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Small vitamin D doses provide small benefits for acute respiratory infections – Meta-analysis March 2021


Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials - March 2021

www.thelancet.com/diabetes-endocrinology DOI:https://doi.org/10.1016/S2213-8587(21)00051-6
David A Jolliffe, PhD; Prof Carlos A Camargo Jr, MD; John D Sluyter, PhD; Mary Aglipay, MSc
Prof John F Aloia, MD; Davaasambuu Ganmaa, PhD

Background
A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.

Methods
For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0–49·9 nmol/L vs 50·0–74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400–1000 IU vs 1001–2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00–15·99 years vs 16·00–64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.

Findings
We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0–95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86–0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65–0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400–1000 IU (0·70 [0·55–0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72–0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00–15·99 years at enrolment (0·71 [0·57–0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86–1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.

Interpretation
Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400–1000 IU for up to 12 months, and age at enrolment of 1·00–15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
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VitaminDWiki comment and other studies

Of the 1500 trials to chose from,
   most of the trials selected by this meta-analysis used <2,000 IU
   about 20% of the trials were too short (<3 months) to expect any response to non-bolus doses

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Breathing Meta-analysis

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20 studies in Breathing with non-daily Intervention

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Breathing items with ACUTE in title

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Items found: 15
Title Modified
Acute respiratory tract infections not reduced by Vitamin D if already have a good level – Jan 2021 30 Sep, 2023
Small doses of vitamin D do not reduce risk of Acute Respiratory Infection - meta-analysis Feb 2022 15 Feb, 2022
Acute viral respiratory infections (RTI) reduced by Vitamin D - 20 reviews - Aug 2020 24 Sep, 2021
Small vitamin D doses provide small benefits for acute respiratory infections – Meta-analysis March 2021 31 Mar, 2021
Acute pneumonia in children 3X less likely if greater than 30 ng of vitamin D – Jan 2021 20 Mar, 2021
Acute respiratory distress – 100 percent of patients were vitamin D deficient– April 2015 09 Jun, 2019
Acute respiratory tract infections prevented by vitamin D (even when ignoring the dose size – Meta-analysis Feb 2017 09 Aug, 2017
Acute Lower Respiratory Infections in Children - associated with low vitamin D – meta-analysis Dec 2014 16 Sep, 2016
Acute respiratory infection treated by vitamin D in 6 of 12 clinical trials – review Nov 2012 15 May, 2016
Acute respiratory infection worsened by too infrequent vitamin D supplementation – RCT June 2015 17 Dec, 2015
Common cold (Acute Rhinosinusitis) 12 percent more likely for every 10 nanogram lower Vitamin D – Oct 2015 13 Oct, 2015
Low dose Vitamin D during pregnancy and infancy results in strange acute respiratory infection response – April 2015 24 Mar, 2015
Acute lower respiratory infection 5X more frequent with low vitamin D intake – June 2012 20 Mar, 2015
Newborn acute lower respiratory tract infection associated with low maternal vitamin D – March 2015 20 Mar, 2015
100 percent of Acute Respiratory Failure patients had low vitamin D - April 2012 21 Jun, 2013


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