PROTOCOL OPEN
Seinäjoki Adul As hma S udy (SAAS): a p o ocol o a 12-
yea eal-li e ollow-up s udy o new-onse as hma diagnosed
a adul age and ea ed in p ima y and specialised ca e
Hannu Kankaan an a
1,2
, Pinja Ilma inen
1
, Te hi Kankaan an a
3
and Leena E Tuomis o
1
npj P ima y Ca e Respi a o y Medicine (2015) 25, 15042; doi:10.1038/npjpc m.2015.42; published online 25 June 2015
BACKGROUND
As hma is cha ac e ised by a iable symp oms o wheeze,
sho ness o b ea h, ches igh ness and/o cough, and by a iable
expi a o y flow limi a ion.
1
As hma can a ec pa ien s a any age
wi h a ying se e i ies. Un il ecen ly, as hma has been conside ed
o be a single, alle gic, eosinophilic, T
H
2-media ed and
glucoco icoid- esponsi e disease.
2,3
Recen ly, clus e analyses
ha e sugges ed ha pa ien s wi h as hma can be di ided in o
di e en pheno ypes, and he age a disease onse was ound as a
key di e en ia ing ac o be ween pheno ypes.
2,3
La e - o adul -
onse disease is less associa ed wi h alle gy han as hma
beginning in childhood. Adul -onse pheno ypes such as la e-
onse eosinophilic (o en se e e), exe cise-induced, obesi y- ela ed
and neu ophilic as hma ha e been p oposed.
2,3
Mos publica-
ions on as hma ha e ocused on alle gic as hma s a ing in
childhood.
2,3
The symp oms in childhood a e o en ansien , and
app oxima ely h ee ou o ou as hma ic child en will ou g ow
hei as hma.
4
In con as , he long- e m p ognosis o adul -onse
as hma is no known, and only wo
5,6
ollow-up s udies o
du a ion o 2–5.8 yea s ha e been published and sugges a less
a ou able ou come. Thus, long- e m, eal-li e, ollow-up s udies
wi h as hma pa ien s ea ed in p ima y ca e a e needed.
Alle gic childhood as hma can usually be ea ed well by inhaled
glucoco icoids,
2–4
whe eas he need o di e en add-on
he apies
7
is common in adul -onse disease and he he apeu ic
esponse may emain insu ficien .
2,3,7
In adul pa ien s wi h
as hma, co-mo bidi ies a e common.
8,9
S ill, a single-disease
pa adigm domina es andomised con olled ials, heal h policy,
deli e y and guidelines.
8
The cu en guidelines on diagnos ics
and ea men o as hma
1,10
o as hma–ch onic obs uc i e
pulmona y disease (COPD) o e lap synd ome
1,11,12
o e us ad ice
and in o ma ion mainly on he epidemiology, isk ac o s,
diagnos ic c i e ia, (ini ial) pha maco he apy and ea men o
exace ba ions. Howe e , when i comes o exac ecommenda-
ions on whe he he diagnos ic s udies and he diagnosis o
as hma should be made in p ima y p ac ice, he ecommenda-
ions, i hey exis a all, a e based on opinion a he han on
e idence. Fu he mo e, a simila lack o in o ma ion emains when
specific ques ions on he o ganisa ion o he ollow-up o
ch onically ill pa ien s wi h as hma a e asked. Examples o such
ques ions a e as ollows: who should pe o m he ollow-up
checks? How o en should hese ollow-up checks be pe o med?
Exac ly wha ollow-up ools should be used?
AIMS
The aim o his s udy is o inc ease he unde s anding on he
diagnos ics and diagnos ic p ocess, o ganisa ion o he long- e m
as hma ca e, he apeu ic ou comes, p ognosis and he ac o s
a ec ing he p ognosis o new-onse as hma diagnosed a
adul age.
METHODS
S udy design, inclusion and exclusion c i e ia
Seinäjoki Adul As hma S udy (SAAS) is a single-cen e (Depa men o
Respi a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland) 12-yea
ollow-up s udy o a o al coho o 259 pa ien s ha ing new-onse as hma
ha was diagnosed a adul age. Howe e , wo pa ien s we e excluded
because hey we e la e ound o ha e a p e ious diagnosis o as hma
du ing childhood, lea ing 257 pa ien s in he o iginal coho . The s udy
was di ided in wo pa s (Figu e 1): he collec ion o he o iginal coho
(phase I) and ollow-up isi (phase II). The o iginal coho was collec ed
be ween 6 Oc obe 1999 and 17 Ap il 2002. Pa ien s we e e e ed o he
hospi al by p ima y-ca e p ac i ione s because o suspicion o as hma.
Inclusion and exclusion c i e ia a e shown in Table 1. Pa ien s wi h
simul aneous as hma and COPD we e no excluded, and he s udy
popula ion includes pa ien s who could be defined as ha ing as hma–
COPD o e lap synd ome, e en hough he inclusion c i e ia o hose
pa ien s a e no exac ly he same as cu en ly used c i e ia o as hma–
COPD o e lap synd ome.
1,11,12
A e 12 yea s, pa ien s we e in i ed o a ollow-up isi (phase II;
10 Decembe 2012 and 31 Oc obe 2013) in which as hma s a us,
co-mo bidi ies (ch onic hini is o obs uc ed nose, alle gic hini is o
conjunc i i is, diabe es, hype ension, co ona y hea disease, COPD and
any o he pa ien - epo ed disease), medica ion (including medica ion o
o he diseases and he disease ea ed), con ol, se e i y and lung unc ion
we e e alua ed (Figu e 1). In addi ion o he da a ga he ed a hese isi s,
da a on as hma ollow-up isi s, exace ba ions, hospi alisa ions, possible
occupa ionally induced as hma and p esc ibed as hma medica ion we e
collec ed om hospi al clinics, p ima y heal h ca e, occupa ional heal h
ca e and p i a e p ac ices o he whole 12-yea ollow-up pe iod. In
addi ion, he use o medica ion ha was ealised, i.e., medica ion bough
om pha macy, will be e ie ed. In addi ion o as hma-specific ac o s,
da a include occupa ional, li es yle and socioeconomic ac o s a he
ollow-up isi .
E hical conside a ions and pe missions
Phase I was o iginally designed as a egis y se ing as an as hma- ela ed
da a exchange pla o m be ween p ima y and specialised ca e, as well as
1
Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland;
2
Depa men o Respi a o y Medicine, Uni e si y o Tampe e, Tampe e, Finland and
3
Police
Uni e si y College, Tampe e, Finland.
Co espondence: H Kankaan an a (hannu.kankaan an a@epshp.fi)
Recei ed 10 Decembe 2014; e ised 29 Ap il 2015; accep ed 12 May 2015
www.na u e.com/npjpc m
All igh s ese ed 2055-1010/15
© 2015 P ima y Ca e Respi a o y Socie y UK/Macmillan Publishe s Limi ed
an as hma- ela ed esea ch egis y. Phase I was pa o hospi al
de elopmen p ojec s (ins i u ional pe mission TU 1114). No in e en ions
ou side no mal clinical p ac ice we e ca ied ou . All pa icipan s in he
o iginal coho ga e w i en in o med consen o be included in he
egis y. Wi h he de elopmen o a common egional elec onic pa ien
eco d sys em, he da a exchange pla o m became unnecessa y, bu he
esea ch egis y emained. The pa icipan s o he ollow-up isi (phase II)
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).
Se ing and backg ound da a
The o ganisa ion o as hma ca e in gene al and especially in he Seinäjoki
Cen al Hospi al dis ic has ecen ly been desc ibed in de ail.
13
As hma is a
common disease needing communi y solu ions.
14
The ac ions o he
Finnish As hma P og amme
14,15
ha e been pu in o p ac ice in he hospi al
dis ic .
13,16
The o iginal coho (phase I) ep esen s no el adul as hma
cases well; o example, he o al numbe o new diagnoses o as hma a
he s udy cen e in 2001 was 133.
16
O hose, 126 pa ien s we e ec ui ed
o phase I o his s udy, ep esen ing 94.7% o new diagnoses o as hma.
The main planned ou comes
P ognosis o new-onse as hma diagnosed a adul age du ing a
12-yea ollow-up. The ques ions he clinician is acing in on o an
adul pa ien wi h newly diagnosed as hma a e as ollows: wha is he
p ognosis o adul -onse as hma in gene al and especially in his pa icula
pa ien ? A e he e any p ognos ic ma ke s ha would help me in
p edic ing he u u e and guide me in planning his/he u u e he apy?
The p ima y ou come is he p ognosis o as hma ( emission, con ol and
se e i y). Howe e , e alua ion o con ol a a single ime poin does no
ep esen he ue mo bidi y o as hma.
17
Ou in en ion is o cha ac e ise
he ue 12-yea p ognosis o as hma, i.e., cumula i e bu den o as hma-
ela ed e en s, which is he second p ima y ou come. Seconda y ou comes
include he ollowing: exace ba ions, hospi alisa ions and mo ali y
because o as hma, mul imo bidi y, lung unc ion and inflamma o y cells
(e.g., blood eosinophils and neu ophils), as well as inflamma o y and o he
ma ke s o in e es
18–21
in he pa hogenesis o as hma such as in e leukins,
adipokines and pe ios in (Figu e 1).
Diagnos ics and ollow-up o pa ien s wi h adul -onse as hma in
p ima y and specialised ca e. The diagnosis o as hma wi h all pa ien s
Figu e 1. Schema ic p esen a ion o he Seinäjoki Adul As hma S udy. The o iginal coho (phase I) was collec ed be ween 6 Oc obe 1999
and 17 Ap il 2002, and ollow-up isi (phase II) was pe o med be ween 10 Decembe 2012 and 31 Oc obe 2013.
Table 1. Inclusion and exclusion c i e ia used in SAAS
Inclusion
c i e ia
●A diagnosis o new-onse as hma made by a espi a o y specialis
●Diagnosis confi med by a leas one o he ollowing objec i e lung unc ion measu emen s:
a
JFEV
1
e e sibili y in spi ome y o a leas 15% and 200 ml
JDiu nal a iabili y (⩾20%) o epea ed e e sibili y (⩾15%/60 l/min) in PEF ollow-up
JA significan dec ease in FEV
1
(15%) o PEF (20%) in esponse o exe cise o alle gen
JA significan e e sibili y in FEV
1
(a leas 15% and 200 ml) o significan mean PEF change in esponse o a ial wi h o al o
inhaled glucoco icoids
●Symp oms o as hma
●Age ⩾15 yea s
Exclusion
c i e ia
●Physical o men al inabili y o p o ide signed in o med consen
●Diagnosis o as hma below he age o 15 yea s
●O no e:
JPa ien s wi h como bidi ies, ei he o he lung disease o any o he significan disease, we e no excluded
JPa ien s we e no excluded because o smoking, alcohol use o any o he li es yle ac o
JRespi a o y symp oms o any o he disease du ing childhood was no a eason o exclude pa ien s, bu a diagnosis o as hma a
age o15 yea s was an exclusion c i e ia
Abb e ia ions: FEV
1
, o ced expi a o y olume in one second; PEF, peak expi a o y flow; SAAS, Seinäjoki Adul As hma S udy.
a
The objec i e lung unc ion c i e ia eflec hose o Na ional and In e na ional Guidelines alid in 1999–2002 and may no exac ly ollow hose alid a he
momen .
1,10
Seinäjoki Adul As hma S udy p o ocol
H Kankaan an a e al
2
npj P ima y Ca e Respi a o y Medicine (2015) 15042 © 2015 P ima y Ca e Respi a o y Socie y UK/Macmillan Publishe s Limi ed
in he p esen s udy was confi med by a espi a o y specialis , bu
diagnos ic s udies o mos pa ien s we e pa ly pe o med al eady in
p ima y ca e. This gi es us he oppo uni y o assess he p opo ion o
diagnoses ha could ha e been done al eady in p ima y ca e and he
diagnos ic ools ha we e able o p o ide su ficien in o ma ion on he
diagnosis o adul -onse as hma in p ima y ca e. All as hma- ela ed ollow-
up isi s o e a 12-yea pe iod bo h in p ima y and specialised ca e a e
collec ed and e alua ed. Thus, he impac o as hma ollow-up isi s on he
ou come o as hma du ing a 12-yea pe iod can be assessed. This gi es us
a possibili y o e alua e whe he , e.g., he place o he pe o me , he
iming o equency o con ol isi s and ac ions pe o med a he con ol
isi can con ibu e o he ou come o as hma and how he ca e o ch onic
as hma should be o ganised.
S a is ical analysis
S a is ical analysis in ol es he basic s a is ical ools o con inuous,
ca ego ical o dicho omous a iables such as - es , nonpa ame ic es s
(e.g., Mann–Whi ney) and analysis o a iance. To e alua e he associa ions
be ween a iables, χ
2
- es , co ela ion ma ixes and eg ession analysis will
be used.
22,23
Usually, he isk o as hma a acks is exp essed as he o al numbe o
e en s pe pa ien o as yea ly incidence o e en s.
17
Howe e , his analysis
does no ake in o accoun he iming o as hma a acks in ela ion o
changes in he o he ac o s in as hma ca e (e.g., change in medica ion).
E en hough Cox eg ession analysis can also in ol e ime-dependen
a iables, i will be ine i able o de elop new ways o exp ess he isk o
as hma a acks in ela ion o o he changes in he condi ion o he pa ien .
The e o e, mo e sophis ica ed s a is ical me hods will be included o
illus a e hese connec ions. Clus e analyses o pa ien s wi h as hma ha e
sugges ed ha pa ien s wi h as hma can be di ided in o di e en
pheno ypes.
24–26
Howe e , he s udies published hus a ha e been
c oss-sec ional and analysed hei subjec s a one single ime poin o a e
only a sho ollow-up. Analysis o pa ien da a wi h a long- e m ollow-up
ime wi h ime-dependen inciden s will equi e a mo e sophis ica ed way
o pe o ming clus e - ype analysis. Thus, we will e alua e whe he he
long- e m ollow-up will iden i y new and/o di e en clus e s among
pa ien s wi h adul -onse disease.
DISCUSSION
The cha ac e isa ion o pheno ypes o as hma is s ill in p ocess.
2,3
As he pheno ypes ha e been cha ac e ised ela i ely ecen ly
(i.e., be ween 2008 and 2014),
24–26
he e has no been enough
ime o long- e m ollow-up s udies o be conduc ed. Ou ecen
published sys ema ic li e a u e e iew
27
iden ified only one
ollow-up s udy
5
o newly diagnosed adul -onse as hma las ing
⩾5 yea s. Ano he 2-yea ollow-up s udy o adul -onse as hma
has been ecen ly published.
6
Thus, he p esen s udy will inc ease
ou knowledge on he long- e m p ognosis o new-onse as hma
diagnosed a adul age. The exclusion c i e ia in mos s udies wi h
as hma a e cu en smoking o smoking his o y ⩾10 pack-yea s,
as well as he p esence o co-mo bidi ies. Howe e , he
he apeu ic esponse in pa ien s wi h as hma who smoke emains
insu ficien .
28,29
A ecen su ey
9
indica ed ha o e 60% o
as hma su e e s ha e one o mo e addi ional co-mo bidi ies.
Fu he mo e, hese co-mo bidi ies associa e wi h unscheduled
as hma ca e among adul s.
8,9
The pa ien popula ion gene ally
included in clinical ials in as hma
7
has been shown o ep esen
only 1.3–5.4% o hose obs uc i e seen by a gene alis .
30
In he
p esen s udy, pa ien s we e no excluded because o smoking o
any significan co-mo bidi y, sugges ing ha he s udy popula ion
mo e closely ep esen s ha seen by a gene alis .
As hma is a common disease needing communi y solu ions.
14
Ea ly diagnosis, ac i e ea men and sel -managemen a e no
possible wi hou he ac i e ole o p ima y-ca e p o essionals. The
key o he implemen a ion o he Finnish As hma P og amme
14,15
was he p ima y-ca e ne wo k o local as hma co-o dina o s
(physicians and nu ses) in local heal h-ca e cen es.
13
The Finnish
As hma P og amme educed, e.g., he numbe o as hma hospi al
days and mo bidi y.
15,31
The published epo s
15,31
gi e indi ec
e idence o suppo he p ima y-ca e-cen ed o ganisa ion o ca e
o ch onic as hma, bu mo e e idence is needed. The Finnish
As hma P og amme was ex ensi ely used in he Seinäjoki Hospi al
dis ic and has been e alua ed.
13,16,32–34
This allows us o
e alua e he diagnos ic p ocess, as well as he ollow-up isi s
made bo h in p ima y and specialised heal h ca e. Acco ding
o he p inciples o he Finnish As hma P og amme,
13–15
a
hypo hesis o be es ed is ha he diagnos ic e alua ions in
pa ien s wi h adul -onse as hma can be pe o med in p ima y
ca e. Simila ly, ano he hypo hesis, suppo ed also by he
li e a u e,
35
is ha specialised nu se-cen ed ollow-up isi s a e
impo an in he ollow-up o mos pa ien s wi h adul -onse
as hma.
DISCLAIMER
None o he sponso s had any in ol emen in he planning, execu ion, d a ing
o w i e-up o his p o ocol.
CONTRIBUTIONS
HK d a ed he pape wi h con ibu ion and app o al om all au ho s. All au ho s
ha e been ac i ely in ol ed in he s udy in di e en capaci ies. LET and HK planned
and d a ed he o iginal s udy p o ocol wi h he help o TK in specific aspec s
conce ning ques ionnai es, s a is ical planning and heal h economic ma e s. PI is
esponsible o da a collec ion, s o age and managing, and mos o he da a
analysing p ocesses, as well as d a ing epo s o he s udy.
COMPETING INTERESTS
HK epo s pe sonal ees and non-financial suppo om Almi all, pe sonal ees om
As aZeneca, pe sonal ees om Chiesi Pha ma AB, pe sonal ees om
GlaxoSmi hKline, pe sonal ees and non-financial suppo om Boeh inge -
Ingelmheim, pe sonal ees om Lei as-Takeda, pe sonal ees om MSD (Me ck
Sha p & Dohme Co p.), pe sonal ees om No a is, pe sonal ees om
Mundipha ma, pe sonal ees om Medi h, pe sonal ees om Resmed Finland and
non-financial suppo om In e mune, ou side he submi ed wo k. LET epo s
pe sonal ees and non-financial suppo om Lei as-Takeda, pe sonal ees and non-
financial suppo om Mundipha ma, pe sonal ees and non-financial suppo om
No a is, and non-financial suppo om Boeh inge -Ingelheim, ou side he
submi ed wo k. The o he au ho s decla e no conflic s o in e es .
FUNDING
This ial is suppo ed by he Finnish An i-Tube culosis Associa ion Founda ion
(Helsinki, Finland), Tampe e Tube culosis Founda ion (Tampe e, Finland), he
Compe i i e S a e Resea ch Funding o Pi kanmaa Hospi al Dis ic (VTR224, VTR31
and VTR14, Tampe e, Finland) and he Medical Resea ch and De elopmen Funds o
Seinäjoki Cen al Hospi al (Seinäjoki, Finland).
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