Although recent guidelines from the Institute of Medicine recommend supplementation with vitamin D only for prevention of bone-related diseases, there is accumulating evidence that vitamin D deficiency is implicated in respiratory disease.
In a recent issue of The Journal of Allergy and Clinical and Immunology (JACI), Keet et al. assessed the relationship between serum vitamin D levels and self-reported wheeze and asthma in a large nationally representative survey (the National Health and Nutrition Examination Study 2005-2006).
Among 6,857 subjects, they found that lower serum vitamin D levels were associated with higher risk of both wheeze and asthma. Delving deeper, they report novel interactions between both age and atopic status and the relationship between vitamin D and wheeze.
In their findings, the relationship between wheeze and lower vitamin D levels was age-dependent, with a much stronger association in older subjects. In addition, although vitamin D deficiency has been associated with higher total IgE, the relationship between vitamin D and wheeze was independent of IgE levels, and was in fact stronger in non-atopic subjects. These findings suggest that vitamin likely affects respiratory health through multiple mechanisms, and underscore the need for more research in this area.
The role of vitamin D in a myriad of physiologic processes has recently become a focus of controversy. Growing evidence suggests a role for vitamin D in the regulation of IgE and the development of allergic sensitization, as well as in lung development, incident asthma, and asthma exacerbation, although the studies are not all consistent.1-3 Despite these data, the Institute of Medicine recently reviewed the literature about vitamin D and concluded that there were insufficient data to recommend supplementation with vitamin D for the prevention of non-bone-related diseases.4 Here we use nationally representative data from the National Health and Nutrition Examination Survey (NHANES) to assess the relationship between vitamin D levels and respiratory outcomes.
Study participants included 6857 US subjects 6 years of age and older who participated in NHANES 2005-2006, as discussed in the Methods section and Table E1 of this article's Online Repository at www.jacionline.org. The relationships between serum vitamin D levels and wheeze, history of asthma, and asthma exacerbation were assessed by means of logistic regression in analyses that accounted for the complex survey methods and were adjusted for age, sex, race/ethnicity, household income, and body mass index (BMI) z score. Analyses were performed with STATA 11.0/SE (StataCorp, College Station, Tex) and R 2.12.2 (R Foundation, Vienna, Austria) software.
Serum vitamin D levels were inversely associated with both current wheeze and asthma in adjusted analyses (Table I and see Table E2 in this article's Online Repository at www.jacionline. org). Each 10 ng/mL decrease in vitamin D level was associated with a 26% greater odds (odds ratio OR, 1.26 95% CI, 1.091.46) of current wheeze and an 8% greater odds of asthma (OR, 1.08 95% CI, 1.01-1.16). Among those with asthma, lower vitamin D levels were associated with increased odds of both emergency department visit and exacerbation in the past year (OR for each 10 ng/mL decrease in vitamin D level: 1.53 95% CI, 1.01-2.32 and 1.38 95% CI, 1.06-1.80, respectively; see Table E3 in this article's Online Repository at www.jacionline. org). Results relating to asthma are described in more detail in the Results section in this article's Online Repository at www. jacionline.org.
The association between a lower vitamin D level and wheeze was similar for asthmatic and nonasthmatic subjects (P = .37 for interaction term). The higher odds of current wheeze associated with lower vitamin D levels was driven by a strong inverse relationship between vitamin D level and current wheeze in older subjects (P = .007 for interaction term, Table I, Fig 1). This was not due to a stronger relationship between vitamin D level and wheeze in patients who reported chronic obstructive pulmonary disease (COPD; OR per 10 ng/mL vitamin D: 1.23 95% CI, 1.02-1.55 for those with COPD and 1.32 95% CI, 1.13-1.55 for those without COPD). Nor was the vitamin D effect among older subjects on current wheeze caused by smoking: the relationship between vitamin D level and wheeze was similar in current, former, and never smokers (ORs of 1.28 95% CI, 1.04-1.57, 1.35 95% CI, 1.03-1.81, and 1.24 95% CI, 0.88-1.74, respectively, for every 10 ng/mL decrease in vitamin D level).
In addition to age, there was a suggestion that the relationship between vitamin D level and current wheeze was also modified by atopy and total IgE level, with a stronger relationship found in nonatopic subjects and among those with lower IgE levels (P = .096 and .08 for the interaction between vitamin D level and atopy and total IgE level, respectively; Table I). Moreover, the relationship between vitamin D level and wheeze was not mediated by either atopy or total IgE level (see Table E4 in this article's Online Repository at www.jacionline.org).
In this broadly representative sample of the US population, lower serum vitamin D levels were associated with increased risk of current wheeze, and this relationship varied by age, suggesting an age-dependent relationship between vitamin D level and wheeze that has not previously been reported. In addition, although vitamin D deficiency is known to be associated with higher total IgE levels in this population,5 the vitamin D/wheeze
TABLE I. Recent wheeze by vitamin D status and group
Wheeze in past year
Category of Unstratified _Age >50 yAtopicHistory of asthma
vitamin D model No (5049) Yes (1808) No (3530) Yes (3327) No (5959) Yes (998)
OR (95% CI) >30 ng/mL 1 by definition
for trend 10 ng/mL
decrease in vitamin D
P value for interaction .007 .097 .37
All analyses are adjusted for age, sex, race/ethnicity, income, and BMI z score. Boldface type indicates statistically significant ORs.
FIG 1. Three-dimensional representation of the predicted probability of wheeze by vitamin D level and age by means of logistic regression. Predicted probabilities of wheeze at a given age and vitamin D level are specified for white female subjects of mean income and BMI zscore. Age is in years and vitamin D level is in nanograms per milliliter.
relationship found here was independent of total IgE level and atopy, implying that vitamin D protects against wheeze by means of a mechanism other than the downregulation of IgE. Indeed, we found that wheeze might be more strongly associated with vitamin D level in nonatopic subjects and those with lower total IgE levels. Taken together, our findings highlight the complexity of the relationships between vitamin D level and respiratory and allergic diseases, suggesting that vitamin D likely modifies respiratory disease risk through multiple mechanisms that manifest as pleiotropic and age-dependent effects.
There are several potential mechanisms to explain the relationship between vitamin D level and wheeze and why vitamin D deficiency might be a stronger risk factor for wheeze in those without atopy and in older persons. The first is that a low vitamin D level is a risk factor particularly for respiratory tract infection. Data from both animal models and human subjects support this hypothesis. Vitamin D directly and indirectly induces production of antimicrobial proteins and has other antimicrobial effects.2,6 In human subjects relative vitamin D deficiency has been associated with recent respiratory tract infection and viral infection accompanying wheeze, and in small interventional studies vitamin D supplementation provided some protection against respiratory tract infection prospectively.2,7 Alternatively or additionally, vitamin D might protect against inflammatory reactions to environmental pollutants and might be broadly important in regulating chronic inflammation in the lung.3 Finally, accumulating evidence suggests a role for vitamin D in lung development; vitamin D deficiency in early life might lead to permanent susceptibility to poorer respiratory outcomes that are not related to atopy.8 Each of these causes of wheeze could be more important in older persons and nonatopic subjects; wheeze in younger persons might be more likely to be related to allergy than it is in older persons. However, because the mechanistic rationale is not entirely clear, this novel finding should be replicated before definitive conclusions can be made.
Ultimately, cross-sectional studies such as this are only a first step in understanding the causal relationships between vitamin D levels and respiratory outcomes. Because data are collected simultaneously on all variables, it is not possible to determine temporal relationships between exposure and outcome. In addition, because vitamin D levels are closely related to both diet and outdoor activity and might be related to socioeconomic status in ways not fully accounted for by the adjustments here, there is potential for unmeasured and residual confounding to complicate the relationships that were evaluated. With those caveats in mind, the strength of this study is that it is of a nationally representative sample of the US population, and the findings extend our current understanding of the role of vitamin D in respiratory and allergic diseases.
In sum, our findings point to a strong protective effect of vitamin D against wheeze and asthma exacerbation in a nationally representative study population, supporting the notion that vitamin D status might influence the risk of respiratory disease. In light of the known association between vitamin D and IgE levels, our findings that the vitamin D/wheeze relationship was strongest for nonatopic subjects and older subjects suggest that vitamin D might modify the risk of allergic and respiratory disease through multiple mechanisms. Taken together, these findings underscore the importance of conducting prospective studies, including clinical trials, to understand better the role of vitamin D in patients with incident asthma and wheeze.
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Asthma should be reduced by vitamin D – literature review Sept 2010 with a nice hypothesis chart - belowVitamin D and wheeze – especially in seniors – Aug 2011
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