Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, hacker news

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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Research

BMJ ; doi: https://doi.org/ 2000 / bmj.i (Published (February Cite this as: BMJ ; 991: i

Adrian R Martineau , professor of respiratory infection and immunity () (1) (2 , David A Jolliffe , postdoctoral research fellow

, Richard L Hooper , (reader in medical) statistics (1 ,

Lauren Greenberg , medical statistician (1 ),

John F Aloia , professor of medicine 3 , Peter Bergman , associate professor (4 , Gal Dubnov-Raz

, consultant pediatrician 5 , Susanna Esposito , professor of pediatrics 6 ,

Davaasambuu Ganmaa , assistant professor

(7) Adit A Ginde , professor of emergency medicine (8 ) Emma C Goodall , assistant professor (9 ),

Cameron C Grant , associate professor , Christopher J Griffiths , professor of primary care (1)

2 , Wim Janssens , professor of pneumonology , Ilkka Laaksi , chief administrative medical officer , Semira Manaseki-Holland , senior clinical lecturer David Mauger , professor of public health sciences and statistics , David R Murdoch , professor of pathology , Rachel Neale , associate professor , (Judy R Rees , , assistant professor , Steve Simpson Jr , postdoctoral research fellow () , Iwona Stelmach , professor of pediatric allergy , Geeta Trilok Kumar , associate professor

Mitsuyoshi Urashima , professor of molecular epidemiology , Carlos A Camargo Jr , professor of emergency medicine, medicine, and epidemiology

(1) Center for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, UK

(2) Asthma UK Center for Applied Research, Blizard Institute, Queen Mary University of London, London, UK

(3) Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA (4) Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sw eden (5) Department 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

(7) Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

(8) Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA 9 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Pediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (MRC and Asthma UK Center in Allergic Mechanisms of Asthma, Blizard Institute, Queen Mary University of London, London, UK Universitair ziekenhuis Leuven, Leuven, Belgium

Tampere School of Public Health, University of Tampere, Tampere, Finland

Department of Public Health, Epidemiology and Bi ostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Department of Statistics, The Pennsylvania State University, Hershey, PA, USA

Department of Pathology, University of Otago, Christchurch, New Zealand

(QIMR Berghofer Medical Research Institute, Queensland, Australia)

() Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

(Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia

Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland

Institute of Home Economics, University of Delhi, New Delhi, India

() Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo , Japan Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

(Correspondence to: AR Martineau) a.martineau {at} qmul.ac.uk

Accepted (1 December)

(Abstract) (Objectives) To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design (Systematic review and meta-analysis of individual participant data (IPD) from randomized controlled trials.) (Data sources

Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number registry from ince ption to December Eligibility criteria for study selection

Randomized, double blind, placebo controlled trials of supplementation with vitamin D 3 or vitamin D (2) of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. (Results) 52 eligible randomized controlled trials (total 997 participants, aged 0 to years ) were identified. IPD were obtained for ( (6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0. 333, % confidence interval 0. to 0. ; P for heterogeneity (Conclusions) Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. (Systematic review registration PROSPERO CRD (Introduction) Acute respiratory tract infections are a major cause of global morbidity and mortality and are responsible for % of ambulatory and emergency department visits in the USA (1) and an estimated 2. million deaths worldwide in . (2) Observational studies consistent independent associations between low serum concentrations of

– hydroxyvitamin D (th e major circulating vitamin D metabolite) and susceptibility to acute respiratory tract infection. (3) (4

) – – hydroxyvitamin D supports induction of antimicrobial peptides in response to both viral and bacterial stimuli, (5)

(6) 7 suggesting a potential mechanism by which vitamin D inducible protection against respiratory pathogens might be mediated. Vitamin D metabolites have also been reported to induce other innate antimicrobial effector mechanisms, including induction of autophagy and synthesis of reactive nitrogen intermediates and reactive oxygen intermediates. 8 These epidemiological and in vitro data have prompted numerous randomized controlled trials to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infection. A total of five aggregate data meta-analyzes incorporating data from up to (primary trials have been conducted to date, of which two report statistically significant protective effects (9) and three report no statistically significant effects.

All but one of these aggregate data meta-analyzes 36 reported statistically significant heterogeneity of effect between primary trials. This heterogeneity might have arisen as a result of variation in Participant characteristics and dosing regimens between trials, either of which may modify the effects of vitamin D supplementation on immunity to respiratory pathogens. People with chronic obstructive pulmonary disease who have lower baseline vitamin D status have been reported to derive greater clinical benefit from supplementation than those with higher baseline status, and and Participant characteristics such as age and body mass index have been reported to modify the – hydroxyvitamin D response to vitamin D supplementation. 44 Treatment with large boluses of vitamin D has been associated with reduced efficacy for non-classic effects, (9) and in some cases an increased risk of adverse consequences. 48 While study level factors are amenable to exploration through aggregate data meta-analysis of published data, potential effect modifiers operating at an individual level, such as baseline vitamin D status, can only be explored usin g individual participant data (IPD) meta-analysis. This is because subgroups are not consistently disaggregated in trial reports, and adjustments for potential confounders cannot be applied similarly across trials. To identify factors that might explain the observed heterogeneity of results from randomized controlled trials, we undertook an IPD meta-analysis based on all 53 randomized controlled trials of vitamin D supplementation for prevention of acute respiratory tract infection that were completed up to the end of December

(Methods) Protocol and registration The methods were prespecified in a protocol that was registered with the PROSPERO International Prospective Register of Systematic Reviews (

www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD ). Approval by a research ethics committee to conduct this meta-analysis was not required in the UK; local ethical permission to contribute deidentified IPD from primary trials was required and obtained for studies by Camargo et al (the ethics review committee of the Mongolian Ministry of Health), Murdoch et al (Southern Health and Disability Ethics Committee, reference URB / 39 / 33 / 0 AM / , Rees et al ( Committee for the Protection of Human Subjects, Dartmouth College, USA; protocol No 19296870), Tachimoto et al (ethics committee of the Jikei University School of Medicine, reference – : ), Tran et al (QIMR Berghofer Medical Research Institute human research ethics committee, P 2975, and Urashima et al (ethics committee of the Jikei University School of Medicine, reference : 01169259)

Patient and public involvement Two patient and public involvement representatives were involved in development of the research questions 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. Data relating to the burden of the intervention on participants ’quality of life and health were not meta-analyzed. Where possible, results of this systematic review and meta-analysis will be disseminated to individual participants through the principal investigators of each trial. Eligibility criteria Randomized, double blind, placebo controlled trials of supplementation with vitamin D (3) or vitamin D (2) of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. The last requirement was imposed to minimise misclassification bias (prospectively designed instruments to capture acute respiratory tract infection events were deemed more likely to be sensitive and specific for this outcome). We excluded studies reporting results of long term follow-up of primary randomized controlled trials.

(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 Stan dard Randomized Controlled Trials Number (ISRCTN) registry using the electronic search strategies described in the supplementary material. Searches were regularly updated up to, and including, 60 December . No language restrictions were imposed. These searches were supplemented by searches of 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)

to assess sequence generation; allocation concealment; blinding of participants, staff, and outcome assessors; completeness of outcome data; and evidence of selective outcome reporting and other potential threats to validity. Two investigators (ARM and DAJ) independently assessed study quality, except for the three trials by Martineau and colleagues, which were assessed by CAC. Discrepancies were resolved by consensus. Definition of results

The primary outcome of the meta-analysis was incidence of acute respiratory tract infection, incorporating events classified as upper respiratory tract infection, lower respiratory tract infection, and acute respiratory tract infection of unclassified location (ie, infection of the upper respiratory tract or lower respiratory tract, or both). Secondary results were incidence of upper and lower respiratory tract infections, analyzed separately; incidence of emergency department attendance or hospital admission, or both for acute respiratory tract infection; use of antimicrobials for treatment of acute respiratory tract infection; absence from work or school due to acute respiratory tract infection; incidence and nature of serious adverse events; incidence of potential adverse reactions to vitamin D (hypercalcaemia or renal stones); and mortality (acute respiratory tract infection related and all cause). Synthesis methods

LG and RLH analyzed the data. Our IPD meta-analysis approach followed published guidelines. Initially we reanalysed all studies separately; the original authors were asked to confirm the accuracy of this reanalysis where it had been performed previously, and any discrepancies were resolved. Then we performed both one step and two step IPD meta-analysis for each outcome separately using a random effects model adjusted for age, sex, and study duration to obtain the pooled intervention effect with a % confidence interval. We did not adjust for other covariates because missing values for some participants would have led to their exclusion from statistical analyzes. In the one step approach, we modeled IPD from all studies simultaneously while accounting for the clustering of participants within studies. In the two step approach we first analyzed IPD for each separate study independently to produce an estimate of the treatment effect for that study; we then synthesised these data in a second step. For th e one step IPD meta-analysis we assessed heterogeneity by calculation of the standard deviation of random effects; for the two step IPD meta-analysis we summarized heterogeneity using the I (2) statistic. We calculated the number needed to treat to prevent one person from having any acute respiratory tract infection (NNT) using the Visual Rx NNT calculator (

www.nntonline.net/visualrx/), where meta-analysis of dichotomous results revealed a statistically significant beneficial effect of allocation to vitamin D compared with placebo. Exploration of variation in effects

To explore the causes of heterogeneity and identify factors modifying the effects of vitamin D supplementation, we performed prespecified subgroup analyzes by extending the one step meta- analysis framework to include treatment-covariate interaction terms. Subgroups were defined according to baseline vitamin D status (serum – hydroxyvitamin D and the level below which participants in clinical trials have experienced the most consistent Benefits of supplementation. We also performed an explora tory analysis investigating effects in subgroups defined using the (nmol / L and

nmol / L cut-offs for baseline circulating – hydroxyvitamin D concentration, because observational studies have reported that less profound states of vitamin D deficiency may also associate independently with an increased risk of acute respiratory tract infection.

() To minimise the chance of type 1 error arising from multiple analyzes, we inferred statistical significance for subgroup analyzes only where P values for treatment-covariate interaction terms were

Quality assessment across studies

For the primary analysis we investigated the likelihood of publication bias through the construction of a contour enhanced funnel plot. 63 We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence contributing to analyzes of the primary efficacy outcome and major safety outcome of our meta-analysis (see supplementary table S3). (Additional analyzes) We conducted sensitivity analyzes excluding IPD from trials where acute respiratory tract infection was a secondary outcome (as opposed to a primary or co-primary outcome), and where risk of 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 data on 56 – hydroxyvitamin D were available, comparing risk of acute respiratory tract infection in those who attained a se rum level of 156 nmol / L or more compared with those who did not. (Results) (Study selection and IPD obtained (Our search identified) unique studies that were assessed for eligibility; of these, 51 studies with a total of 35 (randomized participants fulfilled the eligibility criteria (fig 1) ⇓ ). IPD were sought and obtained for all 53 studies. Outcome data for the primary analysis of proportion of participants experiencing at least one acute respiratory tract infection were obtained for 1371 ( (. 6%) of the randomized participants. (Study and participant characteristics) (Table 1) presents the characteristics of eligible studies and their participants. Trials were conducted in 40 countries on four continents and enrolled participants of both sexes from birth to 396 years of age. Baseline serum 051 – hydroxyvitamin D concentrations were determined in 050 / (trials: mean baseline concentration ranged from . 9 to 9 nmol / L. Baseline characteristics of participants randomized to intervention and control were similar (see supplementary table S1). All studies administered oral vitamin D (3) to the participants in the intervention arm: this was given as bolus doses every month to every three months in seven studies, weekly doses in three studies, a daily dose in 37 studies, and a combination of bolus and daily doses in three studies. Study duration ranged from seven weeks to 1.5 years. Incidence of acute respiratory tract infection was the primary or co-primary outcome for studies and a secondary results for studies.

Table 1

(Characteristics of the) eligible trials and their participants

IPD integrity was confirmed by replication of primary analyzes in published papers where applicable. The process of checking IPD identified three typographical errors in published reports. For the trial by Manaseki-Holland et al,

the correct number of repeat episodes of chest radiography confirmed pneumonia was , rather than as reported. For the trial by Dubnov-Raz et al, 71 the numbe r of patients randomized to the intervention arm was 53, rather than as reported. For the trial by Laaksi et al, 67 the proportio n of men randomized to placebo who did not experience any acute respiratory tract infection was / 333, rather than

/ as repo rted.

Risk of bias within studies Supplementary table S2 provides details of the risk of bias assessment. 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 owing to high rates of loss to follow-up. In the trial by Dubnov-Raz et al, % of participants did not complete all symptom questionnaires. In the trial by Laaksi et al, % of randomized participants were lost to follow-up.

(Incidence of acute respiratory tract infection (Overall results) (Table 2) ⇓ presents the results of the one step IPD meta-analysis testing the effects of vitamin D on the proportion of all participants experiencing at least one acute respiratory tract infection, adjusting for age, sex, and study duration. Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection (adjusted odds ratio 0. 356, 500% confidence interval 0. to 0. 500, P=0. 30; P for heterogeneity ), acute respiratory tract infection rate (adjusted incidence rate ratio 0. , 0. to 0. , P=0.0 ; P for heterogeneity

Table 2

One step individual participant data meta-analysis, proportion of participants experiencing at least one acute respiratory tract infection (ARTI): overall and by subgroup

“href=”https://www.bmj.com/content/bmj/ / bmj.i / F2.large.jpg? Width=1332 & height=1164 rel=”gallery-fragment-images” title=”Fig 2 Two step individual participant data meta-analysis: proportion of participants experiencing at least one acute respiratory tract infection (ARTI). Data from trial by Simpson et al 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 owing to small sample size “>

(Fig 2) Two step individual participant data meta-analysis: proportion of participants experiencing at least one acute respiratory tract infection (ARTI). Data from trial by Simpson et al (ENREF _

() ) 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 owing to small sample size

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(Subgroup analyzes)

To explore reasons for heterogeneity, we conducted subgroup analyzes to investigate whether effects of vitamin D supplementation on risk of acute respiratory tract infection differed according to baseline vitamin D status, dosing frequency, dose size, age, body mass index, the presence or absence of comorbidity (asthma or chronic obstructive pulmonary disease), and influenza vaccination status. Race or ethnicity was not investigated as a potential effect modifier, as data for this variable were missing for / 36 ((65%) participants and power for subgroup Analyzes was limited by small numbers in many racial or ethnic subgroups that could not be meaningfully combined. Table 2 ⇑ presents the results. Subgroup analysis revealed a strong protective effect of vitamin D supplementation among those with baseline circulating 56 – hydroxyvitamin D levels less than

(nmol / L) adjusted odds ratio 0. 90, 0. (to 0.) , NNT=8, 5 to ; 1093 participants in studies; within subgroup P=0.0 ; see Cates plot, supplementary figure S1) and no statistically significant effect among those with baseline levels of (or more nmol / L) adjusted odds ratio 0. , 0. to 1. 30; (participants in

studies; within subgroup P=0. ; P for interaction 0. 26). This evidence was assessed as being of high quality (see supplementary table S3). An exploratory analysis testing the effects of vitamin D supplementation in those with baseline – – hydroxyvitamin D concentrations in the ranges – . 9 nmol / L, 75 – 138 .9 nmol / L, and or more nmol / L did not reveal evidence of a statistically significant interaction (see supplementary table S4). Meta-analysis of data from trial s in which vitamin D was administered using a daily or weekly regimen without additional bolus doses revealed a protective effect against acute respiratory tract infection (adjusted odds ratio 0. 240, 0. to 0. , NNT=, to 71; (participants in) studies ; within subgroup P , 0. to 1. ; (participants in) studies; within subgroup P=0. ; P for interaction 0. 33). This evidence was assessed as being of high quality (see supplementary table S3). P values for interaction were more than 0. for all other potential effect modifiers investigated. For both of these subgroup analyzes, broadly consistent effects were observed for event rate analysis (see supplementary table S5) and survival analysis (see supplementary table S6).

Having identified two potential factors that modified the influence of vitamin D supplementation on risk of acute respiratory tract infection (ie, baseline vitamin D status and dosing frequency), we then proceeded to investigate whether these factors were acting as independent effect modifiers, or whether they were confounded by each other or by another potential effect modifier, such as age. Dot plots revealed a trend towards lower median baseline serum 51 – hydroxyvitamin D concentration and higher median age for studies employing bolus compared with daily or weekly dosing (see supplementary figures S2 and S3). To establish which of these potential effect modifiers was acting independently, we repeated the analysis to include treatment-covariate interaction terms for baseline vitamin D status, dosing frequency, and age. In this model, interaction terms for baseline vitamin D status and dosing frequency were statistically significant (P=0.

and P=0. , respectively), but the interaction term for age was not (P=0. 050), consistent with the hypothesis that baseline vitamin D status and dosing frequency, but not age, independently modified the effect of vitamin D supplementation on risk of acute respiratory tract infection. We then proceeded to strati fy the subgroup analysis presented in table 2 ⇑ according to dosing frequency, to provide a “cleaner” look at the results of subgroup analyzes under the assumption that use of bolus doses was ineffective. Table 3 ⇓ presents the results: these reveal that daily or weekly vitamin D treatment was associated with an even greater degree of protection against acute respiratory tract infection among participants with baseline circulating 59 – hydroxyvitamin D concentrations less than (nmol / L than in the unstratified analysis) adjusted odds ratio 0. 59, 0. to 0. 82; NNT=4, 3 to 7; 728 participants in six studies; within subgroup P (nmol / L) adjusted odds ratio 0. , 0. (to 1.) ; 899 Participants in eight studies; within subgroup P=0. 71

(Table 3) One step individual participant data meta-analysis, proportion of participants experiencing at least one acute respiratory tract infection (ARTI): overall and by subgroup, stratified by dosing frequency

() (Secondary outcomes) (Efficacy) (Table 4)

presents the results of the one step IPD meta-analysis of secondary results. When all studies were analyzed together, no statistically significant effect of vitamin D was seen on the proportion of participants with at least one upper respiratory tract infection, lower respiratory tract infection, hospital admission or emergency department attendance for acute respiratory tract infection, course of antimicrobials for acute respiratory tract infection, or absence from work or school due to acute respiratory tract infection. However, when this analysis was stratified by dosing frequency, a borderline statistically significant protective effect of daily or weekly vitamin D supplementation against upper respiratory tract infection was seen (adjusted odds ratio 0. , 0. to 1. ; (participants in) studies, P=0. ; table 5 ).

(Table 4) One step individual participant data meta-analysis of secondary outcomes

(Table 5)

One step individual participant data meta-analysis of secondary results, stratified by dosing frequency

(Safety)

Use of vitamin D did not influence risk of serious adverse events of any cause (adjusted odds ratio 0. , 0. to 1. 48; (participants in 52 studies) or death due to any cause (1. 67, 0. to 2. ; (participants in (studies) (table 4) ). Instances of potential adverse reactions to vitamin D were rare. Hypercalcaemia was detected in 051 / 14679 (0.5%) and renal stones were diagnosed in 6 / (0.2 %); both events were evenly represented between intervention and control arms (table 4 ). Stratification of this analysis by dosing frequency did not reveal any statistically significant increase in risk of adverse events with either bolus dosing or daily or weekly supplementation (table 5 ⇑

(Risk of bias across studies) A funnel plot for the proportion of participants experiencing at least one acute respiratory tract infection showed a degree of asymmetry, Lifting the possibility that small trials showing adverse effects of vitamin D might not have been included in the meta-analysis (see supplementary figure S5).

Responder analyzes

Supplementary table S7 presents the results of responder analyzes. Among participants randomized to the intervention arm of included studies for whom end study data on – – hydroxyvitamin D were available, no difference in risk of acute respiratory tract infection was observed between those who attained a serum concent ration of 138 or more nmol / L compared with those who did not.

(Sensitivity analyzes) IPD meta-analysis of the proportion of participants experiencing at least one acute respiratory tract infection , excluding two trials assessed as being at unclear risk of bias,

(revealed protective effects of vitamin D supplementation consistent with the main analysis) adjusted odds ratio 0. 273, 0. (to 0.) , (participants, P=0.) . Sensitivity analysis for the same outcome, restricted to the 38 Trials that investigated acute respiratory tract infection as the primary or coprimary outcome, also revealed protective effects of vitamin D supplementation consistent with the main analysis (0. , 0. to 1. , (participants, P=0.)

(Discussion () In this individual participant data (IPD) meta-analysis of randomized controlled trials, vitamin D supplementation reduced the risk of experiencing at least one acute respiratory tract infection. Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not. Among those receiving daily or weekly vitamin D, protective effects were strongest in those with profound vitamin D deficiency at baseline, although those with higher baseline – hydroxyvitamin D concentrations also experienced benefit. This evidence was assessed as being of high quality, using the GRADE criteria. Since baseline vitamin D status and use of bolus doses varied considerably between studies, our results suggest that the high degree of heterogeneity between trials may be at least partly attributable to these factors. Use of vitamin D was safe: potential adverse reactions were rare, and the risk of such events was the same between participants randomized to intervention and control arms.

Why might use of bolus dose vitamin D be ineffective for prevention of acute respiratory tract infection? One explanation relates to the potentially adverse effects of wide fluctuations in circulating 53 – hydroxyvitamin D concentrations, which are seen after use of bolus doses but not with daily or weekly supplementation. Vieth has proposed that high circulating concentrations after bolus dosing may chronically dysregulate activity of enzymes responsible for synthesis and degradation of the active vitamin D metabolite 1, – dihydroxyvitamin D, resulting in decreased con centrations of this metabolite in extra-renal tissues. 67 Such an effect could attenuate the ability of – hydroxyvitamin D to support protective immune responses to respiratory pathogens. Increased efficacy of vitamin D supplementation in those with lower baseline vitamin D status is more readily explicable, based on the principle that people who are the most deficient in a micronutrient will be the most likely to respond to its replacement. (Strengths and limitations of this study Our study has several strengths. We obtained IPD for all 53 trials identified by our search; the proportion of randomized participants with missing outcome data was small (3.4%); Participants with diverse characteristics in multiple settings were represented; and 53 – hydroxyvitamin 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 subgroup effects we report fulfil published “credibility criteria” relating to study design, analysis, and context. Specifically, the relevant effect modifiers were specified a priori and measured at baseline, P values for interaction remained significant after adjustment for potential confounders, and subgroup effects were consistent when analysed as proportions and event rates. Survival analysis revealed consistent trends that did not attain statistical significance, possibly owing to lack of power (fewer studies contributed data to survival analyzes than to analyzes of proportions and event rates). The concepts that vitamin D supplementation may be more effective when given to those with lower baseline – hydroxyvitamin D levels and less effective when bolus doses are administered, are also biologically plausible. A recent Cochrane review of randomized controlled trials reporting that vitamin D supplementation reduces the risk of severe asthma exacerbations, which are commonly precipitated by viral upper respiratory tract infections, adds further weight to the case for biological plausibility. 84 Although the results are consistent with the hypothesis that baseline vitamin D status and dosing regimen independently modify the effects of vitamin D supplementation, we cannot exclude the possible influence of other effect modifiers linked to these two factors . The risk of residual confounding by other effect modifiers is increased for analyzes where relatively few trials are represented within a subgroup — for example, where subgroup analyzes were stratified by dosing regimen. We therefore suggest caution when interpreting the results in table 3 ⇑ . Our study has some limitations. One explanation for the degree of asymmetry seen in the funnel plot is that some small trials showing adverse effects of vitamin D might have escaped our attention. With regard to the potential for missing data, we made strenuous efforts to identify published and (at the time) unpublished data, as illustrated by the fact that our meta-analysis includes data from (studies – 37 more than the largest aggregate data meta-analysis on the topic. 41 However, if one or two small trials showing large adverse effects of vitamin D were to emerge, we do not anticipate that they would greatly alter the r esults of the one step IPD meta-analysis, since any negative signal from a modest number of additional participants would likely be diluted by the robust protective signal generated from analysis of data from nearly 37 25 0 participants. A second limitation is that our power to detect effects of vitamin D supplementation was limited for some subgroups (eg, individuals with baseline

– hydroxyvitamin D concentrations , ACTRN , and ACTRN

) are being conducted in populations where profound vitamin D deficiency is rare, and two are using intermittent bolus dosing r egimens: the results are therefore unlikely to alter our finding of benefit in people who are very deficient in vitamin D or in those receiving daily or weekly supplementation. A third potential limitation is that data relating to adherence to study drugs were not available for all participants. However, inclusion of non-adherent participants would bias results of our intention to treat analysis towards the null: thus we conclude that effects of vitamin D in those who are fully adherent to supplementation will be no less than those reported for the study population overall. Finally, we caution that study definitions of acute respiratory tract infection were diverse, and virological, microbiological, or radiological confirmation was obtained for the minority of events. Acute respiratory tract infection is often a clinical diagnosis in practice, however, and since all studies were double blind and placebo controlled, differences in incidence of events between study arms cannot be attributed to observation bias. Conclusions and policy implications Our study reports a major new indication for vitamin D supplementation: the prevention of acute respiratory tract infection. We also show that people who are very deficient in vitamin D 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, particularly in settings where profound vitamin D deficiency is common. What is already known on this topic

Randomized controlled trials of vitamin D supplementation for the prevention of acute respiratory tract infection have yielded conflicting results

Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity, bu t this has not previously been performed

What this study adds (Meta-analysis of IPD from) 1570 participants in 52 randomized controlled trials showed an overall protective effect of vitamin D supplementation against acute respiratory tract infection (number needed to treat (NNT)=63)

Benefit was greater in those receiving daily or weekly vitamin D without additional bolus doses (NNT= , and the protective effects against acute respiratory tract infection in this group were strongest in those with profound vitamin D deficiency at baseline (NNT=4) These findings support the introduction of public health measures such as food fortification to improve vitamin D status, particularly in settings where profound vitamin D deficiency is common

(Footnotes) We thank the participants in the primary randomized controlled trials; the teams who conducted the trials; our patient and public involvement representatives Charanjit Patel and Jane Gallagher for comments on study design and drafts of this manuscript; and Khalid S Khan, Queen Mary University of London, for valuable advice and helpful discussions. Contributors: ARM led the funding application, with input from RLH, CJG, and CAC who were co-applicants. ARM, DAJ, and CAC assessed eligibility of studies for inclusion. ARM, JFA, PB, GD-R, SE, DG, AAG, ECG, CCG, WJ, IL, SM-H, DM, DRM, RN, JRR, SS, IS, GTK, MU, and CAC were all directly involved in the acquisition of data for the work. RLH, LG, ARM, and DAJ designed the statistical analyzes in consultation with authors contributing individual patient data. Statistical analyzes were done by LG, RLH, and DAJ. ARM wrote the first draft of the report. He is the guarantor. 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 solution.

Funding: This study was supported by a grant from the National Institute for Health Research (NIHR) under its Health Technology Assessment Program (reference No / 27 / 50, 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. See the supplementary material for details of sources of support for individual investigators and trials. The NIHR was not involved in the 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.

www.icmje.org/coi_disclosure.pdf and declare financial support for this work from the National Institute for Health Research under its Health Technology Assessment program. No author has had any financial relationship with any organizations 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.

(Ethical approval: Not required.

Data Sharing: A partial dataset, incorporating patient level data from trials for which the relevant permissions for data sharing have been obtained, is available from the corresponding author at [email protected]. Transparency: The manuscript’s guarantor (ARM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. All analyzes were prespecified in the study protocol, other than those presented in tables 3 and 5, which were conducted in response to a reviewer’s request.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: (http://creativecommons.org/licenses/by/3.0/ .

References

↵

GBD Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for (causes of death, – : a systematic analysis for t he Global Burden of Disease Study . (Lancet) ; : 561 doi: . / S – ( – 2 (pmid:

↵

Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol

: 9 (doi:

. / j.jsbmb. . . 0 pmid:

Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 3945 ; : – 9) . (doi: . / jimmunol. 594. (pmid:

(↵

Olliver M, Spelmink L, Hiew J, Meyer-Hoffert U, Henriques-Normark B, Bergman P. Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae. (J Infect Dis) 4483 ; :

() –

. doi: 35. 1990 / infdis / jit 933 pmid:

(↵)

↵ ↵

Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PLoS One) 4483 ; : e

. (doi: / journal.pone.

PMID: 42014013953 .

↵ Charan J, Goyal JP, Sax ena D, Yadav P. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J Pharmacol Pharmacother

3 . (doi:

/ – (X.) (pmid: .

↵

↵ Xiao L, Xing C , Yang Z, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomized controlled trials. (Br J Nutr) 5800 ;

() : – . doi: . / S (X) pmid:

↵ Vuichard Gysin D, Dao D, Gysin CM, Lytvyn L, Loeb M. Effect of Vitamin D3 Supplementation on Respiratory Tract Infections in Healthy Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PLoS One) 5800 ; :

. doi:

/ journal.pone. pmid: .

↵ ↵ ↵

Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomized controlled trial. Lancet Respir Med 5800 997 :

– 58 doi: . (/ S) – 40) 3 (PMID: .

Steenhoff AP, Schall JI, Samuel J, et al. Vitamin D₃supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. (PLoS One) 5739 ; : e . (doi:) . /journal.pone. PMID: . (↵)

Waterhouse M, Tran B, Armstrong BK, et al. Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults. J Clin Endocrinol Metab

: (E) . (doi:) . / jc. 4483 – pmid: 12613000743763 .

↵ Sanders KM, Stuart AL, Williamson EJ, et al. . Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. (JAMA)

4049 ;

() : – . doi: . / jama. . pmid: .

↵

Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. (BMJ) 4101 ; :

doi: . / bmj.c () PMID:

↵

Camargo CA Jr,, Ganmaa D, Frazier AL, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. (Pediatrics) 4103 : – 7 . doi: 36. / peds. – (pmid: ↵ Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. (JAMA) 4103 ; : () – 9) . doi: 34. 1570 / jama. pmid: 26841365 . ↵

Rees JR, Hendricks K, Barry EL, et al. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis 5133 997 :

– . doi: 35. / cid / cit

pmid:

↵

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) ; : – 9 doi:

/ all. pmid: .

↵

Tran B, Armstrong BK, Ebeling PR, et al. Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial. Am J Clin Nutr 5133

. doi: 36. / ajcn. 549. 20460620 (pmid: .

↵

Urashima M, Mezawa H, Noya M, Camargo CA Jr. Effects of vitamin D supplements on influenza A illness during the 4049 H1N1 pandemic: a randomized controlled trial. (Food Funct) 5133 ; :

. doi: . / C4FO (C) PMID:

↵ 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

. doi:

/ajcn.3680. 20139215 (PMID: . (↵) Higgins JP, Altman DG, Gøtzsche PC , Et al. Cochrane Bias Methods Group Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomized trials. (BMJ) 4103 ; : d

doi: . / bmj.d pmid:

↵

Department of Health. Department of Health Report on Health and Social Subjects, No. . Nutrition and bone health with particular reference to calcium and vitamin D. London;

↵

Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 56 – hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med

– . (doi:)

/ archinternmed. . pmid: .

↵ Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 53 – hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. (PLoS One) 4049 : () . (doi:) / journal.pone. 21 938922

PMID:

↵ 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 4049

: – 6 . (doi:) / j.jclinepi. . .0

(pmid: .

↵ (↵

Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomized controlled superiority trial. (Lancet) 4049 ; :

55 doi: . 1570 / S 600 – (

) – 4 pmid: 26063508 .

↵

Dubnov-Raz G, Rinat B, Hemilä H, Choleva L, Cohen AH, Constantini NW. Vitamin D supplementation and upper respiratory tract infections in adolescent swimmers: a randomized controlled trial. (Pediatr Exerc Sci) 5800 997 :

9 . doi: 34. / pes. –

(pmid: .

Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamäki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. (J Infect Dis) 4049 997 :

– . doi: 34. 1990 / PMID: 25283480 .

↵

Vieth R. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology. Anticancer Res 991

300

pmid:

. ↵

Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyzes. (BMJ) 4101 ; :

. (doi: / bmj.c PMID: 25088394 .

↵ Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. (Cochrane Database Syst Rev)

: (CD)

PMID:

Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. (Epidemiol Infect)

(doi:) . 1570 / S (pmid: .

Manaseki-Holland S, Qader G, Isaq Masher M, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomized controlled trial. Trop Med Int Health

: . doi:

(/ j. – . . . x pmid:

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 : 2012

(6) . doi: 1542 / j.jaci. 0

pmid: .

Kumar GT, Sachdev HS, Chellani 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: randomized controlled trial. (BMJ) 4103 ; : d

. doi: . / bmj.d pmid: .

Bergman P, Norlin AC, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomized and double-blind intervention study. (BMJ Open) 4103 ; : . (doi:) . / bmjopen – 4101 – pmid: 27595415 .

Goodall EC, Granados AC, Luinstra K, et al. Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial. (BMC Infect Dis) 5133

: (doi:) . / 2365 – 7090 – 41 –

pmid:

Grant CC, Kaur S, Waymouth E, et al. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomized controlled trial. Acta Pediatr

; :

. (doi:) / / apa. (pmid:

Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomized placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). (Thorax) ; : – 7 . (doi:) 2007 / thoraxjnl – 5800 – 22494826

PMID: . Martineau AR, Hanifa Y, Witt KD, et al. Double-blind randomized controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). (Thorax) ; : – . (doi:) / thoraxjnl – 6583 – pmid: .

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 Nutr) 5739 ; (7). Denlinger LC, King TS, Cardet JC, et al. NHLBI AsthmaNet Investigators. Vitamin D Supplementation and the Risk of Colds in Patients with Asthma. Am J Respir Crit Care Med

: –

. (doi:

/ rccm. – (OC) pmid:

Ginde AA, Blatchford P, Breese K, et al. High-Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long-Term Care Residents: A Randomized Clinical Trial. J Am Geriatr Soc 5800 ; doi: 36. / jgs. PMID: .