Effects Of Air Pollutants Exposure In Early Life On Asthma/wheezing Among Children Aged 0 To 2 Years

BackgroundAsthma,a chronic disease with reversible airway obstruction and airway hyperresponsiveness,affects an estimated 300 million people worldwide and results in a significant social,financial,and health care burden in many countries.It is also a more common disease among children and affects the health of at least 10 percent of children worldwide.The prevalence of asthma among children in China is still high.Between 2008 and 2019,the incidence rate of asthma among Chinese children under 5 years old has also been increasing.More importantly,the symptoms of childhood asthma are prone to recurrent attacks,and the treatment cost of this disease is high.If childhood asthma is not treated and controlled in time,there is a greater possibility of developing adulthood asthma.Asthma often occurs in early life,and many children with asthma have symptoms or even attacks when they are young.Asthmarelated wheezing and other symptoms will cause sleep and breathing disorders in children,which seriously affects the growth,development,and quality of life for children.Therefore,effective prevention and control of asthma/wheezing among young children are of great significance to improve the health status of children and reduce the incidence of adulthood asthma.There are many factors affecting childhood asthma/wheezing.Among them,the effect of air pollutant exposure on childhood asthma/wheezing has become a hotspot in the research field of public health.In recent years,there are more and more human and animal studies on the relationship between air pollutant exposure in early life and childhood asthma/wheezing,but many problems need to be solved.Firstly,air pollutants in cities are a mixed exposure condition formed by primary pollutants and secondary pollutants emitted by multiple pollution sources.However,most studies only assessed the association between a single pollutant and childhood asthma/wheezing,and the joint effect of combined exposure to air pollutants on childhood asthma/wheezing is still unclear.Secondly,most scholars paid attention to the effect of average exposure level of air pollutants on childhood asthma/wheezing,but rarely considered the effect of cumulative exposure dose.Thirdly,social factors such as environmental governance and prevention measures of coronavirus disease 2019(COVID-19)may cause temporal and spatial differences in the composition of air pollutants.The pathogenic effects of exposure to air pollutants in early life on childhood asthma/asthma still need to be explored.According to the concept of life course epidemiology,when risk factors exposure at different periods of life or under different conditions,they may have different pathogenic models.Some scholars have pointed out that the life course approach includes sensitive period model and risk factor accumulation model.Some studies have identified the sensitive window of childhood asthma/wheezing caused by exposure to air pollutants in early life and analyzed the interaction of air pollutants and other risk factors.However,few studies have explored the sensitive period after birth,and the differences in effects between exposure during pregnancy and exposure after birth have not been discussed,and the interaction among air pollutants has not been reported.If we can comprehensively elucidate the life course approach to asthma/wheezing among young children caused by exposure to air pollutants in early life,we can provide a valuable scientific basis for preventing the occurrence of childhood asthma.ObjectiveThis thesis uses life course epidemiology as the theoretical support to describe the incidence of childhood asthma/wheezing and its influencing factors by conducting a birth cohort,to assess the average exposure level and cumulative exposure dose of air pollutants for individuals in different developmental stages,to analyze the pathogenic effects of air pollutant exposure in early life on asthma/wheezing among children aged 0 to 2 years,and to clarify the life course approach to asthma/wheezing among young children caused by exposure to air pollutants in early life.Not only the results provide a scientific basis for the interpretation of the pathogenic mechanism of environmental pollution on health,but also give theoretical support for preventing childhood asthma/wheezing,improving physical fitness of children,and reducing the incidence of asthma in all ages.Methods1.Study designBased on the design of a prospective cohort study,a birth cohort was established in the urban area of Jinan,Shandong Province,and subjects were followed up to 2 years old to observe the incidence and influencing factors of childhood asthma/wheezing,to explore the etiological effect of the average exposure level of air pollutants in early life on asthma/wheezing among children 0 to 2 years old,and to clarify the onset model in life course approach to childhood asthma/wheezing.Based on the National Immunization Programs,singleton live-born resident infants without congenital diseases who received the second dose of hepatitis B vaccine within one month of birth were recruited as subjects at the vaccination clinics of the Community Healthcare Center.The questionnaire was designed based on the International Study of Asthma and Allergies in Childhood and the previous case-control study of our research group.Three waves of follow-up were conducted at 1,1.5,and 2 years of age at the same vaccination clinics.At baseline and follow-up surveys,face-to-face interviews were conducted with the mothers of subjects.Health outcomes were hospital-diagnosed asthma or wheezing,which were selfreported by the child’s mother at the vaccination clinic.And the date of the first onset of asthma/wheezing was obtained at the time of the follow-up survey.The sample size was estimated using the cohort study design sample size formula for a minimum sample size of 5483 subjects.Besides,in order to explore the joint effect of cumulative exposure dose of air pollutants on childhood asthma/wheezing,due to the large data of cumulative exposure dose calculation and the limitations of working conditions,a nested case-control study design based on the birth cohort was used to analyze the effect.In order to ensure the same length of exposure periods and similar living environment between the cases and controls,risk set matching and a 1:5 ratio were used to match controls for each case according to the gestational age and clinic code of the subjects.2.Air pollutant exposure assessment(1)Data collection:Air pollutant data were obtained from dynamic monitoring data collected by 17 national and provincial urban air quality monitoring stations in Jinan City,between the date of the last menstrual period of the earliest pregnant mother in the birth cohort and the date when the youngest child is 2 years old,the daily 24-hour average concentrations of sulfur dioxide(SO2),nitrogen dioxide(NO2),carbon monoxide(CO),inhalable particles(PM10),fine particulate matter(PM2.5),and the maximum daily 8-hour average concentrations of ozone(O3),as well as the hourly average concentrations of the six pollutants,were obtained,which formed the air pollutant data matrix for the total population exposure over the study period.(2)Individual assessment of average exposure concentration:The home address for mothers during pregnancy and children after birth,as well as the geographic location of the air quality monitoring stations were inverse address resolved to obtain the latitude and longitude of the geographic coordinates of subjects during different exposure periods,and further combined with the last menstrual period of the mother’s current pregnancy,the date of the child’s birth and the date of the child’s first hospital diagnosis of asthma/wheezing,an inverse distanceweighted model(IDW)was constructed to assess the average daily exposure concentrations of ambient air pollutants of subjects during different developmental stages.(3)Individual cumulative exposure dose assessment:According to the assessment method of average exposure concentration,the hourly ambient exposure concentrations of air pollutants during the period from maternal pregnancy to the onset of childhood asthma/wheezing were calculated for each study subject using the IDW model,and the cumulative daily exposure dose of pollutants in the environment was obtained by completing the integration of the irregular area under the exposure curve using the compound Simpson formula.Furthermore,based on the cumulative exposure doses in the environment,the breathing volume of the characteristic population,and the time spent outdoors in different periods,the daily cumulative exposure dose of pollutants inhaled outdoors for each subject was obtained,and then the cumulative exposure doses were summed up day by day to obtain the total cumulative exposure to pollutants inhaled outdoors by individuals in each exposure period.(4)Division of exposure time windows for different developmental stages in early life:Considering the variability of exposure,the pathogenic effect study was conducted after dividing the exposure time in early life into two stages:intrauterine exposure period and after birth exposure period.In addition,the exposure time was divided into exposure weeks to investigate the sensitivity window of air pollutant exposure on childhood asthma/wheezing.3.Statistical Analysis(1)Descriptive analysis:Frequency and composition ratio were used to describe the characterize of subjects;incidence density and cumulative incidence rate were used to reflect the frequency of asthma/wheezing among subjects from birth to age 2,where cumulative incidence rate was calculated by Kaplan-Meier survival curve in survival analysis;the recurrence rate was used to indicate the development of asthma/wheezing;median,interquartile range(IQR),maximum value and minimum value were used to characterize air pollutants.(2)Distribution characteristics analysis:The Log-rank test was used to test whether the differences in the distribution of childhood asthma/wheezing in different subgroups were statistically significant;the Mann-Whitney U test was used to compare the differences in the incidence rate of childhood asthma/wheezing in different groups for air pollutant concentrations;conditional logistic regression was used to compare the difference of environmental factors between case and control groups;the GeoDetector was used to investigate the spatial heterogeneity of the incidence of childhood asthma/wheezing in this study.(3)Correlation analysis:Spearman correlation analysis was used to determine the magnitude of the correlation between air pollutants,temperature,and humidity;Single and multifactorial analyses of the risk factors associated with childhood asthma/wheezing were performed by using Cox proportional-hazard models and stepwise regression methods.(4)Analysis of the pathogenic effects of average exposure levels:A time-dependent Cox proportional-hazard model was used to assess the effects of average exposure levels of air pollutants on childhood asthma/wheezing;a logistic regression model was used to compare the differences in the effects of air pollutants between the intrauterine exposure period and the postnatal exposure period;principal component analysis(PCA)combined with the Cox proportional-hazard models was used to analyze the joint and independent effects of average exposure levels of air pollutants on childhood asthma/wheezing.(5)Analysis of the pathogenic effect of cumulative exposure dose:Lasso regression analysis was used to screen for covariates,and then conditional logistic regression models were constructed to analyze the association between cumulative exposure dose of air pollutants and childhood asthma/wheezing at different exposure periods;weighted quantile sum(WQS)combined with the logistic regression model was first used to obtain the joint effect of cumulative exposure dose of air pollutants on childhood asthma/asthma morbidity,and the WQS index,which represents the total weight of several pollutants,and the contribution weight coefficients of each air pollutant were obtained.The WQS index was further extracted and entered into the multi-factor conditional logistic regression model as an independent variable to calculate the joint effect after adjusting for covariates.(6)Onset model analysis:In exploring the cumulative effect of risk factors,interaction analysis was mainly performed using the likelihood ratio test and the generalized additive model.In the search for the sensitive window,the distributed lag linear model(DLM)incorporating the Cox proportional-hazard models was used to identify the sensitive window period for childhood asthma/wheezing caused by higher average exposure levels for air pollutants in early life.All analyses were performed using R software(version 3.4.0).In all effect models,the hazard ratio(HR)or odds ratio(OR)and its 95%confidence interval(CI)were used to express the magnitude of the association.In the interaction analysis,the P value of the interaction term was less than 0.1,which was considered to be statistically significant.The a level was set at 0.05 for other analyses.And all statistical tests were two-sided.Results1.Incidence rate of asthma/wheezing and its influencing factors among children aged 0 to 2 years(1)Construction of birth cohort:The baseline survey of birth cohort was completed from January 2018 to December 2019,and a total of 6501 single births without congenital diseases were included in the birth cohort;the 2-year follow-up was completed in December 2021,and 5819 children completed three waves of follow-up surveys at the age of 1,1.5,and 2 years,and the loss rate of the three waves of follow-up surveys was 10.5%(682/6501);in addition,all the subjects experienced the implementation period of COVID-19 epidemic prevention and control measures during the follow-up surveys.(2)Incidence of asthma/wheezing:a total of 84 children within 2 years old developed asthma/wheezing,with a cumulative incidence rate of 1.4%and an incidence density of 6/1000 person-years;the recurrence rate of asthma/wheezing among subjects was 14.3%(3/21)between 1 and 1.5 years of age and 42.9%(6/14)between 1.5 and 2 years of age.The results pf GeoDetector showed no statistical difference in spatial heterogeneity with a test statistic q value of 0.046.(3)Risk factors of asthma/wheezing:The results of the multifactor analysis showed that the incidence of asthma/wheezing was positively correlated with respiratory tract infection at the age of 0 to 1(HR=2.04,95%CI:1.16-3.60),use of antibiotics(HR=2.44,95%CI:1.573.79),use of masks(HR=2.01,95%CI:1.18-3.42),open windows often(HR=2.23,95%CI:1.33-3.75),and use of carpets(HR=3.37,95%CI:1.68-6.74),and girl was the protective factor(HR=0.57,95%CI:0.36-0.90).(4)Basic characteristics of subjects related to the epidemic prevention and control:For children 1,1.5,and 2 years old,the median for the time spent in outdoor activities was 0.5 hours,1.3 hours,and 3.0 hours,respectively,and the respiratory infection rate was 65.0%,72.5%,and 71.3%,respectively.Within 2 years of age,the wearing rate of masks was 65.3%,and the use rate of antibiotics was 28.2%.2.Average exposure level of air pollutants at different development periods and their pathogenic effects(1)Average exposure level of subjects:The median(IQR)for average exposure concentration of O3,SO2,PM2.5,PM10,NO2,and CO during intrauterine exposure period was 109.04μg/m3(30.90μg/m3),14.48μg/m3(2.12μg/m3),55.25μg/m3(11.07μg/m3),112.87μg/m3(18.09μg/m3),45.67μg/m3(8.14μg/m3),0.88mg/m3(0.08mg/m3),respectively;it during the postnatal exposure period was 108.85μg/m3(10.62μg/m3),12.41μg/m3(1.30μg/m3),48.52μg/m3(4.26μg/m3),99.78μg/m3(7.75μg/m3),38.42μg/m3(3.62μg/m3),0.83mg/m3(0.04mg/m3),respectively.Dividing the pollutants into different exposure level groups according to median,we only found a significantly higher cumulative incidence of asthma/wheezing in subjects exposed to high levels of O3 after birth than in those exposed to low levels of O3(1.8%vs 1.1%,P=0.030);there was no significant difference in the incidence of asthma/wheezing among different exposure levels of other pollutants.(2)Relationship between the average exposure level of pollutants and asthma/wheezing:In time-dependent Cox proportional-hazard model adjusted for covariates,high levels of O3 and SO2 exposure in early life were both positively associated with childhood asthma/wheezing with HRs(95%CI)of 2.10(1.31-3.37)and 1.81(1.16-2.83).In the logistic regression models after adjusting for the effect of other exposure periods,childhood asthma/wheezing was positively associated with high levels of O3 exposure(OR=1.82,95%CI:1.08-3.12)and high levels of SO2 exposure(OR=2.18,95%CI:1.23-3.90)after birth.(3)Joint and independent effects of average exposure levels on asthma/wheezing:The principal component analysis model extracted postnatal air pollutants as principal component 1(PC1)representing SO2,NO2,CO,PM10,PM2.5 and principal component 2(PC2)representing O3,and childhood asthma/wheezing was associated with both PC1(HR=1.16,95%CI:1.031.31)and PC2(HR=1.28,95%CI:1.00-1.63);in addition,after adjusting for other pollutants and covariates,the HRs and their 95%CIs for the independent effects of O3 and SO2 exposure on asthma/wheezing were 2.44(1.53-3.89)and 2.61(1.41-4.81).3.Cumulative exposure dose of air pollutants at different development stages and their pathogenic effects(1)Cumulative exposure does of subjects:we included 84 cases and 420 controls in the nested case-control study.In the case group,the median(IQR)of SO2,NO2,PM2.5,PM10,O3,and CO during the intrauterine exposure period was 84.27mg/m3(107.45 mg/m3),274.32mg/m3(330.96mg/m3),332.60mg/m3(381.60mg/m3),669.09mg/m3(765.72mg/m3),688.82mg/m3(797.68mg/m3),6336.24mg/m3(6779.46mg/m3),respectively;during the postnatal exposure period,it was 29.38mg/m3(53.83mg/m3),92.79mg/m3(145.76mg/m3),92.11mg/m3(153.52mg/m3),220.33mg/m3(366.20mg/m3),271.88mg/m3(466.92mg/m3),2619.96mg/m3(4606.36mg/m3),respectively.In the control group,the median(IQR)during the intrauterine exposure periods for the six pollutants was 93.83mg/m3(116.18mg/m3),303.74mg/m3(390.21mg/m3),356.47mg/m3(449.36mg/m3),734.47mg/m3(952.07mg/m3),717.69mg/m3(996.98mg/m3),8091.22mg/m3(8250.76mg/m3),respectively;during the postnatal exposure period,it was 24.53mg/m3(38.03mg/m3),78.53mg/m3(111.75mg/m3),80.45 mg/m3(117.70mg/m3),198.06mg/m3(302.28mg/m3),220.96mg/m3(342.34mg/m3),2248.97mg/m3(3412.35mg/m3),respectively.No statistical difference was found between the two groups in the cumulative exposure dose of air pollutants during the intrauterine exposure period.Compared with the control group,the cumulative exposure doses of SO2,NO2,and PM2.5 in the case group during the postnatal exposure period were higher,and the difference was statistically significant(P<0.05).(2)Relationship between the cumulative exposure dose of pollutants and asthma/wheezing:In the conditional logistic regression model,after adjusting for covariates and the cumulative exposure levels of the two exposure periods to each other,positive relationships were found between cumulative postnatal outdoor exposure doses of three pollutants(SO2,NO2,and PM2.5)and childhood asthma/wheezing,with ORs and their 95%CIs of 1.67(1.07-2.60),1.56(1.01-2.42),and 1.57(1.03-2.04),respectively.(3)Joint effect of the cumulative exposure dose of pollutants on asthma/wheezing:The results of the WQS model that initially explored the combined effect of the cumulative exposure dose of air pollutants on childhood asthma/wheezing showed that the WQS index of the cumulative exposure dose of air pollutants in the postnatal exposure period was significantly associated with childhood asthma/wheezing(P=0.020);for every 25 percentile increase in the WQS index exposed after birth,the risk of asthma/wheezing increased by 1.10 times(95%CI:1.03-1.18)in the adjusted model;SO2,PM2.5,and NO2 contributed the most to the WQS index.While there was no statistically significant association between the cumulative exposure dose of air pollutants in the intrauterine exposure period and childhood asthma/wheezing(P=0.080).4.Onset model of childhood asthma/wheezing due to air pollutants(1)Interaction among air pollutants:The main components of pollutants PC1 and PC2 were extracted to construct an interaction item.After adjusting for covariates,ambient temperature,and humidity,the P value of the interaction item was less than 0.001,which indicated that there was interaction among air pollutants in promoting the onset of childhood asthma/wheezing.(2)Interaction between air pollutants and other factors:The results of the likelihood ratio test analysis showed that only the P value of the interaction item between O3 and frequent window opening was less than 0.001.In the infrequent windowing group,the HR(95%CI)of the relationship between exposure to high level O3 and asthma/wheezing was 0.52(0.15-1.78);in the frequent windowing group,the HR(95%CI)was 3.75(2.07-6.79).(3)Sensitive period of asthma/wheezing caused by air pollutants:The results of DLM model showed that an increase of O3 exposure concentration by an IQR was associated with an increased risk of childhood asthma/wheezing from 31st to 37th weeks of intrauterine exposure and 1st to 105th weeks of postnatal exposure,and the sensitive window of boys was from 8th to 74th weeks after birth,and that of girls was from 49th to 105th weeks after birth;whereas there was no sensitivity window for the risk effect of SO2 exposure on childhood asthma/wheezing.Conclusions(1)Exposure to higher concentrations of O3,SO2,NO2,and PM2.5 after birth significantly increased the risk of asthma/wheezing among children within 2 years of age.Therefore,in addition to the classic asthma causing air pollutants such as SO2,NO2,and PM2.5,the effect of O3 on childhood asthma/wheezing should also be paid sufficient attention.(2)In the effects for causing childhood asthma/wheezing,there were two PCs of air pollutants.One represents SO2,NO2,PM2.5,PM10,and CO,as well as the other represents O3.Under combined exposure conditions,the higher the average exposure levels and cumulative exposure doses of air pollutants were,the greater the combined effects of childhood asthma/wheezing were.SO2,NO2,and PM2.5 were the three pollutants that contributed the most to the joint effect of cumulative exposure doses.(3)The onset model of childhood asthma/wheezing induced by exposure to air pollutants included both the risk factors cumulative model and the sensitive period model.On the one hand,there were interactions among air pollutants,as well as between O3 and frequent window opening;on the other hand,the third trimester and the first 2 years of life were sensitive exposure windows for O3-induced childhood asthma/wheezing.(4)The cumulative incidence of asthma/wheezing within 2 years of age in Jinan urban children under COVID-19 epidemic control measures was 1.4%,with a relatively low level of incidence;recurrence rates increased with age.(5)High levels of exposure to air pollutants,male,respiratory tract infection before the age of 1 year,use of antibiotics,use of masks,open windows often,and use of carpets are risk factors that affect the incidence of asthma/wheezing in this population.(6)There was no spatial heterogeneity in the geographical distribution of childhood asthma/wheezing in this birth cohort in the study area.