Prevalence of patients eligible for anti-IL-5 treatment in a cohort of adult-onset asthma

O iginal A icle P e alence o Pa ien s Eligible o An i-IL-5 T ea men in a Coho o Adul -Onse As hma Pinja Ilma inen, PhD a , Leena E. Tuomis o, MD, PhD a , Onni Niemelä, MD, PhD b,c , and Hannu Kankaan an a, MD, PhD a,c Seinäjoki and Tampe e, Finland Wha is al eady known abou his opic? An ibodies agains he IL-5 pa hway ha e been de eloped o he ea men o la e-onse eosinophilic co icos e oid- esis an as hma. Es ima es o 5% o 10% on he p e alence o se e e as hma ha e been p oposed wi h unclea basis. Wha does his a icle add o ou knowledge? The p e alence o se e e as hma was 5.9%, and 2% ulfilled he c i e ia o an i-IL-5 he apy in an unselec ed coho o adul -onse as hma. Only 1 pa ien me c i e ia o bo h g oups, and bo h g oups ep esen a high bu den o heal h ca e. How does his s udy impac cu en managemen guidelines? This s udy on he p e alence o se e e as hma and an i-IL-5 eligible pa ien s indica es ha o 100 pa ien s wi h adul -onse as hma, 6 ha e se e e as hma and 2 a e eligible o an i-IL-5 he apy. BACKGROUND: An ibodies agains he IL-5 pa hway ha e been de eloped o he ea men o la e-onse eosinophilic co icos e- oid- esis an as hma. Howe e , he p e alence o se e e as hma and he p opo ion o pa ien s who could benefi om such ea men among he gene al popula ion o as hma ics emain unknown. OBJECTIVE: To e alua e he p e alence and cha ac e is ics o pa ien s eligible o an i-IL-5 ea men and se e e as hma in an unselec ed coho o adul -onse as hma. METHODS: 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 (n [203). P e - alence was es ima ed based on in o ma ion collec ed a 12-yea ollow-up isi . Heal h ca e use was collec ed om he whole 12-yea ollow-up pe iod. RESULTS: The p e alence o an i-IL-5- ea able pa ien s was 2%, when he ollowing c i e ia we e used: daily use o medium- o-high inhaled co icos e oid (ICS) dose and long-ac ing b 2 - agonis , ‡2 exace ba ions/p e ious yea and blood eosinophil coun ‡300 cells/ m L o ac ion o exhaled ni ic oxide ‡50 ppb. The p e alence o se e e as hma, as defined acco ding o Eu opean Respi a o y Socie y/Ame ican Tho acic Socie y, was 5.9%, and only 1 pa ien me c i e ia o bo h g oups. When compa ed wi h an i-IL-5 eligible pa ien s, se e e as hma ics we e mo e o en cu en smoke s a diagnosis, obese, used highe ICS dose, and had highe blood neu ophils 12 yea s a e diagnosis. Bo h g oups di e ed om nonse e e as hma by a highe numbe o all and unplanned espi a o y- ela ed isi s o heal h ca e. Se e e as hma ics showed he highes numbe o hospi aliza ions. CONCLUSIONS: In a coho o unselec ed consecu i e pa ien s wi h adul -onse as hma, 5.9% ulfilled c i e ia o se e e as hma and 2% qualified o an i-IL-5 ea men . Bo h g oups ep esen a high bu den o heal h ca e and specifically a ge ed ea men could lead o lowe use o heal h ca e a long e m. Ó2019 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 2019;7:165-74) Key wo ds: As hma; Adul ; Adul -onse ; P e alence; In e leukin-5; Eosinophil; Se e e; Mepolizumab; Reslizumab; Ben alizumab 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 Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland The analysis and w i e-up o his s udy was unded by As aZeneca, Mölndal, Sweden. As aZeneca was gi en an oppo uni y o commen he s udy epo be o e i was submi ed o publica ion. The Seinäjoki Adul As hma S udy (SAAS) p ojec has been unded by Finnish An i-Tube culosis Associa ion Founda ion (Helsinki, Finland), Tampe e Tube culosis Founda ion (Tampe e, Finland), 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); nei he As aZeneca no he o he unde s ha e any in ol emen in he planning o execu ion o he SAAS s udy. Conflic s o in e es : P. Ilma inen, L. E. Tuomis o, and H. Kankaan an a epo a g an om As aZeneca ela ed o he submi ed wo k. Ou side he submi ed wo k P. Ilma inen epo s paymen o lec u es om Mundipha ma, O ion Pha ma, and As a Zeneca. L. E. Tuomis o epo s g an s om Chiesi Pha ma AB and O ion Pha ma and paymen o lec u es om Filha y, As a Zeneca, and Mundipha ma. O. Niemelä epo s no conflic o in e es . H. Kankaan an a epo s pe sonal ees and nonfinancial suppo om Almi all, As aZeneca, and Boeh inge -Ingelheim; pe sonal ees om Chiesi Pha ma AB, GlaxoSmi hKline, Lei as-Takeda, MSD, No a is, Mundipha ma, Medi h, Resmed Finland, Roche, and O ion Pha ma; and nonfinancial suppo om In e mune. Recei ed o publica ion Oc obe 4, 2017; e ised May 22, 2018; accep ed o publica ion May 23, 2018. A ailable online June 9, 2018. Co esponding au ho : Pinja Ilma inen, PhD, Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, FIN-60220 Seinäjoki, Finland. E-mail: pinja. ilma inen@epshp.fi. 2213-2198 Ó2019 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 ps://doi.o g/10.1016/j.jaip.2018.05.032 165 Abb e ia ions used ACT- As hma Con ol Tes ATS- Ame ican Tho acic Socie y CI- Confidence in e al ERS- Eu opean Respi a o y Socie y FeNO- F ac ion o exhaled ni ic oxide FEV 1 - Fo ced expi a o y olume in 1 second GINA- Global Ini ia i e o As hma ICS- Inhaled co icos e oid LABA- Long-ac ing b 2 -agonis OCS- O al co icos e oid SA- Se e e as hma SAAS- Seinäjoki Adul As hma S udy Recen ly, as hma has been conside ed o mani es in di e en pheno ypes equi ing di e en ea men app oaches. Age a onse is a c i ical ac o sepa a ing di e en pheno ypes. As hma s a ing in childhood o en coexis s wi h a opy/alle gy, is domi- na ed by Th2 inflamma ion, and esponds well o he apy wi h inhaled co icos e oids (ICS). Howe e , as hma s a ing a adul hood is mo e o en nona opic, less esponsi e o ICS ea men , and has less a o able p ognosis. Adul -onse as hma has been p oposed o consis o subpheno ypes such as obesi y- ela ed, smoking, se e e obs uc i e, mild- o-mode a e/ well-con olled, and a opic as hma. 1-3 La e-onse eosinophilic (o en se e e) as hma has been conside ed o be one o he adul -onse as hma pheno ypes. 1,3 La e-onse eosinophilic as hma is cha ac e ized by pe sis en eosinophilic ai way inflamma ion despi e he use o co icos e- oid he apy. I is associa ed wi h a lowe a e o alle gy; equen ly he e is no ob ious amily his o y o as hma and i is o en se e e om onse . 3 Many o hese pa ien s su e om equen exace ba ions and may espond poo ly o inhaled s e- oid he apy. This condi ion is associa ed wi h subs an ial heal h ca e cos s due o unplanned heal h ca e isi s, eme gency depa men isi s, and hospi al admissions. P e ious s udies ha e emphasized he impo ance o eosinophils in media ing exace - ba ions, 4 and he e o e he esolu ion o eosinophilic inflam- ma ion has been sugges ed as a p omising he apeu ic s a egy o educe exace ba ions. IL-5 is a c i ical cy okine o eosinophil ma u a ion, su i al, and ac i a ion. 5,6 Neu aliza ion o i s e - ec s by an i-IL-5 an ibodies such as mepolizumab o eslizumab leads o he educed numbe o eosinophils. Ben alizumab is an an i-IL5 ecep o an ibody ha deple es eosinophils h ough an ibody-dependen cell-medica ed cy o oxici y. In clinical ials in pa ien s wi h se e e glucoco icoid- esis an eosinophilic as hma, hese an ibodies dec eased exace ba ion a e, had a glucoco icoid-spa ing e ec , and imp o ed as hma- ela ed quali y o li e and lung unc ion. 7-11 Typically, inclusion c i e ia o an i-IL-5 s udies ha e been he use o mode a e- o-high ICS dose oge he wi h long-ac ing b 2 - agonis (LABA) o ano he con olle and a leas 2 exace ba ions equi ing o al co icos e oid (OCS) du ing he p e ious yea . 7-11 Fo blood eosinophil le els, 150, 300, o 400 cells/ m L ha e been used as a c i e ion o inclusion o al e na i ely, ac ion o exhaled ni ic oxide (FeNO) 50 ppb, o spu um eosinophil coun 3%. 7-11 The p opo ion o pa ien s wi h eosinophilic as hma who could benefi om an i-IL-5 he apy among a gene al popula ion o adul -onse as hma ics has, howe e , emained unknown. The p opo ion o pa ien s wi h se e e as hma (SA) has been app oxima ed o be 5% o 10% among all pa ien s wi h as hma. 12 Howe e , he e ha e been di ficul ies in assessing he ue p e alence due o he lack o accu a e defini ion 13 and exclusion o significan pa ien g oups (smoking, aged in- di iduals, and pa ien s wi h significan como bidi ies) om mos published clinical coho s. A Eu opean Respi a o y Socie y/ Ame ican Tho acic Socie y (ERS/ATS) commi ee defined SA as as hma equi ing ea men wi h high ICS dose oge he wi h add-on medica ion o OCS o p e en i om becoming un- con olled o which emains uncon olled despi e his he apy. 12 This s udy was ca ied ou o e alua e he p opo ion o pa ien s ulfilling combina ions o possible clinical c i e ia o he use o an i-IL-5 he apies as well as he p e alence o SA in a eal- li e coho o pa ien s wi h clinically defined adul -onse as hma 12 yea s a e diagnosis. Ano he aim was o compa e he clinical cha ac e is ics o pa ien s wi h non-SA and SA and hose ul- filling c i e ia o an i-IL-5 he apy. METHODS S udy design and pa ien s This s udy is pa o Seinäjoki Adul As hma S udy (SAAS). SAAS (ClinicalT ials.go ID NCT02733016) 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 pa ien s ha ing new-onse as hma diagnosed a adul age (15 yea s). Ins i u ional pe mis- sions 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. Mo e han 94% o he pa ien s diagnosed wi h no el as hma in he s udy si e we e ec ui ed o he s udy. 14 In 2001, he s udy popula ion ep esen ed >38% o no el diagnoses o as hma made o adul s in he whole geog aphical a ea. The p o ocol, inclusion and exclusion c i e ia, and he backg ound da a o he SAAS s udy ha e been published sepa a ely. 14 B iefly, as hma was diagnosed by a espi a o y specialis du ing 1999-2002 based on ypical symp oms, and diagnosis was confi med by objec i e lung unc ion measu emen s. 14 A e diag- nosis, he pa ien s we e ea ed and moni o ed by hei own physician acco ding o he p inciples o Finnish As hma P og am 15 and guidelines. 16 The o al coho consis ed o 257 pa ien s and 203 pa ien s e u ned o he 12-yea ollow-up isi . 17 A his isi , as hma s a us and 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 and inflamma o y pa ame e s we e measu ed. The basic cha ac e is ics, 12-yea p ognosis ( emission and as hma con ol), de ailed smoking cha ac e is ics, and como bidi ies o he s udy coho ha e been p e iously published. 17-19 Da a we e also ga he ed om all as hma- ela ed isi s o heal h ca e (p ima y ca e, p i a e heal h ca e, and hospi al clinics), exac- e ba ions, acu e espi a o y ac in ec ions, and hospi aliza ions du ing he whole 12-yea ollow-up pe iod. Da a om he 12-yea ollow-up isi and he ime in be ween he isi s we e used in assessing he p opo ion o an i-IL-5 eligible pa ien s and SA. To assess adhe ence in hese pa ien s, he numbe s o ICS-con aining inhale s/canis e s and OCS bough om pha macies in 2012-2013 we e e ie ed om Social Insu ance Ins i u ion o Finland. Exace ba ions and medica ion The numbe o exace ba ions was sel - epo ed employing a s uc u ed ques ionnai e filled a 12-yea ollow-up isi o e alua ed om he pa ien eco ds (p e ious yea ). Medica ion o as hma was J ALLERGY CLIN IMMUNOL PRACT JANUARY 2019 166 ILMARINEN ET AL sel - epo ed a s uc u ed ques ionnai e. I he in o ma ion was missing, medica ion was e alua ed om he p e ious as hma- ela ed isi o heal h ca e. Lung unc ion, in lamma o y pa ame e s, and o he clinical measu emen s Lung unc ion measu emen s we e pe o med wi h a spi ome e acco ding o in e na ional ecommenda ions. 20 De ailed in o ma- ion on he lung unc ion measu emen s, de e mina ion o inflam- ma o y pa ame e s, como bidi ies, and on o he clinical measu emen s can be ound in his a icle’s Online Reposi o y a www.jaci-inp ac ice.o g. Se e e as hma SA was defined acco ding o he ATS/ERS Task Fo ce as as hma equi ing ea men wi h high ICS dose oge he wi h add-on medica ion o OCS o p e en i om becoming uncon olled o which emains uncon olled despi e his he apy. 12 Uncon olled as hma was defined as one o he ollowing a he 12-yea ollow-up isi : (1) poo symp om con ol (As hma Con ol Tes [ACT] sco e <20), (2) equen exace ba ions (2 bu s s o OCS in he p e ious yea ), (3) se ious exace ba ions (1 hospi aliza ion in he p e ious yea due o as hma), and (4) ai flow limi a ion (p ee o ced expi a- o y olume in 1 second (FEV 1 )<80% p edic ed). 12 P ima y and seconda y endpoin s The p ima y endpoin o his s udy was o assess he p opo ion o pa ien s who could benefi om an i-IL-5 he apy, ha is, pa ien s ulfilling he ollowing c i e ia: (1) daily use o medium- o- high ICS dose (800 m g budesonide equi alen ) and LABA, (2) 2 exace ba ions pe p e ious yea be o e he 12-yea ollow-up isi , and (3) blood eosinophil le el 300 cells/ m L o FeNO 50 ppb a he 12-yea ollow-up isi in he SAAS coho . The seconda y endpoin s we e o assess he p opo ion o pa ien s wi h SA ( ulfilling ERS/ATS c i e ia) and he p opo ion o pa ien s ulfilling di e en combina ions o he clinical c i e ia ela ed o eligibili y o an i-IL-5 ea men . A u he aim was o see whe he an i-IL-5 eligible pa ien s and SA o e lap. A compa ison o basic and clinical cha ac e is ics and heal h ca e use o pa ien s ulfilling c i e ia o an i-IL-5 he apy o hose ulfilling c i e ia o SA and o he pa ien s wi h non-SA was also assessed as a seconda y endpoin . S a is ical analysis Con inuous da a a e exp essed as mean s anda d de ia ion o median and in e qua ile ange. A compa ison be ween 3 g oups was pe o med by using 1-way analysis o a iance wi h Tukey’s pos hoc, K uskal-Wallis, o c 2 es . Boo s apping 21 was used o es ima e 95% confidence in e al (CI) o he p ima y/seconda y ou come es ima e. By his me hod, 1000 samples wi h eplacemen we e d awn om he o iginal da ase o he same size as he o iginal sample allowing us o quan i y mo e p ecisely he accu acy o p i- ma y ou come es ima e. S a is ical analyses we e pe o med using SPSS so wa e, e sion 23 (IBM SPSS, A monk, NY). P alue <.05 was ega ded as s a is ically significan . RESULTS Pa ien cha ac e is ics The cha ac e is ics o pa ien s a 12-yea ollow-up isi a e shown in Table I. Pa ien s we e mos ly emales, nona opic, o e weigh , and app oxima ely hal had smoking his o y. The p opo ion o daily ICS use s was 76.4%. As hma was uncon- olled in 29.6% o pa ien s. Two pa ien s (1%) we e using con inuous OCS o as hma indica ion a 12-yea ollow-up isi , and 2 pa ien s (1%) o o he indica ion. Pa ien s eligible o an i-IL-5 he apy The p ima y endpoin o his s udy was ulfilled by 4 o 203 (2% o pa ien coho ) (Figu e 1,A). Wi h blood eosinophil cu o se om 150 o 400 cells/ m L, p opo ion a ied be ween 1% and 3% (Figu e 1,A). When c i e ia o exace ba ions and medica ion use we e emo ed, 20.3% o pa ien s ulfilled c i e ia o blood eosinophils 300 cells/ m L o FeNO 50 ppb. Wi h blood eosinophil cu o s om 150 o 400, p opo ion a ied om 58.7% o 14.5% (Figu e 1,B). Some imes as hma exace ba ion may be con used wi h acu e espi a o y ac in ec ion, and consequen ly, an ibio ics o doubling o ICS dose is p esc ibed ins ead o OCS. The e o e, we applied an explo a i e app oach. In addi ion o he pa ien s who we e p esc ibed OCS a leas wice pe yea , he ex ended defini ion included also pa ien s wi h 2 acu e isi s o heal h ca e whe e an ibio ics o doubling o ICS dose was p esc ibed du ing he p e ious yea . In he coho , 11.3% o he pa ien s ulfilled c i e ia o ex ended defini ion o exace ba ions and used medium o high ICS dose and LABA o hei daily he apy. When c i e ia o ele a ed eosinophils (300 cells/ m L) o FeNO (50 ppb) we e added, 3% (n ¼6) pa ien s emained. TABLE I. Cha ac e is ics o pa ien s a 12-yea ollow-up as p e iously epo ed 17 Cha ac e is ic Coho a ollow-up (n [203) Age (y) 58 (14) Male gende , n (%) 85 (41.9) BMI (kg/m 2 ) 28.1 (24.4-31.2) BMI <25, n (%) 59 (29.0) BMI 25-29.99, n (%) 73 (36.0) BMI 30, n (%) 71 (35.0) Smoke s (incl. ex), n (%) 107 (52.7) Smoking his o y, pack-yea 16 (7-30) To al IgE (kU/L) 61 (24-163) Daily ICS use, n (%) 155 (76.4) Blood eosinophils (10 9 /L) 0.17 (0.10-0.27) Blood eosinophils 0.3, n (%) 35 (17.3) P e-BD FEV 1 % 86 (76-96) P e-BD FEV 1 <80% p edic ed, n (%) 61 (30.0) P e-BD FVC % 96 (87-106) P e-BD FEV 1 /FVC 0.73 (0.66-0.79) Pos -BD FEV 1 % 90 (80-98) Pos -BD FEV 1 <80% p edic ed, n (%) 48 (23.6) Pos -BD FVC % 99 (88-107) Pos -BD FEV 1 /FVC 0.75 (0.69-0.80) DL CO (%) 92 (19) DL CO /VA (%) 94 (17) AQ20 sco e 4 (2-7) ACT sco e 22 (19-24) ACT sco e <20, n (%) 56 (27.6) ACT, As hma Con ol Tes ; AQ20, Ai ways Ques ionnai e 20; BD, b onchodila o ; BMI, body mass index; DL CO , di using capaci y; DL CO /VA, di using capaci y adjus ed by he al eola olume; FEV 1 , o ced expi a o y olume in 1 s; FVC, o ced i al capaci y; GINA, Global Ini ia i e o As hma; ICS, inhaled co icos e oid. Shown a e mean (s anda d de ia ion) o median (25 h-75 h pe cen ile). As hma con ol was e alua ed by GINA 2010. 22 J ALLERGY CLIN IMMUNOL PRACT VOLUME 7, NUMBER 1 ILMARINEN ET AL 167 P e alence o se e e as hma We used he ATS/ERS Task Fo ce 12 defini ion o SA. O he pa ien s, 14 (6.9%) we e using high-in ensi y medica ion o as hma (high ICS dose plus second con olle and/o OCS o 50% o he p e ious yea ) and 12 (5.9%) s ill emained un- con olled ulfilling c i e ia o SA. 12 The p opo ion o pa ien s defined as uncon olled acco ding o he ACT sco e <20, 2 exace ba ions las yea , o p eb onchodila o FEV 1 <80% p e- dic ed a e shown in Figu e 2. The e was only 1 pa ien who ulfilled c i e ia o bo h SA and an i-IL-5 eligibili y due o di e en c i e ia o ICS dose, and in u he analyses, his pa- ien was included only in o he an i-IL-5 g oup. Th ee an i-IL-5 eligible pa ien s we e no ega ded as ha ing SA due o ICS dose no classified as high acco ding o ERS/ATS c i e ia. Cha ac e is ics o pa ien s wi h nonse e e as hma, se e e as hma, and hose eligible o an i-IL-5 he apy Pa ien s wi h non-SA, SA, and hose eligible o an i-IL-5 he apy we e simila in espec o gende , age o as hma onse , and lung unc ion pa ame e s a diagnosis and 12-yea ollow-up isi (Table II and Table E1, a ailable in his a icle’s Online Reposi o y a www.jaci-inp ac ice.o g). Pa ien s wi h SA we e mo e o en cu en smoke s a diagnosis (Table E1) and had FIGURE 1. P e alence o pa ien s ul illing di e en combina ions o he clinical c i e ia ela ed o eligibili y o an i-IL-5 he apy in he coho o adul -onse as hma (n ¼203). A, P e alence o pa ien s ul illing di e en c i e ia o he le el o blood eosinophils o FeNO, exace ba ions, and use o medica ion. B, P e alence o pa ien s ul illing di e en c i e ia o he le el o blood eosinophils (B-eos) o FeNO wi hou he need o ul ill c i e ia o equen exace ba ions o use o medium- o-high ICS dose o as hma. FeNO, F ac ion o exhaled ni ic oxide; ICS, inhaled co icos e oid; LABA, long-ac ing b 2 -agonis . J ALLERGY CLIN IMMUNOL PRACT JANUARY 2019 168 ILMARINEN ET AL highe body mass index a he 12-yea ollow-up isi (Table II) when compa ed wi h he 2 o he g oups. In addi ion, pa ien s wi h SA had mo e o en sys emic heuma ic disease, hy oid diso de , o ea ed dyspepsia as como bidi y a 12-yea ollow- up isi (Table E2, a ailable in his a icle’s Online Reposi o y a www.jaci-inp ac ice.o g). Di e ences exis ed in pa ame e s ela ed o as hma medica ion, exace ba ions, symp oms, and as hma con ol, which was expec ed because hese pa ame e s we e used in he ca ego iza ion o pa ien s (Tables II and III). FeNO and o al IgE le el we e he highes in pa ien s ulfilling c i e ia o an i-IL-5 he apy and lowes in pa ien s wi h SA (Table II). Ins ead, blood neu ophils we e highes in pa ien s wi h SA and lowes in an i-IL-5 eligible pa ien s a 12-yea ollow-up isi (Table II). To assess adhe ence o s e oid ea - men he numbe s o ICS-con aining inhale s/canis e s as well as packages o OCS bough om pha macies a ound he ollow-up isi (2012-2013) we e e ie ed. All an i-IL-5-eligible pa ien s had bough se e al ICS-con aining inhale s annually (mean 8.2/ yea ) and a leas 1 OCS package (mean bough o al OCS dose 1688 mg p ednisolone equi alen /2 yea s co esponding o >5 en-day cou ses o 30 mg o al p ednisolone daily). One pa ien classified as ha ing SA had low adhe ence a he ollow-up isi bu be e adhe ence in long e m. All o he emaining 10 pa- ien s classified as ha ing SA had bough (2012-2013) annually se e al ICS-con aining inhale s/canis e s (mean 13.5/yea ) and 8 had bough a leas 1 package o OCS. Two we e on a con in- uous OCS he apy. The mean bough o al OCS dose was 1975 mg p ednisolone equi alen /2 yea s in hose 6 pa ien s no being on a con inuous OCS he apy. Use o heal h ca e in pa ien s wi h nonse e e as hma, se e e as hma, and hose eligible o an i- IL-5 ea men Du ing he 12-yea ollow-up pe iod, he use o heal h ca e was di e en be ween non-SA, SA, and an i-IL-5 g oups: num- be o all as hma- ela ed isi s o heal h ca e and numbe o unplanned isi s ( isi s due o exace ba ions and espi a o y ac in ec ions) we e highe in SA and an i-IL-5 eligible pa ien s when compa ed wi h nonse e e pa ien s (Figu e 3). Pa ien s wi h SA also had mo e equen planned isi s o heal h ca e han pa ien s wi h non-SA (Figu e 3,B). Howe e , he e was no s a is ically significan di e ence be ween SA and an i-IL-5 eligible pa ien s in he numbe o all planned o unplanned heal h ca e isi s. In addi ion, all an i-IL-5 eligible pa ien s had 3 sick lea es in he pas 2 yea s be o e he 12-yea ollow-up isi , whe eas he p opo ion was 16.7% in pa ien s wi h SA (Table III). Howe e , pa ien s wi h SA had mos hospi aliza ions du ing he whole 12-yea ollow-up pe iod (Table III). In o al, an i-IL-5 eligible pa ien s accoun ed o 4.7% o all as hma- ela ed isi s o heal h ca e and 7.9% o unplanned as hma- ela ed isi s o heal h ca e, being 2- o 4- old highe han expec ed. Pa ien s wi h SA accoun ed o 13% o 13.9% o all and unplanned as hma- ela ed isi s o heal h ca e being mo e han double han would be expec ed. In e es ingly, he mos d as ic di e ence was ound in hospi aliza ions: al hough an i-IL- 5 eligible pa ien s accoun ed o only 2% o all hospi al admis- sions ( he same as expec ed), pa ien s wi h SA accoun ed o 31% o all hospi aliza ions, which is 5- old mo e han expec ed. Es ima ion o con idence in e al o he p e alence o an i-IL-5 eligible pa ien s and se e e as hma O he o al coho o adul -onse as hma, 2% we e eligible o an i-IL-5 he apy and 5.9% we e classified as ha ing SA. By using he boo s apping me hod, he 95% CI limi s o hese es ima es a e 0.5% o 4.1% o an i-IL-5 eligible pa ien s and 2.9% o 9.4% o SA. DISCUSSION In his s udy, we ha e e alua ed he p e alence o pa ien s eligible o an i-IL-5 he apy in a coho o adul -onse as hma wi h inclusion o all le els o as hma se e i y and pa ien g oups such as smoke s and hose wi h como bidi ies. O he o al coho , 2% we e ound o ulfill he c i e ia o an i-IL-5 eligi- bili y, namely daily use o medium- o-high ICS dose and LABA, a leas 2 exace ba ions du ing he p e ious yea , blood eosino- phils 300 cells/ m L, and/o FeNO 50 ppb. In addi ion, we e alua ed he p e alence o SA as defined by he ERS/ATS c i e ia in his coho , being 5.9% o all pa ien s (Figu e 4). Fu he mo e, only 1 pa ien ulfilled c i e ia o bo h g oups (Figu e 4). Pa ien s wi h SA and hose who ulfilled c i e ia o an i-IL-5 eligibili y we e sepa a ed om nonse e e pa ien s by highe use o heal h ca e (all and unplanned as hma- ela ed isi s o heal h ca e), showing ha bo h o hese pa ien g oups ep esen a majo bu den o heal h ca e. In addi ion, when compa ing pa ien s wi h SA wi h an i-IL-5 eligible pa ien s, se e e as hma ics we e mo e o en cu en smoke s a diagnosis and we e obese, used highe ICS dose, and had highe blood neu ophils 12 yea s a e diagnosis. Epidemiological s udies on di e en as hma pheno ypes a e a e. To ou knowledge, his is he fi s s udy whe e he p e a- lence o an i-IL-5- ea able as hma among pa ien s wi h adul - onse as hma was e alua ed. The p e alence o an i-IL-5 eligibili y among SA has been assessed in a Belgian SA coho including smoking pa ien s and hose wi h como bidi ies and 30% o pa ien s wi h SA we e ound o be eligible o an i-IL-5. 23 The c i e ia o an i-IL-5 eligibili y we e simila o FIGURE 2. P e alence o se e e as hma (SA) in pa ien s wi h adul -onse as hma. High-in ensi y medica ion e e s o daily use o high ICS dose oge he wi h second con olle (LABA, LTRA, o heophylline), o sys emic s e oid o a leas 50% o he p e ious yea . De ini ion o se e e as hma includes he use o high- in ensi y medica ion and uncon olled as hma as de ined by ACT sco e <20, 2 exace ba ions p e ious yea , and/o p e- b onchodila o FEV 1 <80% p edic ed. ACT, As hma con ol es ; FEV 1 , o ced expi a o y olume in 1 second; ICS, inhaled co i- cos e oid; LABA, long-ac ing b 2 -agonis ; LTRA, leuko iene ecep o an agonis . J ALLERGY CLIN IMMUNOL PRACT VOLUME 7, NUMBER 1 ILMARINEN ET AL 169 he c i e ia used in he p ima y endpoin o ou s udy bu wi h highe ICS dose equi emen (880 m gflu icasone equi alen ) and wi h inclusion o spu um eosinophils 3%. A mul icen e s udy also assessed eligibili y o an i-IL-5 an ibodies mepolizu- mab and eslizumab among “ eal-wo ld”pa ien s wi h SA and ound eligibili ies o 20% and 6% o hese agen s, espec i ely. 24 Howe e , he esul s a e di ficul o compa e wi h ou esul due o di e en pa ien coho s (se e e s gene al) and di e en c i e ia used o eligibili y (eosinophil coun 150 o mepoli- zumab o 400 cells/ m L o eslizumab s 300 cells/ m L in ou TABLE II. Cha ac e is ics o pa ien s wi h nonse e e as hma, se e e as hma, and hose eligible† o an i-IL-5 he apy a 12-yea ollow-up isi Cha ac e is ic Nonse e e Se e e Eligible o an i-IL-5 P alue No. o pa ien s 188 11 4 Female, n (%) 108 (57.4%) 7 (63.6%) 3 (75.0%) .726 Age a onse (y) 47 (37-56) 52 (41-55) 49 (40-70) .748 BMI (kg/m 2 ) 28.4 (5.5) 32.5 (5.8)*25.6 (5.1) .033 Wi h smoking his o y, n (%) 97 (51.6 %) 8 (72.7%) 2 (50.0%) .392 Cu en smoke s, n (%) 26 (13.8%) 4 (36.4%) 0 .086 Pack-yea s o smoke s 16 (7-30) 18 (15-21) 31 (42) .799 A opic, n (%) 63 (37.3%) 3 (30%) 2 (50.0%) .778 Lung unc ion P e-BD FEV 1 (% p ed) 86 (18) 81 (19) 79 (16) .557 Pos -BD FEV 1 (% p ed) 89 (17) 83 (19) 81 (18) .399 Pos -FEV 1 /FVC 0.76 (0.69-0.81) 0.72 (0.68-0.74) 0.71 (0.51-0.79) .150 DL CO /VA, % p edic ed 96 (16) 92 (18) 87 (25) .462 Daily medica ion ICS, n (%) 140 (74.5%) 11 (100%) 4 (100%) .081 LABA, n (%) 82 (43.6%) 10 (90.9%)*4 (100%) .001 LTRA, n (%) 22 (11.7%) 5 (45.5%)*0.005 LAMA, n (%) 5 (2.7%) 2 (18.2%)*1 (25%)*.003 Theophylline, n (%) 2 (1.1%) 2 (18.2%) 0 <.001 No. o add-on d ugs 1 (0-1) 2 (1-2)*1.5 (1-2) <.001 ICS dosez786 (406) 2140 (844)*1333 (577)** <.001 High ICS dose,xn (%) 4 (2.1%) 11 (100%)*1 (25 %)* , ** <.001 Sys emic s e oid, n (%) 1 (0.5%) 3 (27.3%) 0 <.001 Symp oms/quali y o li e AQ20 sco e 4 (1-7) 8 (4-15)*8 (3-10) .005 ACT sco e 22 (20-24) 16 (10-19)*18.5 (13.3-23.8) <.001 ACT 20 144 (76.6%) 1 (9.1%)*2 (50%) <.001 ACT 16-19 26 (13.8%) 5 (45.5%) 0 ACT <16 18 (9.6%) 5 (45.5%) 2 (50%) As hma con ol, GINA 2010, n (%) .055 Con olled 68 (36.2%) 1 (9.1%) 0 Pa ially con olled 69 (36.7%) 4 (36.4%) 1 (25.0%) Uncon olled 51 (27.1%) 6 (54.5%) 3 (75.0%) Inflamma ion Blood eosinophils (10 9 /L) 0.17 (0.10-0.27) 0.13 (0.10-0.28) 0.46 (0.12-0.71) .203 Blood eosinophils 0.3 10 9 /L 31 (16.6%) 2 (18.2%) 2 (50.0%) .217 FeNO (ppb) 11 (5-18) 8 (6-15) 41 (13-56) .043 FeNO 50 ppb 8 (4.5%) 0 2 (50.0 %)* , ** <.001 To al IgE (kU/L) 61 (25-161) 22 (9-76) 307 (67-552) .038 Blood neu ophils (10 9 /L) 3.9 (1.4) 6.3 (2.5)*2.5 (0.6)** <.001 ACT, As hma Con ol Tes ; AQ20, Ai ways Ques ionnai e 20; ATS, Ame ican Tho acic Socie y; BD, b onchodila o ; BMI, body mass index; DL CO /VA, di using capaci y adjus ed by he al eola olume; ERS, Eu opean Respi a o y Socie y; FeNO, ac ion o exhaled ni ic oxide; FEV 1 , o ced expi a o y olume in 1 s; FVC, o ced i al capaci y; GINA, Global Ini ia i e o As hma; ICS, inhaled co icos e oid; LAMA, long-ac ing musca inic ecep o an agonis ; LABA, long-ac ing b 2 -agonis ; LTRA, leuko iene ecep o an agonis . Shown a e n (%) o ca ego ical a iables, and mean (s anda d de ia ion) o median (in e qua ile ange) o con inuous a iables. Bold indica es s a is ical significance (P<.05). *P<.05 s nonse e e. **P<.05 s se e e g oup. †An i-IL-5 eligible pa ien s e e o hose who ulfill c i e ia o he p ima y endpoin o his s udy (daily use o medium- o-high ICS dose and LABA, 2 exace ba ions pe p e ious yea , and blood eosinophil le el 300 cells/ m L o FeNO 50 ppb). zICS dose as budesonide equi alen s ( m g). xBased on ERS/ATS c i e ia. 14 J ALLERGY CLIN IMMUNOL PRACT JANUARY 2019 170 ILMARINEN ET AL s udy, exace ba ion equency 2 o mepolizumab and in ou s udy, 1 o eslizumab). In addi ion, c i e ia o FeNO we e no included in ha s udy consis en ly wi h he Food and D ug Adminis a ioneapp o ed c i e ia o an i-IL-5 an ibodies. ERS/ ATS c i e ia 12 (used in ou s udy) o high ICS dose in SA we e e y s ic and much highe han ha defined by Global Ini ia i e o As hma (GINA), and as a consequence mos an i-IL-5 eligible pa ien s we e no defined as se e e as hma ics in ou s udy. Only 1 pa ien o e lap in hese 2 g oups is a su p ising and in e es ing finding and eflec s he s ic c i e ia o SA by ATS/ERS and con using cu en s a e o mul iple defini ions o high ICS dose. Despi e no belonging o he g oup o SA, all an i-IL-5- ea able pa ien s ulfilled 1 o mo e ea u es o uncon olled as hma (3 pa ien s uncon olled, 1 pa ially con olled acco ding o GINA 2010). I pa ien s wi h SA and hose wi h an i-IL-5 eligibili y a e combined, he p opo ion o an i-IL-5 eligible pa ien s in his g oup is 27%, simila ly o he Belgian egis y. We also e alua ed he p e alence o eosinophilic pheno ype o adul -onse as hma in he whole s udy coho by using di e en cu o poin s. The p opo ions o eosinophilic as hma by using TABLE III. Cha ac e is ics o pa ien s wi h nonse e e as hma, se e e as hma, and hose eligible† o an i-IL-5 he apy du ing he 12-yea ollow-up pe iod Cha ac e is ic Nonse e e Se e e Eligible o an i-IL-5 P alue No. o pa ien s 188 11 4 Lung unc ion decline pe yea z D FEVz(mL) 46 (36) 65 (43) 65 (31) .152 D FEV 1 (% p edic ed) 0.5 (1.0) 1.0 (1.4) 1.2 (0.9) .183 Exace ba ions Use o o al s e oid cou sesx56 (30.1%) 5 (50%) 4 (100%)*.006 No. o OCS bu s s/2 y{1 (1-2) 3 (1-7) 5 (3-9)*.002 3 sick lea es/2 y#3 (2.0%) 1 (16.7%) 3 (100%)††*<.001 Use o heal h ca e Hospi aliza ions, n 0 (0-0) 2 (0-4)*0.5 (0-1.75) .005 1 hospi aliza ion, any espi a o y eason (planned and unplanned) 43 (23.0%) 6 (54.5%) 2 (50.0%) .033 1 hospi aliza ion, any espi a o y eason (unplanned) 17 (9.1%) 4 (36.4%)*1 (25.0%) .013 1 hospi aliza ion, as hma- ela ed (planned and unplanned) 29 (15.6%) 4 (36.4%) 1 (25.0%) .185 1 hospi aliza ion, as hma- ela ed (unplanned) 10 (5.4%) 1 (9.1%) 0 .774 Hospi al days, any espi a o y eason (planned and unplanned) 0 (0-0) 2 (0-22)*1.5 (0-4.5) .015 Hospi al days, any espi a o y eason (unplanned) 0 (0-0) 0 (0-21)*0 (0-2) .007 Hospi al days, as hma- ela ed (planned and unplanned) 0 (0-0) 0 (0-14) 0 (0-4) .134 Hospi al days, as hma- ela ed (unplanned) 0 (0-0) 0 (0-0) 0 (0-0) .746 FeNO, F ac ion o exhaled ni ic oxide; FEV 1 , o ced expi a o y olume in 1 s; ICS, inhaled co icos e oid; LABA, long-ac ing b 2 -agonis ; OCS, o al co icos e oid. Shown a e n (%) o ca ego ical a iables, and mean (s anda d de ia ion) o median (in e qua ile ange) o con inuous a iables. Bold indica es s a is ical significance (P<.05). *P<.05 s nonse e e. †An i-IL-5 eligible pa ien s e e o hose who ulfill c i e ia o he p ima y endpoin o his s udy (daily use o medium- o-high ICS dose and LABA, 2 exace ba ions pe p e ious yea , and blood eosinophil le el 300 cells/ m L o FeNO 50 ppb). zDecline in FEV 1 om he poin o maximal lung unc ion wi hin 2.5 y a e diagnosis (and s a o he apy) o he 12-yea ollow-up isi . xPa ien s who ha e used o al s e oid bu s s a leas once du ing he 12-yea ollow-up pe iod. {Numbe o o al s e oid bu s s in p e ious 2 y be o e 12-y ollow-up isi among hose who needed o al s e oid bu s s. #Sick lea es ela ed o as hma in he pas 2 y be o e he 12-y ollow-up isi . ††One pa ien wi h missing in o ma ion. FIGURE 3. A, As hma- ela ed isi s o heal h ca e in pa ien s wi h nonse e e as hma, se e e as hma, and eligible o an i-IL-5 he apy. B, Planned isi s include as hma- ela ed ollow-up isi s. C, Unplanned isi s include isi s ela ed o exace ba ions and acu e espi a o y ac in ec ions. An i-IL-5 eligible pa ien s e e o hose who ul ill c i e ia o he p ima y endpoin o his s udy (daily use o medium- o- high ICS dose and LABA, 2 exace ba ions pe p e ious yea , and blood eosinophil le el 300 cells/ m L o FeNO 50 ppb). FeNO, F ac ion o exhaled ni ic oxide; ICS, inhaled co icos e oid; LABA, long-ac ing b 2 -agonis . J ALLERGY CLIN IMMUNOL PRACT VOLUME 7, NUMBER 1 ILMARINEN ET AL 171 he cu -poin o 300 o 400 cells/ m L o blood eosinophils we e 17.3% and 10.4%, espec i ely. P e ious s udies ound 26.4% 25 and 16% 26 p e alence by using he same cu o s, espec i ely, bu used selec ed coho s (exclusion o pa ien s wi h coexis ing ch onic obs uc i e pulmona y disease 26 o inclusion o hose wi h egula ea men [medium- o-high ICS dose] o as hma 25 ). So a , li le is known abou he p e alence o SA among all as hma ics e en hough es ima es o 5% o 10% ha e o en been p oposed wi h unclea basis o he es ima e. P e ious pha macy- based s udies ha e ound he p e alence o SA om 3.6% (Du ch s udy) 13 o 4.6% (Is aeli s udy). 27 In he Du ch s udy, only 3.6% we e defined as ha ing SA a e excluding hose wi h poo adhe ence o an inco ec inhala ion echnique. In ou s udy wi h pa ien s ha ing as hma diagnosis clinically confi med by espi- a o y specialis and lung unc ion measu emen s, 5.9% (CI 2.9% o 9.4%) we e classified as ha ing SA acco ding o he defini ion ag eed by he ATS/ERS Task Fo ce. 12 E en hough he p e alence es ima es (3.6% o 4.6%) ob ained om he pha macy-based s udies 13,27 a e somewha lowe , hey all wi hin he 95% CI (2.9% o 9.4%) o SA ob ained in he p esen s udy, and sugges ha pha macy da abase s udies may be a way o wa d o ob ain c ude es ima es o SA. Di e ences in he age o as hma onse , lack o objec i e as hma diagnosis, exclusion o hea y smoke s, and defini ion o SA may a ec he di e ence seen be ween he p e alence o SA in ou and he p e ious s udies. 13,27 SA is no a single disease, bu a he e ogeneous g oup wi h many subpheno ypes. Age a disease onse has been ound as a di e en ia ing ac o o as hma pheno ypes in many s udies, sepa a ing alle gic and a opic ea ly-onse pheno ype om less alle gic adul -onse pheno ypes. 1,3,28,29 Adul -onse sub- pheno ypes such as eosinophilic inflamma ion-p edominan , mild- o-mode a e well-con olled, obese noneosinophilic, smoking as hma, and se e e obs uc i e as hma ha e been iden ified by se e al clus e analyses. 1 La e-onse se e e eosin- ophilic as hma ep esen s only 1 subpheno ype, and in a s udy o his size, a andom p edominance o a pa icula pheno ype may ha e a ec ed he p opo ion o subjec s iden ified as an i- IL-5 eligible. In he Belgian SA egis y, 23 hep e alenceo he eosinophilic pheno ype (blood eosinophils 300 cells/ m L) in he SA coho was 36%. Inflamma ion in ou pa ien s wi h SA was o en neu ophil p edominan . This is in conco dance wi h p e ious s udies in which SA has been associa ed wi h neu ophilic ai way inflamma ion. 30,31 Whe he neu ophilic inflamma ion is due o di e en pa hological mechanisms in SA, o a esponse o high-dose glucoco icoid ea men in hese pa ien s, emains unknown. Neu ophilia as well as low numbe o pa ien s wi h SA wi h ele a ed blood eosinophils in ou coho may also be ela ed o good adhe ence o ICS ea men . To ou knowledge, he e exis no s udies wi h compa ison be ween SA and an i-IL-5 eligible pa ien s. Se e e (uncon olled) as hma has been associa ed wi h he inc eased use o heal h ca e, obesi y, and smoking in p e ious s udies when compa ed wi h nonse e e as hma ics, 27 being consis en wi h ou esul s. Numbe o hospi al admissions and isi s o gene al p ac i ione and as hma specialis ha e been epo ed o be highe in pa ien s wi h SA as compa ed wi h nonse e e pa ien s in ollow-up o 1 yea . 27 In a US s udy wi h 11-mon h ollow-up, pa ien s wi h eosinophilic (400 cells/ m L) SA (se e i y defined solely by use o medica ion) we e epo ed o be mo e o en hospi alized bu had no mo e ou pa ien o eme gency oom isi s when compa ed wi h hose wi h no mal eosinophils. 32 In con as , in ou s udy, an i-IL-5 eligible pa ien s isi ed heal h ca e equen ly, had he high numbe o o al s e oid cou ses and sick lea es, bu hospi- aliza ions we e no inc eased as compa ed wi h SA. F equency o hospi aliza ions in pa ien s wi h SA may be pa ly explained by obesi y and smoking as well as como bidi ies, all being associa ed wi h poo ou come o as hma. 17,19,33 The es ima e o an i-IL-5 eligible pa ien s in his gene al popula ion o as hma ics was 2%. A majo limi a ion o his s udy is he ela i ely small sample size. Howe e , by using boo s ap analysis ela i ely na ow, 95% CI o 0.5% o 4.1% o an i-IL-5 eligibili y was ob ained. Ano he limi a ion a ec ing he gene alizabili y o ou findings is he ela i ely low a e o pa ien s wi h uncon olled as hma in ou coho (29.6%) when compa ed wi h p e ious s udies a ying om 27% o 74%. 34-37 Di e en pa ien popula ion and me hod o assessing con ol o as hma as well as be e adhe ence o ea men in ou s udy may explain he di e ence. On he o he hand, good adhe ence o ea men is essen ial when conside ing biological d ugs and can be conside ed as a s eng h when assessing he p e alence o an i-IL-5 eligibili y. Many pa ien s wi h SA su e om mul imo bidi y (including eflux disease o sinusi is), 38 and i como bidi ies a e add essed p ope ly, his can lead o es o- a ion o as hma con ol and ob ia e he need o p esc ibing a biologic agen . Ou an i-IL-5 eligible pa ien s had e y ew como bidi ies al oge he , and none o he 4 an i-IL-5 eligible pa ien s epo ed eflux disease. Sinusi is was no objec i ely e alua ed in he ollow-up isi in each pa ien bu du ing he 12-yea ime, 3 o he 4 an i-IL-5 eligible pa ien s had had se e al isi s o heal h ca e because o sinus p oblems and we e p esc ibed pe manen nasal s e oid o long- e m hini is. Howe e , we canno exclude he possibili y ha sinus p oblems ha e a ec ed as hma de elopmen in o se e e o m and whe he hey could ha e been be e add essed. In addi ion, ou s udy excluded childhood-onse as hma ics, also limi ing he gene al- izabili y o he findings. FIGURE 4. P e alence o an i-IL-5 eligible as hma, se e e as hma, and nonse e e as hma in coho o adul -onse as hma (SAAS). One pa ien o e lap exis ed in he g oups o an i-IL-5 eligibili y and se e e as hma. CI, Con idence in e al; SAAS, Seinäjoki Adul As hma S udy. J ALLERGY CLIN IMMUNOL PRACT JANUARY 2019 172 ILMARINEN ET AL This s udy was ca ied ou by using c i e ia equi alen o he clinical indica ions app o ed o used in s udies. Despi e he clinical benefi s o an i-IL-5 ea men , he d ugs a e cos ly, and acco ding o a p elimina y cos -e ec i eness analysis o mepoli- zumab, i may exceed commonly used h esholds. 39 The p e- limina y cos -e ec i eness analysis has been based on da a a ailable om clinical ials. Thus, i is possible ha in he u u e an i-IL-5 he apy will be a ge ed di e en ly. Recen s udies sugges ha he cha ac e is ics o pa ien s ob aining be e benefi may include hose wi h highe eosinophil le els 40,41 and as hma onse a e 40 yea s. 42 In summa y, in an unselec ed coho o adul -onse as hma, we ha e shown 2% p e alence o eosinophilic s e oid- esis an exace ba ion-p one as hma ha could benefi om hean i-IL- 5 an ibody and 5.9% p e alence o SA. Only 1 pa ien me c i e ia o bo h g oups. Pa ien s wi h SA and hose eligible o an i-IL-5 he apy di e ed by cu en smoking, obesi y, and mo e neu ophil-p edominan disease in pa ien s wi h SA. 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The s a us o as hma con ol and as hma p esc ibing p ac ices in he Uni ed J ALLERGY CLIN IMMUNOL PRACT VOLUME 7, NUMBER 1 ILMARINEN ET AL 173