key: cord-262773-mfta0emi
authors: Jolliffe, D.; Camargo, C. A.; Sluyter, J.; Aglipay, M.; Aloia, J.; Bergman, P.; Damsgaard, C.; Dubnov-Raz, G.; Esposito, S.; Ganmaa, D.; Gilham, C.; Ginde, A.; Grant, C.; Griffiths, C.; Hibbs, A. M.; Janssens, W.; Khadilkar, A. V.; Laaksi, I.; Lee, M. T.; Loeb, M.; Maguire, J.; Mauger, D. T.; Majak, P.; Manaseki-Holland, S.; Murdoch, D.; Nakashima, A.; Neale, R. E.; Rake, C.; Rees, J.; Rosendahl, J.; Scragg, R.; Shah, D.; Shimizu, Y.; Simpson-Yap, S.; Trilok Kumar, G.; Urashima, M.; Martineau, A. R.
title: Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials
date: 2020-07-17
journal: nan
DOI: 10.1101/2020.07.14.20152728
sha: 
doc_id: 262773
cord_uid: mfta0emi

Objectives: To assess the overall effect of vitamin D supplementation on risk of acute respiratory infection (ARI), and to identify factors modifying this effect. Design: We conducted a systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. Data Sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard RCT Number (ISRCTN) registry from inception to May 2020. Eligibility Criteria for Selecting Studies: Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Results: We identified 40 eligible RCTs (total 30,956 participants, aged 0 to 95 years). Data were obtained for 29,841 (96.5%) of 30,909 participants in 39 studies. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.89, 95% CI 0.81 to 0.98; P for heterogeneity 0.009). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of [≤]12 months (OR 0.82, 95% CI 0.72 to 0.94). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.94, 95% CI 0.81 to 1.08). Risk of bias within individual studies was assessed as being low for all but two trials. A funnel plot showed asymmetry, suggesting that small trials showing non-protective effects of vitamin D may have been omitted from the meta-analysis. Conclusions: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. The overall effect size may have been over-estimated due to publication bias. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.

Conclusions: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. The overall effect size may have been over-estimated due to publication bias. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.

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• A previous individual participant data meta-analysis from 10 • Sub-group analysis revealed most benefit in those with the lowest vitamin D status at baseline and not receiving bolus doses. • We updated this meta-analysis with trial-level data from an additional 14 placebo-controlled RCTs published since December 2015 (i.e. new total of 39 studies with 29,841 participants).

• An overall protective effect of vitamin D supplementation against ARI was seen (NNT=36).

• A funnel plot revealed evidence of publication bias, which could have led to an over-estimate of the protective effect.

• No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration.

• Strongest protective effects were associated with administration of daily doses of 400-1000 IU vitamin D for ≤ 12 months (NNT=8).

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Interest in the potential for vitamin D supplementation to reduce risk of acute respiratory infections (ARI) has increased since the emergence of the COVID -19 pandemic. 1 This stems from findings of laboratory studies, showing that vitamin D metabolites support innate immune responses to respiratory viruses, 2 together with observational studies reporting independent associations between low circulating levels of 25-hydroxyvitamin D (25[OH]D, the widely accepted biomarker of vitamin D status) and increased risk of ARI caused by other pathogens. 3 4 Randomised controlled trials (RCTs) of vitamin D for the prevention of ARI have produced heterogeneous results, with some showing protection, and others reporting null findings. We previously meta-analysed individual participant data from 25 RCTs and showed a protective overall effect that was stronger in those with lower baseline 25(OH)D levels, and in trials where vitamin D was administered daily or weekly rather than in more widely spaced bolus doses. 30 Since the date of the final literature search performed for that study (December 2015) , fifteen RCTs with 19,569 participants fulfilling the same eligibility criteria have been completed and analysed. [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] We therefore sought data from these more recent studies for inclusion in an updated metaanalysis of aggregate (trial-level) data to determine whether vitamin D reduced ARI risk overall, and to evaluate whether effects of vitamin D on ARI risk varied according to baseline 25(OH)D concentration and/or dosing regimen (frequency, dose size, and trial duration).

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Methods were pre-specified in a protocol that was registered with the PROSPERO 

PPI representatives were not involved in the conduct of this study.

Randomised, double-blind, trials of supplementation with vitamin D 3 , vitamin D 2 or 25(OH)D of any duration, with a placebo or low-dose vitamin D control, were eligible for inclusion if they had been approved by a Research Ethics Committee and if data on incidence of ARI were collected prospectively and pre-specified as an efficacy outcome. The latter requirement was imposed in order to minimise misclassification bias (prospectively designed instruments to capture ARI events were deemed more likely to be sensitive and specific for this outcome). Studies reporting results of longterm follow-up of primary RCTs were excluded.

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Summary data from trials which contributed to our previous meta-analysis of individual participant data 30 were extracted from our central database, with permission from the Principal Investigators. Summary data relating to the primary outcome (overall and by sub-group) and secondary outcomes (overall only) from newly identified trials were requested from Principal Investigators. On receipt, they were assessed for consistency with associated publications. Study authors were contacted to provide missing data and to resolve any queries arising from these consistency checks. Once queries had been resolved, clean summary data were uploaded to the study database, which was held in STATA IC v14.2 (StataCorp, College Station, TX).

Data relating to study characteristics were extracted for the following variables: study setting, eligibility criteria, 25(OH)D assay and levels, details of intervention and control regimens, trial duration, case definitions for ARI and number entering primary analysis (after randomisation). Follow-up summary data were requested for the proportions of participants experiencing one or more ARI during the trial, both overall and stratified by baseline serum 25(OH)D concentration, where this was available. We also requested summary data on the proportions of participants who experienced one or more of the following events during the trial: upper respiratory infection (URI); lower respiratory infection (LRI); Emergency Department attendance and/or hospital admission for ARI; death due to ARI or respiratory failure; use of antibiotics to treat an ARI; absence from work or school due to ARI; a serious adverse event; death due to any cause; and potential adverse reactions to vitamin D (hypercalcaemia and renal stones).

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We used the Cochrane Collaboration Risk of Bias tool 46 to assess the following variables: 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. Study quality was assessed independently by two investigators (ARM and DAJ), except for the five trials for which DAJ and/or ARM were investigators, which were assessed by CAC.

Discrepancies were resolved by consensus.

The primary outcome of the meta-analysis was the proportion of participants experiencing one or more ARIs, with the definition of ARI encompassing events classified as URI, LRI and ARI of unclassified location (i.e. infection of the upper and/or lower respiratory tract). Secondary outcomes were incidence of URI and LRI, analysed separately; incidence of Emergency Department attendance and/or hospital admission for ARI; death due to ARI or respiratory failure; use of antibiotics to treat an ARI; absence from work or school due to ARI; incidence of serious adverse events; death due to any cause; and incidence of potential adverse reactions to vitamin D (hypercalcaemia and renal stones).

Data were analysed by DAJ; results were checked and verified by JDS. Our metaanalysis approach followed published guidelines. 47 The primary comparison was of participants randomised to vitamin D vs. placebo: this was performed for all of the outcomes listed above. For trials that included higher-dose, lower-dose and placebo arms, data from higher-dose and lower-dose arms were pooled for analysis of the primary comparison. A secondary comparison of participants randomised to higher vs. lower doses of vitamin D was performed for the primary outcome only. A log odds ratio and its standard error was calculated for each outcome within each trial from the proportion of participants experiencing one or more events in the intervention vs.

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The copyright holder for this preprint this version posted July 17, 2020. . control arm. These were meta-analysed in a random effects model using the Metan package 48 within STATA IC v14.2 to obtain a pooled odds ratio with a 95% confidence interval and a measure of heterogeneity summarized by the I 2 statistic and its corresponding P value. The number needed to treat for an additional beneficial outcome (NNT) was calculated using the Visual Rx NNT calculator (http://www.nntonline.net/visualrx/) where meta-analysis of dichotomous outcomes revealed a statistically significant beneficial effect of allocation to vitamin D vs.

placebo.

To explore reasons for heterogeneity of effect of the intervention between trials we sub-optimal vitamin D status (so-called 'vitamin D insufficiency', 50-74.9 nmol/L). 49 An exploratory analysis restricted to studies with optimal frequency, dose size and duration was also performed.

To investigate factors associated with heterogeneity of effect between subgroups of trials, we performed multivariable meta-regression analysis on trial-level characteristics, namely, dose frequency, dose size and trial duration, to produce an adjusted odds ratio, a 95% confidence interval and a P value for interaction for each factor. Independent variables were dichotomised to create a more parsimonious model The meta-regression analysis excluded data from one trial that included higher-dose, lower-dose and placebo arms, 18 since the higher-dose and lower-dose arms spanned the 1,000 IU/day cut-off, rendering it unclassifiable for the purposes of this analysis.

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For the primary analysis, the likelihood of publication bias was investigated through the construction of a contour-enhanced funnel plot. 50 We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) 51 to assess the quality of the body of evidence contributing to analyses of the primary efficacy outcome and major secondary outcomes of our metaanalysis.

We conducted two exploratory sensitivity analyses for the primary comparison of the primary outcome: one excluded RCTs where risk of bias was assessed as being unclear; the other excluded RCTs in which incidence of ARI was not the primary or coprimary outcome.

This study was conducted without external funding.

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The study selection process is illustrated in Figure 1 compared effects of higher-dose, lower-dose and placebo arms, 18 21 24 41 and 5 compared effects of higher-vs. lower-dose regimens of vitamin D only. 29 32 34 35 37 Aggregate data were sought and obtained for all but 1 study. 45 Table S1 .

Characteristics of the 39 studies contributing data to this meta-analysis and their participants are presented in Table 1 . Trials were conducted in 17 different countries on 4 continents, and enrolled participants of both sexes from birth to 95 years of age.

Baseline serum 25(OH)D concentrations were determined in 32 of 39 trials: mean baseline 25(OH)D concentration ranged from 18.9 to 90.9 nmol/L (to convert to ng/ml, divide by 2.496). Thirty-eight studies administered oral vitamin D 3 to participants in the intervention arm, while 1 study administered oral 25(OH)D. Vitamin D was given as monthly to 3-monthly bolus doses in 12 studies; as weekly doses in 5 studies; as daily doses in 20 studies; and as a combination of bolus and daily doses in 2 studies. Trial duration ranged from 8 weeks to 3 years. Incidence of ARI was primary or co-primary outcome for 21 studies, and a secondary outcome for 18 studies.

Details of the risk of bias assessment are provided in supplementary Table S2 . Two trials were assessed as being at unclear risk of bias due to high loss to follow-up. In the trial by Laaksi and colleagues, 8 37% of randomised participants were lost to follow-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 17, 2020. . up. In the trial by Dubnov-Raz and colleagues, 26 52% of participants did not complete all symptom questionnaires. All other trials were assessed as being at low risk of bias for all seven aspects assessed. Table 2 ; Cates Plot, Figure S1 ).

Heterogeneity of effect was moderate (I 2 40.0%, P for heterogeneity 0.009). The associated NNT was 36 (95% CI 20 to 206).

For the secondary comparison of higher-vs. lower-dose vitamin D, we observed no statistically significant difference in the proportion of participants with at least one ARI (OR 0.86, 95% CI 0.71 to 1.04; 2,889 participants in 9 studies; I 2 8.0%, P for heterogeneity 0.37; Figure S2 ).

To investigate reasons for the observed heterogeneity of effect for the primary comparison of vitamin D vs. placebo control, we stratified this analysis by one participant-level factor (baseline vitamin D status) and by three trial-level factors (dose frequency, dose size, and trial duration). Results are presented in Table 2 Figure S3 ). With regard to dosing frequency, a statistically significant protective effect was seen for trials where vitamin D was given daily (OR 0.75, 95% CI 0.61 to 0.93; 4,005 participants in 18 studies), but not for trials in which it was given weekly (OR 0.97, 95% CI 0.88 to 1.06; 12,562 participants in 5 studies), or monthly to 3-monthly (OR 1.00, 95% CI 0.91 to 1.09; 11,248 participants in 11 studies; Figure   . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 17, 2020. . S4). Statistically significant protective effects of the intervention were also seen in trials where vitamin D was administered at daily equivalent doses of 400-1000 IU ( Figure S5 ). Statistically significant protective effects were also seen for trials with a duration of ≤ 12 months (OR 0.82, 95% CI 0.72 to 0.94; 9,061 participants in 28 studies) but not in those lasting >12 months (OR 1.03, 95% CI 0.95 to 1.11; 18,754 participants in 6 studies; Figure S6 ). An exploratory analysis restricted to placebo-controlled trials investigating effects of daily dosing at doses of 400-1000 IU/day with duration ≤ 12 months showed a statistically significant reduction in the proportion of participants experiencing at least one ARI (OR 0.58, 95% CI 0.45 to 0.75; 1,232 participants in 8 studies; Figure S7 ; Cates Plot, Figure S1 ).

Heterogeneity of effect was low (I 2 0.0%, P for heterogeneity 0.67). The associated NNT was 8 (95% CI 6 to 15).

Multivariable meta-regression analysis of trial-level sub-groups did not identify a statistically significant interaction between allocation to vitamin D vs. placebo and dose frequency, size or trial duration (Table S3) .

Meta-analysis of secondary outcomes was performed for results of placebo-controlled trials only; results are presented in Table 3 . Overall, without consideration of participant-or trial-level factors, vitamin D supplementation did not have a statistically significant effect on the proportion of participants with one or more URI, LRI, courses of antimicrobials for ARI, work/school absences due to ARI, hospitalisations or emergency department attendances for ARI, serious adverse events of any cause, death due to ARI or respiratory failure, death due to any cause, or episodes of hypercalcaemia or renal stones.

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A funnel plot for the proportion of participants experiencing at least one ARI showed left-sided asymmetry, raising the possibility that small trials showing non-protective effects of vitamin D may not have been included in the meta-analysis ( Figure S8 ). An

Egger's regression test for publication bias 52 confirmed asymmetry (P=0.002).

Accordingly, the quality of the body of evidence contributing to analyses of the primary efficacy outcome and major secondary outcomes was downgraded to moderate (Table   S4 ).

Results of exploratory sensitivity analyses are presented in Table S5 . Meta-analysis of the proportion of participants in placebo-controlled trials experiencing at least one ARI, excluding 2 studies assessed as being at unclear risk of bias, 8 pandemic, we used a trial-level approach for this update, which includes data from a total of 29,841 participants in 39 trials. Overall, we report a modest statistically significant protective effect of vitamin D supplementation, as compared with placebo (OR 0.89, 95% CI 0.81 to 0.98). As expected, there was significant heterogeneity (P=0.009) across trials, which might have led to an under-estimate of the protective effect. On the other hand, a funnel plot revealed evidence of publication bias, which might have led to an over-estimate of the protective effect. In contrast to findings of our . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 17, 2020. . previous meta-analysis, 30 we did not observed enhanced protection in those with the lowest 25(OH)D levels at baseline. However, there was evidence that efficacy of vitamin D supplementation varied according to dosing regimen and trial duration, with protective effects associated with daily administration of doses of 400-1000 IU vitamin D given for ≤ 12 months. An exploratory analysis restricted to data from 8 trials fulfilling these design criteria revealed a larger protective effect (OR 0.58, 95% CI 0.45 to 0.75) without significant heterogeneity across trials (P for heterogeneity 0.67).

The magnitude of the overall protective effect seen in the current analysis (OR 0.89, 95% CI 0.81 to 0.98) is similar to the value reported in our previous meta-analysis of individual participant data (adjusted OR 0.88, 95% CI 0.81 to 0.96). 30 In keeping with our previous study, the point estimate for this effect was lower among those with baseline 25(OH)D <25 nmol/L than in those with higher baseline vitamin D status.

However, in contrast to our previous finding, a statistically significant protective effect of vitamin D was not seen in those with the lowest 25(OH)D concentrations. This difference reflects the inclusion of null data from three new RCTs in which vitamin D was given in relatively high doses at weekly or monthly intervals over 2-3 years. 40 42 44 Null results of these studies contrast with protective effects reported from earlier trials in which smaller daily doses of vitamin D were given over shorter periods. 8 9 13 16 These differing findings suggest that the frequency, amount and duration of vitamin D supplementation may be key determinants of its protective efficacy. In keeping with this hypothesis, statistically significant protective effects of vitamin D were seen for meta-analysis of trials where vitamin D was given daily; where it was given at doses of 400-1000 IU/day; and where it was given for 12 months or less. When results of trials that investigated daily administration of 400-1000 IU over ≤ 12 months were pooled in an exploratory meta-analysis, a protective effect was seen (OR 0.58, 95% CI 0.45 to 0.75) with low heterogeneity (I 2 0.0%, P for heterogeneity 0.67) and a NNT of 8 (95% CI 6 to 15).

The current study has several strengths: it contains the very latest RCT data available in this fast-moving field, including findings from a soon-to-be published very large trial conducted using directly-observed, higher-dose, weekly vitamin D supplementation in very deficient children. 42 The inclusion of additional studies allowed us to analyse results of placebo-controlled studies vs. high-dose / low-dose studies separately, and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 17, 2020. . https://doi.org/10.1101/2020.07.14.20152728 doi: medRxiv preprint gave us the power to investigate reasons for heterogeneity of effect observed across trials. For example, we could distinguish the effects of daily vs. weekly dosing, which were previously pooled. 30 Our work also has limitations. Given the need to generate a rapid update of our previous work in the context of the COVID-19 pandemic, we meta-analysed aggregate (trial-level) data, rather than individual participant data; this allowed us to proceed rapidly, without the delays introduced by the need to establish multiple data sharing agreements. However, we did contact authors to get unpublished estimates of effect that were stratified by pre-defined baseline 25(OH)D levels, harmonised across studies: thus, we were able to provide accurate data for the major participant-level effect-modifier of interest. Despite the large number of trials overall, relatively few compared effects of lower-vs. higher-dose vitamin D: our power for this secondary comparison was therefore limited. We lacked the individual participant data to investigate race/ethnicity and obesity as potential effect-modifiers. We also could not account for other factors that might influence the efficacy of vitamin D supplements for ARI prevention (e.g., taking the supplement with or without food) or secular trends that would influence trials, such as the increased societal use of vitamin D supplements; 53 concurrent use of standard dose vitamin D supplements or multivitamins in the "placebo" group would effectively render these as high-vs. low-dose trials and potentially drive results toward the null. A final limitation relates to the funnel plot, which suggests that the overall effect size may have been over-estimated due to publication bias.

In summary, this updated meta-analysis of data from RCTs of vitamin D for the prevention of ARI showed a statistically significant overall protective effect of the intervention. The number needed to treat to prevent one ARI was 36. The protective effect was heterogenous across trials; it also may have been over-estimated due to publication bias. In contrast to findings of our previous meta-analysis of individual participant data, we did not see a protective effect of vitamin D supplementation among those with the lowest baseline vitamin D status. The vitamin D dosing regimen of most benefit was daily and used standard doses (e.g., 400 to 1000 IU) for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.

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This study was conducted without external funding. DAJ is supported by a Barts

Students. The views expressed are those of the authors and not necessarily those of Barts Charity or the Office for Students. Sources of support for individual trials are detailed in Supplementary Material. We thank Dr Emma C Goodall (GlaxoSmithKline plc) for contributing data. We also thank all the people who participated in primary randomised controlled trials, and the teams who conducted them.

DAJ and ARM wrote the study protocol and designed statistical analyses. DAJ, CAC and ARM assessed eligibility of studies for inclusion and performed risk of bias assessments. Statistical analyses were done by DAJ; results were checked and verified by JDS. DAJ and ARM wrote the first draft of the report. All authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

All authors have completed the ICMJE uniform disclosure form. No author has had any financial relationship with any organisations that might have an interest in the submitted work in the previous three years. No author has had any other relationship, or undertaken any activity, that could appear to have influenced the submitted work.

DAJ and ARM are the manuscript's guarantors and they affirm that this is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. All analyses were pre-specified in the study protocol, other than the exploratory analyses whose results are presented in Table S5 and Figure S7 .

Data Sharing: the study dataset is available from d.a.jolliffe@qmul.ac.uk.

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Vitamin D and Acute Respiratory Infections-The PODA Trial

Effect of monthly high-dose vitamin D supplementation on acute respiratory infections in older adults: A randomized controlled trial

Winter cholecalciferol supplementation at 55 degrees N has little effect on markers of innate immune defense in healthy children aged 4-8 years: a secondary analysis from a randomized controlled trial

Vitamin D Supplements and Prevention of Tuberculosis Infection and Disease

Occurrence of infections in schoolchildren subsequent to supplementation with vitamin D-calcium or zinc: a randomized, doubleblind, placebo-controlled trial

High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus doubleblind individual randomisation

Impact of two oral doses of 100,000 IU of vitamin D3 in preschoolers with viral-induced asthma: a pilot randomised controlled trial

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

Cochrane Handbook for Systematic Reviews of Interventions version 6

METAN: Stata module for fixed and random effects meta-analysis, revised 23

Diagnosis and management of vitamin D deficiency

Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

Bias in meta-analysis detected by a simple, graphical test

Longitudinal and secular trends in dietary supplement use: Nurses' Health Study and Health Professionals Follow-Up Study

Pharmacokinetics of oral vitamin D(3) and calcifediol