Acute respiratory tract infections are a major cause of global morbidity and mortality and are responsible for 10% of ambulatory and emergency department visits in the USA and an estimated 2.65 million deaths worldwide in 2013. Observational studies report consistent independent associations between low serum concentrations of 25-hydroxyvitamin D (the major circulating vitamin D metabolite) and susceptibility to acute respiratory tract infection. 25-hydroxyvitamin D supports induction of antimicrobial peptides in response to both viral and bacterial stimuli, suggesting a potential mechanism by which vitamin D inducible protection against respiratory pathogens might be mediated. Vitamin D metabolites have also been reported to induce other innate antimicrobial effector mechanisms, including induction of autophagy and synthesis of reactive nitrogen intermediates and reactive oxygen intermediates. These epidemiological and in vitro data have prompted numerous randomised controlled trials to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infection. A total of five aggregate data meta-analyses incorporating data from up to 15 primary trials have been conducted to date, of which two report statistically significant protective effects and three report no statistically significant effects. All but one of these aggregate data meta-analyses reported statistically significant heterogeneity of effect between primary trials.
This heterogeneity might have arisen as a result of variation in participant characteristics and dosing regimens between trials, either of which may modify the effects of vitamin D supplementation on immunity to respiratory pathogens. People with chronic obstructive pulmonary disease who have lower baseline vitamin D status have been reported to derive greater clinical benefit from supplementation than those with higher baseline status, and participant characteristics such as age and body mass index have been reported to modify the 25-hydroxyvitamin D response to vitamin D supplementation.Treatment with large boluses of vitamin D has been associated with reduced efficacy for non-classic effects, and in some cases an increased risk of adverse outcomes. While study level factors are amenable to exploration through aggregate data meta-analysis of published data, potential effect modifiers operating at an individual level, such as baseline vitamin D status, can only be explored using individual participant data (IPD) meta-analysis. This is because subgroups are not consistently disaggregated in trial reports, and adjustments for potential confounders cannot be applied similarly across trials. To identify factors that might explain the observed heterogeneity of results from randomised controlled trials, we undertook an IPD meta-analysis based on all 25 randomised controlled trials of vitamin D supplementation for prevention of acute respiratory tract infection that were completed up to the end of December 2015.