Seinäjoki Adult Asthma Study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care

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). REFERENCES 1 Global Ini ia i e o As hma Global S a egy o As hma Managemen and P e- en ion. Re ised 2014. A ailable a www.ginas hma.o g. 2 Wenzel SE. As hma pheno ypes: he e olu ion om clinical o molecula app oaches. Na Med 2012; 18:716–725. 3 de Nijs SB, Venekamp LN, Bel EH. Adul -onse as hma: is i eally di e en ? Eu Respi Re 2013; 22:44–52. 4 Bisgaa d H, Bønnelykke K. Long- e m s udies o he na u al his o y o as hma in childhood. J Alle gy Clin Immunol. 2010; 126: 187–197. 5 Rönma k E, Lindbe g A, Wa son L, Lundbäck B. Ou come and se e i y o adul onse as hma— epo om he obs uc i e lung disease in no he n Sweden s udies (OLIN). 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P im Ca e Respi J 2008; 17:226–231. 35 Ma inez-Gonzalez NA, Tandjung R, Djalali S, Hube -Geismann F, Ma kun S, Rosemann T. E ec s o physician-nu se subs i u ion on clinical pa ame e s: a sys ema ic e iew and me a-analysis. PLoS One 2014; 9: e89181. This wo k is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle’s C ea i e Commons license, unless indica ed o he wise in he c edi line; i he ma e ial is no included unde he C ea i e Commons license, use s will need o ob ain pe mission om he license holde o ep oduce he ma e ial. To iew a copy o his license, isi h p://c ea i ecommons.o g/licenses/ by/4.0/ Seinäjoki Adul As hma S udy p o ocol H Kankaan an a e al 4 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