The differential impact of air pollutants on acute urticaria and chronic urticaria: a time series analysis

Several studies have revealed a relationship between short-term exposure to air pollution and the exacerbation of certain skin conditions. This study was developed to expand on these findings by exploring the potential association between exposure to air pollutants including particulate matter, sulfur dioxide, and ozone and the incidence of acute and chronic urticaria in Shenyang, China, from 2016 to 2018. Exposure-response relationships between daily mean concentrations of these airborne pollutants and visits to outpatient dermatological clinics for acute urticaria and chronic urticaria were evaluated via a time series analysis approach using a generalized additive model. This analysis revealed that a 10 μg/m3 increase in daily mean O3_8h concentrations was associated with a 0.36% (95% CI, 0.31–0.41%), 0.35% (95% CI, 0.30–0.40%), and 0.34% (95% CI, 0.29–0.39%) increase in the number of outpatient visits for acute urticaria on that day (lag0), lagging day 1 (lag1), and lagging day 2 (lag2), respectively. O3 levels also had a similar but weaker effect on the frequency of patients seeking outpatient care for chronic urticaria. These analyses also revealed that estimated 0.47% (95% CI, 0.41–0.52%) and 0.46% (95% CI, 0.40–0.51%) increases in dermatological outpatient acute urticaria visits were observed for every 10μg/m3 rise in O3_8h concentrations on cumulative lagging days (lag01 and lag02). Increases in particulate matter (PM2.5, PM10) levels had a similar cumulative effect on patients with chronic urticaria. In summary, these results suggest that short-term O3, PM2.5, and PM10 exposure can increase the risk of acute urticaria and chronic urticaria.


Introduction
Air pollution has been identified as a major cause of adverse health outcomes throughout the world. In an effort to increase public awareness of these risks and to improve health outcomes, regional environmental monitoring departments perform real-time monitoring of airborne pollutants including ozone (monitored over an 8-h period; O 3_ 8h), particulate matter (PM 2.5 , PM 10 ), nitric oxide (NO), sulfur dioxide (SO 2 ), and CO (carbon monoxide), reporting their levels to the public. These airborne pollutants can contribute to or exacerbate a range of respiratory, circulatory, endocrine, and nervous system disorders in exposed individuals, potentially increasing the incidence or mortality rates associated with particular diseases (Clarke et al. 2021;Hamanaka and Mutlu 2018;Hansel et al. 2016;Hayes et al. 2020;Snow et al. 2018;Tiotiu et al. 2020). The skin is the largest organ in the human body and serves as a barrier to the entry of potential pathogens and other environmental threats such as air pollution.
The dermatological effects of chronic exposure to air pollutants have been increasingly well studied in recent years (Abolhasani et al. 2021;Ali et al. 2020;Shamsipour et al. 2020), with some researchers having linked changes in air quality and climatic conditions to skin aging and the incidence of eczema, atopic dermatitis, and acne vulgaris (El Haddad et al. 2021;Fussell and Kelly 2020;Kathuria and Silverberg 2016;Li et al. 2015Li et al. , 2022Liu et al. 2018;Park et al. 2021). Urticaria is the most commonly reported skin condition, occurring in both chronic and acute forms. Affected patients present with raised, erythematous, and generally intensely pruritic wheals with or without angioedema. These rashes can also recur on different parts of the body and in severe cases can be accompanied by systemic symptoms such as fever, abdominal pain, vomiting, diarrhea, and dyspnea. Between 15 and 25% of people are estimated to experience urticaria at some point in their life (Zuberbier 2003).
Despite being a relatively common condition, the etiology of urticaria is complex, and in many cases, the precise cause is unknown. Few studies to date in China or abroad have examined whether urticaria may be aggravated or induced by changes in climate conditions or air pollution levels. As such, this hospital-based study explored the relationship between short-term air pollution and outpatient visits for acute and chronic urticaria in Shenyang, a city in northeastern China. The aim of this study was to clarify the potential effects of short-term exposure to air pollutants on acute and chronic urticaria. The outcomes of this study may aid in the future prevention or treatment of urticaria.

Patients
All outpatient visit records for patients seeking care for acute urticaria and chronic urticaria records were obtained from the computerized database of the Shengjing Hospital of China Medical University, Liaoning, China, during the time period from January 1, 2016, to December 30, 2018. These cases included both new patients and relapsed patients. Study inclusion criteria were as follows: (i) patients diagnosed with urticaria as per the criteria established by the International Classification of Diseases, 10th Revision, and (ii) patients who had lived in Shenyang for a minimum of 3 years. The exclusion criteria were as follows: (i) patients were prescribed drugs but did not see a doctor during their visit, and (ii) the patient's diagnosis or other patient-related data were unclear.

Air pollutants and meteorological data
Daily PM 2.5 , PM 10 , SO 2 , and O 3 levels from January 1, 2016, to December 31, 2018 were obtained from the Shenyang Environmental Monitoring Center. Levels of these pollutants were monitored by 11 state-controlled environmental air quality automatic monitoring stations in Shenyang. Daily meteorological data including average temperature and relative humidity over this same study period were obtained from the Shenyang Meteorological Bureau.

Statistical analysis
A time series is a set of dynamic sequences arranged in chronological order. Daily outpatient visits for acute and chronic urticaria were thus treated as a time series for the present analysis, and a time series analysis was utilized to establish a predictive model based on the available data (Zeghnoun et al. 2001).
In the overall population, the number of daily outpatient visits for urticaria was considered to be a low-probability event, and as such, its distribution was approximated using the Poisson distribution. A time series analysis was therefore performed using a generalized additive model (GAM) to estimate associations between air pollutant levels and the number of daily outpatient visits for acute or chronic urticaria. This GAM approach was used to control for potential confounding variables, such as long-term trends, weekends, and holidays, and was adjusted for variable meteorological parameters including daily mean temperature and relative humidity. The lag effect is a regression analysis that takes into account the health indicators from a given day (day 0) and air pollution levels on previous days in order to study the effects of pollution on previous days on future health ends. We examined the lag effect (lag 0 to lag 6) and the moving average lag effect (lag 01 to lag 06) of air pollutants on daily confirmed cases of urticaria.
Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the magnitude of the measured effect at an α = 0.05. P < 0.05 was regarded as the significance threshold for these analyses. Correlations between air pollutant levels and meteorological variables were assessed through Spearman rank correlation analyses. SPSS 20.0 and the R 3.1.1 MGCV package (http:// www.r-proje ct. org) were used to conduct all analyses.

Descriptive statistics
Demographic characteristics associated with outpatient visits during the study period are summarized by patient age and gender in Table 1. Between January 1, 2016, and December 31, 2018, 35,305 total outpatient visits were recorded, including 20,884 visits associated with cases of acute urticaria and 14,421 visits associated with cases of chronic urticaria. The seasonal distribution patterns of these visits are shown in Fig. 1. Daily outpatient visit counts for acute urticaria were higher than for chronic urticaria, and counts for both were highest in the summer and lowest in the winter.
Mean concentrations of different air pollutants and meteorological factors in Shenyang over the 3-year (1096day) study period are summarized in Table 2. The daily mean concentrations of PM 2.5 , PM 10 , SO 2 , and O 3 _8h over this period were 48.59 μg/m 3 , 82.47 μg/m 3 , 36.06 μg/m 3 , and 94.44μg/m 3 , respectively. The climate in Shenyang consists of four distinct seasons, each of which exhibited different levels of the analyzed air pollutants. Levels of PM 2.5 , PM 10 , and SO 2 were highest during colder seasons (autumn (September-November) and winter (December-February)) and lower in the warmer months (spring (March-May) and summer (June-August)), whereas O 3 exhibited the opposite trend. In all cases, these daily air pollutant concentrations remained below ambient air quality threshold values. The mean daily temperature and relative humidity in the study region were 8.14°C and 62.07%, respectively.

Analysis of correlations between airborne pollutant levels and meteorological factors
Next, Spearman's rank correlation analyses were used to gauge the relationships between airborne pollutant levels and meteorological factors during the study period (Table 3). Levels of PM 2.5 , PM 10 , and SO 2 were highly positively correlated with one another, with this correlation being strongest for PM 2.5 and PM 10 (r = 0.901). In contrast, O 3 levels were negatively correlated with those of PM 2.5 , PM 10 , and SO 2 . Temperature and relative humidity were significantly negatively correlated with levels of PM 2.5 , PM 10 , and SO 2 , with the strongest correlations for these meteorological variables being between temperature and SO 2 (r = −0.713) and between relative humidity and PM 10 (r = −0.201).

Discussion
In the present report, we performed a time series analysis of the effects of air pollution on the incidence of acute urticaria and chronic urticaria in Shenyang, China, from 2016 to 2018. Over this time frame, the daily mean concentrations of PM 2.5 , PM 10 , and SO 2 were almost twice as high as levels outlined in WHO guidelines, indicating that additional focus on the air pollution situation in Shenyang is necessary. We found that acute urticaria and chronic urticaria-related outpatient visits exhibited a seasonal pattern, occurring more -0.463** -0.448** -0.713** 0.643** 1 Relative humidity (%) -0.139** -0.201** -0.136** 0.010 0.199** 1 frequently in the summer relative to the winter, consistent with trends in O 3 levels, although the opposite trend was observed for PM 2.5 , PM 10 , and SO 2 concentrations. Shenyang is a heavily industrialized city in northeastern China that experiences cold winters. Air pollution sources in this region include vehicle exhaust, industrial emissions, construction site dust emission, and coal combustion. Overall, daily air pollutant concentrations were relatively stable with peak levels in the winter, likely because coal is the primary source of energy and heat during the colder months and because lower temperatures are not conducive to air pollutant dispersal. In contrast, O 3 levels were higher during the summer, consistent with the intense solar radiation and higher temperatures during this season, which can increase photochemical reaction intensity and O 3 concentrations near the surface.
Rates of dermatosis are rising, and epidemiological studies suggest that short-term exposure to ambient air pollution can cause adverse effects on skin health (El Haddad et al. 2021;Fussell and Kelly 2020;Kathuria and Silverberg 2016;Li et al. 2015Li et al. , 2022Liu et al. 2018;Park et al. 2021). Herein, we found that exposure to three air pollutants (PM 2.5 , PM 10 , and O 3 ) significantly increased the risk of urticaria outpatient visits, with evidence of cumulative lag effects following such exposure. The impact of O 3 on acute urticaria was more significant than that on chronic urticaria, with the cumulative lag effect of O 3 exposure only remaining significant on 1 and 2 days post-exposure for acute urticaria outpatient visits. We observed no relationship between SO 2 exposure and urticaria outpatient visits. Our findings are similar to those from a study conducted in Shanghai, which found that elevated ground O 3 levels were associated with increased numbers of emergency medical visits for urticaria, eczema, contact dermatitis, and infectious skin diseases, whereas there was no significant relationship between these conditions and exposure to PM 10 , NO 2 , or SO 2 (Xu et al. 2011). In another study conducted in Korea, Lee et al. determined that increases in daily mean O 3 concentrations were linked to increased hospitalization rates for patients with asthma and atopic dermatitis (Lee et al. 2010). Many environmental pollutants have been shown to cause direct oxidative damage, including PM and O 3 , which can catalyze reactive oxygen species (ROS) production that can disrupt cutaneous redox homeostasis and cause skin cell damage (Abolhasani et al. 2021;Hu et al. 2017;Yu et al. 2020). Exposure to a range of O 3 concentrations can alter levels of IgE specific for plant pollen in humans (Beck et al. 2013;Garcia-Gallardo et al. 2013;Rogerieux et al. 2007). The sensitivity of the human body to such O 3 exposure is both dose-and allergen-specific. Exposure to high levels of O 3 on a daily basis may thus drive the incidence of urticaria, asthma, and other allergic diseases. In summary, exposure to lower levels of O 3 during warmer seasons may reduce the incidence of urticaria, although further research is necessary to confirm this hypothesis.
Particulate matter is primarily derived from vehicle and industrial exhaust sources and is primarily composed of aromatic hydrocarbons and other organic compounds that can activate diverse biological processes and drive ROS production (Furue et al. 2014). ROS-mediated oxidative stress is thought to be linked to the pathogenesis of urticaria and other dermatological conditions (Kalkan et al. 2013;Kalkan et al. 2014). Previous studies have suggested that PM2.5 and PM10 exposure is linked to higher rates of acne vulgaris and atopic dermatitis in children and adults (Kathuria and Silverberg 2016;Kramer et al. 2009;Li et al. 2022;Liu et al. 2018;Yunquan et al. 2016). Interestingly, we found that PM 2.5 exposure was associated with stronger cumulative effects on chronic urticaria incidence relative to PM 10 exposure. Certain epidemiological analyses of PM exposure have linked the exposure to these pollutants to skin inflammatory response processes associated with dermatitis, acne, and psoriasis (Liu et al. 2018;Song et al. 2011;Tsuji et al. 2011;Yang et al. 2014).
While the mechanistic basis for our findings remains to be clarified, they are consistent with the results of a few prior studies. For example, Ono et al. found that polycyclic aromatic hydrocarbons (PHAs) in air organic pollutants can attach to the skin and cause cutaneous damage. The activation of aryl hydrocarbon receptor (AhR) signaling in keratinocytes can drive the production of inflammatory cytokines including IL-6 and IL-8 (Ono et al. 2013). Researchers have also shown that metals on the surface of PM can additionally drive ROS production, lipid oxidation, and skin cell apoptosis in a dose-dependent manner (Lefebvre et al. 2016).
There are several limitations to this analysis. For one, this was a large-scale population-based study without any analyses of patients at the individual level, potentially introducing aggregation bias. In addition, the Shengjing Hospital is a general hospital with a higher number of children as patients relative to other hospitals in this region. This may have increased the overall proportion of children in the study population. Differences in climate characteristics, air pollution composition, and personal behaviors may also limit the applicability of these findings to similar analyses conducted in other regions.

Conclusions
Here, we identified a positive association between mean daily air pollutant concentrations and urticaria in Shenyang, China. Exposure to O 3 was identified as a risk factor associated with urticaria, with this relationship being strongest for cases of acute urticaria. PM 2.5 and PM 10 levels were additionally associated with an increase in outpatient visits for chronic urticaria. Together, these analyses confirm the potential for air pollution-induced skin damage and suggest that reducing such pollutant exposure during periods of extensive pollution may be a viable approach to reducing the incidence of urticaria. Data availability All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Declarations
Ethical approval and consent to participate Not applicable.
The paper is exempt from ethical committee approval, since all the information about people used in this study was obtained from computer databases.