Translating Basic Research into Clinical Practice: 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, supported by a significant body of evidence on epidemiological associations between vitamin D insufficiency and worse asthma control. In support of a causal relationship, vitamin D beneficially modulates diverse immunological 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 characterised by a failure of immune tolerance, and development of pathological responses to inhaled aeroallergens, and vitamin D has been extensively shown to support immune regulation. Alarmin cytokines are increasingly implicated in non-allergic eosinophilic inflammation, which vitamin D also regulates. Steroid-resistance and pathological IL-17 responses are features of severe asthma, and vitamin D beneficially enhances the response to steroids in these individuals. Additionally, vitamin D enhances anti-microbial pathways, 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, randomised controlled trials of variable design show inconsistent positive outcomes for vitamin D interventions in asthma. Increased understanding of vitamin D biology reveals methodological issues that might explain certain negative outcomes. Importantly, on systematic review of the trials to-date, vitamin D is beneficial in asthma. The evidence discussed in this review supports the importance of optimising vitamin D in holistic asthma care.