The rationale for the trial rested on vitamin D’s well-documented immunoregulatory properties. The active hormone, generated from the circulating precursor 25-hydroxyvitamin D, can modulate pro- and anti-inflammatory pathways, enhance innate antiviral immunity, improve corticosteroid responsiveness, and promote relaxation of bronchial smooth muscle. In 2017, two influential meta-analyses of randomised trials reported that vitamin D supplementation reduced oral corticosteroid-treated asthma exacerbations by 26 percent and respiratory infections by 12 percent. However, those analyses were limited by the marked under-representation of young children and of individuals with moderate or severe asthma, heterogeneous dosing regimens, and inconsistent concurrent inhaled corticosteroid therapy. Updated systematic reviews published after the trial began subsequently concluded that supplementation had no effect on asthma control or respiratory infections, leaving the field genuinely unsettled.

To resolve the question in the group at greatest risk, investigators led by Francine Ducharme of the Centre Hospitalier Universitaire Sainte-Justine designed the DIVA trial, a multicentre, randomised, triple-blind, placebo-controlled, parallel-group study conducted across nine Canadian paediatric asthma centres between 2018 and 2024. Eligible children were aged one to five years, carried a physician-confirmed asthma diagnosis, had experienced at least one oral corticosteroid-treated exacerbation in the previous six months or two in the preceding year, had viral upper respiratory infections as their primary exacerbation trigger, and had reported multiple such infections in the prior year. Children at risk of vitamin D deficiency or with conditions affecting calcium metabolism were excluded for safety reasons, and the protocol was approved by institutional review boards and Health Canada.

The intervention was deliberately designed to raise vitamin D status rapidly and sustainably. Participants were randomised one-to-one to receive either a hybrid regimen consisting of two oral boluses of 100,000 international units of vitamin D3, given at randomisation and again at roughly three and a half months, plus a daily 400 international unit supplement, or matching placebo. The regimen succeeded biochemically: children in the intervention arm showed a rapid rise in serum 25-hydroxyvitamin D within ten days, with between-group differences of 20 nanomoles per litre at 3.5 months and 28 nanomoles per litre at seven months. By the end of follow-up, 96 percent of supplemented children with available data had reached levels of at least 75 nanomoles per litre, compared with 62 percent of placebo recipients, confirming strong adherence and effective pharmacological exposure.

The primary outcome was the rate of asthma exacerbations requiring rescue oral corticosteroids over seven months, verified through stringent documentation criteria including medical and pharmacy records, with ambiguous cases reviewed by a blinded external adjudicator. Of 365 reported corticosteroid courses, 223 met all five required criteria. The results showed no meaningful difference between groups: children receiving vitamin D experienced a mean of 0.67 exacerbations per child over the treatment period, compared with 0.71 in the placebo arm, yielding an adjusted incidence rate ratio of 0.95 with a confidence interval spanning from 0.70 to 1.30. Per-protocol and sensitivity analyses adjusting for recruitment month, season, and pandemic years produced essentially identical conclusions, and a post hoc analysis found no evidence that the treatment effect changed over the course of the seven-month period.

Secondary outcomes told the same story. Participants averaged nearly two laboratory-confirmed viral respiratory infections per child, identified through multiplex quantitative reverse-transcription polymerase chain reaction testing of nasal specimens for ten respiratory viruses, predominantly rhinovirus and enterovirus, and roughly three caregiver-perceived infections. Neither measure differed between groups, with incidence rate ratios of 0.99 and 0.98 respectively. There were also no significant differences in acute care visits, hospital admissions, intensification of maintenance therapy, the frequency and duration of caregiver-reported asthma flare-ups, symptom intensity scores recorded on a validated daily diary, the intensity and duration of short-acting beta-2 agonist use during episodes, parental quality of life during flare-ups, or days of missed work and activity. In every domain measured, the supplemented and placebo groups were statistically indistinguishable.

Safety monitoring, a critical consideration given the high bolus doses involved, raised no concerns. Adverse events were predominantly mild and similar across groups. Twenty children experienced serious adverse events, thirteen in the placebo group and seven in the vitamin D group, and none were fatal. Among pre-specified events of special interest, one child in each group had clinically significant hypercalcaemia, and in the vitamin D recipient the elevated serum calcium normalised on re-analysis of the same specimen, suggesting a laboratory error. Fourteen children in the intervention group exceeded serum 25-hydroxyvitamin D concentrations of 250 nanomoles per litre without apparent clinical consequences. These findings align with a systematic review of 32 randomised trials in young children concluding that serious harms attributable to high-dose vitamin D supplementation are rare.

The trial did generate one intriguing, though statistically fragile, signal. Among ten pre-specified subgroup analyses, only the interaction between treatment allocation and Global Initiative for Asthma step therapy approached significance, with a p-value of 0.059, hinting at a roughly 33 percent reduction in corticosteroid-treated exacerbations among children receiving the most intensive Step 4 therapy, which involves high-dose inhaled corticosteroids or add-on controllers. The investigators themselves urge caution: after post hoc correction for the false discovery rate, the finding was not significant, and the trial was underpowered. Still, they argue the signal justifies examining effect modification by asthma severity in future systematic reviews, since children with severe asthma were historically excluded from trials and may plausibly benefit from the combined immunomodulatory effects of vitamin D and intensive corticosteroid treatment.

The study’s most important limitation is its size. The protocol called for 865 children to provide 80 percent power to detect a 25 percent relative reduction in exacerbations, but slow accrual, reaching only 38 percent of the target after six years, prompted the Data Safety Monitoring Board to recommend early termination, and 323 children were ultimately randomised. The confidence intervals therefore accommodate reductions or increases in exacerbation rates of up to 30 percent, and the authors are explicit that the findings suggest no benefit but do not constitute proof of no effect. Baseline vitamin D status was also generally adequate, with only six percent of children below 50 nanomoles per litre, raising the possibility of a ceiling effect, although no interaction with baseline status was detected here or in recent reviews. The authors also note that large bolus doses can induce catabolic enzymes such as 24-hydroxylase that may counteract vitamin D activity, though updated reviews have refuted earlier claims that bolus dosing is inherently less effective.

Taken together with the most recent systematic reviews, the DIVA trial indicates that vitamin D3 supplementation, at least in this hybrid bolus-plus-daily formulation, does not confer clinically meaningful protection against severe exacerbations or viral respiratory infections in preschool children with high-morbidity, viral-induced asthma already managed with evidence-based inhaled corticosteroid regimens. The trial nonetheless fills a genuine evidence gap by enrolling the young, severely affected children long under-represented in this literature, and it provides reassuring safety data for high-dose supplementation in this age group. Whether specific subgroups, such as children on the most intensive controller therapy or those with truly deficient baseline status, might still derive benefit remains an open question that future trials and updated meta-analyses will need to address before vitamin D can be recommended as an asthma preventive in early childhood.

Subject of Research: Vitamin D3 supplementation for prevention of viral-induced asthma exacerbations in preschool children

Article Title: High-dose vitamin D 3 supplementation in the prevention of viral-induced asthma in high-morbidity preschoolers (DIVA): a randomised controlled trial in Canada

Article References: Ducharme, F. M., Tse, S. M., Daigneault, P., Lee Yang, C., Radhakrishnan, D., Alizadehfar, R., Turcot, M.-A., Lemire, C., Chen, B. A., Perrem, L., Mailhot, G., Alos, N., Smyrnova, A., Kang Dufour, M.-S., Fernandez, M. C., Jensen, M. E., White, J. H., Sadatsafavi, M., Khamessan, A., & Mâsse, B. (2026). High-dose vitamin D3 supplementation in the prevention of viral-induced asthma in high-morbidity preschoolers (DIVA): a randomised controlled trial in Canada. eClinicalMedicine, 100, Article 104216. https://doi.org/10.1016/j.eclinm.2026.104216

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104216

Keywords: vitamin D3, asthma, preschool children, viral respiratory infections, randomised controlled trial, rhinovirus, oral corticosteroids, inhaled corticosteroids, 25-hydroxyvitamin D, asthma exacerbations, pediatrics, immunoregulation