufficient medical resources. Children in those areas are often better cared by more educated caregivers (resulting in lower case-severity rate). On the other hand, more densely populated areas have a higher severe HFMD detection rate with more sufficient medical facilities (resulting in a higher case-severity rate). Therefore, given both of these trends, the relationship between population density and case-severity rate might be non-significant. Moreover, based on the interpretation of statistical modeling, the non-significance of the population density indicates its impact on the case-severity rate was weaker than the impact from the city development and meteorological indicators. Therefore, we suggest that in addition to physical isolation measures, adequate health resources and timely treatment are crucial for controlling severe HFMD.
This study had two major strengths. First, this is a city-level study. Unlike the individual-level studies focusing on the diagnosis and treatment of clinical cases, results from the current study are crucial for public health decision-making. Second, this is a nationwide study with multiple covariates, which can provide a stable estimation on the associations between case-severity rate and city-specific characteristics.
This study has four main limitations. The first one is the intrinsic nature of ecological study. Conclusions from the current study were based on the population scale, inference on other situations should be careful. The second limitation is related to the data quality. Since our data was collected from surveillance data, under-reporting from surveillance data might introduce extra basis. However, the cumulative numbers from 2008 to 2014 were used as outcome, which are more reliable than single observations under mild under-reporting conditions. The third limitation is that the city-specific EV-A71 infection rate was not included in the core model. This is because that laboratory-based diagnosis of HFMD was only available in a small fraction of the total HFMD cases. Therefore, city-specific EV-A71 infection rate were not available. The final limitation is the study period, which did not extend into most recent years. As the EV71 vaccine was approved for marketing on 3 December 2015 [
24], the epidemiology of HFMD has since changed. Further studies comparing those associations before and after the introduction of the vaccine are necessary.
Conclusion
In conclusion, the case-severity rate is an indicator of severe HFMD disease burden, unlike the incidence of HFMD, which is mainly affected by enterovirus, meteorological factors, and population density. The case-severity rate was closely related to medical resource allocation and the level of city development. Enhancing the medical resource allocation and improving it accessibility among rural population might result in improved disease prevention and control.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.