BMJ · 2017. 2. 16. · Adrian R Martineau 1,2† David A Jolliffe 1 Richard L Hooper1 Lauren...

Confidential: For Review O

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Vitamin D supplementation to prevent acute respiratory

infections: systematic review and meta-analysis of

individual participant data

Journal: BMJ

Manuscript ID BMJ.2016.034434

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 11-Jul-2016

Complete List of Authors: Martineau, Adrian; Queen Mary University of London Jolliffe, David; Queen Mary University of London Hooper, Richard; Queen Mary University of London, Institute of Health Sciences Education Greenberg, Lauren; Queen Mary University of London Aloia, John ; Winthrop University Hospital, Bergman, Peter; Karolinska Institutet, Dept of Laboratory Medicine, Div of Clinical Microbiology Dubnov-Raz, Gal; Edmond and Lily Safra Children's Hospital, Tel Hashomer Esposito, Susanna; Fondazione IRCCS Ca' Granda Ospedale Maggiore policlinico, University of Milan, - Ganmaa, Davaasambuu; Harvard School of Public Health

Ginde, Adit; University of Colorado Denver Goodall, Emma; McMaster University Grant, Cameron; University of Auckland, Paediatrics Griffiths, Chris; Queen Mary, General Practice Janssens, Wim; Universitaire Ziekenhuizen Leuven Laaksi, Ilkka; Tampereen yliopistollinen sairaala Manaseki-Holland, Semira; University of Birmingham Mauger, David; Pennsylvania State University Murdoch, David; University of Otago, Pathology Neale, Rachel; QIMR Berghofer Medical Research Institute Rees, Judith; Dartmouth College Geisel School of Medicine Simpson, Steve; University of Tasmania

Stelmach, Iwona; Uniwersytet Medyczny w Lodzi Trilok-Kumar, Geeta; Institute of Home Economics, Delhi University, Urashima, Mitsuyoshi; Tokyo Jikeikai Ika Daigaku Camargo, Carlos; Massachusetts General Hospital, Harvard Medical School, Emergency Medicine

Keywords: Vitamin D, Acute respiratory infection, Individual patient data meta-analysis, Randomised controlled trials

https://mc.manuscriptcentral.com/bmj

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Vitamin D supplementation to prevent acute respiratory infections: systematic

review and meta-analysis of individual participant data

Adrian R Martineau1,2†

David A Jolliffe1

Richard L Hooper1

Lauren Greenberg1

John F Aloia3

Peter Bergman4

Gal Dubnov-Raz5

Susanna Esposito6

Davaasambuu Ganmaa7

Adit A Ginde8

Emma C Goodall9

Cameron C Grant10

Christopher J Griffiths1,2,11

Wim Janssens12

Ilkka Laaksi13

Semira Manaseki-Holland14

David Mauger15

David R Murdoch16

Rachel Neale17

Judy R Rees18

Steve Simpson Jr19

Iwona Stelmach20

Geeta Trilok Kumar21

Mitsuyoshi Urashima22

Carlos A Camargo Jr23

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1Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK 3Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA 4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 5Dept. of Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel 6 Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy 7Department of Nutrition, Harvard School of Public Health, Boston, MA, USA 8Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA 9Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada 10Department of Paediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 11MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Blizard Institute, Queen Mary University of London, London, UK 12Universitair ziekenhuis Leuven, Leuven, Belgium 13Tampere School of Public Health, University of Tampere, Tampere, Finland 33014 14Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK 15Department of Statistics, The Pennsylvania State University, Hershey, PA, USA 16Department of Pathology, University of Otago, Christchurch, New Zealand 17QIMR Berghofer Medical Research Institute, Queensland, Australia 18 Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA 19Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 20Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland 21Institute of Home Economics, University of Delhi, New Delhi, India 22Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan 23Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA † To whom correspondence should be addressed at Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 58 Turner St, London E1 2AB, UK Tel: +44 207 882 2551 │Fax: +44 207 882 2552 │Email: [email protected]

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Abstract

Objectives: To determine the overall effect of vitamin D supplementation on risk of

acute respiratory infections, and to identify factors modifying this effect.

Design: Individual patient data (IPD) meta-analysis of randomised controlled trials

(RCTs), using one-step logistic regression with random effects adjusting for age, sex,

study duration and clustering by study. Pre-specified sub-group analyses were done to

determine whether effects of vitamin D on risk of acute respiratory infection varied

according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen.

Data Sources: Twenty-five RCTs enrolling a total of 11,321 participants, aged 0 to 95

years.

Study Eligibility Criteria: Double-blind RCTs of vitamin D supplementation in which

data on incidence of acute respiratory infections were collected prospectively and pre-

specified as an efficacy outcome.

Results: IPD were obtained for 10,933/11,321 (96.6%) participants. Vitamin D

supplementation reduced risk of acute respiratory infections among all participants

(adjusted Odds Ratio [aOR] 0.88, 95% CI 0.81 to 0.96, P=0.003; P for heterogeneity

<0.001). Sub-group analysis revealed a strong protective effect among individuals with

baseline 25(OH)D <25 nmol/L (aOR 0.62, 95% CI 0.45 to 0.83, P=0.002), not seen

among those with higher levels (aOR 0.91, 95% CI 0.78 to 1.05; Pinteraction=0.01). A

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protective effect was also seen in individuals receiving daily or weekly vitamin D without

additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91, P<0.001), but not in those

receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10, Pinteraction=0.05).

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.

Conclusions: Vitamin D supplementation was safe, and it protected against acute

respiratory infections overall. Very deficient individuals and those not receiving bolus

doses experienced the most benefit.

Registration: http://www.crd.york.ac.uk/PROSPERO CRD42014013953

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What is already known on this subject?

• Randomised controlled trials of vitamin D supplementation for the

prevention of acute respiratory infection (ARI) have yielded

conflicting results.

• Individual participant data meta-analysis has the potential to identify

factors that may explain this heterogeneity, but has not previously

been performed.

What this study adds

• Meta-analysis of individual participant data from 10,933 participants

in 25 randomised controlled trials demonstrated an overall

protective effect of vitamin D supplementation against ARI (number

needed to treat to prevent one ARI [NNT]=33).

• Sub-group analysis revealed greater benefit in very deficient

individuals (NNT=10) and in those receiving daily or weekly vitamin

D without additional bolus doses (NNT=20).

• Our findings support the introduction of public health measures

such as food fortification to improve vitamin D status in settings

where profound vitamin D deficiency is common.

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Introduction

Acute respiratory infections (ARI) are a major cause of global morbidity and mortality,

responsible for an estimated 2.65 million deaths worldwide in 2013.1 Case-control and

cohort studies report consistent independent associations between low serum

concentrations of 25-hydroxyvitamin D (25[OH]D) - the major circulating vitamin D

metabolite - and susceptibility to ARI.2 The observation that 25(OH)D supports induction

of antimicrobial peptides in response to both viral and bacterial stimuli3-5 suggests a

potential mechanism by which vitamin D-inducible protection may be mediated. These

epidemiological and in vitro data have prompted numerous randomised controlled trials

to determine whether vitamin D supplementation can decrease risk of ARI. A 2013

meta-analysis of 11 of these randomised controlled trials reported a net protective effect

of vitamin D supplementation (OR, 0.64; 95% CI, 0.49 to 0.84), but with significant

heterogeneity of effect between trials (I2 = 72%).6 This heterogeneity may have arisen

as a result of inter-trial variation in participant characteristics and in dosing regimens,

either of which may modify the effects of vitamin D supplementation on immunity to

respiratory pathogens.7 While study-level factors are amenable to exploration via

aggregate data meta-analysis of published data, effect modifiers operating at an

individual level, such as baseline vitamin D status, can only be explored using individual

participant data (IPD) meta-analysis. This is because sub-groups are not consistently

disaggregated in trial reports, and consistent adjustments for potential confounders

cannot be applied.8 In order to identify factors that might explain the observed

heterogeneity of randomised controlled trial results, we undertook an IPD meta-analysis

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based on all 25 randomised controlled trials of vitamin D supplementation for ARI

prevention that have been completed to date.

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Methods

Protocol and Registration

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

International Prospective Register of Systematic Reviews

(http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013953 ).

Research Ethics Committee approval to conduct this meta-analysis was not required in

the UK. Local ethical permission to contribute de-identified IPD from primary trials was

required and obtained for studies by Camargo et al9 (The Ethics Review Committee of

the Mongolian Ministry of Health), Murdoch et al10 (Southern Health and Disability

Ethics Committee, ref. URB/09/10/050/AM02), Rees et al11 (Committee for the

Protection of Human Subjects, Dartmouth College, USA; Protocol # 24381), Tachimoto

et al12 (Ethics committee of the Jikei University School of Medicine, ref 26-333: 7839),

Tran et al13 (QIMR Berghofer Medical Research Institute Human Research Ethics

Committee, P1570) and Urashima et al14 15 (Ethics committee of the Jikei University

School of Medicine, ref 26-333: 7839).

Patient and Public Involvement (PPI)

Two PPI representatives were involved in development of the research question and the

choice of outcome measures specified in the study protocol. They were not involved in

patient recruitment, since this is a meta-analysis of completed studies. PPI

representatives and participants in primary trials are thanked for their contributions in

Acknowledgements.

Eligibility Criteria

Randomized, 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 ARI were collected

prospectively and pre-specified as an efficacy outcome. The latter requirement was

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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 long-term follow-up of primary RCTs were

excluded.

Study Identification and Selection

Two investigators (ARM and DAJ) searched MEDLINE, EMBASE, the Cochrane Central

Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the

International Standard Randomized Controlled Trials Number (ISRCTN) registry using

the electronic search strategies described in Supplementary Material. Searches were

regularly updated up to and including 31st December 2015. No language restrictions

were imposed. These searches were supplemented by searching review articles and

reference lists of trial publications. Collaborators were asked if they knew of any

additional trials. Two investigators (ARM and CAC) determined which trials met the

eligibility criteria.

Data Collection Processes

IPD were requested from the Principal Investigator for each eligible trial, and the terms

of collaboration were specified in a data transfer agreement, signed by representatives

of the data provider and the recipient (Queen Mary University of London). Data were de-

identified at source prior to transfer via email. On receipt, three investigators (DAJ, RLH

and LG) assessed data integrity by performing internal consistency checks and by

attempting to replicate results of the analysis for ARI incidence where this was

published in the trial report. Study authors were contacted to provide missing data and

to resolve queries arising from these integrity checks. Once queries had been resolved,

clean data were uploaded to the main study database, which was held in STATA IC v12

(College Station, TX).

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Data relating to study characteristics were extracted for the following variables: setting,

eligibility criteria, details of intervention and control regimens, study duration and case

definitions for ARI. IPD were extracted for the following variables, where available.

Baseline data were requested for age, sex, cluster ID (cluster-randomized trials only),

racial / ethnic origin, influenza vaccination status, history of asthma, history of chronic

obstructive pulmonary disease, weight, height (adults and children able to stand) or

length (infants), serum 25(OH)D concentration, study allocation (vitamin D vs. placebo)

and details of any stratification or minimization variables. Follow-up data were

requested for total number of ARI, upper respiratory infections (URI) and lower

respiratory infections (LRI) experienced during the trial, time from first dose of study

medication to first ARI / URI / LRI if applicable, total number of courses of antibiotics

taken for ARI during the trial, total number of days off work or school due to ARI

symptoms during the trial, serum 25(OH)D concentration at final follow-up, duration of

follow-up, number and nature of serious adverse events, number of adverse reactions

(incident hypercalcemia or renal stones) and end-trial status (completed vs. withdrew

vs. lost to follow-up vs. died).

Risk of Bias Assessment for Individual Studies

We used the Cochrane Collaboration Risk of Bias tool16 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 three trials

by Martineau and colleagues, which were assessed by CAC. Discrepancies were

resolved by consensus.

Definition of outcomes

The primary outcome of the meta-analysis was incidence of ARI, incorporating events

classified as URI, LRI and ARI of unclassified location (i.e. infection of the upper and/or

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lower respiratory tract). Secondary outcomes were incidence of URI and LRI, analysed

separately; incidence of Emergency Department attendance and/or hospital admission

for ARI; use of antimicrobials for treatment of ARI; rate of work / school absence due to

ARI; incidence and nature of serious adverse events; incidence of potential adverse

reactions to vitamin D (hypercalcaemia and renal stones); and mortality (ARI-related

and all-cause).

Synthesis Methods

Data were analysed by LG and RLH. Our IPD meta-analysis approach followed

published guidelines.8 Initially, all studies were re-analysed separately; the original

authors were asked to confirm accuracy of this re-analysis where it had been performed

previously, and any discrepancies were resolved. Then, for each outcome separately,

we performed both one-step and two-step IPD meta-analysis using a random effects

model adjusted for age, sex and study duration to obtain the pooled intervention effect

with a 95% confidence interval. For one-step IPD meta-analysis, heterogeneity was

assessed by calculation of the standard deviation of random effects; for two-step IPD

meta-analysis, heterogeneity was summarized using the I2 statistic. The number

needed to treat for an additional beneficial outcome (NNTB) 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.

Exploration of variation in effects

In order to explore the causes of heterogeneity and identify factors modifying the effects

of vitamin D supplementation, we performed pre-specified sub-group analyses by

extending the one-step meta-analysis framework to include treatment-covariate

interaction terms. Sub-groups were defined according to baseline vitamin D status

(serum 25[OH]D <25 vs. ≥25 nmol/L), vitamin D dosing regimen (daily or weekly

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administration without bolus dosing vs. administration of a regimen including at least

one bolus dose of at least 30,000 IU vitamin D), dose size (daily equivalent <800 IU vs.

800 – 1999 IU vs. ≥2,000 IU), age (≤1 year vs. 1.1 – 15.9 years vs. 16-65 years vs. >65

years), body mass index (<25 kg/m2 vs. ≥25 kg/m2) and presence vs. absence of

asthma, COPD and previous influenza vaccination. Interaction analyses were adjusted

for potential confounders (age, sex and study duration) in order to ensure that reported

sub-group effects were independent. The 25 nmol/L cut-off for baseline 25(OH)D

concentration in sub-group analyses was selected on the grounds that it is the threshold

for vitamin D deficiency defined by the UK Department of Health,17 and the level below

which participants in clinical trials have experienced the most consistent benefits of

supplementation.18 An exploratory analysis investigating effects in sub-groups defined

using the 50 nmol/L and 75 nmol/L cut-offs for baseline circulating 25(OH)D

concentration was also performed, because observational studies have reported that

less profound states of vitamin D deficiency may also associate independently with

increased risk of ARI.19 20 In order to minimise the chance of type 1 error arising from

multiple analyses, sub-group analyses were not performed for secondary outcomes.

Quality Assessment Across Studies

For the primary analysis, the likelihood of publication bias was investigated through the

construction of a contour-enhanced funnel plot.21 We used the five GRADE

considerations (study limitations, consistency of effect, imprecision, indirectness and

publication bias)22 to assess the quality of the body of evidence contributing to analyses

of the primary efficacy outcome and major safety outcome of our meta-analysis

(Supplementary Table S2).

Additional analyses

We conducted sensitivity analyses excluding IPD from trials where ARI was a

secondary outcome (as opposed to a primary or co-primary outcome), and where risk of

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bias was assessed as being unclear. We also conducted a responder analysis in

participants randomized to the intervention arm of included studies for whom end-study

25(OH)D data were available, comparing risk of ARI in those who attained a serum

25(OH)D ≥75 nmol/L vs. those who did not.

Role of the funding source

The National Institute of Health Research was not involved in study design; in the

collection, analysis or interpretation of data; in the writing of the report; or in the decision

to submit the paper for publication.

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Results

Study selection and individual participant data obtained

The study selection process is illustrated in Figure 1. Our search identified a total of 532

unique studies that were assessed for eligibility; of these, 25 studies with a total of

11,321 randomised participants fulfilled eligibility criteria. IPD were sought and obtained

for all 25 studies. Outcome data for the primary analysis of proportion of participants

experiencing at least one ARI were obtained for 10,933/11,321 (96.6%) randomised

participants.

Study and participant characteristics

Characteristics of eligible studies and their participants are presented in Table 1. Trials

were conducted in 14 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 20/25 trials: mean baseline 25(OH)D concentration ranged from 18.9 to

88.9 nmol/L (to convert to ng/ml, divide by 2.496). All studies administered oral vitamin

D3 to participants in the intervention arm: this was given as monthly to 3-monthly bolus

doses in 7 studies; as weekly doses in 3 studies; as a daily dose in 12 studies; and as a

combination of bolus and daily doses in 3 studies. Study duration ranged from 7 weeks

to 1.5 years. Incidence of ARI was primary or co-primary outcome for 14 studies, and a

secondary outcome for 11 studies.

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IPD integrity was confirmed by replication of primary analyses in published papers

where applicable. The process of checking IPD identified three typographical errors in

published reports. For the 2012 trial by Manaseki-Holland and colleagues,23 the correct

number of repeat episodes of chest radiograph-confirmed pneumonia was 134, rather

than 138 as reported. For the trial by Dubnov-Raz and colleagues,24 the number of

patients randomised to the intervention arm was 27, rather than 28 as reported. For the

trial by Laaksi and colleagues,25 the proportion of men randomised to placebo who did

not experience any ARI was 30/84, rather than 30/80 as reported.

Risk of Bias Within Studies

Details of the risk of bias assessment are provided in supplementary Table S1. 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 due to high rates of loss to follow-up. In

the trial by Dubnov-Raz and colleagues,24 52% of participants did not complete all

symptom questionnaires. In the trial by Laaksi and colleagues,25 37% of randomised

participants were lost to follow-up.

Overall Results, ARI incidence

Results of one-step IPD meta-analysis testing effects of vitamin D on the proportion of

all participants experiencing at least one ARI, adjusting for age, sex and study duration

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are presented in Table 2. Vitamin D supplementation resulted in a statistically significant

reduction in the proportion of participants experiencing at least one ARI (adjusted Odds

Ratio [aOR] 0.88, 95% CI 0.81 to 0.96, P=0.003; P for heterogeneity <0.001; NNTB 33,

95% CI 20 to 101; 10,933 participants in 25 studies; Cates plot, Figure S1). Statistically

significant protective effects of vitamin D were also seen for one-step analyses of ARI

rate (adjusted Incidence Rate Ratio [aIRR] 0.96, 95% CI 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 ARI (aHR 0.95, 95% CI 0.89 to 1.01, P=0.09; P for heterogeneity <0.001; 9,108

participants in 18 studies). Two-step analyses also showed consistent effects for the

proportion of participants experiencing at least one ARI (aOR 0.80, 95% CI 0.69 to 0.93,

P=0.004; P for heterogeneity =0.001; 10,899 participants in 24 studies; Figure 2), ARI

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 ARI (adjusted Hazard Ratio

0.92, 95% CI 0.85 to 1.00, P=0.051; P for heterogeneity =0.14; 9,108 participants in 18

studies). This evidence was assessed as being of high quality (Supplementary Table

S2).

Results of sub-group analyses, ARI incidence

In order to explore reasons for heterogeneity, sub-group analyses were conducted to

investigate whether effects of vitamin D supplementation on ARI risk differed according

to baseline vitamin D status, dosing frequency, dose size, age, body mass index, the

presence or absence of co-morbidity (asthma or COPD) or influenza vaccination status.

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Race/ethnicity was not investigated as a potential effect-modifier, as data for this

variable were missing for 3,680/10,933 (34%) of participants, and power for sub-group

analyses was limited by small numbers in many racial / ethnic sub-groups that could not

be meaningfully combined. Results are presented in Table 2. Sub-group analysis

revealed a strong protective effect of vitamin D supplementation among individuals with

baseline circulating 25(OH)D <25 nmol/L (aOR 0.62, 95% CI 0.45 to 0.83, NNTB 10,

95% CI 6 to 23; 871 participants in 15 studies; within sub-group P=0.002; Cates plot,

Figure S1), and no statistically significant effect among those with baseline 25(OH)D

≥25 nmol/L (aOR 0.91, 95% CI 0.78 to 1.05; 3,844 participants in 20 studies; within sub-

group P=0.19; P for interaction = 0.01). This evidence was assessed as being of high

quality (Supplementary Table S2). An exploratory analysis testing effects in individuals

with baseline 25(OH)D concentrations in the ranges 25-49.9 nmol/L, 50-74.9 nmol/L

and ≥75 nmol/L did not reveal statistically significant protective effects of vitamin D

supplementation within these sub-groups (Supplementary Table S3).

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 of vitamin D

against ARI (aOR 0.81, 95% CI 0.72 to 0.91, NNTB 20, 95% CI 13 to 43; 5,133

participants in 15 studies; within sub-group P<0.001; Cates plot, Figure S1). No such

protective effect was seen among participants in trials where at least one bolus dose of

vitamin D was administered (aOR 0.97, 95% CI 0.86 to 1.10; 5,800 participants in 10

studies; within sub-group P=0.67; P for interaction 0.05). This evidence was assessed

as being of high quality (Supplementary Table S2). P values for interaction were >0.05

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for all other potential effect modifiers investigated. For both of these sub-group

analyses, broadly consistent effects were observed for event rate analysis (Table S4)

and survival analysis (Table S5).

Secondary outcomes, efficacy

Results of one-step IPD meta-analysis of secondary outcomes are presented in Table

3. No statistically significant effect of vitamin D was seen on the proportion of

participants with at least one URI, LRI, hospitalization or emergency department

attendance for ARI, course of antimicrobials for ARI or work/school absence due to ARI.

Event rate analysis revealed no statistically significant effect of allocation on rate of

hospitalizations / emergency department attendances for ARI, but it did show a

reduction in rates of antimicrobial use for ARI (aIRR 0.87, 95% CI 0.79 to 0.96; 2,103

participants in 9 studies, P=0.005) and work / school absence due to ARI (aIRR 0.94,

95% CI 0.88 to 1.00; 1,316 participants in 7 studies, P=0.05).

Secondary outcomes, safety

Administration of vitamin D did not influence risk of serious adverse events of any cause

(aOR 0.98, 95% CI 0.80 to 1.20; 11,224 participants in 25 studies) or death due to any

cause (aOR 1.39, 95% CI 0.85 to 2.27; 11,224 participants in 25 studies) (Table 3).

Instances of potential adverse reactions to vitamin D were rare. Hypercalcaemia was

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detected in 21/3,850 (0.5%), and renal stones were diagnosed in 6/3,841 (0.2%); both

events were evenly represented in intervention vs. control arms (Table 3).

Risk of bias across studies

A funnel plot for the proportion of participants experiencing at least one ARI did not

suggest publication bias in relation to this outcome, since the smaller trials showed

equal spread of results on both sides of the overall odds ratio (Figure S2).

Responder Analyses

Results of responder analyses are presented in Table S6. Among participants

randomised to the intervention arm of included studies for whom end-study 25(OH)D

data were available, no difference in risk of ARI was observed between those who

attained a serum 25(OH)D ≥75 nmol/L vs. those who did not.

Sensitivity Analyses

IPD meta-analysis of the proportion of participants experiencing at least one ARI,

excluding two trials assessed as being at unclear risk of bias24 25 revealed protective

effects of vitamin D supplementation consistent with the main analysis (aOR 0.82, 95%

CI 0.70 to 0.95, 10,744 participants, P=0.01). Sensitivity analysis for the same outcome,

restricted to the 14 trials that investigated ARI as primary or co-primary outcome, also

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revealed protective effects of vitamin D supplementation consistent with the main

analysis (aOR 0.82, 95% CI 0.68 to 1.00, 5,739 participants, P=0.053).

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Discussion

We report results of the first individual participant data meta-analysis of randomised

controlled trials of vitamin D to prevent ARI. In the study population as a whole, vitamin

D supplementation resulted in a 12% to 20% reduction in risk of experiencing at least

one ARI (from one-step and two-step meta-analyses, respectively). Sub-group analysis

revealed a 38% reduction among individuals with baseline circulating 25(OH)D <25

nmol/L, and a 19% reduction in those who received daily or weekly vitamin D

supplementation without additional bolus doses. This evidence was assessed as being

of high quality, using the GRADE criteria.22 Since baseline vitamin D status and use of

bolus doses varied significantly between studies, our results suggest that the high

degree of heterogeneity between trials may be at least partly attributable to these

factors. Administration of vitamin D was safe: potential adverse reactions were very

rare, and the risk of such events was the same among participants randomised to

intervention vs. control arms.

Our study has several strengths. We obtained IPD for all 25 trials identified by our

search; the proportion of randomised participants with missing outcome data was small

(3.4%); participants with diverse characteristics in multiple settings were represented;

and 25(OH)D levels were measured using validated assays in laboratories that

participated in External Quality Assessment schemes. Our findings therefore have a

high degree of internal and external validity. Moreover, the sub-group effects we report

fulfil published ‘credibility criteria’ relating to study design, analysis and context.26

Specifically, the relevant effect modifiers were specified a priori and measured at

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baseline; P values for interaction remained significant after adjustment for potential

confounders; and sub-group effects were consistent when analysed as proportions and

event rates. Survival analysis revealed consistent trends that did not attain statistical

significance, possibly due to lack of power (fewer studies contributed data to survival

analyses than to analyses of proportions and event rates). The concepts that vitamin D

supplementation may be more effective when given to those with lower baseline

25(OH)D levels, and less effective when bolus doses are administered, are also

biologically plausible. 27-29

Our study also has limitations. Some secondary outcomes, such as incidence of URI

and LRI, were only investigated in a sub-set of the included trials. As a result, our study

had limited power to detect effects of vitamin D supplementation on these outcomes,

and null results may have arisen as a consequence of type 2 error. We may also have

lacked power for exploratory sub-group analyses investigating effects of vitamin D

supplementation in narrower strata defined by the 50 nmol/L and 75 nmol/L cut-offs for

baseline 25(OH)D concentration. Thus, although it appears that the strongest protective

effects of vitamin D against ARI are seen in those with 25(OH)D concentrations <25

nmol/L, benefit in individuals with lesser degrees of deficiency cannot be excluded.

Additional randomised controlled trials investigating the effects of vitamin D on risk of

ARI are on-going, and inclusion of data from these studies in future meta-analyses has

potential to increase statistical power to test for sub-group effects. However, all three of

the largest such studies (NCT01169259, ACTRN12611000402943 and

ACTRN12613000743763) are conducted in populations where profound vitamin D

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deficiency is rare, and two are using intermittent bolus dosing regimens: their results are

therefore unlikely to alter our finding of benefit in very deficient individuals, or in those

receiving daily / weekly regimens.

In summary, our study reports a major new indication for vitamin D supplementation: the

prevention of ARI. We also show that very deficient individuals and those receiving daily

or weekly supplementation without additional bolus doses experienced particular

benefit. Our results add to the body of evidence supporting the introduction of public

health measures such as food fortification to improve vitamin D status in settings where

profound vitamin D deficiency is common.

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Acknowledgements

Supported by a grant from National Institute for Health Research (NIHR) under its

Health Technology Assessment (HTA) Programme (Reference Number 13/03/25, to

ARM). The views expressed are those of the authors and not necessarily those of the

National Health Service, the NIHR or the Department of Health. Sources of support for

individual investigators and trials are detailed in Supplementary Material.

We thank all the people who participated in primary randomised controlled trials; the

teams who conducted them; our Patient and Public Involvement representatives Mrs

Charanjit Patel and Ms. Jane Gallagher for comments on study design and drafts of this

manuscript; and Professor Khalid S. Khan, Queen Mary University of London, for

valuable advice and helpful discussions.

Competing Interests

All authors have completed the ICMJE uniform disclosure form. We declare financial

support for this work from the National Institute for Health Research (NIHR) under its

Health Technology Assessment (HTA) Programme. 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.

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Transparency Declaration

ARM is the manuscript’s guarantor and he affirms that the manuscript is an honest,

accurate, and transparent account of the study being reported; that no important

aspects of the study have been omitted; and that there are no discrepancies from the

study as planned.

Data Sharing Statement

Data sharing: a partial dataset, incorporating patient level data from trials for which the

relevant permission for data sharing have been obtained, is available from the

corresponding author at [email protected].

Author Contributions

ARM wrote the first draft of the study protocol, with input from all authors. ARM, DAJ

and CAC assessed eligibility of studies for inclusion. ARM, JFA, GD-R, SE, DG, AAG,

ECG, CCG, WJ, IL, SM-H, DM, DRM, RN, JRR, SS, IS, GTK, MU and CAC contributed

individual patient data. RLH, LG, ARM and DAJ designed statistical analyses in

consultation with authors contributing individual patient data. Statistical analyses were

done by LG, RLH and DAJ. ARM wrote the first draft of the report, which was critically

reviewed and approved by all authors. All authors had full access to all of the data

(including statistical reports and tables) in the study and can take responsibility for the

integrity of the data and the accuracy of the data analysis.

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20. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS ONE 2010;5(6):e11088.

21. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 2008;61(10):991-6.

22. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj 2008;336(7650):924-6.

23. Manaseki-Holland S, Maroof Z, Bruce J, Mughal MZ, Masher MI, Bhutta ZA, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet 2012;379(9824):1419-27.

24. Dubnov-Raz G, Rinat B, Hemila H, Choleva L, Cohen AH, Constantini NW. Vitamin D supplementation and upper respiratory tract infections in adolescent swimmers: a randomized controlled trial. Pediatric exercise science 2015;27(1):113-9.

25. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamaki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis 2010;202(5):809-14.

26. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. Bmj 2010;340:c117.

27. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014;72(1):48-54.

28. Vieth R. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology. Anticancer Res 2009;29(9):3675-84.

29. Hollis BW, Wagner CL. The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab 2013;98(12):4619-28.

30. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009;137(10):1396-404.

31. Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health 2010;15(10):1148-55.

32. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 2011;127(5):1294-6.

33. Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, et al. Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India up to age 6 months: randomised controlled trial. BMJ 2011;342:d2975.

34. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2012;156(2):105-14.

35. Bergman P, Norlin AC, Hansen S, Rekha RS, Agerberth B, Bjorkhem-Bergman L, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open 2012;2(6):e001663.

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36. Marchisio P, Consonni D, Baggi E, Zampiero A, Bianchini S, Terranova L, et al. Vitamin D supplementation reduces the risk of acute otitis media in otitis-prone children. Pediatr Infect Dis J 2013;32(10):1055-60.

37. Goodall EC, Granados AC, Luinstra K, Pullenayegum E, Coleman BL, Loeb M, et al. Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial. BMC infectious diseases 2014;14:273.

38. Grant CC, Kaur S, Waymouth E, Mitchell EA, Scragg R, Ekeroma A, et al. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial. Acta Paediatr 2014.

39. Martineau AR, James WY, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. The lancet. Respiratory medicine 2015;3(2):120-30.

40. Martineau AR, MacLaughlin BD, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70(5):451-7.

41. Martineau AR, Hanifa Y, Witt KD, Barnes NC, Hooper RL, Patel M, et al. Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax 2015.

42. Simpson SJ, van der Mei I, Stewart N, Blizzard L, Tettey P, Taylor B. Weekly cholecalciferol supplementation results in significant reductions in infection risk among the vitamin D deficient: results from the CIPRIS pilot RCT. BMC Nutrition 2015;1(7).

43. Denlinger LC, King TS, Cardet JC, Craig T, Holguin F, Jackson DJ, et al. Vitamin D Supplementation and the Risk of Colds in Patients with Asthma. Am J Respir Crit Care Med 2016;193(6):634-41.

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Confidential: For Review Only30

Table 1: Characteristics of the 25 eligible trials and their participants Study first author, year

Setting Participants Mean age, years (s.d.) [range]

Male: Female

25(OH)D assay, EQA scheme

Mean baseline 25(OH)D, nmol/L (s.d.) [range]

Baseline 25(OH)D <25 nmol/L (%)

Intervention: control

Oral dose of vitamin D3, intervention arm

Control Study duration

ARI definition ARI primary or secondary outcome?

N entering primary analysis/ N randomised (%)

Li-Ng 200930

USA Healthy adults 57.9 (13.6) [21.4 - 80.6]

34:128 RIA (DiaSorin), DEQAS

63.7 (25.5) [16.0 – 156.0]

3/150 (2.0) 84:78 50 µg daily Placebo 3 mo URI: ≥2 URI symptoms in absence of allergy symptoms

Primary 157/162 (96.9)

Urashima 201015

Japan Schoolchildren 10.2 (2.3) [6.0 – 15.0)

242:188 -- Not determined

-- 217:213 30 µg daily Placebo 4 mo URI: influenza A/B diagnosed by RIDT or RIDT-negative ILI

Primary 334/430 (77.7)

Manaseki-Holland 201031

Afghanistan Pre-school children with pneumonia

1.1 (0.8) [0.1 – 3.3)


-- 224:229 2.5 mg bolus once

Placebo 3 mo LRI: repeat episode of pneumonia – age-specific tachypnoea without wheeze

Secondary 453/453 (100.0)

Laaksi 201025

Finland Military conscripts

19.1 (0.6) [18.0 – 21.0]

164:0 EIA (IDS OCTEIA)

75.9 (18.7) [41.9 – 129.0]

0/73 (0.0) 80:84 10 µg daily Placebo 6 mo ARI: medical record diagnosis

Primary 164/164 (100.0)

Majak 201132

Poland Children with asthma

10.9 (3.3) [6.0 – 17.0]

32:16 RIA (BioSource Europe), RIQAS

88.9 (38.2) [31.5 – 184.7]

0//48 (0.0) 24:24 12.5 µg daily Placebo 6 mo ARI: self-report Secondary 48/48 (100.0)

Trilok-Kumar 201133

India Low birthweight infants

0.1 (0.0) [0.0 – 0.3]


Not determined

1,039:1,040 35 µg weekly Placebo 6 mo ARI: medical record diagnosis of events causing hospitalisation

Secondary 2064/2079 (99.3)

Lehouck 201234

Belgium Adults with COPD

67.9 (8.3) [48.0 – 86.0]

145:37 RIA (Diasorin), DEQAS

49.8 (29.2) [9.0 – 159.7]

31/182 (17.0)

91:91 2.5 mg bolus monthly

Placebo 1 yr URI: self-report Secondary 175/182 (96.2)

Manaseki-Holland 201223

Afghanistan Infants 0.5 (0.3) [0.0 – 1.0]

1591:1455 CLA (IDS), DEQAS

27.1 (22.4) [2.6 – 257.2]

333/543 (61.3)

1524:1522 2.5 mg bolus 3-monthly

Placebo 1.5 yr LRI: pneumonia confirmed by chest radiograph

Primary 3011/3046 (98.9)

Camargo 20129

Mongolia 3rd/4th grade schoolchildren

10.0 (0.9) [7.0 – 12.7]

129:118 LC-MS/MS, DEQAS

18.9 (9.7) [3.3 – 61.2]

192/245 (78.4)

143:104 7.5 µg daily Placebo 7 wk ARI: parent-reported ‘chest infections or colds’

Secondary 244/247 (98.8)

Murdoch 201210

New Zealand

Healthy adults 48.1 (9.7) [18.0 – 67.6]


72.1 (22.1) [13.0 – 142.0]

5/322 (1.6) 161:161 2 x 5 mg bolus monthly then 2.5 mg bolus monthly

Placebo 1.5 yr URI: assessed with symptom score

Primary 322/322 (100.0)

Bergman 201235

Sweden Adults with increased susceptibility to ARI

53.1 (13.1) [20.0 – 77.0]

38:102 CLA (DiaSorin), DEQAS

49.3 (23.2) [8.0 – 135.0]

15/131 (11.45)

70:70 100 µg daily Placebo 1 yr URI: assessed with symptom score

Secondary 124/140 (88.6)

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Study first author, year


Male: Female







ARI definition ARI incidence primary or secondary outcome?


Marchisio 201336

Italy Children with recurrent acute otitis media

2.8 (1.0) [1.3 – 4.8]

64:52 CLA (DiaSorin), ISO9001

65.3 (17.3) [24.7 – 120.6]

2/116 (1.7) 58:58 25 µg daily Placebo 6 mo URI: doctor-diagnosed acute otitis media

Primary 116/116 (100.0)

Rees 201311

USA Adults with previous colorectal adenoma

61.2 (6.6) [47.1 – 77.9]

438:321* RIA (IDS), DEQAS

62.5 (21.3) [30.2 – 171.6]

0/759 (0.0) 399:360 25 µg daily Placebo 13 mo (average)

URI: assessed from daily symptom diary

Secondary 759/759 (100.0)

Tran 201413

Australia Healthy older adults

71.7 (6.9) [60.3 – 85.2]

343:301 CLA (DiaSorin), DEQAS

41.7 (13.5) [12.6 – 105.0]

66/643 (10.3)

430:214 0.75 mg bolus vs. 1.5 mg bolus monthly

Placebo 1 yr URI: self-reported cold

Secondary 594/644 (92.2)

Goodall 201437

Canada Healthy university students

19.6 (2.2) [17.0 – 33.0]


-- 300:300 0.25 mg weekly (factorial with gargling)

Placebo 8 wk URI: self-reported cold

Primary 492/600 (82.0)

Urashima 201414

Japan High school students

16.5 (1.0) [15.0 – 18.0]


-- 148:99 50 µg daily Placebo 2 mo URI: influenza A diagnosed by RIDT or RIDT-negative ILI

Primary 247/247 (100.0)

Grant 201438

New Zealand

Pregnant women and offspring

unborn 0:260 (mothers) 121:128 (offspring)

LC-MS/MS, DEQAS

54.8 (25.8) [8.0 – 128.0]

30/200 (15.0)

173:87 (mothers) 164:85 (offspring)

Mothers: 25 µg vs. 50 µg daily Infants: 10 µg vs. 20 µg daily

Placebo 9 mo (3 mo in pregnancy + 6 mo in infancy)

ARI: doctor-diagnosed ARI precipitating primary care consult

Secondary 236/260 (90.8)

Martineau 2015a39 [ViDiCO]

UK Adults with COPD

64.7 (8.5) [40.0 – 85.0]


46.1 (25.7) [0.0 – 160.0]

50/240 (20.8)

122:118 3 mg bolus 2-monthly

Placebo 1 yr URI: assessed from daily symptom diary

Co-primary 240/240 (100.0)

Martineau 2015b40 [ViDiAs]

UK Adults with asthma

47.9 (14.4) [16.0 – 78.0]


49.6 (24.7) [0.0 – 139.0]

36/250 (14.4)

125:125 3 mg bolus 2-monthly

Placebo 1 yr URI: assessed from daily symptom diary

Co-primary 250/250 (100.0)

Martineau 2015c41 [ViDiFlu]

UK Older adults and their carers

67.1 (13.0) [21.4 – 94.0]


42.9 (23.0) [0.0 – 128.0]

60/240 (25.0)

137:103 Older adults: 2.4 mg bolus 2-monthly + 10 µg daily Carers: 3 mg 2-monthly

Older adults: placebo + 10 µg daily Carers: placebo

1 yr URI & LRI, both assessed from daily symptom diary

Co-primary 240/240 (100.0)

Simpson 201542

Australia Healthy adults 32.2 (12.2) [18.0 – 52.0]


67.9 (23.0) [32.0 – 132.0]

0/33 (0.0) 18:16 0.5 mg weekly Placebo 17 wk ARI assessed with symptom score

Primary 34/34 (100.0)

Dubnov-Raz 201524

Israel Adolescent swimmers with vitamin D insufficiency

15.2 (1.6) [12.9 – 18.6]

34:20 RIA (DiaSorin), DEQAS

60.4 (11.9) [28.0 – 74.6]

0/54 (0.0) 27:27 50 µg daily Placebo 12 wk URI assessed with symptom score

Primary 25/54 (46.3)

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Study first author, year


Male: Female







ARI definition ARI incidence primary or secondary outcome?


Denlinger 2016 43

USA Adults with asthma

39.2 (12.9) [18.0 – 85.0]

130:278 CLA (DiaSorin), VDSP/ DEQAS

47.0 (16.9) [10.0 – 74.6]

55/408 (13.5)

201:207 2.5 mg bolus then 100 µg daily

Placebo 28 wk URI assessed with symptom score

Secondary 408/408 (100.0)

Tachimoto 201612

Japan Children with asthma

9.9 (2.3) [6.0 – 15.0]

50:39 RIA (DiaSorin), CAP

74.9 (24.6) [20.0 – 187.2]

1/89 (1.1) 54:35 20 µg daily, first 2 mo.

Placebo 6 mo URI: assessed with symptom score

Secondary 89/89 (100.0)

Ginde, unpublished

USA Institutionalised older adults

80.7 (9.9) [60.0 – 95.0]

45:62 LC-MS/MS, VDSP

57.3 (22.7) [11.7 – 106.1]

12/107 (11.2)

55:52 2.5 mg bolus monthly + ≤25 µg per day equivalent

Placebo + 10-25 µg per day equivalent

1 yr ARI: medical record diagnosis

Primary 107/107 (100.0)

* Sex missing for two participants randomised to intervention arm and subsequently excluded from analysis due to lack of outcome data. 1 µg vitamin D3 = 40 international units (IU); 25(OH)D concentrations reported in ng/ml were converted to nmol/L by multiplying by 2.496. 25(OH)D, 25-hydroxyvitamin D; RIDT, rapid influenza diagnostic test; COPD, chronic obstructive pulmonary disease; D3, vitamin D3 (cholecalciferol); p.o., per os (orally); mo, month; yr, year; wk, week. ARI, acute respiratory infection; CAP, College of American Pathologists, CLA, chemiluminescent assay; DEQAS, Vitamin D External Quality Assessment Scheme; EIA, enzyme immunoassay; EQA, external quality assessment; LC-MS/MS, liquid chromatography tandem-mass spectrometry, RIA, radio-immunoassay; URI, upper respiratory infection; LRI, lower respiratory infection; ILI, influenza-like illness; RIQAS, Randox International Quality Assessment Scheme; VDSP, Vitamin D Standardisation Program of the Office of Dietary Supplements, National Institutes of Health, USA.

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Table 2: One-step individual participant data meta-analysis, proportion of participants experiencing at least one acute respiratory infection: overall and by sub-group

Number of trials

1

Proportion with ≥1 ARI, control group (%)

Proportion with ≥1 ARI, intervention group (%)

Adjusted odds ratio (95% CI)

2 P value

P value for interaction

Overall 25 2204/5225 (42.2) 2303/5708 (40.3) 0.88 (0.81, 0.96) 0.003 -- Baseline 25(OH)D (nmol/L)

<25 15 186/456 (40.8) 141/415 (34.0) 0.62 (0.45, 0.83) 0.002 0.01

≥25 20 1033/1684 (61.3) 1211/2160 (56.1) 0.91 (0.78, 1.05) 0.19 Dosing Regimen Type Bolus dose ≥30,000 IU given 10 994/2786 (35.7) 1097/3014 (36.4) 0.97 (0.86, 1.10) 0.67 0.05 Bolus dose not given 15 1210/2439 (49.6) 1206/2694 (44.8) 0.81 (0.72, 0.91) <0.001 Daily Dose Equivalent, IU

<800 5 629/1321 (47.6) 619/1435 (43.1) 0.80 (0.68, 0.94) 0.006 0.12

800-1999.9 9 945/2796 (33.8) 1023/3077 (33.2) 0.90 (0.79, 1.01) 0.08

≥2000 11 630/1108 (56.9) 661/1196 (55.3) 0.98 (0.81, 1.18) 0.84

Age (years)

≤1 4 832/2744 (30.3) 854/2827 (30.2) 0.94 (0.83, 1.06) 0.33 0.61

1.1-15.9 8 241/513 (47.0) 194/566 (34.3) 0.60 (0.46, 0.77) <0.001

16-65 17 854/1459 (58.5) 885/1592 (55.6) 0.93 (0.79, 1.10) 0.41

>65 11 277/509 (54.4) 370/723 (51.2) 0.86 (0.67, 1.09) 0.21 Body mass index (kg/m

2)

<25 19 972/1943 (50.0) 956/2074 (46.1) 0.85 (0.74, 0.97) 0.02 0.29

≥25 17 659/1039 (63.4) 754/1235 (61.1) 0.95 (0.79, 1.14) 0.58 Co-morbidity: Asthma

2

No 11 518/1008 (51.4) 520/1101 (47.2) 0.82 (0.68, 0.99) 0.04 0.48

Yes 11 296/534 (55.4) 285/542 (52.6) 0.95 (0.73, 1.25) 0.73 Co-morbidity: COPD

No 7 477/763 (62.5) 493/791 (62.3) 1.00 (0.80, 1.26) 0.98 0.38

Yes 6 122/230 (53.0) 120/238 (50.4) 0.84 (0.57, 1.24) 0.38 Influenza vaccination

No 10 255/373 (68.4) 253/407 (62.2) 0.74 (0.52, 1.03) 0.08 0.51

Yes 10 564/779 (72.4) 577/826 (69.9) 0.86 (0.68, 1.09) 0.22 1, some trials did not contribute data to a given sub-group, either because individuals within that sub-group were not represented, or because data relating to the potential effect modifier were not recorded; accordingly the number of trials represented varies between sub-groups. 2, adjusted for age, sex and study duration. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ARI, acute respiratory infection; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IU, international units.

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Table 3: One-step individual participant data meta-analysis, secondary outcomes

Number of trials

Proportion with ≥1 event, control group (%)

Proportion with ≥1 event, intervention group (%)


1

P value

Upper respiratory infection 19 1656/3286 (50.4) 1807/3733 (48.4) 0.93 (0.83, 1.03) 0.15 Lower respiratory infection 9 542/3285 (16.5) 561/3413 (16.4) 0.96 (0.83, 1.10) 0.52 Hospitalization or emergency dept. attendance due to ARI

11 47/3886 (1.2) 40/3986 (1.0) 0.83 (0.54, 1.27) 0.39

Use of antimicrobials for treatment of ARI

9 397/983 (40.4) 413/1121 (36.8) 0.84 (0.69, 1.03) 0.10

Work/school absence due to ARI 7 321/632 (50.8) 319/684 (46.6) 0.87 (0.69, 1.09) 0.22

Serious Adverse Event of any cause 25 216/5371 (4.0) 221/5853 (3.8) 0.98 (0.80, 1.20) 0.83

Death due to ARI/respiratory failure 25 7/5330 (0.1) 6/5802 (0.1) 0.70 (0.23, 2.20) 0.55

Death due to any infection 25 15/5338 (0.3) 16/5812 (0.3) 0.95 (0.46, 1.99) 0.90

Death due to any cause 25 48/5371 (0.9) 56/5853 (1.0) 1.39 (0.85, 2.27) 0.18

Hypercalcaemia 14 9/1739 (0.5) 12/2111 (0.6) - -

Renal stones 14 4/1707 (0.2) 2/2134 (0.1) - -

Rate of event per participant-year, control group

Rate of event per participant-year, intervention group

Adjusted incidence rate ratio (95% CI)

1

P value

Hospitalization or emergency dept. attendance due to ARI

11 0.01 0.01 0.85 (0.57, 1.27) 0.43

Use of antimicrobials for treatment of ARI

9 1.03 0.90 0.87 (0.79, 0.96) 0.005

Work/school absence due to ARI 7 3.61 3.48 0.94 (0.88, 1.00) 0.05

1, adjusted for age, sex and study duration. Abbreviations: ARI, acute respiratory infection; CI, confidence interval.

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Figure 1: PRISMA Diagram of Study Selection

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Figure 2: Two-step individual participant data meta-analysis, proportion of participants

experiencing at least one acute respiratory infection.

Footnote: data from the trial by Simpson and colleagues42 were not included in this two-step meta-analysis, as an estimate for the effect of the intervention in the study could not be obtained in the regression model due to small sample size.

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Vitamin D supplementation to prevent acute respiratory infections: systematic

review and meta-analysis of individual participant data

Supplementary Material

Adrian R Martineau1,2†

David A Jolliffe1

Richard L Hooper1

Lauren Greenberg1

John F Aloia3

Peter Bergman4

Gal Dubnov-Raz5

Susanna Esposito6

Davaasambuu Ganmaa7

Adit A Ginde8

Emma C Goodall9

Cameron C Grant10

Christopher J Griffiths1,2,11

Wim Janssens12

Ilkka Laaksi13

Semira Manaseki-Holland14

David Mauger15

David R Murdoch16

Rachel Neale17

Judy R Rees18

Steve Simpson Jr19

Iwona Stelmach20

Geeta Trilok Kumar21

Mitsuyoshi Urashima22

Carlos A Camargo Jr23

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1Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK 3Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA 4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 5Dept. of Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel 6 Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy 7Department of Nutrition, Harvard School of Public Health, Boston, MA, USA 8Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA 9Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada 10Department of Paediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 11MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Blizard Institute, Queen Mary University of London, London, UK 12Universitair ziekenhuis Leuven, Leuven, Belgium 13Tampere School of Public Health, University of Tampere, Tampere, Finland 33014 14Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK 15Department of Statistics, The Pennsylvania State University, Hershey, PA, USA 16Department of Pathology, University of Otago, Christchurch, New Zealand 17QIMR Berghofer Medical Research Institute, Queensland, Australia 18 Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA 19Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 20Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland 21Institute of Home Economics, University of Delhi, New Delhi, India 22Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan 23Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA † To whom correspondence should be addressed at Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 58 Turner St, London E1 2AB, UK Tel: +44 207 882 2551 │Fax: +44 207 882 2552 │Email: [email protected]

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1. Search Strategies

A. Medline Cochrane Highly Sensitive Search Strategy for identifying randomised controlled trials #1. randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]

#2. animals [mh] NOT humans [mh]

#3. #1 NOT #2 Terms specific to vitamin D #4. Vitamin D OR vitamin D2 OR vitamin D3 OR cholecalciferol OR ergocalciferol OR alphacalcidol OR alfacalcidol OR calcitriol OR paricalcitol OR doxerocalciferol Terms specific to acute respiratory infection #5. Acute Respiratory Infection OR Upper Respiratory Infection OR Lower Respiratory Infection OR Respiratory Tract Infection OR Common Cold OR Sinusitis OR Pharyngitis OR Laryngitis OR Laryngotracheobronchitis OR Tonsillitis OR peritonsillar abscess OR Croup OR Epiglottitis OR supraglottitis OR Otitis Media OR Pneumonia OR Bronchopneumonia OR Bronchitis OR Pleurisy OR Pleuritis Combination of terms to identify randomised controlled trials of vitamin D for the prevention of acute respiratory infection #3 AND #4 AND #5 B. EMBASE Terms for identifying randomised controlled trials #1 ‘randomized controlled trial’/exp OR ‘single blind procedure’/exp OR ‘double blind procedure’/exp OR ’crossover procedure’/exp #2 random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEXT/1 blind*):ab,ti OR trial:ti #3. #1 OR #2 Terms specific to vitamin D

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#4. vitamin AND d OR vitamin AND d2 OR vitamin AND d3 OR cholecalciferol OR ergocalciferol OR alphacalcidol OR alfacalcidol OR calcitriol OR paricalcitol OR doxerocalciferol Terms specific to acute respiratory infection #5. acute AND respiratory AND infection OR upper AND respiratory AND infection OR lower AND respiratory AND infection OR respiratory AND tract AND infection OR common AND cold OR sinusitis OR pharyngitis OR laryngitis OR laryngotracheobronchitis OR tonsillitis OR peritonsillar AND abscess OR croup OR epiglottitis OR supraglottitis OR otitis AND media OR pneumonia OR bronchopneumonia OR bronchitis OR pleurisy OR pleuritis Combination of terms to identify randomised controlled trials of vitamin D for the prevention of acute respiratory infection #3 AND #4 AND #5 C. Cochrane Central Terms specific to vitamin D #1. Vitamin D OR vitamin D2 OR vitamin D3 OR cholecalciferol OR ergocalciferol OR alphacalcidol OR alfacalcidol OR calcitriol OR paricalcitol OR doxerocalciferol Terms specific to acute respiratory infection #2. Acute Respiratory Infection OR Upper Respiratory Infection OR Lower Respiratory Infection OR Respiratory Tract Infection OR Common Cold OR Sinusitis OR Pharyngitis OR Laryngitis OR Laryngotracheobronchitis OR Tonsillitis OR peritonsillar abscess OR Croup OR Epiglottitis OR supraglottitis OR Otitis Media OR Pneumonia OR Bronchopneumonia OR Bronchitis OR Pleurisy OR Pleuritis Combination of terms to identify randomised controlled trials of vitamin D for the prevention of acute respiratory infection #1 AND #2 D. Web of Science TS =(Vitamin D OR vitamin D2 OR vitamin D3 OR cholecalciferol OR ergocalciferol OR alphacalcidol OR alfacalcidol OR calcitriol OR paricalcitol OR doxerocalciferol) AND TS =(Acute Respiratory Infection OR Upper Respiratory Infection OR Lower Respiratory Infection OR Respiratory Tract Infection OR Common Cold OR Sinusitis OR Pharyngitis OR Laryngitis OR Laryngotracheobronchitis OR Tonsillitis OR peritonsillar abscess OR

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Croup OR Epiglottitis OR supraglottitis OR Otitis Media OR Pneumonia OR Bronchopneumonia OR Bronchitis OR Pleurisy OR Pleuritis) AND TS =(placebo* or random* or clinical trial* or double blind* or single blind* or rct) E. ClinicalTrials.gov and ISRCTN Registry Vitamin D AND respiratory AND infection 2. Sources of support for participating trials The trial by Ginde and colleagues was supported by NIH/NIA grant K23AG040708, NIH/NCATS Colorado CTSA Grant UL1TR001082, and the American Geriatrics Society Jahnigen Career Development Scholars Award The trial by Goodall and colleagues was supported in part by the Canadian Institutes of Health Research [OPP 86940] and with in-kind support from Copan Italia, Bresica Italy. The trial by Grant and colleagues was supported by the Health Research Council of New Zealand, Grant Number 09/215R. The trials by Manaseki-Holland and colleagues were supported by New Zealand Aid (ref: GRA/470/2) and The Wellcome Trust (ref: 082476). The trials by Martineau and colleagues were supported by the National Institute for Health Research under its Programme Grants for Applied Research Programme (Reference Number RP-PG-0407-10398). The trial by Simpson and colleagues was supported by the Royal Hobart Hospital Research Foundation. The trial by Trilok Kumar and colleagues was supported by the Department of Biotechnology, Government of India (ref BT/PR-PR7489/PID/20/285/2006), Nutrition Third World and Sight and Life. The trial by Rees and colleagues was supported by the National Cancer Institute at the National Institutes of Health (grant numbers CA098286 and CA098286-S). The trial by Tran and colleagues was supported by the National Health and Medical Research Council of Australia, grant 613655.

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Results Table S1: Risk of Bias Assessment

Se

qu

en

ce

ge

ne

rati

on

All

oc

ati

on

co

nce

alm

en

t

Bli

nd

ing

of

pa

rtic

ipan

ts

an

d p

ers

on

ne

l

Bli

nd

ing

of

ou

tco

me

as

se

ss

me

nt

Inc

om

ple

te o

utc

om

e d

ata

Se

lec

tiv

e r

ep

ort

ing

Oth

er

bia

s

Li-Ng 20091 ��

Urashima 20102 ��

Manaseki-Holland 20103 ��

Laaksi 20104 �� ? ��

Majak 20115 ��

Trilok-Kumar 20116 ��

Lehouck 20127 ��

Manaseki-Holland 20128 ��

Camargo 20129 ��

Murdoch 201210 ��

Bergman 201211 ��

Marchisio 201312 ��

Rees 201313 ��

Tran 201414 ��

Goodall 201415 ��

Urashima 201416 ��

Grant 201417 ��

Martineau 2015a18 [ViDiCO] ��

Martineau 2015b19 [ViDiAs] ��

Martineau 2015c20 [ViDiFlu] ��

Simpson 201521 ��

Dubnov-Raz 201522 �� ? ��

Denlinger 2016 23 ��

Tachimoto 2016 24 ��

Ginde, unpublished �� = low risk of bias; ? = unclear risk of bias;

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Table S2: Summary of Findings Table

Vitamin D3 compared to placebo for prevention of acute respiratory infection (ARI)

Population: children and adults of any age, sex or ethnic origin, with or without co-morbidity Setting: fourteen countries on four continents (Asia, Australasia, Europe, North America) Intervention: oral vitamin D3 (cholecalciferol) supplementation Comparison: oral placebo

Outcomes Anticipated absolute effects* (95% CI)

Relative effect (95% CI)

№ of participants (studies)

Quality of the evidence (GRADE)

Risk with placebo

Risk with Vitamin D

Proportion with at least one ARI, all participants

422 per 1,000

391 per 1,000 (371 to 412)

OR 0.88 (0.81 to 0.96)

10933 (25 RCTs)

⨁⨁⨁⨁

HIGH

Proportion with at least one ARI, baseline 25(OH)D <25 nmol/L

408 per 1,000

299 per 1,000 (237 to 364)

OR 0.62 (0.45 to 0.83)

871 (15 RCTs)

⨁⨁⨁⨁

HIGH

Proportion with at least one ARI, daily or weekly vitamin D (no boluses)

496 per 1,000

444 per 1,000 (415 to 473)

OR 0.81 (0.72 to 0.91)

5133 (15 RCTs)

⨁⨁⨁⨁

HIGH

Proportion with serious adverse event, any cause

40 per 1,000

39 per 1,000 (32 to 48)

OR 0.98 (0.80 to 1.20)

11224 (25 RCTs)

⨁⨁⨁⨁

HIGH

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio

GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

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Table S3: Exploratory one-step individual participant data meta-analysis, proportion of participants experiencing at least one acute respiratory infection by baseline vitamin D status categorised by 25 nmol/L strata

Baseline 25(OH)D (nmol/L)

Number of Trials

Proportion with ≥1 ARI, control group (%)

Proportion with ≥1 ARI, intervention group (%)


1

P value P value for interaction

<25 15 186/456 (40.8) 141/415 (34.0) 0.62 (0.45 to 0.83) 0.002 0.65

25 to 49.9 20 390/710 (54.9) 481/937 (51.3) 1.00 (0.80 to 1.24) 0.99 50 to 74.9 20 406/635 (63.9) 478/813 (58.8) 0.90 (0.70 to 1.15) 0.40 ≥75 17 237/339 (69.9) 252/410 (61.5) 0.69 (0.47 to 1.00) 0.052

1, adjusted for age, sex and study duration. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ARI, acute respiratory infection; CI, confidence interval.

Table S4: One-step IPDMA, ARI event rate: sub-group analyses by baseline vitamin D status and dosing regimen.

N Trials N Individuals

Rate of ARI per participant-year, control group

Rate of ARI per participant-year, intervention group


1 P value

P value for Interaction


<25 15 842 0.86 0.92 0.79 (0.67 to 0.92) 0.002 0.02

≥25 20 3668 2.04 1.70 0.95 (0.90 to 1.00) 0.04 Dosing Regimen Type Bolus dose ≥30,000 IU given 10 5595 0.73 0.76 0.99 (0.94 to 1.05) 0.83

0.11 Bolus dose not given 15 5133 2.23 2.09 0.93 (0.88 to 0.98) 0.008

1, adjusted for age, sex and study duration. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ARI, acute respiratory infection; CI, confidence interval. Table S5: One-step IPDMA, time to first ARI: sub-group analyses by baseline vitamin D status and dosing regimen.

N Trials N Individuals

Median time to first ARI, control group, days (IQR)

Median time to first ARI, intervention group, days (IQR)

Adjusted hazard ratio (95% CI)

1 P value

P value for Interaction


<25 11 562 -- (133 to --) -- (116 to --) 0.85 (0.65 to 1.12) 0.26 0.28 ≥25 13 2441 108 (43 to 331) 133 (47 to 488) 0.97 (0.88 to 1.07) 0.53 Dosing Regimen Type Bolus dose ≥30,000 IU given 8 4795 -- (121 to --) -- (117 to --) 0.98 (0.89 to 1.08) 0.74

0.30 Bolus dose not given 10 4313 138 (57 to 331) 153 (61 to 351) 0.91 (0.84 to 0.99) 0.04

1, adjusted for age, sex and study duration. Abbreviations: --, these values cannot be defined; 25(OH)D, 25-hydroxyvitamin D; ARI, acute respiratory infection; CI, confidence interval.

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Table S6: Responder analysis, one-step IPDMA N trials Proportion with >=1 ARI, (%) Adjusted odds ratio

(95% CI)1

P value

Intervention, end-study 25(OH)D < 75 nmol/L

18 542/1120 (48.4) 1 --

Intervention, end-study 25(OH)D ≥ 75 nmol/L

18 784/1291 (60.7) 0.96 (0.78, 1.18) 0.68

N trials Median time to first ARI, days (IQR)

Adjusted hazard ratio (95% CI)

P value


11 190 (63, --)2 1 --


12 102 (39, 312) 1.02 (0.88, 1.19) 0.76

N trials Rate of ARI per participant-year


P value


18 1.51 1 --


18 2.04 1.01 (0.94, 1.10) 0.72

1, adjusted for age, sex and study duration. 2, 75th centile for time to first ARI in this group cannot be defined

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Figure S1: Cates plot illustrating reduction in risk of acute respiratory infection with vitamin D supplementation in A) all participants, irrespective of baseline vitamin D status, B) participants with baseline serum 25(OH)D concentration <25 nmol/L, and C) participants receiving daily or weekly vitamin D supplementation regimens without any additional bolus doses. A.

B.

C.

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Figure S2: Funnel plot for individual patient data meta-analysis of proportion of participants experiencing at least one acute respiratory infection

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References 1. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al. A randomized controlled trial

of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009;137(10):1396-404.

2. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010;91(5):1255-60.

3. Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health 2010;15(10):1148-55.

4. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamaki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis 2010;202(5):809-14.

5. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 2011;127(5):1294-6.

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7. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2012;156(2):105-14.

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24. Tachimoto H, Mezawa H, Segawa T, Akiyama N, Ida H, Urashima M. Improved Control of Childhood Asthma with Low-Dose, Short-Term Vitamin D Supplementation: A Randomized, Double-Blind, Placebo-Controlled Trial. Allergy 2016.

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