Aglipay M, Birken CS, Parkin PC, et al. Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children. JAMA. 2017;318(3):245-254.
To compare high-dose and standard-dose vitamin D supplementation in the prevention of wintertime viral upper respiratory tract infections (URTIs) in young children
Randomized, double-blind clinical trial
Seven hundred and three healthy children (57.7% male) aged 1 to 5 years were recruited from a practice-based research network in Toronto, Canada.
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 outcomes 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.
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 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 levels of serum vitamin D (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 was small overall.
The study had a 99.4% rate of completion.
In the past decade, there has been significant excitement and interest related to the potential extraskeletal effects of vitamin D, particularly in areas such as cancer, mental health, and immune function.1 Awareness of the prevalence of vitamin D deficiency is on the rise. Inadequate levels of vitamin D may be attributable to a combination of factors, such as a trend towards increased indoor activity and concerns about the risks of sun exposure.2
Vitamin D is involved in the synthesis of antimicrobial constituents in the respiratory epithelium3 and plays many roles in the regulation of innate and adaptive immunity.4 The results of observational and clinical studies have suggest a connection between low levels of serum vitamin D and higher rates of respiratory infections;5,6 however, not all the findings have been consistent. A 2017 meta-analysis of 25 randomized clinical trials (RCTs) conducted in infants, children, and adults found that vitamin D supplementation decreased the risk of acute respiratory infections with no increase in the risk of adverse events.7 However, a 2015 meta-analysis concluded that vitamin D supplementation had no impact on the risk of acute respiratory infections in pediatric populations.8
No adverse effects were reported in this study and the serum vitamin D levels of the high-dose vitamin D group participants remained within a safe range.
This paper details the findings of a randomized placebo-controlled study comparing high-dose and standard-dose vitamin D supplementation for the prevention of viral URTIs in children, using laboratory confirmation of infection. This study did not show an impact on the primary outcome—the incidence of laboratory-confirmed viral URTIs. It did find a statistically significant reduction in the incidence of influenza infections; however, these made up a small proportion of the number of overall infections. The authors determined that further investigation in a population or season with higher influenza prevalence is warranted before drawing conclusions.
There are a few possible explanations for the lack of effect seen in this study. First, the standard-dose vitamin D may have provided sufficient protection from URTIs, preventing a distinction between the 2 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. It has been reported that vitamin D supplementation that achieves a serum level of 30ng/mL is sufficient to reduce the incidence of URTIs in healthy adults.9 At 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). Approximately 60% of the participants were regularly supplementing with vitamin D prior to study start, and approximately 67% were of European ethnicity, a factor known to positively influence endogenous vitamin D synthesis.10 Baseline vitamin D status and the lack of placebo comparison may have obscured a benefit incurred by the 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 averaged 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 low 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, noting that low levels of vitamin D have been associated with the risk of asthma exacerbations,11 a known risk factor for URTIs.12 As a result, patients with asthma may be more likely to benefit from vitamin D supplementation.
No adverse effects were reported in this study and the serum vitamin D levels of the high-dose vitamin D group participants 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. However, given that high-dose vitamin D is safe and it has potential to reduce influenza incidence, it seems reasonable to consider higher doses. Further, this study underscores the importance of ensuring that pediatric populations meet the standard-dose guidelines for vitamin D supplementation.
- Weydert JA. Vitamin D in children’s health. Children. 2014;1(2):208-226.
- Inderjeeth CA, Nicklason F, Al‐Lahham Y, et al. Vitamin D deficiency and secondary hyperparathyroidism: clinical and biochemical associations in older non‐institutionalised Southern Tasmanians. Int Med J. 2000;30(2):209-214.
- Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173(5):2909-2912.
- Chun RF, Adams JS, Hewison M. Immunomodulation by vitamin D: implications for TB. Expert Rev Clin Pharmacol. 2011;4(5):583-591.
- Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8(6):e65835.
- Charan J, Goyal JP, Saxena D, Yadav P. Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis. J Pharmacol Pharmacother. 2012;3(4):300-303.
- Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
- Xiao L, Xing C, Yang Z, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. BJN. 2015;114(7):1026-1034.
- Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PloS One. 2010;5(6):e11088.
- Åkeson PK, Lind T, Hernell O, Silfverdal SA, Öhlund I. Serum vitamin D depends less on latitude than on skin color and dietary intake during early winter in Northern Europe. J Pediatr Gastroenterol Nutr. 2016;62(4):643-649.
- Litonjua AA, Carey VJ, Laranjo N, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA. 2016;315(4):362-370.
- Rawlinson WD, Waliuzzaman Z, Carter IW, Belessis YC, Gilbert KM, Morton JR. Asthma exacerbations in children associated with rhinovirus but not human metapneumovirus infection. J Infect Dis. 2003;187(8):1314-1318.