Re iew A icle
Eme ging Como bidi ies in Adul As hma:
Risks, Clinical Associa ions, and Mechanisms
Hannu Kankaan an a,1,2 Paula Kauppi,3Leena E. Tuomis o,1and Pinja Ilma inen1
1Depa men o Respi a o y Medicine, Sein¨
ajoki Cen al Hospi al, 60220 Sein¨
ajoki, Finland
2Depa men o Respi a o y Medicine, Uni e si y o Tampe e, 33521 Tampe e, Finland
3Depa men o Respi a o y Medicine and Alle gology, Skin and Alle gy Hospi al, Helsinki Uni e si y Hospi al and Helsinki Uni e si y,
00029 Helsinki, Finland
Co espondence should be add essed o Hannu Kankaan an a; hannu.kankaan an a@epshp. i
Recei ed 11 Sep embe 2015; Re ised 1 Decembe 2015; Accep ed 2 Decembe 2015
Academic Edi o : Anshu Ag awal
Copy igh © 2016 Hannu Kankaan an a e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion
License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly
ci ed.
As hma is a he e ogeneous disease wi h many pheno ypes, and age a disease onse is an impo an ac o in sepa a ing he
pheno ypes. Mos s udies wi h as hma ha e been pe o med in pa ien s being o he wise heal hy. Howe e , in eal li e, como bid
diseases a e e y common in adul pa ien s. We e iew he e he eme ging como bid condi ions o as hma such as obesi y, me abolic
synd ome, diabe es melli us ype 2 (DM2), and ca diac and psychia ic diseases. Thei ole as isk ac o s o inciden as hma
and whe he hey a ec clinical as hma a e e alua ed. Obesi y, independen ly o as a pa o me abolic synd ome, DM2, and
dep ession a e isk ac o s o inciden as hma. In con as , he e ec s o como bidi ies on clinical as hma a e less well-known
and mos ly s udies a e lacking. C oss-sec ional s udies in obese as hma ics sugges ha hey may ha e less well con olled as hma
and wo se lung unc ion. Howe e , no long- e m clinical ollow-up s udies wi h hese como bidi ies and as hma we e iden i ied.
These eme ging como bidi ies o en occu in he same mul imo bid adul pa ien and may ha e in common me abolic pa hways and
in lamma o y o o he al e a ions such as ea ly li e exposu es, sys emic in lamma ion, in lammasome, adipokines, hype glycemia,
hype insulinemia, lung mechanics, mi ochond ial dys unc ion, dis u bed ni ic oxide me abolism, and leuko ienes.
1. In oduc ion
As hma is a common ch onic diso de a ec ing mo e han
300 million people all o e he wo ld wi h p e alence among
adul s a ying be ween 0.2 and 21% [1]. Recen ly, he clus e
s udiesha e e ealed ha as hmaisno asinglediseasebu
a he e ogeneous synd ome mani es ing wi h dis inc pheno-
ypes. Age a as hma onse has eme ged as a c i ical ac o
in dis inguishing be ween pheno ypes [2–4]. Pa ien s wi h
ea ly-onse (o childhood-onse ) as hma a e ypically a opic
wi h Th2-p edominan in lamma ion, good esponsi eness o
glucoco icoids, and good p ognosis [5]. In con as , pa ien s
wi h adul - o la e-onse as hma a e o en nona opic, a e
emales, ha e less a ou able p ognosis, and a e mo e likely
o de elop pe sis en ai low limi a ion [2–4, 6, 7]. Mos o
as hma is hough o s a du ing childhood. Howe e , his
has ecen ly been challenged by showing ha , in Uni ed
S a es, adul -onse as hma is he dominan pheno ype in
women om 40 yea s o age [8]. Adul -onse as hma and
adul -onse pheno ypes ha e been associa ed wi h ac o s
such as emale sex, obesi y, occupa ional exposu e, hini is,
espi a o y in ec ions, smoking, s ess ul li e e en s, and
low le el o lung unc ion [2–4]. As ecen ly e iewed in
his jou nal [4] he mechanisms o adul -onse as hma may
include se e al me abolic and in lamma o y componen s ha
a ecommon o heo he diseasessuchasobesi y,me abolic
synd ome (MBO), diabe es melli us ype 2 (DM2), ca dio-
ascula diseases (CVD), and psychia ic diseases.
Mos clinical ials wi h as hma ha e been pe o med
in pa ien s being o he wise heal hy. Howe e , in eal li e,
como bid diseases a e e y common, especially in adul and/
o aging pa ien s. Fo example, in he US 35% o adul people
Hindawi Publishing Co po a ion
Media o s o Inflamma ion
Volume 2016, A icle ID 3690628, 23 pages
h p://dx.doi.o g/10.1155/2016/3690628
2Media o s o In lamma ion
As hma
GERD
Rhini is
A opy/alle gy
Vocal co d dys unc ion
Smoking
COPD
P e iously ecognized
como bidi ies/ ac o s
Obesi y
as hma isk
clinical as hma
(i) Inc eases
(ii) Complica es
Me abolic synd ome
as hma isk (?)
Inc eases
Diabe es melli us
as hma isk
Inc eases
Ca dio ascula
diseases
emales wi h
adul -onse
as hma
High isk in
Men al diseases
as hma isk
clinical as hma
(i) Inc ease
(ii) Complica e
Figu e 1: Eme ging como bidi ies in as hma.
a e obese [9]. In addi ion, i is a he a ule han excep ion ha
pa ien s no only o en p esen wi h one como bid disease
bu also ha e se e al como bidi ies, ha is, su e ing om
mul imo bidi y [10–12].
In ea ly-onse childhood as hma, ood alle gies, a opic
eczema, and alle gic hini is a e common and well-
cha ac e ized como bidi ies [13–16]. Some o he como bid
condi ions such as gas oesophageal e lux ha e gained a lo
o a en ion du ing he yea s [17–19]. The ole o hese com-
o bidi ies has been ho oughly e iewed elsewhe e [13–20].
Ch onic obs uc i e pulmona y disease (COPD) is usually
a ec ing age g oups o 40 yea s and olde . As hma and COPD
sha e many clinical ea u es bo h being ch onic obs uc i e
ai way diseases bu ha ing a iable deg ees o e e sibili y
o ai way obs uc ion [21]. The coexis ence o as hma and
COPD o he ecen ly cha ac e ised as hma-COPD o e lap
synd ome (ACOS) has been e iewed and cha ac e ized in
ea men guidelines o bo h as hma and COPD, o example,
in Global Ini ia i e o As hma (GINA) and Global Ini ia i e
o Ch onic Obs uc i e Lund Disease (GOLD) epo s and
in some na ional guidelines [22–26]. Thus, COPD and ACOS
will no be co e ed by he p esen e iew.
In his e iew, we aim o gi e he eade an o e iew o
he eme ging como bid condi ions o as hma such as obesi y,
MBO, DM2, CVD, and psychia ic diseases (Figu e 1). We
ocusonas hmainadul sandespeciallyonadul -onse
as hma i e idence is a ailable. We ha e i e sepa a e aims in
his e iew i such da a is a ailable: (A) o cha ac e ize he
epidemiological e idence how hese como bidi ies associa e
wi h as hma, (B) o desc ibe he ole o he como bidi y as a
isk ac o o inciden as hma, (C) he possible ole o as hma
as a isk ac o o he inciden como bidi y, (D) he e ec o
he como bidi y on he clinical ou come o as hma, and (E)
o desc ibe he possible common mechanisms ha may link
as hma and he abo emen ioned como bid condi ions.
2. Epidemiologic S udies on
Como bidi ies in As hma
A No wegian s udy on 1 239 533 subjec s o 8–29 yea s old
comp ised al oge he 37 060 as hma pa ien s when as hma
was de ined as using illed p esc ip ions on as hma d ugs
[27]. This s udy showed highe - han-expec ed occu ence
in all o he diseases s udied (a en ion-de ici hype ac i i y
diso de (ADHD), epilepsy, mig aine, men al illness, ca -
dio ascula , au oimmune, gas oesophageal e lux disease
(GERD), alle gy, use o an ibac e ials, and use o an i i als),
excep diabe es, in pa ien s wi h as hma. Fi y-nine pe cen
o he as hma ics had one o mo e o hese ch onic diseases
when he co esponding igu e o gene al popula ion was
18%. In 20–29-yea -olds he g ea es odds a ios o o he
diseases in as hma ics we e o alle gy (OR 4.8 o men, 4.1 o
women), GERD (OR 3.2 in men, 3.5 in women), and ADHD
(OR 2.3 in men, 2.5 in women). The s udy popula ion was 8–
29 yea s old bu s ill showed high p e alence o como bidi y.
In a Canadian popula ion-based s udy (On a io, Canada;
popula ion, 12 million) he bu den o as hma-associa ed
como bidi y as measu ed in a es o hospi alisa ions, eme -
gency depa men isi s, and ambula o y ca e claims was
e alua ed [28]. As hma como bidi y-associa ed ambula o y
claims, eme gency depa men isi s, and hospi alisa ions
we e subs an ial and, in ac , hei numbe s we e much
g ea e han hose due o as hma i sel [28]. In e es ingly,
he heal h bu den due o as hma como bidi y appea ed
subs an ial ega dless o age, gende , socioeconomic s a us,
o li ing in a u al o u ban a ea [28]. App oxima ely hal
o he as hma como bidi y claims we e o o he espi a-
o y condi ions such as uppe espi a o y ac in ec ion,
pneumonia, o alle gic hini is [28]. In a u he s udy by
Ge shon and cowo ke s [29] using he same On a io da a,
como bidi y was e alua ed as indica ed by use o heal h
se ice in 14 disease ca ego ies. In pa ien s wi h as hma,
como bidi y was 46% (0–4 yea s old), 40% (5–17 yea s old),
47% (18–44 yea s old), 49% (45–64-yea s old), and 22% (65
yea soldo mo e)highe hanin hosewi hou as hma[29].
In all age g oups mos o he 14 disease ca ego ies we e mo e
common in pa ien s wi h as hma. The highes como bidi y
(50% o mo e) was ound o espi a o y disease o he
han as hma, psychia ic diso de s, me abolic and immuni y
diso de s, and pe ina al diso de s (0–4 yea s old). Risk o
espi a o ydisease(o he hanas hma)wasapp oxima ely
double, and isk o psychia ic diso de s and in ec ious
diseases was app oxima ely 33% o 51% highe in indi iduals
wi h as hma as compa ed o hose wi hou as hma. In he
oldes age g oup, physician claims we e app oxima ely wice
mo e common o acu e b onchi is and 60% highe o
pneumonia in hose wi h as hma as compa ed o nonas h-
ma ics [29].
The esul s om G ea B i ain among inciden cases o
as hma om p ima y ca e we e simila showing ha pa ien s
wi h as hma (𝑛 = 7931) ha e mo e consul a ions in all
majo o gans sys ems han hei age- and gende -ma ched
nonas hma con ols [30]. The mean age o he pa ien s wi h
as hma in all o he abo emen ioned s udies anged be ween
30 and 32 yea s [28–30] sugges ing ha a conside able
Media o s o In lamma ion 3
p opo ion o he pa ien s ep esen ed as hma beginning
du ing childhood. Analysis o aged (>65) pa ien s wi h
as hma sugges s ha he incidence o como bidi ies inc eases
andmo eclosely esembles ha o COPD[30].Thus,i is
likely ha some como bidi y, such as alle gy, may be linked
o childhood-onse as hma ia common gene ic and en i on-
men al mechanisms. Howe e , o he como bidi ies (obesi y,
diabe es, dep ession, and anxie y diso de s) may be ela ed
o as hma symp oms (e.g., sleep dis u bance con ibu ing o
psychia ic diso de s and obesi y) o i s he apy, o exam-
ple, glucoco icoids inducing sys emic ad e se e ec s [31],
diabe es [32], o inc eased isk o pneumonia [33].
A Ge man elephone in e iew s udy o 2,242 cu en
as hma ics (1,429 women) o a o al o 43,189 s udy indi-
iduals (18 yea s o olde ) e alua ed he p e alence o eigh
di e en heal h condi ions (diabe es melli us, hype ension,
co ona y hea disease, ch onic hea ailu e, s oke, cance ,
os eoa h i is, and dep ession) in pa ien s wi h as hma as
compa ed wi h hose no ha ing cu en as hma [34]. All o
hese eigh heal h condi ions we e mo e p e alen in pa ien s
wi h as hma. Almos e e y i h o he pa ien s wi h as hma
(17.8%) had a leas 3 ch onic condi ions whe eas 8.0% o con-
olswi hnocu en as hmahada leas 3ch oniccondi ions.
In e es ingly, mul imo bidi y (i.e., h ee o mo e ch onic
condi ions) was associa ed wi h inc eased isk o unsched-
uled inpa ien ca e (OR 3.4) and o unscheduled ou pa ien
ca e (OR 2.3) [34].
An analysis o Finnish public sec o employees [35]
epo ed ha as hma inc eased he isk o all-cause long- e m
(sickness absence o disabili y pension >90 days) wo k dis-
abili y (HR 1.8) as compa ed o con ols (no as hma). How-
e e , as hma and one ch onic como bid condi ion inc eased
he isk o long- e m all-cause wo k disabili y wi h HR 2.2
and as hma oge he wi h wo o mo e ch onic condi ions
inc eased he isk wi h HR 4.5 [35]. Acco ding o he s udy
esul s as hma is a mino isk o long- e m wo k disabili y
bu as hma wi h mul iple como bidi ies is a majo isk.
Aging inc eases mo bidi y and also mul imo bidi y in
pa ien s wi h as hma [12]. By no means, mul imo bidi y is no
a unique ea u e o as hma bu a he ep esen s clus e ing o
diseases o ce ain pe sons. In ac , ou o he 40 condi ions
s udied in la ge analysis in Sco land [10], he e was no condi-
ion in which mos people had ha condi ion only [12]. Mul i-
mo bidi y is gene ally associa ed wi h inc eased isk o men-
al heal h diso de s [10, 11]. Fu he , socioeconomic dep i a-
ion is associa ed wi h mul imo bidi y sugges ing clus e ing
o social, economic, and heal h p oblems in ce ain indi id-
uals o in ce ain a eas. Taken oge he , como bidi y is com-
moninas hma;alle gyandobesi ya ecommoninyounge
age g oups, whe eas obesi y, diabe es, GERD, and psychia ic
and ca dio ascula diseases a e ound in olde age g oups.
Respi a o y in ec ions a e ound in all age g oups.
3. Obesi y
3.1. Is Obesi y Associa ed wi h As hma? Does Obesi y Inc ease
he Risk o As hma? The s udies e alua ing he associa ion
be ween obesi y and as hma use gene ally body mass index
(BMI) as a ool. A BMI ≥25 is conside ed o e weigh , while
people wi h BMI ≥30 a e classi ied as obese. BMI is pa icu-
la lyuse ulasi iss anda dized,calcula edin hesameway o
bo h sexes and o adul s o all ages [36].
Obesi y is a isk ac o o as hma, especially among
women [37, 38]. A me a-analysis has been pe o med on he
isk [17]. The isk o as hma was 1.20 o o e weigh and 1.43
o obese men. The co esponding isk es ima es o women
we e 1.25 o o e weigh and 1.78 o obesi y [17]. Also ecen
la ge US and No wegian epidemiological s udies epo odds
a ios anging om 1.29 [39] o 1.84 [40] o obese males and
1.55 [39] o 1.96 [40] o obese emales o ha e o o de elop
as hma as compa ed wi h hei no mal weigh coun e pa s.
Wha does his mean in eal li e? A 25-yea ollow-up in
he Co ona y A e y Risk De elopmen in Young Adul s
(CARDIA) coho gi es us an app oxima ion. App oxima ely
1 ou o 4 obese women ollowed up om he age o 25 de el-
oped as hma du ing he 25-yea ollow-up pe iod, whe eas
app oxima ely 1 ou o 7 no mal weigh women de eloped
as hma [41].
Does inc easing obesi y inc ease he isk o as hma? A
ecen la ge US epidemiological su ey epo ed an associ-
a ion wi h he sel - epo ed doc o -diagnosed as hma and
he class o obesi y. In class I (BMI 30–34.9) obesi y OR o
as hma was 1.27, in class II (BMI 35–39.9) obesi y OR was
1.55, and in class III (BMI ≥40) OR was 1.85 indica ing a
posi i e associa ion be ween he deg ee o obesi y and as hma
[39]. Simila ly, a la ge No wegian coho [40] epo ed an
inc eased odds a io o as hma wi h inc easing BMI (pe
5 kg/m2) in emales (OR 1.32) and in males (OR 1.38). In he
US based su ey [39] a sex di e ence was epo ed by show-
ing ha class III obesi y is signi ican ly mo e s ongly associ-
a ed wi h as hma in women (OR 2.11) han in men (OR 1.40).
Simila ly, a much less p onounced isk o he de elopmen
o as hma was seen be ween no mal weigh and obese men
in he CARDIA s udy [41]. Howe e , he e ec o obesi y on
he de elopmen o as hma may depend on he as hma phe-
no ype. In he long- e m ollow-up o child en hospi alised
because o b onchioli is and many subsequen ly de eloping
as hma, obesi y did no a ec he de elopmen o as hma in
his small coho [42].
Al hough c oss-sec ional s udies o ollow-up o ce ain
coho s in adul s has demons a ed an inc eased p e alence
o as hma in obese indi iduals, many o hese s udies ely
on sel - epo ed weigh and heigh . Ano he possible limi-
a ion o hese s udies is ha mos ely on a sel - epo ed
diagnosis o as hma o symp om-based assessmen o as hma
a he han on physician eco ds, physiologic e alua ion, o
esponse o inhaled he apy. This aises he possibili y ha he
espi a o y symp oms a e ela ed o he physiologic impai -
men om obesi y a he han o as hma [43]. This is espe-
cially impo an wi h ega d o obesi y as obesi y inc eases
he possibili y o misdiagnosis o as hma [44, 45]. Fo exam-
ple, obese subjec s who make u gen isi s o espi a o y
symp oms a e mo e likely o ecei e a misdiagnosis o as hma
[44].
Taken oge he , i appea s ha obesi y is a isk ac o o
as hma. In con as , he ole o as hma as a isk ac o o
obesi y is much less well-known.
4Media o s o In lamma ion
3.2. Obesi y and Clinical As hma. To e alua e he clinical
associa ion be ween as hma and obesi y we e alua ed s udies
ha di ec ly compa ed as hma- ela ed endpoin s in a c oss-
sec ional o longi udinal s udy be ween pa ien s (𝑛≥50)
being no mal weigh o obese and epo ing a leas one
objec i e measu e o lung unc ion. We iden i ied 7 such
s udies [44, 46–51] oge he ha ing 2597 pa ien s wi h as hma
(Table 1(a)). E en hough mos o hese s udies su e om
a small numbe o pa ien s and exclude pa ien s wi h o he
como bidi ies, hey gi e us an idea wha he e ec o
obesi y on as hma may be. All s udies we e c oss-sec ional
and mos ly included all se e i ies o as hma. Mos s udies
excluded smoke s and pa ien s wi h o he como bid s a es
(Table 1(a)). Pa ien s we e adul s (mean age be ween 32 and
57),bu heagea heonse o hediseasewasno epo ed.
Howe e , in i e s udies one can assume ha he popula ion
con ained bo h pa ien s wi h childhood- and adul -onse
as hma (Table 1(a)). The la ge analysis o he Se e e As hma
Resea ch P og am (SARP) [47] e alua ed he e ec o obesi y
on as hma pa ame e s sepa a ely in ea ly-onse (<12 yea s)
and la e-onse (≥12 yea s) as hma. The esul s a e no con-
sis en ac oss he s udies (Table 1(b)). Howe e , he esul s
o hese s udies sugges ha obese pa ien s wi h as hma
a e olde (Table 1(b)). They possibly p esen wi h highe
age a onse and lowe con ol o as hma, use mo e s e oid
cou ses, expe ience mo e hospi al admissions and eme gence
depa men isi s, and ha e lowe lung unc ion al hough
hese di e ences we e no epo ed in all o hese s udies.
Th ee s udies [47–49] p ima ily ec ui ed pa ien s wi h se e e
as hma. The esul s o hese s udies a e mo e consis en wi h
ega d o o al s e oid use du ing p e ious yea , lung unc ion,
and blood eosinophils (Table 1(b)). In suppo o obese
pa ien s p esen ing wi h mo e se e e as hma, he associa ion
o body mass index and as hma se e i y was e alua ed in
he Na ional As hma Su ey in he US [52]. In his la ge
(𝑛 = 3095) elephone su ey obese as hma ics we e epo ed
o p esen wi h symp oms all he ime o e he pas 30 days
(OR 1.7), o ha e g ea e han 2 missed wo k days in he pas
12 mon hs (OR 1.4), o use inhaled co icos e oid (OR 1.3), o
ha e GINA medica ion s ep 2+ as hma (OR 1.4), o p esen
wi h classes II–IV pe sis en as hma (OR 1.4), and o p esen
wi h se e e pe sis en (class IV) as hma (OR 1.4) [52]. In
his coho , 24% (i.e., almos e e y ou h) o no mal weigh
pa ien s we e classi ied o ha e mode a e o se e e as hma,
whe eas he co esponding igu e among obese pa ien s was
35% [52].
These s udies (Tables 1(a) and 1(b)) sugges ha he e
a e no di e ences in in lamma o y ma ke s such as blood
eosinophils ( ou s udies, 𝑛 = 1905), FENO ( h ee s udies),
high- esolu ion compu e ized omog aphy scan (one s udy),
and spu um in lamma o y cell p o iles (one s udy). In addi-
ion, hese s udies sugges ha o he como bidi ies such as
GERD, diabe es melli us, hype ension, and obs uc i e sleep
apnoea synd ome may be mo e common in obese as hma
pa ien s, al hough como bidi ies we e mos ly no analyzed
(Table 1(b)). In e es ingly, wo s udies [47, 51] epo ed a
educed p obabili y o endency o being alle gic when being
obese and ha ing as hma. This is in ag eemen wi h he
esul s ob ained om clus e s udies ha sugges ha he
ecen ly iden i ied g oup o pa ien s wi h adul -onse obese
noneosinophilic as hma pheno ype a e less alle gic/a opic
[2–4].
Fu he , he SARP s udy ound ha he e ec o obesi y is
di e en and mo e p onounced in ea ly-onse as hma han in
la e-onse as hma[47].Thus,as hmabeginninginchildhood,
when being pe sis en , migh be signi ican ly complica ed by
obesi y de eloping la e in li e whe eas as hma beginning
la e in adul hood (possibly o he al eady obese pa ien ) may
no be so much mo e complica ed by obesi y as obesi y may
al eady ha e been a majo d i ing ac o in i s appea ance.
In u u e, i is o u mos impo ance o di e en ia e be ween
pa ien s ha ing as hma and becoming obese la e and obese
pa ien s wi h new-onse as hma.
In a small Canadian s udy [46] (Tables 1(a) and 1(b)),
he g oup o obese as hma ics p esen ed wi h lowe as hma
con olandhad educed o allungcapaci y(TLC),expi a o y
ese e olume (ERV), unc ional esidual capaci y (FRC),
and esidual olume(RV)compa ed o heno malweigh
as hma ics [46]. I is well-known ha obesi y is associa ed
wi h a educ ion in ERV and FRC [53–55], bu i s ill emains
con adic o y, whe he obesi y o BMI as such is associa ed
wi h mo e se e e ai way obs uc ion (FEV1/FVC) (see Tables
1(a) and 1(b)).
How exis ing obesi y a ec s he he apy, con ol, and
p ognosis o as hma in a p ospec i e se ing? We iden i ied
one 12-mon h p ospec i e disease managemen s udy ha
e alua ed he impac o obesi y in as hma [43]. In child en,
he ewasno ela ionshipbe weenBMIandse e i yo
as hma, spi ome y indings, quali y o li e (QoL), o heal h-
ca e u iliza ion. In adul s, he e was no ela ionship be ween
BMI and as hma se e i y o heal h ca e u iliza ion bu highe
BMI was associa ed wi h a signi ican educ ion in QoL and
he BMI had an in e se ela ionship wi h o ced i al capaci y
(FVC) [43]. The associa ion o obesi y wi h as hma con ol
has been analysed in a la ge as hma popula ion (Kaise Pe -
manen e Sou he n Cali o nia) (𝑛=10,233) [56]. O e weigh
and obesi y we e associa ed wi h inc eased ela i e isk
o as hma hospi aliza ions o eme gency depa men isi s
(RR 1.4). Obesi y was associa ed wi h an inc eased isk o
dispensing ≥7 sho -ac ing be a-agonis canis e s [56]. These
analyses sugges ha obesi y may ha e di e en impac on
as hma in younge age g oups han in adul s and ha obesi y
is associa ed wi h mo e as hma symp oms, educed TLC, and
poo e as hma con ol.
3.3. The E ec o Weigh Loss on As hma and he E ec
o Obesi y on Pha maco he apy. Does weigh loss imp o e
as hma con ol? A andomized s udy by S enius-Aa niala and
cowo ke s [57] showed ha weigh loss in 38 obese physician-
diagnosed as hma ics is associa ed wi h imp o emen s in
as hma symp oms, lung unc ion, and heal h s a us. This has
been con i med in ano he s udy [58] showing ha die a y
es ic ion,wi ho wi hou exe cise esul edinag ea e ben-
e i in e ms o as hma con ol. Recen ly, a small con olled
s udy (𝑛=16+6) epo ed ha signi ican weigh loss
( om 115 kg →98 kg/BMI 45 →36.5) was associa ed wi h
a signi ican imp o emen in PC20 (5 →10 mg/mL), FVC%
p edic ed (94 →100), as hma con ol (ACQ sco e 1.4 →0.6),
Media o s o In lamma ion 5
Table 1: (a) Backg ound in o ma ion o clinical s udies e alua ing he e ec o obesi y on as hma in adul s. (b) Resul s o clinical s udies e alua ing he e ec o obesi y on as hma in adul s.
(a)
S udy
Pa ien
wi h
as hma 𝑛Se ing Coun y As hma c i e ia
Se e i y
le els
included
Smoke s
included O he exclusion c i e ia
Onse o
as hma
(child/mixed/
adul )
Gende
(Females%)
Age
(mean;
yea s)
Lessa d e al.,
2008 [46] 88 C oss-
sec ional Canada
Con i meddiagnosisbasedon
b onchodila o esponse o
ai way esponsi eness
measu emen s
All No Cu en smoking o
ex-smoke o ≤6mo Mixed 68–100 32–44
Pakhale e al.,
2010 [44] 346 C oss-
sec ional Canada Sequen ial lung es ing All Yes (?) As hma uled ou using
sequen ial es ing Mixed 66–73 41–47
Holguin e
al., 2011
(SARP
ea ly-onse )
[47]
543 C oss-
sec ional US A 12% inc ease in FEV1a e
a sho -ac ingb onchodila o
o a 20% dec ease in FEV1
a e inhala ion o
me hacholine (PC20,
25 mg/mL)
All No
Cu en smoking o
smoking his o y o 5
yea s o mo e
Childhood-
onse (<12
yea s)
49–65 26–35
Holguin e
al., 2011
(SARP
la e-onse )
[47]
506 C oss-
sec ional US All No
La e-onse
(12 yea s o
mo e)
65–74 39–45
Gibeon e al.,
2013 [48] 666 C oss-
sec ional UK ATS de ini ion o e ac o y
as hma Se e e Yes (?) NR Mixed 65 45
B uno e al.
2014 [49] 102 C oss-
sec ional I aly/F ance ATS 1987 Se e e No
Po en ial con ounding
diagnosis. Any pe sis en
en i onmen al igge ,
COPD, o o he di e en ial
diagnoses
Mixed 56 57
Ramasamy e
al., 2014 [50] 60 C oss-
sec ional India GINA 2009 All No
Smoke (cu en o ex),
ICS/OCS du ing p e ious
mon h, medica ion o
obesi y, hype ension,
diabe es melli us/CAD,
unable o pe o m exhaled
ni ic oxide maneu e
Mixed 50
32–35
(inclu-
sion
20–50
yea s)
Cip andi e
al., 2014 [51] 286 C oss-
sec ional I aly
Documen ed as hma
diagnosis by a specialis based
on a his o y o in e mi en
wheezing in combina ion wi h
e e sibili y o
b onchodila o s and/o BHR
o me hacholine
All No (?)
His o yo lungdisease
o he han as hma,
co ona y a e y disease,
conges i e hea ailu e, co
pulmonale, ecen as hma
exace ba ion o p esence o
acu e (in he las 4 weeks)
o ch onic uppe and/o
lowe espi a o y in ec ions
NR 59 48
NR = no epo ed, FEV1= o ced expi a o y olume in 1 second, ATS = Ame ican Tho acic Socie y, SARP = he Se e e As hma Resea ch Ne wo k, BHR = b onchial hype esponsi eness, ICS = inhaled
co icos e oid, OCS = o al co icos e oid, and CAD = co ona y a e y disease.

6Media o s o In lamma ion
(b)
Age
Age
a
onse
As hma
du a ion
As hma
con ol
Exace ba ions
las yea
O al
s e oids o
as hma in
he
p e ious
yea
Hospi al
admissions
las yea
U gen isi s o
heal h ca e due o
espi a o y
symp oms o ED
isi p eceding yea
Hospi aliza ion
o as hma
e e
In ensi eca euni
o as hma e e o
p e ious yea
O he
Lessa d e al.,
2008 [46] ↔ND ↔↓ND ND ND ND ND ND TLC, ERV, FRC, and RV lowe in
obese as hma ics
Pakhale e al.,
2010 [44] ↑↑ ↔ND ND ND ↔↔ ND ND
Obese indi iduals who make
u gen isi s o espi a o y
symp omsa emo elikely o
ecei e a misdiagnosis o as hma
Holguin e al.,
2011,
ea ly-onse
[47]
↑↔↑ND ND ↑↑ ↑ ND ↑As hma ic subjec s a e
di e en ially a ec ed by obesi y
based on whe he hey had
as hma ea ly (<12 yea s o age)
o la e in li e
Holguin e al.,
2011, la e-onse
[47] ↑↑ ↔ND ND ↔(↑)↑ND ↑
Gibeon e al.,
2013 [48] ↔↔ ↔ ND ND ↑↔↔ ND ↔No di e ence in FENO o spu um
eosinophils
B uno e al.,
2014 [49] ↔ND ↔↓(↑)↑ND ND ↔↔BMI ep esen s pe se a ac o o
he de e io a ion in disease
con ol in se e e as hma
Ramasamy e
al., 2014 [50] (↑)ND ↔ND ND ND ND ND ND ND No di e ence in FENO and
hsCRP
Cip andi e al.,
2014 [51] ↑ND ND ↔ND ND ND ND ND ND No di e ence in FENO
FEV1
(%
p ed.)
FVC
(%
p ed.)
FEV1/FVC LABA
use
Blood
eosinophils To al IgE Alle gic
sensi iza ion GERD Diabe es
melli us Hype ension Obs uc i e
sleep apnea
synd ome
Anxie y/dep ession
Lessa d e al.,
2008 [46] ↔↔ ↔ ND ↔↔↔ ND ND ND ND ND
Pakhale e al.,
2010 [44] ↓ND ND ND ND ND ND ↑↑↑
ND ND
Holguin e al.,
2011,
ea ly-onse
[47]
↓↓ ↓ ↑ ↔↔↔ ND ND ND ND ND
Holguin e al.,
2011, la e-onse
[47] ↓↓ ↔↑↔↔
(↓)ND ND ND ND ND
Gibeon e al.,
2013 [48] ↔↓↔ND ↔↓(↓)↑ND ND ND ND
B uno e al.,
2014 [49] (↓)(↓)↔↑↔↔↔ ↔ ↑↔↑↔
Ramasamy e
al., 2014 [50] ↔↔ ↔ ND ND ND ↔ND ND ND ND ND
Cip andi e al.,
2014 [51] ↓↓ ↓ ND ND ND ↓ND ND ND ND ND
ND = no de ined; FEV1= o cedexpi a o y olumein1second.FVC= o ced i alcapaci y.LABA=long-ac ing2-agonis .GERD=gas oesophageal e luxdisease,TLC= o allung capaci y, ERV = expi a o y
ese e olume, FRC = unc ional esidual capaci y, RV = esidual olume, FENO = o ced exhaled ni ic oxide, hsCRP = high sensi i i y C- eac i e p o ein, and ED = eme gency depa men .
Media o s o In lamma ion 7
and as hma quali y o li e (AQLQ sco e 5.6 →6.1) [59]. In
addi ion, small s udies [60–62] ha e sugges ed ha su gically
induced weigh educ ion is associa ed wi h bene i s in
as hma con ol, symp oms, hype eac i i y, use o medica-
ion, and lung unc ion. Ma ke s o sys emic in lamma ion
(hsCRP, adiponec in, and lep in) we e epo ed o be lowe
a e ba ia ic su ge y, whe eas only a dec ease in mas
cells was epo ed in a g oup o as hma ics unde going
ba ia ic su ge y [61]. Howe e , he published s udies a e
small (ac i ely ea ed as hma pa ien s oge he 27+23+12)
[60–62] and he esul s sugges ha he bene i may diminish
o e ime [60]. Ano he ac o ha makes i di icul o assess
he e ec o weigh loss in e en ions on as hma is ha
ba ia ic su ge y imp o es lung unc ion (e.g., FEV1,FRC,
andTLC)inobesepa ien swi hou as hma[61],sugges ing
ha all imp o emen is no speci ic o as hma. A ecen
sel -con olled case se ies s udy [63] o obese pa ien s wi h
as hma (𝑛 = 2261) and unde going ba ia ic su ge y gi es
hope ha weigh loss and ba ia ic su ge y a e associa ed
wi h clea bene i s in as hma. Signi ican ly ewe eme gency
depa men (ED) isi s o hospi aliza ions o as hma exac-
e ba ionsoccu edwi hin12mon hsa e ba ia icsu ge y
(11% o pa ien s) compa ed o du ing he e e ence pe iod
(22% o pa ien s) and he isk emained low in he subsequen
pe iod o 13 o 24 mon hs a e ba ia ic su ge y (11% o
pa ien s) [63]. In p ac ical e ms his means ha be o e
ba ia ic su ge y 22 pa ien s ou o 100 expe ienced ED
isi o hospi aliza ion and a e su ge y only 11 ou o 100
expe ience such ad e se e en because o as hma.
Obesi y may also a ec he esponse o he pha maco he -
apy o as hma. The basic choices o pha maco he apy [22, 31]
o as hma as such a e alid also in obese as hma ics. Howe e ,
he obese as hma ics may be less esponsi e o s anda d
as hma he apy wi h ICS as compa ed wi h no mal weigh
pa ien s [38] e en hough he indings a e no consis en .
4. Me abolic Synd ome and As hma
Obesi y (high wais ci cum e ence) is a majo componen
o me abolic synd ome, a clus e o me abolic componen s
ha indica e a signi ican ly inc eased isk o ca dio ascula
disease [64]. The o he componen s o me abolic synd ome
include ele a ed iglyce ides, educed high-densi y lipop o-
ein (HDL) choles e ol, high blood p essu e, and ele a ed
glucose o diabe es. In con as , he associa ion o me abolic
synd ome as a synd ome (i.e., no i s single componen s)
wi h as hma has been much less s udied [64]. The No wegian
p ospec i e coho o he No d-T ondelag Heal h S udy om
1995 o 2008 [65] epo ed ha me abolic synd ome was a isk
ac o o inciden as hma (OR 1.6). Among componen s o
me abolic synd ome, wo emained associa ed wi h inciden
as hma: high wais ci cum e ence (OR 1.6) and ele a ed
glucose o diabe es (OR 1.4) [65]. In he CARDIA s udy
abdominal adiposi y, ele a ed blood p essu e, and impai ed
as ing glucose o diabe es we e signi ican ly associa ed wi h
inciden as hma. Howe e , a e adjus men o BMI hei
signi icance was los sugges ing ha BMI as such is an
independen isk ac o o as hma in women [41]. In Ko ean
40–69-yea -old adul s, symp oms sugges i e o as hma such
as wheezing, es ing dyspnea, and pos exe cise dyspnea we e
inc eased in he subjec s o he me abolic synd ome g oup
[66]. Abdominal obesi y and hype ension we e he isk
ac o s o as hma-like symp oms among he componen s o
he me abolic synd ome [66].
The associa ion be ween obesi y and as hma has been
al eady la gely s udied (see abo e sec ions) and he associ-
a ion be ween DM2 and as hma will be deal wi h sepa a ely
in Sec ion 5. Nex , we will sho ly e iew he associa ions
be ween lipid me abolism and hype ension wi h as hma.
The complex choles e ol and lipop o ein biology [67, 68] a e
ou side he scope o he p esen e iew and he o e simplis ic
“good and bad choles e ol” iew does no ep esen he
whole phenomenon. Al hough se e al expe imen al animal
s udies as well as some epidemiological and clinical s udies
in child en and adolescen s [67, 68] sugges an associa ion
be ween choles e ol/lipop o eins and as hma, su p isingly
ew s udies ha e been published on adul s wi h as hma. Two
ea ly s udies [69, 70] epo con lic ing indings in compa ing
he choles e ol/lipop o ein p o iles in adul pa ien s wi h
as hma and heal hy con ols. A e y ecen s udy [71] e alu-
a ed he le els o apolipop o ein A-I and la ge high-densi y
lipop o ein in adul a opic as hma. Se um le els o hese
posi i ely co ela ed wi h FEV1, whe eas se um iglyce ides,
LDL choles e ol, and apoB we e associa ed wi h mo e se e e
ai low obs uc ion [71]. E en hough he co ela ions we e
weakandonlya opicas hma icswe eincluded(possibly
excluding a la ge pa o he nona opic adul -onse as hma
popula ion) in his c oss-sec ional s udy, i aises an in e es -
ing possibili y. I sugges s ha he a he ogenic lipid p o ile
is associa ed wi h educed FEV1in as hma [68] c ea ing an
impo an link be ween me abolic synd ome and as hma.
Da a om Canadian Communi y Heal h Su ey wi h
sel - epo ed o sel - epo ed doc o -diagnosed condi ions
has shown in wo di e en s udies ha pa ien s wi h as hma
we e ha ing app oxima ely 1.4- old isk o high blood p es-
su e [72, 73]. Simila ly, in a sample o Jackson Hea S udy, use
o medica ion o hype ension was mo e common among
hose A ican Ame ican women epo ing cu en doc o -
diagnosed as hma o use o medica ion o ea as hma
[74]. Taking medica ion o hype ension was a signi ican
isk ac o o cu en as hma in his popula ion [74]. A
simila indinghasbeen epo edamongA abAme icans
[75]. Taken oge he , he e is e idence om he epidemio-
logical s udies ha hype ension and as hma a e connec ed.
Howe e , he e is sca ci y o da a om clinical s udies
whe he hype ension complica es as hma o ice e sa. A
ecen s udy using Kaise Pe manen e Sou he n Cali o nia
egis y da a showed ha hype ension is associa ed wi h
ma ke s o inc eased se e i y o as hma such as use o >6
canis e s o sho -ac ing 𝛽2-agonis in a 12-mon h pe iod,
o al co icos e oid dispensing, and his o y o eme gency
depa men isi s o hospi aliza ions [76].
Taken oge he , i s ill emains unclea whe he me abolic
synd ome i sel is a isk ac o o as hma o is he isk ac o
one (o se e al) o i s componen s (obesi y?). In addi ion, he
impac o MBO o i s he apy on clinical as hma emains
mos ly unknown [64].
8Media o s o In lamma ion
5. Diabe es Melli us and As hma
Type I diabe es has been sugges ed o be an au oimmune dis-
ease due o en i onmen al ac o s, possibly i uses, whe eas
ype 2 diabe es melli us has been connec ed wi h obesi y,
insulin esis ance, and sys emic in lamma ion [77–80].
An analysis o he la ge Kaise Pe manen e Medical Ca e
p og am has e alua ed he isk o as hma among hose wi h
diabe es. In adul s (aged ≥18 yea s) wi h no diabe es age- and
sex-adjus ed incidence o as hma was 0.16 pe 1,000 pe son-
yea s and in hose wi h diabe es he co esponding igu e
was 0.41 indica ing a highe isk o inciden as hma [78].
This associa ion be ween inc eased p e alence o as hma
in pa ien s wi h DM2 has also been con i med in a la ge
Danish win s udy [79] and in hospi alized pa ien s [80]. The
p oposed mechanisms how as hma could inc ease he isk o
DM2 include gene ic pleio opy, lung- ela ed in lamma o y
cy okines and hei e ec s on insulin sensi i i y, di ec e ec s
o hypoxia on glucose me abolism, and ad e se ea ly-li e
exposu es and hei e ec s on o gan de elopmen [81]. In
addi ion, se e e as hma is ea ed wi h epea ed cou ses o
pe sis en pe o al glucoco icoids ha may inc ease he
isk o ype 2 diabe es [32] e en hough his has no been
con i med in o he s udies [82, 83]. Risk es ima es o diabe es
in pa ien s wi h as hma ha e a ied om 1.3 o 2.1 [81, 84, 85].
As hma-diabe es associa ion appea ed s onge o adul -
e sus child-diagnosed as hma cases, and o pa icipan s
who we e obese compa ed o hose who we e nonobese [81].
The cu en da a sugges s ha a connec ion be ween as hma
and DM2 diabe es exis s and sugges s ha bo h diseases a e
able o inc ease he isk o he o he disease. In con as , he
e ec o DM2onas hmaou come emainsunknown.
6. Ca dio ascula Diseases and As hma
P e iously connec ion o as hma and a e ioscle osis has
been e alua ed in s udies o as hma mo ali y o in s udies
among elde ly pa ien s wi h as hma. Pa ien s wi h se e e
as hma ha e been epo ed o ha e a highe mo ali y
om ischemic hea disease especially among women [86].
Howe e , such a connec ion be ween hese diseases has no
been ound in elde ly as hma pa ien s [69, 87].
6.1. A e As hma and Ca dio ascula Diseases Associa ed? A
la ge c oss-sec ional s udy (𝑛=16,943)looked o heasso-
cia ions be ween adul -onse as hma and CVDs including
s oke, conges i e hea ailu e, and co ona y hea disease
[88]. Adul -onse as hma (age o onse ≥18 yea s) was ound
o ha e a signi ican associa ion wi h o al CVD (OR 2.1).
Only co ona y hea disease (CHD) was signi ican ly associ-
a ed wi h adul -onse as hma (OR 2.3). In gende s a i ied
analyses, only emales wi h adul -onse as hma showed an
inc ease in he odds o o al CVD (OR 2.4) and CHD (OR
2.9). In con as o expec a ions, o e weigh (BMI 25–30)
emales wi h adul -onse as hma had s onge associa ion
wi h CVD han hose ha ing adul -onse as hma and being
obese (BMI >30) [88]. The limi a ions o he s udy we e
he c oss-sec ional se ing and de ini ion o smoking his o y
(nonsmoke s o cu en smoke s) hus making exclusion o
COPD impossible [88].
6.2. Does As hma Inc ease he Risk o Ca dio ascula Diseases?
O e hepas decadela gecoho s udiesha ebeenpublished
o assess he isk o ca dio ascula e en s as as hma como -
bidi ies. In a la ge coho s udy o heal h insu ance da abase
(𝑛 = 151,620) connec ion o as hma and combined non a al
o a al CHD was assessed [89]. Pa ien s (age ≥18 yea s) wi h
sel - epo ed physician-diagnosed as hma o hospi aliza ion
due oas hmawe e ollowed o 27yea s.Inwomen, he
age-adjus ed CHD a e was highe in hose wi h as hma
han in hose wi hou as hma wi h a HR o 1.2. As hma was
associa ed wi h he isk o de eloping CHD in bo h younge
(<50 yea s) (HR 1.2) and olde (≥50 yea s) women (HR 1.2).
As hma among women became signi ican ly associa ed wi h
CHD e en s al eady a e 10 yea s o ollow-up (HR 1.2).
This sugges s ha women migh ha e a g ea e biological
suscep ibili y o he in lamma o y as hma milieu o o he
ca dio oxic o me abolic e ec s o as hma medica ions [89].
Se e al s udies o he A e ioscle osis Risk in Communi-
ies (ARIC) coho ha e been published conce ning as hma
and CVDs as como bidi y [90]. In a p ospec i e s udy wi h
14 yea s o ollow-up as hma was modes ly associa ed wi h
an inc eased incidence o s oke [91]. In a u he s udy o
hesamecoho [92]e alua ing he ela ionshipbe ween
as hma and ca o id a e y in ima-media hickness (IMT) also
he age a as hma onse was aken in o conside a ion [92].
The weigh ed mean o wall IMT hickness o women wi h
his o y o adul -onse as hma (≥21 yea s) was signi ican ly
g ea e han ha o women wi hou as hma. In con as ,
IMT in women wi h a his o y o childhood-onse (<21
yea s) as hma did no di e subs an ially om nonas hma ic
women. Thi d s udy o he ARIC coho [93] e alua ed inci-
dence o CHD and s oke among as hma sub ypes (as hma
onse <o ≥21 yea s). Women, bu no men, wi h adul -onse
as hma we e ound o ha e a 2- old inc eased a e o CHD
compa ed o hei nonas hma ic coun e pa s.
I iba en and cowo ke s [94] ollowed wo ma ched adul
coho s, he o he wi h as hma and a pa allel as hma- ee
coho . Bo h coho s we e ollowed up o 12 yea s o inci-
den non a al o a al CVD and all-cause mo ali y. As hma
was associa ed wi h a 1.4- old inc eased isk o co ona y hea
disease, a 1.2- old isk o ce eb o ascula disease, a 2.1- old
isk o hea ailu e, and a 3.3- old isk o all-cause mo ali y.
Simila ly o ha oundin heARICcoho [92,93]s onge
associa ions we e no ed among women, bu he e was no da a
on as hma onse o as hma se e i y [94]. Among pa ien s
wi h as hma, 84% used one o mo e as hma medica ion
and pa icula ly hose using o al co icos e oids alone o in
any combina ion wi h as hma medica ions we e a enhanced
isk o de elopingCVD,whichmay e lec ha ha hey
we e ha ing se e e as hma [94]. The e emains a possibili y
ha he medica ion used may inc ease he isk o CVD as
especially 𝛽2agonis s ha e many ad e se ca dio ascula side-
e ec s and con inuous use o glucoco icoids may ha e many
me abolic disad an ages [89, 94].
Recen ly, a long- e m (10 yea s) p ospec i e s udy
epo ed an associa ion o pe sis en as hma and CVD e en s
(co ona y dea h, myoca dial in a c ion, angina, s oke, and
CVDdea h)[95].Allpa icipan s(𝑛 = 6792)we e eeo
CVD a baseline. Sel - epo ed as hma cases (𝑛 = 667)we e
Media o s o In lamma ion 9
classi ied as pe sis en (daily use o con olle medica ion
such as ICS, LTRA, and OS) in 77% and in e mi en (wi hou
con olle medica ion) in 23% o pa ien s. A e a decade o
ollow-up pa ien s wi h pe sis en as hma had a 1.6–1.7- old
highe isk o CVD e en s han nonas hma ics. In addi ion,
ma ke s o sys emic in lamma ion (IL-6, CRP, al a-dime ,
and ib inogen) we e he highes in pa ien s wi h pe manen
as hma e en hough pa ien s we e using mode n con olle
as hma medica ion. Use o con olle medica ion did no
abolish he inc eased isk o CVD e en s [95].
Cu en and o me smoking a e one o he main isk
ac o s o bo h as hma and ca dio ascula diseases. Recen ly
published epo [96] om he Copenhagen Gene al Popu-
la ion s udy coho (𝑛=94,079) assessed p ospec i ely he
isk o as hma and CVD including ischemic hea disease,
myoca dial in a c ion, and ischemic s oke among smoke s
and nonsmoke s. Six pe cen (𝑛 = 5691) had sel - epo ed
as hma, 40% we e ne e smoke s, 43% o me smoke s, and
16% cu en smoke s. Mean ollow-up ime o he s udy
pa ien s (age 20–100 yea s) was 4.5 yea s. Haza d a ios
among indi iduals wi h as hma compa ed o ne e smoke s
wi hou as hma o ischemic hea disease we e 1.5 in o me
smoke s and 2.0 in cu en smoke s. The espec i e co e-
sponding alues we e 1.7 and 3.2 o myoca dial in a c ion
and 1.2 (n.s.) and 3.0 o ischemic s oke. In con as o
p e ious s udies he inc eased isk o ca dio ascula como -
bidi ies in his coho s udy was es ic ed only o smoke s
wi h as hma [96]. Un o una ely da a on he age a as hma
onse was no a ailable as in o he coho s he inc eased isk
o CVD was seen mos ly only in women wi h adul -onse
as hma.Inaddi ion, he ollow-up ime(4.5yea s)is ela i ely
sho o he ne e smoke as hma g oup as hey we e women
wi hameanageo 53.The isko myoca dialin a c ionin
smoking pe sons inc eases mo e ea ly bu in ne e smoke s
(especially women) i clea ly inc eases only a e he age o 60
[97]. In mos as hma como bidi y s udies con ounding e ec
o smoking has been aken in o accoun . Usually pa ien s ha e
been di ided in o g oups o cu en , e e , and ne e smoke s.
Insomes udiesda aonpack-yea sisa ailable.Howe e ,
mo e de ailed in o ma ion like du a ion, in ensi y, and ype
o smoking as well as age o smoking onse and second hand
smoking should be pa o he mul i a ia e models especially
in s udies conce ning as hma and he isk o ca dio ascula
diseases [98].
These c oss-sec ional and coho s udies wi h la ge pop-
ula ions ha e shown ha as hma pa ien s and especially a
subg oup o adul -onse as hma women a e a inc eased isk
o a e ioscle osis. In u u e, i would be impo an o know
whe he o ally con olled as hma would educe he isk
o ca dio ascula como bidi ies. The ole o con empo a y
as hma medica ion o p e en o o enhance incidence o
ca dio ascula diseases also emains obscu e. Fu he mo e,
we lack knowledge o how di e en CVDs a ec as hma
ou come and whe he CVDs a e o impo ance in making
decisions on how o modi y ea men o as hma.
7. Men al Diso de s, Suicide, and As hma
The associa ion be ween as hma and psychological ac o s
has been ecognized o cen u ies [99]. Psychosocial ac o s
ha e long been suspec ed o in luence he onse and cou se o
as hma. These e ec s may be media ed ia di ec in luences
such as in luences on he pulmona y sys em, au onomic
and endoc ine egula ion, and in lamma o y and immune
p ocess (see la e in his pape and [100]). In addi ion, psy-
chosocial ac o s can in luence as hma ia mul iple indi ec
pa hways such as medica ion adhe ence, pe cep ion o ai -
way obs uc ion (ei he o e pe cep ion o unde pe cep ion),
illness belie s, o gene al heal h beha io [100].
A conside able numbe o s udies ha e sugges ed ha
he e is an associa ion be ween some men al diso de s and
as hma,especiallyse e eas hma[99–101].S udiesconduc ed
among clinical and gene al p ac ice samples ha e ound
highe han expec ed a es o anxie y diso de s (pa icula ly
panic diso de ) and o dep ession among adul pa ien s wi h
as hma[99].Howe e , hepublished esul sha eno always
been consis en and me hodological p oblems (e.g., no using
DSM-based diagnos ics and a iabili y in he assessmen o
as hma) make i di icul o d aw clea conclusions [99, 100].
7.1. Is The e Associa ion be ween As hma and Men al Dis-
o de s? TheWo ldMen alHeal hSu eype o medin17
coun ies (𝑛=85,088) using gene al popula ion sample
epo s ha an adul wi h as hma has an inc eased isk o
dep essi e diso de s (OR 1.6) and anxie y diso de (OR 1.5)
as compa ed wi h pe sons no ha ing as hma [101]. A me a-
analysis es ima ing he p e alence o anxie y diso de s in
as hma epo ed ha he a e age p e alence o any anxie y
diso de among adul s wi h as hma was 34% [102]. Mo e
speci ically, he p e alence o panic a acks (25%), panic
diso de (12%), ago aphobia (12%), and gene alized anxie y
diso de (9%) was highe among adul s wi h as hma han in
he gene al popula ion [102]. A ecen me a-analysis has e al-
ua ed he associa ion be ween as hma and dep ession [103].
Pa ien s wi h dep ession had inc eased isk o ha ing as hma
(OR 3.2) as compa ed wi h hose no ha ing dep ession and
pa ien s wi h as hma had an inc eased isk o ha ing dep es-
sion (OR 1.5) as compa ed wi h hose no ha ing as hma
[103]. A simila associa ion has been epo ed om Span-
ishNa ionalHeal hSu ey[104] epo ing ha as hma ic
pa ien s su e mo e o en om anxie y (9.7%) and dep ession
(9%) han pe sons no ha ing as hma (6.6% and 5.5% o
anxie y and dep ession, esp.). Ha ing as hma inc eased he
p obabili y o su e ing om anxie y (OR 1.3) and dep ession
(OR 1.4). Among as hma ics ac o s associa ed wi h su e ing
om anxie y we e olde age, concomi an como bidi ies, and
isi s o GP p ac ices in he las 4 weeks, whe eas ac o s
associa ed wi h dep ession we e emale sex, olde age, wo se
sel - ela ed heal h, concomi an como bidi ies, abs emious
indi iduals, and he need o a endance on eme gency oom
in he las yea [104]. A simila associa ion has been epo ed
also om Ge many epo ing ha li e ime se e e as hma was
signi ican ly associa ed wi h an inc eased isk o a numbe
o anxie y diso de s (any anxie y diso de , panic diso de ,
panic a acks, social phobia, speci ic phobia, and gene alized
anxie y diso de ), bipola diso de , and any se e e men al
diso de [105]. Li e ime nonse e e as hma was signi ican ly
associa ed wi h ha ing any anxie y diso de , no speci ied
anxie y diso de , and wi h any soma o o m diso de [105].
16 Media o s o In lamma ion
o as hma. Tha kind o s udy would equi e a di e en
expe imen al se ing. Fo example, measu emen o ce ain
media o s in la ge popula ion samples and ollowing whe he
hese people la e de elop inciden as hma o no migh help
o esol e hose ques ions.
Fo como bidi ies such as MBO o i s componen s, DM2
and CVD, we lack s udies ha e alua e hei e ec on
clinical as hma. The e exis s some p elimina y e idence on
he dele e ious e ec s o obesi y and men al diso de s on
as hma ou come (Figu e 1). Clinical s udies ha e alua e
long- e m p ognosis and he con ibu ion o obesi y (o o he
como bidi ies) on as hma a e needed. In addi ion, s udies
ha e alua e changes in he como bidi y o e ime on as hma
con ol, exace ba ions, lung unc ion, and d ug usage a e
lacking. Obesi y has been in ocus du ing las yea s. Howe e ,
obesi y i sel is associa ed wi h signi ican como bidi y (such
as diabe es, ca dio ascula diseases, and men al diseases) and
li es yle ac o s (such as smoking, unheal hy die , ch onic
alcohol use, and low le el o physical exe cise) ha may
con ibu e o he as hma ou come. F om he mechanis ic
poin o iew i may be a ional o include pa ien s wi h only
single como bidi y (e.g., obesi y) o as hma s udies a he
ime (see, e.g., Table 1(a)). Howe e , om he pe spec i e
o p ac icing espi a o y specialis o gene al physician his
is no op imal as mos pa ien s su e om mul imo bidi y
a he han om a single disease o a combina ion o wo
speci ic single diseases. Fo example, in Ge many mos
pa ien s (app oxima ely 60%) ha e one o mo e diseases ou
o eigh lis ed in addi ion o as hma [34]. In Sco land wi h a
sample o almos 1.8 million people o all ages, mul imo bidi y
a ec s one in ou people [10]. Mul imo bidi y is o en me in
ch onic diseases and in he elde ly popula ion [12]. S udies
in pa ien s wi h as hma ha do no exclude pa ien s because
o como bidi ies a e hus wa an ed. S udies such as he
Sein¨
ajoki Adul As hma S udy (SAAS) ha e alua e he long-
e m p ognosis o new-onse as hma diagnosed a adul age
and excludes only childhood-onse pa ien s may shed ligh on
his ma e [219].
Many o he como bidi ies associa ed wi h as hma occu
as clus e o diseases a he han as a single combina ion o
as hma wi h a speci ic como bidi y. As many o he sugges ed
media o s a e common o hese diseases, we p opose ha
he e may no be a single mechanism o in e ac ion be ween
as hma and ce ain como bidi y and ano he sepa a e mech-
anism o he in e ac ion be ween as hma and second como -
bidi y, and so o h. Ins ead, we hink ha he e exis s a g oup
o mechanisms ha link wi h each o he and mos link wi h
obesi y and/o componen s o me abolic synd ome. Table 2
p esen s an o e iew o p oposed mechanisms be ween
as hma and ce ain como bidi ies. Se e al media o s (e.g.,
IL-6 and ADMA) a e associa ed wi h as hma and se e al
como bidi ies anging om obesi y o ca dio ascula and
psychia ic ones, sugges ing ha in addi ion o disease-
speci ic media o s he e may be media o s ha d i e he
sys emic in lamma ion playing a majo ole in he clus e o
diseases a ound as hma.
These como bidi ies may ha e common mechanisms and
media o s. The e exis some da a ha obesi y and men al
diseases may complica e as hma ou come, whe eas da a is
lacking on he e ec s o me abolic synd ome, diabe es, and
ca dio ascula diseases on he ou comes o clinical as hma.
Compe ing In e es s
The au ho s decla e ha hey ha e no compe ing in e es s.
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