We found consistent associations between vitamin D deficiency and the presence of allergies in children and adolescents. While there were some protective associations between 25(OH)D deficiency and allergic sensitization in adults, these were not as consistent as in children. This is the first large study evaluating a relationship between 25(OH) D levels and allergic sensitization.
Vitamin D and its immunologic functions have been implicated in a variety of inflammatory and allergic diseases. The anti-inflammatory mechanism of its action has been thought to be due to the suppression of antigen-dendritic cell mediated Th1 response and proliferation [20
], macrophage activation [21
] and cytokine expression such as IL-2 [23
]. An analysis of birth month in patients presenting to the emergency department showed that birth in the fall or winter, when vitamin D levels are lowest, was associated with a higher risk of presenting with food-related acute allergic symptoms.[24
] In a recent study, Sidbury et. al. randomized 11 patients with atopic dermatitis to ergocalciferol 1000 IU or placebo daily for 1 month and found that more children on vitamin D had an improvement in their Investigator’s Global Assessment score [25
]. The same investigators found an association between vitamin D deficiency and atopic dermatitis in obese individuals [26
]. The active form of vitamin D, 1,25-dihydroxyvitamin D3, induces expression of antimicrobial peptides like cathelicidin that may prevent skin infection [27
]. Additionally, vitamin D also down-regulates effector T cell activity and inhibits T cell proliferation and IL-2 production as referred to earlier. Furthermore, topical Vitamin D application has been observed to lead to the expansion of antigen-specific T regulatory cells [28
]. Recent studies have suggested a link between asthma and low vitamin D levels [29
] although further work is necessary in order to provide more evidence. There are currently several ongoing clinical trials (clinicaltrials.gov identifiers: NCT00856947
, NCT00920621) that are investigating the use of vitamin D to improve asthma and allergies, and thus trial data should be forthcoming in the next few years.
The current study assessed whether serum levels of 25(OH)D were related to the prevalence of allergic sensitization. Past studies have shown a non-linear, U-shaped association between low and high vitamin D with increased serum total IgE levels [32
]. We found that in children and adolescents, there was a trend towards higher IgE levels in those with 25(OH)D levels <15 ng/mL compared to ≥30 ng/mL. There are not many participants of NHANES 2005–2006 with high (>40 ng/mL) 25(OH)D levels which may be the reason we did not see a U-shaped association. However, there were more associations present when analyzing the data in 25(OH)D categories compared to as a continuous variable, which suggests either a threshold effect or a U-shaped relationship.
Our results show that children with vitamin D deficiency are more likely to have allergic sensitization to various allergens, both food and environmental. Recent reviews have discussed the possible mechanisms by which Vitamin D is implicated in the regulation of allergic responses [23
], mostly by inhibition of the inflammatory response of innate immune cells. Two smaller, observational studies show results similar to those we present. A large cross-sectional study of asthmatic children in Costa Rica showed that 25(OH)D levels were inversely associated with total serum IgE levels and with dust mite sensitization. [30
] A smaller study of approximately 100 asthmatic children also showed an unadjusted inverse relationship between 25(OH)D levels and total serum IgE and aeroallergen skin tests.[31
] It should be noted that many of the associations found in the unadjusted linear regression were attenuated or disappeared after adjusting for confounders.
It is unclear why associations between 25(OH)D deficiency and allergic sensitization was seen in children and adolescents but not in adults. We found that children and adolescents were more likely to have IgE sensitization to allergens. Previous studies have found that food allergies in children have increased 18% between 1997 and 2007 [13
]. If most food allergies start in childhood, 25(OH)D levels closer to the initiation of the allergy (still in childhood and adolescence), may be more reflective of the vitamin D status at the time of allergic sensitization. In adults, if the allergies started in childhood, levels of 25(OH)D in adulthood may not be reflective of 25(OH)D status at the time of allergic sensitization. It may also be that different mechanisms are responsible for allergic sensitization in adults versus children and adolescents [33
Vitamin D deficiency and insufficiency, although common in children in the US, has been shown to have racial/ethnic predispositions in some groups. Two recent studies have explored prevalence data within the NHANES surveys [7
], and demonstrated that Hispanic and Non-Hispanic black children are at higher risk for deficiency. Hispanic ethnicity was found to be associated with higher cord blood IgE levels in a screening birth cohort of 874 infants in Boston, MA [35
]. Total and allergen-specific IgE has been shown to be consistently higher among those of non-Hispanic black race [36
]. Yang et al. noted that although this might be due to environmental factors such as urban/rural residence, self-reported race continues to be a strong predictor of allergic sensitization [38
]. The prevalence of both vitamin D deficiency and increased atopy in these groups should be explored with future epidemiologic studies.
This study has several limitations, including its cross-sectional design, limiting the determination of causality for the observed atopic differences with vitamin D deficiency. As in any observational study, there are probably measured and unmeasured confounders for which we did not adjust. Notably, IgE levels and allergic symptoms vary by season and geographic location,[39
] both important potential confounder which we did not have available. NHANES samples northern states in the summer and southern states in the winter in order to ensure comparable conditions. Therefore, vitamin D levels may be underestimated and because of the geographic differences in allergies, there may be residual confounding. Another limitation is that we did not adjust for multiple comparisons because of the exploratory hypothesis generating nature of this analysis. However, our study maintains many strengths including information on several thousand participants who are representative of the general US population. The consistent associations between low 25(OH)D levels and most allergens tested in children and adolescents suggests that further research is warranted in this area.
In this nationally representative population, we found consistent associations between 25(OH)D deficiency and a higher prevalence for 11 out of 17 allergens tested in children and adolescents. These associations were not seen in adults. The prevalence of both allergic symptoms and vitamin D deficiency are increasing in the United States, and this study suggests these two phenomena may be linked.