- Research
- Vitamin D …
- Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data
BMJ ; doi: https://doi.org/ 2000 / bmj.i (Published (February Cite this as: BMJ ; 991: i
(7) Adit A Ginde , professor of emergency medicine (8 ) Emma C Goodall , assistant professor (9 ),
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
- () (6) Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca ‘Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
- Department of Public Health, Epidemiology and Bi ostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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- Department of Pathology, University of Otago, Christchurch, New Zealand
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- (Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
(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, IsraelTampere School of Public Health, University of Tampere, Tampere, Finland
Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland
- (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
(Methods) Protocol and registration The methods were prespecified in a protocol that was registered with the PROSPERO International Prospective Register of Systematic Reviews (
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 deidentified at source before transfer by 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 incidence of acute respiratory tract infection 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 v (College Station, TX). 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 acute respiratory tract infection. IPD were extracted for the following variables, where available: baseline data were requested for age, sex, cluster identifier (cluster randomized trials only), racial or ethnic origin, influenza vaccination status, history of asthma, history of chronic obstructive pulmonary disease, body weight, height (adults and children able to stand) or length (infants), serum 55 – hydroxyvitamin D concentration, study allocation (vitamin D versus placebo), and details of any stratification or minimization variables. Follow-up data were requested for total number of acute respiratory tract infections (upper or lower), upper respiratory tract infections, and lower respiratory tract infections experienced during the trial; time from first dose of study drug to first acute respiratory tract infection (upper or lower), upper respiratory tract infection, or lower respiratory tract infection if applicable; total number of courses of antibiotics taken for acute respiratory tract infection during the trial; total number of days off work or school due to symptoms of acute respiratory tract infection during the trial; serum 53 – hydroxyvitamin D concentration at final follow-up; duration of follow-up; number and nature of serious adverse events; number of potential adverse reactions (incident hypercalcaemia or renal stones); and participant status at end of the trial (completed, withdrew, lost to follow-up, died). (Risk of bias assessment for individual studies () We used the Cochrane Collaboration risk of bias tool
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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 resultsLG 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 (
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
() 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
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
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
“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 _
(Subgroup analyzes)
(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).
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,
(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.
- 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)
- Competing interests: All authors have completed the ICMJE uniform disclosure form at
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.
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