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 Feb 15;356:i6583. doi: 10.1136/bmj.i6583.   (Systematic Review)   PMID: 28202713   
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Physician Disciplines Relevance to practice Is this news?
General Internal Medicine-Primary Care(US)
General Practice(GP)/Family Practice(FP)
Pediatrics (General)
Respirology/Pulmonology
Infectious Disease
Public Health
Pediatric Neonatology

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Abstract
Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels >/=25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

Comments from Clinical Raters
General Internal Medicine-Primary Care(US)
This is news to me. As a doctor practicing in the Pacific Northwest, I believe this will change my practice. I had previously focused on patients with or at risk for falls for vitamin D levels.
General Practice(GP)/Family Practice(FP)
As a family physician in area with high prevalence of Vitamin D deficiency, I find this strong and well done meta-analysis added to the importance and pleiotropic action of vitamin D. However, I am not sure if this study will change the practice as the vitamin D supplementation is recommended for more important issues (e.g., hypocalcemia).
General Practice(GP)/Family Practice(FP)
Clearly, this article underscores the need to request vitamin D levels in a family practice setting. Vitamin D has always been considered as a use or not use based on some arthritis and osteoporosis conditions. This study is quite convincing to support the recommendation of vitamin D testing and utilization of vitamin D supplementation to prevent acute respiratory tract infections.
Infectious Disease
This large individual patient meta-analysis showed a clinically useful reduction in respiratory infection in subjects taking vitamin D supplements, and the effect was largest in those with low initial levels of vitamin D. This has important public health implications.
Pediatric Neonatology
As a neonatologist, I cannot understand the reticence I see occasionally with some colleagues about starting babies on oral daily vitamin supplements. I'm not aware of a significant downside, the opportunity for better bone health is real, and now this. All babies should be on vitamins.
Pediatrics (General)
This very large and carefully "vetted" meta-analysis should prove that Vitamin D supplementation (especially in those with Vitamin D deficiency) helps prevent acute respiratory tract infections. However, the drawbacks of this study for the average clinician are the very complex statistical analyses involved, and with the very large number of clinical participants, only very small differences between treated vs control group values can reach (very) high levels of statistical significance. An example is Table 2 where the % difference between infections in the control vs intervention group is only 42.2 vs 40.3%, yet the P value is < 0.003; or Table 5 with only a 3% difference. Also, as the authors themselves point out, a caveat is that various study definitions were used to define acute respiratory tract infection, and confirmatory radiologic, microbiologic / virologic testing was not done in most of the individual studies.
Public Health
Although there remains some heterogeneity in the results, the risk of Vit D supplementation is low and the benefit is of public health importance. We seem to have enough evidence to change policy either in advising a daily supplement (especially to those as risk for deficiency) as well as food supplementation.
Respirology/Pulmonology
This meta-analysis of RCTs finds that Vitamin D supplementation reduced the risk of acute respiratory tract infections, but only when given as daily or weekly doses and not as a high dose bolus. No effects on adverse consequences of RTIs were observed. Results were driven by children and those who were Vitamin D deficient. Substantial statistical heterogeneity was observed and the main paper does not make it clear whether the subgroup analyses account for this heterogeneity. Therefore, it is not clear whether this study answers the clinical question. These results would not seem enough to support Vitamin D supplementation in the general population for this purpose (although there may be other reasons for doing so).
Respirology/Pulmonology
As an adult pulmonologist in the midwest where vitamin D insufficiency/deficiency is common, this study validates my tendency to obtain levels in less active individuals who are home-bound and tend toward vitamin-D-poor diets.
Respirology/Pulmonology
This is a well conducted study with high quality evidence. The results are very promising. With little side effects of Vit D3 supplementation for very low levels of serum Vit D, further recommendations on screening for Vit D deficiency in high risk patients with recurrent acute respiratory tract infections must be considered.