Impact of two oral doses of 100,000 IU of vitamin D3 in preschoolers with viral-induced asthma: a pilot randomised controlled trial

Abstract

Background: New evidence supports the use of supplemental vitamin D in the prevention of exacerbation of asthma; however, the optimal posology to sufficiently raise serum levels while maximising adherence is unclear. The objective was to ascertain the efficacy of high-dose vitamin D₃ in increasing serum vitamin D in preschoolers with asthma and provide preliminary data on safety and efficacy outcomes.

Methods: We conducted a 7-month, triple-blind, randomised, placebo-controlled, pilot trial of children aged 1-5 years with viral-induced asthma. Participants were allocated to receive two oral doses of 100,000 IU vitamin D₃ (intervention) or identical placebo (control) 3.5 months apart, once in the fall and once in the winter. Serum 25-hydroxyvitamin D (25OHD) was measured by tandem mass spectrometry at baseline, 10 days, 3.5 months, 3.5 months + 10 days, and 7 months. The main outcome was the change in serum 25OHD from baseline (Δ25OHD) over time and at 3.5 and 7 months; other outcomes included the proportion of children with 25OHD ≥ 75 nmol/L, safety, and adverse event rates.

Results: Children (N = 47) were randomised (intervention, 23; control, 24) in the fall. There was a significant adjusted group difference in the Δ25OHD (95% confidence interval) of 57.8 (47.3, 68.4) nmol/L, p < 0.0001), with a time (p < 0.0001) and group*time interaction effect (p < 0.0001), in favour of the intervention. A significant group difference in the Δ25OHD was observed 10 days after the first (119.3 [105.8, 132.9] nmol/L) and second (100.1 [85.7, 114.6] nmol/L) bolus; it did not reach statistical significance at 3.5 and 7 months. At 3.5 and 7 months, respectively, 63% and 56% of the intervention group were vitamin D sufficient (≥ 75 nmol/L) compared to 39% and 36% of the control group. Hypercalciuria, all without hypercalcaemia, was observed in 8.7% of intervention and 10.3% of control samples at any time point. Exacerbations requiring rescue oral corticosteroids, which appear as a promising primary outcome, occurred at a rate of 0.87/child.

Conclusion: Two oral boluses of 100,000 IU vitamin D_3,once in the fall and once in the winter, rapidly, safely, and significantly raises overall serum vitamin D metabolites. However, it is sufficient to maintain 25OHD ≥ 75 nmol/L throughout 7 months in only slightly more than half of participants.

Trial registration: ClinicalTrials.gov, NCT02197702 (23 072014). Registered on 23 July 2014.

Keywords: Asthma; Child; Cholecalciferol; Paediatric; Pilot study; Randomised controlled trial; Viral-induced; Vitamin D.

Fig. 1

Patient selection. The flow of patients is depicted from screening to analysis; 274 children were screened, 102 were not eligible (non-mutually exclusive reasons for ineligibility are listed). Of the 172 provisionally eligible children, 77 could not be reached to confirm eligibility and 48 were not interested in study participation. Of the 47 randomised children, 23 were allocated to receive vitamin D and 24 to receive placebo supplementation. With one child in each group with no measurement of serum 25-hydroxyvitamin D (25OHD) after baseline, 22 and 23 children in the vitamin D and placebo groups were analysed for the main outcome. URTI, Upper respiratory tract infection

Fig. 2

Change from baseline in serum 25-hydroxyvitamin D (25OHD) levels over 7 months. The adjusted mean change from baseline in 25OHD is presented with 95% confidence interval at each time point, in the vitamin D (filled circles) and placebo (open squares) groups over the 7-month study period; values were adjusted for vitamin D intake, ethnicity, sex, environmental tobacco exposure, school-days missed, and asthma management strategy. In the lower panel, the adjusted mean changes from baseline (95% CI) for each group and the adjusted mean group difference in the change from baseline (95% CI) are recorded at 10 days (d) (after 1st bolus), 3.5 months (mo), 3.5 months + 10 days (after 2nd bolus) and 7 months

Fig. 3

Serum 25-hydroxyvitamin D (25OHD) levels over 7 months. The 25OHD values are presented by group at various time points. a Crude total serum 25OHD in the vitamin D (filled boxes) and control (open boxes) groups over the 7-month study period. The median is depicted by the horizontal bar, with the lower and upper limits of each box representing the 25% and 75%; these numerical values are also recorded in the lower panel as median (25%, 75%) at each time point. Error bars represent the minimum and maximum of the distribution. b Adjusted marginal means for the total serum 25OHD are presented in the vitamin D (filled circles) and control (open squares) groups over the 7-month study period, after adjustment for asthma phenotype, sex, ethnicity, environmental tobacco exposure, school-days missed, baseline vitamin D intake, baseline serum 25OHD, and asthma management strategy. Error bars represent the 95% confidence interval of the mean. In the lower panel, their numerical values are recorded by group at each point in time along with the adjusted mean group difference (95% CI). Using a generalised linear mixed model, a statistically significant overall group (p < 0.0001), time (p < 0.0001), and group*time (p < 0.0001) interaction was documented. In both graphs, the dotted line represents the 75 nmol/ L on the y-axis. Total 25OHD was comprised overwhelmingly of 25-hydroxyvitamin D₃, with 3-epimer-25-hydroxyvitamin D₃ and 25-hydroxyvitamin D₂