Environmental and sensitization variations among asthma and/or rhinitis patients between 2008 and 2018 in China

Abstract Background Little is known about the changes in allergen sensitization in China secondary to the environmental variations over the past decade. We aimed at investigating the variations in sensitization among asthma and/or rhinitis patients in China between 2008 and 2018. Methods This study analyzed cross‐sectional data from national surveys conducted in China in 2008 and 2018. After finishing the questionnaire, participants underwent serum specific IgE measurements. A total of 2322 and 2798 patients were enrolled in 2008 and 2018, respectively. The significance of differences in sensitization rates among four regions of China were assessed. Correlation analysis was used to identify the associations of sensitization with climate change and planting of Artemisia desertorum between the two surveys. Results Compared with 2008, the general sensitization rate to mites significantly increased in 2018, which ranked highest among all tested allergens. Sensitization to pollens, especially Artemisia vulgaris, showed the greatest increase in the north. The annual mean temperature, rainfall and relative humidity in all four regions, and the Artemisia desertorum coverage in the northeastern area, increased significantly in 2018 as compared with 2008. From 2008 to 2018, an increase in Dermatophagoides pteronyssinus sensitization was significantly associated with an increase in relative humidity (r = 0.54, p = 0.037). The increase in A. vulgaris sensitization was significantly associated with the increase in the A. desertorum planting area (r = 0.67, p = 0.006) and with a decrease in rainfall (r = −0.59, p = 0.021). Conclusions House dust mites remain the most important allergen in Chinese individuals with asthma and/or rhinitis. Pollen sensitization dramatically increased in northern China. Increases in sensitization to dust mites and Artemisia were related to the increases in humidity and planting area of A. desertorum.


| INTRODUCTION
Recent epidemiological studies revealed that the prevalence of allergic rhinitis and asthma dramatically increased in China. 1,2 Exposure to aeroallergens is one of the crucial factors in inducing sensitization and affects development of asthma and rhinitis. 3,4 In 2008, to better represent sensitization rates in rhinitis and asthma, the China Alliance of Research on Respiratory Allergic Disease (CARRAD) conducted a national cross-sectional study on allergen sensitization in outpatients with asthma and rhinitis. The study demonstrated that house dust mites were the most prevalent allergens in China. The allergen sensitization rates varied by geographic location. 5 Although the results of this survey provided a reference for allergy and clinical immunology in China, the environmental factors underlying the variations in the prevalence of allergen sensitization remain unknown. In follow-up, regional epidemiological studies on sensitization rates of airway diseases were performed. 6,7,8 However, those studies had limited value being locoregional in scope and not defining precisely disease states among study subjects.
One decade has passed since our last national multi-center epidemiologic survey in 2008. Since then, tremendous transformations have taken place in China such as more westernized living and working styles, urbanization, and increases in temperature and humidity. Especially in the north, regional governments The studies covered mid-temperate, warm-temperate, subtropical, and tropical zones of China. Uniform protocol, questionnaire, allergen testing set, and operating procedures were used among all study centers. Questionnaire interviewers were trained before the study. Results of the questionnaire and blood tests were sent monthly to one study center for data analysis. Quality control reports were then prepared for all study centers. At multiple levels data were verified by the investigators. All questionnaire and blood test data were coded and input into a programmed database by two workers. The entered data were checked for outof-range values and logic mistakes. The study protocol was approved by the ethics review board of each study center. All the participants gave written informed consent to participate in the study. Details about the survey participants are found in Appendix S1.

| OUTCOME MEASURES
Patients with rhinitis, asthma, and asthma with rhinitis were identified by evaluation of history, questionnaire, and relevant tests.
Rhinitis was defined as symptoms of sneezing, or a running, itchy, or blocked nose, in the absence of a cold or flu. 9 Asthma was defined as a history of recurrent dyspnea, wheezing, or cough episodes; positive airway reversibility testing (FEV 1 increasing ≥12% and 200 ml after inhalation of 400 mg of salbutamol); or positive airway responsiveness testing (FEV 1 decreasing ≥20% upon administration of ≤7.8 μg of histamine). 10 The 2008 and 2018 studies employed the same standardized questionnaire to record WANG ET AL.

| STATISTICAL ANALYSIS
According to the region and sex distributions in age groups in 2008, the population in the 2018 survey was randomly sampled and adjusted for 8 age groups (5-7, 8-10, 11-14, 15-24, 25-34, 35-44, 45-54, and 55-65 years). Between-group differences in baseline characteristics were compared using standardized differences before and after stratified sampling. 12 Changes in temperature, humidity, rainfall, and A. desertorum coverage were treated as continuous variables. Geographical area, children age groups, adult age groups, and disease groups were treated as categorical variables. We assessed the significance of differences using ANOVA for continuous variables and the χ 2 test for categorical variables. The with rhinitis, 140 with asthma, and 787 asthmatics with rhinitis. After stratified sampling, the two groups were balanced in terms of gender, age group, and geographical region (Table 1).

| Comparison of allergen sensitization rates
As shown in Table 2 Adults showed a greater increase in sensitization rate to mites (all p < 0.01), while children had a greater increase in sensitization rates to dog dander, P. nigra, A. artemisifolia, and A. vulgaris (all p < 0.01). Sensitivity to A. alternata was significantly higher in children than in adults in both cohorts (both p < 0.01).

| Comparison of allergen sensitization grades
Compared to 2008, results from 2018 found that in northern China, high-degree pollen sensitization (IgE grade 4-6) and low-degree sensitization to dog dander increased in children and adults, whereas high-degree mite sensitization increased only in adults (all p < 0.05; Figure 1A). In eastern China, grade 6 sIgE levels to mites (D. pteronyssinus and D. farinae) were observed in greater numbers of children (both p < 0.05). High-level sIgE sensitization to dog dander declined in adults (p < 0.001; Figure 1B). In central China, mite    (D. pteronyssinus and D. farinae) sIgE levels (grades 4-6) were increased in adults (both p < 0.05; Figure 1C). In the southern coast, high-degree sensitization to mites increased, whereas sensitization to Art v decreased in both children and adults (all p < 0.05). All degrees of sensitization to A. alternata significantly decreased in children (p < 0.01; Figure 1D).
Comparison of sensitization rates in patients with different disease phenotypes by stratification to age groups.

| Association of changes in climate or Artemisia desertorum planting and sensitization
The mean temperature in urban areas ranged from 11.3°C in the Art v, Artemisia vulgaris; Alt a, Alternaria alternata; *p < 0·05, **p < 0·01, ***p < 0·001 significant negative correlation was observed between the increase in A. vulgaris sensitization and the decrease in rainfall (r = −0.59, p = 0.021; Figure 4E).

| DISCUSSION
The present study covered geographically dispersed regions in China, had a large sample size, and included a range of allergens analyzed using sIgE-mediated sensitization prevalence over the last decade.
The data of this study are the first from China to show that the sensitizations to almost all indoor and outdoor aeroallergens Increased sensitization to common inhaled allergens was seen in other countries including Germany and Korea, 13,14 which were in agreement with the results of the present study, suggesting a worldwide trend. These changes in sensitization rates may be attributed to the adoption of modern lifestyle, economic development, as well as climate change which increased allergenicity of pollen. 15 Our data showed an upward trend in A. vulgaris sensitization rates reaching 30.3% in northern China, a threefold higher rate compared with that in 2008. Weed pollen, especially that of A. vulgaris, is a major outdoor allergen in northern China. 16 We noted a link between expanded planting of A. desertorum and sensitization rates.
The increased expanse of this plant is attributed to its use as a windbreak and as a means of limiting sand displacement in the desert steppe of northwest China. Although the core distribution area is in Inner Mongolia, Gansu, and Shanxi, recent data showed a tendency Liaoning, and Hebei). 17 The prevalence of allergic respiratory diseases with sensitization to Artemisia was increased dramatically in another study. 7 23,24 We found an association between the increasing sensitization to D. pteronyssinus and increasing humidity in a number of urban centers. Ambient humidity alters room microclimate and mite prevalence in different geographical locations. 25 Additionally, increased urbanization and human activity is associated with greater atmospheric humidity. 26 Population growth in urban centers is also associated with increased use of air conditioning, which is itself an important risk factor for allergies. 11 Moreover, as lifestyle changes, people spend more time indoors, which also drives the increase in sensitization to dust mites.
We also found that pet allergens increased in teenagers with rhinitis. Still, the prevalence of sensitization to cat or dog dander varied among the four zones in China. Geographic variation in the sensitization to furry animals was attributed to early life exposure and rate of pet ownership. 27 We showed that sensitization to A. alternata was higher in children than in adults, with a specific increase in the central region. Our finding is in accordance with previous studies.
Sensitization to A. alternata may have a genetic component. 32 It is suggested that routine A. alternata sIgE screening is suitable for children with allergies under 15 years of age. A. alternata is a hydrophilic fungus that is active in dampness. 33 Other factors associated with Alternaria sensitization may include male gender, non-smoker, living in urban areas, or using new building materials. 34 A. alternata can also cause a plant disorder called leaf spot disease. 35 This might explain our results that found in northern China, an arid area with high plant density, a high rate of A.
Of note, in our study, the majority of centers that had partici- the 2008 survey, especially the study participants. Therefore, agestratified sampling was conducted before comparison to adjust for the differences between regions and age groups. Despite some minor bias in sample size of disease phenotypes, which cannot be completely excluded, we made an effort to ensure the consistency of the two surveys.
Our study also has several limitations. First, the study was not a prospective follow-up study. Thus, it could not evaluate the incidence of allergic respiratory disease. Second, the sensitization rate of the two studies referred to symptomatic patients, rather than the general population, and thus it was difficult to generalize our results to the entire Chinese population. Third, only considering humidity increases over time cannot determine the exact association between the sensitization rate and urbanization, including population growth and density, household income and other factors. Fourth, dust samples from study patient family members, as a surrogate for evaluating home allergen exposure, were not collected. Fifth, specific molecular indicators for A.
desertorum sensitization still need to be identified. Finally, although we found an association between A. desertorum and Artemisia sensitization, dynamic collection and analysis of the first-line data of pollen storm through pollen-monitoring stations is warranted to confirm this observation.

| CONCLUSIONS
Using nationwide epidemiological study data, we found that the prevalence of sensitization to house dust mites (D. pteronyssinus, D. farinae, and B. tropicalis), pollens (P. nigra, A. artemisifolia, and A. vulgaris), and animals (dog dander) in individuals with asthma 12 of 14and/or rhinitis significantly increased in China over the last decade.These findings suggest that policies need to be adjusted to mitigate human-induced climate change and reduce the artificial planting of A. desertorum, to limit sensitization to dust mites and Artemisia.