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.
In the overall analysis 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  found that an extremely low wind speed exerted certain protective effect which were consistent with our research in pre-vaccination period and overall analysis. But study conducted in Hefei indicated that wind speed can increase the risk of HFMD while Huang et. al  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 analyses before vaccination and throughout the study period, 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 . On the other hand, high relative humidity can also limit sweating and then affect the metabolism of children . The correlation between rainfall and HFMD was not found in the overall analysis which is consistent with a study in Huainan , but low rainfall before vaccination would increase the risk of HFMD which were contradictory to previous findings [9, 30-32]. But our results in pre-vaccination period is still interpretable. On the one hand, low precipitation increases host outdoor activity and effective contacts between susceptible and infectious individuals, which may subsequently promote the spread of HFMD infection . moreover, unlike temperature and humidity, rainfall’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 PM10 increases risk of HFMD while PM2.5 is not associated with the development of HFMD, which was supported by many studies [13, 19, 33, 34]. The mechanism to explain this relationship between PM10 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 . 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 . found that high concentration of O3 has a certain protective effect on foot and mouth disease. Thus, we need more research to explore the real relationship between them. Studies in Shenzhen and Ningbo found a significant association between NO2 and the incidence of HFMD [15, 35] which demonstrated the reliable of our result in pre-vaccination. The possible mechanism is as follows: NO2 dissolves in water on the surface of the digestive tract and forms acidic substances, which can induce inflammation of the digestive tract mucosa through physical and chemical interactions and weaken immunity and increase the risk of enterovirus infection . We find a significant association between SO2 and HFMD from 2014-2020 which supposed by a study in Hefei found that SO2 increases the risk of HFMD [11, 37]. 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 . 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 .
We found that low temperatures, high relative humidity, and high concentrations of O3, NO2 and CO have adverse effect on HFMD in post-vaccination period. This suggests that even after vaccination, we should pay attention to living hygiene especially toy and hand hygiene, under adverse weather conditions. 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  and Liu et al . 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, 39]. 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.