Background
Asthma is a chronic allergic respiratory disease with a heterogeneous background involving both genetic and environmental factors. In 2016, 339.4 million people worldwide were affected by asthma [
1]. In China, the prevalence of asthma was 3.02% in children under 14 years old (95%CI:2.97–3.06%) [
2]. Corticosteroids therapy can relieve the symptoms of asthma, however, the prevalence of asthma still increased significantly over the past 20 years [
3,
4]. Exposure to all ergens in the pollutants is one of the major risk factors of asthma in children [
5]. Evidence currently available has shown that many environmental factors, including allergens, airborne irritants, unfavorable weather conditions and adverse indoor environment, are associated with asthma progression [
6,
7]. Inhalable particulate matter (PM) including PM
2.5 and PM
10 (inhalable particles with an aerodynamic diameter less than or equal to 2.5 μm and 10 μm, respectively), is known as major environmental hazardous factors that impact human health [
8‐
11]. Previous epidemiological studies have shown that high concentrations of PM
2.5 and PM
10 are associated with elevated mortality rate and increased incidence of many diseases, such as respiratory diseases, cardiovascular diseases, central nervous system diseases and inflammation [
12‐
14]. In China, PM has become a major cause of air pollution due to rapid industrialization and urbanization in recent years [
15,
16]. This fact leads to growing concerns on the part of hospitals, government and the public about the health risks associated with PM. In particular, the ability of stakeholders to predict the impact of PM on public health is essential for hospitals to take timely and efficient actions to handle overwhelming outpatient volume caused by hazardous environmental conditions.
Most of the studies conducted worldwide addressed the relationship between PM exposure and asthma in terms of long-term effects and few assessed the impact of PM exposure on asthma control rate [
17].Many studies address the transient effect of indoor and ambient pollutants and allergens on asthma exacerbation but less is known for particulate matters [
18,
19]. On the other hand, current empirical studies examining the toxic effects of PM exposure were mostly conducted in cell lines and mouse models based on case-control design. Real world evidence derived from electronic health record (EHR) is likely to provide more pragmatic and accurate estimate of the effects of PM exposure [
20,
21].
It has been well documented that PM exposure causes specific immune responses in the airway [
22‐
24]. PM induces inflammation, apoptosis, increased secretion of T-cell cytokines, and DNA damage [
25,
26]. Asthmatic symptoms are documented in 14% of children worldwide [
27]. Children are more susceptible to PM-related diseases because of higher breathing rates, narrower airways, immature lung tissue, and longer exposure time to outdoor ambient air [
28,
29].
Xiamen is located on the southeast coast of China. The city is in typical subtropical climate zone. No study is available to address the short-term effects of PM on childhood asthma exacerbation and control rate in this area. Considering the increasing PM pollution in this area and growing public health concern over PM, there is a need to obtain further epidemiological evidences for public health service to take proper preventive measure to control the risk caused by PM exposure. Therefore,we designed this study to evaluate the effects of PM exposure on childhood asthma exacerbation and control rate.
Discussion
Our study confirmed that the exposure to PM2.5and PM10 within one or two week sposed significant risk to exacerbation of childhood asthma in Xiamen, China. The risk of PM exposure was independent on the effects of other pollutants, weather conditions, or individual variation. In addition, our data suggested that the effect of exposure to PM lasted for at least weeks.
The association between PM exposure and the risk of asthma has been studied in different regions of the world and consensus have been reached that high exposure to PM causes increased risk of exacerbation and admission rate [
34]. For example, one study conducted in Seattle, Washington suggested that for every 11 μg/m3 increase in PM
2.5 concentration, the OR of childhoodasthma was 1.15 (95% CI: 1.08 to 1.23) [
35]. An Australian survey which sampled 36,024 hospitalized patients with asthma showed that the impacts of PM
2.5, NO
2, PM
10and pollen in the cold season on hospitalization for asthma were 30.2% (95% CI: 13.4 to 49.6%), 12.5% (95% CI: 6.6 to 18.7%), 8.3% (95% CI: 2.5 to 14.4%), and 4.2% (95% CI: 2.2~6.1%), respectively [
36]. Taiwanese scholars used the open data of the government to investigate the air pollution in different urban models using time-stratified case crossover studies and conditional logistic regression analysis in 4237 hospitalized children with asthma in Taipei and Kaohsiung from 2001 to 2010 [
37]. The results showed that the risk of hospitalization for childhood asthma was significantly correlated with air pollutants. After being adjusted by season, the air pollution in Kaohsiung City had greater impact on the hospitalization of childhood asthma than that in Taipei.
Although many studies addressed the effects of PM exposure on asthma risk in the long-term [
17], less is known about the transient effects of PM exposure in the scale of weeks. Several recent studies address the effects of PM exposure on asthma exacerbation in short-term in Ningbo, Taipei, Seoul and Detroit [
38‐
41]. According to these reports, the highest effect size of PM exposure on asthma exacerbation ranges from5 to 10 days. In order to accommodate the lagged effect we estimated the effect size for one week and two weeks of exposure, respectively. Our data confirm PM exposure as a risk factor to asthma exacerbation and the effect peaks at two weeks of exposure, which is consistent to prior studies. Moreover, our results suggest PM exposure has a negative effect on the disease control rate, which provided extra evidence for the hazardous impact of PM on childhood asthma. In an investigation of commuters, PM2.5 exposure was associated with lower FEV1% predicted among participants with below-median asthma control (3 h postcommute: -7.2 [95% CI = − 11.8, − 2.7]) [
42]. A study in El Paso, Texas showed positive associations between Asthma Control Questionnaire (ACQ) scores and 96-h effects of PM
10, PM
2.5, black carbon, NO2 and ozone. In this study, the ACQ was used to evaluate asthma control [
43]. Scottish scholars found that there is an exposure-response relationship between indoor PM
2.5 concentration and poorer asthma control in children prescribed inhaled corticosteroids (ICS) [
44]. The effect of PM
2.5 in this study is reported after 5 days of exposure.
Prior studies use different measures to quantify the level of exposure to PM [
39,
40]. In this study, we used the “Technical Regulation on Ambient Air Quality Index” (AQI, HJ 633–2012) [
33] issued by Chinese government as an official standard classify air quality and use the total number of days of level 2 and 3 as a measure of exposure. The regional AQI is based on air-pollution measures from different sites and normalized for geological variations hence more accurate and comprehensive. In addition, the use of AQI makes our data directly applied to the regulation policies of pollution control and public health. There are other ways to measure the exposure to PM, such as the average concentration. Our results based on exposure days are consistent with and complementary to the prior studies.
PM exposure is not a stand-alone risk of asthma exacerbation. It has been previously shown that weather conditions, other environmental exposure, infections and self-management all contribute to the exacerbation of asthma. Our study is based on case-crossover design where each subject serves as its own control. Such a design can effectively remove inter-subject variations such as self-management. As for the weather conditions, temperature, barometric pressure and humidity are tightly correlated with each other, therefore, we kept only temperature to avoid collinearity. Co-morbid infections are not directly measured in the data we obtained but at the same time strongly affect the exacerbation of asthma. Therefore, we used surrogate variables such as the record of fever in the history of present illness.
To estimate the effect of PM exposure on DCR, we combine the uncontrolled and partly controlled subject into one group. The same classification is used in prior clinical studies of asthma exacerbation [
31,
32]. Plus, around 20% of partly controlled asthma will develop into uncontrolled disease and has a risk of exacerbation (0.1%) [
45,
46].
In spite of the growing concern over air pollution caused by PM, the hospitals and public health services in China still lack accurate regional assessment of the risk posed by PM exposure, which is required for risk management and preventative measures. The resultsofour study provided basis for preventative and clinical management of the exacerbation risk of asthma. In particular, we also described a method based on case-crossover design that can apply to other regions of the country.
Real-world evidence (RWE) has become increasingly important in medical and epidemiological research. Our study based on information extracted from local EHR database provides a plausible pipeline to address environmental risk factors using RWE, which enables more accurate estimate of the effects in large population. On the other hand, unknown bias factors can confound the analysis based on RWE, therefore we have considered all possible covariates. More importantly, the case-crossover design is based on self-control, thus, less affected by sampling biases.
Finally, the biological mechanism of the toxicity of PM is not fully elucidated inhuman. However, many studies confirm that the toxicity of PM is related to the immunogenicity and the consequential immune responses using cell line and animal model [
47]. In OVA-sensitized mice, exposure to PM promote the proliferation of peribronchial lymph nodes and the activation of T-help cell subtype 2 which provokes inflammation in airway [
48,
49]. Other studies suggest exposure to PM result in an increment of both neutrophils and eosinophils [
50]; it also causes imbalance activities of Th1/Th2 through the activation of TNF- α and suppression of INF-γ [
51,
52]. Moreover, prior studies also demonstrate that exposure to PM affect with the activities of monocytes and macrophages [
53]. A number of pathological changes, such as inflammatory cell infiltration, bronchial smooth muscle thickening, and bronchial mucosal injury are observed following the exposure to PM [
54]. More recent study shows that certain transcription factors, such as Toll-like receptor and nuclear factor-erythroid 2-ralated factor 2(Nrf2) signaling pathway are involved in the inflammatory responses in the airway of asthmatic mice [
55].
The physicochemical property of PM varies substantially due to the source of pollutant as well as climate. It is still not clear what is the exact molecular basis underlying the toxicity of PM. Our results are constrained to the local conditions in Xiamen and may differ from other regions due to the different chemical features of PM. To address the question, systematic chemical description of the PM is needed in future study.