Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

Health technology assessment

Jan 2019

DOI: 10.3310/hta23020

Citations:265

Influential Citations:10

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Design: randomized, double-blind, placebo-controlled trials of vitamin D supplementation; Participants: birth to 95 years, both sexes, varied health status; trials conducted in 15 countries.

Intervention

Oral vitamin D3 supplementation; regimens included daily dosing, weekly dosing, monthly to quarterly bolus dosing (bolus doses of at least 30,000 IU), and combinations of bolus and daily dosing; durations ranged from 7 weeks to 1.5 years.

Results

Vitamin D supplementation reduces ARI risk; overall reduction in the proportion of participants with at least one ARI (adjusted OR 0.88; 95% CI 0.81 to 0.96; NNT 33). ARI rate also reduced (adjusted IRR 0.96; 95% CI 0.92 to 0.997). Time to first ARI not significantly affected (adjusted HR 0.95; 95% CI 0.89 to 1.01). Stronger protection in those with baseline 25(OH)D < 25 nmol/L (adjusted OR 0.58; 95% CI 0.40 to 0.82; NNT 8). Daily or weekly regimens without bolus doses showed protection (adjusted OR 0.81; 95% CI 0.72 to 0.91; NNT 20); bolus dosing did not (adjusted OR 0.97; 95% CI 0.86 to 1.10). For asthma, reduced rate of exacerbations requiring systemic corticosteroids (IRR 0.74; 95% CI 0.56 to 0.97). COPD exacerbations showed no overall benefit, but protection in those with baseline deficiency (p=0.003). Safety: no increase in serious adverse events; hypercalcaemia and renal stones were rare and occurred at similar rates in both arms. Implications: supports public health measures like vitamin D fortification to reduce ARI burden; daily/weekly regimens preferred for ARI prevention; more IPD data could refine subgroup effects.

Limitations

Power limited for some subgroups (e.g., very low baseline 25(OH)D with bolus dosing); adherence data not available for all participants; heterogeneity in dosing regimens and baseline vitamin D status; ARI definitions varied and virological confirmation limited; potential small-study bias suggested by funnel plot.

Abstract

BACKGROUND Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. OBJECTIVES To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. DATA SOURCES MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. STUDY SELECTION Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected. STUDY APPRAISAL Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. RESULTS We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. LIMITATIONS Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. CONCLUSIONS Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013953. FUNDING The National Institute for Health Research Health Technology Assessment programme. show less