Free Vitamin D₃ Inferior to Total Concentrations in Predicting Asthma Response

The results of an analysis of data from the VIDA trial (Study of the Effect of Vitamin D as an Add-on Therapy to Corticosteroids in Asthma; ClinicalTrials.gov Identifier: NCT01248065) published in the Annals of Allergy, Asthma, & Immunology found no associations between free concentration (C_f ) vitamin D₃ levels and rates of treatment failure or exacerbations in adults with asthma. 

John J. Lima, PharmD, of Nemours Children’s Health System in Jacksonville, Florida, and colleagues explored the relationship between vitamin D and the outcomes of the VIDA trial to determine the associations between C_f vitamin D₃ and treatment failure during a reduction of inhaled corticosteroids (ICS) in VIDA participants.

Vitamin D status (vitamins D₂ and D₃) is determined by circulating total concentrations (C_tot) of vitamin D₃ but not concentrations of active 1,25-dihydroxyvitamin D₃. Serum concentrations of vitamin D₃ ≥30 ng/mL are required for the skeletal actions of vitamin D and concentrations ≥50 ng/mL are necessary for the extraskeletal pleiotropic effects of vitamin D. However, serum concentrations of vitamin D₃ may not be an accurate measure of vitamin D status because of uncertainties concerning the methods of measuring C_tot concentrations of vitamin D₃. Genetic variations have shown significant differences in C_tot vitamin D₃ concentrations in certain ethnic populations, including individuals with substantial African ancestry, such as African Americans and some Hispanic groups, compared with individuals of European descent.

Determining the relationship between this vitamin and asthma is important, however, because hypovitaminosis D has been associated with an increased risk for asthma, reduced lung function, increased airway responsiveness, asthma exacerbations, and a reduced response to glucocorticoids in individuals with asthma.

The primary finding of this analysis demonstrated that there is no association between C_f or changes in C_f and the outcomes following vitamin D₃ supplementation. However, the investigators noted that this is not consistent with the previous VIDA finding that vitamin D supplementation improved the efficacy of inhaled corticosteroids when participants achieved levels ≥30 ng/mL. The researchers did not anticipate the inconsistency between C_f and C_tot level associations with response outcomes, particularly in view of the strong relationship between C_f and C_tot and the predictions of the C_f  hormone hypothesis that only C_f  concentrations of vitamin D₃ diffuse across the cell membrane and undergo metabolism to 1,25-dihydroxyvitamin D₃, which activates the vitamin D receptor.

In addition, the investigators noted that this observation is not congruent with others that reported that C_f levels are more closely associated with skeletal markers, atopy, and lung function in children with asthma than C_tot levels. C_f concentrations of vitamin D₃ were in fact inferior to C_tot concentrations in predicting responsiveness to vitamin D supplementation in the VIDA trial, the researchers concluded.

The investigators argued that their results justify further studies to investigate the relationship between C_f  and C_tot vitamin D concentrations as biomarkers of skeletal and extraskeletal actions of vitamin D supplementation in patients with asthma. They also suggested that future studies of vitamin D supplementation in patients with asthma measure both C_f and C_tot levels of vitamin D₃.

Reference

Lima JJ, Castro M, King TS, et al. Association of free vitamin D₃ concentrations and asthma treatment failures in the VIDA trial [published online June 13, 2018]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2018.06.001