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Vitamin D supplementation to prevent asthma exacerbations: a
systematic review and meta-analysis of individual participant
data
David A Jolliffe, PhD, Lauren Greenberg, MSc, and Richard L Hooper, PhD
Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of
Medicine and Dentistry
Prof Christopher J Griffiths, DPhil,
Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of
Medicine and Dentistry; Asthma UK Centre for Applied Research, Blizard Institute
Prof Carlos A Camargo Jr, MD,
Queen Mary University of London, London, UK; Department of Emergency Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Conor P Kerley, PhD,
Dublin City University, Glanevin, Dublin, Ireland
Megan E Jensen, PhD,
Priority Research Centre Grow Up Well, University of Newcastle, Newcastle, NSW, Australia
Prof David Mauger, PhD,
Department of Statistics, The Pennsylvania State University, Hershey, PA, USA
Prof Iwona Stelmach, PhD,
Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland
Prof Mitsuyoshi Urashima, MD, and
Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
Prof Adrian R Martineau, PhD
Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of
Medicine and Dentistry; Asthma UK Centre for Applied Research, Blizard Institute
Correspondence to: Prof Adrian R Martineau, Centre 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, a.martineau@qmul.ac.uk.
Contributors
ARM led the funding application, with input from RLH, CJG, and CAC Jr who were coapplicants. DAJ, CAC Jr, and ARM assessed
eligibility of studies for inclusion. DAJ, CJG, CAC Jr, CPK, MEJ, DM, IS, MU, and ARM were all directly involved in the acquisition
of data for the Article. RLH designed the statistical analyses in consultation with the authors contributing individual patient data.
Statistical analyses were done by LG, DAJ, and RLH. ARM wrote the first draft of the Article. All authors revised the Article
critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all
aspects of the Article in ensuring that questions related to the accuracy or integrity of any part of the Article were appropriately
investigated and resolved.
Declaration of interests
We declare no competing interests.
Europe PMC Funders Group
Author Manuscript
Lancet Respir Med. Author manuscript; available in PMC 2018 May 01.
Published in final edited form as:
Lancet Respir Med
. 2017 November ; 5(11): 881–890. doi:10.1016/S2213-2600(17)30306-5.
Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts
Summary
Background—A previous aggregate data meta-analysis of randomised controlled trials showed
that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with
systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D
status is unknown.
Methods—For this systematic review and one-step and two-step meta-analysis of individual
participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled
Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of
vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of
asthma exacerbation, published between database inception and Oct 26, 2016. We analysed
individual participant data requested from the principal investigator for each eligible trial,
adjusting for age and sex, and clustering by study. The primary outcome was the incidence of
asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression
models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were
done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to
baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass
index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels;
post-hoc subgroup analyses were done according to sex and study duration. This study was
registered with PROSPERO, number CRD42014013953.
Findings—Our search identified 483 unique studies, eight of which were eligible randomised
controlled trials (total 1078 participants). We sought individual participant data for each and
obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of
asthma exacerbation requiring treatment with systemic corticosteroids among all participants
(adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56–0·97; p=0·03; 955 participants in seven
studies; high-quality evidence). There were no significant differences between vitamin D and
placebo in the proportion of participants with at least one exacerbation or time to first
exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic
corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of
less than 25 nmol/L (aIRR 0·33, 0·11–0·98; p=0·046; 92 participants in three studies; moderate-
quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58–
1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values
for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not
show that the effects of this intervention are stronger in any one subgroup than in another. Six
studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of
bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (
I
2=0·0,
p=0·56).
Interpretation—Vitamin D supplementation reduced the rate of asthma exacerbations requiring
treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of
this intervention differed across subgroups of patients.
Funding—Health Technology Assessment Program, National Institute for Health Research
(reference number 13/03/25).
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Introduction
Asthma affects more than 300 million people worldwide and is estimated to cause almost
400 000 deaths annually.1,2 Asthma mortality arises primarily during episodes of acute
worsening of symptoms, termed exacerbations, which are commonly precipitated by viral
upper respiratory infections.3 Virus-induced asthma exacerbations are associated with
increased production of pro-inflammatory cytokines such as interleukin 17A, which
exacerbate allergic airway responses.4 Vitamin D metabolites support antiviral responses in
respiratory epithelial cells5 and inhibit production of interleukin 17A in peripheral blood
mononuclear cells isolated from patients with severe asthma.6 Low circulating
concentrations of the major circulating vitamin D metabolite, 25-hydroxyvitamin D
(25[OH]D), are associated with increased risk of asthma exacerbation in both children7 and
adults,8 and eight double-blind, placebo-controlled, randomised controlled trials (RCTs)9–
16 have been published investigating the effects of vitamin D supplementation on the risk of
asthma exacerbation. So far, six meta-analyses incorporating data from trials of vitamin D
for the management of asthma have been done: four reported protective effects of vitamin D
supplementation against asthma exacerbation,17–20 one reported no such effect,21 and one
did not attempt a meta-analysis for the outcome of exacerbation.22 The most recent of these,
a Cochrane systematic review20 and aggregate data meta-analysis including data from both
children and adults and restricted to double-blind, placebo-controlled RCTs found that
vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment
with systemic corticosteroids by 36%.20 However, insufficient access to individual
participant data (IPD) meant that subgroup analyses could not be done to address the
question of whether protective effects of vitamin D supplementation against asthma
exacerbation are stronger in individuals with low baseline vitamin D status; the theory being
that individuals with the lowest baseline levels of a micronutrient might be expected to
derive the greatest benefit from its replacement. In keeping with this hypothesis, protective
effects of vitamin D supplementation against acute respiratory infection23 and acute
exacerbations of chronic obstructive pulmonary disease24,25 have been reported to be
strongest in individuals with low circulating 25(OH)D concentrations. We therefore set out
to obtain IPD from double-blind, placebo-controlled RCTs investigating the effects of
vitamin D supplementation on the risk of asthma exacerbation, and then to meta-analyse the
data to obtain an updated estimate of the overall effectiveness of the supplementation and to
determine whether the effects of this intervention vary according to baseline vitamin D
status.
Methods
Search strategy and selection criteria
The methods for this systematic review and one-step and two-step meta-analysis were
described in an outline protocol that was registered with the PROSPERO International
Prospective Register of Systematic Reviews. The outline protocol includes populations of
people at risk of acute respiratory infection, and people with asthma and chronic obstructive
pulmonary disease. This systematic review and meta-analysis of individual participant data
focuses on people with asthma. A systematic review and meta-analysis of individual
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participant data in people with acute respiratory infection has been previously published.23
Research ethics committee approval was not required in the UK to do this meta-analysis;
local ethical permission to contribute de-identified IPD from primary RCTs was required
and obtained for studies by Urashima and colleagues9 and Tachimoto and colleagues14
(ethics committee of the Jikei University School of Medicine). Findings are reported
according to the PRISMA guidelines for IPD meta-analysis.26
Double-blind, placebo-controlled RCTs of supplementation with vitamin D3 or vitamin D2
in patients with asthma were eligible for inclusion if they had been approved by a research
ethics committee and if data on incidence of asthma exacerbation were reported.
Two investigators (DAJ and ARM) searched MEDLINE, Embase, the Cochrane Central
Register of Controlled Trials, and Web of Science using the electronic search strategies
described in the appendix (p 1). We regularly updated our searches from database inception
up to and including Oct 26, 2016. No language restrictions were imposed. We supplemented
these searches by searching review articles and reference lists of trial publications.
Collaborators were asked if they knew of any additional RCTs. Three investigators (DAJ,
CAC Jr, and ARM) determined which studies met the eligibility criteria.
Data analysis
We requested IPD 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 before transfer via email. On receipt, three investigators (DAJ, RLH, and LG)
assessed data integrity by doing internal consistency checks and by attempting to replicate
results of the analysis for incidence of asthma exacerbations where this was published in the
trial report. We contacted study authors to obtain 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 version 12 (College Station, TX, USA).
We extracted data relating to study characteristics for the following variables: setting,
eligibility criteria, details of intervention and control regimens, and study duration. Where
available, we extracted IPD for certain variables relating to baseline characteristics and
follow-up data. Baseline data were requested for age, sex, racial or ethnic origin, weight,
height, serum 25(OH) D concentration, study allocation (vitamin D
vs
placebo), and details
of stratification variables if applicable. Follow-up data were requested for the total number
of asthma exacerbations requiring treatment with systemic corticosteroids, resulting in
emergency department attendance or hospital admission, or both, and as defined in the trial
protocol; time from first dose of study drug to first asthma exacerbation requiring treatment
with systemic corticosteroids; occurrence of serious adverse events and potential adverse
reactions to vitamin D supplementation (hypercalcaemia or renal stones); serum 25(OH)D
concentration at final follow-up; and duration of participant follow-up.
We used the Cochrane Collaboration Risk of Bias tool27 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;
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and other potential threats to validity. We assessed selectivity of reporting either by
comparing study protocols against study reports or by specifically asking study authors
whether all prespecified outcomes were reported. Two investigators (ARM and DAJ)
independently assessed study quality, except for the trial by Martineau and colleagues,12
which was assessed by CAC Jr. Discrepancies were resolved by consensus.
The primary outcome of the meta-analysis was incidence of asthma exacerbation requiring
treatment with systemic corticosteroids. We selected this outcome on the basis that
requirement for systemic corticosteroids is a widely recognised indicator of exacerbation
severity.28 We measured the primary outcome as rate of asthma exacerbations, proportion of
participants with at least one exacerbation, and time to first exacerbation. Secondary
outcomes were incidence of exacerbations resulting in emergency department attendance or
hospital admission, or both; incidence of exacerbations as defined in the protocol of the
primary trial; incidence of serious adverse events; incidence of potential adverse reactions to
vitamin D (hypercalcaemia and renal stones); and mortality (asthma related and all cause).
Effects of the intervention on event rates, dichotomous outcomes, and time to first event
were expressed as rate ratios (RRs), odds ratios (ORs), and hazard ratios (HRs), respectively.
LG, DAJ and RLH analysed the data. Our IPD meta-analysis approach followed published
guidelines.29 Initially, all studies were reanalysed separately; the original authors were
asked to confirm accuracy of this reanalysis where it had been done previously, and any
discrepancies were resolved. Then, for each outcome separately, we did both one-step and
two-step IPD meta-analyses. In the one-step approach, IPD from all studies were modelled
simultaneously while accounting for the clustering of participants within studies. We used
mixed models, with a random effect for study and fixed effects for age and sex, to obtain the
pooled intervention effect with a 95% CI. We analysed event rates using mixed-effect
Poisson regression; proportions using mixed-effects logistic regression, additionally adjusted
for duration of participant follow-up; and survival data using mixed-effects parametric
survival models. We did not adjust for other covariates because missing values for some
participants would have led to their exclusion from statistical analyses. In the two-step
approach, IPD were first analysed for each separate study independently to produce an
estimate of the treatment effect for that study. We analysed event rates using Poisson
regression, with adjustment for age and sex; proportions using logistic regression with
adjustment for age, sex, and duration of participant follow-up; and survival data using
parametric survival models, with adjustment for age and sex. We then calculated a weighted
average of the individual treatment effect estimates using the DerSimonian and Laird
procedure for random-effects meta-analysis.30 For the two-step IPD meta-analysis, we
summarised heterogeneity using the
I
2 statistic.
To investigate the causes of heterogeneity and identify factors modifying the effects of
vitamin D supplementation, we did prespecified subgroup analyses by extending the one-
step meta-analysis framework to include treatment-covariate interaction terms. Subgroups
were defined according to baseline vitamin D status (serum 25[OH]D <25 nmol/L
vs
≥25
nmol/L), age (<16 years
vs
≥16 years), ethnic or racial origin (African-American, Afro-
Caribbean, or black African origin
vs
Asian origin
vs
white European origin
vs
other or
mixed origin), body-mass index (<25 kg/m2
vs
≥25 kg/m2), vitamin D dosing regimen (daily
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or weekly 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 <2000 IU
vs
≥2000 IU), and concomitant asthma treatment (use of inhaled corticosteroids
vs
not). The
25 nmol/L cutoff for baseline 25(OH)D concentration in the subgroup analyses was selected
because it is the threshold for vitamin D deficiency defined by the UK Department of
Health31 and because, below this level, vitamin D supplementation protects most strongly
against acute respiratory infection.23 We also did an exploratory analysis investigating
effects in subgroups defined using the 50 nmol/L and 75 nmol/L cutoffs for baseline
circulating 25(OH)D concentration because observational studies have reported that less
profound states of vitamin D deficiency might associate independently with increased risk of
asthma exacerbation.7,8 We also did exploratory subgroup analyses by sex and study
duration (<6 months
vs
≥6 months) in response to comments from reviewers. Statistical
significance was inferred for subgroup effects in which the p value for the treatment-
covariate interaction terms was less than 0·05. We did a responder analysis in participants
randomly assigned to the intervention arm of included studies for whom end-study 25(OH)D
data were available, comparing risk of asthma exacerbations treated with systemic
corticosteroids in participants who attained a serum 25(OH)D of 75 nmol/L or higher
vs
participants who did not.
For the primary analysis of rate of exacerbations requiring systemic steroids, the likelihood
of publication bias was investigated through the construction of a contour-enhanced funnel
plot.32 We used the five GRADE considerations (study limitations, consistency of effect,
imprecision, indirectness, and publication bias)33 to assess the quality of the body of
evidence contributing to the principal analyses of rate of exacerbations requiring systemic
steroids, the proportion of participants with at least one exacerbation requiring emergency
department attendance or hospital admission, or both, and the proportion of participants with
at least one serious adverse event.
Data were analysed using STATA IC, version 12. This study was registered with the
PROSPERO, number CRD42014013953.
Role of the funding source
The National Institute of Health Research had no role in study design, data collection, data
analysis, or data interpretation, or writing of the report. The corresponding author had full
access to all the data in the study and had final responsibility for the decision to submit for
publication.
Results
Our search identified 483 unique studies that we assessed for eligibility, of which eight
studies with a total of 1078 randomly assigned participants fulfilled eligibility criteria (figure
1). We sought IPD for all eight studies, which we obtained for seven (total 978 participants);
data were not obtained for one study (100 participants) because the corresponding author did
not respond to invitations to contribute IPD to this meta-analysis. Outcome data were
obtained for 955 (98%) of 978 randomly assigned participants in these seven studies.
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The seven analysed RCTs were done in six different countries on three continents, and
enrolled participants of both sexes aged 1·6–85·0 years (table 1). Five RCTs with a total of
297 included participants enrolled children, and two RCTs with a total of 658 included
participants enrolled adults (table 1). Baseline serum 25(OH)D concentrations were
determined in six RCTs, ranging from undetectable to 187·2 nmol/L; table 1). All studies
administered oral vitamin D3 to participants in the intervention arm: this was given as a
bolus dose every 2 months in one study (100 000 IU per bolus); as a daily dose in four
studies (ranging from 500 IU/day to 2000 IU/day; and as a combination of bolus and daily
doses in two studies (100 000 IU bolus then 400–4000 IU/day). Study durations ranged from
15 weeks to 1 year. Details of the number of asthma exacerbations treated with systemic
corticosteroids and the proportion of participants experiencing at least one such event by arm
and study are presented in appendix (p 3). In two RCTs,9,10 no asthma exacerbations
requiring treatment with systemic corticosteroids arose, and in one trial,14 only one asthma
exacerbation requiring treatment with systemic corticosteroids arose. Effect estimates could
not be calculated for these three studies individually; accordingly, these studies contributed
data to the one-step, but not the two-step, meta-analyses.
IPD integrity was confirmed by replication of primary analyses in published papers where
applicable. The process of checking IPD revealed two discrepancies with primary reports. In
the trial by Urashima and colleagues,9 the relative risk for asthma exacerbation was
calculated using denominators based on the study population as a whole, irrespective of
whether or not the participants had asthma (n=334). By contrast, we calculated this figure
using denominators based on the number of children with asthma for whom outcome data
were available (n=99). In the trial by Castro and colleagues,11 IPD detailed 14 serious
adverse events arising in participants randomly assigned to placebo, as compared with 13
such events reported in the published manuscript.
Details of the risk of bias assessment are provided in appendix (p 4). All RCTs, but one,
were assessed as being at low risk of bias for all aspects analysed. The trial by Kerley and
colleagues16 was assessed as being at unclear risk of bias due to its high rate of loss to
follow-up (12 of 51 participants), although we found no evidence to suggest differential rates
of loss to follow-up between the intervention and control arms (seven of 24 participants
vs
five of 27).
Overall, in the one-step IPD meta-analysis, vitamin D supplementation resulted in a
significant reduction in the rate of asthma exacerbations requiring treatment with systemic
corticosteroids (adjusted incidence RR [aIRR] 0·74, 95% CI 0·56–0·97; p=0·03; 955
participants in seven studies; table 2). This evidence was assessed as being of high quality
(appendix p 5). The two-step IPD meta-analysis revealed a similar effect size among 719
participants in four studies (aIRR 0·69, 0·52–0·92, p=0·01; pheterogeneity=0·56; figure 2). In
the analyses of the proportion of participants with at least one asthma exacerbation treated
with systemic corticosteroids, the effect estimates favoured vitamin D but the differences
between groups were not significant, in both the one-step analysis (adjusted OR [aOR] 0·75,
95% CI 0·51–1·09, p=0·13; 955 participants in seven studies) and two-step analysis (aOR
0·69, 0·46–1·02, p=0·06; pheterogeneity=0·74; 719 participants in four studies; appendix p 8).
Similarly, for the analyses of time to first exacerbation, the effect estimates favoured vitamin
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D but the differences between groups were not significant, in both the one-step analysis
(adjusted HR [aHR] 0·78, 95% CI 0·55–1·10; p=0·16; 868 participants in five studies) and
two-step analysis (aHR 0·74, 0·52–1·05, p=0·09; pheterogeneity=0·58; 680 participants in three
studies; appendix p 9).
We did subgroup analyses to investigate whether the effects of vitamin D supplementation
on rate of asthma exacerbations requiring treatment with systemic corticosteroids differed
according to baseline vitamin D status, age, ethnic or racial origin, body-mass index,
administration of bolus-dose vitamin D, amount of vitamin D administered, and concomitant
use of inhaled corticosteroids (table 2). We also did exploratory post-hoc subgroup analyses
by sex and study duration (table 2). Vitamin D supplementation significantly reduced the
rate of asthma exacerbations treated with systemic corticosteroids in individuals with
baseline circulating 25(OH)D of less than 25 nmol/L (aIRR 0·33, 95% CI 0·11–0·98; 92
participants in three studies; within subgroup p=0·046; table 2). Vitamin D supplementation
did not result in a statistically significant reduction in exacerbation rate in participants with
baseline 25(OH)D of 25 nmol/L or higher (aIRR 0·77, 0·58–1·03; 764 participants in six
studies; within subgroup p=0·08). The treatment-covariate interaction term (ratio of aIRRs)
for this subgroup analysis was 0·56 (95% CI 0·20–1·52, pinteraction=0·25). Quality
assessments of these within-subgroup effects were downgraded to moderate due to their
relative imprecision (appendix p 5).
An exploratory analysis testing the effects of vitamin D supplementation in individuals with
baseline 25(OH)D concentrations in the ranges of 25–49·9 nmol/L, 50–74·9 nmol/L, and 75
nmol/L or higher did not reveal evidence of effect modification (pinteraction=0·40) or
significant protective effects of vitamin D supplementation within these subgroups
(subgroup with baseline 25[OH]D of 25·0–49·9 nmol/L: aIRR 0·79, 95% CI 0·50–1·23 [306
participants in six studies; within subgroup p=0·29]; subgroup with baseline 25[OH]D of
50·0–74·9 nmol/L: aIRR 0·76, 0·48–1·22 [334 participants in six studies; within subgroup
p=0·26]; subgroup with baseline 25[OH]D of 75 nmol/L or higher: aIRR 0·79, 0·37–1·69
[120 participants in five studies; within subgroup p=0·54]; figure 3). p values for interaction
for all other subgroup analyses were also higher than 0·05 (table 2; appendix p 7 for end-
study 25[OH]D level pairwise analyses).
Results of the one-step IPD meta-analysis of secondary efficacy outcomes are presented in
table 3. Vitamin D supplementation reduced the proportion of people with at least one
asthma exacerbation resulting in emergency department attendance or hospital admission, or
both (aOR 0·46, 95% CI 0·24–0·91; 955 participants in seven studies; p=0·03). No
significant effect of vitamin D supplementation was seen on risk of having at least one
asthma exacerbation as defined in the protocols of primary RCTs (aOR 0·81, 0·58–1·11; 955
participants in seven studies; p=0·19).
Results of the one-step IPD meta-analysis of safety outcomes are also reported in table 3. No
participant had hypercalcaemia or renal stones. Vitamin D supplementation did not affect the
risk of having at least one serious adverse event of any cause (aOR 0·87, 95% CI 0·46–1·63;
955 participants in seven studies; p=0·66). Only one trial participant died, which was due to
a road traffic accident.
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A funnel plot for the outcome of rate of asthma exacerbations treated with systemic
corticosteroids did not suggest publication bias in relation to this outcome because the
smaller RCTs showed equal spread of results on both sides of the overall adjusted rate ratio
(appendix p 10). No relation between effect size and study size was apparent (appendix p 6).
Discussion
We report results of the first IPD meta-analysis of RCTs of vitamin D to reduce the risk of
asthma exacerbations. In the study population as a whole, vitamin D supplementation
reduced the rate of asthma exacerbations treated with systemic corticosteroids, as compared
with placebo (0·30 events per person per year
vs
0·43 events per person per year; p=0·03),
and the proportion of people having at least one exacerbation requiring emergency
department attendance or hospital admission, or both (3%
vs
6%; p=0·03). Subgroup
analyses revealed that reductions in exacerbation rate with vitamin D were statistically
significant in participants with baseline circulating 25(OH)D concentration levels less than
25 nmol/L, but not in people with baseline levels of 25(OH)D of 25 nmol/L or higher.
Vitamin D supplementation was safe at the doses administered: no instances of
hypercalcaemia or renal stones were seen, and serious adverse events were evenly
distributed between participants randomly assigned to vitamin D versus placebo.
Our findings from analysing the study population as a whole are consistent with those of our
recent aggregate data meta-analysis of RCTs of vitamin D for the management of asthma,
which reported protective effects against asthma exacerbations treated with systemic
corticosteroids of similar magnitude (IRR 0·64, 95% CI 0·46–0·90).20 The present study
represents a significant advance because access to IPD has allowed us to do subgroup
analyses to assess whether specific factors modify the effects of vitamin D supplementation
on risk of asthma exacerbations. We hypothesised that the protective effects of vitamin D
supplementation against asthma exacerbation would be strongest in participants with the
lowest baseline vitamin D status, as has been previously reported for the outcome of acute
respiratory infection.23 We saw a statistically significant rate reduction in participants with
baseline 25(OH)D of less than 25 nmol/L, but not in participants with 25(OH)D of 25
nmol/L or higher. However, the p value for interaction for this subgroup analysis was non-
significant (pinteraction=0·25); formally, therefore, we have not shown that effects are stronger
in one group than in the other. p values for interaction were also higher than 0·05 for
subgroup analyses relating to age, sex, racial or ethnic origin, body weight, vitamin D
dosing regimen, use of inhaled corticosteroids, and study duration. These factors might not
modify the effects of vitamin D supplementation on exacerbation risk; alternatively, we
might have lacked statistical power to detect the relevant interactions. Several additional
RCTs are ongoing (eg, NCT01419262, NCT01728571, NCT02197702, and NCT02424552),
and, in due course, we hope to include IPD from these studies in an updated meta-analysis,
increasing the power for subgroup analyses.
Although vitamin D reduced the risk of asthma exacerbations requiring treatment with
systemic corticosteroids, no significant effect was seen on the risk of asthma exacerbations
as originally defined in the protocols of the primary trials. In the majority of trials, the
original definition of exacerbation was broader than the one prespecified for this meta-
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analysis—eg, encompassing events that resulted in dips in peak expiratory flow rate or
FEV1 that were not treated with systemic corticosteroids.11,12 Differing efficacies of
vitamin D supplementation for these two outcomes might suggest that this intervention
specifically reduces risk of more serious exacerbations. Alternatively, less stringent
definitions of exacerbation in primary trial protocols might have resulted in a degree of
misclassification with a consequent increase in noise: signal ratio that might have obscured a
real effect of vitamin D on exacerbation risk.
Our study has several strengths. The included studies were of high quality, and of sufficient
duration for steadystate 25(OH)D concentrations to be attained among participants randomly
assigned to receive vitamin D3. The proportion of randomly assigned participants with
missing outcome data was small (2·4%), and 25(OH)D concentrations were measured using
validated assays in laboratories that participated in external quality assessment schemes. The
analysis contained participants with diverse characteristics in multiple settings, incorporating
new data from a trial16 done in children with severe asthma that was published after the date
of the final literature search for our previous aggregate data meta-analysis.20 Our findings
therefore have a high degree of internal and external validity.
Our study also has some limitations. We did not obtain IPD for one eligible trial;13 however,
this study was relatively small (n=100) and has previously been assessed as being at high
risk of bias.20 Notably, this study reported strong protective effects of vitamin D against
asthma exacerbation;13 as such, if exclusion of its findings leads to a bias, it is likely to be a
bias towards the null. Interpretation of the funnel plot (appendix p 10) is limited by the small
number of studies included, but the fact that the smaller RCTs showed an equal spread of
results on both sides of the overall adjusted rate ratio provides some reassurance that
publication bias was not a major issue in our meta-analysis; an impression that is reinforced
by the absence of an association between effect size and study size (appendix p 6). Power for
some subgroup analyses was limited; this is an inescapable problem in view of the small
number of published RCTs in this field. Where 95% CI for estimates of effect from
subgroup analyses were wide, we downgraded our quality assessment of subgroup findings
to moderate (appendix p 5).
In conclusion, our IPD meta-analysis confirms results from our previous aggregate data
meta-analysis showing that vitamin D supplementation safely reduces the rate of asthma
exacerbations overall. However, we did not find definitive evidence that effects of this
intervention differed across subgroups of patients. In view of the low cost of this
intervention and the major economic burden associated with asthma exacerbations, vitamin
D supplementation represents a potentially cost-effective strategy to reduce this important
cause of morbidity and mortality.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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Acknowledgments
This study was supported by a grant from National Institute for Health Research (NIHR) under its Health
Technology Assessment Program (reference number 13/03/25) to ARM. The views expressed are those of the
authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health.
We thank all the people who participated in the primary randomised controlled trials; the teams who did them; 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) and Christopher C Cates (St
George’s University of London) for valuable advice and helpful discussions.
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Research in context
Evidence before this study
Before doing this study, we searched the PROSPERO International Prospective Register
of Systematic Reviews, ClinicalTrials.gov, and MEDLINE for published or ongoing
meta-analyses of randomised controlled trials of vitamin D supplementation in people
with asthma, without language restrictions, from database inception to Sept 30, 2014,
using the search terms “vitamin D” and “asthma”. A Cochrane meta-analysis of
aggregate data from double-blind, placebo-controlled, randomised controlled trials found
that vitamin D supplementation reduced the rate of asthma exacerbations requiring
treatment with systemic corticosteroids (rate ratio 0·64, 95% CI 0·46–0·90). Whether this
effect is restricted to patients with lower baseline vitamin D status (25-hydroxyvitamin D
<25 nmol/L) is not known; an individual participant data meta-analysis could resolve this
issue, but this has not previously been done.
Added value of this study
Our meta-analysis of individual participant data from 955 participants in seven
randomised controlled trials provides an updated pooled estimate of the protective effects
of vitamin D against asthma exacerbations requiring treatment with systemic
corticosteroids overall. Uniquely, our meta-analysis also investigates whether the effect of
vitamin D on risk of asthma exacerbation varies according to baseline 25-hydroxyvitamin
D concentrations.
Implications of all the available evidence
Overall, vitamin D reduced the rate of asthma exacerbations treated with systemic
corticosteroids, as compared with placebo (0·30 events per person per year
vs
0·43 events
per person per year; p=0·03). Subgroup analysis revealed that vitamin D reduced the rate
of asthma exacerbations treated with systemic corticosteroids in people with a baseline
25-hydroxyvitamin D of less than 25 nmol/L (0·19 events per person per year
vs
0·42
events per person per year; p=0·046), but vitamin D supplementation did not result in a
statistically significant reduction in exacerbation rate in participants with baseline 25-
hydroxyvitamin D of 25 nmol/L or higher. We did not find definitive evidence that effects
of this intervention differed across subgroups of patients.
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Figure 1. Study selection
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Figure 2. Two-step individual participant data meta-analysis, event rate for asthma
exacerbations requiring treatment with systemic corticosteroids
Weights are from the random-effects analysis. No asthma exacerbations requiring treatment
with systemic corticosteroids arose in the trials by Urashima and colleagues9 and Majak and
colleagues.10 Only one such event arose in the trial by Tachimoto and colleagues;14 as
such, an adjusted incidence rate ratio could not be calculated for this study.
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Figure 3. Effects of vitamin D supplementation on asthma exacerbation rate by baseline
circulating 25(OH)D concentration categorised by 25 nmol/L strata
Shown are the results of one-step individual participant data meta-analysis. The incidence
rate ratio is adjusted for age and sex. Mean and 95% CI are presented. 25(OH)D=25-
hydroxyvitamin D.
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Table 1
Characteristics of trials and participants included in individual participant data meta-analysis
Setting Participants Age (years) Male:female 25(OH)D assay; EQA
scheme Baseline 25(OH)D (nmol/L) Participants
with baseline
25(OH)D <25
nmol/L
Intervention: control Oral dose of
vitamin D3
(intervention
arm)
Participants
with 25(OH)D
≥75 nmol/L at
final follow-up
Control Study duration Participants
with available
outcome data/
participants
randomly
assigned to a
group
Urashima
et al
(2010)9
Japan Schoolchildren with asthma 9.5 (2·1;
6·0–15·0) 56:43 ·· Not determined ·· 43:56 1200 IU/day ·· Placebo 4 months 99/110 (90%)
Majak et
al
(2011)10
Poland Schoolchildren 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%) 24:24 500 IU/day 16/24 (67%) Placebo 6 months 48/48 (100%)
Castro et
al
(2014)11
USA Adults with asthma 39·2 (12·9;
18·0–85·0) 130:278 CLA (DiaSorin); VDSP 47·0 (16·9;
10·0–74·6) 55/408 (13%) 201:207 100 000 IU
bolus then
4000 IU/day
143/174 (82%) Placebo 28 weeks 408/408 (100%)
Martineau
et al
(2015)12
UK Adults with asthma 47·9 (14·4;
16·0–78·0) 109:141 LC-MS/MS; DEQAS 49·6 (24·7;
0·0–139·0) 36/250 (14%) 125:125 120 000 IU
bolus once
every 2
months
40/107 (37%) Placebo 1 year 250/250 (100%)
Tachimoto
et al
(2016)14
Japan Schoolchildren 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%) 54:35 800 IU/
day, first 2
months
34/54 (63%) Placebo 6 months 89/89 (100%)
Kerley et
al
(2016)16
Ireland Schoolchildren with asthma 8·6 (2·8;
5·0–15·0) 24:15 LC-MS/MS; DEQAS 54·4 (17·4;
26·0–92·0) 0/39 (0%) 17:22 2000 IU/day 13/17 (76%) Placebo 15 weeks 39/51 (76%)
Jensen et
al
(2016)15
Canada Pre-schoolchildren with asthma 2·9 (1·1;
1·6–5·5) 7:15 LC-MS/MS; DEQAS 64·2 (14·0;
42·0–87·0) 0/22 (0%) 11:11 100 000 IU
bolus then 400
IU/day
7/8 (88%) 400 IU
vitamin
D3 per
day
6 months 22/22 (100%)
Data are mean (SD; range) or n/N (%), unless stated otherwise. 40 IU vitamin D3 equals 1 µg. 25(OH)D concentrations reported in ng/mL were converted to nmol/L by multiplying by 2·496. 25(OH)D=25-hydroxyvitamin D. EQA=external quality assessment. IU=international
unit. RIA=radio-immunoassay. RIQAS=Randox International Quality Assessment Scheme. CLA=chemiluminescent assay. VDSP=Vitamin D Standardisation Program of the Office of Dietary Supplements, National Institutes of Health, USA. LC-MS/MS=liquid chromatography
tandem-mass spectrometry. DEQAS=Vitamin D External Quality Assessment Scheme. CAP=College of American Pathologists.
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Table 2
One-step individual participant data meta-analysis of rate of asthma exacerbations
requiring treatment with systemic corticosteroids
Number of
participants;
number of
trials*
Event rate per
participant-year
(control group)
Event rate per
participant-year
(intervention
group)
Adjusted incidence
rate ratio (95% CI)
†
p value pinteraction‡
Overall 955; 7 121/284·7 (0·43) 85/286·6 (0·30) 0·74 (0·56–0·97) 0·03 NA
Baseline 25(OH)D (nmol/L)
<25 92; 3 14/33·0 (0·42) 6/32·2 (0·19) 0·33 (0·11–0·98) 0·046 0·25
≥25 764; 6 107/233·8 (0·46) 79/240·2 (0·33) 0·77 (0·58–1·03) 0·08 ··
Age (years)
<16 290; 5 26/57·6 (0·45) 19/61·8 (0·31) 0·64 (0·34–1·20) 0·16 0·56
≥16 665; 3 95/227·2 (0·42) 66/224·7 (0·29) 0·70 (0·51–0·97) 0·03 ··
Sex
Female 547; 7 80/163·6 (0·49) 47/167·7 (0·28) 0·61 (0·43–0·88) 0·008 0·17
Male 408; 7 41/121·1 (0·34) 38/118·9 (0·32) 0·91 (0·58–1·42) 0·67 ··
Ethnic or racial origin
African-American, Afro-
Caribbean, or black African
origin
154; 3 28/46·4 (0·60) 14/43·4 (0·32) 0·54 (0·29–1·03) 0·06 0·32
Asian origin 207; 5 6/42·0 (0·14) 4/48·5 (0·08) 0·81 (0·19–3·51) 0·78 ··
White European origin 520; 5 80/177·8 (0·45) 59/172·3 (0·34) 0·79 (0·56–1·11) 0·17 ··
Other or mixed 74; 3 7/18·6 (0·38) 8/22·3 (0·36) 0·88 (0·31–2·53) 0·81 ··
Weight
Not overweight 381; 7 38/110·5 (0·34) 26/104·5 (0·25) 0·91 (0·55–1·51) 0·71 0·31
Overweight
§
574; 7 83/174·3 (0·48) 59/182·0 (0·32) 0·68 (0·49–0·95) 0·02 ··
Bolus-dose vitamin D given
No 275; 4 13/53·8 (0·24) 10/58·9 (0·17) 0·65 (0·26–1·63) 0·36 0·49
Yes 680; 3 108/230·9 (0·47) 75/227·6 (0·33) 0·71 (0·52–0·95) 0·02 ··
Daily dose equivalent (IU)
<2000 258; 4 13/52·1 (0·25) 10/58·6 (0·17) 0·62 (0·26–1·44) 0·26 0·78
≥2000 697; 3 108/232·7 (0·46) 75/228·0 (0·33) 0·73 (0·54–0·98) 0·03 ··
Received inhaled corticosteroids
No 92; 4 1/18·8 (0·05) 4/26·1 (0·15) 1·11 (0·07–18·40) 0·94 0·19
Yes 764; 5 120/248·0 (0·48) 81/246·3 (0·33) 0·71 (0·54–0·95) 0·02 ··
Study duration (months)
<6 138; 2 13/25·0 (0·52) 9/19·4 (0·46) 0·50 (0·18–1·37) 0·18 0·62
≥6 816; 5 108/259·8 (0·42) 76/267·2 (0·28) 0·72 (0·53–0·96) 0·03 ··
NA=not applicable. IU=international unit. 25(OH)D=25-hydroxyvitamin D.
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*
Some trials did not contribute data to a given subgroup, either because individuals within that subgroup were not represented or because data
relating to the potential effect modifier were not available, accordingly the number of trials represented varies between subgroups.
†
Adjusted for age and sex.
‡
pinteraction values are between adjusted rate ratios in the subgroup.
§
Overweight defined as body-mass index
Z
score of 1·0 or more for participants younger than 19 years and as body-mass index of 25 kg/m2 or
more for participants aged 19 years or older.
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Table 3
One-step individual participant data meta-analysis of secondary outcomes
Number of
participants;
number of trials*
Participants with
one or more event
(control group)
Participants with one
or more event
(intervention group)
Adjusted odds ratio
(95% CI)*p value
Asthma exacerbation resulting
in emergency department
attendance or hospital
admission, or both
955; 7 28/480 (6%) 14/475 (3%) 0·46 (0·24–0·91) 0·03
Asthma exacerbation as defined
in primary trial 955; 7 123/480 (26%) 105/475 (22%) 0·81 (0·58–1·11) 0·19
Serious adverse event of any
cause 955; 7 22/480 (5%) 20/475 (4%) 0·87 (0·46–1·63) 0·66
Hypercalcaemia 955; 7 0/480 (0%) 0/475 (0%) ·· ··
Renal stones 955; 7 0/480 (0%) 0/475 (0%) ·· ··
Death due to asthma
exacerbation 955; 7 0/480 (0%) 0/475 (0%) ·· ··
Death due to any cause 955; 7 0/480 (0%) 1/475 (<1%)
†
·· ··
*
Adjusted for age, sex, and duration of participant follow-up.
†
Death due to road traffic accident.
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