COPD: problems in diagnosis and measurement

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1 Eur Respir J 3; 21: Suppl. 41, 4s 12s DOI:.1183/ Prited i UK all rights reserved Copyright #ERS Jourals Ltd 3 Europea Respiratory Joural ISSN COPD: problems i diagosis ad measuremet S.T. Weiss*, D.L. DeMeo*, D.S. Postma # COPD: problems i diagosis ad measuremet. S.T. Weiss, D.L. DeMeo, D.S. Postma. #ERS Jourals Ltd 3. ABSTRACT: Chroic obstructive pulmoary disease (COPD) is the most rapidly risig cause of death i idividualsw65 yrs of age, the most rapidly growig segmet of the USA populatio. Advacig the cliical research ageda for COPD etails careful cosideratio of several issues ad problems: defiig COPD, reliace o physiological testig, outcome measuremets ad comorbidities. I additio, issues pertaiig to the recet dramatic icrease i chroic obstructive pulmoary disease mortality i females, smokig susceptibility ad the relatioship of respiratory symptoms with hyperresposiveess, as well as chroic obstructive pulmoary disease heterogeeity, are discussed. Eur Respir J 3; 21: Suppl. 41, 4s 12s. *Chaig Laboratory, Brigham & Wome9s Hospital, Bosto, MA, USA. # Uiversity Hospital, Groige, The Netherlads. Correspodece: S.T. Weiss, 181 Logwood Aveue, Chaig Laboratory, Bosto, MA 2115, USA. Fax: Scott.weiss@chaig.harvard.edu Keywords: Airway hyperresposiveess, comorbidities, exacerbatio, pulmoary fuctio testig, outcome measuremet Received: August 21 2 Accepted after revisio: February 3 Chroic obstructive pulmoary disease (COPD) is a major public health problem. Recet prevalece estimates suggest that y15 millio people have COPD; i 1996, 14.1 millio people had chroic brochitis ad 1.8 millio had emphysema [1]. This disease is the most steeply risig cause of death i idividuals w65 yrs of age, which represets the most rapidly growig segmet of the USA populatio. Disability from COPD is expected to rise by with ageig of the populatio ad the icrease i disease prevalece. It will be the fifth-leadig cause of disability-adjusted life years lost [2], ad it will rise worldwide from beig the sixth to the third most commo cause of death [1]. Excessive focus o the sigle evirometal factor of cigarette smokig has bee to the detrimet of COPD research, as it has teded to miimise a uderstadig of geetic, developmetal ad other evirometal risk factors that may be importat i disease susceptibility ad disease progressio. Although cigarette smokig is most certaily the major risk factor for the developmet of COPD [3], oly a small percetage of cigarette smokers develop the disease [4]. I additio, a variable respose to cigarette smokig clearly suggests geetic susceptibility. This article briefly cosiders a series of importat issues that eed attetio i COPD research. These issues iclude defiig ad diagosig the disease, uderstadig the problems iheret i relyig o physiological testig aloe to make a diagosis, the importace of ot discoutig childhood episodes as irrelevat to adult pathology, the lack of well-defied pheotypes for trackig the disease, risk factors (related to sex, hyperresposiveess, respiratory symptoms), geetics ad the importat issue of comorbidities. Oly careful cosideratio of these problems ad a attempt at mitigatig their ramificatios will allow the advacemet of the cliical research ageda for COPD ad improve treatmet for what is a serious, life-threateig disease. Defiig chroic obstructive pulmoary disease Oe of the critical issues i COPD research has bee the lack of a cohesive defiitio for the disease. The lack of a iteratioal stadard has cofouded the comparability of COPD studies. True icidece ad prevalece treds may be obscured by this defiitioal variability, illustrated i a study by VIEGI et al. [5] that compared prevalece rates of COPD i the Po Delta Valley, Italy, usig Europea Respiratory Society (ERS) ad America Thoracic Society (ATS) criteria. I subjects o46 yrs of age, ERS criteria suggested a 12.2% prevalece of COPD compared with a 57% prevalece by ATS criteria. Of ote, cliical criteria suggested a prevalece of 28.8% [5]. The Global Iitiative for Chroic Obstructive Lug Disease (GOLD) represets a viable iteratioal effort to codify the defiitios ad criteria for diagosis ad maagemet of COPD [6]. Accordig to the GOLD criteria, "COPD is a disease state characterised by airflow limitatio that is ot fully reversible. The airflow limitatio is usually both progressive ad associated with a abormal iflammatory respose of the lugs to oxious particles or gases" [7]. Spirometric evaluatio should be used to cofirm the diagosis whe suggestive symptomatology is preset. Chroic cough ad sputum productio have a variable relatioship to airflow limitatio, which is the sie qua o of COPD [8]. The epidemiological maifestatios of the disease (chroic cough, phlegm ad dyspoea o exertio) ad the pathological maifestatios (elarged ad icreased umbers of mucus-secretig glads, destructio of the lug parechyma ad the developmet of emphysema) have a statistically sigificat, but ot a high degree of, correlatio with COPD cofirmed by physiological testig. Some idividuals with airflow obstructio do ot have severe emphysema ad some idividuals with emphysema do ot have airflow limitatios [9, ]. Epidemiological studies demostrate that respiratory symptoms may precede or follow the developmet of airflow limitatio by may

2 COPD DIAGNOSIS AND MANAGEMENT 5s Table 1. Risk factors for the developmet of chroic obstructive pulmoary disease Host susceptibility factors Age Airway resposiveess Allergy Sex Geetics years. The presece or absece of symptoms also depeds largely o the costellatio of risk factors to which a idividual is exposed (table 1). Importatly, peak flow aloe has a low specificity for the diagosis of COPD, as decremets i peak flow ca be preset i other pulmoary diseases. Whe spirometry is performed, a diagosis of COPD is cosidered to be preset if the postbrochodilator forced expiratory volume i oe secod (FEV1) isv8% of the predicted value i combiatio with a FEV1/forced vital capacity (FVC) ratio of v7% [11]. Recetly, stadards of severity have also bee defied with a goal toward global uiformity i the diagosis of COPD [11] (table 2). It should be oted that the role of classifyig idividuals ito GOLD stage (with absece of airflow limitatio but presece of cough ad sputum) may ot actually be useful for idetifyig the idividuals "at risk" for future developmet of obstructive pulmoary disease. VESTBO ad LANGE [12] aalysed 5- ad 15-yr data from The Copehage City Heart Study usig multivariate regressio techiques; this aalysis suggested that GOLD stage did ot effectively idetify the future developmet of airways obstructio at these time poits [12]. Physiological testig Evirometal risk factors Smokig Occupatioal exposures (Idoor) Air pollutio Diet Evirometal allerges Table 2. Classificatio of chroic obstructive pulmoary disease (COPD) by severity Stage Classificatio Characteristics At risk Chroic respiratory symptoms, smokig ad ormal spirometry 1 Mild COPD FEV1 o8% pred FEV1/FVC v7% 2 Moderate COPD FEV1 3 8% pred FEV1/FVC v7% 3 Severe COPD FEV1 v3% pred FEV1/FVC v7% All spirometry is postbrochodilator. FEV1: forced expiratory volume i oe secod; % pred: % predicted; FVC: forced vital capacity. Adapted from [7] with permissio. Pulmoary fuctio testig is reproducible ad FEV1 tracks cosistetly durig growth from a early age, which ca be used to track idividuals over time [13] (fig. 1). Pulmoary fuctio testig is geerally ot admiistered to patiets durig routie outpatiet visits. This greatly hiders the potetial for COPD diagosis at early stages of the disease ad has direct relevace to prevalece estimates ad the cliical practices of COPD [14]. Spirometry has bee demostrated to be a efficiet method for detectio of airway obstructio i outpatiet cliics i specifically targeted higher-risk groups. I a large-scale effort to demostrate the efficacy of spirometry for screeig, ZIELINSKI ad BEDNAREK [15] offered spirometry to 11,27 idividuals w39 yrs of age with at least 11 pack-yrs of smokig. Spirometric criteria for obstructive lug disease were observed i FEV1 L Height m Fig. 1. Growth of forced expiratory volume i oe secod (FEV1) for seve selected male childre followed for repeatability over a 11-yr iterval. Idividuals track alog their growth curves. From the lower to the upper lie, the percetage smoothed percetiles of FEV1 by height are 3,, 25, 5, 75, 9 ad 97%, respectively. Reproduced from [13] with permissio. 24.3% of the cohort. Of 2, participats who were lifetime ever-smokers, 14.4% had demostrable airway obstructio [15]. Recet treds i the prevalece of COPD are suggested i the third Natioal Health ad Nutritio Examiatio Survey (NHANES III) [14]. Outcome measures icluded a physicia diagosis of asthma, chroic brochitis, emphysema, respiratory symptoms ad low lug fuctio. Low lug fuctio was defied as both a FEV1/FVC ratio of v.7 ad a FEV1v8% pred. Of the cohort of,5 idividuals, 6.8% had low lug fuctio as defied ad 8.5% reported a diagosis of COPD. The majority (63.3%) of those idividuals with documeted low lug fuctio had o prior physicia diagosis of COPD. Data from this NHANES study also suggested that a sigificat amout of disease remais udiagosed whe i the mild stage, thus uderestimatig the actual prevalece ad burde of disease [14]. The classic estimates are that 15% of all adults w55 yrs of age have udiagosed airflow limitatio. This icreases with advacig age ad may reach as high as 3 4% i idividualsw7 yrs of age [16, 17]. I Spai, a similar observatio was made regardig uderdiagosis of COPD. I a large populatio study of 4,45 males ad females (aged 4 69 yrs), the prevalece of COPD was 9.1%; although the majority of this disease was observed i curret ad former smokers, there was a compoet of disease that was observed amog osmokers. I 78.2% of cases there was o prior physicia diagosis of COPD. Idividuals who were male, w6 yrs, more educated ad had w15 pack-yrs of smokig were more likely to have received a prior diagosis of COPD [18]. I a sample of 353 idividuals i a British geeral practice, 58 patiets had obstructive lug disease oted with screeig spirometry; 52% had o prior diagosis of lug disease [19]. The use of spirometry i health cliics is importat to be able to estimate the true burde of COPD ad its impact o health as the populatio ages. Variability i patters of cliical presetatio is commo i COPD, which also makes diagosis difficult. Patiets may ot focus o respiratory complaits whe they visit a physicia. Declie of pulmoary fuctio is preset i all idividuals with ageig, thus, most older persos will accommodate their physical activity to ecompass their respiratory reserve. Cosequetly, they will ot cosult a physicia for respiratory complaits aloe or metio them to the physicia durig a visit. This is particularly true i Wester idustrialised

3 6s S.T. WEISS ET AL. society, i which people do ot have to egage i streuous physical activity ad ca thus modify their persoal ad occupatioal activities to be eergy ad breath coservig. It is ot uusual for some iterveig evet such as a respiratory illess to cause a patiet to visit a physicia. Yet, most likely, ad erroeously, the patiet will attribute shortess of breath to that specific episode rather tha accept the evet as part of a gradual uderlyig, uremittig declie i pulmoary fuctio. The et result of these patters is that physicias are ot predisposed to perform pulmoary fuctio testig. Cosequetly, a substatial portio of COPD remais udiagosed [14]. Risk factors ad diagostic obstacles Risk cosideratios i COPD should be divided ito risk for disease developmet ad risk for disease progressio. Itrisic to the cosideratio of risk for the developmet of COPD are both host susceptibility ad evirometal factors, as eumerated i table 1 ad discussed below. Childhood asthma ad icreased airways resposiveess may also represet the most importat evets that mark susceptibility for lug fuctio declie ad subsequet developmet of COPD []. Durig childhood, pulmoary fuctio icreases ad give that symptoms are loosely correlated with pulmoary fuctio, asthma-type symptoms ted to declie with lug growth. Childhood evets are importat i that they reduce maximal lug growth ad may precipitate early declie [21] (fig. 2). A retrospective study of asthma icidece rates i Rochester, MN, USA, showed that 4% of childre who wheezed durig their first year of life wet o to develop asthma ad that 9% of all asthma was diagosed by age 6 yrs [22]. Most adults who are susceptible to lug damage from smokig have also had some childhood episode or illess that marked them as susceptible for developig COPD [23], which is of cocer with regard to treds i COPD. Data from the Natioal Health Iterview Survey revealed that self-reported asthma rates have icreased by 75% durig the years The most sigificat icrease was i childre from birth to 4 yrs of age, whose rates were oted to icrease by 6% [24]. These treds may ifluece the future burde of disease secodary to COPD. Ufortuately, adult patiets with respiratory problems are ofte uable to recall those episodes from the distat past. Cosequetly, both patiets ad physicias regard curret symptoms to be ew-oset adult disease, whe, i fact, the symptoms may represet a recrudescece of disease that bega early i life. Although differet aspects of idoor air pollutio such as chroic biomass or wood smoke may be relevat to the developmet of obstructive lug disease [25 28], globally, cigarette smokig is the most importat evirometal risk that cotributes to COPD [3]. Factors that appear to be importat host characteristics with regard to susceptibility to smokig-related COPD iclude geetic predispositio, female sex, the presece of uderlyig asthma or airways resposiveess ad, possibly, the presece of uderlyig allergy a) b) FEV1 % ormal level of age group FEV1 % ormal level of age group c) d) Age yrs Age yrs Fig. 2. The four phases of growth ad declie i lug fuctio through the life cycle; curves begi at birth ad proceed through the life course. a) Decreased itra-uterie growth, b) decreased growth, c) shorteed plateau ad d) icreased rate of declie. Childhood evets may reduce maximal lug growth ad may precipitate early declie. The shaded areas idicate periods of time durig differet ages i which differet mechaisms cotribute to processes that may result i low forced expiratory volume i oe secod ad, potetially, chroic obstructive pulmoary disease later i life. Reproduced from [21] with permissio.

4 COPD DIAGNOSIS AND MANAGEMENT 7s [29, 3]. Whe a patiet with such host susceptibilities begis to smoke cigarettes, disease is produced at a much lower dose (as measured by pack-yrs of cigarette smokig) [4]. Sice idividuals vary i their geetic susceptibility to cigarette smokig, there is substatial variatio i the pulmoary fuctio for ay give dose of cigarette smokig [4] (fig. 3). Regardless of smokig status, however, cliicias are much more likely to diagose males with COPD ad females with asthma or asthmatic brochitis. I a logitudial study, females w4 yrs of age are ofte deemed "asthmatic" whe compared with males of the same age ad with similar symptoms [31]. The combiatio of recall bias o the part of the patiet ad diagostic bias o the part of the physicia cosequetly creates diagostic ucertaity ad potetial misdiagosis of COPD [32]. FEENSTRA et al. [33] recetly showed that there will be a icrease i the burde of COPD a) % of populatio b) % of populatio c) % of populatio d) % of populatio e) % of populatio Predicted FEV1 % Fig. 3. Percetage distributio of predicted forced expiratory volume i oe secod (FEV1) values i subjects with varyig pack-yrs of smokig: a), b), c) 21 4, d) 41 6 ad e) w6 pack-yrs. Subjects with respiratory symptoms before age 16 yrs were excluded. The dashed vertical lie idicates the % predicted poit for FEV1. The arrows idicate media FEV1 ad the short vertical lies idicate the mea. The horizotal lies represet 1 SD. Reproduced from [4] with permissio. betwee This will result i a 43% icrease i prevalece of COPD for males ad a 142% icrease for females. Allergy Allergic pheotypes represet immediate hypersesitivity to atige ad may maifest as a elevatio i total or specific immuoglobuli E, elevated total eosiophil couts ad positive ski-test reactios to specific allerges. Ski-test reactivity icreases util age 15 yrs [34] ad the declie i reactivity after age 35 yrs cofouds the measuremet of this itermediate pheotype i idividuals suspected to have COPD. Although the fidigs of associatio betwee ski-test reactivity ad FEV1 have ot bee cosistet [35 37], GOTTLIEB et al. [37] ivestigated this prospectively ad foud that positive ski-test reactivity predicted icreased rates of declie i FEV1 ad FEV1/FVC ratio. It has also bee suggested that immediate type-i hypersesitivity is a risk factor for the developmet ad progressio of COPD [3]. I this model, atopy may ifluece childhood asthma ad thus limit maximally attaied lug growth, accelerate FEV1 declie ad ehace iteractio with cigarette smoke, thus promotig lug fuctio declie ad the developmet of COPD [3]. Airway hyperresposiveess Airway hyperresposiveess to methacholie may help idetify idividuals susceptible to the developmet of COPD ad those susceptible to progressive lug fuctio declie [38]. This itermediate pheotype is ot oly a cardial feature i asthma, but also a importat fidig i a subset of idividuals with COPD [3, 37, 38]. Baselie levels of lug fuctio, age ad smokig history all play a role i this pheotype. I some idividuals, airway hyperresposiveess predicts a acceleratio i lug fuctio declie ad the developmet of COPD [38]; i others, this pheotype may predict COPD-related mortality [39]. I at-risk idividuals, airway resposiveess may be demostrated i the majority of istaces whe it is actually measured [4]. However, methacholie challege is ofte avoided i idividuals already suspected of havig low lug fuctio. A importat cosideratio is that airway hyperresposiveess may be a cause ad ot a result of COPD. A 25-yr study i the Netherlads demostrated that icreased airway hyperresposiveess is a idepedet risk factor for declie i FEV1 [41]. I a study of idividuals with early-oset COPD, those with icreased airway hyperresposiveess had a accelerated declie i FEV1 [42]. It is still debatable whether hyperresposiveess improved by ati-iflammatory therapy may improve the course of the disease. Oe study has show that ihaled corticosteroids improved hyperresposiveess after 4 yrs of treatmet. Despite this improvemet, pulmoary fuctio declie did ot cease [43]. Respiratory symptoms Respiratory symptoms have bee associated with lower levels of pulmoary fuctio [44 47], although patiets may uderestimate the morbidity associated with their disease. I a large iteratioal telephoe screeig of 1,921 households (i the USA, Caada, Frace, Italy, Germay, the Netherlads, Spai ad the UK), 3,265 idividuals with probable obstructive lug disease were idetified. For example, amog idividuals with the most severe breathlessess ad limitatio (uable to leave home secodary to dyspoea), 35.8% described their

5 8s S.T. WEISS ET AL. disease as mild; of those uable to ambulate for a few miutes o level groud, 6.3% described their disease as mild [48]. Although the impairmet associated with chroic cough was observed predomiatly i males [44], it has bee reported that females ad males with chroic cough ad chroic mucus hypersecretio have a accelerated declie i FEV1 [45, 46] ad greater mortality from COPD [47]. Whether these symptoms are markers of pathological alteratio of the airways is ot kow. The relatioship betwee symptoms ad hyperresposiveess has bee studied i Vlagtwedde/Vlaardige i the Netherlads. The more severe hyperresposiveess a subject had without respiratory symptoms, the more likely they were to develop respiratory symptoms i later life [49]. Furthermore, i a subsequet aalysis, it has bee show that idividuals with hyperresposiveess ad eosiophilia are more proe to develop respiratory symptoms [5]. Thus, both hyperresposiveess ad eosiophilia may costitute risk factors for the developmet of symptoms ad are worthwhile measurig i studies assessig COPD risk. These parameters may also be useful for assessig the impact of prevetio ad itervetio strategies. Sex ad sex differeces A differece has always existed i the prevalece of COPD i males ad females, with males havig higher rates. The gap betwee males ad females has bee arrowig, however, ad the icreased rates of females smokig cigarettes i the last 3 yrs have bee associated with steadily icreasig rates of COPD i females. Figure 4 illustrates that females have bee catchig up with males rapidly i COPD mortality, particularly durig the last decade [51]. MANNINO et al. [52] aalysed data cocerig death from ad foud that although mortality rates for males with COPD have started to stabilise, these rates were cotiuig to icrease amog females. There are alterative explaatios for icreasig COPD mortality amog females. Oe proposal is that females are more susceptible tha males to the effects of cigarette smoke. For ay give level of smokig, females have a lower FEV1 [53]. Furthermore, there have bee sigificatly greater rates of FEV1 declie amog female smokers compared with male smokers, as show i a epidemiological settig i the Netherlads [54]. Fially, a sex differece i severe, earlyoset COPD has bee demostrated [55]. I the offsprig of 84 idividuals with severe, early-oset COPD, there was a markedly elevated prevalece (71.4%) i females. Curret or exsmokig female first-degree relatives appeared to have a sigificatly greater risk of a low FEV1, with odds ratios of 1.91 for FEV1v8% pred ad 3.65 for FEV1v3% pred. These data suggest that females may be more susceptible to the developmet of COPD. Iterestigly, there was o sigificat risk for chroic brochitis i females, although there was a risk i males. CHEN et al. [56] showed that females have more severe small airway disease for a similar level of smokig (fig. 5). Emphysema occurs predomiatly i the small airways ad this fidig may suggest a greater likelihood for females to develop emphysema whe smokig. LEYNAERT et al. [57] demostrated that females were more likely to have airway hyperresposiveess tha males; this could ot be explaied by sex differeces i the presece of asthma, respiratory symptoms, atopy or lug fuctio. A brochocostrictive respose to methacholie was associated with heavy tobacco cosumptio oly i females. They cocluded that the excess of airway hyperresposiveess i females is ot due to their havig a smaller lug fuctio size or airway calibre tha males, but to a greater susceptibility to the effects of cigarette smokig [57]. Airway hyperresposiveess is a risk factor for both the developmet ad progressio of COPD. The more severe the hyperresposiveess, the more rapid the declie i pulmoary fuctio [35, 42, 58, 59]. Thus, the higher prevalece of airways hyperresposiveess i females may ideed explai the differece betwee males ad females with respect to smokig-iduced COPD. Females i the Lug Health Study had greater airway hyperresposiveess to methacholie tha males with mild COPD [59]. Notably, sex differeces i this group of idividuals with established COPD were ot sigificat with respect to the ifluece of hyperresposiveess o lug fuctio declie. Coversely, females have a greater degree of hyperresposiveess to methacholie irrespective of pulmoary fuctio [6]. Thus, it is still possible that the ehaced severity of hyperresposiveess i females may cotribute to their greater susceptibility to cigarette smoke ad other evirometal risk factors that ifluece pulmoary fuctio. Airway size is aother factor possibly cotributig to differeces betwee sex susceptibility to the effects of cigarette smoke. Betwee males ad females at a youg age, differeces Deaths per l l l s s s s s l l l l l l l l l l l l l l l l s s s s s s s s s s s s s s Breath test observed versus predicted value Year Fig. 4. Mortality due to chroic obstructive pulmoary disease (COPD). Female mortality from COPD has icreased steadily i the USA over the last several decades, largely as a result of their icreased cigarette smokig. &: male; $: total; +: female. Adapted from data from [51] Pack-yrs Fig. 5. Slope of Phase III of the sigle breath itroge test: differeces i females (...) ad males ( ). Females have more severe small airway disease tha males for a similar level of cigarette smokig. Reproduced from [56] with permissio

6 COPD DIAGNOSIS AND MANAGEMENT 9s MEF 4% TLC L s TLC L Fig. 6. Growth of lugs ad airways i youg males ad females aged yrs. Females have larger airways i relatio to lug size tha males. Males demostrated more proouced airway growth compared with females, resultig i airways equal to or larger tha those i females with the same lug volume. This figure shows logitudial chage of log maximal expiratory flow (MEF) versus chage of total lug capacity (TLC) based o idividual slopes ad itercepts. 9% Cofidece bads for symptomatic males (&), asymptomatic males (p), symptomatic females (&) ad asymptomatic females (u) are show. Reproduced from [61] with permissio. already exist that may accout for the ehaced effect of smokig i females. Youg females have larger airways i relatio to lug size tha youg males [61] ad specific airway resistace is lower at ay give height i females (fig. 6). Thus, relevat to the developmet of COPD, smoke particles may impact males ad females differetly. Geetics Most COPD is ot secodary to a 1 -atitrypsi deficiecy, the oly curretly prove geetic risk for this disease [62, 63]. Istead, most COPD represets the expressio of a complex geetic disease, resultig from a iteractio betwee host ad evirometal factors [64]. Most studies of COPD geetics have focused upo itermediate pheotypes ad pulmoary fuctio parameters. Twi studies have show that the cocordace of lug fuctio was larger i moozygotic tha i dizygotic twis [65]. I a cohort of idividuals with COPD, SILVERMAN et al. [66] studied 4 first-degree relatives of 44 probads with severe, early-oset COPD. First-degree relatives of probads had sigificatly lower FEV1 ad FEV1/ FVC ratios whe compared with cotrols havig similar smokig histories. Reduced spirometry i first-degree relatives was foud i curret or exsmokers oly [66]. These reports suggest both familial aggregatio of COPD (idepedet of protease ihibitor type) ad the importace of gee-byeviromet iteractios betwee cigarette smoke ad still uidetified geetic iflueces. Recet publicatios have foud multiple geetic loci ivolved i spirometric pheotypes associated with COPD [65, 67 7]. The variability i gee-to-gee ad gee-by-eviromet iteractios, both i the susceptibility ad the progressio of COPD, costitutes the challege of dissectig the geetics of COPD. Evirometal risk factors Cigarette smoke is the most importat evirometal challege that iflueces lug fuctio declie ad the developmet of COPD. The dose/effect relatioship betwee cigarette smoke ad lug fuctio declie depeds upo whe a idividual is exposed. Amog those smokers already with a low FEV1, lug ijury ad decrease i lug fuctio secodary to cigarette smokig is more impressive. I the Lug Health Study [42], middle-aged smokers who cotiued smokig for 5 yrs had further losses of FEV1 of several hudred millilitres. Importatly, however, COPD has bee idetified i osmokers as well, with 4% of males ad 5% of females reportig physicia-diagosed COPD. Therefore, other related evirometal risks are importat cotributors. Occupatioal ad air pollutio exposures may result i the developmet of a obstructive pheotype [71, 72], ad evirometal awareess ad cotrol should be a acillary feature addressed i miimisig patiet risk for the developmet ad progressio of COPD. Risk for disease exacerbatio It is still debatable whether exacerbatios of COPD costitute a risk factor for accelerated declie i lug fuctio [73]. However, exacerbatios costitute a large idividual burde ad have a dramatic impact o the quality of life ad eed for healthcare [74]. Risk factors for exacerbatios have ot bee studied extesively, although a wide variety have bee proposed. Bacterial [75, 76] ad viral [77] ifectios are importat factors that ifluece exacerbatios of COPD. Exacerbatio may be maifest as icreased sputum productio with the developmet of purulet features ad icreased dyspoea. I oe study, daily wheeze ad brochitic symptoms cotributed to a higher frequecy of exacerbatio [74]. KESSLER et al. [78] reported that risk factors for hospitalisatio icluded a low body mass idex ad poor performace o a 6-mi walk test, but gas exchage impairmet ad pulmoary ad haemodyamic dysfuctio were the most importat risks. Importatly, oe study suggests that may patiets ultimately hospitalised with COPD exacerbatio have modifiable characteristics that impact o susceptibility (such as lack of iflueza vacciatio, improper use of medicatios, ogoig cigarette smoke exposure) [79]. These deficiecies i outpatiet maagemet may be addressed to help limit disease exacerbatio. I this same study, previous hospital admissios, lower FEV1 ad uderprescriptio of log-term oxyge therapy were idepedetly associated with a higher risk of admissio for a COPD exacerbatio [79]. Logitudial studies are urgetly eeded to assess relevat determiats of COPD-related exacerbatios ad hospitalisatio. Disease outcome measuremet Despite the uderstadig of the host susceptibility factors, COPD diagosis remais a challege. Frequetly, COPD is diagosed oly whe the disease has already progressed. It is ot possible to measure lug tissue damage or small airway disease at a early stage. This early stage is precisely whe a perso should be wared about the egative effects of evirometal stimuli ad whe a physicia could itervee to limit the progressio of these chages i lug tissue ad airway walls. COPD is defied physiologically o the basis of pulmoary fuctio level, ad spirometry has become the primary edpoit for cliical trials. Although kowledge is icreasig [8, 81], relatively little is kow about the iflammatory processes i COPD. Ulike other diseases, where there are viable biomarkers to moitor the iflammatory process, COPD lacks established itermediate pheotypes that ca be utilised to track the disease progressio ad serve as surrogate markers ad outcome variables i cliical trials. This is a tremedous problem both for determiig the

7 s S.T. WEISS ET AL. ecoomic ad social burdes of COPD, as well as determiig efficacy ad effectiveess i cliical studies. Oe such moitorig tool may be iduced sputum or exhaled air codesate. Sputum eosiophilia appears to be preset i some idividuals with COPD ad has bee associated with a better oral corticosteroid respose [82]. To date, o study has ivestigated prospectively whether this ca be utilised i cliical practice to assess ihaled steroid respoders. It has bee well established that exhaled hydroge peroxide (H 2 O 2 ) is icreased i patiets with COPD [83]. Oe study ivestigated the effect of 6 mg N-acetylcysteie (NAC) o exhaled air codesate with H 2 O 2 ad lipid peroxidatio products [83]. After 9 ad 12 moths of treatmet, the NAC group exhaled 23-fold ad 26-fold less H 2 O 2 tha those who received placebo. No sigificat effect of NAC admiistratio o lipid peroxidatio products was oted over the whole treatmet period. These results idicate that log-term oral admiistratio of NAC atteuates H 2 O 2 formatio i the airways of COPD subjects ad provides support for the atioxidat actio of the drug. However, further studies are ecessary to estimate the cliical sigificace of this fidig [84]. Oe other potetial biomarker of COPD is high-resolutio computed tomography (HRCT), which haresses the aatomical ad pathological features of COPD together with cuttig-edge techology. I fact, refiemet of this techique may prove useful i addressig the presece of risk for lug obstructio before spirometric abormalities develop. SANDERS et al. [85] ad SANTIS et al. [86] showed that 68 8% of smokers had demostrable evidece of emphysema o HRCT i the presece of ormal spirometry. Although HRCT as a cliical techique is still beig developed, it may provide a mucheeded lik betwee the aatomy ad physiology ad allow for earlier recogitio ad maagemet of disease susceptibility factors. Fially, COPD is a heterogeeous disease. Some patiets with COPD have evidece of brochitis i the airway wall. Others have small ad almost udetectable airway disease with covetioal pulmoary fuctio testig ad others may have a loss of elasticity i lug tissue. It is clear that these disease characteristics suggest differet uderlyig disease processes. Cotiuig to cosider these disparate groups as oe group may obscure risk factors for disease developmet or progressio. I groupig these differet pheotypes, a clear uderstadig of the variable expressio of COPD is lost. Cosequetly, the opportuity to select adequate measures to address the uderlyig differeces is also lost. Therefore, better tools are eeded to assess the various aetiological ad pathogeic aspects of COPD. The goals are to slow ad, ultimately, to prevet the developmet of emphysema. Comorbidities I geeral, COPD has its oset i idividuals durig their 6s ad 7s. Smokig, which is the major risk factor for COPD, is also a risk factor for atherosclerosis, cacer ad coroary artery disease, ad thus the potetial for severe ad sigificat comorbidities ifluecig the course ad atural history of COPD is substatial. Most studies have bee uable to characterise the COPD populatio accurately with regard to their comorbidities. Subsequetly, the ifluece of these comorbidities o the results of cliical trials ad the atural history of disease progressio is poorly uderstood. Coclusios COPD is a major public health problem. Although reliable physiological testig ca defie disease severity ad occurrece, this testig is ot uiformly applied to high-risk populatios. There are major ucertaities with regard to diagoses based o symptoms because symptoms that mark the susceptible adult are usually ot remembered or reported at the time of disease oset. A additioal major cocer is diagostic misclassificatio. Risk factors other tha smokig, such as airway hyperresposiveess ad atopy/allergy, eed to be studied further, as do sex ad geetic differeces that may impact susceptibility. Fially, ivestigators lack repeatable, reliable markers of airway iflammatio ad burde of disease, idepedetly of spirometric testig that would allow moitorig of disease progressio ad effects of therapy i cliical trials. Highresolutio computed tomography may provide a mucheeded biomarker for use i chroic obstructive pulmoary disease ivestigatios, but its role has still to be established. Most chroic obstructive pulmoary disease presets i older idividuals with other diseases ad thus assessmet of the impact of comorbid coditios o the atural history of chroic obstructive pulmoary disease are urgetly eeded to place this disease i better cotext. The future cliical ageda for chroic obstructive pulmoary disease research will deped o the ability to solve these problems. Refereces 1. Natioal Heart, Lug ad Blood Istitute. 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