"D-feat D Flu?" Vitamin D and Pediatric Influenza

Abstract & Commentary

By Russell H. Greenfield, MD, Editor

Synopsis: The promising results of this study suggest that timely supplementation with vitamin D3 may help prevent seasonal influenza A, though not influenza B, in school-aged children. A side finding was that children with asthma taking vitamin D3 experienced fewer exacerbations, though not a lesser rate of influenza A infection. I hope this trial will be replicated, and with measurement of 25-OH D levels, in both children and adults, to help tease out the role of vitamin D in flu prevention.

Source: Urashima M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school- children. Am J Clin Nutr 2010 Mar 10; doi:10.3945/ajcn.2009.29094.

The authors of this Japanese multicenter (12 hospitals and 8 outside physicians), randomized, double-blind, placebo-controlled, parallel-group trial investigated whether vitamin D supplements might impact the incidence of influenza A in school children during winter and early spring. Children aged 6-15 years (mean age 10.2 years, with 65% having started nursery school or kindergarten at 3 years or older) were enrolled from November to early December in 2008 and then asked to begin taking their study drugs within the first 2 weeks of December. Subjects were randomized to receive daily divided doses of either 1,200 IU of vitamin D3 or placebo from December 2008 through March 2009. Parents were provided with eight numbered bottles, each containing 90 tablets of either 200 IU vitamin D or placebo identical in appearance. The children were to take 3 tablets twice daily. Pre-study questionnaires collected demographic data and medical history, while the post-study questionnaire focused on answers to questions about compliance with study protocol, outdoor activities, specific food intake, and illnesses that may have occurred. Daily logs were also completed. Compliance was measured in part by direct viewing of the supplement bottles on clinic visits. Primary outcome of interest was the incidence of influenza A, diagnosed by outpatient rapid influenza antigen testing using a nasopharyngeal swab specimen.

A total of 430 schoolchildren/parent pairs were randomized but there was significant study attrition, with 50 and 46 children being lost to follow-up in the active and placebo groups, respectively (intention-to-treat analysis was used). Compliance with the study medication was very high (96%). Influenza A occurred in 18/167 (10.8%) of children in the vitamin D group compared with 31/167 (18.6%) in the placebo group (relative risk [RR] = 0.58), with peak incidence occurring from middle to late January. Between days 31 and 60, influenza A occurred significantly less often in the vitamin D group than in the placebo group (5.4% vs. 13.2%; RR = 0.41), but there was no difference in the development of influenza A between the two groups early or late in the trial. In subgroup analysis it was shown that a reduction in occurrence in influenza A was more prominent in children who previously had not been taking vitamin D and in those who had started nursery school after age 3 years (starting nursery school before age 3 years may increase the chances of exposure to influenza and of obtaining immunity). In children with a previous history of asthma, exacerbations occurred in 2 children taking vitamin D3 vs. 12 children in the placebo group (RR = 0.17). The incidence of influenza B and antigen-testing negative flu-like illness was not different between the two groups. No serious adverse effects were identified, including urinary stones.

The authors concluded that vitamin D3 supplementation during the winter and early spring may have a preventive effect against the development of childhood influenza A infection.

Commentary

This is a very interesting study. As the authors note, one hypothesis regarding the seasonal pattern of influenza infections reflects the seasonal oscillation of vitamin D levels as a reflection of sun exposure. It is known both that vitamin D up-regulates innate immunity and that serum levels of vitamin D decrease during the winter months when people spend more time indoors. Vitamin D may also function to lessen inflammation in the body, and some data suggest a protective effect of vitamin D against uncomplicated upper respiratory tract infection.

Some might think the dose of vitamin D employed in this study was high, but vitamin D supplementation in the range of 200-2,000 IU in schoolchildren over the course of a year has been shown to be safe.1

There are limitations to the data (aren't there always?). Unfortunately, but understandably considering the patient population, 25-hydroxyvitamin D levels were not obtained, so a threshold level for any preventive activity remains unknown. The sample size was small, a significant number of children were lost to follow-up, and an unspecified number of children apparently began taking vitamin D supplements in addition to the study medication after randomization (why was this not prohibited?).

It is notable that vitamin D did not have an impact against influenza B, nor did it lessen the risk of influenza A in children with asthma (although it appeared to lessen the risk of asthma attacks). In addition, a consideration is the number of pills that children were asked to consume every day, though this could be easily remedied.

Limitations aside, the results of this trial are intriguing. Could adequate repletion of vitamin D together with appropriate vaccination help lessen the incidence of seasonal influenza A? Maybe. This type of trial should be replicated both in children and in adults.

Reference

1. Maalouf J, et al. Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. J Clin Endocrinol Metab 2008;93:2693-2701.