Adrian R Martineau, David A Jolliffe, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, Davaasambuu Ganmaa, Adit A Ginde, Emma C Goodall, Cameron C Grant, Wim Janssens, Megan E Jensen, Conor P Kerley, Ilkka Laaksi, Semira Manaseki-Holland, David Mauger, David R Murdoch, Rachel Neale, Judy R Rees, Steve Simpson, Iwona Stelmach, Geeta Trilok Kumar, Mitsuyoshi Urashima, Carlos A Camargo, Christopher J Griffiths, Richard L Hooper
Journal: Health technology assessment (Winchester, England) 2020;23(2):1-44
PMID: 30675873
Low blood levels of vitamin D have been linked to an increased risk of colds, flu and chest infections, collectively termed ‘acute respiratory infections’ (ARIs). The main aim of this study was to determine the overall effect of vitamin D supplementation on the risk of ARI and serious adverse events. The study is a systemic review which included randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration for analysis. Authors obtained raw data on a total of 10,933 people from 25 trials. Results indicate that vitamin D supplementation reduced the risk of having at least one ARI. Furthermore, vitamin D had greater protective effects when it was given daily or weekly to people with the lowest vitamin D levels: the risk of having at least one ARI was reduced from 60% to 32% in these individuals. Authors conclude that their findings add to the body of evidence supporting the introduction of public health measures, such as food fortification, to improve vitamin D status in settings in which profound vitamin D deficiency is common.
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 D or vitamin D 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 < 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; = 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; = 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; = 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.
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