In an ED-based cohort of FA patients in Boston, we found that birth in fall or winter was associated with FA in children aged <5 years but not in older age groups. This rather simple but novel finding expands on the known risk factors associated with development of FA. In prior studies we have observed that a higher absolute latitude – in both northern and southern hemispheres – is a risk factor for FA/anaphylaxis as measured by rates of epinephrine autoinjector prescriptions,12, 13
anaphylaxis admissions,12, 13
and infant hypoallergenic formula prescriptions.14
Sheehan and colleagues recently expanded on this work by describing a similar association between latitude and food-related anaphylaxis admissions in US children.23
Taken together, these findings suggest a potential role for UVB exposure and/or vitamin D insufficiency in the pathogenesis of FA in children. Although we are confident of the SoB-FA association in our cohort, we readily acknowledge that other factors such as infections, maternal and infant dietary patterns, and exposure to indoor pollutants may contribute to FA pathogenesis and the observed seasonal patterns. Lessening the likelihood of these factors being the dominant explanation for the influence of SoB is that unlike vitamin D, none has been as closely linked to risk of atopic diseases. Additional studies will be necessary to address this specifically.
To examine the robustness of our finding, we examined the SoB-FA association in several subgroups. Although statistical power was limited, we identified a consistent association in patients <5 years presenting with an acute allergic reaction attributed to a suspected food allergen trigger. We recognize that children classified under a specific allergen (e.g., milk) might also be allergic to another food (e.g., concurrent peanut allergy) and this may biologically underly the presenting food allergic reaction. Confirmatory testing was not a feasible and part of this study and the present study cannot rule-out that the SoB-FA finding is more (or less) important for particular food allergens. The presence of co-morbid allergic conditions did not influence the SoB-FA ratio of ~40% vs. ~60% of light/dark season births in patients <5 years.
Interestingly, the only association of SoB in adult FA patients was in the group reporting a concomitant diagnosis of asthma. This raises the possibility that there may be an extended influence of UVB exposure and/or vitamin D insufficiency on the pathogenesis of lifelong asthma per se12, 13
– a topic that goes beyond the scope of this report. FA can develop during adulthood and it is possible that late-onset FA has a different pathogenesis than that seen in children. However, the general absence of a SoB-FA association in adults does not exclude a role for UVB/vitamin D in development of FA in adulthood.
An association of SoB and risk of disease years later is not unprecedented. For example, SoB has been linked with risk of several immune-mediated diseases including multiple sclerosis and Crohn's disease in adults.25, 26
In addition, risks of multiple sclerosis and Crohn's disease have also been associated with latitude, further implicating a role of UVB and vitamin D in these conditions.25, 27
Birth month has been associated with risk of atopic dermatitis, recurrent wheezing and aeroallergen sensitization in childhood, suggesting that exposure to seasonal allergens in an early developmental period may contribute to the development of atopic disease.28-31
Of particular relevance to our study is an association between birth in fall or winter and food allergen-specific IgE in children less than one year of age.32, 33
In a population of infants at high risk for atopic diseases fall/winter birth was associated with elevated cord blood total IgE levels, and increased IgE levels in cord blood were in turn associated with a > 3-fold incidence of urticaria due to FA by twelve months of age.34
We speculate that vitamin D may be the factor that mediates the observed association between SoB and childhood FA as there is inadequate UVB intensity for synthesis of active vitamin between the months of November and April in Boston.35
Studies have observed associations between vitamin D receptor polymorphisms and risk of atopic disease.36, 37
The mechanisms by which vitamin D could contribute to the prevention of FA include the promotion of maturation from the natural Th2 bias of the newborn, development of the adaptive immune system, effective management of infections, and healing of inflamed tissues. Vitamin D is known to have immunomodulatory effects on both Th1 and Th2 responses and affect production of the tolerogenic cytokine IL-10.18, 38
Birth in low UVB exposure months has been associated with lower cord blood levels of vitamin D and the tolerogenic cytokine IL-10.39, 40
Our study has several potential limitations. The analysis was cross-sectional and not longitudinal which limited the amount of information available to us. With >1,000 total subjects, and a P value of 0.002 for light/dark seasons in the primary group of interest (children <5 years), we believe that the findings are not due to chance. The absence of a detectable association in many patients (FA patients >5 years), and absence of a fall/winter finding in three control groups, reinforces that our methods are sound and that the results are not due a systematic study error.
Similar to other cross-sectional studies of FA, this study was not designed to gather confirmatory information on specificity of food-allergen trigger or actual number of specific food allergies in patients. Such information could be gathered in future studies by evaluation of specific IgE antibodies, skin prick testing and double blind-placebo controlled challenges. It is possible that a fraction of cases were in actuality not food-related but these would have been a minority and their inclusion would be expected to obscure, rather than create, an association. Our approach identified a relatively “pure” cohort of FA cases but information in the medical record was subject to limitations related to documentation (such as the condition of asthma is more likely to documented by an ED provider than, for example, hay fever).
The slight excess of summer births in the control groups was consistent with a national trend of slightly more births in the summer.41
Combining month of birth into seasons and light/dark groups was necessary for statistical analysis. We acknowledge that these are broad time periods but implemented grouping based on actual seasonal UVB exposure in the Boston area.42
It would be expected that any artifactual impact of such grouping would be to mask an association rather than expose one. It is possible that the pre-specified age groups may obscure additional information but doing so was necessary to permit sufficiently powered calculations and, as noted for the grouping of birth months and seasons, are unlikely to create an association.
We identified a large number of FA patients seeking care in the ED and believe them to be representative of FA patients in general. Even though a large percentage of patients met criteria for food-related anaphylaxis, the magnitude of the association of SoB was similar to that observed in patients that did not meet criteria for anaphylaxis. To more broadly apply our findings, it will be helpful to replicate this study in other populations and at different global latitudes. Our vitamin D-FA hypothesis assumes that patients in this study born in fall or winter have lower vitamin D levels or predicts a trajectory of low vitamin D levels. Additional studies will need to pursue this specifically. The strong influence of season on vitamin D status in Boston20
suggests that our inference is sound. With regards to vitamin D contributing to the trend of increasing FA, data in adults (which is likely reflective of children) suggests that vitamin D insufficiency in the U.S. has become more common over the past 20 years.43
Examination of the role of vitamin D could be addressed by future studies designed to measure serum 25-hydroxyvitamin D levels at different developmental time periods and make assessments of food-specific IgE antibodies, skin prick testing, clinical FA and ex vivo
immune system function.
In summary, we found that birth in fall/winter was 50% more common among children <5 years with FA compared to birth in spring/summer. This finding adds to an increasing body of evidence that UVB exposure and/or vitamin D insufficiency may be involved in the pathogenesis of FA. Our findings, combined with the current understanding of risks of atopy, suggest that dysfunction during critical periods of immune system development may have persistent consequences. The model of UVB/vitamin D insufficiency contributing to development of an atopic phenotype suggests a potential opportunity for primary prevention. However, until results are available from prospective randomized controlled trials that formally test the vitamin D-FA hypothesis, it would be premature for parents to disregard current policies regarding safe sun exposure or to increase vitamin D intake for the specific prevention of food allergy.