Increasing COPD awareness

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1 Eur Respir J 2006; 27: DOI: / CopyrightßERS Jourals Ltd 2006 SERIES THE GLOBAL BURDEN OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Edited by K.F. Rabe ad J.B. Soriao Number 4 i this Series Icreasig COPD awareess J. Zieliski*, M. Bedarek*, D. Górecka*, G. Viegi #, S.S. Hurd ", Y. Fukuchi +, C.K.W. Lai 1, P.X. Ra e, F.W.S. Ko 1, S.M. Liu e, J.P. Zheg e, N.S. Zhog e, M.S.M. Ip** ad P.A. Vermeire ## CONTENTS Early detectio of COPD by high-risk populatio screeig J. Zieliski, M. Bedarek ad D. Górecka COPD ad females G. Viegi Raisig awareess of COPD S.S. Hurd COPD: the Japaese experiece Y. Fukuchi COPD: the Chiese experiece C.K.W. Lai, P.X. Ra, F.W.S. Ko, S.M. Liu, J.P. Zheg, N.S. Zhog ad M.S.M. Ip AFFILIATIONS *Secod Dept of Respiratory Medicie, Natioal Tuberculosis ad Lug Diseases Research Istitute, Warsaw, Polad. # Pulmoary Evirometal Epidemiology Uit, CNR Istitute of Cliical Physiology, Pisa, Italy. " Global Iitiative for Chroic Obstructive Lug Disease, Gaithersburg, MD, USA. + Dept of Respiratory Medicie, School of Medicie, Jutedo Uiversity, Tokyo, Japa. 1 Dept of Medicie ad Therapeutics, EARLY DETECTION OF COPD BY HIGH RISK-POPULATION SCREENING Summary Early diagosis ad smokig cessatio are the oly available methods to stop the progressio of chroic obstructive pulmoary disease (COPD). The aim of this study was to evaluate the effects of early detectio of airflow limitatio (AL) i a populatio with high risk for COPD, usig spirometric screeig. Smokers aged o40 yrs with a smokig history of o10 pack-yrs were ivited to visit a local outpatiet chest cliic for simple spirometry (forced expiratory volume i oe secod (FEV1) ad forced vital capacity (FVC)). Smokig history was recorded, followed by smokig cessatio advice relatig the results of spirometry to the smokig behaviour. Subjects who did ot fulfil the above criteria (youger ad/or osmokers) were also screeed. A total 110,355 subjects were ivestigated; they were aged yrs ad 58.2% were males. Of the total amout of subjects, 64% were curret smokers, 25.1% were former smokers ad 10.9% were lifelog osmokers. Spirometry tests were withi ormal values for 70.3%, ad 20.3% showed sigs of AL: this was mild i 7.6%, moderate i 6.7% ad severe i 5.9%. The remaiig 8.3% of subjects preseted with a restrictive patter of vetilatory impairmet. Airflow limitatio was foud i 23% of smokers aged o40 yrs with a history of o10 pack-yrs. This study cocluded that large-scale volutary spirometry screeig of the populatio with high risk for COPD detects a large umber of subjects with AL. Itroductio COPD is a major cause of morbidity ad mortality worldwide, ad evidece suggests that the mortality rate is icreasig [1 3]. Assumig that the curret treds i mortality cotiue, COPD will move from the sixth leadig cause of death worldwide i 1990, to the third i 2020 [4]. Recet epidemiological studies i Europe demostrated that COPD affects,9% of the adult populatio, mostly smokers [5 7]. A atioal survey o spirometric sigs of AL i a represetative sample of the US populatio of o25 yrs, has show that AL was preset i 8.8% of the ivestigated subjects [8]. The Chiese Uiversity of Hog Kog, **Dept of Medicie, Uiversity of Hog Kog, Hog Kog, e Guagzhou Istitute of Respiratory Disease, Guagzhou Medical College, Guagzhou, Chia. ## Laboratory of Pulmoology, Uiversity of Atwerp, Atwerp, Belgium. CORRESPONDENCE P.A. Vermeire Uiversity of Atwerp (Campus Drie Eike) Uiversiteitsplei 1 Wilrijk Atwerp B-2610 Belgium Fax: paul.vermeire@skyet.be Received: March Accepted after revisio: August Previous articles i this series: No. 1: Chapma KR, Maio DM, Soriao JB, et al. Epidemiology ad costs of chroic obstructive pulmoary disease. Eur Respir J 2006; 27: No. 2: Lopez AD, Shibuya K, Rao C, et al. Chroic obstructive pulmoary disease: curret burde ad future projectios. Eur Respir J 2006; 27: No. 3: Maio D.M., Watt G., Hole D., et al. The atural history of chroic obstructive pulmoary disease. Eur Respir J 2006; 27: This article has supplemetary material accessible from Europea Respiratory Joural Prit ISSN Olie ISSN c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 833

2 INCREASING COPD AWARENESS J. ZIELINSKI ET AL. COPD is diagosed very late i its atural history. I the Natioal Health ad Nutritio Examiatio Survey (NHANES) III, 71.7% of subjects with a mild AL did ot have a curret diagosis of obstructive lug disease [8]. Oly half of the subjects with moderate-to-severe pulmoary fuctio impairmet had bee diagosed ad treated. A late diagosis results i high cost of treatmet (direct medical costs) ad idirect costs [9, 10]. There is o effective pharmacological treatmet kow to reduce the progressio of the disease [11 13]. Early detectio of the disease combied with smokig-cessatio cousellig ad treatmet seems to be the oly curretly available method to cotrol COPD [14, 15]. There are two approaches to detectio of COPD at a early precliical phase: case fidig [16, 17] ad high riskpopulatio screeig [18]. The aim of this study was to evaluate the effects of large-scale detectio of COPD by offerig free spirometric screeig to the populatio at high risk for COPD. The high-risk populatio was defied as smokers aged o40 yrs with a smokig history of o10 pack-yrs. Methods Orgaisatio of the project The Kow the Age of Your Lug project was sposored by the Miistry of Health, Warsaw, Polad. The Natioal Tuberculosis ad Lug Diseases Research Istitute i Warsaw (Polad) was resposible for implemetatio ad coordiatio of the project. The Istitute developed a questioaire o respiratory symptoms ad smokig history for persos screeed. Writte educatioal ad smokig cessatio materials were developed for study participats. A cetral database was developed ad maaged by the Istitute, which performed fial aalysis of the results. The Istitute was also resposible for a publicity campaig (TV, radio broadcasts, ad local ad atioal press) regardig the causes ad symptoms of COPD. The project was coducted i 98 outpatiet chest cliics throughout the coutry. All physicias received 2 days of traiig to esure cosistecy of iterrelated reliability i the use of the protocol for the ivestigatios. Data from each of the participatig cetres were electroically dowloaded ito the study database. Target populatio The target populatio cosisted of curret ad former smokers aged o40 yrs with a smokig history of o10 pack-yrs. They were ivited to udergo free spirometry through mass media appeals ad advertisemets displayed i public places. Primary care physicias i the cities ivolved were asked to ecourage eligible patiets to participate i the project. Although the target populatio was defied as smokers aged o40 yrs, it was decided that all persos who were cocered with their lug health would be icluded i the programme. Procedures All subjects completed a questioaire cotaiig demographic ad athropometric data, a short history of ay previous or preset lug disease ad a history of smokig. Subjects declarig past diagosis of asthma, brochiectasis or sequelae of tuberculosis were excluded. Simple spirometry was the performed by a experieced certified techicia at the lug fuctio laboratory of the cliic. All health professioals ivolved i the project had udergoe 2 days of traiig to assure quality cotrol of spirometry. FVC ad FEV1 were recorded followig America Thoracic Society (ATS) guidelies [19]. The followig spirometers were used i this study: Alpha 3 spirometer (Vitalograph Ltd, Maids Moreto, Buckigham, UK), Peumo 2000 (ABC Med., Kraków, Polad), Lugtest 500 or Lugtest 1000 (MES, Kraków, Polad) ad the Peumoscree (Jaeger, Würtzburg, Germay). All models used i the study fulfilled ATS criteria [19]. Models requirig frequet calibratio were calibrated daily. AL was diagosed if the FEV1/FVC ratio was,0.7 [1]. The severity of AL was classified accordig to the Europea Respiratory Society (ERS) guidelies as mild (FEV1 o70% predicted), moderate (FEV % pred) ad severe (FEV1,50% pred) [20]. Predicted values were those of the Europea Commuity of Coal ad Steel approved by the ERS [21]. The visit was cocluded by a iterview with the physicia ivolved i the project. Durig the iterview, the physicia showed the patiet their spirometry result o the modified Flecher s ad Peto s graph ad explaied the relatioship betwee smokig ad the progressio of the disease, as well as the beefits of quittig smokig. Curret smokers were strogly advised to stop smokig ad received a booklet o how to stop smokig. The relatively high risk of lug cacer, myocardial ifarctio ad stroke i subjects with a low FEV1 was also addressed. Subjects with ewly detected AL received a referral letter to their primary care physicia recommedig further diagostic evaluatio ad treatmet. Statistical aalysis Tests were cosidered sigificat whe p,0.05. Data distributio was aalysed usig the Kologomorov Smirov test with Lilliefors correctio. Quatitative data are expressed as mea SD. Betwee-group characteristics were described usig ANOVA. Homogeeity of variace was assessed usig Levee s test. If data showed ormal distributio ad homogeous variace, Fisher s ANOVA was applied. Post hoc comparisos were performed usig Scheffe s test, verified with Tukey s for differet N tests (Spjotvoll Stolie modificatio). For oormal data distributio or o-homogeous variace, a oparametric Kruskal Wallis H test was used. To characterise relatio stregth betwee variables, Pearso correlatios were used. Categorised qualitative betwee-group aalyses were performed usig the Pearso Chi-squared test with appropriate correctios for N. Results Demographic Betwee October 2000 ad December 2003, 110,355 subjects were ivestigated. Their mea age was yrs. Of the subjects, 64,189 (58.2%) were males ad 46,166 (42.8%) were females; the mea age was yrs for males ad yrs for females. There were 16,829 subjects (15.25% of the total) who were,40 yrs or ever-smokers, or both. 834 VOLUME 27 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

3 J. ZIELINSKI ET AL. INCREASING COPD AWARENESS Attitudes towards smokig The smokig status was ot reported i 2% of the participats. Of the participats, 64% were curret smokers ad 25.1% were former smokers. The remaiig 10.9% declared themselves as lifelog osmokers. Smokig history of curret ad former smokers averaged pack-yrs. Spirometry Of the 110,355 spirometries performed, 1.5% (51,693) were techically usatisfactory ad were ot icluded i the aalysis; 70% (77,616) of the results were withi ormal limits. AL was diagosed i 20.3% (22,022) of the subjects, mild i 7.6% (8,244), moderate i 6.7% (7,319) ad severe i 5.9% (6,459). The remaiig 8.3% (9,024) had a restrictive patter of vetilatory impairmet. Of the curret ad former smokers (o10 pack-yrs) aged o40 yrs, 23% (18,479) had spirometric sigs of AL. Mild AL was foud i 8.43% of those subjects, moderate i 7.6% ad severe i 6.97%. Detailed results of spirometry i curret ad former smokers stratified for age ad smokig itesity categories are show i table 1. Prevalece ad severity of AL icreased with age ad tobacco exposure. AL was more frequet i males tha females (23.9% versus 15.7%, p,0.001), reflectig higher tobacco exposure i males. I additio, the severity of AL was more advaced i males tha i females (7.55% versus 3.88%, p,0.001). However, there was o differece i frequecy of restrictive patter of vetilatory impairmet betwee males ad females (8.34% i males ad 8.36% i females, p50.91). AL was foud i 12% (1,262) of lifelog osmokig subjects (table 2). There was o differece i the frequecy of AL ad its severity betwee males ad females. Restrictio was more frequet i females (p,0.001). There was also a sigificat tred i AL prevalece with icreasig tobacco exposure (table 3). Whe the cohort of curret ad former smokers was stratified to specific age groups (,35, o35, o40 ad o45), the prevalece of AL detected was 7.53%, 21.88%, 22.32% ad 23.97%, respectively. Respiratory symptoms Respiratory symptoms ad sputum productio were reported by 52.53% of participatig subjects with ormal lug fuctio. Oe-third (33.48%) of subjects with AL did ot report ay respiratory symptoms, whereas the rest declared chroic cough or chroic cough with sputum productio. TABLE 1 Results of spirometry i 95,185 curret ad former smokers stratified for age ad smokig exposure groups Category Airflow limitatio Restricted Normal Mild # Moderate " Severe + Total Aged o40 yrs, 6777 (8.43) 6100 (7.60) 5602 (6.97) (22.98) 7047 (8.76) (68.25) o10 pack-yrs Aged o40 yrs, 495 (5.67) 436 (4.99) 370 (4.24) 1301 (14.90) 583 (6.68) 6847 (78.42),10 pack-yrs Aged,40 yrs, 161 (4.69) 92 (2.68) 28 (0.82) 281 (8.18) 99 (2.88) 3054 (88.93) o10 pack-yrs Aged,40 yrs, 97 (3.71) 63 (2.41) 23 (0.88) 183 (6.99) 100 (3.82) 2334 (89.19),10 pack-yrs Total 7530 (7.90) 6691 (7.02) 6023 (6.33) (21.27) 7829 (8.23) (70.51) Data are preseted as (%). # : classified as forced expiratory volume i oe secod (FEV1) o70% predicted; " : FEV % pred; + : FEV1,50% pred. TABLE 2 Spirometry i 10,195 lifelog osmokers Variable Total Males Females Males versus females p-value Subjects Normal lug fuctio 8038 (78.84) 2781 (80.42) 5257 (78.03),0.01 Airflow limitatio 1262 (12.38) 434 (12.55) 828 (12.29) 0.73 Mild # 554 (5.43) 201 (5.81) 353 (5.24) 0.25 Moderate " 422 (4.14) 125 (3.61) 297 (4.41) 0.06 Severe (2.81) 108 (3.12) 178 (2.64) 0.18 Restrictio 895 (8.78) 243 (7.03) 652 (9.68),0.001 Data preseted as (%), uless otherwise stated. # : classified as forced expiratory volume i oe secod (FEV1) o70% predicted; " : FEV % pred; + : FEV1,50% pred. c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 835

4 INCREASING COPD AWARENESS J. ZIELINSKI ET AL. TABLE 3 Results of spirometry i curret ad former smokers accordig to smokig-exposure categories Pack-yrs, o40 Airflow limitatio 1486 (13.08) 3346 (15.97)* 4412 (19.00) (23.06) (31.83) 1 Mild # 592 (5.21) 1415 (6.75) e 1717 (7.39) e 1637 (8.92)** 2170 (10.18)*** Moderate " 501 (4.41) 1060 (5.06) e 1495 (6.44) e 1382 (7.53)* 2266 (10.63) 1 Severe (3.46) 871 (4.16) e 1200 (5.17) e 1213 (6.61)* 2348 (11.02) 1 Data preseted as (%). # : classified as FEV1 o70% predicted; " : FEV % pred; + : FEV1,50% pred. Sigificat differeces betwee first ad other colums are as follows: *: p,0.05; **: p,0.01; ***: p,0.001; 1 :p,0.0001; e : osigificat. Discussio The preset study reports the results of the first large-scale attempt to detect COPD by spirometric screeig of the populatio with high risk of the disease. Of the ivestigated curret or former smokers aged o40 yrs exposed to o10 packyrs of smokig (fulfillig the etry criteria for the high-risk populatio), 23% preseted with spirometric sigs of AL. The high yield of subjects with AL i the preset study was comparable to results from the Lug Health Study, which screeed.73,000 smokers aged yrs [22]. Of the subjects screeed for that study, 30% preseted with sigs of AL. The higher yield of subjects with AL i the Lug Health Study may be explaied by higher tobacco exposure. The preset subjects had a history of 29 pack-yrs, whereas patiets i the Lug Health Study group had a history of 40 pack-yrs. The prevalece of AL i lifelog osmokers i the preset study was 12%. Cotrary to NHANES III survey results, there was o differece i prevalece of AL betwee ever-smokig males ad females [8]. The results of the study cofirmed that AL was largely udiagosed. Of the 6% of the study populatio who were foud to have severe AL o spirometry, oe had bee diagosed previously by a physicia. This study also cofirmed that the prevalece of AL icreased with cumulative tobacco exposure. The results of the preset study may be compared with the effectiveess of the case-fidig method. VAN SCHAYCK et al. [23] reported the results of spirometric screeig of smokers aged yrs who were seekig medical attetio i a geeral practitioer s office. Of 201 smokers who were ot takig drugs for a pulmoary coditio, 169 produced a reliable spirogram. Of these, 18% preseted with FEV1,80% pred. However, effectiveess of the method was low. By testig oe smoker per day, a average practice could idetify oe patiet with a impairmet of lug fuctio per week. Such a low yield was probably related to the characteristics of patiets attedig the primary care physicia s office. Usually, middle-aged healthy smokers seek medical advice for a acute medical coditio, which is ot a suitable time to perform spirometry. Presece or absece of cough ad sputum productio was ot helpful i heraldig AL. Slightly more tha half of subjects with ormal spirometry preseted with respiratory symptoms. I cotrast, AL was foud i 67% of subjects with symptoms ad also i 33% of subjects who reported o respiratory symptoms. These fidigs are i agreemet with the results of a recet study by BUFFELS et al. [24], who aalysed the usefuless of spirometry performed by geeral practitioers i early diagosis of COPD. They foud that the umber of ewly diagosed cases of COPD icreased by 42% with spirometry compared to the diagosis based o a questioaire o sigs ad symptoms of COPD aloe. The mai problem with spirometric measuremets performed i the primary care settig is their accuracy. EATON et al. [25] foud that oly 30% of 1,000 spirometries performed i the primary care settig icluded at least two acceptable recordigs. Isufficiet quality of spirometries performed i the primary care settig was also reported recetly by SCHERMER et al. [26], which is i cotrast with the high repeatability of spirometries performed by experieced persoel reported by ENRIGHT et al. [27]. Aother potetially egative effect of spirometric screeig is the risk of reiforcig the smokig habit i smokers with ormal spirometry. It seems that those fears are usubstatiated. A recet study by GORECKA et al. [28] showed that 8.4% of smokers with ormal lug fuctio stopped smokig after spirometry combied with simple smokig-cessatio advice. There is o agreemet regardig the lower age limit for screeig of subjects for early diagosis of COPD; it rages from 35 to 45 yrs [23, 29]. The preset data suggest that screeig should start from 35 yrs of age. However, the differece i the overall yield of subjects with AL i the age group o35 yrs ad o45 yrs is oly 2% (21.88% versus 23.9% of AL detected, respectively). This would support the opiio that screeig should start from 45 yrs of age. However, at that age, the prevalece of severe AL diagosed durig screeig was already oe-third of the total umber of the curret subjects with AL. This ca hardly be called a early diagosis. The preset study has some limitatios. The idex FEV1/FVC,70% was arbitrarily accepted as a sig of AL [1, 2]. The use of such a fixed cut-off poit may lead to uderestimatio of AL i the yougest subjects ad overestimatio of AL i the oldest subjects. Although the mea age of the studied subjects was 53 yrs, 27% of subjects were aged.60 yrs i whom the lower limit of ormal for FEV1/FVC was,70% [30, 31]. The umber of subjects,30 yrs of age i whom AL may have bee uderestimated was 2.8%. 836 VOLUME 27 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

5 J. ZIELINSKI ET AL. INCREASING COPD AWARENESS Aother problem is the reliability of the spirometric measuremets. It has bee assumed that the quality of measuremets was good. They were performed i specialised lug fuctio labs by experieced certified techicias. Oly 1.5% of spirometric results were ot evaluable. Recetly, ENRIGHT et al. [27] cofirmed very high reliability of spirometric measuremets performed by pulmoary fuctio techicias i a laboratory settig. Both methods (case-fidig ad high risk-populatio screeig) have positive ad egative aspects. Cosiderig the large umber of middle-aged smokers that should be screeed for COPD, there is a fuctio for both. Primary care physicias should perform forced spirometry i patiets fulfillig the criteria for high risk of COPD. This approach could be reiforced by ivitig (via a letter or phoe call) smokers aged o40 yrs registered i their practice to report for spirometric tests. Such a method was used recetly by STRATELIS et al. [32]. All smokers aged yrs from a commuity of 88,000 ihabitats were ivited (by posters) to visit their primary health cetre for a free spirometry testig. A total of 512 (9.6%) of ivited smokers respoded. Spirometry showed sigs of AL i 27% of participats; AL was mild i 85% of participats. I coutries where office spirometry equipmet is ucommo i the primary care settig, largescale spirometric screeig of healthy smokers should be developed. Early diagosis ad effective behavioural ad pharmacological itervetios have led to substatial reductios i the prevalece of ad mortality from cardiovascular diseases over the last 40 yrs. The time has ow come to adopt a similar strategy to cotrol the disease that is the third leadig cause of death i developed coutries. A icreasig umber of sustaied quitters amog subjects with mild-to-moderate AL would substatially reduce morbidity ad mortality from COPD. COPD AND FEMALES Summary This sectio is maily based upo two Moographs [33, 34] ad the Europea Lug White Book [35] published by the ERS. Geder differeces i obstructive airway diseases result from the iteractio of sex-depedet geetic factors ad sociocultural geder differeces i childhood, adolescece ad adulthood. Gee/evirometal iteractios occur i asthma ad COPD. Sex differeces i lug physiology ad immue respose ifluece the patters of obstructive pulmoary diseases. Icreasig evidece supports the view that sex hormoes ifluece airway behaviour throughout the huma lifespa. There are also differeces i evirometal factors betwee geders, relatig to the frequecy ad the type of exposure (smokig, occupatio, air pollutio etc.) for which females appear to be at greater risk. More attetio should therefore be paid to the home eviromet. I additio, the cliical patter of diseases may differ betwee geders. There are geder differeces i the perceptio ad reportig of symptoms, which are also reflected i diagostic labellig ad maagemet. Thus, more epidemiological research should be devoted to studyig hormoal iflueces ad sociocultural-depedet risk factors. Stadardisatio for geder is to be replaced by stratificatio. Iformatio about the reproductive history of females ad their curret edocrie status should be further pursued i aetiological research ad i the evaluatio of the treatmet outcomes. Fially, some origial fidigs o geder-related differeces from the Po Delta [7, 36 40] ad Pisa [38, 39, 41] surveys i Italy are preseted i this sectio. Itroductio I November 2003, the ERS released the first comprehesive report o lug diseases i Europe, the Europea Lug White Book [35]. Take together, lug diseases i 1990 were resposible for 9.4 millio deaths worldwide, represetig 18.7% of overall mortality ad rakig first amog the specific causes of death. I 2010, COPD will represet the fourth cause of death i Europe ad, i 2020, the third worldwide [4]. There were 2.2 millio deaths caused by COPD worldwide i 1990, which is likely to become 4.7 millio i COPD also costs more tha asthma (J38.7 versus J17.7 billio), due i particular to i-patiet care ad lost workig days [35]. Much of what is kow about the epidemiology of obstructive pulmoary diseases i females has recetly bee reviewed i two issues of the Europea Respiratory Moograph [33, 34]. Two other review articles were also published i 2004 [42, 43]. Sex ad geder KAUFFMANN ad BECKLAKE [44] describe the ifluece of sex ad geder o the developmet of respiratory diseases. I particular, sex differeces cocer geetic ad biological factors, whereas geder resemblace cocers evirometal ad sociocultural factors. These two aspects ifluece the path that leads from risk factors to perceptio of health effects, as reported by the subject. There are the followig sex ad geder differeces i risk factors of obstructive pulmoary diseases. 1) Sex-specific risk factors: hormoal levels (adroges, oestroge, progesteroe), for which there are limited data; mestrual cycle (follicular phase, luteal phase), for which there are epidemiological data o premestrual asthma; pill (durig, after), for which there are limited data; pregacy (which icludes three differet trimesters, labour, the ifluece of the mother o the foetus, the ifluece of the foetus o the mother, umber of pregacies, treatmet for havig a baby, chages i respiratory treatmet durig pregacy, lactatio), for which there are epidemiological data o chagig asthma status durig pregacy, but few data o determiats of chage; meopause (atural/other, hormoe replacemet therapy), for which there is evidece of decreased asthma icidece with partial reversal uder hormoe replacemet. 2) Evirometal factors that are commo to both geders, with marked differeces i the prevalece or ature betwee geders or for which sex/geder may be a modifyig factor, are show i table 4. A example of greater female susceptibility to smokig is foud i a paper by GOLD et al. [46], who preseted a decreased FEV1 growth rate i females who smoked more tha five cigarettes per day compared with males. Aother example pertais to the relative risk of hospitalisatio for COPD i the c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 837

6 INCREASING COPD AWARENESS J. ZIELINSKI ET AL. TABLE 4 Evirometal factors commo to both geders Factors with a marked differece i prevalece or ature betwee geders Passive smokig. Evidece suggests more females are exposed ad that they may be more susceptible tha males [44]. Alcohol cosumptio. Evidece suggests more males are exposed [44]. Hygiee/cosmetic products. Evideces suggests more females are exposed [44]. Time-activity patters, which are geder related [44]. Idoor exposures [44]. Home eviromet (cleaig ad cookig), which is kow to be more uder the cotrol of females, thus more females are exposed [44]. Hobbies. It is kow that males are more likely to be ivolved i idustrial processes i home workshops (wood ad metal work, automobile restoratio, use of low molecular weight asthmages, e.g. isocyaates) [44]. Occupatioal exposure, which is almost male-specific for exposure to mieral dust (e.g. coal, hard rock mie dust) ad to asthmages (such as chemicals, isocyaates), whereas more females are exposed i textiles/maufacturig/dry cleaig. I agriculture there are fewer geder differeces [44]. Icome, which is geerally higher i males [44]. Factors i which sex/geder may be a modifyig elemet Active smokig. Curret kowledge shows geder-specific cohort chages (cultural) ad females ted to be more susceptible [44]. Childhood ifectios, for which it is kow that youg males are more susceptible (geetic?) [44]. Sport/exercise, which is geerally practiced more by youg males ad is more valued i males [44]. Occupatioal factors [44]. Nutritio, which appears more uder the cotrol of females [44]. Socioecoomic status [44]. Air pollutio, to which females may be more susceptible [45]. Glopstrup Populatio Studies [47], which showed this to be much higher i females tha males either i those smokig 1 30 pack-yrs or i those smokig.30 pack-yrs. Similar results were foud by the same authors i the Copehage City Heart Study [47], i which smokers were stratified ito three groups (1 20, ad.40 pack-yrs). It is also importat to poit out the presece of diagostic bias of asthma i relatio to geder [48]. The icidece of attacks of shortess of breath with wheezig are always higher i males tha i females i every age group, while the reverse is true for icidece of asthma diagosis. BECKLAKE [49] comprehesively reviewed the factors accoutig for the differeces betwee males ad females i airway physiology. They occur throughout the lifespa from the preatal period. There is evidece that the female foetus is more mature tha the male foetus i terms of surfactat productio from 32 to 38 weeks gestatio. I the peri- ad post-atal period of,1 yr, there is evidece that female eoates are at a lower risk for respiratory distress sydrome ad more resposive to hormoe accelerators of surfactat productio tha male eoates. Moreover, the lugs of female ifats are smaller o average tha those of male ifats but they have higher absolute as well as size-corrected flow rates tha male eoates. I childhood, up to,10 yrs, although youg females lugs cotiue to be smaller tha youg males lugs, their specific airway resistace is lower. From 6 10 yrs, large airways grow proportioally to lug volumes i youg females lugs but lag behid i youg males lugs, whereas small airways grow faster tha lug volumes i youg females lugs but grow proportioally i youg males lugs. Furthermore, forced expiratory flow rates are higher i youg females lugs tha i youg males lugs, cotrollig for volume. From early adolescece up to mid-tees, the peak velocity for icrease i height occurs,2 yrs earlier i adolescet females tha i adolescet males. FEV1 i relatio to height ad FEV1/FVC remai higher i female tha i male adolescets. I later adolescece (mid-to-late tees), growth velocity for FVC plateaus i females after height stabilises, but cotiues at a lower pace i males util their mid-20s. Further growth of total lug capacity (TLC) is slower i female tha male adolescets ad growth of flow rates relative to TLC appear to be dysaaptic i females ad isotropic i males. Fially, effort-idepedet flow rates remai higher i females tha i males. I early adulthood (late tees to mid-20s), lug volumes (TLC, FVC) remai stable i youg females but cotiue to icrease i youg males. These physiological factors have bee the basis for the explaatio of higher icidece of brochial resposiveess i females tha i males, ad for the higher susceptibility of females to air pollutio, icludig cigarette smokig [45 47]. There is also evidece of sex differeces i markers of atopy i the female s life cycle, preseted i a logitudial study i Tucso, Arizoa (USA) [50 52]. For example, below the age of 5, more females appear to be ski-test positive tha males; the same appears to be the case i those aged yrs ad.75 yrs. I cotrast, levels of immuoglobuli (Ig)E are always higher i males. Thus, the sex differeces i IgE are cosistet, whereas those i ski-test positivity are icosistet. There are also geder differeces i the relatioship of reported shortess of breath with FEV1. Data from the Frech study PAARC (Pollutio Atmospherique Affectios Respiratoires Chroiques) show that for each quitile of FEV1, females report a much higher prevalece of shortess of breath [53]. I the same study, there are also data o the icidece of asthma, which is higher i males up to the age of 14; betwee 15 ad 19 yrs of age, the icidece is the same i both sexes, while it becomes higher i females up to 49 yrs of age. I the eldest age group examied (50 54 yrs), the icidece becomes higher agai i males. I the Po Delta survey [36], females have bee show to have higher rates of brochial hyperresposiveess tha males. Cofirmatio of these fidigs came from a recet geeral populatio survey i 838 VOLUME 27 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

7 J. ZIELINSKI ET AL. INCREASING COPD AWARENESS six Caadia locatios [54]. I a multivariate model, female geder has bee associated with a icreased risk for brochial hyperresposiveess (provocative dose causig a 20% fall i FEV1 f1 mg); odds ratio (OR) 2.16, 95% cofidece iterval (CI) Smokig Issues pertaiig to active smokig are reviewed i a paper by SLAMA [55]. I two importat cohort studies (oe performed i the Uited States, the other i Copehage, Demark), the risk of disease icidece is still higher i males for cacer of the lug, while all tobacco-related cacer icideces ad the risk of all respiratory disease i those with.15 cigarettes smoke daily are higher i Daish females; i the America study, females show a icreased risk of cacer of the oesophagus ad COPD [56, 57]. I the Copehage Cetre for Prospective Populatio Studies, PRESCOTT et al. [58] foud that females have higher relative risks of death from respiratory disease tha males i each smokig category; for example, i females ad males, respectively, i ex-smokers OR 2.96 (CI ) versus 1.39 ( ), i curret smokers of 1 14 g?day -1 OR 5.21 ( ) versus 2.42 ( ), ad i curret smokers of.24 g?day -1 OR ( ) versus 4.68 ( ). Furthermore, Daish female smokers have also show a steeper declie i FEV1 tha male smokers [47]. The World Health Orgaizatio (WHO) Atlas, published i 2003, provides recet data o smokig prevaleces across the world [59]. Curretly, about 1 billio males ad 250 millio females across the world smoke, with marked geographical differeces betwee the sexes. The highest rates i males are foud i Asia, especially Chia. Coversely, i females, the highest rates are i Frace, Germay, ad Norway. I Norway ad Swede, the proportio of female smokers is similar to the proportio of males. EZZATI ad LOPEZ [60] have estimated that i the year 2000, 3.84 millio deaths i males ad 1 millio i females worldwide were due to smokig. The mortality fractio attributed to smokig raged betwee 91/92% for lug cacer ad 84/77% for COPD i males, whereas i females it raged betwee 70/72% for lug cacer ad 62/61% for COPD. I their studies, ULRIK [61] ad WATSON et al. [62] reported o geder similarities i smokig habits ad dissimilarities i the atural history of asthma ad COPD. Accordig to recet data from the US ad Demark, the historical tred of decrease i smokig habit has bee much steeper i males tha females, ad i the year 2000, more females were smokers tha males (.40% i Demark ad 25 30% i the US) [63, 64]. This pheomeo is explaied by the sequetial birth cohorts versus mea age at smokig iitiatio i males ad females i the US [65]. Mea age was almost steady (aroud yrs) i males from 1901 to 1951, whereas females from the 1901 birth cohort started to smoke at a mea age of 30 yrs; female mea age decreased substatially up to the same age as males i the 1951 birth cohort. PRIDE ad SORIANO [66] have described the historical tred i tobacco cosumptio i the UK for the period ad the prevalece of smokig i Eglad for the last quarter of the 20th cetury. I the last decade, the geder differeces have almost vaished. It is clear that i some coutries, like Demark, the observed umber of deaths from COPD after the 1990s has already rise higher i females tha i males. Furthermore, MANNINO [67] recetly reported that i the year 2000 the absolute umbers of female deaths due to COPD i the US exceeded male deaths for the first time. COPD ad geder The umber of females hospitalised due to COPD i Caada was estimated to exceed the umber of males by the year 2001, with the gap icreasig steeply up to 2016 [68]. Similarly, the umber of COPD deaths i females was projected to exceed that i males by the year 2006, with the gap icreasig steeply up to Coversely, i Sigapore, rates per 10,000 COPD hospitalisatios (18.2 versus 94.1) ad mortality (6.9 versus 28.2) have bee lower i females tha i males, respectively, i the period The distributio of COPD betwee the two geders shows a lik to latitude [35]. I coutries i Norther Europe, the differece i age-adjusted COPD death rates betwee males ad females is slight, whereas it is quite large i Easter ad Souther Europea coutries. The data of SORIANO et al. [69] show a icreasig tred i COPD diagosis i females from 1990 to 1997 (a 69% icrease compared with a 25% icrease i males). At the ed of the period, i patiets yrs old, UK physicias diagosed more COPD i females tha i males; i patiets aged yrs, they diagosed slightly more i males. The prevalece differece remaied elevated amog males ad females.65 yrs. However, after the diagosis had bee made, although females with COPD had the same patter as males, survival i males was worse at ay give level of severity. CHAN-YEUNG et al. [68] recetly reviewed the data for developig coutries, idicatig the persistece of a male female gradiet i terms of COPD hospitalisatio ad mortality rates, as well as tobacco-smokig habit. For the year 2001, they reported a world COPD prevalece of 1.01%, with a rage from 0.18% i Africa to 1.68% i Wester Pacific regios of WHO. HALBERT et al. [70] summarised the prevalece estimates of COPD, showig clearly that there are still differeces betwee males ad females but that these differeces are lower i the populatios i which spirometry has bee applied, such as Italy ad Norway. I additio, the authors show that the figures based o WHO were largely uderestimated. The Italia phase of the Europea Commuity Respiratory Health Survey determied that i subjects aged yrs i the geeral populatio, the prevalece of chroic brochitis was 11.8% i males ad 12.0% i females [71]. I a multiple logistic regressio model, female sex was associated with a sigificatly icreased OR (1.22, 95% CI ) of havig the coditio. The preset author s ow epidemiological data collected i the Po Delta Study i Italy were used to compare the prevalece rates of COPD severity, accordig to the Global Iitiative for Chroic Obstructive Lug Disease (GOLD) criteria [2], betwee males ad females of the geeral populatio (age rage: 8 78 yrs; fig. 1) [7, 36 40]. The author foud a additioal stage, called pre-risk 0, i which people with habitual cough or phlegm did ot meet the defiitio of chroic symptoms. About 35% of males were classified as c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 839

8 INCREASING COPD AWARENESS J. ZIELINSKI ET AL. GOLD stage pre-risk 0, 0, 1, 2, 3 or 4 compared to almost 23.4% of females. A total of 17.7% males have show sigs of pre-risk 0 ad 0 versus 13.6% of females. I 12.3% of males ad 7.3% of females, sigs of mild COPD were oted. Moderate ad severe COPD were aroud 5% i males ad 2.5% i females. By defiitio, 100% of those with either cough or phlegm were i the absece category, 100% of those with either habitual cough or phlegm (ot meetig the defiitio of chroic ) were i the pre-risk 0 category, ad 100% of those with either chroic cough or phlegm were i the at risk category (fig. 2). a) 14.2% 12.3% 4.5% 0.4% Although GOLD classificatio does ot take ito accout symptoms whe airflow obstructio is already preset to gradual severity of COPD, there is a icreasig tred to have a larger proportio of patiets with airflow obstructio ad simultaeous presece of symptoms i mild-to-severe COPD both i males ad females. I the latter category,,80% of subjects are symptomatic. Evirometal risk factors i females A paper by BLANC [72] discusses domestic evirometal exposures ad their potetial cotributio to respiratory diseases amog females. These evirometal factors are as follows: 1) biomass fuels, which expose females to particulates ad ca cause airway obstructio; 2) gas fuels, which expose females to itroge dioxide ad ca cause asthma exacerbatios; 3) cleaig agets, which ca expose females to hypochlorite/chlorie gases or other irritats ad ca produce irritat lug ijury, irritat brochitis ad asthma; ad 4) evirometal tobacco smoke, which exposes females to irritats ad carcioges ad ca cause respiratory symptoms ad cacer. I their paper, WAI ad TARLO [73] cite examples of lug diseases i occupatios that are relatively commo amogst females, as a) % % Percetage b) 7.3% 2.2% 0.3% % b) % Percetage % FIGURE 1. Prevalece of chroic obstructive pulmoary disease (COPD) severity by geder i the Po Delta survey, i a) males (51,214) ad b) females (51,250). &: absece; q: pre-risk 0; p: at risk of COPD; h: mild COPD; &: moderate COPD; &: severe COPD. Absece Pre-risk 0 At risk Mild Moderate Severe FIGURE 2. Distributio of chroic obstructive pulmoary disease severity accordig to symptoms i Po Delta survey, i a) males ad b) females. h: absece of symptoms; &: occasioal symptoms; &: chroic symptoms. 840 VOLUME 27 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

9 J. ZIELINSKI ET AL. INCREASING COPD AWARENESS well as some causative agets, such as occupatioal asthma, which ca occur i: 1) healthcare workers exposed to atural rubber latex or psyllium ad other pharmaceutical agets or formaldehyde; 2) food idustry workers (e.g. bakers, farmers, food processors) exposed to flour, ezymes, storage mites, eggs ad other foods; ad 3) house cleaers, exposed to commo idoor allerges, cleaig agets, ad irritat mixtures. Brochitis ca occur i other idustries/occupatios i which workers are exposed to irritat dusts, fumes ad smoke. A recet ATS Statemet reported estimates o the populatio attributable risk due to occupatioal exposure. They were: 15% for asthma; 15% for chroic brochitis; 19% for lug fuctio impairmet; 14% for dyspoea; ad 14% for wheezig [74]. Geder differeces i obstructive airway diseases To summarise, geder differeces i obstructive airway diseases result from the iteractio of sex-depedet geetic factors ad sociocultural differeces durig childhood, adolescece ad adulthood [44]. These are aspects of gee/evirometal iteractios, which occur i asthma ad COPD. Sex differeces i lug physiology ad immue respose ifluece the patters of obstructive pulmoary diseases. There is icreasig evidece to support the view that sex hormoes ifluece airway behaviour throughout the huma lifespa [49]. There are also differeces i evirometal factors betwee geders, related to the frequecy ad the type of exposure (smokig, occupatio, air pollutio etc.), for which females appear at greater risk. More attetio should therefore be paid to the home eviromet. Also, the cliical patter of diseases may be differet betwee geders. Geder differeces i the perceptio ad reportig of symptoms ad subsequetly i diagostic labellig ad maagemet should also be take ito accout. Thus, more epidemiological research should be devoted to studyig hormoal iflueces ad socioculturaldepedet risk factors. It is importat that stadardisatio for geder is replaced by stratificatio. The reproductive history of females ad their curret edocrie status should also be further pursued i aetiological research ad i the evaluatio of treatmet outcomes. Chagig COPD epidemiology Fially, it is importat to poit out that COPD epidemiology is chagig. I a follow-up study i Tucso, Arizoa (USA), SILVA et al. [75] clearly showed that active asthma at baselie is a sigificat risk factor for subsequet developmet of chroic brochitis, emphysema ad COPD. VIEGI et al. [40] have recetly published a paper describig the proportioal Ve diagram of obstructive lug disease i the Italia geeral populatio. These data cofirm that there is overlap betwee asthma, chroic brochitis ad emphysema, ad idicate that up to 15 categories of subjects ca be classified with the diagoses related to COPD [76]. Overall,,18% of the Italia geeral populatio samples report either the presece of obstructive lug diseases or show spirometric sigs of airflow obstructio. After stratifyig by sex (figs 3 ad 4) i the Po Delta Sample [7, 36 40], this percetage climbed to 21.9% of a) b) Chroic brochitis Chroic brochitis Emphysema Emphysema 0.49% 0.16% 0.25% 0.58% 0.08% 0.41% 0.33% 0.08% 0.16% 0.33% 3.46% 1.81% Asthma Airflow obstructio 13.77% FIGURE 3. Distributio of obstructive lug diseases a) with ad b) without airflow obstructio i Po Delta sample males. Asthma c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 841

10 INCREASING COPD AWARENESS J. ZIELINSKI ET AL. males compared with 13.9% of females. The proportio of those with airflow obstructio i the absece of ay respiratory diagosis is 10.96% i the whole populatio sample (13.77% i males; 8.24% i females). I the Pisa sample, rhiitis has bee show to be a idepedet risk factor for developig cough, with the exceptio of commo colds, i a 6-yr follow-up, without ay differece betwee males ad females [41]. Coclusio I coclusio, the priorities of epidemiological research o COPD should be as follows [35]. 1) To perform log-term geeral populatio surveys with subjective (questioaires) ad objective (spirometry, biomarkers) tools i order to improve the kowledge of the atural history (iceptio, exacerbatios, deaths, costs) of COPD. 2) To implemet studies to determie the most effective smokig-cessatio itervetios ad smokig-prevetio techiques. 3) To develop ew therapeutic modalities that ihibits the declie i lug fuctio. RAISING AWARENESS OF COPD Summary With the exceptio of smokig cessatio, factors i the developmet ad maifestatio of COPD have ot received the attetio of scietists or experts i healthcare delivery warrated by the public health importace of this chroic lug disease. To raise awareess of COPD ad for subsequet effective maagemet of the disease, a team approach is required that icludes multiple disciplies. At a local level, effective dissemiatio ad implemetatio of healthcare recommedatios seem to be based o the characteristics of the message, the recogitio of exteral barriers that require chage, ad how prepared cliicias are to make chage. Judgig from the success of the asthma coalitio groups, developig coalitio groups for COPD should be a valuable mechaism that brigs awareess campaigs to the local level. Various iitiatives of the GOLD programme ad the US COPD Coalitio that aim to raise global awareess of COPD, are described i this sectio. Raisig awareess of COPD at global, atioal ad local levels, should evetually result i reductio of the global burde of COPD. Itroductio Healthcare professioals, commuity leaders, policy makers, govermet agecies, the pharmaceutical idustry ad the public must all work together to develop ad provide effective healthcare delivery strategies for patiets with COPD. However, with the exceptio of smokig cessatio, factors i the developmet ad maifestatio of COPD have ot received the attetio of scietists or experts i healthcare delivery warrated by the public health importace of this chroic lug disease. Programmes that raise awareess about COPD, its importace as a public health problem, its symptoms, how to make a diagosis ad how to maage those who are afflicted with this chroic coditio are beig implemeted i several coutries. These are based o GOLD [1, 2]. Through the etwork of idividuals ivolved i the GOLD programme, it is aticipated that much will be leart about how the diagosis, treatmet ad prevetio of COPD ca be promoted ad effectively implemeted i a variety of healthcare settigs. a) b) Chroic brochitis Emphysema Chroic brochitis Emphysema 0.64% 0.32% 0.08% 0.08% 0.24% 0.08% 0.24% 0.16% 0.80% 3.04% Airflow obstructio Asthma 8.24% Asthma FIGURE 4. Distributio of obstructive lug diseases a) with ad b) without airflow obstructio i Po Delta sample females. 842 VOLUME 27 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

11 J. ZIELINSKI ET AL. INCREASING COPD AWARENESS For may years, healthcare workers have had a rather ihilistic approach to the care of COPD patiets. Awareess programmes desiged to make a positive impact will be required. Effective maagemet of COPD is o loger the resposibility of the pulmoary disease specialist aloe, but requires a team approach that icludes multiple disciplies. At all stages, patiets ad their families should be actively ivolved i programmes desiged to raise awareess of COPD. Itervetios to promote behavioural chages amog health professioals The traslatio of research fidigs to impact o public health requires strategies to promote behaviour chages amog healthcare professioals. May approaches have bee take ad there is icreasig literature o dissemiatio ad implemetatio. A Cochrae Group [77] coveed to examie the literature o itervetios that promote the implemetatio of research fidigs, icludig: dissemiatio ad implemetatio of guidelies; cotiuig medical educatio; strategies, such as audit, feedback ad computerised decisio support systems; target groups, icludig urses ad primary healthcare professioals; ad particular types of behaviour, such as diagostic testig, prescribig or aspects of prevetive care. Although there were commo methodological problems i may of the studies, ad heterogeeous issues were addressed, a umber of cosistet themes were idetified that may help to desig programmes of awareess for COPD. For example, passive dissemiatio of iformatio (such as publicatio of cosesus cofereces i professioal jourals or the mailig of educatioal materials) was geerally foud to be ieffective i alterig practices. The use of computerised decisio support systems led to improvemets i performace i such areas as decisios o drug dosage, provisio of prevetive care ad geeral cliical maagemet of patiets, but ot i diagosis (a importat issue i the area of COPD). Patiet-mediated itervetios seemed to improve the provisio of prevetive care (i studies coducted i North America). At a local level, effective dissemiatio ad implemetatio of healthcare recommedatios seemed to be based o the characteristics of the message, the recogitio of exteral barriers requirig chage ad how prepared cliicias are to make chage. Raisig the awareess of patiets/families Outreach educatio programmes of the Natioal Heart, Lug ad Blood Istitute (NHLBI) ad the Natioal Istitutes of Health (NIH) have take several approaches to raisig the awareess of patiets ad their families i relatio to specific health topics, such as high blood pressure, cholesterol ad obesity as risk factors for cardiovascular disease ad stroke. I 1990, the NHLBI iitiated the Natioal Asthma Educatio ad Prevetio Program to raise awareess of the burde of asthma ad to implemet recommedatios for effective treatmet ad prevetio [78]. The NHLBI educatio outreach programmes are coducted through a coordiatig committee comprised of represetatives from member orgaisatios, icludig govermet agecies, medical ad healthcare orgaisatios ad patiet groups. For example, the Natioal Asthma Educatio ad Prevetio Program icludes allergy, respiratory, emergecy care, ad primary care medical orgaisatios; orgaisatios represetig respiratory therapists, urses, allied health persoel ad teachers; NIH istitutes supportig asthma research; ad patiet groups, such as the Mothers of Asthmatics. Together, these orgaisatios developed recommedatios for asthma maagemet ad prevetio (guidelies), established aveues for programme dissemiatio of iformatio (programme awareess) ad worked o tools to evaluate programme effectiveess. Multiple idicators (icludig reductio i mortality; fig. 5) provide evidece that a coordiated programme of good scietific iformatio ad a etwork of parter orgaisatios (stakeholders) to assure programme awareess ad iformatio dissemiatio ca impact o patiet care. Amog the lessos leared from the NHLBI Natioal Asthma Educatio ad Prevetio Program has bee the importace of establishig local coalitio groups to work at the commuity level to raise awareess of asthma ad to improve asthma care. This approach utilizes local etworks to ehace the dissemiatio ad utilizatio of sciece-based iformatio to chage kowledge, practice, ad behaviour. It provides iformatio about the target audiece (demographics, behaviours, local media, local leaders), ad is a meas to raise the resources for patiet awareess campaigs. The programme has also developed ad tested a variety of commuicatio chaels icludig televisio/video, audio/ radio, prit, ad support materials targeted to local ews media outlets. Based o the success of the asthma coalitio groups, developig coalitio groups for COPD should be a valuable mechaism to brig COPD awareess campaigs to the local level. Raisig global awareess of COPD: the GOLD programme GOLD was iitiated i 1997 i cooperatio with the WHO ad the NHLBI to icrease awareess of COPD, ad with the ultimate goal of decreasig morbidity ad mortality from this disease. The objective of GOLD is to improve prevetio ad Number of deaths Iflammatio i asthma Asthma Guidelies NAEPP Self-maagemet programme Drug developmet Year FIGURE 5. Aual mortality from asthma (total populatio). NAEPP: Natioal Asthma Educatio ad Prevetio Program. Reproduced from a lecture delivered by C. Lefat, durig the Presidet s Lecture, at the America Thoracic Society meetig With permissio from C. Lefat (persoal commuicatio, Gaithersburg, MD, USA). c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 4 843