Respiratory tract symptoms are prevalent in children.1 Several epidemiologic studies have found an association between long-term air pollution exposure and asthma2–6 or wheeze.2,7,8 However, other studies show no association between air pollution and respiratory symptoms.9–11 Differences in study design, and in exposure assessment and outcome definitions, may contribute to the apparently inconsistent findings. Furthermore, certain susceptibility factors may play a role, including early-life exposure, sex, and genetics.12–15
Air pollution exposure during the first years of life seems to be particularly relevant to respiratory disorders later in childhood.8,13,16,17 Specific subtypes of asthma, such as allergic and nonallergic asthma, may be caused by air pollution, but results are inconsistent.4,8,13,18 Many studies have looked at the effects of air pollution on prevalence of asthma symptoms or their exacerbation, but only a few prospective studies have analyzed the contribution of air pollution exposure to the onset of disease.4,8,10 Given that the prevalence of respiratory symptoms changes with age, and that not all children who experience symptoms in early life develop asthma at older ages, it may be important to study both prevalence and incidence of asthma symptoms throughout childhood.
We have previously reported an association between exposure to traffic-related air pollution during the first year of life and development of respiratory symptoms at the age of 4 years in the population-based birth cohort BAMSE.8 Recently, the 12-year follow-up of this cohort was completed, which enables us to study the association between traffic-related air pollution and the development of asthma and related symptoms longitudinally up to 12 years of age.
The BAMSE study is based on a well-characterized cohort of children followed up prospectively from birth. Study design, recruitment, criteria for inclusion, and data collection procedures have been described elsewhere.19 In brief, 4089 children born between 1994 and 1996 in four municipalities in Stockholm County, representing urban and suburban environments, were enrolled. Data on residential characteristics and socioeconomic factors and parental allergic diseases, pet contact, and others were collected with a baseline questionnaire sent to parents when the child was approximately 2 months old. Repeated follow-ups were carried out at 1, 2, 4, 8, and 12 years; parents filled in similar questionnaires with a main focus on the children’s symptoms related to wheezing and allergic diseases. Information on various exposures was also collected. Response rates were 96%, 94%, 91%, 84%, and 82%. Blood was obtained from 2614 children (64%) at the age of 4 years and from 2480 children (61%) at the age of 8 years. The study was approved by the ethical committee of Karolinska Institutet.
Air Pollution Exposure Assessment
The assessment of exposure to locally emitted air pollution from traffic was based on a successively refined methodology for estimating individual long-term source-specific exposure, as has been described in detail elsewhere.20 In brief, the lifetime residential, daycare, and school addresses have been georeferenced, and time-weighted average outdoor levels of selected pollutants were calculated by use of emission inventories and dispersion models of the Stockholm and Uppsala Air Quality Management Association.
The local contribution to annual mean levels of traffic-PM10 and traffic-NOx (not including regional background) was calculated using a Gaussian air quality dispersion model and a wind model, both part of the Airviro Air Quality Management System (SMHI, Norrköping, Sweden; http://airviro.smhi.se). Air pollution concentrations were calculated for all addresses in the years 1994 to 2008, that is, from the year when the first child was born until the end of the 12-year follow-up. Emission databases for NOx were available for the years 1990, 1995, 2000, 2002, 2003, 2004, 2006, and 2010. The model calculations of NOx concentrations were interpolated to obtain estimates for all years during the period of interest. PM10 model calculations were performed only for the year 2004 and applied to all years during the study period. There were 106 addresses in the most polluted street segments in the Stockholm inner city with multistory buildings on both sides. For these addresses, a street-canyon contribution was calculated using the SMHI-Airviro street-canyon model (http://airviro.smhi.se). To obtain air pollution levels that are comparable with measured levels of PM10 and NOx, the regional background of 10 µg/m3 PM10 and 3 µg/m3 NOx, respectively, should be added to our estimates.21
Definition of Health Outcomes
Wheezing was based on parental reporting in the questionnaires. We classified wheeze as one or more episodes and as three or more episodes, during the 12 months before each questionnaire.
For children at 1 and 2 years, asthma was defined as three or more episodes of wheeze in combination with treatment with inhaled corticosteroids or signs of bronchial hyperreactivity without concomitant respiratory infection. At 4, 8, and 12 years, at least four episodes of wheeze in the last 12 months, or at least one episode in combination with prescription of inhaled corticosteroids, was required for a diagnosis of asthma.22 Incident asthma was defined as asthma at a given age without having fulfilled the definition of asthma at any previous time. Incident wheeze was defined in the same way. Furthermore, children with asthma were classified as having allergic asthma if the child fulfilled the criteria of asthma at 4 or 8 years and was also sensitized to common inhalant allergens at the corresponding age and as having nonallergic asthma if not. Sensitization status was defined as blood immunoglobulin E (IgE) level of ≥0.35 kUA/L to common inhalant allergens, analyzed with Phadiatop® (a mix of common inhalant allergens: birch, timothy, mugwort, cat, dog, horse, mold [Cladosporium herbarum], and house dust mite [Dermatophagoides pteronyssinus]).
We assessed associations between air pollution exposure and asthma outcomes combined with sensitization using multinomial logistic regression; the results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Longitudinal associations between air pollution levels and repeated questionnaire reports of binary asthma outcomes were analyzed using logistic regression models applying generalized estimating equations with stationary correlation structure to account for correlations among repeated observations in the same subject.23 The models incorporated terms for an interaction between time indicator variable and exposure to evaluate the effect of exposure over time. To assess effect modification by sex and allergic heredity, we entered into the models variables representing the product of air pollutant exposure and the potential modifiers. All results are presented across the same unit of change in exposure (value of 5th to 95th percentile difference in the estimated outdoor levels during the first year of life, which was 7.2 µg/m3 for PM10 and 46.8 µg/m3 for NOx) to make the associations comparable across the various exposure periods. The final models were adjusted for covariates that were selected based on earlier literature and changed the OR by >5%: municipality, socioeconomic status, heredity (mother or father with doctor’s diagnosis of asthma and asthma medication or with doctor-diagnosed hay fever in combination with furred animals or pollen allergy), and the year the house was built. Parental socioeconomic status was classified as blue-collar, white-collar, and others (students, unemployed) according to the Nordic standard occupational classification and the Swedish socioeconomic classification.24
Exposure time windows were defined as the first year of life, current exposure (12 months before the date of a questionnaire), and average exposure since the date of the previous follow-up. For analyses of the effects of exposure during infancy, 3633 children (89%) were included with information on exposure, confounders, and outcomes under study at a minimum three of five time points. There were 3477 subjects (85%) available for analyses of the effects of average air pollution exposure since the previous follow-up. A total of 2518 and 2378 children were included in the analyses of asthma in combination with IgE sensitization at the ages of 4 and 8 years, respectively. All statistical analyses were performed with STATA Release 11.1 (StataCorp, College Station, TX).
Table 1 shows the distribution of selected risk factors by asthma status across the first 12 years of life. Children who had ever experienced asthma symptoms up to 12 years of age more often came from families of blue-collar workers and more often had parents with allergies. The distribution of risk factors was similar in the study population and the original cohort (eTable 1; http://links.lww.com/EDE/A625). For the first five time periods of life (the first year of life, second year of life, and averages of 2–4, 4–8, and 8–12 years), the mean local contributions above regional background to the children’s outdoor air pollution exposure levels were 4.2, 3.9, 3.6, 3.5, and 4.6 µg/m3 for traffic-PM10 and 21.4, 18.6, 13.4, 10.6, and 7.8 µg/m3 for traffic-NOx (Fig. 1). Children who lived more centrally (Stockholm municipality), in older buildings, and who came from families of high socioeconomic status, experienced an average higher air pollution levels (data not shown). The correlations between estimated PM10 and NOx concentrations in the various time periods were high, and therefore, multipollutant models were not feasible (eg, r = 0.96 between NOx and PM10 exposure levels during the first year of life).
A total of 3.9%, 5.9%, 7.0%, 6.2%, and 6.7% of the children included in the analyses met the asthma definition criteria at 1, 2, 4, 8, and 12 years of age, respectively (Table 2). Among asthma cases, 34% were sensitized to common inhalant allergens at the age of 4 years and 58% at the age of 8 years. At least one episode of wheezing during the last 12 months was reported by approximately 15% during the first 4 years of life, with a decreasing trend to the age of 12 years. The incidence of wheeze symptoms seemed to be highest during the first 2 years of life. All symptoms were more prevalent in boys than girls.
The associations between air pollution exposure and wheeze and asthma are presented in Figures 2 and 3. Detailed quantitative results are found in eTable 2 (http://links.lww.com/EDE/A625). Exposure during the first year of life tended to have positive overall effects on both prevalent and incident wheeze and asthma symptoms during the first 12 years of life; the OR for a 5th to 95th difference in traffic-PM10 exposure and prevalence of asthma was 1.3 (95% CI = 0.7–2.2) and for at least one episode of wheeze was 1.2 (95% CI = 0.8–1.6). The association seemed strongest for asthma at 12 years of age (2.0 [1.1–3.5]). The same pattern was seen for asthma incidence.
Table 3 shows the association between exposure to air pollution during the first year of life and development of allergic and nonallergic asthma symptoms at 4 and 8 years of age. Air pollution exposure during infancy was associated with nonallergic asthma at 8 years of age (ORs for a 5th to 95th percentile difference in traffic-PM10 = 3.8 [95% CI = 0.9–16]). A suggestion of increased risk was observed at the age of 4 years (1.6 [0.5–5.3]). This association seemed stronger when using traffic-NOx as an indicator of exposure (2.4 [1.0–5.6]). No significant interactions with air pollution were seen for sex (P = 0.21) or heredity (P = 0.57 and 0.48, for one and two affected parents, respectively).
No overall effect was observed with average air pollution exposure since the date of previous follow-up (ORs for a 5th to 95th difference in traffic-PM10 exposure = 0.9 [95% CI = 0.6–1.3] and 0.9 [95% CI = 0.6–1.4] for prevalent and incident asthma, respectively; Fig. 3). Similar absence of effects was seen in relation to exposure during the preceding 12 months (data not shown).
In our study, we found a suggestion of positive associations between exposure to traffic-related air pollution during infancy and overall risks of respiratory symptoms in children over the first 12 years of life. Associations seemed strongest for the oldest children and for nonallergic asthma. No overall association was observed between air pollution exposure after the first year of life and development of asthma symptoms.
This study is an extension of previous analyses within the BAMSE cohort at 4 years, in which exposure to traffic-related air pollution was associated with various indicators of airway disease, and in particular, with persistent wheeze.8 In the current analyses, we have added information on air pollution exposure at subsequent home addresses, and at daycare and school addresses, together with health data from repeated questionnaires up to 12 years of age and clinical examinations at 4 and 8 years. Response rates were high during the entire follow-up, with 82% of the subjects continuing in the study at the age of 12 years. Availability of health data from the repeated questionnaires at several points in time allowed us to assess incident disease and longitudinal effects. Furthermore, objective measures, such as serum levels of IgE, were obtained from more than 60% of the original cohort at 4 and 8 years, which enabled us to investigate various asthma phenotypes.
It has been suggested that timing of the exposure might be important for childhood respiratory morbidity.25 We investigated several time aspects of long-term exposure, including early-life exposure and current exposure (during the last year), and average exposure between follow-ups. In general, the strongest effect was observed in relation to exposure during infancy, which is in line with previous studies indicating that prenatal and early-life periods represent critical windows for the effects of exposure on development of childhood asthma and related symptoms.8,13,16,17,26 An alternative explanation might be that the exposure classification method based on home address has less error early in life, before children start to go to daycare and schools.
Our findings suggest that traffic-related air pollution primarily increases the risk of nonallergic asthma symptoms. Experimental research suggests that such effects may be linked to changes in the formation of reactive oxygen species, alterations in antioxidant defense, and increased nonallergic inflammation.27 Furthermore, other epidemiologic studies have also shown higher risks of nonallergic asthma in relation to air pollution exposure compared with allergic asthma,4,13 supporting the hypothesis that air pollutants stimulate nonspecific irritative rather than allergic inflammatory changes in the airways. Compared with allergic asthmatics, nonallergic asthmatics have a higher sensitivity of the nasal and bronchial epithelia to nonallergic stimuli such as air pollutants, strong smells, cold air, respiratory viruses, and others.28 Children with an allergic predisposition may spend more time indoors compared with those without an allergic predisposition, and therefore, their exposure to air pollution could differ.29
The evidence regarding effects of long-term exposure to air pollution on respiratory symptoms is limited because only a few studies have investigated the development of disease up to school age, with estimates of outdoor air pollution exposure based on small spatial scales and by timing exposure before the development of symptoms. A cohort study in the Netherlands demonstrated positive associations between levels of traffic-related air pollution at the birth address and incidence and prevalence of asthma in children who were followed up from birth until 8 years of age. (For an interquartile range difference in PM2.5 exposure at birth address corresponding to 3.2 µg/m3, the OR for prevalence and incidence of asthma was 1.26 [95% CI = 1.04–1.51] and 1.28 [95% CI = 1.10–1.49], respectively).4 The authors observed similar effects for NO2 and soot. In contrast, a Norwegian study did not find any association of either early-life or lifetime average traffic-related exposures with asthma onset or with current respiratory symptoms in 9- to 10-year-old children in Oslo (a difference in NO2 exposure during the first year of life, equivalent to 27.3 µg/m3, was associated with a risk of 0.82 [95% CI = 0.67–1.02], for doctor-diagnosed asthma onset).10 We found no overall association between average air pollution exposure after the first year of life and asthma symptoms, which could be partly attributable to declining trends in air pollution levels throughout the study period. The introduction of catalytic converters in private cars during the early 1990s, which coincided with the initiation of our cohort, led to a subsequent reduction of the emissions for several of the air pollutants—a decline that continued as older vehicles were replaced.30 In the Norwegian study with levels of outdoor air pollution comparable to those in Sweden, it has been suggested that the exposure levels might have been too low to identify notable associations with asthma symptoms.10
Our exposure assessment methodology aimed to estimate individual exposure to exhaust particles and road dust, which have fundamentally different origins and characteristics. We used NOx as an indicator for exhaust particles because NOx (or NO2) levels in the Stockholm area have been shown to correlate well with both soot31 and particle number concentrations,32 whereas PM10 mostly represents particles mechanically generated from road dust.33 For the current study, the individual exposure estimates for each study subject were obtained from a time- and space-resolved dispersion model enhanced by addition of street-canyon contribution for addresses in the most polluted street segments. Cross-validation of dispersion models against ambient measurements suggests fairly good model performance in predicting ambient concentrations of traffic-related pollutants.34 The exposure assessment was also enhanced by including not only residential addresses but also addresses of daycares and schools.
There are several limitations in this study. One is that PM10 concentrations could be calculated only for the year 2004. However, studded tire use in the Stockholm area and traffic work in the inner city have been stable during the last decades, suggesting that the emissions of PM10 may not have changed much.33 Furthermore, the influence of road moisture on the yearly variations of PM10 concentrations, which has crucial impact on PM10, could not be resolved with available data.35 In the current study, PM10 and NOx concentrations were highly correlated. Therefore, we were not able to separate the effects of these pollutants. Some misclassification of air pollution exposure is possible, partly because modeling of air pollution may give error in the exposure estimates and because outdoor exposure may not measure true personal exposure, although children (especially infants) are likely to spend most of their time in their own neighborhoods. In addition, because all traffic-related exposures were assessed independently from health outcomes and potential confounders, systematic error is unlikely, and random error would probably attenuate exposure-response associations.
Misclassification of the outcome is often an issue in studies in which asthma and wheeze are assessed by parental questionnaires, particularly in young children who have less distinctive symptoms. Furthermore, reporting could be influenced by differing diagnostic practices among doctors. Childhood asthma is not a homogeneous disease, and various phenotypes of wheeze and asthma have been defined based on prognosis, allergic status, and lung function.36,37 Questionnaire reports have generally been used in large epidemiologic studies for which more accurate diagnostics are often not feasible, and asthma is usually defined according to a certain number of wheezing episodes in the last 12 months. In young children, the term asthma is often replaced by wheezing, which may also include symptoms over time and classifications such as transient, persistent, or late-onset wheezing.38 Because many children who experience wheeze early in life will outgrow their symptoms, manifest asthma is difficult to define before school age.39 In this study, we observed the highest risk of asthma related to air pollution exposure in older children (ie, 8 or 12 years) when asthma presumably can be defined more reliably. Similar trends were also seen in the Prevention and Incidence of Asthma and Mite Allergy study, in which the strongest associations between early exposure to air pollutants and asthma were seen in 7- to 8-year-old children.4 Further studies are, however, needed to confirm that exposure to air pollutants early in life is associated with asthma development in school age.
In conclusion, the current study found a suggestion of positive overall associations between exposure to air pollution from road traffic during the first year of life and risk of respiratory symptoms in children over the first 12 years of life, with the strongest effect suggested for nonallergic asthma.
We thank all children and parents participating in the BAMSE cohort and the nurses and other staff working in the BAMSE project.
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