The temporal-spatial association of respiratory manifestations and air pollution in children referred to the Emergency Department of Akbar Children’s Hospital,

Background Air pollution causes many respiratory disorders, especially in children and the elderly. These disorders include asthma exacerbations, bronchiolitis, and pneumonia. Research on the association between air pollution and respiratory disorders helps to reevaluate environmental policies in developing countries. Methods This descriptive cross-sectional study was conducted on 932 children with respiratory manifestations admitted from December 2017 to December 2019 at the Emergency Department of Akbar Children’s Hospital of Mashhad University of Medical Sciences, Mashhad, Iran. Air pollution indices such as concentration of sulfur dioxide (SO 2 ), nitrogen dioxide (NO2), carbon monoxide (CO), and particulate matter (PM) smaller than 2.5 and 10 μm and other parameters, including the air quality index (AQI), air temperature, and humidity level from 2017 to 2019, were retrieved from Mashhad Environmental Pollution Monitoring Center. Demographic and clinical data of patients were collected from patients’ hospital documents. We used descriptive analytical methods such as central tendency, variability, and frequency distribution to report and analyze demographic and clinical data through tables and diagrams. The association between air pollution indices and respiratory manifestations was examined by the Spearman correlation test. The correlation between the AQI and total hospital admissions and asthma-related hospital admissions was also evaluated by the Spearman correlation test. Results Hospital admissions due to respiratory manifestations were not associated with the AQI of each month ( p -value = 0.794). The concentration of SO 2 was correlated with respiratory-related hospital admissions (correlation coefficient = 0.487, p -value = 0.016) but not asthma attacks. Conclusion Generally, our cross-sectional study showed no statistically considerable association between air pollution and hospital admissions due to respiratory manifestations and asthma attacks in children. Of the air pollution indices, only SO 2 concentration was associated with respiratory-related hospital admissions but not asthma attacks.


Background
The prevalence of respiratory disorders has increased significantly among children over the last few years, highly related to air pollution.Persistent exposure to photochemical and traffic-related pollutants, especially in highly polluted cities of developing countries, can deteriorate lung growth and function.Consequently, the respiratory morbidity and mortality increase among children [1].Air pollution can affect the respiratory system by stimulating oxidative stress and inflammatory processes, modulating the immune system, and altering genetic and epigenetic mechanisms [2].Traffic-related air pollution containing gases such as nitrogen dioxide (NO2), nitric oxide (NO), nitrogen oxides (NOX), and ozone (O3), as well as particles less than 2.5 µm and 10 µm in diameter, can contribute to the development and exacerbation of asthma and other allergic diseases [3].Although the development of asthma was not related to air pollution in previous studies, recent studies have found notable associations [4].Based on estimations of the United Nations International Children's Emergency Fund (UNICEF), the level of air pollution is sixfold higher than the standards in the living places of almost 300 million children around the world, which accounts for the deaths in 600,000 children under the age of 5 each year [5].Considering the relative immaturity of respiratory and immune systems and the more outdoor activity children engage in, they are more vulnerable to adverse outcomes of air pollution.
Additionally, the peripheral airways of infants are more prone to inflammatory narrowing than adults because of anatomic differences; therefore, the chance of irritation-induced airway obstruction increases in children [6].Asthmatic children may also experience more severe symptoms in exposure to air pollution since they do not stop their activity even during asthma exacerbations.The other biological factors involving children's susceptibility to pollution exposure refer to different ways of metabolizing, detoxifying, and excreting environmental stimuli [7].The acute complications of air pollution consist of lung inflammation, reduction of lung function, increase in episodes of asthma attacks, respiratory and cardiac hospital admissions, and also a higher incidence rate of premature death.Long-term exposure to air pollution can result in respiratory diseases like asthma, bronchitis, and premature death; however, outcomes of chronic exposure are not as complicated as acute ones [8].This study evaluated the association between air pollution and respiratory manifestations among children referred to the Emergency Department of Akbar Children's Hospital, Mashhad, Iran.

Method
This descriptive cross-sectional study was conducted on 932 children with respiratory manifestations admitted from December 2017 to December 2019 at the Emergency Department of Akbar Children's Hospital of Mashhad University of Medical Sciences, Mashhad, Iran.Patients who were not admitted to the hospital or without their parents' consent were excluded.Demographic and clinical data of patients, including age, sex, living place, past medical history, chief complaint, the duration of hospital admission, the duration of admission at the intensive care unit (ICU), season of hospital admission, mortality rate, and final diagnosis, were collected from hospital documents and recorded into a checklist as well.The air quality index (AQI), air temperature, and humidity level from 2017 to 2019 were retrieved from the Mashhad Environmental Pollution Monitoring Center.Air pollution indices include the concentration of sulfur dioxide (SO 2 ), carbon monoxide (CO), nitrogen dioxide (NO 2 ), and particulate matter (PM) smaller than 2.5 and 10 μm.The formula for calculating the AQI is as follows: (AQI p ): The air quality index for pollutant (p) (C p ): The estimated concentration of pollutant (p) (BP Hi ): The breakpoint that is greater than or equal to (C p ) (BP Lo ): The breakpoint that is less than or equal to (C p ) (I Hi ): The AQI value corresponding to (BP Hi ) (I Lo ): The AQI value corresponding to (BP Lo ).This formula converts pollutant concentrations into an AQI value, which can be used to inform the public about air quality.The breakpoints (BP) and the corresponding AQI values (I) are determined based on health impact categories and are provided in Table 1.The highest AQI value calculated from individual pollutants is reported as the AQI for the location [9].
The review board of Mashhad University of Medical Sciences approved the study, and the children's parents filled out the informed consent form.We used descriptive analytical methods such as central tendency, variability, and frequency distribution to report and analyze demographic and clinical data through tables and diagrams.The association between air pollution indices and the prevalence of asthma attacks and other respiratory signs and symptoms was examined by the Spearman correlation test.The AQI and total hospital admission and asthma-related hospital admission were shown in two diagrams separately, and their correlation was evaluated by the Spearman correlation test as well.Data analysis was performed using the Statistical Package for Social Science (SPSS) version 25. p-value < 0.05 was considered statistically significant in this study.

Results
Altogether The majority of patients (312 out of 932) were admitted to the hospital during winter, and hospital admission was more prevalent in spring (237/932), autumn (232/932), and summer (151/932), respectively.Figure 1 demonstrates the season of hospital admissions due to respiratory manifestations.
Most patients diagnosed with asthma and bronchiolitis were admitted to the hospital in autumn and winter, respectively.In contrast, the frequency of pneumoniarelated hospital admissions was almost the same during different seasons of the year.Figure 2 shows the season of hospital admission with a diagnosis of asthma, bronchiolitis, and pneumonia.Table 3 demonstrates the survival and mortality rate association with age, sex, and final diagnosis.There was a significant correlation between the final diagnosis and mortality of patients (p-value < 0.001).Thirty-one out of 932 patients died, of which 22.6% were diagnosed with pneumonia, and 77.4% had another diagnosis, while none of the patients with asthma or bronchiolitis died.Similarly, asthma attacks were not associated with the AQI of each month (p-value = 0.311).Figure 4 shows asthma attack-related hospital admissions and the AQI of each month from January 2018 to December 2019.
More concentration of sulfur dioxide (SO 2 ) was remarkably associated with an increase in the total number of hospitalized patients with respiratory manifestations (correlation coefficient = 0.487, p-value = 0.016) but not with an asthma attack (correlation coefficient = 0.382, p-value = 0.066).The total number of hospital admissions due to asthma attacks and other respiratory manifestations was not correlated to the concentrations of carbon monoxide (CO), nitrogen dioxide (NO 2 ), and also particulate matter (PM) smaller than 2.5 and 10 μm.The results   of the correlation between the total number of hospital admissions due to respiratory manifestations and asthma attacks and the concentration of air pollution indices of each month are summarized in Table 4.

Discussion
Children are more vulnerable to air pollution-induced respiratory disorders because of immature immune and respiratory systems, more permeability of airway epithelium, higher respiratory and resting metabolic rate due to growing and larger surface area per unit body weight, and smaller airways leading to earlier obstruction [8,10].Children have higher air intake because of more outdoor activity than adults, making them more susceptible to air pollution [8].Air pollution can cause various respiratory disorders, including asthma attacks and respiratory infections such as pneumonia, bronchiolitis, and tuberculosis [2].In our study, patients' final diagnoses were bronchiolitis, asthma attack, and pneumonia.Of these, the correlation between asthma attacks and the AQI was studied, and no significant correlation was found.In contrast, Evangelisti et al. investigated the association between air pollution and hospital admission due to bronchiolitis.The results revealed that short-term exposure to PM 10 , PM 2.5 , and NO 2 was significantly correlated to bronchiolitis [11].Two other studies demonstrated the remarkable relation between severe bronchiolitis and exposure to PM 10 , PM 2.5 , and NO 2 [12,13].Darrow et al. have researched upper respiratory tract infection (URI) and air pollution in 0-4-year-old children and concluded that short-term exposure to NO 2 , PM 10 , and PM 2.5 can lead to a higher hospital admission rate due to pneumonia [14].Similarly, Liu et al. showed a statistically significant association between URI and concentration of SO 2 , CO, NO 2 , PM 10 , and PM 2.5 [15].Bronchiolitis is among the most common causes of children's hospital admission during winter [16].However, asthma exacerbations occur mostly in the autumn season [17].Likewise, our results showed that most bronchiolitis and asthmatic patients were admitted to a hospital in winter and spring, respectively.Similarly, Hoeppner et al. found that hospital admission due to bronchiolitis increases during winter [18].We also investigated the association between asthma attacks and the concentration of air pollution indices (SO 2 , CO, NO 2 , PM 10 , and PM 2.5 ), and none of them was associated with hospital admission due to asthma attacks.Similarly, using traffic proximity and density as proxies for air pollution exposure, some earlier studies found no remarkable association between asthma development and air pollution [19][20][21].In contrast, some other studies showed a notable correlation between the concentration of SO 2 , NO 2 , and PM 2.5 and a higher prevalence of asthma attacks [3,22,23].We found that the concentration of air pollution indices (CO, NO2, PM 10 , and PM 2.5 ) did not correlate to hospital admission due to respiratory signs and symptoms such as cough, fever, dyspnea, respiratory distress, and wheezing, but the concentration of SO 2 did.Our results also showed no significant association between the AQI and hospital admission because of asthma attacks and other respiratory signs and symptoms.Correspondingly, Nicolai's research demonstrated that nonspecific respiratory symptoms like chronic cough are associated with long-term exposure to SO 2 but not asthma [24].Similarly, Pan et al. showed that the prevalence of respiratory symptoms such as persistent cough and phlegm has increased in exposure to SO 2 [25].
Another study also showed that short-term exposure to SO 2 is strongly associated with hospital admission due to respiratory diseases, especially among children aged 0-4 [26].Likewise, Mansourian et al. found a significant association between SO 2 and PM 10 concentrations and respiratory-related children's hospital admissions in Isfahan, Iran [27].Similar to our study, Ranzi and his colleagues found that exposure to traffic-related pollution is weakly associated with respiratory issues in children during the first 7 years of their lives [28].Another study, based on a large Swedish birth cohort, showed that asthma is not significantly associated with exposure to air pollutants [29].Exposure to NO 2 can trigger asthma attacks by increasing leukotriene production [30].Unlike our study, several studies demonstrated a remarkable association between the concentration of NO 2 and the development of respiratory symptoms [31,32].Clark et al. found that early exposure to air pollutants such as NO 2 , carbon monoxide (CO), nitric oxide (NO), PM 10 , SO 2 , and black carbon can contribute to the development of asthma in preschool ages [4].A similar study showed higher concentrations of NO 2 and PM 2.5 , which resulted in asthma symptoms and boosted its prevalence [33].Contrary to our study, a higher PM concentration resulted in more respiratory symptoms and asthma exacerbation among 6-to 12-year-old children exposed to petrochemical pollution.Seemingly, more exposure to PM was concomitant with higher rates of hospital admission for respiratory disorders, especially asthma attacks [1].Another study suggested higher levels of PM 2.5 can contribute to new-onset wheeze among 5-to 7-year-old children [34].A metaanalysis comprised of 41 studies also showed a remarkable association between the development of asthma and exposure to NO 2 , PM 2.5 , and PM 10 [35].This study also found a significant correlation between the final diagnosis and mortality of patients.Thirty-one out of 932 patients died, of which 22.6% were diagnosed with pneumonia and 77.4% had another diagnosis.Pneumonia was reported as the most prevalent cause of death among children aged more than 5 years old suffering from respiratory diseases [36].In 2019, 740,180 children died from pneumonia, which accounts for 14% of all deaths in children under the age of 5 [37].From 1968 to 2000, pneumonia, asthma, and cystic fibrosis were responsible for 73% of all respiratory mortality among 1-to 16-year-old patients in England and Wales [38].

Conclusion
The present study investigated the association of air pollution with the respiratory health of children admitted at one of the pediatric hospital centers in Mashhad, Iran.Mashhad is one of the most extensive and most populated cities in Iran.A few similar researches have studied the association between air pollution and the respiratory health of Iranian children.As air pollution is accelerating and its health effects are devastating, more research is necessary to improve environmental health policies in developing countries.Generally, our cross-sectional study showed no statistically significant association between air pollution and hospital admissions due to respiratory manifestations in children; however, achieving comprehensive results requires more investigation into the enormous population exposed to air pollution for a long time.

Figure 3
Figure 3 shows the number of hospital admissions due to respiratory manifestations and the AQI of each month from January 2018 to December 2019.Hospital admissions due to respiratory manifestations were not associated with the AQI of each month (p-value = 0.794).Similarly, asthma attacks were not associated with the AQI of each month (p-value = 0.311).Figure4shows asthma attack-related hospital admissions and the AQI of each month from January 2018 to December 2019.

Fig. 1 Fig. 2
Fig. 1 The season of hospital admission because of respiratory manifestations

Fig. 3 Fig. 4
Fig.3The number of hospital admissions due to respiratory manifestations and the AQI index of each month from January 2018 to December 2019

Table 2
Demographic and clinical data of 932 patients

Table 3
The association of mortality and survival with age, sex, and final diagnosis

Table 4
Correlation between the total number of hospital admissions due to respiratory manifestations and asthma attacks and concentration of air pollution indices of each month a Carbon monoxide b Nitrogen dioxide c Sulfur dioxide d Particulate matters less than 10 μm e Particulate matters less than 2.5