Ever dispense of prescribed allergy medication in children growing up close to traffic: a registry-based birth cohort

A strength of the study was the large register-based health outcome data which prevents recall and awareness bias, although other types of biases may exist due to different health-seeking behavior [11]. A strength was that most of these biases can however be reduced since we had confounder information which was used to stratify e.g., on socio-economic status. A limitation was the low power for nasal anti-allergic medication, which was inevitable since this is a rare health outcome in young age. However, that the results for the larger study population, which had more power, were the same as for the cohort with questionnaire information strengthens that there is no higher incidence of allergy in areas with high traffic pollution.

A major strength was also the exposure data in this study. Residential addresses for each year since birth were known, which exclude a migration bias which could otherwise be expected to dilute the effects. We also had validated high quality exposure data for NO_X, modeled with a high resolution, which further minimize the risk of other exposure misclassification biases which could be expected to dilute the effects. The exposure situation in the area has been described in more detail in a previous article. Mean NO_X at birth year was 17 μg/m³, and the percentile distribution was 9.2, 11.8, 17.6, 21.1, and 24.6 μg/m³ (10th, 25th, 50th, 75th, and 90th percentile). Min, Max = (6.1, 45.9) μg/m³ [7].

A limitation was that prescribed dispensed medication does not cover all allergy medication use, since some are bought over the counter without prescription. Children with dispense of prescribed allergy medication may be a highly selected subgroup [11], and the results for this group may not be generalizable to all children with allergy. However, we believe that many parents are likely to go to a doctor when their preschool children have allergic problems, and that a large proportion of young allergic children get allergy prescription compared to if allergy develops in older age when over-the-counter medication may make up a larger proportion. The validity of dispensed allergy medication as a proxy for allergy incidence might thus decrease with age, since it is likely that adults buy over-the-counter medication for e.g., allergic rhinitis without seeing a doctor, and dispensed medication may then represent a small selection with more severe disease. We believe this may become an increasing problem if the cohort is followed after early childhood. A doctor prescription is however likely to be more specific for allergic symptoms than over-the-counter medication, in all age groups, since clinical examination/anamnesis excludes infectious rhinitis as a cause.

It should be noted that the overall prescription of nasal corticosteroids in Scania has been increasing during 2006–2011 [19], something which may explain that children born in 2008–2009 had a higher incidence of nasal anti-allergics than children born earlier in this study. However, this did not affect our results since we adjusted for year of birth. Finally, it should be noted that nasal corticosteroids are not exclusively prescribed for allergic disease, but can also be prescribed e.g. for nasal polyposis.

Overall, epidemiological studies have shown conflicting results of the relation between traffic and allergy. In a review 2009 of the relation between air pollution and sensitization in four birth cohorts, three of the birth cohorts found some association with sensitization, while one did not [4]. However, there was heterogeneity both in what health outcome was associated with air pollution and also in the exposure assessment. In some of the individual studies associations have been found with inhalant exposure such as pollen [20, 21]. In other studies however, associations were mainly found with food allergens [22, 23]. In a meta-analysis by Gruzieva et al. [3], a standardized modelling technique was applied to all the four cohorts, and also a fifth cohort, and this meta-analysis found no overall association between air pollution and allergic sensitization. In a recent meta-analysis by Bowatte et al. [2], of birth cohort studies, they found that increasing exposure to PM 2.5 was associated with sensitization to both aero- and food allergens. There was also some evidence that traffic related air pollution was associated with hay fever [24].

Few have investigated the relation with allergic rhinitis in childhood, but there has been positive association in some cohorts and cross-sectional studies [20, 25‐30], while some studies have found no association [31‐36]. No other study has used medication data as a proxy for allergy in long-term studies of traffic, although medication data has been associated with short-term effects of pollen [37, 38] and to measure the relation to other risk factors [8].

We have in a previous cross-sectional study found an association with allergic but not non-allergic asthma and rhinitis in adults [16]. We however found no association with asthma medication in childhood in the present cohort [7]. We have therefore hypothesized that there may only be an association between long-term exposure to air pollution and asthma after early childhood.

For respiratory outdoor allergens such as birch pollen, it has been suggested that nitration by Nitrogen Dioxide (NO₂) and Ozone (O₃) increases allergenicity [39‐42]. Antibodies to pollen may cross-react with food allergens, but there is also support that diesel exhaust particles could block oral tolerance mechanisms and thereby contribute to food allergen sensitization per se [43].

A general theory with experimental support is that air pollution shifts Th1/Th2 response in the immune system, thereby promoting allergy development of the Ig-E-mediated type [44]. Particles can both act as immunomodulators but also as vectors for respiratory exposure, and also facilitate uptake by antigen-presenting-cells [45, 46].

In summary, there is ample evidence from experimental studies that do support a relation between air pollution and allergy, in a number of different possible ways [1, 47‐50]. However, it is also very clear that the development of allergy and sensitization is not simple, and the mechanisms for allergy development are mainly unknown. This can be illustrated by the simple fact that it has still not been established if growing up in a household with furred animals is a risk factor, or a protecting factor, for allergy [51]. No clear dose-relation between allergy development and allergen exposure has been found [52].

Our study adds to the many studies which do not support a clear relation between traffic exposure and allergy development in early childhood. However, some studies find an association. It is obvious that this relationship in case it exists, is not a simple one, and may be overridden by other risk factors.

A complicating factor is that manifest allergy is a combination of genetic factors, allergy-promoting and allergy-protecting factors, and also actual exposure to allergen. The result in this study weakly suggests that people living in areas with high levels of NO_X may even develop allergy to a lesser degree then people living in unpolluted areas. It is unlikely that traffic is a protecting factor, but more likely that actual exposure to allergen or other allergen-promoting factors differ. One factor that may differ between urban and rural areas are pollen counts, it has been shown in one study that rural areas had pollen with higher allergenicity, but a lower total level of pollen [53]. Further studies may try to get more data on local variations in pollen counts or birch-intensity in different areas. Further studies of this child cohort in older age should also try to complement with other allergy information data, since it is uncertain how good dispensed allergy medication is as a proxy since it can be bought over the counter. Using complementary measures of allergy would also be useful for result comparison, since few countries have national medication registry data, which limits the number of countries which can reproduce the present study design.