Maternal vitamin D intake during pregnancy has previously been associated with asthma symptoms in childhood epidemiologic (6
) studies, while variants in the vitamin D receptor have been associated with asthma in genetic studies (22
). To our knowledge, this is the first study to demonstrate an inverse association between circulating levels of vitamin D and markers of asthma severity and allergy. We found that vitamin D deficiency exists even in an equatorial population of children with asthma, and that lower levels of vitamin D are associated with increased odds of hospitalization for asthma, increased bronchodilator responsiveness, and increased eosinophil count and IgE levels.
Vitamin D does not naturally occur in most foods that humans eat. The primary sources of this vitamin are natural production in the skin secondary to sun exposure, and secondarily from fortified foods and supplements (24
). Although cutaneous production due to UVB radiation is considered the most important source of vitamin D, self-reported sun exposure alone is not a reliable marker of vitamin D sufficiency (25
). In fact, vitamin D deficiency has been documented in healthy subjects despite reports of abundant solar exposure in Honolulu, Hawaii (latitude 21°N) (25
), Beirut, Lebanon (latitude 33°N) (26
), and Australia (latitude 27–43°S) (27
). This is likely due to a combination of behavioral factors (e.g., sunscreen use, increased time spent indoors, and clothing coverage) and intrinsic factors such as skin melanin content, decreased cutaneous production of vitamin D3
, or increased cutaneous destruction of vitamin D3
. Vitamin D deficiency is especially problematic during winter months in more northerly populations, and unlikely to be corrected without supplements (28
). The mean daily intake of dietary vitamin D in healthy adolescents in Costa Rica is 185 IU/day (29
), which is slightly less than the recommended 200 IU/day, and much less than the 800 to 1,000 IU/day recommended for those without adequate sun exposure (20
). Our finding of insufficient vitamin D levels in 28% of asthmatic children in the Central Valley of Costa Rica (latitude 10°N) supports previous findings that deficiency occurs even in sun-replete areas of the world.
Although a definitive role for vitamin D in the pathogenesis of asthma has not been determined, vitamin D may be related to asthma severity in several ways. First, vitamin D influences the immune system through its effects on helper T cell type 1, helper T cell type 2, and regulatory T cells (30
). For example, Xystrakis and colleagues have shown that vitamin D restores the capability of regulatory T cells from steroid-resistant patients with asthma to secrete IL-10 (a potent antiinflammatory cytokine) in response to steroids (8
). Second, current vitamin D intake may influence lung function in patients with asthma, similar to its potential effects in nonasthmatics (33
), although we did not observe this in our cohort. Third, vitamin D stimulation has been shown to influence microarray gene expression signatures in bronchial smooth muscle cells. The most significantly affected pathways involved cell movement, growth, and survival, and may suggest a role for vitamin D in airway remodeling (34
). Fourth, polymorphisms in the gene encoding the vitamin D receptor (VDR
) have been associated with asthma phenotypes in two studies (22
). Of note, none of these polymorphisms resulted in an amino acid change in the translated protein, suggesting that the mechanism of increased asthma susceptibility is related to regulation of VDR
expression. Finally, vitamin D intake during pregnancy may have effects on lung growth and development in neonates (6
In our cohort, only 39% of children were receiving inhaled corticosteroids or leukotriene inhibitors, despite a socialized health care system. Although this value may be lower than what might be expected based on current guidelines (35
), it is similar to usage rates seen in Latin America (36
), Europe (37
), Asia (38
), and the United States (39
). Current evidence suggests that antiinflammatory medications are underutilized even in environments in which the ability to afford these medications is not an issue (40
), which is the case in Costa Rica. Although urgent visits for asthma were high in this population, this is because this variable includes unscheduled visits not only to emergency departments but also to a physician's office, a nebulization room, or a health care center. On the other hand, the rate of hospitalization in this cohort (5%) is similar to that seen in Europe (7%) and likely indicates a more severe asthma exacerbation (37
There is debate regarding what constitutes a normal circulating vitamin D level. Historical levels were derived from a normal distribution from humans who were presumed to be disease free (41
), but this value is believed to be inaccurate as these individuals are likely sun deprived because of confounding factors such as clothing, sunscreen, and skin pigmentation (16
). Other biomarkers such as parathyroid hormone, bone mineral density, and calcium absorption have been proposed as adjuvant studies to determine vitamin D sufficiency as it relates to bone health. These studies suggest that vitamin D deficiency occurs at 25(OH)vitamin D levels less than 32 ng/ml (15
). Still others categorize 25(OH) vitamin D less than 20 ng/ml as deficient, from 20 to less than 30 ng/ml as insufficient, and 30 ng/ml or more as sufficient (19
). In our analyses, we used vitamin D levels mostly as a continuous variable, except for the analyses presented in . It should be stated again that these cutoffs for vitamin D levels were determined with overall bone health in mind. In terms of non–bone-related outcomes and in particular for asthma and other atopic disorders, there are still insufficient data to determine an optimal level for prevention of exacerbations.
This cohort includes cases only, because of its original design as a family-based genetic study. Without a control group we are unable to make inferences regarding incident asthma. Although the role of vitamin D in the prevention of incident asthma is an interesting area for future research, on the basis of earlier studies we suspect that vitamin D influences the development of asthma at a much younger age, or even prenatally (6
). Therefore, we think the proper study design for that research question would be a birth (or prebirth) cohort study or clinical trial. A clinical trial of vitamin D supplementation given to pregnant women to prevent asthma in their offspring has been funded (HL091528).
We cannot establish causality of increased asthma morbidity due to low vitamin D levels because of the cross-sectional design of our study. A plausible alternative explanation for the observed association is that subjects with more severe asthma are likely to spend more time indoors, and therefore have lower vitamin D levels. However, most of the observed associations between vitamin D levels and markers of allergy and asthma severity remained significant and/or were only slightly attenuated after controlling for other markers of disease severity such as use of antiinflammatory medications and measures of airway responsiveness.
Another possible alternative explanation is that higher vitamin D levels reflect a higher intake of dietary vitamin D, which may be correlated with the intake of other nutrients that may modify asthma severity, such as vitamin E. Although we do not have nutritional information for these children, an earlier nutritional survey of adolescents in San José showed that the mean vitamin D intake was below recommended guidelines (29
), suggesting that the primary source of vitamin D in this study population is sun exposure. In a different study, the effect of maternal vitamin D intake during pregnancy on subsequent wheezing by their children was independent of maternal intake of vitamin E, zinc, and calcium (7
). Higher vitamin D intake may also be related to socioeconomic status (SES). We adjusted for an indicator of SES (parental education) in all our analyses. Although there could be residual confounding of our results by SES, Costa Rica has a socialized health care system and a high literacy rate, both of which should reduce potential confounding by health care disparities related to SES.
In summary, we found a strong inverse relationship between circulating levels of vitamin D and several markers of allergy and asthma severity. Our data suggest that additional work needs to be done to determine the potential beneficial role that vitamin D might play, if any, in established human allergy and asthma. These studies should include in vitro and animal studies to further elucidate the mechanisms for the role of vitamin D, and eventual clinical trials of vitamin D supplementation to prevent exacerbations. In addition, common polymorphisms in the vitamin D receptor and other genes in the vitamin D pathway should be further characterized, especially as they relate to circulating vitamin D levels and asthma severity.