Vitamin D in Asthma Mechanisms of Action and Considerations for Clinical Trials

There is increasing interest in the therapeutic utility of vitamin D in asthma, which is supported by a significant body of evidence on epidemiologic associations between vitamin D insufficiency and worse asthma control. In support of a causal relationship, vitamin D beneficially modulates diverse immunologic pathways in heterogeneous asthma endotypes, regulating the actions of lymphocytes, mast cells, antigen-presenting cells, and structural cells to dampen excessive inflammatory responses. Allergic asthma is characterized by a failure of immune tolerance and the development of pathologic responses to inhaled aero-allergens, and vitamin D has been extensively shown to support immune regulation. Alarmin cytokines are increasingly implicated in nonallergic eosinophilic inflammation, which vitamin D also regulates. Steroid resistance and pathologic interleukin (IL)-17 responses are features of severe asthma, and vitamin D beneficially enhances the response to steroids in these individuals. Additionally, vitamin D enhances antimicrobial pathways, which is of relevance to infection-precipitated asthma exacerbations. These mechanisms support a role for vitamin D as secondary prevention to reduce exacerbations and inflammation in asthma. Similar mechanisms, and effects on fetal lung development, likely underlie a primary prevention therapeutic role in pregnancy for vitamin D to reduce the development of asthma in children. However, randomized controlled trials of variable design show inconsistent positive outcomes for vitamin D interventions in asthma. Increased understanding of the biological characteristics of vitamin D reveals methodological issues that might explain certain negative outcomes. Importantly, on systematic review of the trials to date, vitamin D is shown to be beneficial in asthma. The evidence discussed in this review supports the importance of optimizing vitamin D in holistic asthma care.