Ozone Pollution and Acute Exacerbation of Asthma in Residents of China: An Ecological Study

Introduction

Ozone pollution becomes a worrisome risk factor for global morbidity and mortality.¹ Although O₃ in the stratosphere plays a protective role against ultraviolet irradiation, O₃ is one of the key oxidants and greenhouse gases in the atmosphere, contributing to climate change, affecting human and vegetation health.^2,3 It should be noted that high concentrations of O₃ are now common in densely populated areas and contribute to respiratory conditions.⁴

Asthma has become the second leading cause of death among chronic respiratory diseases around the world.⁵ According to the Global Burden of Disease estimated that 420 thousand people around the world died from asthma in 2016, more than 1000 per day. The prevalence of asthma between 2010 and 2012 was 1.24% among individuals aged >14 years and 3.02% among individuals aged <14 years in mainland China. It is estimated that there are approximately 30 million asthmatic patients in China.^6,7 Multiple epidemiological studies have shown ongoing associations between high levels of O₃ and poor early-life lung growth, development of allergic sensitization, development of asthma, airway inflammation, acutely impaired lung function, respiratory tract infections, and asthma exacerbations.^8–10 The Asthma Global Burden Report estimated that appropriate 9–23 million of patients with asthma exacerbation should be attributed to O₃.⁹ Additionally, most of the deaths of asthma occurred due to asthma exacerbations.¹⁰ A recent meta-analysis including 67 studies reported that short-term effects of exposure to O₃ were associated with asthma exacerbations.¹¹ Available studies focused on the short-term and instantaneous effect of O₃ exposure on asthma exacerbation. However, a lack of studies investigated the cumulative and delayed effects between O₃ and asthma exacerbation.

Severe air pollution events were reported in Shijiazhuang for a long time between 2010 and 2016. The daily average concentration of O₃ was recorded to reach 109.5 μg/m³ in non-heating season.¹² In the present study, we aimed to evaluate the lag and cumulative effect of high concentration of O₃ on the risk of asthma exacerbation in Shijiazhuang. Then, we further estimated the interactive effect of O₃ and SO₂, NO₂ on asthma exacerbation onset for a strong correlation of SO₂ and O₃ (r = 0.67), and NO₂ and O₃ (r = 0.66) found from a previous study.¹³ Finally, we also investigate the interaction of O₃ with meteorological factors.

Methods

Study Area

Shijiazhuang, the capital of Hebei Province, is one of the most heavily polluted cities in Hebei Province and one of the largest transport hubs and industrial cities in the North China Plain. The geographical location of hospitals and air quality monitoring stations in Shijiazhuang is shown in Figure 1.

Figure 1 The geographical location of hospitals (red circles denote public hospitals) and air quality monitoring stations (blue circles denote air quality monitoring station) in Shijiazhuang.

Health Data Collection

Daily counts of asthma exacerbation were obtained for the years 2010–2016 from the 22 tertiary hospitals and secondary hospitals. These hospitals accounted for 60% of tertiary hospitals and secondary hospitals and served most of the asthma patients residing in Shijiazhuang. The Electronic Medical System provided patients’ information including gender, age, admission and discharge dates, place of residence, and history of diseases. The data on asthma exacerbation was aggregated by the date of self-reported onset of exacerbation symptoms, rather than by the date of hospital admission. All the patients with the standard diagnostic criteria for asthma exacerbations in primary and secondary diagnoses were included in the analysis. Both emergency department visits and hospital admissions due to asthma were regarded as acute exacerbations of asthma. The asthma exacerbations were identified by the 9th Edition International Classification of Disease (ICD-9) code (J45.000, J45.003, J45.007, J45.100, J45.800, J45.900, 45.902, J45.903, J45.904, and J46.x00) over the study period. The patients were limited to residents in Shijiazhuang City which includes 13 counties (Qiaodong, Qiaoxi, Xinhua, Yuhua, Changan, Zhengding, Luquan, Gaocheng, Jingxing, Jingxing mining area, Yuanshi, Jinzhou, Luancheng) during 2010–2016.

Environmental Data

We used an 8-hour daily maximum O₃ concentration to evaluate the risks for asthma exacerbations. The 8-hour maximum concentration represents the highest 8-hour average in the relevant 24-hour period. Available evidence suggested that O₃ concentration measured as an 8-hour daily maximum was suitable for estimating the risk of asthma exacerbations.¹⁴ Daily average meteorological data including mean temperature (°C) and relative humidity (%) were extracted from the Hebei Meteorological Bureau. All the data on air pollutants and meteorological factors were collected at the national standard weather station in Shijiazhuang.

Statistical Analysis

Firstly, a descriptive analysis was performed to describe the distribution of daily concentration of O₃ and asthma exacerbation cases during the study period. The over-dispersed GAMs were then used to examine the associations between O₃ and asthma exacerbations for that the number of daily cases follows a quasi-Poisson distribution.^15–17 For the cumulative and delayed effects of environmental factors on health outcomes, a PDLM was used to assess the effect of O₃ on asthma exacerbation risk. PDLM is the distributed lag non-linear model (DLNM) that defines lag intervals through polynomial variables, which has the advantage of accounting for collinearity between different lag days and is thus more suitable for exploring the cumulative health risks of O₃ exposure than single lag days or moving average.^18–20 O₃ was introduced into the models by establishing a cross-basis function using the PDLM to account for its potentially lagged and nonlinear effects. Degrees of freedom (df) for the splines function were chosen according to the integral generalized cross validation (GCV) method. The GCV scores can be taken as an estimate of the mean square prediction error based on the leave-one-out cross-validation estimation process. Former studies suggested that the acute effect of exposure to air pollutants on the exacerbation of respiratory conditions always happened within 7–14 days.^11,21–23 Results of model diagnostics suggested that a 14-day lag period was applicable and robust for our models. Previous studies have limited the lag period to several hours to 7 days which may underestimate the cumulative effect of O₃ on asthma exacerbation risk.¹¹ Taken together, 14 days were chosen as the optimal lag period. Time-varying confounders were adjusted in models, including an indicator variable of day of week (DOW) and a binary variable of public holidays. The formula for the main model is summarized as:

Where Yt donates the daily count of asthma exacerbation cases on day t; [E(Yt)] is the expected daily count on day t; t is the calendar time; αis the intercept; β is effect estimate of interest; PDLM is the PDLM for each air pollutants to be examined; air pollutants represents other air pollutants except for O₃ and was used to adjust for the influence of other pollutants on asthma exacerbation. tem and hum indicate the daily mean temperature and relative humidity, respectively. s() represents the thin-plate spline function. s(time) was used to control the seasonal and long-term trends. Holiday and DOW were adjusted for the confounding effect of public holidays and the day. The optimal df was assessed by GCV criteria which was automatically selected by R software.²⁴ Finally, the interactions of O₃and NO₂, SO₂, temperature, humidity were explored using a GAM with the thin plate splines function.

R software (Version 3.4.4) was used to conduct all statistical analyses using the “mgcv” package and the “spline” package. Two side p-values less than 0.05 were considered statistically.

Ethical Considerations

The work described was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki), approved by the Ethics Committee of the Hebei Province Hospital of Traditional Chinese Medicine. Written informed consent was assent obtained from all participants prior to enrollment.

Results

Basic Variable Characteristics

The detailed statistical information on air pollutants and meteorological factors is summarized in Table 1. There were 7270 asthma patients involving 4216 males (57.9%) and 3054 females (42.1%). The daily average male-to-female ratio, average patient age, and average count of cases were 1.40, 43.1 years old, and 3.00 per day. The daily average concentrations of O₃, NO₂, SO₂, CO, PM_2.5, and PM₁₀ were 90.8µg/m³, 60.3µg/m³, 73.3µg/m³, 2.08µg/m³, 106.9µg/m³, and 185.3µg/m³, respectively. The daily mean temperature and relative humidity were 13.2°C and 60.9%.

Table 1 Descriptive Statistics on Asthma Cases, Air Pollutants, Meteorological Factors in Shijiazhuang During 2010–2016

Preliminary Analysis

Figure 2 presents the time-series distributions of the daily asthma exacerbation cases and O₃ concentration during the study period in Shijiazhuang. The long-term trend and seasonality of the number of asthma exacerbation cases were both mild. The concentrations of O₃ were obviously higher in the warm season (May–October) than in the cold season (November–April).

Figure 2 The time-series distributions of the daily asthma exacerbation cases and O3 in Shijiazhuang, China from 2010 to 2016.

Spearman correlation coefficients for asthma exacerbation cases, meteorological factors, and air pollutants are presented in Figure 3, where all correlations were significant at the level of p less than 0.05. A medium level of correlation was observed between O₃ exposure and daily asthma exacerbation cases (r_s=0.505). The O₃ was slightly and positively associated with SO₂ (r_s=0.401), NO₂ (r_s=0.336), temperature (r_s=0.320), and humidity (r_s=0.166) during the study period. The correlation coefficient between PM_2.5 and PM₁₀ was as high as 0.968, and therefore only PM_2.5 was included in the models to avoid the influence of collinearity.

Figure 3 Coefficients of Spearman correlation between asthma exacerbation cases and air pollutants and meteorological factors in Shijiazhuang, China from 2010 to 2016. (Y-axis: the cases of asthma, concentration of pollution, relative humidity and temperature. X-axis: the same with the Y-axis).

Figure 4 shows the exploratory results from the GAM. A nonlinear relationship was found between asthma exacerbation cases and O₃, NO₂, SO₂, CO, PM_2.5, PM₁₀ as well as average temperature, while asthma exacerbation cases were linearly associated with relative humidity.

Figure 4 Relationship between air pollutants, meteorological variables and asthma exacerbation cases (Y-axis: the predicted value of asthma cases as the independent variables changed. X-axis: the distribution of variables (including ozone, other air pollutants, temperature, humidity and time) in the asthma patients).

Regression and Interaction Analysis

Table 2 presents the relative risks (RRs) and 95% CIs for asthma exacerbations for different day lags of O₃ concentration. The significant association for asthma exacerbations due to O₃ occurred on lag 1, lag 5–10. Each 10 μg/m³ increase in O₃ led to a 1.92% (95% CI = 0.80–3.03%) increase in the risk of asthma exacerbation on day lag 7. The cumulative effects of O₃ on the risk of asthma exacerbation indicated an increasing trend. The cumulative risk increased 18.9% (95% CI = 12.8–25.4%) on the 14th day.

Table 2 Relative Risks with 95% CI of Asthma Exacerbations in Shijiazhuang During 2010–2016 Based on 10 μg/m3 Increases in the Fine Particulate Matter (O3) Concentration

As shown in Figure 5, it is shown the interaction of O₃ with NO₂, SO₂, temperature, and relative humidity on asthma exacerbation cases using the three-dimensional diagram. With controlling for the air pollutants, long-term trends, and seasonality, the risk of asthma exacerbation on days lag 7 increased when the O₃ and SO₂ concentrations were both at a high level, while its significant interactive effects with NO₂, temperature, and humidity were not observed.

Figure 5 The interaction of O3 and SO2, NO2, temperature as well as relative humidity on asthma exacerbation cases at present day in Shijiazhuang, China from 2010 to 2016, the interaction of O3 with SO2 (top left); the interaction of O3 with NO2 (top right); the interaction of O3 with temperature (bottom left); the interaction of O3 with relative humidity (top right).

Model Diagnostics

The model diagnostic was conducted with the result in Figure 6. There was no obvious autocorrelation in the deviance residual analysis. The result of the model diagnostic showed that PDLMs were robust in our study.

Figure 6 The result of model diagnostic of PDLM on 14-day lag.

Discussion

Our study has extended the previous findings by confirming the association between high-level O₃ exposure and acute exacerbation of asthma among Chinese adults and interaction with SO₂. The results of this study revealed a positive and significant association of O₃ exposure with asthma exacerbation. The cumulative effects of O₃ on the risk of asthma exacerbation indicated an increasing trend.

A number of studies have already provided important evidences that ground-level O₃ is an established trigger for exacerbating asthma and is associated with higher rates of emergency department visits for asthma.^11,25 Accumulating pieces of evidence has shown that ozone-effect on asthma exacerbation almost covered all age groups of populations.^26–29 Huang et al and Liu et al found that O₃ exposure was significantly associated with increased risks of acute pediatric asthma attacks (aged 0–14; RR = 1.023 on the present day)²⁶ and pediatric asthma ED visits (aged 0–18; RR = 1.009, 95% CI = 1.001–1.017).²⁷ Robles et al provided evidence that worse asthma symptoms were strongly associated with higher O₃ exposure in adolescents aged 12–17 years old (β=0.10, 95% CI = 0.004–0.20, p = 0.042).²⁸ Linet al indicated that asthma patients with exacerbation requiring hospitalization were exposed to a higher level of 8-hour daily maximum O₃ (aged ≥18 years old; OR 1.009, 95% CI 1.001 to 1.016).²⁹ An all-age study conducted in Texas reported that the estimated risk of O₃ exposure on hospital admissions for asthma was highest for children (aged 5–14; RR = 1.047, 95% CI = 1.025–1.069), lower for younger adults (aged 15–64; RR = 1.018, 95% CI = 1.005–1.032) and null for older adults (aged 0–18; RR = 1.002, 95% CI = 0.981–1.023).³⁰ Similar results were observed in our study that an increase in O₃ concentration on the exacerbation of asthma was associated with the risk of asthma exacerbation among adults aged 20–65 on day lag 7 (RR = 1.019, 95% CI = 1.008–1.030). Thus, all of this evidence reminds us that public policies on the prevention of asthma exacerbations from high-level O₃ should focus on all age groups of asthma patients rather than a particular age group of the population. In addition, the results of a large and comprehensive meta-analysis suggested that O₃ measured as 1-hour or 8-hour daily maximum concentration was more consistently associated with asthma exacerbations than 24-hour average concentration and this association was more robust in regions where O₃ concentrations were higher.¹⁴ Therefore, our study was robust, for the concentration of O₃ measured as 8-hour maximum in our study and daily average concentration of O₃ remained at high levels during the study period.

Previous studies suggested that an O₃ concentration at 80 µg/m³ was a threshold for an increased risk of asthma attacks, and the effect of O₃ on asthma exacerbation was significant in children when the concentration was higher than 100 µg/m³.²⁶ Our study reported that each 10 μg/m³ increase in O₃ concentration was associated with a 1.92% (95% CI = 0.08–3.03%) increased risk of asthma exacerbation at lag 7 and a 17.8% (95% CI = 11.7–24.3%) increased cumulative risk of asthma exacerbation at the 14th day, taking the median concentration of O₃ on 80 µg/m³ in Shijiazhuang during the study period as a reference value. Although Air Quality Standard of World Health Organization showed that the daily maximum 8-hour average ozone concentration of less than 100 µg/m³ can be considered safe, this evidence alarm that O₃ has initiated to trigger the exacerbation of asthma among adults when the concentration of O₃ reached 80 µg/m³. There will be a great contribution to decreasing the risk of asthma exacerbation to control the concentration of O₃ under 80 µg/m³. However, there were more than 100 days per year with the concentration of O₃≥80 µg/m³ in Shijiazhuang from 2010 to 2016. It is valuable to focus on that concentration of O₃ from 337 major Chinese cities averaged 139 mg/m³ in 2018 and 148 mg/m³ in 2019.(http://www.mee.gov.cn) A lot of efforts still remain to be done in controlling the air pollution in Shijiazhuang and around the country in the future.

Former studies have provided much evidence that O₃, NO_2, and SO₂ exposures were associated with emergency department visits and hospital admissions due to asthma.¹¹ Our study firstly points to the interaction between O₃ exposure and SO₂, rather than NO₂, on asthma exacerbations. This complex interaction is associated with the development and progression of asthma exacerbation.¹⁰ There were no direct proofs of interaction between O₃ exposure and SO₂ on asthma exacerbations in previous available studies, but much indirect evidence suggested that interplay exists between O₃ and SO₂. There was a strong correlation between O₃ and SO_2.^13,30 A COVID-19 study conducted in 120 Chinese cities suggested that an increase of SO₂ was associated with a higher risk of confirmed case counts at a high level of O₃.³¹ Ground-level ozone concentrations are not only affected by emission reduction measures, but also by changes in meteorological conditions. Variations in temperature and relative humidity associated with changes in atmospheric circulation all that influence the photochemical reactions of O₃.³² However, we did not find the interactive effect of O₃ exposure and temperature as well as relative humidity on asthma exacerbations.

Our study firstly investigated the association between O₃ exposure and asthma exacerbations under a high-level O₃ concentration and a long lag period. A few limitations in this study were worth mentioning. Firstly, underreporting bias is unavoidable for cases of asthma exacerbations. Confirmed patients of asthma exacerbations may not be diagnosed due to atypical symptoms and included in the study. Then, the time-series study did not consider the personal influence of individual characteristics on the risk of asthma exacerbations, such as socioeconomic conditions and living and working environment. Finally, our study cannot investigate the effect from variations in emissions and meteorology separately.

Conclusions

To conclude, people with asthma disease should avoid exposure to high-level concentrations of O₃, especially together with the SO₂ pollution, by limiting their outdoor activities to reduce the chance of emergency department visits and hospital admissions due to asthma. The results of our study can be taken into account in designing health precaution guidelines or policies and medical resources for healthcare systems.