O iginal A icle
Clus e Analysis on Longi udinal Da a o Pa ien s
wi h Adul -Onse As hma
Pinja Ilma inen, PhD
a
, Leena E. Tuomis o, MD, PhD
a
, Onni Niemelä, MD, PhD
b,c
, Minna Tommola, MD
a
,
Jussi Haanpää, MSc
d
, and Hannu Kankaan an a, MD, PhD
a,e
Seinäjoki and Tampe e, Finland
Wha is al eady known abou his opic? Many pheno ypes o as hma ha e been iden ified in p e ious clus e analyses,
mos ly on he basis o c oss-sec ional da a wi h limi ed inclusion o pa ien s. Some s udies ha e p o ided sho - e m 1- o
3-yea p ognosis o he pheno ypes.
Wha does his a icle add o ou knowledge? This is he fi s s udy ha epo s long- e m 12-yea p ognosis o clus e s
o adul -onse as hma s a ing om diagnosis. We epo di e en disease p ognoses o smoking, obesi y- ela ed, emale,
a opic, and non hini ic as hma.
How does his s udy impac cu en managemen guidelines? In o ma ion on long- e m ou come o as hma can be
used o in o m and mo i a e pa ien s. We show he poo es ou come and he mos unme needs in he he apy o smoking
and obesi y- ela ed as hma, sugges ing need o special guidance.
BACKGROUND: P e ious clus e analyses on as hma a e based
on c oss-sec ional da a.
OBJECTIVE: To iden i y pheno ypes o adul -onse as hma by
using da a om baseline (diagnos ic) and 12-yea ollow-up
isi s.
METHODS: The Seinäjoki Adul As hma S udy is a 12-yea
ollow-up s udy o pa ien s wi h new-onse adul as hma.
K-means clus e analysis was pe o med by using a iables om
baseline and ollow-up isi s on 171 pa ien s o iden i y
pheno ypes.
RESULTS: Fi e clus e s we e iden ified. Pa ien s in clus e
1(n[38) we e p edominan ly nona opic males wi h mode a e
smoking his o y a baseline. A ollow-up, 40% o hese pa ien s
had de eloped pe sis en obs uc ion bu he numbe o pa ien s
wi h uncon olled as hma (5%) and hini is (10%) was he
lowes . Clus e 2 (n [19) was cha ac e ized by olde men wi h
hea y smoking his o y, poo lung unc ion, and pe sis en
obs uc ion a baseline. A ollow-up, hese pa ien s we e mos ly
uncon olled (84%) despi e daily use o inhaled co icos e oid
(ICS) wi h add-on he apy. Clus e 3 (n [50) consis ed mos ly
o nonsmoking emales wi h good lung unc ion a diagnosis/
ollow-up and well-con olled/pa ially con olled as hma a
ollow-up. Clus e 4 (n [25) had obese and symp oma ic
pa ien s a baseline/ ollow-up. A ollow-up, hese pa ien s had
se e al como bidi ies (40% psychia ic disease) and we e
ea ed daily wi h ICS and add-on he apy. Pa ien s in clus e
5(n[39) we e mos ly a opic and had he ea lies onse o
as hma, he highes blood eosinophils, and FEV
1
e e sibili y a
diagnosis. A ollow-up, hese pa ien s used he lowes ICS dose
bu 56% we e well con olled.
CONCLUSIONS: Resul s can be used o p edic ou comes o
pa ien s wi h adul -onse as hma and o aid in de elopmen o
a
Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland
b
Depa men o Labo a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland
c
Uni e si y o Tampe e, Tampe e, Finland
d
Depa men o Clinical Physiology, Seinäjoki Cen al Hospi al, Seinäjoki, Finland
e
Depa men o Respi a o y Medicine, Uni e si y o Tampe e, Tampe e, Finland
This s udy was suppo ed by he Finnish An i-Tube culosis Associa ion Founda-
ion (Helsinki, Finland), he Tampe e Tube culosis Founda ion (Tampe e,
Finland), he Jalma i and Rauha Ahokas Founda ion (Helsinki, Finland), he
Resea ch Founda ion o he Pulmona y Diseases (Helsinki, Finland), he
Compe i i e S a e Resea ch Financing o he Expe Responsibili y A ea o
Tampe e Uni e si y Hospi al (Tampe e, Finland), and he Medical Resea ch
Fund o Seinäjoki Cen al Hospi al (Seinäjoki, Finland). None o he sponso s
had any in ol emen in he planning and execu ion o his s udy o in he w i ing
o his a icle.
Conflic s o in e es : P. Ilma inen has ecei ed lec u e ees om MundiPha ma.
L. E. Tuomis o has ecei ed lec u e ees om Mundipha ma and has ecei ed
a el suppo om Takeda, Chiesi, and O ion. M. Tommola has ecei ed
lec u e ees om As aZeneca and GlaxoSmi hKline. H. Kankaan an a has
ecei ed lec u e and consul ancy ees and a el suppo om Almi all,
As aZeneca, and Boeh inge Ingelheim; has ecei ed consul ancy ees om
Chiesi Pha ma AB; has ecei ed lec u e and consul ancy ees om
GlaxoSmi hKline, Lei as-Takesa, and No a is; has ecei ed lec u e ees om
MSD, Mundipha ma, Medi h, Resmed Finland, and O ion Pha ma; has
ecei ed a el suppo om In e mune; and has ecei ed consul ancy ees
om Roche. The es o he au ho s decla e ha hey ha e no ele an
conflic s o in e es .
Recei ed o publica ion Oc obe 25, 2016; e ised Janua y 3, 2017; accep ed o
publica ion Janua y 31, 2017.
A ailable online Ap il 25, 2017.
Co esponding au ho : Pinja Ilma inen, PhD, Depa men o Respi a o y Medicine,
Seinäjoki Cen al Hospi al, Hanneksen inne 7, Seinäjoki 60220, Finland. E-mail:
pinja.ilma inen@epshp.fi.
2213-2198
Ó2017 The Au ho s. Published by Else ie Inc. on behal o he Ame ican Academy
o Alle gy, As hma & Immunology. This is an open access a icle unde he CC
BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
h p://dx.doi.o g/10.1016/j.jaip.2017.01.027
967
Abb e ia ions used
ACOS- As hma-COPD o e lap synd ome
ACT- As hma con ol es
AQ20- Ai ways Ques ionnai e 20
BD- B onchodila o
COPD- Ch onic obs uc i e pulmona y disease
FVC- Fo ced i al capaci y
ICS- Inhaled co icos e oid
Max
0-2.5
- Maximum lung unc ion du ing he fi s 2.5 yea s a e
diagnosis (and s a o an i-inflamma o y he apy)
SAAS- Seinäjoki Adul As hma S udy
pe sonalized he apy (NCT02733016 a ClinicalT ials.
go ). Ó2017 The Au ho s. Published by Else ie Inc. on
behal o he Ame ican Academy o Alle gy, As hma &
Immunology. This is an open access a icle unde he CC BY-
NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-
nd/4.0/). (J Alle gy Clin Immunol P ac 2017;5:967-78)
Key wo ds: As hma; Adul -onse ; La e-onse ; Clus e analysis;
Pheno ypes; Follow-up; Longi udinal; Smoking; Obesi y;
Ea ly-onse
Adul - o la e-onse as hma has been sugges ed o be a
dis inc i e pheno ype o as hma.
1,2
Pa ien s wi h adul -onse
as hma ha e lesse alle gic p ocesses, lowe lung unc ion
despi e sho e du a ion o disease, and mo e o en a p onounced
eosinophilic inflamma ion wi hou e idence o T
H
2eassocia ed
inflamma ion when compa ed wi h pa ien s wi h childhood-
onse as hma.
1
These findings sugges ha adul -onse as hma
is mo e he e ogeneous when compa ed wi h childhood-onse
as hma. In p e ious s udies, subpheno ypes o adul -onse
as hma such as eosinophil-p edominan , mild o mode a e
well-con olled, obesi y- ela ed, smoking, and se e e obs uc i e
as hma ha e been p oposed.
3,4
To iden i y pheno ypes o as hma, unsupe ised hie a chical
clus e analyses ha e been ca ied ou . Howe e , he clus e an-
alyses ha e mos ly been based on c oss-sec ional da a on pa ien s
wi h mixed du a ion o as hma.
2,4-6
As hma is known as a disease
wi h a high deg ee o a iabili y, making one ime poin a agile
basis o clus e analysis. Fu he mo e, no in o ma ion on he
diagnos ic phase has been included in he p e ious analyses. In
addi ion, many p e ious analyses ha e clus e ed pa ien s wi h
se e e as hma,
7,8
lea ing milde o ms wi h less a en ion. Some
s udies ha e in ol ed sho ollow-ups (1-3 yea s).
6,7,9,10
In a
p e ious p ospec i e longi udinal analysis o se e e as hma, he
clus e s did no show clus e -specific disease cou ses ega ding
ou come o as hma, sugges ing a po en ial limi a ion in he way
o pe o ming cu en clus e analyses.
9
In addi ion o he na u al
disease a iabili y, many ac o s such as he apy, li es yle, and
como bidi ies may modi y he disease cou se. Reliabili y o he
esul s o a clus e analysis would be inc eased by including
clinical da a om se e al ime poin s o he disease ollow-up in o
he analysis.
He e, we used a long- e m ollow-up app oach o cons uc
pheno ypes o adul -onse as hma by ca ying ou a clus e
analysis wi h inclusion o a iables om diagnosis o a 12-yea
ollow-up isi . This app oach p o ides no el insigh s in o he
pheno ypes o as hma wi h p ognos ic significance.
METHODS
Pa ien s and s udy design
The p esen s udy was pa o he Seinäjoki Adul As hma S udy
(SAAS), which is a p ospec i e, single-cen e (Seinäjoki Cen al
Hospi al, Seinäjoki, Finland), 12-yea ollow-up s udy o a coho o
consecu i e whi e pa ien s ha ing new-onse as hma diagnosed a
adul age (15 yea s). SAAS has been egis e ed on ClinicalT ials.go
wi h ID NCT02733016. Ins i u ional pe missions (TU1114 and
LET) we e ob ained and he pa icipan s ga e w i en in o med
consen o he s udy p o ocol app o ed by he E hics Commi ee o
Tampe e Uni e si y Hospi al, Tampe e, Finland (R12122). The
p o ocol, inclusion and exclusion c i e ia, and he backg ound da a o
SAAS ha e been published elsewhe e.
11
B iefly, as hma was diagnosed
by a specialized espi a o y physician du ing he pe iod 1999 o 2002
on he basis o ypical clinical symp oms and confi med by objec i e
lung unc ion measu emen s.
11,12
The main diagnos ic ea u es o
as hma in each clus e a e p esen ed in Table E1 in his a icle’s
Online Reposi o y a www.jaci-inp ac ice.o g. Smoke s and pa ien s
wi h como bidi ies we e no excluded. A e diagnosis, he pa ien s
we e ea ed and moni o ed in specialized o p ima y ca e as
equi ed. The o al coho consis ed o 257 pa ien s and 203 pa ien s
comple ed he ollow-up isi (mean ollow-up ime, 12.2 yea s;
ange, 10.8-13.9 yea s). A 12-yea ollow-up isi , as hma s a us
and disease con ol, como bidi ies, and medica ion we e e alua ed
using s uc u ed ques ionnai es and lung unc ion was measu ed.
Da a on as hma- ela ed isi s o heal h ca e and hospi aliza ions we e
also collec ed om p ima y ca e, occupa ional heal h ca e, p i a e
clinics, and hospi als. A e excluding hose wi h missing da a,
171 pa ien s wi h adul -onse as hma emained in he coho o
clus e analysis (Figu e 1).
Lung unc ion, como bidi ies, in lamma o y
pa ame e s, and o he clinical measu emen s
Lung unc ion was measu ed wi h a spi ome e acco ding o in-
e na ional ecommenda ions.
13
The ollowing we e he lung unc-
ion measu emen poin s: (1) baseline ( ime o as hma diagnosis),
(2) he maximum p eb onchodila o FEV
1
(P e-BD FEV
1
) du ing
he fi s 2.5 yea s a e diagnosis (Max
0-2.5
) (and a e s a o
an i-inflamma o y he apy), and (3) 12-yea ollow-up.
14
De ailed
in o ma ion on de e mina ion o lung unc ion, inflamma o y pa-
ame e s, and como bidi ies can be ound in his a icle’s Online
Reposi o y a www.jaci-inp ac ice.o g. As hma con ol was assessed
acco ding o he Global Ini ia i e o As hma 2010 epo .
15
Pa ien s
filled ou he Ai ways Ques ionnai e 20 (AQ20) a baseline isi and
AQ20 and as hma con ol es (ACT) ques ionnai es a he ollow-
up isi . The AQ20 is a sho and simple well- alida ed ques ion-
nai e o measu e and quan i y dis u bances in he ai way-specific
quali y o li e.
16
ACT is a widely used pa ien sel -adminis e ed
ool o iden i ying hose wi h poo ly con olled as hma.
17
Va iable selec ion
Inpu a iables o he clus e analysis we e selec ed on he basis o
ac o analysis (see Table E2 in his a icle’s Online Reposi o y a
www.jaci-inp ac ice.o g). Basic and clinical a iables included in
ac o analysis we e chosen o co e as wide a ange as possible om
diagnosis o 12-yea ollow-up isi and a e u he discussed in his
a icle’s Online Reposi o y a www.jaci-inp ac ice.o g.
Clus e analysis and disc iminan analysis
Clus e analysis was ca ied ou by using a 2-s ep p ocess. Fi s ,
Wa d hie a chical clus e analysis was pe o med o p ee alua ion o
J ALLERGY CLIN IMMUNOL PRACT
JULY/AUGUST 2017
968 ILMARINEN ET AL
he numbe o clus e s. Then, K-means analysis was ca ied ou by
using he p especified numbe o clus e s (5). S epwise disc iminan
analysis was pe o med o iden i y a iables disc imina ing be ween
he p especified clus e s. S a is ically significan esul s we e expec ed
o mos o he compa isons because he objec i e o he clus e
analysis was o di e en ia e he pa icipan s in o dis inc pheno ypes
o adul -onse as hma.
O he s a is ical analyses
Con inuous da a a e exp essed as mean SD o median and
in e qua ile ange. G oup compa isons we e pe o med by 1-way
analysis o a iance wi h he Tukey pos hoc es , he K uskal-
Wallis es , o he chi-squa e es . S a is ical analyses we e
pe o med by using SPSS so wa e, e sion 22 (IBM Co po a ion,
A monk, NY) and MATLAB, e sion 8.6 (Ma hwo ks, Na ick,
Mass).
RESULTS
Pa ien s’cha ac e is ics
Cha ac e is ics o he o al coho a baseline and ollow-up a e
p esen ed in Table E3 in his a icle’s Online Reposi o y a www.
jaci-inp ac ice.o g. Pa ien s we e mos ly emales (58.5%) and
nona opic (63.5%), wi h age a as hma onse anging om 15 o
77 yea s. A diagnosis, mos pa ien s we e s e oid-nai e. A he
12-yea ollow-up poin , 78.9% we e daily use s o inhaled
co icos e oid (ICS) and 50.9% we e daily use s o ICS and
add-on medica ion.
Clus e analysis
By pe o ming Wa d hie a chical and K-means clus e ana-
lyses, 5 clus e s we e iden ified. The basic cha ac e is ics o hese
clus e s a e shown in Figu e 2. Clus e 1 was cha ac e ized by low
p e alence (10.5%) o hini is (non hini ic as hma), whe eas
clus e 2 had he highes smoking his o y (smoking as hma).
Clus e 3 consis ed mainly (98%) o women ( emale as hma),
and mos pa ien s in clus e 4 we e obese om diagnosis o
12-yea ollow-up isi (obesi y- ela ed as hma). Clus e 5 mos ly
included a opic pa ien s wi h he ea lies onse o as hma (ea ly-
onse a opic adul as hma). Basic and clinical cha ac e is ics o
he clus e s a baseline and a ollow-up a e p esen ed in
Tables I-IV. The e we e no majo di e ences in he main
diagnos ic ea u es be ween g oups (see Table E1 in his a icle’s
Online Reposi o y a www.jaci-inp ac ice.o g).
Clus e 1: Non hini ic as hma. Clus e 1 (n ¼38
[22.2%]) was cha ac e ized by lack o hini is, male p edomi-
nance (60.5%), onse o as hma a middle age, and second
highes smoking his o y (Figu e 2). P opo ion o pa ien s wi h
pe manen b onchial obs uc ion (pos -BD FEV
1
/ o ced i al
capaci y [FVC] <0.7) inc eased om 10.8% o 39.5% om
diagnosis o 12-yea ollow-up isi . This clus e also showed he
highes weigh gain, wi h he p opo ion o obese pa ien s
inc easing om 18.4% o 39.5%. As hma was uncon olled in
only 5.3% o he pa ien s, e en hough mos (55.9%) we e
ea ed wi h low-dose ICS o no daily ICS (Table I). Clus e 1
showed mode a e loss o FEV
1
du ing he ollow-up and he
lowes use o heal h ca e (Figu es 3 and 4). Pa ien s had 1 co-
mo bidi y on a e age a he 12-yea ollow-up isi , he mos
p e alen being ch onic obs uc i e pulmona y disease (COPD)
and hype ension (Table IV).
Clus e 2: Smoking as hma. Clus e 2 was he smalles
clus e (n ¼19 [11.1%]) and was p edomina ed by olde males.
Almos 80% o pa ien s had smoking his o y and 44.4% showed
b onchial obs uc ion a diagnosis and could be cha ac e ized as
ha ing as hma-COPD o e lap synd ome (ACOS).
18
Howe e ,
he smoking clus e did no di e om o he clus e s on he basis
o di using capaci y. The pa ien s had poo lung unc ion, high
symp oms, and uncon olled as hma despi e 94.7% being unde
daily ICS he apy, 73.4% wi h mode a e- o high-dose ICS, and
78.9% wi h long-ac ing
b
2
agonis a ollow-up. E en hough
lung unc ion significan ly imp o ed a e s a o he apy, he
annual decline in FEV
1
was s eep (78 mL on a e age) om he
maximum poin o lung unc ion o he 12-yea ollow-up isi
(Figu e 4;Table II). This was he only g oup wi h no dec ease in
blood eosinophils o symp oms om diagnosis o ollow-up
(Figu e 4). The pa ien s had 3 como bidi ies on a e age
(Table IV) and equen heal h ca e use (Figu e 3). O he pa-
ien s, 36.8% had been hospi alized o as hma (Figu e 3,B) and
his clus e accoun ed o 35.8% o all hospi al ea men
pe iods.
Clus e 3: Female as hma. This g oup was he la ges (n ¼
50 [29.2%]) and consis ed o women wi h a wide ange in he
age o as hma onse . Clus e 3 con ained mo e (44%) pa ien s
wi h no mal weigh (body mass index <25) compa ed wi h o he
clus e s and showed he lowes smoking his o y. Fo y pe cen
epo ed being symp oma ic al eady du ing childhood e en
hough hey we e no diagnosed as ha ing as hma. P e-BD FEV
1
was no mal (>80% p edic ed) in 78% a diagnosis and in 90%
a ollow-up, and he annual decline in FEV
1
was he lowes (31
mL). Blood eosinophils we e he second highes and he AQ20
symp om sco e was a a a he mode a e le el o 6 ou o 20 a
diagnosis, and bo h educed du ing he ollow-up (Figu e 4).
E en hough lung unc ion measu ed by spi ome y and
inflamma ion we e wi hin no mal ange and 78% we e unde -
going ICS ea men a he 12-yea ollow-up isi , 64% o he
pa ien s we e pa ially con olled o uncon olled and heal h ca e
use was ela i ely high (Table I;Figu e 3). Female clus e
accoun ed o 29.0% o all as hma- ela ed isi s.
Clus e 4: Obesi y- ela ed as hma. This clus e (n ¼25
[14.6%]) mos ly con ained nona opic emales wi h he oldes age
Yea s 1999-2002
Baseline isi
Pa ien s wi h new diagnosis o as hma
(age ≥ 15 yea s) we e included
n = 260
Pa ien s excluded
n = 32 missing in o ma ion
on inpu a iables o
clus e analysis
Yea s 2012-2013
12-yea ollow-up isi
n = 203
Res
p
onse a e=79 %
Pa ien s excluded
n = 1 consen wi hd awn
n = 2 childhood as hma
Pa ien s los du ing ollow-up
n = 22 dead
n = 9 could no be eached
n = 5 signi ican como bidi ies
n = 18 o he easons
Final s udy popula ion
n = 171
Visi s o
heal hca e
Hospi aliza ions
FIGURE 1. Flow cha o he s udy.
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 5, NUMBER 4
ILMARINEN ET AL 969
o as hma onse . On a e age, pa ien s we e obese om diagnosis
o he 12-yea ollow-up poin wi hou gaining mo e weigh
du ing his ime. The pa ien s we e mul imo bid a ollow-up
(Table IV), wi h he mos p e alen como bidi ies being hype -
ension, diabe es, and psychia ic diseases. As hma was uncon-
olled in 48% o he pa ien s a ollow-up e en hough 92%
we e unde going ICS ea men , 50% used high-dose ICS, and
72% we e on add-on medica ion (Table I). A diagnosis, 44%
showed p e-BD FEV
1
o mo e han 80% p edic ed. Lung
unc ion imp o ed on s a o he apy and emained ela i ely
s able h oughou ollow-up (Figu e 4,A). Respi a o y symp-
oms, use o o al s e oids, and heal h ca e use we e all a high
le els (Figu es 3 and 4).
Clus e 5: Ea ly-onse a opic adul as hma. This
g oup was he second la ges (n ¼39 [22.8%]) and consis ed o
he younges pa ien s wi h mean age o as hma onse a 33 11
yea s. Almos hal had su e ed om espi a o y symp oms
du ing childhood, 59% we e a opic, and 90% had nonalle gic
o alle gic hini is (Table I). O his clus e , 59% showed p e-
BD FEV
1
o mo e han 80% a diagnosis and 84% could be
e e sed o FEV
1
o mo e han 80% p edic ed by BD.
Re e sibili y was in gene al he highes . Lung unc ion ini ially
showed a good esponse o s e oids, e en hough he loss o
lung unc ion a e he maximum poin was also he second
s eepes . A diagnosis, hese pa ien s showed he highes blood
eosinophils (Table III), which educed un il he 12-yea ollow-
up isi (Figu e 4). As hma was con olled in 56% o he
subjec s and use o medica ion was he lowes , because 56%
we e using low-dose ICS o no medica ion and only 17.9%
we e ea ed by long-ac ing
b
2
agonis (Table I). Use o s e oid
bu s s was in equen and use o heal h ca e was among he
lowes (Figu e 3).
Valida ion
Fo alida ion, we ca ied ou K-means algo i hm 10 imes by
he lea e-one-ou me hod o ensu e s abili y and epea abili y o
he model. This me hod showed 94.4% epea abili y.
Disc iminan analysis
By using a s epwise me hod o disc iminan analysis, 12 ou o
17 a iables we e ound o significan ly disc imina e be ween he
clus e s: he diagnos ic a iables we e pos -BD FEV
1
/FVC, FEV
1
e e sibili y, and maximal change in FEV
1
( om diagnosis o
Max
0-2.5
), whe eas he ollow-up a iables included hini is,
numbe o d ugs in use o ea como bidi ies, p e-BD FEV
1
,
pack-yea s, body mass index, limi a ion o ac i i ies (none/any),
and basic a iables o sex, age a as hma onse , and symp oms o
as hma o less han 16 yea s, o which hini is, pos -BD FEV
1
/
FVC, numbe o d ugs in use o ea como bidi ies, and sex
we e ound o be he s onges disc imina ing a iables. Du a ion
o symp oms be o e diagnosis, blood eosinophils and neu o-
phils, e e sibili y a ollow-up, and ACT sco e we e no ound as
s a is ically significan disc iminan s. The pe cen age o co ec
classifica ion on he basis o he 12 disc imina ing a iables was
94.7% (da a no shown).
DISCUSSION
In his s udy, we iden ified pheno ypes o adul -onse as hma
by using longi udinal da a and basic and clinical a iables anging
om he diagnos ic phase o he 12-yea ollow-up isi . Ou
coho included smoke s and pa ien s wi h como bidi ies. The
ollowing 5 pheno ypes we e iden ified: (1) non hini ic
con olled o pa ially con olled as hma wi h low use o medi-
ca ion and heal h ca e; (2) smoking as hma o ACOS wi h poo
lung unc ion, high symp oms, and high use o medica ion and
heal h ca e; (3) emale as hma wi h no mal clinical pa ame e s
FIGURE 2. Basic cha ac e is ics o clus e s. In A-F, C1 o C5 e e o he clus e numbe s. O e all P alues a e shown. In Band F, he ed
lines shown a e means. In D, means a e shown. BMI, Body mass index; DG, diagnosis.
J ALLERGY CLIN IMMUNOL PRACT
JULY/AUGUST 2017
970 ILMARINEN ET AL
TABLE I. Gene al ea u es o clus e s
Fea u es
Clus e 1:
non hini ic (n [38)
Clus e 2:
smoking (n [19)
Clus e 3:
emale (n [50)
Clus e 4:
obese (n [25)
Clus e 5:
a opic (n [39)
P alue
be ween
clus e s
P alue
be ween
clus e s
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
Demog aphic cha ac e is ics and an hopome ics
Females, n (%) 15 (39.5) 2 (10.5)*49 (98)†16 (64) 18 (46.2) <.001
Age (y), mean SD 50 12 63 12 55 96694312†55 12†57 86983311†45 11†<.001 <.001
BMI (kg/m
2
), mean 
SD
28.1 5.5z29.9 6.5 27.8 4.0 28.1 4.9 26.3 4.3 27.1 4.8 32.7 5.2†32.8 5.3zxjj 24.9 3.5 26.8 3.9 <.001 <.001
Obese (BMI >30), n (%) 7 (18.4) 15 (39.5) 8 (42.1)z7 (36.8) 7 (14.0) 13 (26.0) 17 (68.0)zjj{ 18 (72.0)†4 (10.3) 9 (23.1) <.001 .001
Smoke s, n (%) 20 (52.6) 20 (52.6) 15 (78.9)jj 15 (78.9)jj 17 (34) 18 (36) 11 (44) 11 (44) 19 (48.7) 21 (53.8) .020 .027
Cu en smoke , n (%) 7 (18.4) 7 (18.4) 5 (26.3) 3 (15.8) 5 (10) 8 (16) 4 (16) 0 9 (23.1) 8 (20.5) .425 .225
Pack-yea s o smoke s,
median (IQR)
17 (12-23)jj 19 (15-29)zjj 29 (14-34)*zjj 33 (15-38)zjj 5 (2-10) 6 (2-18) 15 (10-20) 15 (10-25) 4 (3-7) 6 (3-15) <.001 <.001
Symp oms o as hma
<16 y, n (%)
0 1 (5.3) 20 (40.0)*{1 (4.0) 19 (48.7)*x{ <.001
Symp oms o as hma
be o e diagnosis (mo),
median (IQR)
18 (9-60) 24 (11-36) 12 (9-36) 24 (24-60)zjj 12 (8-24) .008
A opic, n (%) 9 (27.3) ND 5 (31.3) ND 19 (40.4) ND 2 (9.1) ND 22 (57.9)*ND .003 ND
No. o posi i e SPT,
median (IQR)
0 (0-1) ND 0 (0-2) ND 0 (0-2)*ND 0 (0-0) ND 1.5 (0-3)*x{ ND .001 ND
Rhini is, n (%) ND 4 (10.5)†ND 14 (73.7) ND 44 (88) ND 24 (96) ND 35 (89.7) ND <.001
As hma con ol and quali y o li e
AQ20 sco e, median
(IQR)
5 (3-7) 2 (1-4) 8 (5-10) 8 (5-11)zjj{ 6 (4-10) 4 (2-6) 10 (7-13)zjj{ 7 (4-9)z{ 4 (2-9) 2 (1-5) <.001 <.001
ACT sco e, median
(IQR)
ND 23 (21-24) ND 20 (13-21)zjj{ ND 22 (19-24) ND 19 (15-22)z{ ND 23 (21-25) ND <.001
ACT sco e <20, n (%) ND 5 (13.2) ND 9 (47.4)z{ ND 13 (26.0) ND 15 (60.0)zjj{ ND 5 (12.8) ND <.001
Con olled, n (%) ND 16 (42.1) ND 2 (10.5) ND 18 (36) ND 4 (16) ND 22 (56.4)*xND <.001
Pa ly con olled, n (%) ND 20 (52.6)xND 1 (5.3) ND 21 (42)xND 9 (36) ND 11 (28.2) ND .007
Uncon olled, n (%) ND 2 (5.3) ND 16 (84.2)zjj{ ND 11 (22){ND 12 (48)z{ ND 6 (15.4) ND <.001
Exace ba ions
O al s e oids, n (%)#2 (5.4) 4 (21.1) 6 (12.2) 7 (29.2) 2 (5.1) .026
T ea men
Daily ICS use , n (%)** 1 (2.6) 27 (71.1) 1 (5.3) 18 (94.7) 6 (12.2) 39 (78) 2 (8.0) 23 (92) 2 (5.1) 28 (71.8) .479 .089
ICS dose,†† median
(IQR)
900 (800-1600) 800 (400-1000) 800 (700-1600) 900 (700-1400) 800 (400-1000) 800 (575-1000) 1000 (800-1400) 1000 (475-1525) 800 (800-1600) 800 (400-800) .220 .163
Low/none ICS dose, n (%) ND 19 (55.9) ND 4 (26.7) ND 18 (40) ND 6 (30) ND 20 (55.6) ND .109
Medium ICS dose, n (%) ND 7 (20.6) ND 4 (26.7) ND 11 (24.4) ND 4 (20) ND 11 (30.6) ND .871
(con inued)
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 5, NUMBER 4
ILMARINEN ET AL 971

bu ela i ely high use o heal h ca e; (4) obesi y- ela ed as hma
wi h como bidi ies, high symp oms, and high use o medica ion
and heal h ca e; and (5) a opic well-con olled as hma wi h onse
ea lie in adul hood. Ins ead o cha ac e izing pheno ypes in one
poin o disease, we p o ide pheno ypes based on 12-yea
ollow-up da a.
Ou esul s show bo h simila i ies o and di e ences om hose
o p e ious clus e analyses based on c oss-sec ional da a wi h
mixed du a ion o as hma. Mos p e ious analyses ha e excluded
smoke s o hea y smoke s and only ew ha e iden ified smoking
as hma.
6,19
Clus e A in he Coho o Reali y and E olu ion o
Adul As hma in Ko ea (COREA) s udy
6
esembled ou smoking
clus e in many espec s. Howe e , in ou s udy, he smoking
clus e showed an annual decline in FEV
1
ha was he s eepes o
all g oups in con as o he esul s o he COREA smoking clus e
in 1-yea ollow-up. Many nega i e ou comes p e iously associa ed
wi h smoking as hma we e e iden in ou smoking clus e ,
including lowe as hma- ela ed quali y o li e (based on AQ20
sco e), equen heal h ca e use, and se e e/uncon olled
as hma.
20-22
E en hough he pa ien s in he smoking clus e
ypically show i e e sible ai flow limi a ion and como bidi y
p ofiles esembling ha o COPD, no mal a e age di using ca-
paci y in each clus e sugges s ha he main diagnosis is as hma
and no emphysema. In addi ion, he diagnosis o as hma was
made by a espi a o y specialis and each pa ien ulfilled he
diagnos ic c i e ia o as hma including objec i e lung unc ion
measu emen s showing b onchial a iabili y. This smoking g oup,
al hough being he smalles one, was esponsible o mo e han a
hi d o all as hma- ela ed hospi aliza ions, highligh ing he sig-
nificance o his g oup o heal h ca e cos s. Ob iously, much e -
o s should be ocused on ad ising pa ien s o s op smoking as
ea ly as possible, e en be o e onse o as hma and be o e as hma
u ns om a milde o m o di ficul - o- ea smoking as hma wi h
high bu den o bo h indi idual and heal h ca e.
Obesi y- ela ed emale-p edominan as hma is a clus e iden-
ified in ou s udy as well as in some p e ious s udies,
2,5,7,10
and
ou esul s add by p o iding da a on p ognosis o he long- e m
obesi y. Ou esul s on his clus e suppo p e ious findings
indica ing equen symp oms and exace ba ions, high use o
heal h ca e, high medica ion, and a nona opic, noneosinophilic
disease cha ac e is ic. This clus e is also p one o c ea e a high
bu den o heal h ca e, as e idenced by he mos equen use o
o al co icos e oids and o heal h ca e se ices. To u he add on
p e ious s udies, we ound he highes numbe o como bidi ies
in he obese clus e and especially a high p e alence o psychia ic
como bidi y (40%). Consis en ly, in a p e ious s udy, he
highes dep ession sco e was shown in he la e-onse obese clus e
in a coho o se e e as hma.
7
Howe e , in e ac ion be ween
obesi y, psychia ic diseases, and as hma equi es u he
s udies.
23,24
Recen ly, we showed ha mul imo bidi y is associ-
a ed wi h inc eased symp oms o as hma, which may be pa ly
ela ed o sys emic inflamma ion in hese pa ien s.
25
Sys emic
inflamma ion has been associa ed wi h high s e oid dose in he
ea men o adul -onse as hma.
25
The e o e, mul imo bidi y
and sys emic inflamma ion may be ele an in u ning
as hma in o symp oma ic and s e oid- esis an in obese pa ien s.
Howe e , weigh loss has esul ed in imp o ed symp oms, lung
unc ion, as hma con ol, and heal h s a us,
23
sugges ing ha i
would benefi his subg oup.
In addi ion o he obesi y- ela ed emale-p edominan g oup,
we iden ified a nonobese clus e o emales wi h good lung
TABLE I. (Con inued)
Fea u es
Clus e 1:
non hini ic (n [38)
Clus e 2:
smoking (n [19)
Clus e 3:
emale (n [50)
Clus e 4:
obese (n [25)
Clus e 5:
a opic (n [39)
P alue
be ween
clus e s
P alue
be ween
clus e s
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
High ICS dose, n (%) ND 8 (23.5) ND 7 (46.7) ND 16 (35.6) ND 10 (50)zND 5 (13.9) ND .022
LABA, n (%) ND 16 (42.1) ND 15 (78.9) ND 25 (50) ND 18 (72) ND 7 (17.9) ND <.001
LTRA, n (%) ND 5 (13.2) ND 1 (5.3) ND 8 (16) ND 11 (44)zjj ND 2 (5.1) ND <.001
Theophylline, n (%) ND 0 ND 0 ND 2 (4) ND 1 (4) ND 0 ND .419
LAMA, n (%) ND 0 ND 5 (26.3)zjj{ ND 0 ND 2 (8) ND 0 ND <.001
BMI, Body mass index; LABA, long-ac ing
b
2
agonis ; LTRA, leuko iene ecep o an agonis ; ND, no de e mined; SPT, skin p ick es .
*P<.05 s clus e 4 a co esponding ime poin (baseline o ollow-up).
†P<.05 o all o he clus e s a co esponding ime poin (baseline o ollow-up).
zP<.05 s clus e 5 a co esponding ime poin (baseline o ollow-up).
{P<.05 s clus e 1 a co esponding ime poin (baseline o ollow-up).
xP<.05 s clus e 2 a co esponding ime poin (baseline o ollow-up).
jjP<.05 s clus e 3 a co esponding ime poin (baseline o ollow-up). Pai ed compa ison be ween baseline and ollow-up is no shown.
#A leas 2 cou ses o o al s e oids du ing he 2 p e ious yea s be o e he ollow-up isi .
**Baseline ICS use s e e o hose who used ICS daily be o e diagnosis.
††Baseline ICS dose is he s a ing dose a diagnosis. Low-dose ICS e e s o 400
m
g, medium-dose ICS o >400e800
m
g, and high-dose ICS o >800
m
g budesonide equi alen s.
15
J ALLERGY CLIN IMMUNOL PRACT
JULY/AUGUST 2017
972 ILMARINEN ET AL
TABLE II. Lung unc ion o clus e s (mean SD)
Cha ac e is ic
Clus e 1:
non hini ic (n [38)
Clus e 2:
smoking (n [19)
Clus e 3:
emale (n [50)
Clus e 4:
obese (n [25)
Clus e 5:
a opic (n [39)
P alue
be ween
clus e s
P alue
be ween
clus e s
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
Lung unc ion
P e-BD FEV
1
, % e 82 15 85 14*53 18†63 19†90 12 96 13 78 13*79 16*81 14*86 12*<.001 <.001
Pos -BD FEV
1
,% e 8616 89 14*60 18†67 20†94 13 98 13 83 14*81 16*z92 12 92 12 <.001 <.001
P e-BD FVC, % e 90 16 97 14 73 17*zx 90 15*95 12 103 14 84 13*88 14*93 15 98 14 <.001 <.001
Pos -BD FVC, % e 92 16 100 16 81 16*z93 14 96 13 103 14 86 12*z90 14*97 13 99 14 <.001 .007
P e-BD FEV
1
/FVC,
% e
0.75 0.08*0.71 0.08*0.57 0.11†0.57 13†0.80 0.07 0.76 0.05 0.76 0.06 0.72 0.10 0.74 0.10*0.72 0.07 <.001 <.001
Pos -BD FEV
1
/FVC,
% e
0.77 0.07*0.72 0.08*0.58 0.12†0.58 0.14†0.83 0.07 0.78 0.05 0.78 0.08 0.72 0.10*0.81 0.08 0.76 0.07 <.001 <.001
FEV
1
e e sibili y (mL) 166 137 134 147*267 251 142 172*139 142 47 69 144 211 62 104 407 204*xjj 195143*xjj <.001 <.001
FEV
1
e e sibili y
(% change)
5.6 5.3 4.8 5.2*15.0 16.4*zxjj 6.8 7.7*5.9 7.8 1.8 2.8 6.2 8.8 3.2 5.3 14.2 13.6*xjj 6.6 5.6*<.001 <.001
Di using capaci y
DL
CO
/VA (% e ) 104 17 100 15 94 21 88 28 100 20 95 14 99 18 93 13 107 16 97 14 .155 .107
Annual change in lung
unc ion om
Max
0-2.5
o
ollow-up{
D
FEV
1
(mL/y) 49 32*78 54*31 24 46 30 59 40*<.001
D
FVC (mL/y) 37 32 48 63 24 31 40 39 38 49 .173
Maximal change in FEV
1
(
D
om diagnosis o
Max
0-2.5
)
D
FEV
1
(mL#) 266 365 972 899*zxjj 161 252 184 239 561 459*xjj <.001
DL
CO
, Di using capaci y o he lung o ca bon monoxide; e , e e ence; VA, al eola olume.
*P<.05 s clus e 3 a co esponding ime poin (baseline o ollow-up).
†P<.05 o all o he clus e s a co esponding ime poin (baseline o ollow-up).
zP<.05 s clus e 5 a co esponding ime poin (baseline o ollow-up).
xP<.05 s clus e 1 a co esponding ime poin (baseline o ollow-up).
jjP<.05 s clus e 4 a co esponding ime poin (baseline o ollow-up). Pai ed compa ison be ween baseline and ollow-up is no shown.
{Annual change in FEV
1
o FVC om poin o maximal lung unc ion wi hin 2.5 y a e s a o he apy o he 12-y ollow-up isi .
#
D
FEV
1
when deduc ing p e-BD FEV
1
alue a diagnosis om p e-BD FEV
1
alue a poin o maximal lung unc ion wi hin 2.5 y om s a o he apy; eflec s ea ly esponse o ea men .
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 5, NUMBER 4
ILMARINEN ET AL 973
unc ion and a wide ange in he age o as hma onse . The
p e iously defined clus e s “leas se e e as hma wi h no mal lung
unc ion,”“middle-age onse , emale-dominan ,”and “la e-onse
mild as hma”
6,7,19
show esemblance o ou emale clus e ,
including p edominance o nonobese emales, no mal lung
unc ion,
6,7,19
and s able lung unc ion in he sho ollow-
ups.
6,7
Low smoking his o y, low body mass index, low coun o
como bidi ies, and high eosinophils a diagnosis may ha e
a ec ed he good o e all p ognosis o he emale clus e . How-
e e , he heal h ca e use was ela i ely high in his g oup gi en
ha many clinical pa ame e s we e wi hin no mal ange. This
may be explained by emales’s onge pe cep ion o symp oms
and lowe h eshold o con ac heal h ca e when compa ed wi h
males.
26
In addi ion, emale pa ien s wi h simila se e i y o
as hma as he co esponding male pa ien s ha e shown be e
lung unc ion bu wo se as hma- ela ed quali y o li e.
26
In his
clus e , lung unc ion based on spi ome y was mo e s able when
compa ed wi h lung unc ion in o he g oups, bu peak expi a-
o y flow ollow-up migh ha e shown a iable obs uc ion and
disease ac i i y. In addi ion, whe he pa ame e s such as blood
eosinophils o ai way hype esponsi eness be e co ela e o
disease ac i i y and symp oms emains unclea . In he emale
clus e , oughly hal o he pa ien s we e a e ile age, and he
o he hal a menopausal o pos menopausal age a as hma onse ,
sugges ing ha no uni o m sex ho monee ela ed mechanism
explains he pa hophysiology o as hma in his clus e . Howe e ,
ho monal aspec s p obably play a significan ole in he pa ho-
genesis and cou se o he disease,
26-31
e en hough he mecha-
nisms a e likely mul i ac o ial. P esence o symp oms a
childhood in 40% o he pa ien s also sugges s he in ol emen
o T
H
2- ela ed mechanisms and some o e lap wi h clus e 5.
Simila o p e ious findings,
32
mos pa ien s in ou s udy had
a coexis ing alle gic o nonalle gic hini is. Howe e , we also
iden ified a nona opic mild o mode a e male-p edominan
as hma wi hou hini is, which o ou knowledge has no been
epo ed p e iously. Despi e he second highes smoking his o y,
40% p e alence o pe manen b onchial obs uc ion, and obesi y
a ollow-up, hese pa ien s had significan ly be e p ognosis
when compa ed wi h hose in clus e s 2 and 4. Rhini is has been
associa ed wi h mo e se e e as hma,
32,33
sugges ing ha lack o
hini is is a significan de e minan associa ed wi h he a o able
p ognosis in his g oup. Male p edominance, mode a e smoking
his o y, and he highes weigh gain sugges ha pa hophysio-
logical mechanisms in his clus e a e ela ed o hose ea u es.
As hma in obese men has been epo ed o be less o en se e e
when compa ed wi h ha in obese women
26
and obesi y- ela ed
as hma may ha e impo an sex-specific di e ences conce ning
he media o s o he disease.
34,35
Fo example, in a ecen s udy,
no simila di e ence exis ed in sys emic inflamma ion be ween
nonobese and obese males as seen in emales.
35
Lowe le el o
sys emic inflamma ion could also con ibu e o lesse numbe o
como bidi ies and be e p ognosis o as hma. Fu he s udies a e
needed o e alua e he pa hophysiological mechanisms in his
clus e .
Clus e 5 in ou s udy fi s well wi h he p e ious findings o
he impo an ole o age o onse in defining he pheno ype.
1,3
A opy, childhood symp oms, ea lies onse o as hma, good
s e oid- esponsi eness, and la ge FEV
1
e e sibili y suppo he
conclusion ha his clus e ep esen s he adi ional ea ly-onse
as hma bu s a ing a ea ly adul hood. In addi ion, he good
p ognosis s eng hens he iew.
36
A co esponding adul -onse
TABLE III. In lamma o y bioma ke s o clus e s, median (IQR)
Bioma ke
Clus e 1:
non hini ic (n [38)
Clus e 2:
smoking (n [19)
Clus e 3:
emale (n [50)
Clus e 4:
obese (n [25)
Clus e 5:
a opic (n [39)
P alue
be ween
clus e s
P alue
be ween
clus e s
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
Blood eosinophils
(10
9
/L)
0.20 (0.11-0.32) 0.14 (0.09-0.25) 0.20 (0.17-0.48) 0.23*(0.13-0.43) 0.30 (0.16-0.44) 0.16 (0.10-0.28) 0.22 (0.18-0.32) 0.13 (0.06-0.25) 0.38†(0.27-0.60) 0.20 (0.12-0.28) .008 .035
To al IgE (kU/L) 95 (28-278) 54 (23-159) 100 (70-552) 95 (24-315) 64 (27-147) 66 (21-138) 62 (22-125) 61 (24-118) 108 (56-409) 67 (30-383) .099 .464
Blood neu ophils
(10
9
/L)
ND 3.5 (2.9-4.7) ND 4.0 (3.4-4.7) ND 3.8 (2.5-5.2) ND 4.4 (3.2-5.3) ND 3.5 (2.9-4.0) ND .215
FENO (ppb) ND 10 (4-18) ND 10 (5-21) ND 11 (5-18) ND 8 (5-18) ND 16 (6-24) ND .364
FeNO, F ac ional exhaled ni ic oxide; IQR, in e qua ile ange; ND, no de e mined.
*P<.05 s clus e 4 a co esponding ime poin (baseline o ollow-up).
†P<.05 s clus e 1 a co esponding ime poin (baseline o ollow-up). Pai ed compa ison be ween baseline and ollow-up is no shown.
J ALLERGY CLIN IMMUNOL PRACT
JULY/AUGUST 2017
974 ILMARINEN ET AL
TABLE IV. Como bidi ies o clus e s
Como bidi y
Clus e 1:
non hini ic (n [38)
Clus e 2:
smoking (n [19)
Clus e 3:
emale (n [50)
Clus e 4:
obese (n [25)
Clus e 5:
a opic (n [39)
P alue
be ween clus e s
P alue
be ween
clus e s
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
Hype ension, n (%) 4 (10.5) 9 (23.7) 4 (21.1) 13 (68.4)*†z3 (6.0) 7 (14.0) 12 (48.0)*†z19 (76.0)*†z2 (5.1) 6 (15.4) <.001 <.001
Diabe es, n (%) 0 4 (10.5) 0 7 (36.8)†z0 3 (6.0) 3 (12.0) 11 (44.0)*†z0 2 (5.1) <.001 <.001
Co ona y hea
disease, n (%)
1 (2.6) 5 (26.3)†z0 2 (8.0) 0 <.001 <.001
COPD, n (%) 2 (5.4) 9 (23.7)†8 (44.4)x10 (52.6)†zjj 0 1 (2.0) 0 2 (8.0) 1 (2.6) 3 (7.7) <.001 <.001
Any psychia ic
disease, n (%)
ND 3 (7.9) ND 1 (5.3) ND 5 (10) ND 10 (40)*†zND 3 (7.7) ND .001
Dep ession, n (%) ND 1 (2.6) ND 1 (5.3) ND 3 (6.0) ND 7 (28)*ND 2 (5.1) ND .004
Pain ul condi ion,
n(%)
ND 3 (7.9) ND 2 (10.5) ND 2 (4) ND 5 (20) ND 1 (2.6) ND .090
T ea ed dyspepsia,
n(%)
ND 1 (2.6) ND 2 (10.5) ND 4 (8) ND 6 (24) ND 1 (2.6) ND .020
To al no. o
como bidi ies,
median (IQR)
ND 1 (0-2)zND 3 (1-4)*†zND 0.5 (0-1) ND 3 (2.5-4)*†zND 0 (0-1) ND <.001
No. o d ugs{, median
(IQR)
ND 1 (0-3) ND 3 (2-9)*†zND 1 (0-2) ND 6 (4-7)*†zND 0 (0-2) ND <.001
IQR, In e qua ile ange; ND, no de e mined.
*P<.05 s clus e 1 a co esponding ime poin (baseline o ollow-up).
†P<.05 s clus e 3 a co esponding ime poin (baseline o ollow-up).
zP<.05 s clus e 5 a co esponding ime poin (baseline o ollow-up).
xP<.05 s all clus e s a co esponding ime poin (baseline o ollow-up).
jjP<.05 s clus e 4 a co esponding ime poin (baseline o ollow-up). Pai ed compa ison be ween baseline and ollow-up is no shown.
{Numbe o d ugs in use o ea como bidi ies.
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 5, NUMBER 4
ILMARINEN ET AL 975