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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data
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BMJ 2017
https://www.bmj.com/content/356/bmj.i6583?utm_source=adestra&utm_medium=email&utm_campaign=usage&utm_content=americas-covid19&utm_term=tbmj
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.
Risk of bias within studies
Supplementary table S2 provides details of the risk of bias assessment. All but two trials were assessed as being at low risk of bias for all aspects assessed. Two trials were assessed as being at unclear risk of bias owing to high rates of loss to follow-up. In the trial by Dubnov-Raz et al,36 52% of participants did not complete all symptom questionnaires. In the trial by Laaksi et al,37 37% of randomised participants were lost to follow-up.
Incidence of acute respiratory tract infection
Overall results
Table 2 presents the results of the one step IPD meta-analysis testing the effects of vitamin D on the proportion of all participants experiencing at least one acute respiratory tract infection, adjusting for age, sex, and study duration. Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96, P=0.003; P for heterogeneity <0.001; NNT=33, 95% confidence interval 20 to 101; 10 933 participants in 25 studies; see Cates plot, supplementary figure S1). Statistically significant protective effects of vitamin D were also seen for one step analyses of acute respiratory tract infection rate (adjusted incidence rate ratio 0.96, 95% confidence interval 0.92 to 0.997, P=0.04; P for heterogeneity <0.001; 10 703 participants in 25 studies) but not for analysis of time to first acute respiratory tract infection (adjusted hazard ratio 0.95, 95% confidence interval 0.89 to 1.01, P=0.09; P for heterogeneity <0.001; 9108 participants in 18 studies). Two step analyses also showed consistent effects for the proportion of participants experiencing at least one acute respiratory tract infection (adjusted odds ratio 0.80, 0.69 to 0.93, P=0.004; P for heterogeneity 0.001; 10 899 participants in 24 studies; fig 2), acute respiratory tract infection rate (adjusted incidence rate ratio 0.91, 0.84 to 0.98, P=0.018; P for heterogeneity <0.001; 10 703 participants in 25 studies), and time to first acute respiratory tract infection (adjusted hazard ratio 0.92, 0.85 to 1.00, P=0.051; P for heterogeneity 0.14; 9108 participants in 18 studies). This evidence was assessed as being of high quality (see supplementary table S3).
Subgroup analyses
To explore reasons for heterogeneity, we conducted subgroup analyses to investigate whether effects of vitamin D supplementation on risk of acute respiratory tract infection differed according to baseline vitamin D status, dosing frequency, dose size, age, body mass index, the presence or absence of comorbidity (asthma or chronic obstructive pulmonary disease), and influenza vaccination status. Race or ethnicity was not investigated as a potential effect modifier, as data for this variable were missing for 3680/10 933 (34%) participants and power for subgroup analyses was limited by small numbers in many racial or ethnic subgroups that could not be meaningfully combined. Table 2 presents the results. Subgroup analysis revealed a strong protective effect of vitamin D supplementation among those with baseline circulating 25-hydroxyvitamin D levels less than 25 nmol/L (adjusted odds ratio 0.58, 0.40 to 0.82, NNT=8, 5 to 21; 538 participants in 14 studies; within subgroup P=0.002; see Cates plot, supplementary figure S1) and no statistically significant effect among those with baseline levels of 25 or more nmol/L (adjusted odds ratio 0.89, 0.77 to 1.04; 3634 participants in 19 studies; within subgroup P=0.15; P for interaction 0.01). This evidence was assessed as being of high quality (see supplementary table S3). An exploratory analysis testing the effects of vitamin D supplementation in those with baseline 25-hydroxyvitamin D concentrations in the ranges 25-49.9 nmol/L, 50-74.9 nmol/L, and 75 or more nmol/L did not reveal evidence of a statistically significant interaction (see supplementary table S4).
Meta-analysis of data from trials in which vitamin D was administered using a daily or weekly regimen without additional bolus doses revealed a protective effect against acute respiratory tract infection (adjusted odds ratio 0.81, 0.72 to 0.91, NNT=20, 13 to 43; 5133 participants in 15 studies; within subgroup P<0.001; see Cates plot, supplementary figure S1). No such protective effect was seen among participants in trials where at least one bolus dose of vitamin D was administered (adjusted odds ratio 0.97, 0.86 to 1.10; 5800 participants in 10 studies; within subgroup P=0.67; P for interaction 0.05). This evidence was assessed as being of high quality (see supplementary table S3). P values for interaction were more than 0.05 for all other potential effect modifiers investigated. For both of these subgroup analyses, broadly consistent effects were observed for event rate analysis (see supplementary table S5) and survival analysis (see supplementary table S6).
Having identified two potential factors that modified the influence of vitamin D supplementation on risk of acute respiratory tract infection (ie, baseline vitamin D status and dosing frequency), we then proceeded to investigate whether these factors were acting as independent effect modifiers, or whether they were confounded by each other or by another potential effect modifier, such as age. Dot plots revealed a trend towards lower median baseline serum 25-hydroxyvitamin D concentration and higher median age for studies employing bolus compared with daily or weekly dosing (see supplementary figures S2 and S3). To establish which of these potential effect modifiers was acting independently, we repeated the analysis to include treatment-covariate interaction terms for baseline vitamin D status, dosing frequency, and age. In this model, interaction terms for baseline vitamin D status and dosing frequency were statistically significant (P=0.01 and P=0.004, respectively), but the interaction term for age was not (P=0.20), consistent with the hypothesis that baseline vitamin D status and dosing frequency, but not age, independently modified the effect of vitamin D supplementation on risk of acute respiratory tract infection.
We then proceeded to stratify the subgroup analysis presented in table 2 according to dosing frequency, to provide a “cleaner” look at the results of subgroup analyses under the assumption that use of bolus doses was ineffective. Table 3 presents the results: these reveal that daily or weekly vitamin D treatment was associated with an even greater degree of protection against acute respiratory tract infection among participants with baseline circulating 25-hydroxyvitamin D concentrations less than 25 nmol/L than in the unstratified analysis (adjusted odds ratio 0.30, 0.17 to 0.53; NNT=4, 3 to 7; 234 participants in six studies; within subgroup P<0.001; see Cates plot, supplementary figure S4). Moreover, use of daily or weekly vitamin D also protected against acute respiratory tract infection among participants with higher baseline 25-hydroxyvitamin D concentrations (adjusted odds ratio 0.75, 0.60 to 0.95; NNT=15, 9 to 86; 1603 participants in six studies; within subgroup P=0.02; see Cates plot, supplementary figure S4). The P value for interaction for this subgroup analysis was 0.006, indicating that protective effects of daily or weekly vitamin D supplementation were statistically significantly greater in the subgroup of participants with profound vitamin D deficiency. No other statistically significant interaction was seen; notably, bolus dose vitamin D supplementation did not offer any protection against acute respiratory tract infection even when administered to those with circulating 25-hydroxyvitamin D concentrations less than 25 nmol/L (adjusted odds ratio 0.82, 0.51 to 1.33; 304 participants in eight studies; within subgroup P=0.43).
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