Introduction
Hand food and mouth disease (HFMD) poses a substantial burden to health in mainland China and there is no specific treatment for it. During 2013 to 2016 prior to the introduction of Enterovirus 71 (EV71) vaccine, the incidence and mortality of HFMD have been leading the type C notifiable infectious diseases, affecting an average of more than 2.2 million children every year in China (
http://www.nhc.gov.cn/). Three inactivated monovalent EV71 vaccines had been licensed in China in 2016, the efficacy against EV71-associated HFMD reached 98.8%. Nevertheless, there is no consensus on the cross-protection of vaccines against non-EV71-associated HFMD [
1‐
4]. Although vaccination has been promoted on a large scale after 2016, the average number of reported cases of HFMD in China still remains high during the period from 2017 to 2019, about 2 million per year, dominated by coxsackievirus A16 (CVA16), coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) (
http://www.nhc.gov.cn/). Whereas the pandemic of Coronavirus disease 2019 (COVID-19) further complicates the situation. During the pandemic, the incidence of most notifiable infectious diseases in China showed a downward trend, including HFMD [
5‐
7].
Environmental factors, such as temperature, relative humidity, wind speed, precipitation, and air pollutants, have been reported to pay an important role in the transmission of HFMD before the introduction of vaccine [
8‐
11]. Climatic factors have been recognized to have effects on the reproduction of the virus, while pollutants are thought to affect the susceptibility of individuals resulting in increased number of HFMD cases [
11‐
13]. A role for vaccination in these associations was hypothesized in previous study, which speculate that the human defense mechanism may regard some particles as a virus, and virus vaccination may have a beneficial effect on these particles [
14]. Several epidemiological studies have also demonstrated that vaccine might modify the adverse effects of pollutants on some disease [
14,
15]. In addition, due to COVID-19, governments have imposed restrictions on the movement of people, vehicles, and suspended industrial activities, resulting in a significant reduction in pollution levels [
16]. Accordingly, we postulated that the relationship between environment factors and HFMD may be different in pre-vaccination, post-vaccination or COVID-19 epidemic periods. The evidence of the positive association between HFMD and environment factors have been cumulated these years. However, the relationship between environmental factors and HFMD after the introduction of vaccine need to further prove. Therefore, we analyzed the incidence of HFMD and environmental factors from 2014–2020.
Discussion
In this study, We applied the distributed lag nonlinear model (DLNM) to explore the relationship between climate, air pollution and HFMD incidence in terms of variables and lag days. The results suggest that high relative humidity, high precipitation and extremely high and low levels of PM10, O3, SO2 and CO will increase the risk of HFMD from 2014 to 2020. And high concentration of air pollutants has the greatest impact on 0–1-year-old children.
From 2014 to 2020, we don’t find an association between extremely level of temperature and HFMD. The relationship between temperature and HFMD before the introduction of EV71 vaccine has been explored by many studies and they agreed that temperature changed the incidence of HFMD by affecting the survival and transmission of pathogen as well as human activities and behaviors [
21‐
23]. A study in Guilin [
13] found that an extremely low wind speed exerted certain protective effect which were consistent with our research. But study conducted in Hefei indicated that wind speed can increase the risk of HFMD while Huang et. al [
24] found no statistically significant association between wind speed and HFMD. This discrepancy may be attributed to the possible confounding effects caused by geographic and socioeconomic distribution. In addition, we found that high relative humidity increased the incidence of HFMD, but this effect was not statistically significant. Numbers of previous studies have found this effect to be meaningful [
25‐
27]. On the one hand, under the condition of high relative humidity, HFMD-related pathogens may be able to thrive depending on humidity, resulting in longer survival times, and have stronger infectiousness [
28]. On the other hand, high relative humidity can also limit sweating and then affect the metabolism of children [
27]. The correlation between rainfall and HFMD was not found in our study which is consistent with a study in Huainan [
29]. It worth noting that precipitation’s values at most days were zero, which could further cause the estimation of exposure–response relationship to progress toward a null value, therefore, different reference values will lead to changes in the impact of precipitation.
Our study found that almost all air pollutants are associated with the risk of HFMD, especially at an extremely high concentration from 2014–2020. Study results show PM
10 increased the risk of HFMD while PM
2.5 is not associated with the development of HFMD, which was supported by many studies [
13,
19,
30,
31]. The mechanism to explain this relationship between PM
10 and HFMD is that HFMD is mainly spreads through fecal–oral transmission or through close contact and exposure to air pollution makes children more vulnerable to intestinal infections by hand contact. Thus, HFMD viruses attached to ambient particles may be transported over long distances under favorable weather condition [
12,
13]. Gu et al. [
15]. found that both moderate and high concentrations of ozone increased the risk of HFMD, and we found that high and low concentration of ozone increased the risk of HFMD from 2014–2020. However, Yu et al. [
13]. found that high concentration of O
3 has a certain protective effect on foot and mouth disease. Thus, we need more research to explore the real relationship between them. We find a significant association between SO
2 and HFMD from 2014–2020 which supposed by a study in Hefei found that SO
2 increases the risk of HFMD [
11,
32]. Although the mechanism of SO
2 on hand-foot-mouth disease is not clear, the effect of SO
2 on respiratory disease has been widely demonstrated [
33]. Thus, we consider that SO
2, like other particulates, affects the immunity of children to increase the risk of enterovirus infection. Our overall analysis suggests that CO increased the risk of HFMD, but studies on CO and HFMD are limited. Yan et al. found a positive effect of CO but insignificant [
34]. Although there is no evidence prove that CO is related to the incidence of HFMD, the effect of health is well known. A number of studies demonstrated that chronic CO exposure appears to impart adverse health effects, especially with cardiovascular events [
33].
We found that the relationship between environmental factors and HFMD was not consistent before and after the introduction of the vaccine. The independent effects of air pollution and influenza vaccination on childhood HFMD have been extensively investigated, but no study have investigated potential effect modification by vaccination for the relationship between environmental factors and HFMD. A case-crossover study conducted in Taiwan, China [
14] and Liu et al. [
15]. demonstrated that vaccine might modify the adverse effects of pollutants on some disease. Although the previous studies have different study designs, participant’ characteristics, vaccine types, and health outcomes with our study, they provide indirect support for our findings that vaccine might modify the adverse effects of environmental factors on HFMD. It should be mentioned that we include the number of vaccinations in the sensitivity analysis to consider the effect of collinearity between vaccination and environmental factors. The results suggest that this effect has little effect on the results, which further proves the reliability of our results. Overall, our findings provided the new evidence on supporting the increase in vaccine use for HFMD in Chinese children and adolescents who expose to ambient air pollution.
During the COVID-19 epidemic period, the number of HFMD cases in Chengdu decreased significantly, and the impact of environmental factors on the incidence was not significant. Aside from suspending classes, the government, also took other measures such as closing management in the community, isolating at home and closing all kinds of leisure places, which may reduce contact and airborne diseases [
7,
35]. In addition, extremely weather factors and air pollutants have no significant impact on HFMD because of the lack of outdoor activities. It is worth noting that although our results show that there is a correlation between the incidence of HFMD during COVID-19 's period, due to the broad confidence interval and limited sample size, this findings should be interpreted with caution.
In conclusion, our study can only demonstrated that the relationship between HFMD and environmental factors after the introduction of vaccine and COVID-19 epidemic is different from that before vaccine introduction. But whether the relationship was altered by the vaccine and COVID-19 needs to be confirmed by more studies.
The results of stratified analysis showed that Children aged 0–1 years is more affected by high relative humidity due to their immune system is not yet well developed. In addition, the low concentration of air pollutants has the greatest impact on the 6–14 age group, while the high concentration of air pollutants has the greatest impact on the 0–1 age group. Since the age group is analyzed from the overall data, the impact of low concentrations of air pollutants on the 6–14 age group may be attributed to a lack of vaccine protection and more outdoor activities to increase the risk of infection. High concentrations of air pollutants are more likely to attack young children with immature immune mechanisms, thus increasing the risk of the disease. As mentioned above, the goverment should pay more attention to the sensitive group of children when making policies.
There are several limitations to this study. First, cases of negative infection or asymptomatic symptoms may not be included in passive surveillance data, leading to an underestimate of the impact. Second, this study is essentially an ecological study and ecological fallacies are inevitable.
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