A longitudinal analysis of associations between traffic-related air pollution with asthma, allergies and sensitization in the GINIplus and LISAplus birth cohorts

Introduction

The rapid rise in asthma and allergic diseases in recent decades suggests a role for environmental factors. Whether traffic-related air pollution (TRAP) contributes to the development of childhood asthma, allergy and related symptoms has been the topic of several studies. Although a review in 2010 concluded that the evidence of an association between TRAP and asthma onset and prevalence remains insufficient to infer a causal relationship (Tager et al., 2010), support for this association continues to build, including from genetic and gene-environment studies (Carlsten & Melén, 2012; Holloway et al., 2012). The evidence for other non-asthma allergic phenotypes, such as allergic rhinitis, eczema and aeroallergen sensitization, is generally weaker (Fuertes et al., 2013; Tager et al., 2010).

Several epidemiological studies have examined the link between air pollution and allergic diseases in children in early life (Clark et al., 2010; Morgenstern et al., 2007; Brauer et al., 2002; Gehring et al., 2002) and childhood (Carlsten et al., 2010; Morgenstern et al., 2008; Nordling et al., 2008; Brauer et al., 2007; McConnell et al., 2006). All of these aforementioned studies report positive associations with at least one respiratory or allergic health outcome, despite the challenges associated with accurately assessing air pollution exposure levels and allergic health status in young children. A study on older children (10–11 years) found no association between TRAP and general sensitization, although sensitization to house dust mites was associated with lifetime air pollution exposure (Oftedal et al., 2007). Two recent large cross-sectional multi-center European studies found no clear association between individually assigned TRAP exposures and asthma or wheeze at four to five and eight to 10 years in approximately 10,000 children (A Mölter, A Simpson, D Berdel, B Brunekreef, A Custovic, J Cyrys, J de Jongste, F de Vocht, E Fuertes , U Gehring, O Gruzieva, J Heinrich, G Hoek, B Hoffmann, C Klümper, M Korek, T Kulbusch, S Lindley, D Postma, C Tischer, A Wijga, G Pershagen, R Agius, unpublished data) and sensitization at four to six and eight to 10 years in approximately 7,000 children (Gruzieva et al., in press).

Only two longitudinal epidemiological analyses incorporating health data from birth up to eight years of age have been conducted. Gehring et al. (2010) reported positive associations between TRAP and the incidence and prevalence of asthma and the prevalence of asthma symptoms in a study of 3,863 Dutch children (Gehring et al., 2010). Positive associations were also found for allergic rhinitis, but only among non-movers. No associations were found for sensitization at eight years, despite a previous positive finding at four years in this same cohort (Brauer et al., 2007). Gruzieva et al. (2012) also found no association between TRAP and allergic sensitization at eight years in a Swedish birth cohort (Gruzieva et al., 2012), again despite a previous documented association at four years of age (Nordling et al., 2008). These results may suggest that the timing of air pollution exposure is important. This hypothesis, as well as the long-term impact of air pollution on allergic disease prevalence in later childhood, is best explored in the context of longitudinal birth cohorts (Bråbäck & Forsberg, 2009).

Recently, the 10 year follow-ups of the “German Infant study on the influence of Nutrition Intervention plus environmental and genetic influences on allergy development” (GINIplus) and “influence of Life style factors on the development of the Immune System and Allergies in East and West Germany plus the influence of traffic emissions and genetics” (LISAplus) birth cohort studies were completed. These studies are unique in their long-term and frequent follow-up, large sample sizes, extensive health, demographic and lifestyle information, as well as the availability of air pollution estimates at different time points during life (birth, six and 10 years). Previously published results from these cohorts suggest a possible adverse role of TRAP on symptoms before the first two years of life (Morgenstern et al., 2007; Gehring et al., 2002) and several allergic outcomes at six years (Morgenstern et al., 2008) for children living in the Munich (GINI/LISA South) area. In the northern part of these cohorts (Wesel area, GINI/LISA North), associations were found only with the prevalence of eczema (Krämer et al., 2009). The current study builds on these past efforts by examining whether nitrogen dioxide (NO₂), particles with aerodynamic diameters less than 2.5 µg/m³ (PM_2.5) mass, PM_2.5 absorbance and ozone concentrations, the latter of which has not been previously considered in the context of the GINIplus and LISAplus studies, are associated with the prevalence of asthma, allergic rhinitis and aeroallergen sensitization among children followed for 10 years in three areas in Germany.

Methods

Results

In total, 6,604 children had available information on at least one health outcome and air pollutant, 3655 of which also had available sensitization data at one time point (flow chart of study population provided in Fig. S1). Population characteristics and the prevalence of health outcomes at the age of 10 years are provided for the total population and by study area (Table 2), and for the subset of children who provided blood samples that were assessed for aeroallergen sensitization (Table S1).

Compared to the original cohorts, children included in this study and the subset who provided blood samples were less likely to have been exposed to furry pets early in life or to have moved at least once between birth and 10 years, but more likely to have participated in the nutritional intervention (GINIplus participants only) and to have a parent with more than 10 years of education and a history of atopy. Furthermore, the children included in the main analyses were less likely to have been exposed to smoke in utero. The subset of children who provided blood samples were less likely to have been exposed to tobacco smoke in utero and during early life (1–4 years) or later childhood (6–10 years).

Distribution of outcomes

The period prevalences of doctor diagnosed asthma and allergic rhinitis are presented in Fig. 1. In the total population, the annual prevalence of doctor diagnosed asthma and allergic rhinitis ranged from 1.1% to 3.5% and from 1.6% to 10.0%, respectively. The distribution of doctor diagnosed asthma and allergic rhinitis prevalence across areas was similar. Only at age nine and 10 were the rates of doctor diagnosed allergic rhinitis significantly different across areas. The pooled prevalence of reported eye and nose symptoms rose steadily with age and differed by area (3.7%, 6.8% and 13.3% for ages four, six and 10 years, respectively), as did the prevalence of aeroallergen sensitization (29.0% and 40.2% for ages six and 10 years, respectively). The prevalence of eye and nose symptoms and aeroallergen sensitization was highest in GINI/LISA South and lowest in GINI/LISA North at almost all ages.

Discussion

In a longitudinal analysis of two German birth cohorts followed for 10 years, we did not find consistent evidence that TRAP exposure increases the risk of asthma, allergic rhinitis or aeroallergen sensitization in later childhood. The risk estimates for children living in two of the areas investigated (GINI/LISA North and LISA East) were null or elevated and those for the third (GINI/LISA South) tended to be below one. Given the heterogeneous area-specific effects, the risk estimates for the total population were inconclusive.

The factors driving the differing associations observed across areas are unknown. The sources of pollutants which likely differ by area may be one explanation; air pollution in all three areas is predominantly attributable to traffic-sources but industry also contributes to air pollution levels in GINI/LISA North (Beelen et al., 2013; Eeftens et al., 2012a). It is also possible that residual confounding may be influencing the results. We attempted to adjust for individual-level socio-economic status using parental education as a proxy in the final models, and marital status at the time of birth and household income per person (calculated according to Sausenthaler et al., 2011) in sensitivity analyses, but these indicators may be imperfect markers of socio-economic factors. Socio-economic data at the neighborhood level is not available for a large proportion of participants, but has been shown not to strongly influence associations between air pollution and allergic outcomes in recent cross-sectional multi-center European studies (A Mölter, A Simpson, D Berdel, B Brunekreef, A Custovic, J Cyrys, J de Jongste, F de Vocht, E Fuertes , U Gehring, O Gruzieva, J Heinrich, G Hoek, B Hoffmann, C Klümper, M Korek, T Kulbusch, S Lindley, D Postma, C Tischer, A Wijga, G Pershagen, R Agius, unpublished data, and Gruzieva et al., in press). Effect estimates also remained robust upon adjustment for surrounding green space and population density.

The overall null findings reported here for the total population are in line with those of two large recent multi-center European studies on asthma (A Mölter, A Simpson, D Berdel, B Brunekreef, A Custovic, J Cyrys, J de Jongste, F de Vocht, E Fuertes , U Gehring, O Gruzieva, J Heinrich, G Hoek, B Hoffmann, C Klümper, M Korek, T Kulbusch, S Lindley, D Postma, C Tischer, A Wijga, G Pershagen, R Agius, unpublished data) and sensitization (Gruzieva et al., in press), in which GINI/LISA South and GINI/LISA North were included. The current work differs from these previous studies in several respects. The current study uses a longitudinal analytical approach to optimize the use of the long-term prospectively collected health outcome data from three to 10 years, whereas the previous two studies examined cross-sectional associations at two time points. Furthermore, the two multi-center studies did not include the LISA East area, nor were allergic rhinitis or nose and eye symptoms considered as outcomes or ozone as an air pollutant. With respect to studies with a long-term longitudinal design, our findings for the total study population are in contrast to the positive associations observed between TRAP and asthma, as well as allergic rhinitis among non-movers, in a Dutch birth cohort followed for eight years (Gehring et al., 2010), but in line with the null associations for sensitization found in this Dutch cohort and in a similar Swedish birth cohort followed for eight years (Gruzieva et al., 2012).

The area-specific findings reported for the GINI/LISA North area are generally in line with a previous study in this area which examined associations with outcomes up to six years of age (Krämer et al., 2009). For GINI/LISA South, the current findings are more challenging to reconcile with those reported for outcomes up to six years of age (Morgenstern et al., 2008). The sample sizes differ slightly between this previous and the current analyses (3577 and 3941 children included, respectively), the definitions were not identical for all outcomes and there were some differences in the methodologies of the exposure assessment. In the previous work, exposure estimates were derived using a LUR model developed as part of the TRAPCA project (Brauer et al., 2003). This initial model was subsequently applied to the GINI/LISA South metropolitan area (TRAPCA II), which includes the city of Munich and the surrounding districts (Morgenstern et al., 2007). Exposure estimates derived from this TRAPCA II model were significantly positively associated with several health outcomes at six years among GINIplus and LISAplus participants living in GINI/LISA South (Morgenstern et al., 2008). In contrast, the current analysis for this area, which yielded null or negative associations, is based on estimates derived from a different LUR model developed almost a decade later as part of the ESCAPE collaboration. The ESCAPE models explain more variation than the TRAPCA II models and the root-mean standard errors of the ESCAPE models are lower than for TRAPCA II. The distribution of PM_2.5 mass and absorbance concentrations are similar between the two datasets, however, the NO₂ estimates are lower in the more recently derived ESCAPE dataset. The lower estimated NO₂ concentrations may reflect true decreases as the air pollution measurements for the ESCAPE models were taken a decade after those for the TRAPCA models and actual air pollution levels have decreased in GINI/LISA South during this time.

To date, very few studies have reported on associations with ozone. In the current study, results were generally non-significant, with only two positive associations found for LISA East. A few factors may have hindered our ability to detect consistent associations. First, the resolution of the database (1 × 1 km) used to estimate ozone concentrations to the home address was lower than for the other pollutants. Second, as the spatial distribution of ozone is more even than for other pollutants, with the exception of areas very close to traffic, detecting true associations may be more difficult. Third, ozone concentrations are likely higher in rural areas compared to areas with greater traffic densities. However, effect estimates remained similar when the analyses were stratified into the inner city of Munich and surrounding areas (for GINI/LISA South) or when those not living in the city area were excluded (for GINI/LISA North).

Although the present work is among the very few studies which can utilize such a rich and large longitudinal dataset, certain limitations should be acknowledged. Participation bias is always a concern for cohorts with a long follow-up. Children included in this study differed from those in the initial birth cohort with regard to several characteristics and this non-random retention of participants may have affected the effect estimates. Of the 9086 children who were recruited in the GINIplus and LISAplus cohorts at birth, 5078 participated in the 10 year follow-up (55.9%). Outcome misclassification is also a concern when analyzing data collected by questionnaires, but objective measures of aeroallergen sensitization were available for 55.3% (3655/6604) of the study population. No systematic differences between the results for the three parent-reported outcomes and the objective aeroallergen sensitization outcome are apparent. Furthermore, a positive response for asthma and allergic rhinitis was based on a parental-report of a doctor diagnosis and not only on a report of symptoms. The responses at the older ages are also likely more accurate as allergic disorders are easier to diagnose in later childhood. Finally, the data used to inform the LUR regression models for GINI/LISA South and North were collected approximately a decade after the commencement of the birth cohorts (∼ five years for LISA East) under the implicit assumption that the spatial variability in air pollution estimates would not have changed since the baseline periods of the cohorts. Three studies provide evidence supporting this assumption for NO₂ over a period of seven to twelve years (Wang et al., 2013; Cesaroni et al., 2012; Eeftens et al., 2011).

A greater importance of early-life exposures has been hypothesized as a possible explanation for why positive associations with TRAP and sensitization have been found at four years of age but not at eight years in a Swedish birth cohort (Gruzieva et al., 2012), a finding that was also observed in a Dutch birth cohort (Gehring et al., 2010). One previous study has considered the relative importance of TRAP exposure timing and reported that NO and PM₁₀in utero exposures have an independent effect from post-birth exposures, although it was not possible for the authors to conclude which period may be most important (Clark et al., 2010). Similarly, the high correlation between exposures at birth and those at six and 10 years in the current study rendered it challenging to disentangle the effects of these distinct exposure periods.

Although we conducted several sensitivity analyses to reduce potential moving-related exposure misclassification and noted no changes in the results, it is possible that some exposure misclassification remains, especially at the older ages when children spend a larger proportion of their time at school. However, a Swedish and French study showed that exposures from traffic assessed at the home address are good approximations of those at schools, possibly because schools tend to be located in the close vicinity of homes (Gruzieva et al., 2012; Reungoat et al., 2005). Additionally, a study conducted in the United States found little differences between time-weighted averages of diesel exposures estimated at all addresses where a child spent more than eight hours per week and those estimated only at the home address (Ryan et al., 2008).

Conclusions

We did not find consistent evidence that TRAP increases the risk of childhood asthma or allergic diseases in later childhood using data from German birth cohort participants followed for 10 years. Heterogeneous results were noted across the three geographical areas investigated.

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