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2017;356:i6583 | doi: 10.1136/bmj.i6583
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open access Vi amin D supplemen a ion o p e en acu e espi a o y ac
in ec ions: sys ema ic e iew and me a-analysis o indi idual
pa icipan da a
Ad ian R Ma ineau,1,2 Da id A Jolli e,1 Richa d L Hoope ,1 Lau en G eenbe g,1 John F Aloia,3
Pe e Be gman,4 Gal Dubno -Raz,5 Susanna Esposi o,6 Da aasambuu Ganmaa,7 Adi A Ginde,8
Emma C Goodall,9 Came on C G an ,10 Ch is ophe J G i i hs,1,2,11 Wim Janssens,12 Ilkka Laaksi,13
Semi a Manaseki-Holland,14 Da id Mauge ,15 Da id R Mu doch,16 Rachel Neale,17 Judy R Rees,18
S e e Simpson,J 19 Iwona S elmach,20 Gee a T ilok Kuma ,21 Mi suyoshi U ashima,22 Ca los A Cama go J 23
ABSTRACT
Objec i es
To assess he o e all e ec o i amin D
supplemen a ion on isk o acu e espi a o y ac
in ec ion, and o iden i y ac o s modi ying his e ec .
Design
Sys ema ic e iew and me a-analysis o indi idual
pa icipan da a (IPD) om andomised con olled
ials.
Da a sOu ces
Medline, Embase, he Coch ane Cen al Regis e o
Con olled T ials, Web o Science, ClinicalT ials.go , and
he In e na ional S anda d Randomised Con olled T ials
Numbe egis y om incep ion o Decembe 2015.
eligibili y c i e ia O s uDy selec iOn
Randomised, double blind, placebo con olled ials o
supplemen a ion wi h i amin D3 o i amin D2 o any
du a ion we e eligible o inclusion i hey had been
app o ed by a esea ch e hics commi ee and i da a
on incidence o acu e espi a o y ac in ec ion we e
collec ed p ospec i ely and p especi ied as an e icacy
ou come.
esul s
25 eligible andomised con olled ials ( o al 11 321
pa icipan s, aged 0 o 95 yea s) we e iden i ied. IPD
we e ob ained o 10 933 (96.6%) pa icipan s. Vi amin
D supplemen a ion educed he isk o acu e
espi a o y ac in ec ion among all pa icipan s
(adjus ed odds a io 0.88, 95% con idence in e al
0.81 o 0.96; P o he e ogenei y <0.001). In subg oup
analysis, p o ec i e e ec s we e seen in hose
ecei ing daily o weekly i amin D wi hou addi ional
bolus doses (adjus ed odds a io 0.81, 0.72 o 0.91)
bu no in hose ecei ing one o mo e bolus doses
(adjus ed odds a io 0.97, 0.86 o 1.10; P o
in e ac ion=0.05). Among hose ecei ing daily o
weekly i amin D, p o ec i e e ec s we e s onge in
hose wi h baseline 25-hyd oxy i amin D le els <25
nmol/L (adjus ed odds a io 0.30, 0.17 o 0.53) han in
hose wi h baseline 25-hyd oxy i amin D le els ≥25
nmol/L (adjus ed odds a io 0.75, 0.60 o 0.95; P o
in e ac ion=0.006). Vi amin D did no in luence he
p opo ion o pa icipan s expe iencing a leas one
se ious ad e se e en (adjus ed odds a io 0.98, 0.80
o 1.20, P=0.83). The body o e idence con ibu ing o
hese analyses was assessed as being o high quali y.
cOnclusiOns
Vi amin D supplemen a ion was sa e and i p o ec ed
agains acu e espi a o y ac in ec ion o e all.
Pa ien s who we e e y i amin D de icien and hose
no ecei ing bolus doses expe ienced he mos
bene i .
sys ema ic e iew egis a iOn
PROSPERO CRD42014013953.
In oduc ion
Acu e espi a o y ac in ec ions a e a majo cause o
global mo bidi y and mo ali y and a e esponsible o
10% o ambula o y and eme gency depa men isi s in
he USA1 and an es ima ed 2.65 million dea hs wo ld-
wide in 2013.2 Obse a ional s udies epo consis en
independen associa ions be ween low se um concen-
a ions o 25-hyd oxy i amin D ( he majo ci cula ing
i amin D me aboli e) and suscep ibili y o acu e espi-
a o y ac in ec ion.3 4 25-hyd oxy i amin D suppo s
induc ion o an imic obial pep ides in esponse o bo h
i al and bac e ial s imuli,5-7 sugges ing a po en ial
mechanism by which i amin D inducible p o ec ion
agains espi a o y pa hogens migh be media ed. Vi a-
min D me aboli es ha e also been epo ed o induce
o he inna e an imic obial e ec o mechanisms,
including induc ion o au ophagy and syn hesis o
eac i e ni ogen in e media es and eac i e oxygen
in e media es.8 These epidemiological and in i o da a
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o:
A R Ma ineau
[email p o ec ed]k
Addi ional ma e ial is published
online only. To iew please isi
he jou nal online.
ci e his as: BMJ 2017;356:i6583
h p://dx.doi.o g/10.1136/bmj.i6583
Accep ed: 01 Decembe 2016
WhAT IS AlReAdy knoWn on ThIS TopIC
Randomised con olled ials o i amin D supplemen a ion o he p e en ion o
acu e espi a o y ac in ec ion ha e yielded con lic ing esul s
Indi idual pa icipan da a (IPD) me a-analysis has he po en ial o iden i y ac o s
ha may explain his he e ogenei y, bu his has no p e iously been pe o med
WhAT ThIS STudy AddS
Me a-analysis o IPD om 10 933 pa icipan s in 25 andomised con olled ials
showed an o e all p o ec i e e ec o i amin D supplemen a ion agains acu e
espi a o y ac in ec ion (numbe needed o ea (NNT)=33)
Bene i was g ea e in hose ecei ing daily o weekly i amin D wi hou addi ional
bolus doses (NNT=20), and he p o ec i e e ec s agains acu e espi a o y ac
in ec ion in his g oup we e s onges in hose wi h p o ound i amin D de iciency a
baseline (NNT=4)
These indings suppo he in oduc ion o public heal h measu es such as ood
o i ica ion o imp o e i amin D s a us, pa icula ly in se ings whe e p o ound
i amin D de iciency is common
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ha e p omp ed nume ous andomised con olled ials
o de e mine whe he i amin D supplemen a ion can
dec ease he isk o acu e espi a o y ac in ec ion. A
o al o i e agg ega e da a me a-analyses inco po a ing
da a om up o 15 p ima y ials ha e been conduc ed
o da e, o which wo epo s a is ically signi ican p o-
ec i e e ec s9 10 and h ee epo no s a is ically signi -
ican e ec s.11-13 All bu one o hese agg ega e da a
me a-analyses11 epo ed s a is ically signi ican he e o-
genei y o e ec be ween p ima y ials.
This he e ogenei y migh ha e a isen as a esul o
a ia ion in pa icipan cha ac e is ics and dosing egi-
mens be ween ials, ei he o which may modi y he
e ec s o i amin D supplemen a ion on immuni y o
espi a o y pa hogens.14 People wi h ch onic obs uc-
i e pulmona y disease who ha e lowe baseline i a-
min D s a us ha e been epo ed o de i e g ea e
clinical bene i om supplemen a ion han hose wi h
highe baseline s a us,15 16 and pa icipan cha ac e is-
ics such as age and body mass index ha e been
epo ed o modi y he 25-hyd oxy i amin D esponse o
i amin D supplemen a ion.17 18 T ea men wi h la ge
boluses o i amin D has been associa ed wi h educed
e icacy o non-classic e ec s,9 and in some cases an
inc eased isk o ad e se ou comes.19 While s udy le el
ac o s a e amenable o explo a ion h ough agg ega e
da a me a-analysis o published da a, po en ial e ec
modi ie s ope a ing a an indi idual le el, such as base-
line i amin D s a us, can only be explo ed using indi-
idual pa icipan da a (IPD) me a-analysis. This is
because subg oups a e no consis en ly disagg ega ed
in ial epo s, and adjus men s o po en ial con-
ounde s canno be applied simila ly ac oss ials.20 To
iden i y ac o s ha migh explain he obse ed he e o-
genei y o esul s om andomised con olled ials, we
unde ook an IPD me a-analysis based on all 25 an-
domised con olled ials o i amin D supplemen a ion
o p e en ion o acu e espi a o y ac in ec ion ha
we e comple ed up o he end o Decembe 2015.
Me hods
P o ocol and egis a ion
The me hods we e p especi ied in a p o ocol ha was eg-
is e ed wi h he PROSPERO In e na ional P ospec i e
Regis e o Sys ema ic Re iews (www.c d.yo k.ac.uk/
PROSPERO/display_ eco d.asp?ID=CRD42014013953).
App o al by a esea ch e hics commi ee o conduc his
me a-analysis was no equi ed in he UK; local e hical
pe mission o con ibu e deiden i ied IPD om p ima y
ials was equi ed and ob ained o s udies by Cama go
e al21 ( he e hics e iew commi ee o he Mongolian Min-
is y o Heal h), Mu doch e al22 (Sou he n Heal h and
Disabili y E hics Commi ee, e e ence URB/09/10/050/
AM02), Rees e  al23 (Commi ee o he P o ec ion o
Human Subjec s, Da mou h College, USA; p o ocol No
24381), Tachimo o e al24 (e hics commi ee o he Jikei
Uni e si y School o Medicine, e e ence 26-333: 7839),
T an e al25 (QIMR Be gho e Medical Resea ch Ins i u e
human esea ch e hics commi ee, P1570), and U ashima
e al26 27 (e hics commi ee o he Jikei Uni e si y School o
Medicine, e e ence 26-333: 7839).
Pa ien and public in ol emen
Two pa ien and public in ol emen ep esen a i es
we e in ol ed in de elopmen o he esea ch ques ions
and he choice o ou come measu es speci ied in he
s udy p o ocol. They we e no in ol ed in pa ien
ec ui men , since his is a me a-analysis o comple ed
s udies. Da a ela ing o he bu den o he in e en ion
on pa icipan s’ quali y o li e and heal h we e no
me a-analysed. Whe e possible, esul s o his sys em-
a ic e iew and me a-analysis will be dissemina ed o
indi idual pa icipan s h ough he p incipal in es iga-
o s o each ial.
eligibili y c i e ia
Randomised, double blind, placebo con olled ials o
supplemen a ion wi h i amin D3 o i amin D2 o any
du a ion we e eligible o inclusion i hey had been
app o ed by a esea ch e hics commi ee and i da a on
incidence o acu e espi a o y ac in ec ion we e col-
lec ed p ospec i ely and p especi ied as an e icacy ou -
come. The las equi emen was imposed o minimise
misclassi ica ion bias (p ospec i ely designed ins u-
men s o cap u e acu e espi a o y ac in ec ion e en s
we e deemed mo e likely o be sensi i e and speci ic o
his ou come). We excluded s udies epo ing esul s o
long e m ollow-up o p ima y andomised con olled
ials.
s udy iden i ica ion and selec ion
Two in es iga o s (ARM and DAJ) sea ched Medline,
Embase, he Coch ane Cen al Regis e o Con olled
T ials (CENTRAL), Web o Science, ClinicalT ials.go ,
and he In e na ional S anda d Randomized Con-
olled T ials Numbe (ISRCTN) egis y using he
elec onic sea ch s a egies desc ibed in he supple-
men a y ma e ial. Sea ches we e egula ly upda ed
up o, and including, 31 Decembe 2015. No language
es ic ions we e imposed. These sea ches we e sup-
plemen ed by sea ches o e iew a icles and e e -
ence lis s o ial publica ions. Collabo a o s we e
asked i hey knew o any addi ional ials. Two in es-
iga o s (ARM and CAC) de e mined which ials me
he eligibili y c i e ia.
Da a collec ion p ocesses
IPD we e eques ed om he p incipal in es iga o o
each eligible ial, and he e ms o collabo a ion we e
speci ied in a da a ans e ag eemen , signed by ep e-
sen a i es o he da a p o ide and he ecipien (Queen
Ma y Uni e si y o London). Da a we e deiden i ied a
sou ce be o e ans e by email. On eceip , h ee in es-
iga o s (DAJ, RLH, and LG) assessed da a in eg i y by
pe o ming in e nal consis ency checks and by a emp -
ing o eplica e esul s o he analysis o incidence o
acu e espi a o y ac in ec ion whe e his was pub-
lished in he ial epo . S udy au ho s we e con ac ed
o p o ide missing da a and o esol e que ies a ising
om hese in eg i y checks. Once que ies had been
esol ed, clean da a we e uploaded o he main s udy
da abase, which was held in STATA IC 12 (College
S a ion, TX).
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Da a ela ing o s udy cha ac e is ics we e ex ac ed
o he ollowing a iables: se ing, eligibili y c i e ia,
de ails o in e en ion and con ol egimens, s udy
du a ion, and case de ini ions o acu e espi a o y
ac in ec ion. IPD we e ex ac ed o he ollowing
a iables, whe e a ailable: baseline da a we e
eques ed o age, sex, clus e iden i ie (clus e an-
domised ials only), acial o e hnic o igin, in luenza
accina ion s a us, his o y o as hma, his o y o
ch onic obs uc i e pulmona y disease, body weigh ,
heigh (adul s and child en able o s and) o leng h
(in an s), se um 25-hyd oxy i amin D concen a ion,
s udy alloca ion ( i amin D e sus placebo), and
de ails o any s a i ica ion o minimisa ion a iables.
Follow-up da a we e eques ed o o al numbe o
acu e espi a o y ac in ec ions (uppe o lowe ),
uppe espi a o y ac in ec ions, and lowe espi a-
o y ac in ec ions expe ienced du ing he ial; ime
om i s dose o s udy d ug o i s acu e espi a o y
ac in ec ion (uppe o lowe ), uppe espi a o y ac
in ec ion, o lowe espi a o y ac in ec ion i applica-
ble; o al numbe o cou ses o an ibio ics aken o
acu e espi a o y ac in ec ion du ing he ial; o al
numbe o days o wo k o school due o symp oms o
acu e espi a o y ac in ec ion du ing he ial; se um
25-hyd oxy i amin D concen a ion a inal ollow-up;
du a ion o ollow-up; numbe and na u e o se ious
ad e se e en s; numbe o po en ial ad e se eac ions
(inciden hype calcaemia o enal s ones); and pa ici-
pan s a us a end o he ial (comple ed, wi hd ew,
los o ollow-up, died).
isk o bias assessmen o indi idual s udies
We used he Coch ane Collabo a ion isk o bias ool28 o
assess sequence gene a ion; alloca ion concealmen ;
blinding o pa icipan s, s a , and ou come assesso s;
comple eness o ou come da a; and e idence o selec i e
ou come epo ing and o he po en ial h ea s o alid-
i y. Two in es iga o s (ARM and DAJ) independen ly
assessed s udy quali y, excep o he h ee ials by Ma -
ineau and colleagues, which we e assessed by CAC.
Disc epancies we e esol ed by consensus.
De ini ion o ou comes
The p ima y ou come o he me a-analysis was inci-
dence o acu e espi a o y ac in ec ion, inco po a ing
e en s classi ied as uppe espi a o y ac in ec ion,
lowe espi a o y ac in ec ion, and acu e espi a o y
ac in ec ion o unclassi ied loca ion (ie, in ec ion o
he uppe espi a o y ac o lowe espi a o y ac , o
bo h). Seconda y ou comes we e incidence o uppe
and lowe espi a o y ac in ec ions, analysed sepa-
a ely; incidence o eme gency depa men a endance
o hospi al admission, o bo h o acu e espi a o y
ac in ec ion; use o an imic obials o ea men o
acu e espi a o y ac in ec ion; absence om wo k o
school due o acu e espi a o y ac in ec ion; inci-
dence and na u e o se ious ad e se e en s; incidence
o po en ial ad e se eac ions o i amin D (hype cal-
caemia o enal s ones); and mo ali y (acu e espi a-
o y ac in ec ion ela ed and all cause).
syn hesis me hods
LG and RLH analysed he da a. Ou IPD me a-analysis
app oach ollowed published guidelines.20 Ini ially we
eanalysed all s udies sepa a ely; he o iginal au ho s
we e asked o con i m he accu acy o his eanalysis
whe e i had been pe o med p e iously, and any dis-
c epancies we e esol ed. Then we pe o med bo h one
s ep and wo s ep IPD me a-analysis o each ou come
sepa a ely using a andom e ec s model adjus ed o
age, sex, and s udy du a ion o ob ain he pooled in e -
en ion e ec wi h a 95% con idence in e al. We did
no adjus o o he co a ia es because missing alues
o some pa icipan s would ha e led o hei exclusion
om s a is ical analyses. In he one s ep app oach, we
modelled IPD om all s udies simul aneously while
accoun ing o he clus e ing o pa icipan s wi hin
s udies. In he wo s ep app oach we i s analysed IPD
o each sepa a e s udy independen ly o p oduce an
es ima e o he ea men e ec o ha s udy; we hen
syn hesised hese da a in a second s ep.20 Fo he one
s ep IPD me a-analysis we assessed he e ogenei y by
calcula ion o he s anda d de ia ion o andom e ec s;
o he wo s ep IPD me a-analysis we summa ised he -
e ogenei y using he I2 s a is ic. We calcula ed he num-
be needed o ea o p e en one pe son om ha ing
any acu e espi a o y ac in ec ion (NNT) using he
Visual Rx NNT calcula o (www.nn online.ne / isu-
al x/), whe e me a-analysis o dicho omous ou comes
e ealed a s a is ically signi ican bene icial e ec o
alloca ion o i amin D compa ed wi h placebo.
explo a ion o a ia ion in e ec s
To explo e he causes o he e ogenei y and iden i y ac-
o s modi ying he e ec s o i amin D supplemen a ion,
we pe o med p especi ied subg oup analyses by ex end-
ing he one s ep me a-analysis amewo k o include
ea men -co a ia e in e ac ion e ms. Subg oups we e
de ined acco ding o baseline i amin D s a us (se um
25-hyd oxy i amin D <25 ≥25 nmol/L), i amin D dosing
egimen (daily o weekly wi hou bolus dosing e sus a
egimen including a leas one bolus dose o a leas
30 000 IU i amin D), dose size (daily equi alen <800
IU, 800-1999 IU, ≥2000 IU), age (≤1 yea , 1.1-15.9 yea s,
16-65 yea s, >65 yea s), body mass index (<25 ≥25), and
p esence compa ed wi h absence o as hma, ch onic
obs uc i e pulmona y disease, and p e ious in luenza
accina ion. To ensu e ha epo ed subg oup e ec s
we e independen , we adjus ed in e ac ion analyses o
po en ial con ounde s (age, sex, and s udy du a ion).
The 25 nmol/L cu -o o baseline 25-hyd oxy i amin D
concen a ion in subg oup analyses was selec ed on he
g ounds ha i is he h eshold o i amin D de iciency
de ined by he UK Depa men o Heal h,29 and he le el
below which pa icipan s in clinical ials ha e expe i-
enced he mos consis en bene i s o supplemen a ion.30
We also pe o med an explo a o y analysis in es iga ing
e ec s in subg oups de ined using he 50 nmol/L and 75
nmol/L cu -o s o baseline ci cula ing 25-hyd oxy i a-
min D concen a ion, because obse a ional s udies ha e
epo ed ha less p o ound s a es o i amin D de iciency
may also associa e independen ly wi h an inc eased isk
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o acu e espi a o y ac in ec ion.31 32 To minimise he
chance o ype 1 e o a ising om mul iple analyses, we
in e ed s a is ical signi icance o subg oup analyses
only whe e P alues o ea men -co a ia e in e ac ion
e ms we e <0.05.
Quali y assessmen ac oss s udies
Fo he p ima y analysis we in es iga ed he likelihood
o publica ion bias h ough he cons uc ion o a con-
ou enhanced unnel plo .33 We used he i e GRADE
conside a ions (s udy limi a ions, consis ency o e ec ,
imp ecision, indi ec ness, and publica ion bias)34 o
assess he quali y o he body o e idence con ibu ing
o analyses o he p ima y e icacy ou come and majo
sa e y ou come o ou me a-analysis (see supplemen-
a y able S3).
addi ional analyses
We conduc ed sensi i i y analyses excluding IPD om
ials whe e acu e espi a o y ac in ec ion was a sec-
onda y ou come (as opposed o a p ima y o co-p ima y
ou come), and whe e isk o bias was assessed as being
unclea . We also conduc ed a esponde analysis in pa -
icipan s andomised o he in e en ion a m o
included s udies o whom end s udy da a on
25-hyd oxy i amin D we e a ailable, compa ing isk o
acu e espi a o y ac in ec ion in hose who a ained a
se um le el o 75 nmol/L o mo e compa ed wi h hose
who did no .
Resul s
s udy selec ion and iPD ob ained
Ou sea ch iden i ied 532 unique s udies ha we e
assessed o eligibili y; o hese, 25 s udies wi h a o al
o 11 321 andomised pa icipan s ul illed he eligibili y
c i e ia ( ig 1). IPD we e sough and ob ained o all 25
s udies. Ou come da a o he p ima y analysis o p o-
po ion o pa icipan s expe iencing a leas one acu e
espi a o y ac in ec ion we e ob ained o 10 933
(96.6%) o he andomised pa icipan s.
s udy and pa icipan cha ac e is ics
Table 1 p esen s he cha ac e is ics o eligible s udies
and hei pa icipan s. T ials we e conduc ed in 14
coun ies on ou con inen s and en olled pa icipan s
o bo h sexes om bi h o 95 yea s o age. Baseline
se um 25-hyd oxy i amin D concen a ions we e de e -
mined in 19/25 ials: mean baseline concen a ion
anged om 18.9 o 88.9 nmol/L. Baseline cha ac e is-
ics o pa icipan s andomised o in e en ion and con-
ol we e simila (see supplemen a y able S1). All
s udies adminis e ed o al i amin D3 o pa icipan s in
he in e en ion a m: his was gi en as bolus doses
e e y mon h o e e y h ee mon hs in se en s udies,
weekly doses in h ee s udies, a daily dose in 12 s udies,
and a combina ion o bolus and daily doses in h ee
s udies. S udy du a ion anged om se en weeks o 1.5
yea s. Incidence o acu e espi a o y ac in ec ion was
he p ima y o co-p ima y ou come o 14 s udies and a
seconda y ou come o 11 s udies.
IPD in eg i y was con i med by eplica ion o p ima y
analyses in published pape s whe e applicable. The
p ocess o checking IPD iden i ied h ee ypog aphical
e o s in published epo s. Fo he 2012 ial by
Manaseki-Holland e al,35 he co ec numbe o epea
episodes o ches adiog aphy con i med pneumonia
was 134, a he han 138 as epo ed. Fo he ial by
Dubno -Raz e al,36 he numbe o pa ien s andomised
o he in e en ion a m was 27, a he han 28 as
epo ed. Fo he ial by Laaksi e al,37 he p opo ion o
men andomised o placebo who did no expe ience any
acu e espi a o y ac in ec ion was 30/84, a he han
30/80 as epo ed.
isk o bias wi hin s udies
Supplemen a y able S2 p o ides de ails o he isk o
bias assessmen . All bu wo ials we e assessed as
being a low isk o bias o all aspec s assessed. Two
ials we e assessed as being a unclea isk o bias
owing o high a es o loss o ollow-up. In he ial by
Dubno -Raz e al,36 52% o pa icipan s did no com-
ple e all symp om ques ionnai es. In he ial by Laaksi
e al,37 37% o andomised pa icipan s we e los o ol-
low-up.
incidence o acu e espi a o y ac in ec ion
O e all esul s
Table 2 p esen s he esul s o he one s ep IPD
me a-analysis es ing he e ec s o i amin D on he
p opo ion o all pa icipan s expe iencing a leas one
acu e espi a o y ac in ec ion, adjus ing o age, sex,
and s udy du a ion. Vi amin D supplemen a ion
esul ed in a s a is ically signi ican educ ion in he
p opo ion o pa icipan s expe iencing a leas one
acu e espi a o y ac in ec ion (adjus ed odds a io
0.88, 95% con idence in e al 0.81 o 0.96, P=0.003; P
o he e ogenei y <0.001; NNT=33, 95% con idence
in e al 20 o 101; 10 933 pa icipan s in 25 s udies; see
Ca es plo , supplemen a y igu e S1). S a is ically
Addi ional s udies iden i ied
h ough o he sou ces, including
con ac wi h esea che s (n=3)
S udies iden i ied h ough da abase sea ches
(n=717):
Medline (n=261)
Coch ane CENTRAL (n=146)
Embase (n=52)
Web o Science (n=258)
A ailable da a:
IPD ob ained o eligible s udies (n=25)
Randomised pa icipan s wi h ou come da a o p ima y analysis (n=10 933)
Randomised pa icipan s wi h missing ou come da a o p ima y analysis (n=388)
Analysis, p opo ion expe iencing ≥1 acu e espi a o y ac in ec ions:
One s ep: da a om 10 933 pa icipan s in 25 s udies analysed
Two s ep: da a om 10 899 pa icipan s in 24 s udies analysed (34 pa icipan s in one s udy
excluded – ea men e ec no es imable)
Unique s udies a e duplica es emo ed (n=532)
S udies wi h o al o 11 321 andomised pa icipan s eligible; IPD sough o all (n=25)
Excluded (no ele an , e iew a icle, no andomised con olled ials,
acu e espi a o y ac in ec ion no p especi ied as e icacy ou come) (n=507)
ig 1 | low o s udy selec ion. iPD=indi idual pa icipan da a
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RESEARCH
5
able 1 | cha ac e is ics o he 25 eligible ials and hei pa icipan s
e e ence
se ing
(s udy
du a ion)
Pa icipan s
(male: emale)
mean (sD)
age, yea s
( ange)
25(OH)D
no in
in e en ion:
con ol g oup O al dose o i amin D3
a i no en e ing
p ima y
analysis/no
andomised (%)
assay, eQa
scheme
mean (sD)
baseline le el,
nmol/l ( ange)
baseline le el
<25 nmol/l (%) De ini ion
Ou come
ype
Li-Ng 200941 USA
(3 mon hs)
Heal hy adul s
(34:128)
57.9 (13.6)
(21.4-80.6)
RIA (DiaSo in),
DEQAS
63.7 (25.5)
(16.0-156.0)
3/150 (2.0) 84:78 50 µg daily, placebo URTI: ≥2 URTI
symp oms in
absence o alle gy
symp oms
P ima y 157/162 (96.9)
U ashima 201027 Japan
(4 mon hs)
Schoolchild en
(242:188)
10.2 (2.3)
(6.0-15.0)
-- ND -- 217:213 30 µg daily, placebo URTI: in luenza A/B
diagnosed by RIDT
o RIDT-nega i e ILI
P ima y 334/430 (77.7)
Manaseki-
Holland 201042
A ghanis an
(3 mon hs)
P eschool child en
wi h pneumonia
(257:196)
1.1 (0.8)
(0.1-3.3)
-- ND -- 224:229 2.5 mg bolus once, placebo LRTI: epea episode
o pneumonia—age-
speci ic achypnoea
wi hou wheeze
Seconda y 453/453 (100.0)
Laaksi 201037 Finland
(6 mon hs)
Mili a y consc ip s
(164:0)
19.1 (0.6)
(18.0-21.0)
EIA (IDS OCTEIA) 75.9 (18.7)
(41.9-129.0)
0/73 (0.0) 80:84 10 µg daily, placebo ARTI: medical
eco d diagnosis
P ima y 164/164 (100.0)
Majak 201143 Poland
(6mon hs)
Child en wi h
as hma (32:16)
10.9 (3.3)
(6.0-17.0)
RIA (BioSou ce
Eu ope), RIQAS
88.9 (38.2)
(31.5-184.7)
0/48 (0.0) 24:24 12.5 µg daily, placebo ARTI: sel epo Seconda y 48/48 (100.0)
T ilok-Kuma
201144
India
(6 mon hs)
Low bi hweigh
in an s (970:1109)
0.1 (0.0)
(0.0-0.3)
-- ND ND 1039:1040 35 µg weekly, placebo ARTI: medical
eco d diagnosis o
e en s esul ing in
hospi al admission
Seconda y 2064/2079
(99.3)
Lehouck 201215 Belgium
(1 yea )
Adul s wi h COPD
(145:37)
67.9 (8.3)
(48.0-
86.0)
RIA (Diaso in),
DEQAS
49.8 (29.2)
(9.0-159.7)
31/182 (17.0) 91:91 2.5 mg bolus mon hly,
placebo
URTI: sel epo Seconda y 175/182 (96.2)
Manaseki-
Holland 201235
A ghanis an
(1.5 yea s)
In an s (1591:1455) 0.5 (0.3)
(0.0-1.0)
-- ND ND 1524:1522 2.5 mg bolus 3-mon hly,
placebo
LRTI: pneumonia
con i med by ches
adiog aphy
P ima y 3011/3046
(98.9)
Cama go 201221 Mongolia
(7weeks)
3 d/4 h g ade
schoolchild en
(129:118)
10.0 (0.9)
(7.0-12.7)
LC-MS/MS,
DEQAS
18.9 (9.7)
(3.3-61.2)
192/245 (78.4) 143:104 7.5 µg daily, placebo ARTI: pa en
epo ed “ches
in ec ions o colds”
Seconda y 244/247 (98.8)
Mu doch 201222 New Zealand
(1.5 yea s)
Heal hy adul s
(81:241)
48.1 (9.7)
(18.0-67.6)
LC-MS/MS,
DEQAS
72.1 (22.1)
(13.0-142.0)
5/322 (1.6) 161:161 2×5 mg bolus mon hly hen
2.5 mg bolus mon hly,
placebo
URTI: assessed wi h
symp om sco e
P ima y 322/322 (100.0)
Be gman 201245 Sweden
(1 yea )
Adul s wi h
inc eased
suscep ibili y o
ARTI (38:102)
53.1 (13.1)
(20.0-77.0)
CLA (DiaSo in),
DEQAS
49.3 (23.2)
(8.0-135.0)
15/131 (11.45) 70:70 100 µg daily, placebo URTI: assessed wi h
symp om sco e
Seconda y 124/140 (88.6)
Ma chisio 201346 I aly
(6mon hs)
Child en wi h
ecu en acu e
o i is media
(64:52)
2.8 (1.0)
(1.3-4.8)
CLA (DiaSo in),
ISO9001
65.3 (17.3)
(24.7-120.6)
2/116 (1.7) 58:58 25 µg daily, placebo URTI: doc o
diagnosed acu e
o i is media
P ima y 116/116 (100.0)
Rees 201323 USA
(13 mon hs,
a e age)
Adul s wi h
p e ious colo ec al
adenoma
(438:321*)
61.2 (6.6)
(47.1-7 7.9)
RIA (IDS), DEQAS 62.5 (21.3)
(30.2-171.6)
0/759 (0.0) 399:360 25 µg daily, placebo URTI: assessed
om daily symp om
dia y
Seconda y 759/759 (100.0)
T an 201425 Aus alia
(1 yea )
Heal hy olde
adul s (343:301)
71.7 (6.9)
(60.3-85.2)
CLA (DiaSo in),
DEQAS
41.7 (13.5)
(12.6-105.0)
66/643 (10.3) 430:214 0.75 mg bolus 1.5 mg
bolus mon hly, placebo
URTI: sel epo ed
cold
Seconda y 594/644 (92.2)
Goodall 201447 Canada
(8 weeks)
Heal hy uni e si y
s uden s (218:382)
19.6 (2.2)
(17.0-33.0)
-- ND -- 300:300 0.25 mg weekly ( ac o ial
wi h ga gling), placebo
URTI: sel epo ed
cold
P ima y 492/600 (82.0)
(Con inued)

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RESEARCH
6
able 1 | cha ac e is ics o he 25 eligible ials and hei pa icipan s
e e ence
se ing
(s udy
du a ion)
Pa icipan s
(male: emale)
mean (sD)
age, yea s
( ange)
25(OH)D
no in
in e en ion:
con ol g oup O al dose o i amin D3
a i no en e ing
p ima y
analysis/no
andomised (%)
assay, eQa
scheme
mean (sD)
baseline le el,
nmol/l ( ange)
baseline le el
<25 nmol/l (%) De ini ion
Ou come
ype
U ashima 201426 Japan
(2 mon hs)
High school
s uden s (162:85)
16.5 (1.0)
(15.0-18.0)
-- ND -- 148:99 50 µg daily, placebo URTI: in luenza A
diagnosed by RIDT
o RIDT nega i e ILI
P ima y 247/247 (100.0)
G an 201448 New Zealand
(9 mon hs:
3mon hs in
p egnancy +
6 mon hs in
in ancy)
P egnan women
and o sp ing
(0:260 (mo he s)
121:128 (o sp ing))
unbo n LC-MS/MS,
DEQAS
54.8 (25.8)
(8.0-128.0)
30/200 (15.0) 173:87 (mo he s)
164:85 (o sp ing)
Mo he s: 25 µg 50 µg daily
In an s: 10 µg 20 µg daily,
placebo
ARTI: doc o
diagnosed ARTI
p ecipi a ing
p ima y ca e
consul a ion
Seconda y 236/260 (90.8)
Ma ineau
2015a16 (ViDiCO)
UK (1 yea ) Adul s wi h COPD
(144:96)
64.7 (8.5)
(40.0-
85.0)
LC-MS/MS,
DEQAS
46.1 (25.7)
(0.0-160.0)
50/240 (20.8) 122:118 3 mg bolus 2-mon hly,
placebo
URTI: assessed
om daily symp om
dia y
Cop ima y 240/240 (100.0)
Ma ineau
2015b49 (ViDiAs)
UK (1 yea ) Adul s wi h as hma
(109:141)
47.9 (14.4)
(16.0-78.0)
LC-MS/MS,
DEQAS
49.6 (24.7)
(0.0-139.0)
36/250 (14.4) 125:125 3 mg bolus 2-mon hly,
placebo
URTI: assessed
om daily symp om
dia y
Cop ima y 250/250 (100.0)
Ma ineau
2015c50 (ViDiFlu)
UK (1 yea ) Olde adul s and
hei ca e s
(82:158)
67.1 (13.0)
(21.4-94.0)
LC-MS/MS,
DEQAS
42.9 (23.0)
(0.0-128.0)
60/240 (25.0) 137:103 Olde adul s: 2.4 mg bolus
2-mon hly+10 µg daily.
Ca e s: 3 mg 2-mon hly,
olde adul s: placebo+10 µg
daily. Ca e s: placebo
URTI and LRTI, bo h
assessed om daily
symp om dia y
Cop ima y 240/240 (100.0)
Simpson 201551 Aus alia
(17weeks)
Heal hy adul s
(14:20)
32.2 (12.2)
(18.0-52.0)
LC-MS/MS,
DEQAS
67.9 (23.0)
(32.0-132.0)
0/33 (0.0) 18:16 0.5 mg weekly, placebo ARTI assessed wi h
symp om sco e
P ima y 34/34 (100.0)
Dubno -Raz
201536
Is ael
(12weeks)
Adolescen
swimme s wi h
i amin D
insu iciency
(34:20)
15.2 (1.6)
(12.9-18.6)
RIA (DiaSo in),
DEQAS
60.4 (11.9)
(28.0-74.6)
0/54 (0.0) 27:27 50 µg daily, placebo URTI assessed wi h
symp om sco e
P ima y 25/54 (46.3)
Denlinge 201652 USA
(28weeks)
Adul s wi h as hma
(130:278)
39.2 (12.9)
(18.0-85.0)
CLA (DiaSo in),
VDSP
47.0 (16.9)
(10.0-74.6)
55/408 (13.5) 201:207 2.5 mg bolus hen 100 µg
daily, placebo
URTI assessed wi h
symp om sco e
Seconda y 408/408 (100.0)
Tachimo o
201624
Japan
(6mon hs)
Child en wi h
as hma (50:39)
9.9 (2.3)
(6.0-15.0)
RIA (DiaSo in),
CAP
74.9 (24.6)
(20.0-187.2)
1/89 (1.1) 54:35 20 µg daily, i s 2 mon hs,
placebo
URTI: assessed wi h
symp om sco e
Seconda y 89/89 (100.0)
Ginde, 201653 USA (1 yea ) Olde ca e home
esiden s (45:62)
80.7 (9.9)
(60.0-
95.0)
LC-MS/MS, VDSP 57.3 (22.7)
(11.7-106.1)
12/107 (11.2) 55:52 2.5 mg bolus mon hly+≤25
µg pe day equi alen ,
placebo+10-25 µg pe day
equi alen
ARTI: medical
eco d diagnosis
P ima y 107/107 (100.0)
25(OH)D=25-hyd oxy i amin D; RIDT= apid in luenza diagnos ic es ; COPD=ch onic obs uc i e pulmona y disease; D3, i amin D3 (cholecalci e ol); ARTI=acu e espi a o y ac in ec ion; CAP=College o Ame ican Pa hologis s;
CLA=chemiluminescen assay; DEQAS=Vi amin D Ex e nal Quali y Assessmen Scheme; EIA=enzyme immunoassay; EQA=ex e nal quali y assessmen ; LC-MS/MS=liquid ch oma og aphy andem-mass spec ome y; RIA= adioimmunoassay;
URTI=uppe espi a o y ac in ec ion; LRTI=lowe espi a o y ac in ec ion; ILI=in luenza-like illness; RIQAS=Randox In e na ional Quali y Assessmen Scheme; VDSP=Vi amin D S anda disa ion P og am o he O ice o Die a y Supplemen s,
Na ional Ins i u es o Heal h, USA.
1 µg i amin D3=40 in e na ional uni s (IU); 25(OH)D concen a ions epo ed in ng/mL we e con e ed o nmol/L (mul iplying by 2.496)
*Sex missing o wo pa icipan s andomised o in e en ion a m and subsequen ly excluded om analysis owing o lack o ou come da a.
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RESEARCH
7
signi ican p o ec i e e ec s o i amin D we e also seen
o one s ep analyses o acu e espi a o y ac in ec ion
a e (adjus ed incidence a e a io 0.96, 95% con idence
in e al 0.92 o 0.997, P=0.04; P o he e ogenei y
<0.001; 10 703 pa icipan s in 25 s udies) bu no o
analysis o ime o i s acu e espi a o y ac in ec ion
(adjus ed haza d a io 0.95, 95% con idence in e al
0.89 o 1.01, P=0.09; P o he e ogenei y <0.001; 9108
pa icipan s in 18 s udies). Two s ep analyses also
showed consis en e ec s o he p opo ion o pa ici-
pan s expe iencing a leas one acu e espi a o y ac
in ec ion (adjus ed odds a io 0.80, 0.69 o 0.93,
P=0.004; P o he e ogenei y 0.001; 10 899 pa icipan s
in 24 s udies; ig 2), acu e espi a o y ac in ec ion a e
(adjus ed incidence a e a io 0.91, 0.84 o 0.98,
P=0.018; P o he e ogenei y <0.001; 10 703 pa icipan s
in 25 s udies), and ime o i s acu e espi a o y ac
in ec ion (adjus ed haza d a io 0.92, 0.85 o 1.00,
P=0.051; P o he e ogenei y 0.14; 9108 pa icipan s in
18 s udies). This e idence was assessed as being o high
quali y (see supplemen a y able S3).
Subg oup analyses
To explo e easons o he e ogenei y, we conduc ed
subg oup analyses o in es iga e whe he e ec s o
i amin D supplemen a ion on isk o acu e espi a o y
ac in ec ion di e ed acco ding o baseline i amin D
s a us, dosing equency, dose size, age, body mass
index, he p esence o absence o como bidi y (as hma
o ch onic obs uc i e pulmona y disease), and in lu-
enza accina ion s a us. Race o e hnici y was no
in es iga ed as a po en ial e ec modi ie , as da a o
his a iable we e missing o 3680/10 933 (34%) pa ic-
ipan s and powe o subg oup analyses was limi ed by
small numbe s in many acial o e hnic subg oups ha
could no be meaning ully combined. Table 2 p esen s
he esul s. Subg oup analysis e ealed a s ong p o ec-
i e e ec o i amin D supplemen a ion among hose
wi h baseline ci cula ing 25-hyd oxy i amin D le els
less han 25 nmol/L (adjus ed odds a io 0.58, 0.40
o0.82, NNT=8, 5 o 21; 538 pa icipan s in 14 s ud-
ies; wi hin subg oup P=0.002; see Ca es plo ,
supplemen a y igu e S1) and no s a is ically signi i-
can e ec among hose wi h baseline le els o 25 o
mo e nmol/L (adjus ed odds a io 0.89, 0.77 o 1.04;
3634 pa icipan s in 19 s udies; wi hin subg oup
P=0.15; P o in e ac ion 0.01). This e idence was
assessed as being o high quali y (see supplemen a y
able S3). An explo a o y analysis es ing he e ec s o
i amin D supplemen a ion in hose wi h baseline
25-hyd oxy i amin D concen a ions in he anges
25-49.9 nmol/L, 50-74.9 nmol/L, and 75 o mo e nmol/L
able 2 | One s ep indi idual pa icipan da a me a-analysis, p opo ion o pa icipan s expe iencing a leas one acu e espi a o y ac in ec ion
(a i): o e all and by subg oup
a iables
no o
ials*
P opo ion wi h ≥1
a i, con ol g oup (%)
P opo ion wi h ≥1 a i,
in e en ion g oup (%)
adjus ed odds
a io (95% ci)† P alue
P alue o
in e ac ion
O e all 25 2204/5225 (42.2) 2303/5708 (40.3) 0.88 (0.81 o 0.96) 0.003 --
Baseline 25(OH)D (nmol/L):
<25 14 137/249 (55.0) 117/289 (40.5) 0.58 (0.40 o 0.82) 0.002 0.01
≥25 19 1027/1639 (62.7) 1179/1995 (59.1) 0.89 (0.77 o 1.04) 0.15
Dosing egimen ype:
Bolus dose ≥30 000 IU gi en 10 994/2786 (35.7) 1097/3014 (36.4) 0.97 (0.86 o 1.10) 0.67 0.05
Bolus dose no gi en 15 1210/2439 (49.6) 1206/2694 (44.8) 0.81 (0.72 o 0.91) <0.001
Daily dose equi alen (µg):
<20 5629/1321 (47.6) 619/1435 (43.1) 0.80 (0.68 o 0.94) 0.006
0.12 20-50 9945/2796 (33.8) 1023/3077 (33.2) 0.90 (0.79 o 1.01) 0.08
≥50 11 630/1108 (56.9) 661/1196 (55.3) 0.98 (0.81 o 1.18) 0.84
Age (yea s):
≤1 4 832/2744 (30.3) 854/2827 (30.2) 0.94 (0.83 o 1.06) 0.33
0.61
1.1-15.9 8241/513 (47.0) 194/566 (34.3) 0.60 (0.46 o 0.77) <0.001
16-65 17 854/1459 (58.5) 885/1592 (55.6) 0.93 (0.79 o 1.10) 0.41
>65 11 277/509 (54.4) 370/723 (51.2) 0.86 (0.67 o 1.09) 0.21
Body mass index (kg/m2):
<25 19 972/1943 (50.0) 956/2074 (46.1) 0.85 (0.74 o 0.97) 0.02 0.29
≥25 17 659/1039 (63.4) 754/1235 (61.1) 0.95 (0.79 o 1.14) 0.58
As hma:
No 11 518/1008 (51.4) 520/1101 (47.2) 0.82 (0.68 o 0.99) 0.04 0.48
Yes 11 296/534 (55.4) 285/542 (52.6) 0.95 (0.73 o 1.25) 0.73
COPD:
No 7477/763 (62.5) 493/791 (62.3) 1.00 (0.80 o 1.26) 0.98 0.38
Yes 6122/230 (53.0) 120/238 (50.4) 0.84 (0.57 o 1.24) 0.38
In luenza accina ion:
No 10 255/373 (68.4) 253/407 (62.2) 0.74 (0.52 o 1.03) 0.08 0.51
Yes 10 564/779 (72.4) 577/826 (69.9) 0.86 (0.68 o 1.09) 0.22
25(OH)D=25-hyd oxy i amin D; COPD=ch onic obs uc i e pulmona y disease; 1 µg i amin D3=40 in e na ional uni s (IU).
*Some ials did no con ibu e da a o a gi en subg oup, ei he because indi iduals wi hin ha subg oup we e no ep esen ed o because da a ela ing o he po en ial e ec modi ie we e no
eco ded; acco dingly he numbe o ials ep esen ed a ies be ween subg oups.
†Adjus ed o age, sex, and s udy du a ion.
doi: 10.1136/bmj.i6583 |
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2017;356:i6583 | he bmj
RESEARCH
8
did no e eal e idence o a s a is ically signi ican
in e ac ion (see supplemen a y able S4).
Me a-analysis o da a om ials in which i amin D
was adminis e ed using a daily o weekly egimen wi h-
ou addi ional bolus doses e ealed a p o ec i e e ec
agains acu e espi a o y ac in ec ion (adjus ed odds
a io 0.81, 0.72 o 0.91, NNT=20, 13 o 43; 5133 pa ici-
pan s in 15 s udies; wi hin subg oup P<0.001; see Ca es
plo , supplemen a y igu e S1). No such p o ec i e e ec
was seen among pa icipan s in ials whe e a leas one
bolus dose o i amin D was adminis e ed (adjus ed
odds a io 0.97, 0.86 o 1.10; 5800 pa icipan s in 10
s udies; wi hin subg oup P=0.67; P o in e ac ion 0.05).
This e idence was assessed as being o high quali y (see
supplemen a y able S3). P alues o in e ac ion we e
mo e han 0.05 o all o he po en ial e ec modi ie s
in es iga ed. Fo bo h o hese subg oup analyses,
b oadly consis en e ec s we e obse ed o e en a e
analysis (see supplemen a y able S5) and su i al
analysis (see supplemen a y able S6).
Ha ing iden i ied wo po en ial ac o s ha modi ied
he in luence o i amin D supplemen a ion on isk o
acu e espi a o y ac in ec ion (ie, baseline i amin D
s a us and dosing equency), we hen p oceeded o
in es iga e whe he hese ac o s we e ac ing as
independen e ec modi ie s, o whe he hey we e
con ounded by each o he o by ano he po en ial e ec
modi ie , such as age. Do plo s e ealed a end owa ds
lowe median baseline se um 25-hyd oxy i amin D con-
cen a ion and highe median age o s udies employing
bolus compa ed wi h daily o weekly dosing (see supple-
men a y igu es S2 and S3). To es ablish which o hese
po en ial e ec modi ie s was ac ing independen ly, we
epea ed he analysis o include ea men -co a ia e
in e ac ion e ms o baseline i amin D s a us, dosing
equency, and age. In his model, in e ac ion e ms o
baseline i amin D s a us and dosing equency we e
s a is ically signi ican (P=0.01 and P=0.004, espec-
i ely), bu he in e ac ion e m o age was no (P=0.20),
consis en wi h he hypo hesis ha baseline i amin D
s a us and dosing equency, bu no age, independen ly
modi ied he e ec o i amin D supplemen a ion on isk
o acu e espi a o y ac in ec ion.
We hen p oceeded o s a i y he subg oup analysis
p esen ed in able 2 acco ding o dosing equency, o
p o ide a “cleane ” look a he esul s o subg oup
analyses unde he assump ion ha use o bolus doses
was ine ec i e. Table 3 p esen s he esul s: hese
e eal ha daily o weekly i amin D ea men was
associa ed wi h an e en g ea e deg ee o p o ec ion
agains acu e espi a o y ac in ec ion among pa ic-
ipan s wi h baseline ci cula ing 25-hyd oxy i amin D
Li-Ng 2009
U ashima 2010
Manaseki-Holland 2010
Laaksi 2010
Majak 2011
T ilok-Kuma 2011
Lehouck 2012
Manaseki-Holland 2012
Cama go 2012
Mu doch 2012
Be gman 2012
Ma chisio 2013
Rees 2013
T an 2014
Goodall 2014
U ashima 2014
G an 2014
Ma ineau 2015 (ViDiCO)
Ma ineau 2015 (ViDiAs)
Ma ineau 2015 (ViDiFlu)
Dubno -Raz 2015
Denlinge 2016
Tachimo o 2016
Ginde 2016
Simpson 2015
O e all: I
2=53.3%, P=0.001
No e: Weigh s a e om andom e ec s analysis
0.85 (0.44 o 1.64)
0.90 (0.58 o 1.41)
0.60 (0.41 o 0.88)
0.51 (0.27 o 0.96)
0.20 (0.05 o 0.82)
0.92 (0.77 o 1.11)
1.00 (0.53 o 1.90)
1.08 (0.89 o 1.30)
0.38 (0.22 o 0.65)
0.97 (0.30 o 3.15)
0.42 (0.20 o 0.89)
0.44 (0.21 o 0.95)
1.03 (0.72 o 1.49)
0.92 (0.65 o 1.30)
0.66 (0.45 o 0.98)
1.43 (0.73 o 2.78)
0.77 (0.43 o 1.36)
0.87 (0.48 o 1.57)
0.71 (0.38 o 1.31)
1.13 (0.66 o 1.95)
0.23 (0.01 o 3.82)
1.52 (1.02 o 2.28)
0.45 (0.11 o 1.89)
0.44 (0.19 o 1.02)
Excluded
0.80 (0.69 o 0.93)
3.48
5.36
6.12
3.58
1.00
8.69
3.57
8.58
4.36
1.43
2.89
2.84
6.35
6.60
5.94
3.41
4.12
3.98
3.74
4.38
0.28
5.86
1.01
2.44
0.00
100.00
0.125 0.25 0.5 124
S udy Adjus ed odds a io
(95% CI)
Adjus ed odds a io
(95% CI)
Weigh
(%)
33/76 (43.4)
69/167 (41.3)
126/229 (55.0)
54/84 (64.3)
11/24 (45.8)
458/1030 (44.5)
29/89 (32.6)
245/1505 (16.3)
53/103 (51.5)
155/161 (96.3)
39/62 (62.9)
38/58 (65.5)
276/360 (76.7)
96/197 (48.7)
80/234 (34.2)
17/99 (17.2)
53/80 (66.3)
75/118 (63.6)
93/125 (74.4)
58/103 (56.3)
10/11 (90.9)
93/207 (44.9)
5/35 (14.3)
24/52 (46.2)
14/16 (87.5)
Con ol
32/81 (39.5)
68/167 (40.7)
97/224 (43.3)
39/80 (48.8)
4/24 (16.7)
438/1034 (42.4)
30/86 (34.9)
260/1506 (17.3)
44/141 (31.2)
154/161 (95.7)
26/62 (41.9)
26/58 (44.8)
303/399 (75.9)
185/397 (46.6)
70/258 (27.1)
32/148 (21.6)
94/156 (60.3)
76/122 (62.3)
85/125 (68.0)
83/137 (60.6)
10/14 (71.4)
110/201 (54.7)
4/54 (7.4)
17/55 (30.9)
16/18 (88.9)
In e en ion
P opo ion wi h ≥1 ARTI (%)
ig 2 | wo s ep indi idual pa icipan da a me a-analysis: p opo ion o pa icipan s expe iencing a leas one acu e espi a o y
ac in ec ion (a i). Da a om ial by simpson e al we e no included in his wo s ep me a-analysis, as an es ima e o he
e ec o he in e en ion in he s udy could no be ob ained in he eg ession model owing o small sample size
he bmj |
BMJ
2017;356:i6583 | doi: 10.1136/bmj.i6583
RESEARCH
9
able 3 | One s ep indi idual pa icipan da a me a-analysis, p opo ion o pa icipan s expe iencing a leas one acu e espi a o y ac in ec ion (a i): o e all and by subg oup, s a i ied by dosing
equency
a iables
bolus dosing Daily o weekly dosing
no o
ials*
P opo ion wi h
≥1 a i, con ol
g oup (%)
P opo ion wi h ≥1
a i, in e en ion
g oup (%)
adjus ed odds
a io (95% ci)† P alue
P alue o
in e ac ion
no o
ials*
P opo ion wi h
≥1 a i, con ol
g oup (%)
P opo ion wi h ≥1
a i, in e en ion
g oup (%)
adjus ed odds
a io (95% ci)† P alue
P alue o
in e ac ion
O e all 10 994/2786 (35.7) 1097/3014 (36.4) 0.97 (0.86 o 1.10) 0.67 -- 15 1210/2439 (49.6) 1206/2694 (44.8) 0.81 (0.72 o 0.91) 0.001 --
Baseline 25(OH)D (nmol/L):
<25 873/142 (51.4) 77/162 (47.5) 0.82 (0.51 o 1.33) 0.43 0.42 664/107 (59.8) 40/127 (31.5) 0.30 (0.17 o 0.53) <0.001 0.006
≥25 8550/910 (60.4) 663/1121 (59.1) 1.02 (0.83 o 1.24) 0.87 11 477/729 (65.4) 516/874 (59.0) 0.75 (0.60 o 0.95) 0.02
Daily dose equi alen (µg):
<20 . . . . .
0.56
5629/1321 (47.6) 619/1435 (43.1) 0.80 (0.68 o 0.94) 0.006 0.82
20-50 3467/1931 (24.2) 542/2127 (25.5) 0.95 (0.81 o 1.10) 0.50 6478/865 (55.3) 481/950 (50.6) 0.81 (0.66 o 1.01) 0.06
≥50 7527/855 (61.6) 555/887 (62.6) 1.03 (0.83 o 1.28) 0.81 4103/253 (40.7) 106/309 (34.3) 0.85 (0.58 o 1.24) 0.39
Age (yea s):
≤1 2 321/1634 (19.6) 322/1637 (19.7) 0.99 (0.83 o 1.19) 0.93
0.72
2511/1110 (46.0) 532/1190 (44.7) 0.91 (0.77 o 1.08) 0.30 0.37
1.1-15.9 150/100 (50.0) 35/93 (37.6) 0.62 (0.35 o 1.11) 0.11 7191/413 (46.2) 159/473 (33.6) 0.59 (0.45 o 0.79) <0.001
16-65 8432/678 (63.7) 466/716 (65.1) 1.15 (0.90 o 1.48) 0.27 9422/781 (54.0) 419/876 (47.8) 0.79 (0.63 o 0.99) 0.04
>65 8191/374 (51.1) 274/568 (48.2) 0.85 (0.65 o 1.12) 0.25 386/135 (63.7) 96/155 (61.9) 0.88 (0.52 o 1.52) 0.66
Body mass index (kg/m2):
<25 8215/372 (57.8) 231/417 (55.4) 1.01 (0.72 o 1.40) 0.97 0.70 11 757/1571 (48.2) 725/1657 (43.8) 0.82 (0.71 o 0.95) 0.009 >0.99
≥25 8406/677 (60.0) 509/867 (58.7) 1.00 (0.80 o 1.25) 0.98 9253/358 (70.7) 245/367 (66.8) 0.83 (0.59 o 1.17) 0.30
As hma:
No 5303/484 (62.6) 323/523 (61.8) 0.95 (0.71 o 1.28) 0.75 0.40 6215/524 (41.0) 197/578 (34.1) 0.74 (0.58 o 0.95) 0.02 0.40
Yes 4224/371 (60.4) 232/364 (63.7) 1.18 (0.85 o 1.65) 0.32 772/163 (44.2) 53/178 (29.8) 0.60 (0.37 o 0.98) 0.04
COPD:
No 5410/632 (64.9) 436/656 (66.5) --‡ --‡ --‡ 267/131 (51.1) 57/135 (42.2) --‡ --‡ --‡
Yes 4117/223 (52.5) 119/231 (51.5) --‡ --‡ --‡ 25/7 (71.4) 1/7 (14.3) --‡ --‡ --‡
In luenza accina ion
No 5119/163 (73.0) 121/178 (68.0) --‡ --‡ --‡ 5136/210 (64.8) 132/229 (57.6) --‡ --‡ --‡
Yes 5286/396 (72.2) 294/421 (69.8) . . . 5 278/383 (72.6) 283/405 (69.9)
25(OH)D=25-hyd oxy i amin D; COPD=ch onic obs uc i e pulmona y disease; 1 µg i amin D3=40 in e na ional uni s (IU).
*Some ials did no con ibu e da a o a gi en subg oup, ei he because indi iduals wi hin ha subg oup we e no ep esen ed o because da a ela ing o he po en ial e ec modi ie we e no eco ded; acco dingly he numbe o ials ep esen ed
a ies be ween subg oups.
†Adjus ed o age, sex, and s udy du a ion.
‡Values could no be es ima ed as models did no con e ge.