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Aglipay M, Birken CS, Parkin PC, et al. Effect of High Dose Vitamin D Supplementation Compared to Standard Dose in Winter on Viral Upper Respiratory Tract Infections in Young Healthy Children.JAMA. 2017;318(3):245-254.
Objective
Comparison of high-dose and standard-dose vitamin D supplementation in the prevention of winter upper respiratory tract viral infections (URTIs) in young children
Draft
Randomized, double-blind clinical trial
Participant
703 healthy children (57.7% male) aged 1 to 5 years were recruited from a practice-based research network in Toronto, Canada.
intervention
Participants received either 2,000 IU or 400 IU per day of supplemental vitamin D.
Primary outcome measures
The number of laboratory-confirmed viral URTIs was the primary study outcome. Secondary endpoints included the number of influenza infections, the number of non-influenza infections, patient-reported URTIs, time to first URTI, and serum vitamin D levels after study completion.
Key insights
There was no difference in the number of laboratory-confirmed URTIs between the high-dose group (1.05; 95% confidence interval [CI]: 0.91-1.19) and the standard-dose group (1.03; 95% CI: 0.90-1.16) and no difference in parent-reported URTIs or time to first URTI. At study completion, the high-dose group had higher serum vitamin D levels (48.7 ng/ml; 95% CI: 46.9-50.5 ng/ml vs. 36.8 ng/ml; 95% CI: 35.4-38.2 ng/ml). The incidence of influenza was 50% lower (incidence rate ratio [IRR]: 0.50; 95% CI: 0.28-0.89) in the high-dose vitamin D group, although the number of influenza infections overall was low.
The study had a completion rate of 99.4%.
Practice implications
Over the past decade, there has been considerable excitement and interest surrounding the potential extraskeletal effects of vitamin D, particularly in areas such as cancer, mental health, and immune function.1Awareness of the prevalence of vitamin D deficiency is increasing. Inadequate vitamin D levels can be due to a combination of factors, such as: B. a trend towards increased activity indoors and concerns about the risks of sun exposure.2
Vitamin D is involved in the synthesis of antimicrobial components in the respiratory epithelium3and plays many roles in regulating innate and adaptive immunity.4Results from observational and clinical studies suggest an association between low serum vitamin D levels and higher rates of respiratory tract infections;5.6however, not all results were consistent. A 2017 meta-analysis of 25 randomized clinical trials (RCTs) conducted in infants, children and adults found that vitamin D supplementation reduced the risk of acute respiratory infections without increasing the risk of adverse events.7However, a 2015 meta-analysis concluded that vitamin D supplementation had no effect on the risk of acute respiratory infections in pediatric populations.8
No side effects were reported in this study and serum vitamin D levels of participants in the high-dose vitamin D group remained within a safe range.
This paper describes the results of a randomized placebo-controlled trial comparing high-dose and standard-dose vitamin D supplementation for the prevention of viral URTIs in children using laboratory confirmation of infection. This study showed no impact on the primary endpoint – the incidence of laboratory-confirmed viral URTIs. A statistically significant reduction in the incidence of influenza infections was found; However, these only made up a small part of the total number of infections. The authors noted that further study in a population or season with higher influenza prevalence is warranted before drawing conclusions.
There are several possible explanations for the lack of effect observed in this study. First, the standard dose of vitamin D may have provided sufficient protection against URTIs, preventing discrimination between the two doses. The research ethics board involved in this study prohibited the use of placebo based on the recommendations of the American Academy of Pediatrics.
Second, vitamin D may provide more benefit in a population with lower serum vitamin D levels. Vitamin D supplementation reaching a serum level of 30 ng/mL has been reported to be sufficient to reduce the incidence of URTIs in healthy adults.9At baseline, both the high-dose and standard-dose groups had mean serum vitamin D levels greater than 30 ng/mL (mean [SD] = 35.9 ng/mL [12.3] and 36.9 ng/mL [11.7], respectively). About 60% of participants were taking vitamin D regularly before the start of the study, and about 67% were of European descent, a factor known to positively influence endogenous vitamin D synthesis.10Baseline vitamin D status and lack of a placebo comparison may have obscured any benefit accrued to study participants.
A third explanation for the lack of effect is the size of the study sample. The sample size of 300 children was determined based on a power calculation that assumed an average of 4 laboratory-confirmed URTIs per 4-month winter season. However, both groups in this study had, on average, only one URTI per child per season (standard-dose group, 1.03; high-dose group, 1.05), with the majority of children experiencing no infections during the study period. This small number of infections may have limited the ability to detect a statistically significant response.
The authors acknowledge that certain subpopulations of children may be more likely to benefit from vitamin D supplementation and note that low vitamin D levels have been associated with the risk of asthma exacerbations.11a known risk factor for URTIs.12As a result, patients with asthma may be more likely to benefit from vitamin D supplementation.
No side effects were reported in this study and serum vitamin D levels of participants in the high-dose vitamin D group remained within a safe range. This suggests that the high-dose supplementation regimen was safe in this pediatric population.
Overall, these results do not support the use of routine high-dose vitamin D supplementation in the general pediatric population. Given that high-dose vitamin D is safe and has the potential to reduce influenza incidence, it seems reasonable to consider higher doses. Additionally, this study highlights the importance of ensuring pediatric populations meet standard dosage guidelines for vitamin D supplementation.