Short-term Effects of Multiple Ozone Metrics on Outpatient Visits For Urticaria in Lanzhou

Background Although mounting evidence suggests that short-term exposure to ozone increases the risk of respiratory disease, cardiovascular disease and mortality, there are few studies comparing the effects of ozone in relation to urticaria in China. Objective To evaluate the risks for urticaria exacerbations related to ambient ozone measured as 1-h maximum (O 3 -1 h max), maximum 8-h (O 3 -8 h max) and 24-h average (O 3 -24 h avg) concentrations. Methods We calculated three metrics of ozone, 1-h maximum, maximum 8-h and 24-h average based 31 on the hourly data. Generalized additive models with poisson regression incorporating natural spline 32 functions were used to investigate short-term effects on urticaria associated with ambient ozone 33 pollution in Lanzhou, China, using 5 years of daily data (2013-2017). We also examined the association by sex, age and season. 1.17%~2.79%), susceptible to O 3 the associations between ozone and urticaria more evident Conflict of interest None declared. Availability of data and materials Weather data are available Outpatient data were obtained from the three major tertiary hospitals through the Health Information 61 System, which has not deposited in publicly available repositories. Therefore, it is available from the 62 corresponding author on reasonable request. Air quality data are obtained form 4 monitoring stations 63 interspersed in study areas.


Introduction
In the human body, the skin is the part that comes into most frequent and extensive contact 84 with the external environment, and it serves as a defense barrier, constantly exposed to air 85 pollutants and sensing changes in the environment. Urticaria is a common allergic disease with 86 recurring symptoms and pronounced itching, and the prevalence of urticaria has been increasing 87 worldwide over the past decade (Zuberbier et   for the study (e.g., from the current day, lag0 to previous 7 days, lag7) and cumulative day lags (e.g.,

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from the current day and the previous 1, lag01 to the previous 8 days, lag07). Third, we also assessed 167 the robustness of the results in terms of the df values for calendar time (5, 6 and 8 df per year), and 168 temperature (4-6), and by adjusting for other pollutants, including SO2, NO2, PM2.5 and CO. 169 Additionally, the associations stratified by sex (female and male), age (≤18 years, 19-64 years and ≥ 170 65 years) and season (spring, summer, autumn and winter) were examined. The statistical significance 171 of subgroup differences was tested through Z-test: (̂1 −̂2)±1.96√Ŝ1 2 + Ŝ2 2 (where ̂1 and ̂2 172 were the estimated for age and sex group, and Ŝ1 2 and Ŝ2 2 were respective standard errors.)

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All analyses were conducted in R Programming Language (V.3.2.2, R Development Core Team) using 174 the "mgcv" packages. The results of the statistical test were two-sided with p-values<0.05 considered 175 statistically significant. The estimated effect is expressed as the percentage excess risk (ER%) and its 176 95% confidence interval (95% CI) for urticaria outpatients per 10 μg/m3 O3 component increase.

Results
The results of the descriptive analysis of O3 concentration and meteorological factors and 180 daily outpatient visits for urticaria are shown in Table 1  The Spearman correlation coefficients between air pollutants and meteorological factors are 192 described in Table 2 The results show that O3-1 h max, O3-8 h max and O3-24 h avg are highly O3-24 h avg, respectively. Therefore, the effect values for lag2 were chosen as the best lag times 203 for O3-1 h max, O3-8 h max and O3-24 h avg in this study. We also found that O3-24 h avg 204 always had the highest effect value when the effect values were compared in terms of increasing 205 concentrations of the same unit (10 μg/m 3 or IQR) (see table 4). 206 Fig.1 shows the effect of lag2 on urticaria outpatient attendances for every 10 μg/m 3 increase 207 in the O3 exposure index for the different measurement methods. When stratified by gender, the 208 effect of O3 was greater in women than in men, with an increase of 0.52%, 0.63% and 1.25% for every 10 μg/m 3 increase in O3-1 h max, O3-8 h max and O3-24 h avg, respectively, which were 210 not statistically significant. When stratified by age, the effect of O3 was more pronounced in those 211 aged ≥65 years, but was not statistically significant. 212 In Fig.2, it is shown whether the relationship between O3 and the number of urticaria 213 outpatient visits varies with season for the different measures. We found that the effect values for 214 O3 were slightly higher in summer and autumn than in the other two seasons, but were not 215 statistically significant. 216 As shown in Table 5, when SO2 and CO are introduced into the model, the excess risk of 217 different indicators O3 are reduced but still have statistical significance (p<0.05). When PM2.5 was 218 introduced, the excess risk increased and it was also statistically significant. However, when NO2 219 was introduced into the model, the results were significantly different. Among them, the effect 220 value of O3-1 h max increased to 1.26% (95%CI: 0.73%~1.79%) after adding pollutant NO2, 221 while the excess risk of O3-8 h max and O3-24 h avg showed a downward trend, respectively 1.15% 222 and 2.63%, both of which were statistically significant. 2014), however, concluded that there was a negative correlation between O3 concentration and the occurrence of rash. This inconsistency may be related to factors such as the climatic characteristics 239 of the study area, socio-economic conditions, and the age distribution of the study population. 240 In this study, three measurement methods of O3 exposure index increased by 10μg/m 3 , and 241 the number of urticaria outpatients increased to different degrees, which meant O3-1 h max, O3-8 242 h max and O3-24 h avg increased by 0.58%, 0.82% and 2.17% for every 10μg/m 3 increase on lag2 243 day, suggesting that O3 has a significant short-term impact on urticaria outpatient visits. By 244 comparing the results of three different O3 exposure indicators, it can be seen that O3-24 h avg has 245 the largest effect value, and O3-1 h max has the smallest effect value. Therefore, although the 246 O3-8 h max concentration index is currently used as an index that can better represent the acute 247 health effects of O3 (Yang et al. 2012). However, in this study, the significance of the other two 248 exposure indicators cannot be ignored. 249 In a stratified study by sex and age, it was found that outpatient visits for female urticaria 250 were more affected by O3 concentration than men. The increase in outpatient visits for people over 251 65 was related to O3 concentration. Because there are few similar documents, the accuracy of the 252 results has not been confirmed. 253 This study found in the seasonal stratification that the relationship between O3 and urticaria 254 outpatient visits is more prominent in summer and autumn. There is no statistical significance, but  In this study, it was found that ozone has a strong correlation with particulate matter and that 270 the effect value of O3 increases and is statistically significant after the introduction of PM2.5 into 271 the model. It has been shown that certain conditions are favourable for the rapid production of 272 ozone and secondary particulate matter, leading to a complex superposition of ozone and fine 273 particulate pollutants in the atmosphere. As particulate matter is a complex pollutant and its 274 composition varies considerably depending on its regional origin, it is not possible to confirm 275 whether particulate matter is a confounding factor for ozone or a modifying effect, and more 276 research evidence is needed in the future. 277 It has long been recognized that environmental exposure to ozone affects skin health. By 278 evaluating the skin of hairless mice exposed to ozone, Thiele et al (1997) found a decrease in 279 vitamins C and E and the formation of malondialdehyde, a marker of lipid peroxidation, in the 280 epidermis of hairless mice exposed to varying levels of ozone at increasing and decreasing doses.

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In this study, it was found that an increase in atmospheric ozone concentrations in Lanzhou 291 increased the number of urticaria outpatient visits, with a maximum lag time of lag1 for O3-1 h 292 maximum concentration, lag2 for O3-8 h maximum concentration and lag2 for O3-24 h mean 293 concentration. There was significant differences in the three ozone exposure indicators for 294 urticaria outpatient visits, and it could be seen that O3-24 h avg had the largest effect value. 295 Based on gender, age and seasonal analyses at different exposure levels, it was also found that 296 there was a higher increase in urticaria outpatient visits when O3 was applied to females, elder 297 population, summer and autumn compared to the rest of the population. The results of the study 298 provide richer evidence for a comprehensive assessment of the acute effects of ozone on 299 dermatological diseases and can provide more technical support for policy makers to revise their 300 public health policies accordingly.  Results of grouped analyses by gender and age on the association between a 10μg/m3 increases in the average concentration of O3-8h and daily outpatient visits for urticaria Figure 2 Shows the season-strati ed results from a single-day lag and a multi-day cumulative lag.