1. Introduction
Asthma is a common chronic disease in childhood and has become an increasing problem in the last few decades because numerous studies have revealed an increasing trend of asthma prevalence in both developed and developing countries [
1,
2,
3,
4,
5,
6,
7,
8]. In Taiwan, children’s asthma is a major health issue, and evidence has shown that the prevalence of children’s asthma has also increased dramatically over the last 40 years [
9,
10]. The overall 8-year prevalence of asthma in children was 15.7% according to a national survey from 2000 to 2007 [
11]. Although the factors behind the changing pattern remain unclear, many personal and environmental factors have contributed to asthma risk, such as tobacco smoke, chemical fumes, weather conditions, and air pollution [
12,
13,
14,
15,
16]. In addition, many industrial factories in Taiwan, especially in west-central Taiwan, play an important role in the process of economic development, but they contribute to various kinds of pollutants to the ambient air, which may trigger the increase of asthma risk [
17].
Of the environmental factors, air pollution is one of the widespread environmental threats to human health. In particular, the issue of the association between air pollutants and asthma has been extensively discussed. The literature has proven that air pollution is a significant factor of asthma exacerbations, especially in susceptible populations who may be at risk for exacerbation of asthma from the toxic effects of airborne particulate matter (PM) [
18,
19,
20,
21]. Potential pathways for pulmonary effects propose that air pollutants can bypass the body’s natural defenses and provoke an inflammatory response in the lungs, especially from fine particulate matter (PM
2.5, particulate matter with an aerodynamic diameter ≤2.5 μm) [
22].
Several studies have revealed the influence of PM
2.5 on increased medication use, hospital admission, and emergency room visits for asthma attack in children [
23,
24,
25,
26,
27,
28]; however, some studies found nonsignificant impacts of PM
2.5 on asthma hospitalization [
29,
30]. Current studies have no clear explanations for the conflict in this regard [
29,
30]. The reasons may include variability in population characteristics and geographic variation. Some researchers have pointed out the space-time variation of PM composition and concentrations [
31], which could partially explain the spatial differences in the health effects for mortality and morbidity [
32]. The same levels of PM
2.5 may still have different chemical compositions, which result in various adverse health effects. Epidemiological studies have demonstrated a strong spatial variation in the chemical component of PM that causes geographic disparities in human health [
14,
32,
33,
34,
35].
The time-series studies in PM
2.5 have found out the temporal pattern of associations between daily counts of health end-points and daily concentration on the current and a few preceding days [
34,
36,
37]. Such lagged effects caused by PM
2.5 have been observed in asthma and other respiratory symptoms, such as cough and wheeze, while the results are different from 3 to 4 days [
38,
39] or 2–6 days [
40,
41,
42]. One possible reason for the different lags affected by PM
2.5 is because different lagged effects may provide insight into different biologic mechanisms of reaction to PM
2.5 [
43]. Moreover, earlier research applied linear modeling approaches to assess the lagged effect between ambient air pollution and health effects [
41,
44,
45]. However, the choice in the number of lags was not objective in different models, and the linear relationship between a health outcome and a lag is also doubtful. Recently, more studies have applied nonlinear models and reached more solid findings [
14,
46,
47,
48].
In this study, we hypothesized that the health impact of PM2.5 on asthma has a nonlinear lagged influence and that the district level of PM2.5 concentration might have different effects on asthma incidence. Thus, we adopted a spatiotemporal model for investigating the nonlinear relationship between PM2.5 concentrations and children’s asthma clinic visits with consideration of spatial autocorrelation and lagged effects. Our research aims comprise: first, evaluating the lagged effects of the daily PM2.5 concentration on the morbidity of asthma; and second, investigating geographic disparities of asthma risk after controlling for air pollutants and weather conditions.
3. Results
The number of annual clinic visits for children’s asthma was 172,696 in 2005, 157,278 in 2006, 162,837 in 2007, 148,439 in 2008, 150,680 in 2009, and 148,450 in 2010. The daily average of children’s asthma clinic visits was 4.70 cases (standard deviation (SD) = 14.28) in Yunlin County, while Changhua County only had 3.03 (SD = 7.94) children’s asthma clinic visits per day. Daily measurements of ambient pollutants and meteorological factors during the study period are summarized in
Table 1. In particular, the mean daily average of PM
2.5 was 37.22 μg/m
3 (SD = 18.87) in Changhua County and 37.26 μg/m
3 (SD = 19.38) in Yunlin County, and both were higher than the World Health Organization (WHO) guideline value (25 μg/m
3). In addition, during the study period, 27.99% of days blow northeast wind in Changhua County, and 26.27% of days blow south wind in Yunlin County.
Figure 2 shows a clear seasonality on the temporal variation of daily averaged PM
2.5 concentration and daily clinic visits for children’s asthma. A total of 1543 days (70.4%) has the daily mean of PM
2.5 concentration exceeding the WHO standard of 25 μg/m
3 during the study period. On average, the study area had 180.22 daily clinic visits (SD = 51.84) for children’s asthma. A higher number of clinic visits more likely happened during springs and winters.
Figure 3a depicts the geographic distribution of the average crude rate of daily children’s asthma and a higher rate more likely concentrated on a few eastern inland districts.
Figure 3b presents the geographic distribution of daily average PM
2.5 concentrations, in which there was a higher-density distribution from the western coast to the eastern inland districts in the whole study area, especially in the southeastern area.
Table 2 shows a significant RR of children’s asthma in each DOW compared to Sunday, whereas Monday had the highest RR by 2.07 (95% CI = 2.04–2.11;
p-value < 0.0001). Moreover, compared to a southerly wind, a significantly lower RR was highly likely in a westerly wind (RR = 0.82; 95% CI = 0.76–0.89;
p-value < 0.0001) and a northwesterly wind (RR = 0.89; 95% CI = 0.82–0.97;
p-value = 0.0076). Only a northerly wind was significantly positively associated with children’s asthma (RR = 1.03; 95% CI = 1.00–1.06;
p-value = 0.0272). Furthermore, increased asthma visits were significantly associated with cPM and SO
2. When cPM increased one interquartile range (=17.60 μg/m
3), the RR for children’s asthma significantly increased 1.42% (95% = 1.01–1.83;
p-value < 0.0001). Similarly, when SO
2 increased one interquartile range (=1.66 ppb), the RR significantly increased 1.25% (95% CI = 0.43–2.08;
p-value = 0.0028).
Figure 4a demonstrates the effect of PM
2.5 concentration changes on children’s asthma along with lagged days, suggesting a higher RR of children’s asthma simultaneously increased when lagged day and PM
2.5 concentration also increased. However, in each lagged day, the RR of children’s asthma gradually decreased when PM
2.5 concentration increased over 80 μg/m
3. A contour plot shown in
Figure 4b presents a clear variation of RR by PM
2.5 concentration and lagged day, indicating that a RR greater than 1 happened from present day and 4-day lag when PM
2.5 concentration increased between 60 and 80 μg/m
3.
Compared to the reference level of PM
2.5 (35 μg/m
3), a higher concentration at the 75th percentile (49.24 μg/m
3) and 95th percentile (73.02 μg/m
3) of PM
2.5 had a RR significantly higher than 1 from 1 to 6 lagged days as shown in
Figure 5a,b. Compared to the present day, a higher RR was more likely to happen at 2-day lag, and it was significantly greater than 1 when PM
2.5 increased from 36.17 μg/m
3 to 81.26 μg/m
3 (
Figure 5c). The range of PM
2.5 having a significant RR greater than 1 was shorter along with more lags. For instance, at 6-day lag, a significant RR greater than 1 can be only observed for the concentration of PM
2.5 between 38.25 μg/m
3 and 76.71 μg/m
3 (
Figure 5d).
Figure 5e shows an overall PM
2.5 effect on children’s asthma after accumulating all RRs from each lagged day along with PM
2.5 concentration. The result displays a significant increase of RR when PM
2.5 increased over 35 μg/m
3. The cumulative RR reached the highest level by 1.08 (95% CI = 1.05, 1.11) as PM
2.5 increased as high as 64.66 μg/m
3. The increment of RR turned downward when PM
2.5 was over 64.66 μg/m
3, and no significant RR greater than 1 was observed when PM
2.5 was higher than 85.25 μg/m
3.
Several districts were identified to have a higher RR for children’s asthma in Changhua County and Yunlin County. In
Figure 6a, districts with a higher RR were more located in Changhua County, while the highest one was observed in the Huwei District (RR = 172.80; 95% CI = 162.83–183.39) at the center of Yunlin County, which is the second significant district for local industries, medical care, economy, and employment.
Figure 6b reveals a total of 22 districts (13 in Changhua County and 9 in Yunlin County) with a RR significantly higher than 1 after controlling for the other confounding variables. Meanwhile, children living in 47.83% of the total 46 districts were vulnerable to asthma.
4. Discussion
Air pollutants, especially in PM
2.5, have been implicated as a potential risk factor for human health, and have raised the greatest public health threat globally according to the WHO’s report [
60]. This study selected children as the study population because children are very sensitive to air pollution. We investigated the exposure-lag-response association between children’s asthma and PM
2.5 within the lag period, resulting in significantly lagged effects on children’s asthma, especially from 2-day lag to 6-day lag. In addition, this study revealed several high-risk districts after controlling for ambient air pollutants and weather conditions. The finding not only verified the evidence of geographic disparities on children’s asthma, but also provided a priority order of at-risk areas for advanced interventions or preventions.
The main feature of this study is taking the nonlinear properties into account for assessing associations between children’s asthma clinic visits and exposure to ambient air pollution. While some previous studies have examined the linear association between PM
2.5 and asthma [
23,
24,
25,
61,
62], actually at-risk children may not have any asthma symptoms during the concurrent day when being exposed to air pollutants. Meanwhile, the admissions observed on a particular day can be related to the air pollution observed on previous days. Therefore, using a linear model cannot reflect the true relationship of PM
2.5 and health, and the lag itself may not be linearly correlated as well. The more lags we consider, the more nonlinearity among lags should be explicit.
Previous epidemiological research on asthma has usually defined lagged effects as linear terms in a model [
25,
26,
27,
28], while this modeling strategy assumed that those lagged terms were linearly independent with each in nature. This study adopted the DLNM, which is more flexible in defining the relationships among lags and emphasizes the interactions between PM
2.5 concentrations and lags. Thus, the linearity assumption is no longer needed. In fact, recent studies had applied the DLNM more frequently to research lagged effects of air pollution on asthma. For instance, a Sweden study used this model to analyze air pollution data on primary health care visits for asthma, resulting in a significant finding from NO
2 [
63]. A similar application with the same model in Hong Kong evaluated the association of asthma emergency room visits among children with ozone concentration [
64]. More importantly, our model includes a spatial function to adjust for spatial heterogeneity among 46 districts. The rationale of including the spatial function is to present a possible phenomenon known as harvesting, which appears as a raised risk ratio at a short lag followed by an apparent protective effect at a longer lag [
65]. In other words, without including the spatial function in the DLNM, the effect of harvesting may be ignored, and may cause a monotone increasing trend in a disease risk as the concentration of an air pollutant increases. The situation has been well-investigated and discussed in a previous study of acute respiratory disease and PM
2.5 [
66].
We explored the temporal lag patterns of the effects of PM
2.5 concentrations on children’s asthma clinic visits to conclude that PM
2.5 was correlated with 1–6-day lags. Among the 6-day lagged effect, the first 3 days have the greatest relative risks. Consistent with our results, previous studies have suggested the lagged effect on different asthma outcomes to be at most 6 days. For instance, Ko et al. reported stronger lagged effect estimates from lag of 0–4 days for asthma hospitalization in Hong Kong [
67]. Slaughter et al. examined the relationship between PM
2.5 and asthma attack in children and found a significant effect for 0–1 day lag [
25]. A longer lagged effect, up to 5 days, was observed among children [
40]. The possible mechanism leading to the lagged effect could partly be explained by inflammation in the alveolar region of the lung caused by the smaller particles in the pollutant mixture [
68]. The efficient deposition of ultrafine particles has been shown to be able to penetrate deep into the lungs and in particular in subjects with asthma [
69]. In addition to differences in biological mechanism, the different lagged effects could be attributed to patient behavior patterns. Several days are needed for exacerbation to become severe enough to lead to a clinic visit. This would explain why the increase in asthma clinic visits was delayed. The finding of the lagged effects of asthma from the exposure to high PM
2.5 episodes provides an important reference for governmental agencies to assess the health effects of the PM
2.5 events, which have occurred frequently in recent years throughout Taiwan, in terms of clinic visits and their associated economic costs from the national health insurance plan.
The short-term time effect should be considered as a confounding factor for clinic visits due to the fact that seeking medical treatment varies by the day of the week. In Taiwan, generally the open time in most hospitals is from Monday morning to Saturday afternoon. Therefore, people who need to see a doctor on Sunday would wait until the following Monday to be admitted. The situation reflects a higher RR on Monday in our model, which illustrates the temporal pattern of medical treatment associated with the short-term time effect.
Because of a variety of air pollutants generated by certain sources, such as transportation and industry, are the major sources of CO and NO
x, having those co-pollutants as confounding factors in the model is necessary. However, the correlation between CO and NO
x is as high as 0.81, causing the collinearity problem in the model. Although no previous study has examined whether collinearity will affect the estimation on a cross-basis function in the DLNM, we still alternatively used a single predictor by the CO/NO
x ratio to avoid potential biases. In addition, the CO/NO
x ratio has been frequently used in air quality assessment, where a high value indicates that mobile sources are the predominant contributors of these two compounds, while a low value of rationality indicates that point sources contribute from industrial sources [
70,
71]. Thus, this should be an adequate replacement rather than using CO and NO
x separately in the same model.
The spatial function of our model identified a significant excessive asthma risk in 22 districts after controlling for confounding variables. The finding concluded that those districts may have other unobserved risk factors, while we can only examine why children living in those districts are more vulnerable to asthma than children living in the other districts. Those unobserved factors may attribute to socioeconomic deprivation, other unobserved pollutants, or uneven medical resources. In our study, we observed that the high RR regions are mostly those locations with major medical centers, such as Douliu, Huwei, Beikang, and the Mailiao Townships in Yunlin County. This suggests that the spatial disparity of medical resources can be an important confounding factor in the spatial distribution of clinic visits for asthma.
This study revealed the concentration-response relationship from the population-based clinic visits data. As a result, our finding can provide a solid background for a governmental agency to develop an effective strategy to mitigate the health effects from PM2.5 concentration. Two limitations should be noted regarding this study. First, this study was not able to adjust for potential confounders at the individual level, such as body mass index, exposure to environmental tobacco smoke, genetic information, and allergens, because no such information is available in the NHIRD. Second, we were unable to identify the composition of PM2.5 from monitoring stations because of differences in pollutant composition across space and time and different influences during specific exposure periods.