Daily physical activity and lung function decline in adult-onset asthma: a 12-year follow-up study

Full Te ms & Condi ions o access and use can be ound a h p://www. and online.com/ac ion/jou nalIn o ma ion?jou nalCode=zec 20 Eu opean Clinical Respi a o y Jou nal ISSN: (P in ) 2001-8525 (Online) Jou nal homepage: h p://www. and online.com/loi/zec 20 Daily physical ac i i y and lung unc ion decline in adul -onse as hma: a 12-yea ollow-up s udy Juho Loponen, Pinja Ilma inen, Leena E. Tuomis o, Onni Niemelä, Minna Tommola, Pen i Nieminen, Lau i Leh imäki & Hannu Kankaan an a To ci e his a icle: Juho Loponen, Pinja Ilma inen, Leena E. Tuomis o, Onni Niemelä, Minna Tommola, Pen i Nieminen, Lau i Leh imäki & Hannu Kankaan an a (2018) Daily physical ac i i y and lung unc ion decline in adul -onse as hma: a 12-yea ollow-up s udy, Eu opean Clinical Respi a o y Jou nal, 5:1, 1533753, DOI: 10.1080/20018525.2018.1533753 To link o his a icle: h ps://doi.o g/10.1080/20018525.2018.1533753 © 2018 The Au ho (s). Published by In o ma UK Limi ed, ading as Taylo & F ancis G oup. View supplemen a y ma e ial Published online: 24 Oc 2018. Submi you a icle o his jou nal A icle iews: 97 View C ossma k da a Daily physical ac i i y and lung unc ion decline in adul -onse as hma: a 12-yea ollow-up s udy Juho Loponen a,b , Pinja Ilma inen a , Leena E. Tuomis o a , Onni Niemelä c , Minna Tommola a , Pen i Nieminen d , Lau i Leh imäki b,e and Hannu Kankaan an a a,b a Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland; b Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland; c Depa men o Labo a o y Medicine and Medical Resea ch Uni , Seinäjoki Cen al Hospi al and Uni e si y o Tampe e, Seinäjoki, Finland; d Medical In o ma ics and S a is ics Resea ch G oup, Uni e si y o Oulu, Oulu, Finland; e Alle gy Cen e, Tampe e Uni e si y Hospi al, Tampe e, Finland ABSTRACT Backg ound: The e is a lack o knowledge on he associa ion be ween daily physical ac i i y and lung unc ion in pa ien s wi h as hma. Objec i e: This s udy aims o examine he associa ion be ween daily physical ac i i y and as hma con ol, lung unc ion, and lung unc ion decline in pa ien s wi h adul -onse as hma. Design: This s udy is pa o Seinäjoki Adul As hma S udy (SAAS), whe e 201 pa ien s we e ollowed o 12 yea s a e as hma diagnosis. Daily physical ac i i y was assessed a ollow-up by a s uc u ed ques ionnai e and used o classi y he popula ion in o subg oups o low (≤240 min) o high (>240 min) physical ac i i y. Th ee spi ome y e alua ion poin s we e used: 1. diagnosis, 2. he maximum lung unc ion du ing he i s 2.5 yea s a e diagnosis (Max 0-2.5 ), 3. ollow-up a 12 yea s. Resul s: High physical ac i i y g oup had slowe annual FEV 1 (p<0.001) and FVC (p<0.018) decline. Addi ionally, he high physical ac i i y g oup had highe FEV 1 alues a ollow-up, and highe FEV 1 /FVC a ios a ollow-up and diagnosis. The e was no di e ence in BMI, smoking, medica ion, o equency o physical exe cise be ween high and low physical ac i i y g oups. Di e ences emained signi ican a e adjus men s o possible con ounding ac o s. Conclusion: This is he i s demons a ion o an associa ion be ween long- e m FEV 1 decline and daily physical ac i i y in clinical as hma. Low physical ac i i y is independen ly associa ed wi h as e decline in lung unc ion. Daily physical ac i i y should be ecommended in ea men guidelines in as hma. ARTICLE HISTORY Recei ed 12 Janua y 2018 Re ised 26 Sep embe 2018 Accep ed 26 Sep embe 2018 KEYWORDS As hma; adul ; adul -onse ; FEV 1 decline; lung unc ion decline; physical ac i i y; sys emic in lamma ion In oduc ion Physical ac i i y has been shown o ha e se e al heal h bene i s such as educing he isk o ischemic hea dis- ease, diabe es and colon cance [1]. Mos o he p e ious esea ch on physical ac i i y has ocused on mode a e o igo ous in ensi y ac i i ies such as unning whe eas less is known on he low in ensi y e e yday mo emen which cons i u es he majo i y o he physical ac i i y accumu- la ed h oughou he day. A s uc u ed exe cise p og am is o en used as an in e en ion in s udies, bu he es o he daily physical ac i i y is equen ly o e looked. Caspe sen e al. [2] de ined physical ac i i y as ‘any bodily mo emen p oduced by skele al muscles ha equi es ene gy expendi u e’and physical exe cise as ‘a subse o physical ac i i y ha is planned, s uc u ed, and epe i i e and has as a inal o an in e media e objec i e he imp o emen o main enance o physical i ness’. These de ini ions a e cu en ly used by he Wo ld Heal h O ganiza ion (WHO) [3]. Physical ac i i y hus includes all human mo emen whe eas physical exe cise is high o mode a e in ensi y mo emen conduc ed wi h a pu pose o sho e pe iods o ime. I is impo an o di e en ia e be ween hese wo e ms since di e en in ensi ies o physical ac i i y ha e di e en e ec s on he body [4]. Thus, i is c ucial o s udy physical ac i i y as a whole ins ead o ocusing solely on he mode a e o igo ous in ensi y ac i i ies. In he con ex o his s udy he e m physical ac i i y includes all physical ac i i ies om loun- ging a ound he shopping mall o going o a jog and he e m exe cise only means mode a e o high in ensi y ac i i ies. CONTACT Juho Loponen [email p o ec ed] Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, FIN-60220 Seinäjoki, Finland This s udy is egis e ed a www.ClinicalT ials.go wi h iden i ie numbe NCT02733016. Supplemen a y da a o his a icle can be accessed he e. EUROPEAN CLINICAL RESPIRATORY JOURNAL 2018, VOL. 5, 1533753 h ps://doi.o g/10.1080/20018525.2018.1533753 © 2018 The Au ho (s). Published by In o ma UK Limi ed, ading as Taylo & F ancis G oup. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License (h p://c ea i ecommons.o g/licenses/by-nc/4.0/), which pe mi s un es ic ed non-comme cial 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 ch onic in lamma o y disease o he ai ways. O e he pas yea s esea che s ha e iden i ied se e al pheno ypes o as hma e ealing he he e ogene- i y o he disease [5,6]. Age o onse o as hma has been ound as a key di e en ia ing ac o be ween he phe- no ypes. I has been shown ecen ly ha he adul - onse pheno ypes di e as ly om childhood-onse as hma [5,6]. Childhood as hma is o en an a opic disease cha ac e ized by high numbe s o b onchial eosinophils and high se um le els o IgE wi h a good esponse o glucoco icoid ea men . In con as , pa ien s wi h disease onse a adul hood ha e o en mo e se e e as hma ha a ely emi s [7]. Recen ly, as hma diagnosed a adul -age has been shown o con- s i u e a majo i y among all new cases o as hma [8], and i seems ha se e al li es yle ac o s such as ciga - e e smoking and obesi y a e majo ac o s in adul - onse as hma [6,9]. Since he concep o adul -onse pheno ypes is a he new, only ew s udies exis on i and he e is no clea consensus on he bes he apy o hese pa ien s. Occasionally, adul -onse as hma may also be di icul o dis inguish om ch onic obs uc i e pulmona y disease (COPD) due o he o e lap o symp oms and isk ac o s [10]. Physical exe cise has been shown o be a bene icial ac o in he con ol o as hma [11]. Physical exe cise educes sys emic and b onchial in lamma ion, and inc eases maximal oxygen up ake [12,13]. Mos esea ch on daily physical ac i i y in as hma ocuses ei he on he isk o de eloping as hma o exe cise- induced b onchocons ic ion. The e a e no published long- e m s udies on daily physical ac i i y in pa ien s wi h clinical as hma. Daily physical ac i i y has been s udied ex ensi ely in COPD whe e highe le els o physical ac i i y decele a e lung unc ion decline and imp o e he quali y o li e [14,15]. P e ious epo s ha e shown ha high physical ac i i y is associa ed wi h be e lung unc ion, slowe lung unc ion decline, and lowe mo ali y also in he gene al popula ion [16,17]. Howe e , so a he e a e no p e ious s udies on he associa ion be ween physical ac i i y and lung unc ion change o e se e al yea s in pa ien s wi h clinical as hma. The aim o his s udy was o examine he associa ion be ween daily physical ac i i y and as hma con ol, lung unc ion, o lung unc ion decline in pa ien s wi h adul -onse as hma. Ma e ials and me hods S udy popula ion and design 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. The s udy p o ocol and he inclusion and exclusion c i e ia ha e been p e iously published [18]. S udy popula ion consis s o 260 consecu i e pa ien s who we e diagnosed wi h adul -onse as hma in 1999–2002 by a espi a o y physician (Figu e 1). Pa ien s we e ec ui ed om he diagnos ic isi . Diagnosis was based on ypical symp oms, and i was con i med by objec i e lung unc ion measu e- men s [18]. Smoke s (cu en o ex-) and pa ien s wi h co- mo bidi ies we e included in he s udy. The pa ien s we e ea ed and moni o ed acco ding o Finnish As hma P og am guidelines [19] ei he in he specialized ca e o in p ima y ca e. The collec ion o esea ch da a has been p e iously epo ed [7,9,10,20]. A diagnosis, da a was collec ed on lung unc ion, blood eosinophils, he ini ial pha maco he apy, and as hma symp oms by Ai ways Ques ionnai e 20 (AQ20) [21]. A opy was de ined as a leas one posi i e esponse (≥3 mm) in skin p ick owa d common ae oalle gens. A e 12 yea s pa ien s we e in i ed o a e-e alua ion (2012–2013), and 201 (77%) Figu e 1. Flow cha o he s udy. 2J. LOPONEN ET AL. pa ien s a i ed o he ollow-up isi . A ollow-up in o - ma ion was collec ed on as hma s a us, medica ion, and co-mo bidi ies by s uc u ed ques ionnai e. Lung unc ion, blood eosinophils and neu ophils, IgE le els, ac ion o exhaled ni ic oxide (FeNO), in e leukin-6 (IL-6), and high sensi i i y C- eac i e p o ein (hsCRP) we e measu ed. Pa ien s also illed As hma Con ol Tes (ACT) [22], AQ20, and a s uc u ed li es yle ques ionnai e. Speci ically ained esea ch nu se e iewed all ques ion- nai es wi h he pa ien s o limi misunde s andings. A w i en in o med consen was ob ained o a 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). De e mina ion o physical ac i i y The le el o physical ac i i y was assessed a ollow-up by a s uc u ed ques ionnai e. O e all daily physical ac i i y was assessed by an open ques ion: ‘How many minu es in a day do you spend mo ing?’A e p e-e alua ion, pa ien s we e di ided in o high and low daily physical ac i i y g oups. Cu o -poin was es ablished a 240 min o daily physical ac i i y pe day. The equency o physical exe cise was es ima ed by he ollowing ques ion: ‘How o en do you ake pa in leisu e ime ac i i ies o a leas hal an hou so ha you a e a leas somewha b ea hless and swea y?’This ques ion had eigh choices anging om ne e o e e yday. In his s udy, physical ac i i y ime and physical exe cise equency a e assessed as hei own a i- ables and a e no o be con used wi h each o he . De e mina ion o lung unc ion Lung unc ion was assessed using a spi ome e (Vmax Enco e 22, Viasys Heal hca e, Palm Sp ings, CA, USA) acco ding o in e na ional ecommenda ions [23]and Finnish e e ence alues [24]. Pos -b onchodila o mea- su emen s we e aken 15 min a e inhala ion o salbu a- mol (400 µg). A e he ini ia ion o as hma he apy, only p e-b onchodila o spi ome y was measu ed on mos o he pa ien s, and he e o e we e alua ed he changes in p e-b onchodila o spi ome y alues h oughou he s udy. Lung unc ion measu emen poin s we e: (1) base- line (i.e. ime o as hma diagnosis), (2) he maximum lung unc ion (Max 0-2.5 ) du ing he i s 2.5 yea s a e diagnosis (i.e. a e s a o an i-in lamma o y he apy) based on he highes p e-b onchodila o FEV 1 % p e- dic ed, and (3) a e 12 yea s o ollow-up (Figu e 2)[9]. S a is ical analyses Con inuous da a is exp essed as mean (SD) o a iables wi h no mal dis ibu ion and as median and in e qua - ile ange o a iables wi h skewed dis ibu ion. To assess di e ences be ween high and low physical ac i i y g oups, we used Mann-Whi ney es o con inuous a iables wi h skewed dis ibu ions, independen sam- ples - es o con inuous a iables wi h no mal dis i- bu ion, and Chi-Squa e es o ca ego ized a iables. Mul iple linea eg ession analysis was pe o med o analyze ac o s associa ed wi h FEV 1 decline om poin o Max 0-2.5 o he ollow-up isi . To a oid mul icollinea - i y, explana o y a iables we e checked o s ong (>0.7) mu ual co ela ion. Pa ien s whose BMI di e ed o e 3 SD (n=4)o whoseFEV 1 decline di e ed o e 3.3 SD (n=3) om mean we e emo ed om he linea eg ession ana- lysis as ou lie s o ensu e homoscedas ici y. Fo wa d, back- wa d and en e me hods we e used o imp o e model i . S a is ical analyses we e pe o med using SPSS so wa e, e sion 23 (IBM SPSS, Chicago, IL, USA). A p- alue <0.05 was ega ded as s a is ically signi ican . Resul s Pa ien cha ac e is ics Cha ac e is ics o he pa ien s who a ended he ollow- up isi a e shown a eTable 1. The median age o he s udy popula ion was 45 (SD 14) yea s a diagnosis and 58% we e emales. O he pa ien s, 53% had smoking his o y. The p opo ion o daily inhaled glucoco icoid use s was 8% a diagnosis, 96% a Max 0-2.5 , and 76% a Figu e 2. Rep esen a ion o he h ee lung unc ion measu emen poin s. EUROPEAN CLINICAL RESPIRATORY JOURNAL 3 ollow-up. Pa ien s epo ed a median o 360 (in e - qua ile ange 180–540) min o daily physical ac i i y. When pa ien s we e di ided in o wo g oups based on he le el o daily physical ac i i y (≤240 min s. >240 min) he g oup wi h he highe amoun o phy- sical ac i i y was younge and hey had ea lie as hma- onse (Table 1). The high physical ac i i y g oup included a highe pe cen age o emales han he low physical ac i i y g oup. The high physical ac i i y g oup also included less pa ien s wi h pos -b onchodi- la o FEV 1 /FVC<0.7 and a his o y o smoking o a leas 10 pack yea s (Table 1), cha ac e is ics which may indica e an as hma-COPD o e lap synd ome (ACOS) [25]. No ably, he e we e no di e ences in BMI, smok- ing s a us, medica ion o as hma, o equency o physical exe cise be ween he wo g oups (Table 1). Associa ion be ween physical ac i i y and lung unc ion Lung unc ion was signi ican ly di e en be ween he high and low physical ac i i y g oups. The high physical ac i i y g oup had highe p e- and pos -b onchodila o FEV 1 - alues a ollow-up (Table 2) bu only p e-b onchodila o FEV 1 - alue was highe a diagnosis (eTable 2). FEV 1 /FVC- a ios (p e- and pos -BD) we e signi ican ly di e en a diagnosis and a ollow-up be ween he g oups (Table 2, eTable 2). A e emo al o pa ien s wi h pos -b onchodi- la o FEV 1 /FVC<0.7 and a smoking his o y o a leas 10 pack yea s (eTable 3), which may indica e he p esence o ACOS [25], pos -b onchodila o FEV 1 /FVC- a io a ol- low-up emained signi ican ly lowe in he low ac i i y g oup (p= 0.032). This indica es ha possible ACOS is no explaining he esul s. Associa ion be ween physical ac i i y and lung unc ion decline When e alua ing lung unc ion decline om Max 0-2.5 o ollow-up isi in he high and low physical ac i - i yg oups,amo e apiddeclineinFEV 1 (ml and % o e e ence) and FVC (ml) in he g oup wi h less daily physical ac i i y was obse ed (Table 3, Figu e 3). The measu emen poin o Max 0-2.5 was chosen because he pa ien s had un ea ed as hma a diagnosis, and hei lung unc ion imp o ed signi i- can ly du ing he ollowing mon hs due o s a o as hma he apy. The e o e, compa isons be ween diagnos ic and ollow-up alues would be compa i- sons be ween un ea ed and ea ed as hma. The di e ences be ween he g oups emained signi ican when pa ien s wi h pos -b onchodila o FEV 1 / FVC<0.7 and a smoking his o y o a leas 10 pack yea s we e emo ed om he coho (eTable 4). The equency o physical exe cise had no e ec on lung unc ion decline (da a no shown). Associa ion be ween daily physical ac i i y, as hma con ol, and symp oms o as hma The high and low physical ac i i y g oups had no signi ican di e ence in as hma con ol o symp oms when measu ed by using AQ20 o e all sco es (eTable 5) o ACT (Table 4). Howe e , when analyz- ing he sepa a e ques ions in ACT and AQ20 ques- ionnai es, di e ences we e ound. The low physical ac i i y g oup had mo e sho ness o b ea h and a wo se sel -pe cei ed as hma con ol (ACT ques ions 2and5;Table 4). In AQ20 ques ionnai e he low physical ac i i y g oup epo ed mo e b ea hlessness in ques ions 3 (b ea hlessness du ing ga dening) (p= 0.002), 13 (b ea hlessness du ing housewo k) (p= 0.020) and 10 (di icul ies in ge ing a ound hehousedue oches p oblems)(p= 0.028) (eTable 5). Table 1. Basic subjec cha ac e is ics by physical ac i i y g oups. ≤240 min o physical ac i i y/day >240 min o physical ac i i y/day p- alue* Numbe o pa ien s 74 127 Age (yea s) 61 (13) 57 (14) 0.036 Age o onse (yea s) 49 (13) 44 (14) 0.029 Males 39 (53%) 45 (35%) 0.018 Du a ion o daily physical ac i i y (min) 135 (90–180) 480 (360–600) <0.001 Pa ien s exe cising a leas 3 imes pe week 43 (58%) 69 (54%) 0.660 BMI (kg/m 2 ) 28.7 (5.2) 28.4 (5.8) 0.807 Ex o cu en smoke 38 (51%) 68 (54%) 0.772 Pack yea s (o ex- and cu en smoke s) 20 (10–32) 15 (4–27) 0.067 Pos -b ochodila o FEV 1 / FVC <0.7 and a leas 10 pack yea s 17 (24%) 16 (13%) 0.050 Pa ien s wi h a leas one co-mo bidi y 51 (70%) 76 (60%) 0.172 Numbe o co-mo bidi ies, COPD included 1(0–3) 1 (0–2) 0.091 Daily ICS use s 60 (81%) 93 (73%) 0.233 ICS dose (μg budesonide equi alen ) 800 (400– 1000) 800 (280– 1000) 0.393 Pa ien s who ecei ed o al co icos e oids 30 (41%) 35 (28%) 0.062 Daily add-on medica ion (includes LABA) 39 (53%) 62 (49%) 0.661 A opy 18 (27%) 49 (42%) 0.055 *S a is ical signi icances we e e alua ed using Mann-Whi ney es , inde- penden samples - es o Chi-squa e es , espec i ely. Resul s a e dis- played as median (in e qua ile ange), mean (SD), o n(%). BMI: body mass index; FEV 1 : o ced expi a o y olume in 1 s; FVC: o ced i al capaci y; COPD: ch onic obs uc i e pulmona y disease; ICS: inhaled co icos e oid; LABA: long ac ing be a-ad enocep o agonis . 4J. LOPONEN ET AL. Associa ion o daily physical ac i i y, sys emic and ai way in lamma o y pa ame e s Blood neu ophils, eosinophils, FeNO, IL-6, and hsCRP we e measu ed. No di e ences we e obse ed in any o hese bioma ke s o in lamma- ion be ween he high and low ac i i y g oups (eTable 6). Fac o s associa ed wi h lung unc ion decline To assess whe he lowe physical ac i i y emains s a is ically signi ican ac o associa ed wi h mo e apid lung unc ion decline in pa ien s wi h adul - Figu e 3. Changes in mean P e-BD FEV 1 (mL) du ing 12 yea s o ollow-up in he g oups o <240 o ≥240 min o daily physical ac i i y. Table 2. Lung unc ion a ollow-up by physical ac i i y g oups. ≤240 min o physical ac i i y/day >240 min o physical ac i i y/day p- alue* FVC (% e ) p e-BD 95 (16) 98 (15) 0,222 FVC (% e ) pos -BD 97 (16) 99 (14) 0,269 FEV1 (% e ) p e-BD 81 (19) 88 (16) 0,004 FEV1 (% e ) pos -BD 84 (18) 91 (16) 0,004 FEV1/FVC p e-BD 0.71 (0.63–0.78) 0.75 (0.69–0.79) 0,002 FEV1/FVC pos -BD 0.72 (0.65–0.79) 0.77 (0.71–0.81) 0,001 *S a is ical signi icances we e e alua ed using Mann-Whi ney es o independen samples - es . Resul s a e displayed as median (in e qua ile ange) o mean (SD).FVC: o ced i al capaci y; BD: b onchodila o ; FEV1: o ced expi a o y olume in 1 s. Table 3. Annual p e-BD lung unc ion decline om Max 0-2.5 o ollow-up by physical ac i i y g oup. ≤240 min o physical ac i i y/day >240 min o physical ac i i y/day p- alue* ΔFVC/yea , p e-BD (ml) −43.6 (42.1) −29.3 (39.7) 0.018 ΔFVC/yea , p e-BD (%) −0.12 (1.14) 0.03 (0.95) 0.325 ΔFEV1/yea , p e-BD (ml) −58.8 (37.3) −41.4 (34.2) 0.001 ΔFEV1/yea , p e-BD (%) −0.83 (1.13) −0.39 (0.97) 0.005 ΔFEV1/ΔFVC - a io/yea , p e-BD −0.0052 (−0.0101 o −0.0019) −0.0041 (−0.0075 o −0.0016) 0.062 *S a is ical signi icances we e e alua ed using Mann-Whi ney es o independen samples - es . Resul s a e displayed as median (in e qua ile ange) o mean (SD). FVC: o ced i al capaci y, BD: b onchodila o , FEV1: o ced expi a o y olume in 1 s. Table 4. As hma con ol and symp oms a ollow-up. ≤240 min o physical ac i i y/day >240 min o physical ac i i y/day p- alue* Uncon olled as hma** 27 (36.5) 32 (25.2) 0.234 ACT sco e a ollow-up 22 (17–24) 22 (20–24) 0.159 ACT Q2 sho ness o b ea h a leas 3–6 imes/week 22 (29.7) 16 (12.6) 0.005 ACT Q5 as hma somewha con olled, poo ly con olled, no a all con olled 25 (33.8) 25 (19.7) 0.029 *S a is ical signi icances we e e alua ed using Chi-squa e es o Mann- Whi ney es . Resul s a e displayed as n(%) o median (in e qua ile ange). ACT: as hma con ol es . **As assessed acco ding o GINA 2010 as p e iously desc ibed [18]. EUROPEAN CLINICAL RESPIRATORY JOURNAL 5 onse as hma a e adjus ing o age, sex, smoking, BMI, a opy, and use o inhaled glucoco icoid, we ca ied ou mul iple linea eg ession analysis. Daily physical ac i i y ≤240 min emained s a is ically sig- ni ican ly associa ed wi h mo e apid decline in FEV 1 in adjus ed analysis. O he explana o y ac o s o as e lung unc ion decline we e sex (male), a opy, and a highe BMI. (Table 5)Du ing hebuildingo his linea eg ession model o he a iables we e ied bu inclusion o hese a iables ga e he bes model. Discussion The aim o his s udy was o examine he signi icance o daily physical ac i i y in adul -onse as hma. Ou da a indica es ha highe daily physical ac i i y is associa ed wi h slowe decline in lung unc ion e en when adjus - ing o sex, age, BMI, a opy, medica ion, and smoking. High and low physical ac i i y g oups in his s udy had no di e ence in BMI, smoking, medica ion, in e leukin- 6, hs-CRP, IgE, blood neu ophil o eosinophil coun s, FeNO le els, o he equency o exe cise. The ac ha he e was no di e ence in BMI was su p ising since high BMI has been linked o low physical ac i i y [26]. The low cu -o poin o 240 min could explain he absence o di e ences in in lamma o y ma ke s. Also, di e - ences in die a y habi s and ene gy expendi u e can explain he absence o BMI di e ence. High physical ac i i y g oup had a highe pe cen age o emales, which sugges s ha emales do mo e low in ensi y phy- sical ac i i ies in his se up. The e was no di e ence in bioma ke s o sys emic in lamma ion be ween he g oups wi h lowe and highe daily physical ac i i y e en hough i has been shown ha egula physical exe cise can educe sys emic in lamma ion [27]. The equency o exe cise was no associa ed wi h lung unc- ion decline in his s udy, which was expec ed since he e we e no signi ican di e ences in he equency o exe cise be ween he wo g oups o high and low le els o daily physical ac i i y. To ou knowledge his s udy is he i s o examine he associa ion be ween daily physical ac i i y and FEV 1 decline in clinical as hma. Ou inding is sup- po ed by a simila associa ion ecen ly epo ed be ween leisu e ime ac i i y and lung unc ion change in pe sons ha ing sel - epo ed as hma in a popula ion based coho o he No d-T øndelag Heal h S udy [28]. Ou s udy has se e al s eng hs. All as hma ics we e ca e ully diagnosed by a espi a o y physician, and he diagnosis was e i ied wi h spi ome y, se ial peak low measu es, o measu es o b onchial hype eac i i y. Mos pa ien s we e ea ed wi h a leas inhaled gluco- co icoids be ween Max 0-2.5 and ollow-up. Smoke s and pa ien s wi h co-mo bidi ies we e no excluded making his a eal li e s udy. Du ing 1999–2002 a conside able p opo ion o no el as hma diagnoses in he egion we e made a Seinäjoki Cen al Hospi al and >94% o he pa ien s ob aining diagnosis o as hma in his hospi al a he s udy pe iod ook pa in he s udy [18]. The e o e, his s udy popula ion well ep esen s a p ima y ca e popula ion wi h as hma. Howe e , pa ien s wi h e y mild o seasonal as hma may ha e been excluded since pa ien s had o ill he s ic lung unc ion c i e ia [18]. The cu -o poin o high and low le els o daily physical ac i i y in his s udy was chosen a 240 min o physical ac i i y pe day. The cu -o poin di ided he coho in o he lowes one hi d agains he wo highes hi ds. The pa ien s we e made well awa e o wha he ques ion mean so ha all misunde s andings could be minimized. Pa ien s in his s udy had a median o 360 min o daily physical ac i i y, which is simila o le els measu ed by accele ome e s in pa ien s wi h ch onic diseases ( ange 308–395 min) [29–31]. The cu -o poin o 240 min o physical ac i i y is a ela- i ely low le el conside ing ha e en olde ca e home esiden s in he UK [32] and aged (73–98 yea -olds) Icelandic people [33] accumula ed 122–190 min o daily physical ac i i y. The cu -o poin was in en ion- ally se a his ela i ely low le el o allow examina ions o he e ec s o e y low amoun s o physical ac i i y. The mos signi ican limi a ion o his s udy is he absence o spi ome ic pos -b onchodila o alues a Max 0-2.5 . This is due o he ac ha he pa ien s we e ea ed acco ding o he Finnish as hma guidelines whe e sys ema ic eco ding o pos -b onchodila o y alues was no ecommended a ha ime. E en hough he pa ien s’es ima es on hei physical ac i i y a e close o measu ed alues on simila coho s, i would ha e been op imal o eco d daily physical ac i i y using accele ome e s. In addi ion, physical ac i i y was Table 5. Associa ion o explana o y ac o s wi h lung unc ion decline om Max 0-2.5 o ollow-up in mul iple linea eg ession. Va iable Es ima e (Δml) 95% Con idence In e al p- alue (Cons an ) −22.39 −69.16 o 24.39 0.346 Physical ac i i y o e 240 min/day 17.90 8.00 o 27.80 <0.001 Sex ( emale) 13.12 3.08 o 23.16 0.011 Age a ollow-up −0.23 −0.59 o 0.13 0.209 BMI a ollow-up −1.01 −2.02 o −0.01 0.048 No a daily ICS use a ollow-up 1.40 −10.15 o 12.95 0.811 A opy −11.38 −21.72 o −1.04 0.031 E e smoke a ollow-up −1.97 −11.70 o 7.76 0.690 n = 173 (ou lie s: n = 7, missing da a: n = 21), BMI: body mass index, ICS: inhaled co icos e oid. 6J. LOPONEN ET AL. assessed only a ollow-up isi . Howe e , i has been shown ha mos o ou heal h ela ed habi s a e o med du ing childhood o ea ly adul hood and decline slowly o emain cons an du ing adul hood. Signi ican changes in heal h ela ed habi s a e unlikely o happen wi hou a comp ehensi e li es yle in e en ion [34,35]. The e o e, i can be assumed ha he high physical ac i i y g oup had highe ac i i y le els also a diagnosis. Simila indings o ou s udy ha e been p e iously ob ained in pa ien s wi h COPD and in gene al popu- la ion [14,16]. Du ing an 11-yea ollow-up in pa ien s wi h COPD, low physical ac i i y g oup had a as e decline in lung unc ion (−4.8 ml/yea as e d op o FEV 1 ,−7.7 ml/yea as e d op o FVC) when com- pa ed o high physical ac i i y g oup [14]. Slowe FEV 1 decline wi h highe physical ac i i y has been de ec ed on gene al popula ion also [16]. In ou s udy FEV 1 declined 17.4 ml/yea as e , and FVC declined 14.3 ml/yea as e in he low ac i i y g oup. Sex (male), high equency o disease exace ba ions, old age, absence o glucoco icoid ea men , and smoking ha e been ound o accele a e FEV 1 decline in as h- ma ics [9,36,37]. A e adjus ing o hese ac o s wi h mul iple linea eg ession analysis, he associa ion o physical ac i i y wi h FEV 1 decline emained signi i- can . Exace ba ions we e no included in he linea eg ession, bu he e was no di e ence in he p opo - ion o hose pa ien s ecei ing o al co icos e oid ea men du ing he ollow-up pe iod be ween he physical ac i i y g oups sugges ing ha he e was no di e ence in exace ba ions. The indings a e clinically signi ican , since emis- sion a e in adul onse as hma is low [7] and mos pa ien s su e om as hma o decades. The linea i y o he e ec o physical ac i i y on lung unc ion emains unclea . We ound one daily physical ac i i y in e en ion s udy in pedia ic pa ien s wi h as hma [38], and no change in FEV 1 was egis e ed du ing a one-week ollow-up. Also, in a ecen c oss-sec ional s udy [39] daily physical ac i i y had no e ec on spi ome ic alues o heal hy adolescen s. In pa ien s wi h childhood-onse as hma he e is a posi i e asso- cia ion be ween physical ac i i y and lung unc ion du ing a 3 week pe iod [40], bu his could be due o se e al acu e b onchodila ions o pa ien s uncon- sciously adjus ing hei daily ac i i y acco ding o hei lung unc ion ea lie ha day. In ligh o his e idence i seems likely ha daily physical ac i i y does no cause long e m imp o emen s in FEV 1 , bu ha i slows down FEV 1 decline. Howe e , as he da a on physical ac i i y was collec ed a ollow-up isi , he ela ion be ween lung unc ion decline and physical ac i i y le el may also e lec ha hose wi h mo e apid lung unc ion decline a e p one o dec ease hei le el o physical ac i i y. Conclusion This s udy highligh s he impo ance o ac i e li es yle and he pe ils o seden a y habi s. Mode n physical ac i i y guidelines ocus on highe in ensi y ac i i ies, bu i would be impo an o include low in ensi y ac i i ies o hese guidelines o mo e holis ic app oach. Mo e s udies wi h a p ecise analysis o he ac i i y in ensi y a e needed o u he explo e he e ec o physical ac i i y on pa ien s wi h as hma. Acknowledgmen s Aino Sepponen (Dep o Respi a o y Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland) is g a e ully acknowl- edged o he help h ough all he s ages o his wo k. Funding This s udy was sponso ed by Tampe e Tube culosis Founda ion (Tampe e, Finland), he Finnish An i- Tube culosis Associa ion Founda ion (Helsinki, Finland), Jalma i and Rauha Ahokas Founda ion (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 (VTR,Tampe e,Finland),and heMedicalResea ch Fund o Seinäjoki Cen al Hospi al (Seinäjoki, Finland) [G an numbe 1717/6044]. None o he sponso s pa ici- pa ed in he planning, execu ion, d a ing, o w i ing o his s udy. Con ibu o s JL analyzed and in e p e ed he da a, and w o e he manusc ip .HK,LL,ONandLET designed he s udy. PI con ibu ed o he s udy design, in e p e a ion o he da a, and w i ing o he manusc ip . MT con ibu ed o he planning o lung unc ion decline analyses. PN p o- ided s a is ical ad ice and commen ed on d a s o he manusc ip .HK,PI,LL,ON,LETandMTcommen ed on d a s o he manusc ip . All au ho s accep ull esponsibili y o he conduc o he s udy, had access o he da a, and con olled he decision o publish. JL is he gua an o . Compe ing in e es s Weha e eadandunde s oodEu opeanClinical Respi a o y Jou nal policy on decla a ion o in e es s and decla e he ollowing. JL, ON and PN ha e no hing o disclose. PI epo s pe sonal ees om Mundipha ma, pe - sonal ees om O ion, pe sonal ees om As aZeneca, ou side he submi ed wo k. LT epo s o he om Takeda, Chiesi and O ion, o he om TEVA, o he om EUROPEAN CLINICAL RESPIRATORY JOURNAL 7 Filha y, ou side he submi ed wo k. MT epo s pe sonal ees om As a Zeneca, pe sonal ees om Boeh inge Ingelheim, pe sonal ees om Filha y, pe sonal ees om GlaxoSmi hKline, ou side he submi ed wo k. LL epo s pe sonal ees om Boeh inge -Ingelheim Finland, pe sonal ees om O ion Pha ma, pe sonal ees om GSK, pe sonal ees om Chiesi, pe sonal ees om Mundipha ma, pe sonal ees om As a Zeneca, pe sonal ees and non- inancial suppo om No a is, pe sonal ees and non- inancial suppo om Te a, pe sonal ees om ALK, ou side he submi ed wo k. HK epo s pe so- nal ees and non- inancial suppo om Almi all, g an s, pe sonal ees and non- inancial suppo om As aZeneca, pe sonal ees om Chiesi Pha ma AB, pe sonal ees om GlaxoSmi hKline, pe sonal ees and non- inancial suppo om Boeh inge -Ingelheim, pe sonal ees om Lei as- Takeda, pe sonal ees om MSD, 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, non- inancial suppo om In e mune, pe sonal ees om Roche, pe sonal ees om O ion Pha ma, ou side he submi ed wo k. No es on con ibu o s Juho Loponen, BM. Cu en ly a medical s uden a Uni e si y o Tampe e. Academic in e es s include physical ac i i y, in lamma ion and as hma. Pinja Ilma inen, PhD. Resea che a Seinäjoki Cen al Hospi al, Finland. He esea ch ocuses on in lamma o y lung diseases and especially pheno ypes and media o s o adul -onse as hma. Leena E Tuomis o, MD, PhD. Senio espi a o y specialis a Seinäjoki Cen al Hospi al. He esea ch in e es s include adul -onse as hma om diagnosis o p ognosis. Onni Niemelä, MD, Ph.D. P o esso o Labo a o y Medicine a Seinäjoki Cen al Hospi al and Uni e si y o Tampe e. Resea ch in e es s include li e diseases, as hma, exe cise physiology and in lamma ion. Minna Tommola, MD. Consul an in espi a o y medicine in Cen al Finland Cen al Hospi al, Jy äskylä, Finland. Resea ch in e es s include smoking and as hma. Pen i Nieminen, PhD. Cu en ly an associa e p o esso in medical in o ma ics and da a-analysis a he Uni e si y o Oulu. Resea ch in e es s include scien i ic communica ion, bios a is ics and medical educa ion. Lau i Leh imäki, MD, PhD. Consul an in espi a o y med- icine a Alle gy Cen e, Tampe e Uni e si y Hospi al, Finland. He also wo ks as associa e p o esso a Facul y o Medicine and Li e Sciences a Uni e si y o Tampe e. His main clinical in e es is se e e as hma and his esea ch ocuses on in lamma o y lung diseases. Hannu Kankaan an a, MD, PhD. Head o Respi a o y Medicine a Seinäjoki Cen al Hospi al, Seinäjoki, Finland. He also wo ks as a p o esso o espi a o y medicine a he Facul y o Medicine and Li e Sciences a Uni e si y o Tampe e. His main esea ch in e es is adul -onse as hma. ORCID Juho Loponen h p://o cid.o g/0000-0003-3129-2221 Pinja Ilma inen h p://o cid.o g/0000-0002-8758-2431 Minna Tommola h p://o cid.o g/0000-0003-4201-389X Hannu Kankaan an a h p://o cid.o g/0000-0001-5258- 0906 Re e ences [1] Kyu HH, Bachman VF, Alexande LT, e al. Physical ac i i y and isk o b eas cance , colon cance , diabe es, ischemic hea disease, and ischemic s oke e en s: sys- ema ic e iew and dose- esponse me a-analysis o he Global Bu den o Disease S udy 2013. BMJ. 2016;354:3857. [2] Caspe sen CJ, Powell KE, Ch is enson GM. Physical ac i i y, exe cise, and physical i ness: de ini ions and dis inc ions o heal h- ela ed esea ch. Public Heal h Rep. 1985;100:126–131. [3] Wo ld Heal h O ganiza ion. 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