Vi amin C supplemen a ion o as hma (Re iew)
Kau B, Rowe BH, A nold E
This is a ep in o a Coch ane e iew, p epa ed and main ained by The Coch ane Collabo a ion and published in The Coch ane Lib a y
2010, Issue 12
h p://www. hecoch anelib a y.com
Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figu e 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figu e 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 1 FEV1 (L) - p e-exe cise
challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Analysis 1.2. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 2 FEV1 (L) - pos -exe cise
challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 1.3. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 3 FVC (L) - p e-exe cise challenge. 21
Analysis 1.4. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 4 FVC (L) - pos -exe cise
challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.5. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 5 PEFR (L/min) - p e-exe cise
challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.6. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 6 PEFR (L/min) - pos -exe cise
challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 2.1. Compa ison 2 O al i amin C s placebo (sho e m s udies), Ou come 1 FEV1 (% d op) pos -exe cise. 23
Analysis 2.2. Compa ison 2 O al i amin C s placebo (sho e m s udies), Ou come 2 Symp om sco es (As hma Quali y
o Li e Ques ionnnai e). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Analysis 3.1. Compa ison 3 O al i amin C s placebo (long- e m s udies), Ou come 1 IgE (IU/ml se um) - absolu e
alues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Analysis 3.2. Compa ison 3 O al i amin C s placebo (long- e m s udies), Ou come 2 FEV1 mL 4 mon hs. . . . 25
Analysis 3.3. Compa ison 3 O al i amin C s placebo (long- e m s udies), Ou come 3 Peak Flow (L/min) 4 mon hs. 26
Analysis 3.4. Compa ison 3 O al i amin C s placebo (long- e m s udies), Ou come 4 Geome ic mean dec ease in inhaled
co icos e oid use (µg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
26FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iVi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
[In e en ion Re iew]
Vi amin C supplemen a ion o as hma
Bal inde Kau 2, B ian H Rowe3, Elizabe h A nold1
1Popula ion Heal h Sciences & Educa ion, S Geo ge’s, Uni e si y o London, London, UK. 2P ima y Ca e & Social Medicine, Facul y
o Medicine, London, UK. 3Depa men o Eme gency Medicine, Uni e si y o Albe a, Edmon on, Canada
Con ac add ess: Elizabe h A nold, Popula ion Heal h Sciences & Educa ion, S Geo ge’s, Uni e si y o London, C anme Te ace,
Too ing, London, SW17 0RE, UK. [email p o ec ed].
Edi o ial g oup: Coch ane Ai ways G oup.
Publica ion s a us and da e: Edi ed (no change o conclusions), published in Issue 12, 2010.
Re iew con en assessed as up- o-da e: 28 Oc obe 2008.
Ci a ion: Kau B, Rowe BH, A nold E. Vi amin C supplemen a ion o as hma. Coch ane Da abase o Sys ema ic Re iews 2009, Issue
1. A . No.: CD000993. DOI: 10.1002/14651858.CD000993.pub3.
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
A B S T R A C T
Backg ound
Vi amin C is one o he key an ioxidan i amins which is abundan in he ex acellula luid lining he lung and low i amin C in ake
has been associa ed wi h pulmona y dys unc ion.
Objec i es
To e alua e he e idence o he e icacy o i amin C in he ea men o as hma.
Sea ch s a egy
The Coch ane Ai ways Re iew G oup as hma egis e was sea ched and bibliog aphies o s udies iden i ied we e also checked o u he
ials. This e iew has been upda ed by sea ches o Augus 2008.
Selec ion c i e ia
Only andomised con olled ials we e eligible o inclusion. S udies we e conside ed o inclusion i hey deal wi h he ea men o
as hma using i amin C supplemen a ion. Two independen e iewe s iden i ied po en ially ele an s udies using p e-de ined c i e ia
and selec ed s udies o inclusion.
Da a collec ion and analysis
Da a we e abs ac ed independen ly by wo e iewe s. In o ma ion on pa ien s, me hods, in e en ions, ou comes and esul s was
ex ac ed using s anda d o ms.
Main esul s
Nine s udies me he e iew en y c i e ia, andomising a o al o 330 pa icipan s. S udy design a ied and he epo ing was gene ally
poo . Fi e ials con ibu ed nume ical da a o he e iew. They p o ided ou come da a on lung unc ion, symp om sco es, IgE le els
and inhaled s e oid use. One small s udy showed a signi ican di e ence in % d op in FEV1 pos -exe cise.
1Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Au ho s’ conclusions
A p esen , e idence om andomised-con olled ials is insu icien o ecommend a speci ic ole o i amin C in he ea men o
as hma. Fu he me hodologically s ong and la ge-scale andomised con olled ials a e needed in o de o add ess he ques ion o he
e ec i eness o i amin C in child en wi h as hma.
P L A I N L A N G U A G E S U M M A R Y
Vi amin C supplemen a ion o as hma
As hma is a ch onic in lamma o y disease o he ai ways cha ac e ised by wheeze and b ea hlessness. One heo y o he obse ed
inc ease in he numbe o people wi h as hma is he ’wes e n’ die wi h i ’s lack o nu ien s om esh ood. We e iewed e idence om
nine ials o he an ioxidan i amin C as a ea men o as hma. In gene al he ials we e small, a ied g ea ly in hei design and he
epo ing was poo . F om he a ailable e idence i is no possible o ecommend ei he he use o a oidance o i amin C supplemen s
in as hma.
B A C K G R O U N D
As hma is now ecognised as a ch onic in lamma o y disease e-
sul ing in e e sible ai ways b onchocons ic ion (Holga e 1990).
The incidence and p e alence o as hma has inc eased in many
coun ies o e he pas ew decades. The mos ma ked inc ease
has been obse ed in child en (S achan 1999;Lewis 1996). This
may be due o changing en i onmen al exposu es o he inc eased
suscep ibili y o popula ions wi h educed hos esis ance (Sea on
1994).
One hypo hesised cause o his inc ease is ha changes in “wes -
e n” die ha e p oduced a educ ion in hos esis ance o e ime. In
pa icula ecen in e es has ocused on he associa ion be ween
an i-oxidan s in die s and heal h ou comes. C oss-sec ional s udies
show ha in equen ui consump ion is associa ed wi h educed
lung unc ion, bo h in child en (Cook 1997) and adul s (Bu land
1999). In addi ion, he Na ional Food Su ey has documen ed a
d op in he consump ion o an ioxidan ood sou ces such as esh
ui and ege ables in coun ies such as G ea B i ain since he
1950’s (Sea on 1994).
Vi amin C is one o he key an ioxidan i amins which is abun-
dan in he ex acellula luid lining he lung. Low i amin C in-
ake is associa ed wi h pulmona y dys unc ion (Schwa z 1994).
Bo h adul s (Olusi 1979) and child en (Ade ele 1985) wi h as hma
ha e been ound o ha e lowe concen a ions o i amin C when
compa ed o no mal subjec s. Pa ien s wi h as hma may ha e low
supplies o i amin C o an inc eased demand o i amin C in
he ace o an oxidan load esul ing in deple ion. The e is a need
o cla i y whe he supplemen a ion wi h i amin C may b ing
bene i s in educing mo bidi y, imp o ing pulmona y unc ion o
quali y o li e in pa ien s wi h as hma.
The e ha e been h ee ecen e iews o he li e a u e on he ole
o i amin C in as hma (Bielo y 1994;Ha ch 1995;Mon eleone
1997). Howe e , he e iew by Bielo y e al (Bielo y 1994) only
sea ched he English language li e a u e using MEDLINE and
ga e no u he de ails as o how he s udies had been loca ed.
The o he wo e iews did no speci y hei me hodology. These
e iews eached di e en conclusions. Bielo y e al (Bielo y 1994)
concluded ha he ole o i amin C in as hma was unclea and
ha cu en li e a u e did no suppo i s use. The e iew by Ha ch
e al (Ha ch 1995) ound 7 ou o 11 s udies indica ed ha i amin
C supplemen a ion migh e e se o imp o e as hma symp oms.
The e iew by Mon eleone e al (Mon eleone 1997) o e s he
opinion ha i amin C p o ides a sho e m p o ec i e e ec
on ai way esponsi eness, bu less clea impac on o he objec i e
lung unc ion measu emen s. All h ee e iews ecommend u he
s udies in o he ole o i amin C in as hma. As a i s s ep, a e iew
using he Coch ane me hodology isneeded o sys ema ically weigh
he quali y o he exis ing e idence be o e ecommending any
u u e s udies.
O B J E C T I V E S
To de e mine he o e all e icacy o i amin C supplemen a ion
in pa ien s wi h s able ch onic as hma.
M E T H O D S
2Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
C i e ia o conside ing s udies o his e iew
Types o s udies
To be eligible, all s udies needed o be andomised-con olled ials
(RCTs). Double-blinded ials we e p e e ed, bu single blind and
open s udies we e also e iewed o possible inclusion.
Types o pa icipan s
S udies we e conside ed o inclusion i hey ec ui ed adul s and/
o child en wi h ch onic s able as hma, seasonal as hma o hose
wi h exe cise-induced b onchospasm. S udies o o he alle gic con-
di ions such as hay e e , alle gic hini is and eczema we e only
conside ed i he esul s o subjec s wi h as hma we e p esen ed
sepa a ely. Vi amin C s udies, which epo ed ou comes on pa-
ien s wi h as hma sepa a ely as a sub-g oup, we e also conside ed
o inclusion.
Types o in e en ions
Vi amin C supplemen a ion compa ed o placebo o “s anda d
ca e”. We conside ed s udies ha adminis e ed i amin C ia any
ou e, dosage o dose in e al. Bo h single dose and longe - e m
s udies we e conside ed o inclusion.
Types o ou come measu es
P ima y ou come measu es
1) Lung unc ion (e.g. FEV1, PEFR)
2) Symp oms (e.g. symp om sco es)
Seconda y ou come measu es
3) Func ional ou comes (e.g. quali y o li e, sickness absence, ex-
e cise capaci y)
4) Non-speci ic b onchial hype - eac i i y (BHR) o his amine o
me hacholine
5) Immunological ma ke s (IgE le els)
6) As hma medica ion equi emen s (e.g. addi ional s e oid o
b onchodila o usage)
7) Heal h se ice u ilisa ion (e.g. GP a endance, hospi al admis-
sions)
8) As hma exace ba ions
Sea ch me hods o iden i ica ion o s udies
Elec onic Sea ches
T ials we e iden i ied using he Coch ane Ai ways G oup Spe-
cialised Regis e o ials, which is de i ed om sys ema ic sea ches
o bibliog aphic da abases including he Coch ane Cen al Reg-
is e o Con olled T ials (CENTRAL), MEDLINE, EMBASE,
CINAHL, AMED and PsycINFO, and handsea ching o espi a-
o y jou nals and mee ing abs ac s (please see he Ai ways G oup
Module o u he de ails). All eco ds in he Specialised Regis e
coded as ’as hma’ we e sea ched using he ollowing e ms:
asco bic* o “ i amin c” o an ioxid*
The mos ecen sea ch was conduc ed in Augus 2008.
O he sou ces
Re e ence lis s o all p ima y s udies and e iew a icles we e e-
iewed o addi ional e e ences. Au ho s o iden i ied ials we e
con ac ed.
Da a collec ion and analysis
Re ie al o s udies
All ials ha appea ed po en ially ele an we e assessed by wo
independen e iewe s o ele ance using abs ac and i le om
he elec onic sea ch. Using ex s om all po en ially ele an a i-
cles, inal inclusion was also de e mined independen ly by wo e-
iewe s. Disag eemen s abou s udy inclusion we e esol ed wi h
discussion.
Assessmen o me hodological quali y
The quali y o included s udies was assessed using he Coch ane
app oach. A isk o bias able was comple ed o each s udy as-
sessing he epo ing o me hod o andomisa ion, alloca ion con-
cealmen and blinding. Each i em was judged as being adequa e,
unclea o inadequa e. Any disag eemen s be ween e iewe s we e
esol ed by discussion.
Da a abs ac ion
Da a we e ex ac ed independen ly by wo e iewe s and en-
e ed in he Coch ane Collabo a ion So wa e, Re iew Manage
(Re Man). Fo s udies whe e he o iginal da a we e no p esen ed,
when possible, hey we e ex ac ed om g aphically ep esen a-
ions. S udy ou comes ha we e epo ed pos -b onchial challenge
(e.g. exe cise o his amine) we e analysed sepa a ely om ou comes
3Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
ha did no in ol e b onchial challenge o when esul s we e e-
po ed be o e such challenges (bu pos -dose i amin C adminis-
a ion).
S a is ical conside a ions
Ou comes om included ials we e combined using Re Man. Fo
con inuous ou comes he weigh ed mean di e ence (WMD) wi h
ixed e ec was used o es ima e he indi idual e ec sizes and 95%
con idence in e als (95% CI). I he e we e any dicho omous
ou comes he Pe o ixed o andom e ec model was o be used o
es ima e he pooled odds a io (OR) and 95% CI.
The main planned compa ison o s a is ical conside a ion was
any o m o dose o i amin C supplemen a ion e sus placebo
o “s anda d ca e”. I he e we e adequa e included s udies, he
ollowing p e-de ined sub-g oup analysis we e planned:
1. Single dose e sus ch onic adminis a ion o i amin C
2. Die a y ad ice o inc ease i amin C consump ion e sus no
in e en ion
3. O al i amin C e sus in a enous i amin C supplemen a ion
4. Adul s e sus child en
5. Males e sus emales
R E S U L T S
Desc ip ion o s udies
See: Cha ac e is ics o included s udies;Cha ac e is ics o excluded
s udies.
De ails o he sea ch his o y and esul s can be ound in Table
1. Fo he 2008 upda e, 39 new e e ences we e iden i ied and
he ull ex o 15 o hese we e e ie ed. One addi ional in-
cluded s udy (Tecklenbu g 2007), an ex ension o a p e iously in-
cluded s udy (Foga y 2003), and 5 u he excluded s udies we e
iden i ied. The e iew now con ains a o al o nine s udies which
mee he inclusion c i e ia. Fu he de ails can be ound in he
able, “Cha ac e is ics o included s udies”. A o al o wel e s ud-
ies we e excluded a e examining he ull- ex pape . Please see
“Cha ac e is ics o excluded s udies” o u he de ails.
Table 1. Sea ch his o y
Sea ch da es Resul s
Janua y 2001 Thi y- i e abs ac s we e iden i ied om he sea ch o he Coch ane Ai ways G oup egis e , o which
6 me he inclusion c i e ia (Anah 1980, Ande son 1983, Cohen 1997, Ko danksy 1979, Malo 1986,
Schach e 1987) and 5 we e added as excluded s udies.
Janua y 2001 - Ap il 2004 Twen y- ou abs ac s we e iden i ied by he upda ed sea ch. Two addi ional included s udies (Foga y
2003, O’Sulli an 2000) and 4 excluded s udies we e added o he e iew.
The included s udies we e conduc ed in he USA (Ko dansky
1979;Schach e 1982,Tecklenbu g 2007), Nige ia (Anah 1980),
Sou h A ica (Ande son 1983), Canada (Malo 1986), Is ael
(Cohen 1997) and he UK (Foga y 2003;O’Sulli an 2000).
Th ee s udies examined he impac o i amin C supplemen a-
ion on exe cise challenge es s in subjec s wi h a con i med diag-
nosis o exe cise-induced as hma (Cohen 1997;Schach e 1982,
Tecklenbu g 2007). Two s udies examined he impac o i a-
min C adminis a ion on b onchial hype esponsi eness o his-
amine challenge es s in pa icipan s wi h as hma (Malo 1986;
O’Sulli an 2000). Fou s udies examined he impac o i amin
C on b onchial hype esponsi eness o alle gen challenge in sub-
jec s sensi i e o agweed alle gen (Ko dansky 1979), equency o
as hma exace ba ions due o in ec ion (Anah 1980), lung unc ion
and immunological ma ke s in pa ien s wi h as hma (Ande son
1983) and clinical con ol o as hma in p ima y ca e (Foga y
2003).
Th ee o he s udies (Anah 1980;Ande son 1983;Foga y 2003)
ollowed a pa allel s udy design and he emaining 6 used c osso e
designs. Da a om he wo ypes o s udy designs we e p esen ed
sepa a ely in Re Man. No usable da a could be ex ac ed om he
epo s o ou s udies (Anah 1980;Ko dansky 1979;Malo 1986;
O’Sulli an 2000), despi e a emp s a au ho con ac .
Se en s udies (Anah 1980;Foga y 2003;Ko dansky 1979;Malo
1986;O’Sulli an 2000;Schach e 1982,Tecklenbu g 2007) in-
ol ed adul pa ien s, one s udy (Ande son 1983) in ol ed only
child en and one (Cohen 1997) had bo h adul s and child en.
The smalles s udy had six pa icipan s (Ko dansky 1979). O h-
e s anged om 8 o 41. The la ges was Foga y 2003 wi h 210
pa icipan s. This e iew con ains a o al o 330 andomised pa -
icipan s.
All ea men s we e adminis e ed o ally, ei he as able s o as an
o al solu ion. Th ee s udies (Anah 1980;Ande son 1983;Foga y
4Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
2003) ea u ed long- e m supplemen a ion wi h 1 g i amin C
daily o 14 weeks, 6 mon hs and 16 weeks, espec i ely. Ano he
long- e m s udy (Ko dansky 1979) used 500 mg i amin C sup-
plemen a ion daily o se en days. One s udy looked a supple-
men a ion wi h 1500mg o e a sho - e m pe iod o wo weeks
(Tecklenbu g 2007) and he emaining ou s udies (Cohen 1997;
Malo 1986;O’Sulli an 2000;Schach e 1982) used single doses
o i amin C 2g, 2g, 2g and 500 mg, espec i ely.
Two o he c osso e s udies (Cohen 1997,Tecklenbu g 2007)
men ioned a washou pe iod. None o he o he c osso e s udies
(Ko dansky 1979;Malo 1986;O’Sulli an 2000;Schach e 1982)
epo ed a washou pe iod. I has been sugges ed ha a e a single
o al dose o i amin C, a leas 1-2 days is equi ed o exc e ion
depending on p e-exis ing body le els (Ba es 2001).
Included s udies epo ed dispa a e ou come measu es, which
made agg ega ion o he pu pose o a me a-analysis di icul . Mos
o he s udies did no epo he ac ual da a in he published pape s
o did no p o ide su icien da a o a me a-analysis, al hough
a emp s we e made o con ac he au ho s o da a. Ou come
measu es included a a ie y o lung unc ion es s, symp oms and
symp om sco es, immune ma ke s and educ ion in he use o in-
haled s e oids.
Risk o bias in included s udies
In gene al, he epo ing quali y o he s udies was poo . All he in-
cluded s udies we e epo ed as being andomised, howe e , only
one s udy (Foga y 2003) epo ed he me hod o andomisa ion
and jus h ee o he nine s udies epo ed he me hod o alloca-
ion concealmen (Anah 1980,Foga y 2003,Malo 1986). Fou
s udies epo ed he me hod o blinding (Anah 1980,Malo 1986,
Schach e 1982,Tecklenbu g 2007), while one s udy was inad-
equa ely blinded (Ande son 1983) and he emaining ou we e
unclea .
None o he s udies adequa ely epo ed all h ee me hods o
andomisa ion, alloca ion concealmen o blinding. Anah 1980,
Foga y 2003 and Malo 1986 ga e he mos de ailed accoun . An
o e iew o ou judgmen s o a e p esen ed in Figu e 1 and Figu e
2.
5Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Figu e 1. Me hodological quali y summa y: e iew au ho s’ judgemen s abou each me hodological quali y
i em o each included s udy.
6Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Figu e 2. Me hodological quali y g aph: e iew au ho s’ judgemen s abou each me hodological quali y
i em p esen ed as pe cen ages ac oss all included s udies.
E ec s o in e en ions
O he nine included s udies, i e ha e con ibu ed nume ical
da a o he e iew: Ande son 1983,Cohen 1997,Foga y 2003,
Schach e 1982 and Tecklenbu g 2007. Fou s udies (Anah 1980;
Ko dansky 1979;Malo 1986;O’Sulli an 2000) did no epo
da a in an manne ha pe mi ed u he analysis and au ho con-
ac has been unsuccess ul. Howe e , none o hese s udies ound a
signi ican di e ence o he e ec o i amin C on lung unc ion
o symp oms.
I was only possible o combine da a o one ou come (FEV1). Fo
all o he ou comes, s udies could no be combined s a is ically,
because hose which add essed simila compa isons used di e en
in e en ions o ou come a iables. Fo example, he e we e h ee
s udies whe e he p o ec i e e ec s o i amin C we e in es iga ed
using exe cise challenge. All h ee epo ed pulmona y unc ion
ou comes, bu Cohen 1997 epo ed absolu e mean alue pos -
exe cise, Schach e 1982 epo ed absolu e change pos -exe cise
and Tecklenbu g 2007 was a wo week in e en ion s udy a he
a single dose s udy, and epo ed maximum p ecen age all om
baseline.
P ima y ou comes
Lung unc ion
Single dose s udies
FEV1(L) - p e-exe cise challenge: no signi ican di e ence (Cohen
1997,Schach e 1982)
FEV1 (L) - pos -exe cise challenge: no signi ican di e ence
(Cohen 1997,Schach e 1982)
FVC (L) - p e-exe cise challenge: no signi ican di e ence (
Schach e 1982)
FVC (L) - pos -exe cise challenge: no signi ican di e ence
(Schach e 1982)
PEFR (L/min) - p e-exe cise challenge: no signi ican di e ence
(Schach e 1982)
PEFR (L/min) - pos -exe cise challenge: no signi ican di e ence
(Schach e 1982)
Sho e m s udies
FEV1 (%) d op pos -exe cise: a signi ican di e ence was shown in
a ou o i amin C: 6.5 (95% con idence in e al 0.05 o 12.95),
P=0.05 (Tecklenbu g 2007)
Long e m s udies
FEV1 mL a ou mon hs:no signi ican di e ence (Foga y 2003)
Peak Flow L/min (mo ning and e ening) a 4 mon hs: no signi i-
can di e ence (Foga y 2003)
Symp om Sco es
One s udy (Tecklenbu g 2007) epo ed da a on symp om sco es
(As hma Quali y o Li e Ques ionnai e). The e was no signi ican
di e ence.
Seconda y ou comes
IgE (IU/ml se um) - absolu e alues a one mon h: no signi ican
di e ence (Ande son 1983)
IgE (IU/ml se um) - absolu e alues a h ee mon hs:no signi ican
di e ence (Ande son 1983)
IgE (IU/ml se um) - absolu e alues a six mon hs: no signi ican
di e ence (Ande son 1983)
Dec ease in inhaled co icos e oid use (µg): no signi ican di e -
ence (Foga y 2003)
The e we e no da a om any o he included s udies o heal h
se ice u ilisa ion.
7Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Foga y 2003
Me hods Randomised placebo-con olled double-blind pa allel g oup ial.
S udy was powe ed o de ec a 310ml change in FEV1, a 20l/min inc ease in PEFR o a 1.5 old
in ai way eac i i y ela i e o placebo.
Pa icipan s Pa ien s we e iden i ied om compu e eco ds o 24 gene al p ac ices in No ingham, UK. A he
s a o he s udy he e we e 95 pa icipan s in he i amin C g oup and 106 in he placebo g oup
(and 99 in a hi d g oup andomised o magnesium). Vi amin C g oup: 37 males, mean age 42,
mean daily inhaled s e oids 715ug, numbe o long ac ing be a 2 agonis s 20, cu en smoke s 5,
mean pack yea s 1.2, mean die a y i amin C 90mg.
Placebo g oup: 42 males, mean age 40, mean daily inhaled s e oids 618ug, numbe o long ac ing
be a 2 agonis s 14, cu en smoke s 4, mean pack yea s 1.1, mean die a y i amin C 82mg.
In e en ions Pa allel compa ison o daily supplemen a ion wi h i amin C 1g/day and placebo.
Ou comes FEV1, FVC, PD20, mo ning and e ening PEFR, be a 2 use, symp oms.
No es Randomisa ion was s a i ied acco ding o dose o egula co icos e oids usage.
An ex ension o he ial p o ided da a on he educ ion in use o inhaled s e oids. Nine y wo
o he o iginal pa icipan s ag eed o con inue aking hei alloca ed supplemen o a u he 10
weeks and en e a co icos e oid educ ion p o ocol.
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Yes Pa icipan s we e andomly assigned using a an-
dom numbe gene a o .
Alloca ion concealmen ? Yes Pa icpan s we e alloca ed by an indi idual code
numbe . The code was b oken only a e he las
pa icipan le he ial. All andomisa ion a-
ble p epa a ion and dispensing we e ca ied ou
independen ly om he ec ui men and assess-
men o pa icipan s.
Blinding?
All ou comes
Unclea S udy is desc ibed as double-blind bu he ap-
pea ance o he able s is no speci ically men-
ioned
Ko dansky 1979
Me hods Randomised double-blind placebo con olled ial wi h c osso e design.
Pa icipan s 6 adul s (2 emale, 4 male) in Bal imo e, USA, wi h agweed sensi i e as hma, de ined by skin-
p ick posi i i y. Tes ed ou o he agweed season. Asymp oma ic and no on ea men .
In e en ions 500mg once daily i amin C o 7 days compa ed o lac ose placebo.
14Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Ko dansky 1979 (Con inued)
Ou comes PD20 FEV1, PD35 SGaw, es ed on day 7, 3h s a e dose o placebo/ i amin C
No es Da a no p esen ed in an abs ac able o ma , no eply om au ho o da e.
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Unclea Me hod o andomisa ion no desc ibed
Alloca ion concealmen ? Unclea Me hod o alloca ion no desc ibed
Blinding?
All ou comes
Unclea S udy desc ibed as double blind bu me hod
o blinding (e.g. iden ical placebo pill) no de-
sc ibed
Malo 1986
Me hods Randomised double blind placebo con olled c osso e s udy.
Pa icipan s 16 adul s (3M; 13F) wi h as hma ha me he ATS c i e ia. Age ange 19-59, mean 43.1 (SD 7.7)
y s, mean du a ion o as hma 10.5 y s (SD 14.6).
In e en ions The subjec s we e s udied on 4di e en days. Subjec s ecei ed ea men o placebo which consis ed
o 250ml o a anspa en and odou less swee liquid in which was dissol ed ei he 2g asco bic acid
o placebo. One hou la e spi ome y measu ed and his amine challenge done un il PC20 eached.
Ou comes FEV1, FVC, PC20
No es Da a no p esen ed in an abs ac able o ma . Values epo ed o di e en days a he han di e en
g oups. No eply om au ho o da e.
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Unclea Me hod o andomisa ion no desc ibed
Alloca ion concealmen ? Yes Concealmen o ea men s we e done using
codes. The o al solu ions we e p epa ed by hos-
pi al pha macy.
Blinding?
All ou comes
Yes O al solu ions we e desc ibed as being o simila
as e
15Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
O’Sulli an 2000
Me hods Randomised double-blind, c oss-o e placebo con olled s udy.
Pa icipan s Ten mild (ATS c i e ia) as hma ic pa icipan s.
In e en ions Each pa icipan comple ed wo ea men pe iods wi h inges ion o ei he 2g o asco bic acid o
placebo 45 minu es p io his amine b onchop o oca ion.
Ou comes Spi ome y was measu ed be o e, du ing and a e he his amine challenges.
No es Abs ac only published, da a no p esen ed in an abs ac able o ma , no eply om au ho o da e.
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Unclea Me hod o andomisa ion no desc ibed
Alloca ion concealmen ? Unclea Me hod o alloca ion no desc ibed
Blinding?
All ou comes
Unclea S udy desc ibed as double blind bu me hod
o blinding (e.g. iden ical placebo pill) no de-
sc ibed
Schach e 1982
Me hods Randomised double-blind con olled ial, c osso e design.
Pa icipan s 12 adul s (5 male, 7 emale) wi h exe cise-induced as hma, ne e on co icos e oids o admi ed o
hospi al.
In e en ions Single dose o 500 mg i amin C o ally o suc ose placebo. S udy done on 2 subsequen days. 90
minu es pos does subjec s unde wen exe cise challenge. No washou indica ed. Exe cise challenge
in inc emen al wo kload and un il subjec s hea a e each 170bpm o he subjec a igued. Pul-
mona y unc ion was measu ed be o e & a e o al dose and a e exe cise.
Ou comes FVC, FEV1, PEFR be o e and a e exe cise challenge on cyclegome e o 170bpm o exhaus ion.
No es
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Unclea Me hod o andomisa ion no desc ibed
Alloca ion concealmen ? Unclea Me hod o alloca ion no desc ibed
16Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Schach e 1982 (Con inued)
Blinding?
All ou comes
Yes Iden ical placebo capsule
Tecklenbu g 2007
Me hods Randomised, double-blind, c osso e ial o e 5 consecu i e weeks
Pa icipan s Eigh pa icipan s (2 male, 6 emale) wi h physician diagnosed mild- o-mode a e as hma and doc-
umen ed exe cise-induced b onchocons ic ion. Pa icpan s we e ec ui ed om Uni e si y popu-
la ion and he local communi y and we e ac i e.
In e en ions Asco bic acid supplemen 1500mg/day (3x500mg capsules) o placebo (suc ose) (3 capsules). Man-
u ac u ed by NOW Foods. Pa icpan s we e andomised o ac i e ea men o placebo o wo
weeks. The e was a wash-ou pe iod o one week and hen he pa icpan s c ossed o e .
Pa icpan s we e ad ised o a oid oods ha we e high in i amin C du ing he s udy.
Ou comes Pulmona y unc ion (FEV1) p e-and pos -exe cise; Exhaled ni ic oxide (FENO) p e- and pos -
exe cse; sypm om ques ionnai e
No es S udy conduc ed in he USA
Risk o bias
I em Au ho s’ judgemen Desc ip ion
Adequa e sequence gene a ion? Unclea Me hod o andomisa ion no desc ibed
Alloca ion concealmen ? Unclea Me hod o alloca ion concealmen no de-
sc ibed.
Blinding?
All ou comes
Yes Ma ching placebo manu ac u ed by he same
company as he ac i e ea men .
Cha ac e is ics o excluded s udies [o de ed by s udy ID]
S udy Reason o exclusion
Cuomo 2004 S udy used a combined supplemen o i amin C, i amin E and o he an ioxidan s
Fo as ie e 2000 No a andomised con olled ial (be o e and a e ques ionnai e su ey).
G ozdjako a 2005 S udy used a combined supplemen o i amin C, Coenzyme Q10 and α- ocophe ol.
17Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
(Con inued)
Konge ud 2003 No a andomised con olled ial and in e en ion no es ing e icacy o i amin C. S udy examined he le els
o asco bic acid in induced spu um o as hma ic pa ien s compa ed o heal hy olun ee s.
Mi ic 1991 No a andomised con olled ial. All subjec s gi en placebo i s han ollowed la e wi h all pa ien s ecei ing
i amin C.
Mohsenin 1983 S udy did no ha e a placebo a m (only had be o e and a e e ec s o i amin C adminis a ion).
Mohsenin 1987 S udy used heal hy subjec s and excluded subjec s who had as hma.
Mu phy 2002 S udy used a combina ion o i amin C and α- ocophe ol
Omenaas 2003 Pos al ques ionnai e no a andomised con olled ial.
Panina 2002 S udy used a complex o o al an ioxidan s. I is no clea ha he s udy was andomised.
Romieu 2002 S udy used bo h i amin C and E in he in e en ion g oup.
Ting 1983 S udy did no ha e a placebo a m and was no andomised (only had be o e and a e e ec s o i amin C).
18Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
D A T A A N D A N A L Y S E S
Compa ison 1. O al i amin C s placebo (single-dose s udies)
Ou come o subg oup i le No. o
s udies
No. o
pa icipan s S a is ical me hod E ec size
1 FEV1 (L) - p e-exe cise challenge 2 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
1.1 Absolu e alues 2 46 Mean Di e ence (IV, Fixed, 95% CI) 0.36 [-0.35, 1.08]
2 FEV1 (L) - pos -exe cise
challenge
2 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
2.1 Absolu e alues 1 22 Mean Di e ence (IV, Fixed, 95% CI) 0.27 [-0.39, 0.93]
2.2 Absolu e change 1 24 Mean Di e ence (IV, Fixed, 95% CI) 0.13 [-0.05, 0.31]
3 FVC (L) - p e-exe cise challenge 1 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
3.1 Absolu e alues 1 24 Mean Di e ence (IV, Fixed, 95% CI) -0.10 [-2.62, 2.42]
4 FVC (L) - pos -exe cise challenge 1 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
4.1 Absolu e change 1 24 Mean Di e ence (IV, Fixed, 95% CI) 0.13 [-0.03, 0.29]
5 PEFR (L/min) - p e-exe cise
challenge
1 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
5.1 Absolu e alues 1 24 Mean Di e ence (IV, Fixed, 95% CI) -0.40 [-4.00, 3.20]
6 PEFR (L/min) - pos -exe cise
challenge
1 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
6.1 Absolu e change 1 24 Mean Di e ence (IV, Fixed, 95% CI) 0.49 [-0.07, 1.05]
Compa ison 2. O al i amin C s placebo (sho e m s udies)
Ou come o subg oup i le No. o
s udies
No. o
pa icipan s S a is ical me hod E ec size
1 FEV1 (% d op) pos -exe cise 1 0 Mean Di e ence (Fixed, 95% CI) 6.5 [0.05, 12.95]
2 Symp om sco es (As hma
Quali y o Li e Ques ionnnai e)
1 0 Mean Di e ence (Fixed, 95% CI) 0.5 [-0.24, 1.24]
Compa ison 3. O al i amin C s placebo (long- e m s udies)
Ou come o subg oup i le No. o
s udies
No. o
pa icipan s S a is ical me hod E ec size
1 IgE (IU/ml se um) - absolu e
alues
1 Mean Di e ence (IV, Fixed, 95% CI) Sub o als only
1.1 1 mon h 1 16 Mean Di e ence (IV, Fixed, 95% CI) 4.0 [-140.42,
148.42]
1.2 3 mon hs 1 16 Mean Di e ence (IV, Fixed, 95% CI) -312.0 [-628.21,
4.21]
19Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
1.3 6 mon hs 1 16 Mean Di e ence (IV, Fixed, 95% CI) -143.0 [-425.38,
139.38]
2 FEV1 mL 4 mon hs 1 Mean Di e ence (Fixed, 95% CI) To als no selec ed
3 Peak Flow (L/min) 4 mon hs 1 Mean di e ence (Fixed, 95% CI) To als no selec ed
3.1 Mo ning 1 Mean di e ence (Fixed, 95% CI) No es imable
3.2 E ening 1 Mean di e ence (Fixed, 95% CI) No es imable
4 Geome ic mean dec ease in
inhaled co icos e oid use (µg)
1 61 Mean Di e ence (IV, Fixed, 95% CI) 38.0 [-20.46, 96.46]
Analysis 1.1. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 1 FEV1 (L) - p e-
exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 1 FEV1 (L) - p e-exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e alues
Cohen 1997 11 2.7 (0.94) 11 2.2 (0.96) 80.5 % 0.50 [ -0.29, 1.29 ]
Schach e 1982 12 2.6 (2.32) 12 2.8 (1.66) 19.5 % -0.20 [ -1.81, 1.41 ]
-10 -5 0 5 10
Fa ou s Placebo Fa ou s Vi amin C
20Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Analysis 1.2. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 2 FEV1 (L) - pos -
exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 2 FEV1 (L) - pos -exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e alues
Cohen 1997 11 1.93 (0.78) 11 1.66 (0.8) 100.0 % 0.27 [ -0.39, 0.93 ]
Sub o al (95% CI) 11 11 100.0 % 0.27 [ -0.39, 0.93 ]
He e ogenei y: no applicable
Tes o o e all e ec : Z = 0.80 (P = 0.42)
2 Absolu e change
Schach e 1982 12 0.21 (0.19) 12 0.08 (0.26) 100.0 % 0.13 [ -0.05, 0.31 ]
Sub o al (95% CI) 12 12 100.0 % 0.13 [ -0.05, 0.31 ]
He e ogenei y: no applicable
Tes o o e all e ec : Z = 1.40 (P = 0.16)
Tes o subg oup di e ences: Chi2= 0.16, d = 1 (P = 0.69), I2=0.0%
-1 -0.5 0 0.5 1
Fa ou s Placebo Fa ou s Vi amin C
Analysis 1.3. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 3 FVC (L) - p e-
exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 3 FVC (L) - p e-exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e alues
Schach e 1982 12 3.9 (2.98) 12 4 (3.32) 100.0 % -0.10 [ -2.62, 2.42 ]
-10 -5 0 5 10
Fa ou s Placebo Fa ou s Vi amin C
21Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Analysis 1.4. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 4 FVC (L) - pos -
exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 4 FVC (L) - pos -exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e change
Schach e 1982 12 0.1 (0.23) 12 -0.03 (0.17) 100.0 % 0.13 [ -0.03, 0.29 ]
-1 -0.5 0 0.5 1
Fa ou s Placebo Fa ou s Vi amin C
Analysis 1.5. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 5 PEFR (L/min) - p e-
exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 5 PEFR (L/min) - p e-exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e alues
Schach e 1982 12 5.6 (4.97) 12 6 (3.98) 100.0 % -0.40 [ -4.00, 3.20 ]
-10 -5 0 5 10
Fa ou s Placebo Fa ou s Vi amin C
22Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
Analysis 1.6. Compa ison 1 O al i amin C s placebo (single-dose s udies), Ou come 6 PEFR (L/min) -
pos -exe cise challenge.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 1 O al i amin C s placebo (single-dose s udies)
Ou come: 6 PEFR (L/min) - pos -exe cise challenge
S udy o subg oup Vi amin C g oup Placebo g oup Mean Di e ence Weigh Mean Di e ence
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Absolu e change
Schach e 1982 12 0.59 (0.53) 12 0.1 (0.83) 100.0 % 0.49 [ -0.07, 1.05 ]
-4 -2 0 2 4
Fa ou s Placebo Fa ou s Vi amin C
Analysis 2.1. Compa ison 2 O al i amin C s placebo (sho e m s udies), Ou come 1 FEV1 (% d op) pos -
exe cise.
Re iew: Vi amin C supplemen a ion o as hma
Compa ison: 2 O al i amin C s placebo (sho e m s udies)
Ou come: 1 FEV1 (% d op) pos -exe cise
S udy o subg oup Expe imen al Con ol Mean Di e ence (SE) Mean Di e ence Weigh Mean Di e ence
N N IV,Fixed,95% CI IV,Fixed,95% CI
Tecklenbu g 2007 0 0 6.5 (3.29) 100.0 % 6.50 [ 0.05, 12.95 ]
To al (95% CI) 100.0 % 6.50 [ 0.05, 12.95 ]
He e ogenei y: no applicable
Tes o o e all e ec : Z = 1.98 (P = 0.048)
-100 -50 0 50 100
Fa ou s placebo Fa ou s i amin C
23Vi amin C supplemen a ion o as hma (Re iew)
Copy igh © 2010 The Coch ane Collabo a ion. Published by John Wiley & Sons, L d.
