Outcome and severity of adult onset asthma Report from the obstructive lung disease in northern Sweden studies (OLIN)

Transcription

1 Respirtory Medicine (2007) 101, Outcome nd severity of dult onset sthm Report from the obstructive lung disese in northern Sweden studies (OLIN) Ev Rönmrk,b,, Anne Lindberg, Louise Wtson c, Bo Lundbäck,b The OLIN Studies, Deprtment of Medicine, Sunderby Centrl Hospitl of Norrbotten, Luleå, Sweden b Lung nd Allergy Reserch, Ntionl Institute of Environmentl Medicine, Krolinsk Institutet, Stockholm, Sweden c World wide Epidemiology, GlxoSmithKline, Greenford, Middlesex, UK Received 10 Mrch 2007; ccepted 12 June 2007 Avilble online 8 August 2007 KEYWORDS Asthm; Adults; Remission; Severity; Predictors Summry Bckground: Studies of longitudinl chnges in severity nd the long-term outcome of sthm in epidemiologicl settings re uncommon. Aim: To ssess the outcome of incident sthm in cohort of subjects who developed sthm fter the ge of 20 yers. Methods: This is prospective study of the outcome of 309 subjects with incident sthm being included in cse-referent study bsed on ll dults ged yers living in three municiplities/towns in Northern Sweden. The subjects fulfilled the criteri for incident sthm defined s onset of symptoms common in sthm within 12 months prior to the study nd verified bronchil vribility. In 2003, 250 (81) of the subjects with sthm were re-exmined with structured interview, lung-function test nd methcholine test. Results: At follow-up, 237 (95) subjects still hd n ctive sthm, i.e. they hd symptoms or used sthm medicines. Among those with ctive sthm, 65 were using inhled cortico-steroids. Severity grding (GINA 2000) showed tht 21 hd mild intermittent sthm, 30 mild persistent, 44 moderte persistent, nd 5 severe sthm, contrsting to 75 with moderte or severe sthm t entry. Higher ge, higher BMI nd low lung function were ssocited with greter sthm severity. Twelve subjects (5) were in remission. Predictors for remission were non-sensitistion nd norml lung function. Age, sex, BMI, nd smoking hbits were not significntly different between those in remission nd those not. Corresponding uthor. The OLIN Studies, Stdsvikens vårdcentrl, Robertsviksgtn 9, SE Luleå, Sweden. Tel.: ; fx: E-mil ddress: ev.ronmrk@teli.com (E. Rönmrk) /$ - see front mtter & 2007 Elsevier Ltd. All rights reserved. doi: /j.rmed

2 Outcome of dult onset sthm 2371 Conclusions: Remission of dult onset sthm ws low. Severity of sthm chnged considerbly over time, however, the overll chnge ws towrds milder disese probbly s result of tretment. & 2007 Elsevier Ltd. All rights reserved. Introduction Longitudinl studies of the long-term outcome of sthm nd chnges in severity over time re few. In prticulr follow-ups of subjects with n dult onset of sthm re uncommon. Asthm is defined s chronic disese. However, remission of sthm my occur, nd is more common in children 1,2 thn in dults. 3,4 The proportion remitting sthm in popultion is dependent upon the ge composition of the smples nd the length of follow-up, s relpses of sthm re common mong teengers 5 nd young dults 6 post remission period. Furthermore, different definitions of remission ffect the observed remission rtes. 7 Most studies bout the outcome of sthm re bsed on cohorts of children or young dults, i.e. studies of sthm ptients dignosed t young ge. Clinicl remission of childhood sthm, i.e. no symptoms nd no use of sthm medicines, hs been reported to be round 50. 2,8 Using these criteri for remission, 10-yer follow-up of popultion study bsed cohort of dult sthmtics resulted in remission of 6. 9 Predictors of remission re not well known, however, low level of lung function in childhood, 1,4 high degree of bronchil hyper-rectivity, 10 nd being llergic 11,12 re reported to be negtive fctors for remission. On the contrry, some studies hve not found ny ssocition between topy nd remission of sthm. 1,7 Although the severity of sthm vries over time 13 nd my be relted to long-term outcome, fctors relted to degree of severity re not well known nd understood. Some studies hve reported tht severe sthm mong dults is more common mong non-llergic subjects, prticulrly mong the middle-ged. 14 However, chnge of severity over time nd fctors relted to chnge in severity re poorly studied in popultion-bsed studies of sthm. Within the Obstructive Lung Disese in Northern Sweden Studies (OLIN) severl cohorts re under study. One of them is well-chrcterised cohort of subjects with dult onset sthm, which hs been followed-up. The im of this study ws to identify fctors relted to the severity of sthm in the cohort, chnge in severity, remission rte of sthm, nd predictors of remission. Mterils nd methods Study popultion The sthm cohort consisted of cses with incident dult sthm recruited from 1995 to 1999 in Northern Sweden. Briefly, the cohort consisted t inception of 309 subjects ged yers t time of inclusion. The inclusion criteri were history of sthm with onset of symptoms common in sthm within the lst 12 months prior to the inclusion nd physiologiclly verified bronchil vribility either by methcholine test, reversibility test, or pek expirtory flow (PEF) vribility. The cohort nd the inclusion criteri t bseline hve been reported in detil elsewhere. 15 Thus, the exmintion t inclusion included structured interview, lung-function test, methcholine test, nd further skin prick test (SPT). A reversibility test or mesures of morning nd evening PEF ws performed in subjects with contr-indiction for methcholine testing. The methcholine test ws not performed in subjects with FEV 1 o65 of predicted, in subjects with ischemic or other crdiovsculr disese, or in pregnnt women. Subjects with previous childhood sthm were excluded from the study. The follow-up visits were performed in 2003, nd the men follow-up time ws 70 months (SD 17). At the followup visit, 250 sthmtics prticipted t structured interview, 237 stisfctorily completed lung-function test, nd 187 methcholine test. The sme methods were used t the follow-up visits s t the study inclusion. The ethicl committee t the University of Umeå pproved the studies. Structured interview The interview questionnire included questions from the OLIN questionnire, 16 the Interntionl Union Aginst Tuberculosis nd Lung Diseses (IUATLD) questionnire, 17 nd the interview questionnire developed for the Europen Community Respirtory Helth Survey (ECRHS). 18 Thus, questions bout fmily history of sthm nd llergy, rhinitis, hy fever, eczem, smoking hbits nd occuption were included. Skin prick test (SPT) The tests were performed with llergen in 50 glycerol using lncet with tip of 1 mm. The llergens were ct, dog, horse, birch, timothy, mugwort, Dermtophgides frine, D. pteronyssinus, Cldosporium nd Alternri (Soluprick, ALK, Denmrk). A positive rection ws recorded if the dimeter of the whel ws X3 mm fter 15 min. Lung-function test nd methcholine test The lung-function tests were performed following the Americn Thorcic Society (ATS) recommendtions 19 using dry spirometer, Mijnhrdt Victest 5. Swedish reference vlues were used. 20 Methcholine tests were performed with n Aiolos nebulizer nd n electricity-driven compressor. The method ws clibrted ginst the method described by Hrgreve nd Juniper. 21

3 2372 E. Rönmrk et l. Definitions Remission of sthm: Four different criteri for remission were defined. First, subjects were defined s hving remitted from their sthm if they did not report ny wheeze or ttcks of shortness of breth during the lst 12 months, nd hd not used ny sthm medicines during the lst 12 months. Further definitions included lso norml lung function nd no hyper-rectivity defined s PC 20 t two different cutoffs of the concentrtion of methcholine chloride, X4 mg/ml nd X8 mg/ml, respectively. Fmily history of sthm: Asthm mong fther, mother or sibling. Smoking hbits: Smoking hbits were clssified bsed on the reported smoking hbits both t bseline nd t followup. Subjects were defined s smokers if they smoked every week or hd stopped smoking within the preceding 12 months. Those who hd stopped smoking X12 months prior to the first study were clssified s ex-smokers. Five smoking ctegories were creted: non-smokers, ex-smokers, smokers, quitters, nd strters or re-strters. Rhinitis: Subjects reported tht they often hd nsl blocking or running nose. Eczem: Subjects reporting pst or present eczem. Body mss index (BMI): Weight in kilogrms divided by the squre of the height in meters (kg/m 2 ). Positive skin test: A wel X3 mm to ny of the tested llergens. Asthm severity: Grding the severity of sthm followed the GINA clssifiction from yer 2000 bsed on dy nd night symptoms, lung function, nd mediction. 22 As the GINA-clssifiction ws developed lter thn the initil study design, the frequency of night symptoms ws not surveyed t the inclusion visit of the study. Further, it ws not possible to retrospectively seprte moderte nd severe dy symptoms, why moderte nd severe dy symptoms re grouped together in the inclusion dt. Sttisticl methods Sttisticl nlyses were performed using SPSS version Comprisons of proportions were tested with chi-squre test or Fishers 0 exct test. Continuous dt is expressed in men 7SD, nd comprisons of mens were tested with twotiled Student s t-test. One wy nlysis of vrince (ANOVA) ws used for test for trends. A p-vlue of o0.05 ws regrded s sttisticlly significnt. Covrites used in the nlyses tht my influence both severity nd remission of sthm included ge, sex, smoking hbits, BMI, llergic sensitistion, concomitnt rhinitis, nd level of FEV 1 in percent of predicted. Multiple logistic regression models were performed using these independent vribles s risk fctors (odd rtios, OR, with 95 confidence intervls, CI) of sthm severity. The dependent vrible sthm severity ws dichotomised first by combining the moderte nd severe sthm groups versus the combintion of the two milder groups, nd secondly by compring the severe sthm group versus the three other severity groups. The study lcked power to test predictors of remission by using multivrite nlyses. Results Of the 309 sthmtics included in the originl cohort, the mjority were still living in the re nd were invited to the follow-ups, nd 250 subjects prticipted corresponding to 81 of the cohort. The prticiption rte ws lowest, 58, mong subjects ged yers, while it ws in ll other 10-yer ge groups. The prticiption rte ws lower mong men (Tble 1). Remission Twelve subjects, 4.8, fulfilled the first criteri for remission, i.e. did not report ny wheeze or ttcks of shortness of breth nd hd not used ny sthm medicines during the lst 12 months. When the criterion of the remission were strengthened, nd lso bsence of bronchil hyper-rectivity ws included in the criteri, the remission rte decresed further (Fig. 1). The observtion time ws similr in the subjects who hd remitted their sthm nd those who hd not. Subjects in remission hd sttisticlly higher men FEV 1 predicted t the study inclusion compred with subjects who did not remit their sthm. No mjor difference in PC 20 t study inclusion ws found between those in remission nd those not. None of the 12 subjects in remission hd been smoker during the study period, while 23 of those with continuing sthm hd been smoker t either enrolment, follow-up, or t ny time during the study period, p ¼ Absence of rhinitis nd negtive SPT were more common mong remitters. Age, sex, or BMI did not differ significntly between those in remission nd those not (Tble 2). Ever hving hd eczem or fmily history of sthm did not influence remission. Neither did use of ICS t Tble 1 Among subjects with incident sthm; number of invited, prticipnts, nd subjects in remission t follow-up, by ge nd sex. Age t onset of sthm Sex y y y y Men Women All Invited, n Prticipted, n () 52 (58) 84 (89) 72 (88) 42 (93) 76 (71) 174 (86) 250 (81) Remission, n () (4,8) Remission defined s no symptoms nd no use of sthm mediction during the lst 12 months.

4 Outcome of dult onset sthm 2373 ny time during the study period: 92 mong those in remission versus 88 mong those still hving sthm. Symptoms nd mediction in non-remitters Among the 238 subjects still hving sthm t follow-up, 78 reported wheeze during the lst 12 months, 91 ttcks of shortness of breth, nd 28 reported night symptoms. Sixtyfive percent of the subjects were using inhled corticosteroids (ICS) s mono-therpy or in combintion with longcting bet-2-gonists (LABA), nd 25 were using fixed combintion of ICS nd LABA t follow-up. Further, 49 used or hd used mediction for rhinitis or rhino-conjunctivitis. Severity grding Grding of severity of sthm using the yer 2000 GINAclssifiction t follow-up showed tht 21 hd mild intermittent sthm, 30 mild persistent, 44 moderte persistent, nd 5 severe sthm. At study inclusion, the Definition of remission used No medicines, no symptoms, FEV 1 >80 of predicted, nd PC20 >8mg/ml No medicines, no symptoms, FEV 1 >80 of predicted, nd PC20 >4mg/ml No medicines, no symptoms, nd FEV 1 >80 of predicted No use of sthm medicines, nd no sthm symptoms Figure 1 Remission of sthm in reltion to different criteri of remission. corresponding figures hd been 9, 16, while 75 hd either moderte persistent or severe sthm. At enrolment, the severity clss driver ws symptoms, while t followup use of medicines ws the most importnt driver of severity clss (Tble 3). The chnge of severity clss from bseline to follow-up did not follow ny specific pttern, nd the severity grde vried considerbly from enrolment to follow-up (Fig. 2). At follow-up, severity of sthm (GINA 2000) ccording to bi-vrite nlysis ws not significntly relted to llergic sensitistion, lthough 25 of those with severe sthm hd positive skin prick test compred to 39 of those with mild intermittent nd 46 with mild persistent sthm. Low FEV 1 nd incresing ge were relted to incresed sthm severity (Tble 4). Subjects with severe sthm t followup hd significntly incresed their BMI during the study period (Tble 4). No significnt difference in smoking hbits between the severity groups ws found, however, nine of the 12 subjects with severe sthm hd never been smokers. Rhinitis hd no influence on the severity of sthm (Tble 4). According to multivrite nlyses, only low FEV 1 t the follow-up visit ws significntly relted to severe sthm: OR 0.92 (95 CI ) for decrese in percent of predicted with 1 unit. When moderte nd severe sthm were combined, the combintion ws significntly ssocited with low FEV 1 (OR 0.95, 95 CI ) nd incresing ge. Compred with the ge group o35 yers, ge 455 yers yielded n OR of 5.6 ( ), ge yers OR 3.1 ( ) nd ge yers OR 2.7 ( ) for moderte nd severe sthm. No other significnt ssocitions were found using the multivrite nlyses. Discussion To the best of our knowledge, this is the first study investigting the longitudinl outcome of n dult sthm cohort only including subjects with dult onset sthm with the strict exclusion of subjects who hd sthm during Tble 2 Bsic chrcteristics in subjects in remission nd in subjects still hving sthm t the follow up visit. Vrible Still hving sthm (n ¼ 238) Remission (n ¼ 12) p-vlue Age t follow-up, men yer (SD) 44.2 (10.4) 40.5 (6.5) Sex, women, () BMI t follow-up, men (SD) 26.8 (4.6) 26.4 (6.1) BMI chnge from bseline, men (SD) +0.9 (2.1) +1.1 (2.2) FEV 1 predicted t bseline, men (SD) 92.6 (13.7) (12.5) FEV 1 predicted t follow-up, men (SD) 95.2 (15.1) (13.2) Positive skin prick test t bseline, () Rhinitis t bseline, () Rhinitis t follow-up, () Smoking ny time during study period, () Smoking ctegories during the study Non-smokers n ¼ 108 n ¼ 7 Ex-smokers n ¼ 75 n ¼ 5 Quitters n ¼ 19 n ¼ 0 Smokers n ¼ 29 n ¼ 0 Strters nd re-strters n ¼ 7 n ¼ 0

5 2374 E. Rönmrk et l. Tble 3 Asthm severity bsed on dy symptoms, night symptoms, lung function, sthm mediction use, nd over ll scoring t bseline (time for onset of sthm) nd t follow-up ccording to the GINA clssifiction. Severity Dy symptoms Night symptoms Lung function Asthm mediction Over ll scoring Bseline Follow-up Bseline Follow-up Bseline Follow-up Bseline Follow-up Bseline Follow-up b Mild intermittent Mild persistent Moderte 71.0 b 19.3 persistent Severe persistent 0.4 Percentges by severity () of ll prticipnts. not ble to clssify. b moderte or severe symptom clss. childhood. All subjects hd their first onset of sthm symptoms between the ges of 20 to 59 yers, nd their sthm nd symptoms common in sthm s well hd lsted less thn 12 months t the beginning of the observtion period. The study confirms tht dult onset sthm is chronic disese with low remission rte. The rte of clinicl remission ws 0.8/100/yer. The remission rte ws even lower, 0.5/100/yer, when bsence of bronchil hyperrectivity nd norml lung function were dded to the criteri defining remission. The vlidity of the results must be judged s high due to number of resons. The prticiption both t enrolment 15 nd follow-up ws high, nd the loss of follow-up ws low. The dignosis of sthm hd high specificity s both history of sthm nd physiologicl verifiction of the dignosis ws required, while sensitivity ws not optiml. The enrolled sthmtics hd ll contcted helth cre for their symptoms before the exmintions tht preceded inclusion. 15 Subjects with mild intermittent sthm my not hve been included nd remission my hve been somewht underestimted. Nevertheless, ll enrolled sthmtics hd cliniclly relevnt disese, which demnded them to seek helth cre. Inter-observer bis could be voided s the sme tem exmined the ptients both t enrolment nd t follow-up. Previous studies focusing on remission hve been bsed on sthmtics identified in cross-sectionl studies 4,9 or in clinicl settings, 7,8 nd the durtion of sthm before the strt of follow-up in these studies hs vried considerbly. A well-defined Dutch cohort of sthmtics ws followed-up fter 25 yers. 7 The sthmtics were yers old t entry, nd in totl were 181 subjects followed-up. When remission ws defined s no symptoms, 40 were in remission nd the verge remission rte ws 1.6/100/yer. Further, 20 were not hyper-rective, while only bout 10 hd norml lung function, no hyper-rectivity, nd were free from symptoms corresponding to n nnul remission rte of 0.4/100/yer, 7 result similr to ours. In Northern Sweden, n sthm cohort derived from generl popultion smple ws identified by using cliniclly defined criteri of sthm bsed on medicl history nd physiologiclly verified bronchil vribility. At 10-yer follow-up, the men nnul remission rte ws 0.6/100/yer. 9 Remission in tht study ws defined s no symptoms nd no use of sthm medicines during the lst 12 months. Remission of sthm hs lso been studied within the US Tucson-studies in cohort of sthmtics including teengers t entry. The remission rte ws higher, 22 during 9-yer follow-up. 4 The dignosis of sthm s well s reports bout remission in the Tucson study nd some other US studies 23,24 were limited to questionnire reports without physicl exmintion or lung function testing. Thus the reported remission rtes were bsed on reports by the ptients nd no other informtion thn bsence of symptoms ws vilble. When the ge composition is even younger t study entry, remission rtes re seen to increse. A recently published 12 yer follow-up of Dnish smple ged 7 17 yers t entry yielded remission of In 30-yer follow-up of Dutch childhood-sthm cohort, 52 were in clinicl remission, lthough 57 of those in clinicl remission still were hyper-rective. 8 The greter proportion of those who were hyper-rective cn in prt be explined by results from

6 Outcome of dult onset sthm n=179 n=22 n=37 Gin 1 Gin 2 Gin 3/4 GINA clss t enrolment n= n= GINA clss GINA clss GINA clss n=179 GINA clss t follow-up GINA clss 1=mild intermittent; clss 2=mild persistent; clss 3=moderte persistent; clss 4=severe persistent Figure 2 Chnge of severity clss from inclusion to follow-up. Tble 4 Chrcteristics of prticipnts by sthm severity t follow-up. Severity of sthm Mild intermittent Mild Persistent Moderte persistent Severe persistent Difference by severity, p-vlue Femle sex, () Positive skin prick test, () Age, men yer Smoking hbits t follow-up, () Non-smokers Ex-smokers Smokers Rhinitis t follow-up, () BMI t follow-up Chnge in BMI FEV 1 of pred t follow-up, o0.001 men ICS users o0.001 Ever use of mediction for rhinitis, () BMI ws significntly relted with moderte nd severe sthm versus mild intermittent nd mild persistent, p ¼ nother Dutch study showing eosinophils, T-cells, mst cells nd interleukin-5 in the mucos of sthmtics in clinicl remission. 26 The somewht greter proportion in remission without hyper-rectivity in our study compred with the Dutch studies 7,8 my be result of rther short follow-up period of five to six yers since the onset of sthm nd thus

7 2376 E. Rönmrk et l. short time for remodelling to occur. As smoking ws inversely relted to remission, the reltively low proportion of smokers in our study my hve contributed to the slightly higher remission rte compred with the first referred Dutch study 7 nd our previous study bsed on prevlent cses of sthm. 9 As found in the Dutch nd the Tucson study, 4,7 predictors of remission in our study were mild disese nd norml lung function t onset of sthm. Active smoking decresed the possibility of remission, s did rhinitis nd llergic sensitistion. Interestingly, fctors for development of sthm in the sme cohort ws studied by cse-referent model nd risk fctors for incident sthm in dulthood were fmily history of sthm, rhinitis, incresed BMI, ex- smoking, nd llergic sensitiztion. 15 An importnt result ws the observtion tht severity of sthm chnged considerbly over time. The GINA guidelines from yer 2000 suggest four severity grdes of sthm. 22 When using the GINA-clssifiction of severity, three out of four of the sthmtics hd moderte or severe sthm t enrolment minly due to frequent symptoms, but less thn hlf were clssified s moderte or severe t follow-up. At enrolment only 9 hd mild intermittent sthm versus 21 t follow-up. The lrge proportion clssified s moderte or severe ccording to GINA t entry my t lest in prt be result relted to the new onset of disese. At onset, the lrge mjority reported frequent symptoms. Thus most cses of incident sthm did not strt s mild intermittent or mild persistent sthm. The incident sthm subjects would not hve been dpted to their irwy symptoms, which my explin the frequent reporting of symptoms. Our result of chnged severity is not supported by results from the ECRHS, which found severity t bseline to be n importnt determinnt of severity t follow-up. 27 This result of the ECRHS my be explined by the fct tht the sthmtics in the ECRHS were identified by cross-sectionl survey in contrst to the sthmtics in our study. The chnge of severity observed in our study my reflect the nture nd course of sthm in ptients introduced to sthm mediction. A further contributing fctor to the observed decline in overll severity could be the recent onset of sthm, which my hve been ccompnied by vrying ptho-physiologicl processes nd remodelling of irwys prllel to tretment with ICS in two-thirds of the cohort, delying processes tht decrese reversibility including remodelling of the irwys. 28,29 The min reson in the lrge proportionl decrese in severity is probbly n effect of tretment, minly mintennce tretment with ICS. 22,29 In these sthmtic subjects with n dult onset, somewht less thn hlf were sensitised to common irborne llergens when dignosed. 15 Additionlly, the risk fctor pttern ws similr both in the topic nd the non-topic sthmtics, results conforming to dt from the ECRHS. 30 Remission ws however, inversely ssocited with llergic sensitistion, results in ccordnce with some studies, 11,12 but in contrst with other. 1,7 Our study shows tht in dults, topy is risk fctor for the chronicity of sthm. The lower proportion of sensitised severe sthmtics in our study conforms to the results from the Europen study of severe dult sthm, Enfumos, 14 which showed tht the mjority of severe sthmtics hd reduced risk of being sensitised to common ero-llergens. The results conform lso to Dnish study, in which prognosis with regrd to lung function ws poorer in subjects with non-topic compred with topic sthm. 31 Multivrite nlyses indicted tht low lung function t entry ws ssocited with incresed severity. Also incresing ge ws significntly ssocited with severity, nd the ssocition ws confirmed by the multivrite nlyses. Incresed BMI did not rech sttisticl significnce s risk for moderte or severe sthm in the multivrite setting. However, in subjects with severe sthm t follow-up, BMI hd incresed with 2.9 units (men), which reflects n verge weight increse of bout 9 kg, results in ccordnce with French study showing overweight to be relted to uncontrolled sthm. 32 Thus, weight reduction could be n importnt strtegy for improvement in sthm mong obese subjects. 33 However, the risk fctor pttern for severe sthm is still poorly understood. In conclusion, the nnul remission rte of newly identified cses of dult onset sthm followed over five yers ws less thn 1. Remission ws relted to mild disese, norml lung function t onset, bsence of llergic sensitistion, rhinitis, nd being non-smoker. Atopy ws predictor of sustined sthm, nd increse in BMI ws relted to severe sthm t follow-up. Incresing ge nd low lung function were predictors of severe sthm. Severity of sthm ccording to the GINA-clssifiction vried considerbly though the reltively short follow-up period nd tended to decrese probbly s result of tretment. Conflict of interest sttement Louise Wtson ws employed by GlxoSmithKline for the yers , who hve been prtil sponsors of the study. None of the other uthors hve ny conflict of interest to declre in reltion to this work. Acknowledgements The uthors thnk Ann-Christin Jonsson, Krin Östling, nd Ingrid Nes for help with collecting of the dt. The study ws supported by the Swedish Council for working Life (RALF), Centre for Environmentl Reserch, Umeå (CMF), the Swedish Hert-Lung Foundtion, the Swedish Foundtion for Helth Cre Science nd Allergy Reserch (Vårdl), the Swedish Asthm-Allergy Foundtion, nd Norrbotten s locl helth uthorities. Additionl finncil support ws provided by GlxoSmithKline. References 1. Gerritsen J, Koeter GH, Postm DS, Schouten JP, Knol K. Prognosis of sthm from childhood to dulthood. Am Rev Respir Dis 1989;140: Strchn DP, Butlnd BK, Anderson HR. Incidence nd prognosis of sthm nd wheezing illness from erly childhood to ge 33 in ntionl British cohort. BMJ 1996;312: Mc Whorter WP, Polis MA, Kslow RA. Occurrence, predictors, nd consequences of dult sthm in NHANES I nd follow-up survey. Am Rev Respir Dis 1989;139:721 4.

8 Outcome of dult onset sthm Bronnimn S, Burrows B. A prospective study of the nturl history of sthm. Remission nd relpse rtes. Chest 1986;90: Norrmn E, Nyström L, Jönsson E, Stjernberg N. Prevlence nd incidence of sthm nd rhinoconjunctivitis in Swedish teengers. Allergy 1998;53: Sers MR, Greene JM, Willn AR, Wiecek EM, Tylor DR, Flnnery EM, et l. A longitudinl, popultion-bsed, cohort study of childhood sthm followed to dulthood. N Engl J Med 2003;349(15): Pnhuysen CIM, Vonk JM, Koeter GH, Schouten JP, Alten vn R, Bleecker, et l. Adult ptients my outgrow their sthm. A 25- yer follow-up study. Am J Respir Crit Cre Med 1997;155: Vonk JM, Postm DS, Boezen HM, Grol MH, Schouten JP, Koeter GH, et l. Childhood fctors ssocited with sthm remission fter 30 yer follow up. Thorx 2004;59: Rönmrk E, Jönsson E, Lundbäck B. Remission of sthm in the middle-ged nd elderly: report from the Obstructive Lung Disese in Northern Sweden Study. Thorx 1999;54: Roord RJ, Gerritsen J, Alderen vn WMC, Schouten JP, Veltmn JC, Weiss ST, et l. Risk fctors for the persistence of respirtory symptoms in childhood sthm. Am Rev Respir Dis 1993;148: Kelly WJW, Hudson I, Pheln PD, Pin MC, Olinsky A. Atopy in subjects with sthm followed to the ge of 28 yers. J Allergy Clin Immunol 1990;85: Mrtinez FD, Wright AL, Tussig LM, Holberg CJ, Hlonen M, Morgn WJ, et l. Asthm nd wheezing in the first six yers of life. N Eng J Med 1995;332: Limb SL, Brown KC, Wood RA, Wise RA, Eggleston PA, Tonsci J, et l. Adult sthm severity in individuls with history of childhood sthm. J Allergy Clin Immunol 2005;115: Abrhm B, Anto JM, Brreiro E, et l. The EMFUMOSA Crosssectionl Europen multicenter study of the clinicl phenotype of chronic severe sthm. Eur Respir J 2003;22: Rönmrk E, Andersson C, Nyström L, Forsberg B, Järvholm B, Lundbäck B. Obesity increses the risk for incident sthm mong dults. Eur Respir J 2005;25: Lundbäck B, Nyström L, Rosenhll L, Stjernberg N. Obstructive lung disese in northern Sweden: respirtory symptoms ssessed in postl survey. Eur Respir J 1991;4: Burney PG, Litinen LA, Perdrizet S, Huckuf H, Tttersfield AE, Chinn S, et l. Vlidity nd repetbility of the IUATLD (1984). Bronchil Symptoms Questionnire: n interntionl comprison. Eur Respir J 1989;2: Burney PG, Luczynsk CM, Chinn S, Jrvis D. The Europen Community Respirtory Helth Survey. Eur Respir J 1994;7: Americn Thorcic Society. ATS sttement. Snowbird workshop on stndrdiztion of spirometry. Am Rev Respir Dis 1979;119: Berglund E, Birth G, Grimby G, Kjellmer I, Sndqwist L, Söderholm B. Spirometric studies in norml subjects. Forced expirogrms in subjects between 7 nd 70 yers of ge. Act Med Scnd 1963;173: Juniper E, Frith P, Dunnett C, Cockcroft D, Hrgreve F. Reproducibility nd comprison of responses to inhled histmine nd methcholine. Thorx 1978;33: Globl Inititive for Asthm. Globl strtegy for sthm mngement nd prevention; 2003, / 23. Broder I, Higgins MW, Mthews KP, Keller JB. Epidemiology of sthm nd llergic rhinitis in totl community, Tecumseh, Michign. J Allergy Clin Immunol 1974;54: Schchter EN, Doyle CA, Beck GJ. A prospective study of sthm in rurl community. Chest 1984;85: Porsbjerg C, von Linstow ML, Ulrik CS, Nepper-Christensen S, Bcker V. Risk fctors for onset of sthm: 12-yer prospective follow-up study. Chest 2006;129(2): vn den Toorn LM, Overbeek SE, de Jongste JC, Lemn K, Hoogsteden HC, Prins JB. Airwy inflmmtion is present during clinicl remission of topic sthm. Am J Respir Crit Cre Med 2001;164: de Mrco R, Mrcon A, Jrvis D, Accordini S, Almr E, Bugini M, et l. Europen Community Respirtory Helth Survey Therpy Group. Prognostic fctors of sthm severity: 9-yer interntionl prospective cohort study. J Allergy Clin Immunol 2006;117(6): Gronke L, Knniess F, Holz O, Jorres RA, Mgnussen H. The reltionship between irwy hyper-responsiveness, mrkers of inflmmtion nd lung function depends on the durtion of the sthmtic disese. Clin Exp Allergy 2002;32: Jeffery PK. Remodelling in sthm nd chronic obstructive lung disese. Am J Respir Crit Cre Med 2001;164:S de Mrco R, Pttro C, Loctelli F, Svnes C, ECRHS Study Group. Influence of erly life exposures on incidence nd remission of sthm throughout life. J Allergy Clin Immunol 2004;113: Ulric CS, Bcker V, Dirksen A. A 10 yer follow up of 180 dults with bronchil sthm: fctors importnt for decline in lung function. Thorx 1992;47: Sint-Pierre P, Bourdin A, Chnez P, Dures JP, Godrd P. Are overweight sthmtics more difficult to control. Allergy 2006; 61(1): Stenius-Arnil B, Pouss T, Kvrnström J, Grönlund E-L, Ylikhri M, Mustjoki P. Immedite nd long term effects of weight reduction in obese people with sthm: rndomised controlled study. BMJ 2000;320: