Shijiazhuang city has serious air pollution and chronically poor air quality due to its geographical location and production capacity structure. In this paper, we have obtained relatively complete distribution characteristics of urticaria by describing and analyzing the time trends and demographic characteristics of urticaria in Shijiazhuang in recent years. A time-series study was used to investigate the relationship between environmental factors and urticaria outpatient visits in Shijiazhuang city from 2014 to 2019. Previous studies have shown that temperature and humidity are important meteorological factors affecting urticaria (Konstantinou et al., 2011; Maltseva et al., 2021; Pezzolo et al., 2016; Zhang et al., 2021; Zhou et al., 2018). However, studies on the association between pollution factors and urticaria are scarce and the findings are inconsistent. Liu et al. showed that PM2.5, PM10, and NO2 were significantly associated with an increase in the number of urticaria outpatient visits, but no relationship was found between SO2 and the number of urticaria clinic visits (Liu et al., 2018). Wang et al. found that SO2 increased the risk of urticaria outpatient visits (Wang et al., 2021c). We used a distributed lag nonlinear model to explore the effects of air pollutants and meteorological factors on urticaria outpatient visits. We found that high concentrations of CO, NO2, O3, and high temperatures increased the risk of urticaria outpatient visits, while low concentrations of NO2, O3, and high humidity would act as a protective factor. Therefore, more research is needed in the future to investigate the effects of air pollutants on outpatient visits for urticaria.
The seasonal distribution suggests that the peak number of outpatient visits for urticaria is concentrated between June and August each year, with a certain seasonality and periodicity, a finding that is consistent with previous studies (Banerjee et al., 2010; Kim et al., 2013; Konstantinou et al., 2011). Multiple factors, both biotic and abiotic, may be responsible for this trend. In summer, high temperatures provide an environment for fleas, rodents, and mites to thrive. In particular, children are more susceptible to their bites leading to urticaria (Howard and Frieden, 1996). In addition, high ultraviolet light radiation in summer is more likely to impair the function of the immune system, leading to the development of urticaria (Kim et al., 2013).
We used a distributed lagged nonlinear model to investigate the relationship between CO and daily outpatient visits for urticaria. We found that the dose-response curve was approximately inverted "V" type, with the risk peaked at 6mg/m3 (RR = 1.388, 95%CI: 1.093, 1.761). High concentrations of CO increased the risk of daily outpatient visits for urticaria compared with low concentrations, with the greatest risk occurring at 0-day lag. In addition, the cumulative effect increased progressively with increasing lag period. A study in Taiwan found a positive correlation between CO and the number of daily urticaria patient visits, especially for male patients (RR = 2.06, 95%CI: 1.48, 2.87) and older patients (RR = 4.67, 95%CI: 1.63, 13.37) (Tseng et al., 2021). A Korean study showed that each 100 ppb increase in CO was associated with a 5.00% (95% CI: 1.10%, 8.80%) increase in the number of daily outpatient visits for patients with atopic dermatitis (Oh et al., 2018). A Canadian study found that exposure to high concentrations of CO significantly increased the risk of daily emergency room visits for patients with urticaria, which is consistent with our findings (Kousha and Valacchi, 2015). CO is an odorless, colorless, and tasteless gas produced from the incomplete combustion of carbon compounds (Huang et al., 2021). High concentrations of CO exposure may lead to unconsciousness or death. Meanwhile, CO is strong oxidizing agent, triggering oxidative stress and skin barrier dysfunction could be reasons for this relationship (Abolhasani et al., 2021).
In terms of NO2, we found that the risk of urticaria outpatient visits increased with increasing NO2 concentration. Low concentrations of NO2 were protective factors against urticaria, whereas high concentrations of NO2 increased the risk of urticaria outpatient visits. Studies have found that environmental NO2 exposure may cause a range of skin diseases through the interaction of air pollutants with the immune system (Abolhasani et al., 2021). A Japanese study showed that the prevalence of urticaria among elementary school students attending urban schools was 12.4%, second only to atopic dermatitis, due to higher levels of NO2 in cities (Guo et al., 2019; Hu et al., 2022). In addition, positive associations of NO2 with urticaria visits were found in a study in Beijing, China (Wang et al., 2021). A study in Taiwan showed that the women were particularly susceptible to higher concentrations of NO2 on the visit day (Tseng et al., 2021). A Canadian study also reported that higher values of NO2 led to higher visit numbers for urticarial patients (Kousha and Valacchi, 2015). More and more epidemiological evidence showed that NO2 exposure has adverse effects on various skin diseases, but the exact mechanisms are mainly unclear (Kathuria and Silverberg, 2016). An epidemiological study in Germany found that human epidermal barrier function was disrupted when short-term exposed to low concentrations of NO2 (Eberlein-König et al., 1998). However, our study did not find a significant association between low concentrations of NO2 and urticaria. The inconsistency of the results might be due to the difference in study designs, exposure levels, along with individual confounders (such as age, gender, and socioeconomic status). Some studies have found that NO2 exposure may affect the skin by indirect inflammation or oxidative stress injury (Araviiskaia et al., 2019; Furue et al., 2019). A study in Chengdu, China suggests that dissolved NO2 in water may stimulate the skin microbiota and then disrupt immune function, facilitating the development of diseases (Li et al., 2018). There are too few studies on the relationship between NO2 and urticaria, a large number of studies are still needed to demonstrate these relationships in the future.
We found an "S" type dose-response curve for O3 and urticaria outpatient visits, with low concentrations of O3 being protective against urticaria and high concentrations of O3 increasing the risk of outpatient visits for urticaria. The cumulative effect of O3 on urticaria outpatient visits was greatest at 14 days lag. A Canadian study also confirmed that exposure to O3 environments increases the risk of developing urticaria (Kousha and Valacchi, 2015). Furthermore, if ground-level O3 concentrations increase, the number of emergency department visits for skin conditions such as urticaria and eczema increases in Shanghai (Xu et al., 2011). This is consistent with the results of our study. It is known that worldwide, O3 causes hundreds of thousands of premature deaths and tens of millions of dermatology-related emergency room visits each year (Zhang et al., 2019). Previous studies have demonstrated that O3 is a strong oxidant present in the air that induces antioxidant depletion and lipid peroxidation, causing oxidative stress in the skin, leading to chronic skin tissue damage and aggravating skin diseases such as contact dermatitis and urticaria (Fuks et al., 2019; Petracca et al., 2021). O3 cannot penetrate human skin, but O3 oxidizes biomolecules through the formation of free radicals and reactive intermediates. In particular, the reaction of O3 with polyunsaturated fatty acids (PUFA), which are surfactants present at the air-cell interface, results in the formation of reactive oxygen species such as peroxyl radicals, malondialdehyde (MDA) (Petracca et al., 2021; Pryor et al., 1995). These bioactive products can act as signaling molecules that penetrate into the subcutaneous layers and cause further damage (McDaniel et al., 2018). It has also been shown that low concentrations of O3 are protective factors against skin diseases, and ozone water therapy, topical ozone oil, and ozone autologous blood therapy have been widely used to treat various skin diseases (Zeng and Lu, 2018). Moreover, emerging evidence suggests that O3 also plays an important role in the management and prevention of various skin diseases, including infectious skin diseases, skin-related allergic diseases, erythroderma scales, wound healing, and ulcer recovery (Wang, 2018). Therefore, different concentrations of O3 can exhibit dual beneficial or harmful effects, with moderate O3 concentrations acting as a protective agent for humans. However, long-term exposure to high concentrations of O3 can trigger a range of allergic reactions. The effect of different concentrations of O3 is complex, and further studies are needed to investigate this issue.
We found that the dose-response curve of temperature and urticaria outpatient visits is approximate "M" type. It has two peaks, the first of which is not statistically significant. High temperature increases the risk of urticaria outpatient visits. The cumulative effect was greatest at lag 0. The effect of low temperature on urticaria, on the other hand, was not statistically significant. The mechanisms for the increased risk of urticaria due to high temperature are unclear, but it may be that increased temperature favors the proliferation of fungi and bacteria and that the body is more easily exposed to allergens, causing oxidative stress in the body and thus increasing the risk of urticaria (Demain, 2018; Gonçalves et al., 2021). It has also been shown that temperature changes alter allergen exposure and may also disrupt the immune system's specific tolerance to allergens, compromising the body's immune system and causing an increased risk of urticaria (Ray and Ming, 2020). This reminds us to reduce the risk of urticaria by going out less in hot weather. In addition to this, warmer climates can lead to an expansion of the distribution of the processional moth, which carries urticarial bristles that can more easily cause urticaria in humans and other warm-blooded animals (Battisti et al., 2017; Vasseur et al., 2022). A study in Poland showed a direct correlation between temperature and daily Artemisia pollen levels, with higher temperatures leading to a longer Artemisia pollen season and a significant increase in human exposure to allergens, causing chronic urticaria in 14.3% of patients (Stach et al., 2007). It has also been shown that cold exposure causes the development of allergic reactions such as urticaria and angioedema, and its pathophysiology is believed that cold exposure leads to the formation of IgE from auto allergens, which can stimulate the release of pro-inflammatory mediators from skin mast cells, causing the development of cold urticaria and a series of allergic reactions (Işk et al., 2014; Maltseva et al., 2021). Our study did not find an effect of low temperature on urticaria, and the effect of temperature on urticaria remains to be explored because of the small number of relevant studies.
For relative humidity, we found that the dose-response curve between humidity and urticaria outpatient visits was close to the "S" type. High humidity is a protective factor for urticaria outpatient visits compared to low humidity. An interesting German study found that a complex syndrome of urticaria and allergic reactions induced by strenuous exercise could be prevented in humid and warm weather (von Vigier et al., 1995). In contrast, a Croatian study showed that higher air humidity was a predisposing factor for exercise-type allergic reactions (Plavec and Vuljanko, 2010). The results of the two studies may be inconsistent due to geographical reasons and individual differences. A European epidemiological study elucidated that acute childhood urticaria showed similar epidemiological patterns in Northern and Southern Europe regardless of expected differences in genetic, geographical, and environmental background, with humidity significantly and negatively associated with the incidence of acute urticaria (Konstantinou et al., 2011). This is consistent with the results of our study.
The present study has several advantages. First, Shijiazhuang is one of the representative cities in northern China with severe pollution, which provides a natural site for us to study the relationship between air pollutants, meteorological factors, and urticaria. Second, this study explores the distribution characteristics and demographic features of urticaria for the first time, and it helps us to keep abreast of current disease patterns. Finally, we used a distributed lag nonlinear model to quantify the effects of air pollutants and meteorological factors on daily outpatient visits for urticaria, and examined in depth the effects of extreme air pollutants concentrations and meteorological factors on daily outpatient visits for urticaria. The robustness of the results was evaluated by changing the degrees of freedom for time trends (6–8 dfs/year), and the results were found to be stable and reliable.
However, our study has several limitations. First, we collected data from only three hospitals in Shijiazhuang for outpatient visits for urticaria, which may lead to information bias in the study results due to insufficient study population, and the findings still need to be validated on a larger population. In addition, the air pollutant data were obtained from seven fixed monitoring sites in Shijiazhuang, and we assumed that the population in each area of Shijiazhuang was exposed to the same level of air pollutant concentrations. In fact, the exposure levels varied in each area of the population, which introduced measurement bias. Previous studies have shown that indoor air pollutants and meteorological factors have a certain impact on urticaria. Individual exposure levels differed indoors and outdoors, and we only examined the effects of outdoor air pollutants and meteorological factors on urticaria outpatient visits. Finally, due to limitations in data availability, we did not assess the effects of other confounding factors on urticaria outpatient visits, such as health status, occupation, marital status, and educational status.