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A Multicenter Study of Prevalence and Risk Factors for Allergic Rhinitis in Primary School Children in 5 Cities of Hubei Province, China

Background: Few data are available concerning the prevalence and risk factors for allergic rhinitis (AR) in school children in Hubei Province which is located in the central part of China. This study investigated the epidemiological features of AR among school children in Hubei Province. Methods: A cross-sectional questionnaire survey on AR in school children was carried out in 5 cities in Hubei Province by cluster sampling from June to September 2018. Questionnaires were filled out by children and their parents jointly. The diagnostic criteria of AR were according to the SFAR. Questions from the questionnaire were used to examine the pattern of AR. Logistic regression analysis was used to assess the risk factors for childhood allergies. Results: The total prevalence rate of AR was 16.16%, with 24.31% (Wuhan), 4.34% (Xiangyang), 4.31% (Tianmen), 10.92% (Jingmen), and 11.42% (Huangshi), respectively. The prevalence of AR was positively correlated with gross domestic product per capita (p < 0.05). Multivariate analysis revealed that male, city of Wuhan, family history of allergy, food allergy, drug allergy, air purifier, exposure to dust, living in towns or urban area before 2 years old, maternal age for 26–35 years old, and frequent application of antibiotics increased the risk of AR, while daily outdoor time for 1–2 h, daily sleeping time >8 h, siblings, and breastfeeding for >6 months reduced the risk significantly. Conclusion: We found the apparent geographic variation of children allergies in Hubei Province. Both genetic and environment factors had impacts on the prevalence of AR in school children. Public policies should specifically target at the local risk factors for different areas.


Introduction
Allergic rhinitis (AR) is a symptomatic disorder when inhaled particles contact the nasal mucosa and induce an immunoglobulin E-mediated inflammatory response, which is characterized by sneezing, nasal obstruction, and mucous discharge [1]. Epidemiological studies have revealed that the prevalence of AR has increased progressively in more developed countries over the past few years and currently affects 10-40% of adults and 2-25% of children worldwide [2][3][4]. In recent decades, a rising trend of AR in China has been observed, with a widely varying prevalence particularly [5,6]. The trend of AR incidence has become a significant economic burden on the general public [7].
AR has been proved to be an important risk factor that will cause many disorders, especially in children. It has been verified that AR exerted significant effects on students' social performance, emotion, memory, sleep quality, and psychosocial interactions [8,9]. To date, the only one nationwide survey of the prevalence of AR in children in China demonstrated that the mean prevalence in 8 metropolitan cities of provinces in 4 regions was 9.8% [10]. There are few studies on the prevalence of AR in Hubei Province, which is located in the central part of China and one of the important economic trading centers in China. Because of the different geographical locations of the cities in Hubei Province, the environment and development status of each city is dramatically different. Different levels of economic development and urbanization among cities in Hubei Province over the past years also changed the lifestyle features of inhabitants. The aim of the present study was to determine the recent prevalence rates and risk factors of AR in children from 5 major cities in Hubei Province in China, to provide baseline information for clinicians and health policymakers.

Study Design
A cross-sectional survey was undertaken among children aged 6-12 years in 5 cities of Hubei Province from June 2018 to September 2018, using a cluster-stratified sampling method. The 5 cities included Wuhan, Xiangyang, Jingmen, Huangshi, and Tianmen, which were major cities in Hubei Province with different economic levels. Xiangyang is situated in the northwest part of Hubei Province, Tianmen and Jingmen in central Hubei Province, Wuhan in east Hubei Province, and Huangshi is located in southeast Hubei Province. They were located from north to south throughout Hubei Province. Therefore, the survey results are geographically and economically representative to some extent.
The target sample size equaled 544 per city which was calculated referring to the survey of Zhang et al. [11]. The calculating formula was N = Z 2 P (1 − P)/d 2 , where N is the sample size, Z is the statistic for a level of confidence (equal to 1.96 for the level of confidence of 95%), P is the estimated prevalence of AR and is equal to 0.15 based on previous epidemiological surveys, and d is precision, here chosen to be 0.03. However, considering nonresponse bias, the sample size was set to at least 800 per city. In each city, 2 urban districts were randomly selected, and 1-3 primary schools were chosen at random in each selected district. A total of 10,757 children were randomly selected, of whom 5,553 were from Wuhan, 1,981 from Xiangyang, 859 from Tianmen, 980 from Jingmen, and 1,384 from Huangshi. The study was approved by the Ethics Review Committee of Renmin Hospital of Wuhan University (2017K-C047). Questionnaires The questionnaire was designed by the authors with reference to the International Study of Asthma and Allergies in Childhood (ISAAC) [12], the European Community Respiratory Health Survey (ECRHS) [13], and Score for Allergic Rhinitis (SFAR) [14], including questions regarding nasal symptoms, duration and severity, self-reported allergens, and concomitant and family history of allergic disease as well as related factors. The questionnaire was distributed in the form of 2-dimensional code and filled out by children and their parents jointly through the Wechat online system. The confirmed data were collected and imported into a form for further analysis.

Working Definitions
The diagnostic criteria of AR were according to the SFAR (shown in Table 1). The SFAR was calculated by summing the score obtained under the different items of the questionnaire. To ensure credibility and accuracy, 268 participants from Hubei Province were included in the diagnosis validation of SFAR, and their result of serum-specific IgE was used to assess the SFAR cutoff value. On the basis of the receiver operator characteristic curve (shown in Fig. 1a) and the Youden's index (shown in Fig. 1b), the best cutoff value was set at ≥7, which allowed the SFAR to be adequately sensitive (91.9%) and specific (73.8%) (shown in Fig. 1c). So, an SFAR ≥7 is adopted to define the presence of AR in our study. Self-report was used to diagnose the allergic comorbidity and infective diseases.

Collecting Data for Population and Socioeconomic Status
To assess the association between the standardized prevalence of AR and population or socioeconomic status in 2018, we obtained the data from the National Bureau of Statistics of China (http://www.stats.gov.cn).

Statistical Analysis
Data were computer-entered by 2 researchers (double data entry greatly reduces errors). SPSS statistical software (version 23.0) was used for analysis. Measurements are given as means with standard deviations; count data are shown as rates or ratios. Percentage or mean ± SD was used to describe categorical and continuous variables, respectively. The t test and χ 2 test or Fisher's exact test were used to analyze the differences between subgroups. Multivariate logistic regression was performed, a stepwise regression model, to assess the relationship of AR with the potential risk factors. Subjects with missing values were excluded from the regression model. p < 0.05 was considered statistically significant.

Subject Characteristics and Prevalence of AR
In total, 10,757 valid questionnaires were returned from the primary school children and their parents (Wuhan 5,553, Xiangyang 1,981, Tianmen 859, Jingmen 98, and Huangshi 1,384). The mean age of the sample was 9.12 years (SD = 1.76), with 5,809 male students (54.0%) and 4,948 female students (46.0%). Among the respondents, 1,738 (16.16%) diagnosed AR totally. The prevalence rate of AR was 24.31% (Wuhan), 4.34% (Xiangyang), 4.31% (Tianmen), 10.92% (Jingmen), and 11.42% (Huangshi), respectively. The incidence of AR in Wuhan is significantly higher than other cities (p < 0.05) and that in Xiangyang and Tianmen was significantly lower than other cities (p < 0.05). In addition, there was no statistical difference between Xiangyang and Tianmen, as well as between Jingmen and Huangshi. The overall percentage of male patients was larger than the female patients (18.66 vs. 13.22%; p < 0.05). The distribution of age and gender in all AR children in 5 cities is shown in Table 2.

Self-Reported Symptoms and Allergens
Of the 1,738 who were diagnosed with AR, nasal blockage was the most common complaint, with an incidence of 92.23% (1,603). One thousand five hundred twenty (87.46%) children complained about sneezing, 1,517 (87.28%) were troubled by nasal itching, and 1,381 (79.46%) had running nose. Each nasal symptom had similar degree of effects on daily activities (p > 0.05). The number of AR patients who showed itching eye and bronchial symptoms was 1,135 (65.30%) and 1,295 (74.51%), respectively. Cough (70.48%) was found to be the most common bronchial symptom and more serious than chest tightness, wheezing, and dyspnea.   Season features and triggers of nasal symptoms are shown in Figure 2 and Table 3. Dust mites or dust was the most common factor triggering nasal symptoms compared to temperature change, cold air, pollen, pet, soot, and others. Moreover, 56.67% patients showed seasonal onset. Season incidence had 2 peaks: one in spring (March 32.05% and April 31.42%) and one in autumn (October 32.68%). We combined the data of each city of AR because the tendency between 5 cities was similar.

Self-Reported Comorbidities
Other allergic diseases combined with AR include eczema (14.27%), allergic conjunctivitis (8.92%), asthma (8.29%), urticaria (8.11%), and atopic dermatitis (1.61%). Eczema was the most common one of these. The incidence of all combined allergic diseases was higher in the AR-positive group than in the AR-negative group, showing a statistical meaning (p < 0.05; shown in Fig. 3a). The previous infective disease of all participants is shown in Figure 3b, covering bronchitis, amygdalitis, nasosinusitis, varicella, and pneumonia. The incidence of all infective diseases in the AR-positive group was significantly higher than that in the AR-negative group, except varicella (p < 0.05).

The Influences of Population Size and Socioeconomic Status
The prevalence of AR was positively correlated with gross domestic product (GDP) per capita (r = 0.8796, p < 0.05). But, there was no correlation with the size of the population of the cities (p > 0.05), neither the GDP of each city (p > 0.05), as shown in Table 4.

Potential Risk Factors
The univariate analysis and the multivariate analysis revealing potential risk factors associated with AR are shown in Tables 5 and 6, respectively. We found male, city of Wuhan, family history of allergy, food allergy, drug allergy, air purifier, exposure to dust, living in towns or urban area before 2 years old, maternal age for 26-35 years old, and frequent application of antibiotics increased the risk of AR, while daily outdoor time for 1-2 h, daily sleeping time >8 h, siblings, and breastfeeding for >6 months reduced the risk significantly.

Discussion
AR is a major burden on affected children and their families and is becoming a serious challenge to public health organization and healthcare providers. In the last 2 decades, the prevalence of AR in China dramatically increased [5,15]. Several time trend research studies in European and Asian countries showed that the incidence of AR in primary school children is on the rise [16][17][18][19]. In the context of the global trend of increasing prevalence of AR, the overall epidemiological data on primary school children in Hubei Province are scarce. Hubei Province is situated in the middle part of China and spans 4° of latitude (from 29°01′N to 33°6′N) and over 8° of longitude (from 108°21′E to 116°07′E) with the population of >59 million. It has an area of around 185,900 square kilometers and is traditionally divided into 13 prefectural-level divisions. Besides, the regional large span could lead to unbalanced incidence of atopic illness. Therefore, in order to investigate the prevalence of AR in Hubei Province and its association with factors such as locations, socioeconomic status, and self-reported allergens and so on, our survey explored the prevalence of children aged 6-12 years in 6 major cities in Hubei Province by combining a questionnaire with SFAR.
In contrast to the methods previously used for epidemiological research including postal questionnaire surveys, face-to-face interviews, and telephone interviews, our online questionnaire survey reduced the waste of time and money and was more convenient to be collected and arranged. In our study, diagnosis validation of SFAR was described in detail above, making it applicable to this survey in large sample capacity and areas far away from the laboratory.
The overall prevalence of 5 cities of Hubei Province in our study was 16.16% (Wuhan 24.31%, Xiangyang 4.13%, Tianmen 4.31%, Jingmen 10.92%, and Huangshi 11.42%).  Our survey showed a geographic variation in the prevalence of AR across different regions of Hubei Province, and the prevalence rates of AR are higher in more developed areas than developing areas. Multivariate logistic regression revealed that the standardized prevalence of AR was positively correlated with GDP per capita. Wuhan, the capital of Hubei Province, is more developed than the other 4 cities and has the highest incidence of AR. In contrast to the surveys from developed countries that higher socioeconomic status predicted lower prevalence of allergies [20][21][22], the present study suggested that higher individual-level socioeconomic status predicted higher prevalence of AR which was consistent with previous studies in China [10].
These may be probably a consequence of the rapid development of industries and living standard, which resulted in changes in environment factors. There are accumulating pieces of evidence that environmental factors play important roles in the etiology of AR. A study, which was conducted on the relationship between air pollution and AR in Taiwanese school children, demonstrated that the prevalence of AR was significantly associated with sulfur dioxide, carbon dioxide, and nitric oxides [23]. Compared with other cities, Xiangyang and Tianmen have a lower level of urbanization, which may result in a lower concentration of urban air pollution. This may explain why the prevalence of AR in Xiangyang and Tianmen was the lowest. Consistent with other surveys in several Chinese cities [24], we found that the incidence of nasal symptoms has a distinct seasonal variation, which showed 2 peaks in spring and autumn. Frequent and severe temperature changes are reported to be the most common cause of nasal symptoms during spring and autumn. Meanwhile, spring and autumn are often the peak seasons for pollen transmission. These factors may be responsible for the seasonal variation.
In our survey, we found that male, family history of allergy, food or drug allergy, air purifier, exposure to dust, living in towns or urban area before 2 years old, maternal age for 25-35 years old, and frequent application of antibiotics increased the risk of AR. The prevalence of AR in males was significantly higher than that in females, indicating a gender-based difference, in line with data from previous studies. It is probable that both hormonal changes with age and genetic susceptibility contribute to such difference [25]. As previous studies have shown, family history [26], food allergy, and drug allergy [27] are risk factors for AR in children, which is consistent with our findings. Air purifier is used to purify air and reduce the pollutants indoor. But, we found that using air purifiers was a risk factor for AR in children. We speculated the reason might be related to the emission of the exhaust gas from the air purifier, such as carbon dioxide and ozone.
In our study, living in towns or urban area before 2 years old increased the risk of AR, which could be attributed to different lifestyle and vehicle exhaust between urban areas and rural areas. Previous studies have found that exposure to traffic-related air pollution during early childhood or pregnancy could increase the incidence of AR in children [28,29]. On the other hand, a number of studies have shown that living on a farm at preschool age had a protective effect on allergies [30][31][32], suggesting that endotoxin exposure in childhood may influence the likelihood of developing AR. Several research studies indicated that antibiotics given was associated with AR [30]. We found that children taking antibiotics more than once a year were 3.39 times approximately more likely to develop AR than children taking antibiotics less than once a year. Therefore, it is important that doctors should avoid the overuse of antibiotics for reducing the risk of AR in children.
Our data demonstrated that daily outdoor time for 1-2 h, daily sleeping time >8 h, siblings, and breastfeeding for >6 months could reduce the risk of AR in children, which is consistent with previous research studies [33][34][35] approximately. It could be speculated that moderate outdoor activities, plenty of time to sleep, and breastfeeding may be appropriate to prevent AR. Furthermore, interestingly, we found a higher rate of intestinal parasitic infections in AR than in healthy people by using univariate analysis, whereas the multivariate analysis revealed that intestinal parasitic infections did not affect the risk of AR (p > 0.05). Previous studies showed that the reduced exposure to parasites in a rural village of Bolivian Chaco associates with higher prevalence of grass pollen sensitization [36]. Recently, research has reported that infection with intestinal parasitic may selectively protect from pollen allergy because of the cross-react between them, which may behave as blocking antibodies and inhibiting allergic sensitization in susceptible individuals [37]. A Cuba study found that current intestinal parasitic infection protects against atopic dermatitis in children while past infections are risk factors for allergy [38]. Above all, the association between infections and allergy was apparently influenced by many underlying factors. The interactions differ depending on the type of intestinal parasitic and on the time of infestation. Therefore, further studies are needed to determine the relationship between infections and AR.
In conclusion, this is the first population-based random sample study that reported the prevalence of AR in primary school children in Hubei Province, which preliminarily looked into the characteristics of AR in this population. The study found strong evidence of the connection between social, behavioral, and biological factors and AR in primary school children in Hubei Province, indicating that strategies to reduce exposure to risk factors for childhood AR could be broadened. Presently, the study has limitations in that the sample size is small and only a limited number of risk factors were evaluated. AR is one of the most common diseases in young children in Hubei Province, which is higher in developed areas than in developing areas, suggesting an important role of lifestyle and environmental risk factors for AR in children. Public policies should specifically target at the local risk factors for different areas.