http://dx.doi.org/10.4046/trd.2011.71.4.271 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2011;71:271-277 CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 만성폐쇄성폐질환평가테스트의유용성 Original Article 경상대학교의학전문대학원호흡기내과학교실 김유은, 이상수, 김차영, 이승훈, 임수진, 조유지, 정이영, 김호철, 황영실, 이종덕 The Usefulness of the Chronic Obstructive Pulmonary Disease Assessment Test Yu Eun Kim, M.D., Sang Su Lee, M.D., Cha Young Kim, M.D., Seung Hun Lee, M.D., Su Jin Lim, M.D., Yu Ji Cho, M.D., Yi Yeong Jeong, M.D., Ho Cheol Kim, M.D., Young Sil Hwang, M.D., Jong Deog Lee, M.D., Ph.D. Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University College of Medicine, Jinju, Korea Background: A chronic obstructive pulmonary disease (COPD) assessment test (CAT) has recently been developed as a short and simple method for assessing the quality of life in COPD patients. The object of this study was to assess the usefulness of the Korean version of the CAT for assessing COPD patients in an outpatient clinic. Methods: The study included 60 COPD patients in a stable state from an outpatient clinic. The authors investigated the frequency of acute exacerbation during aprevious year through reviewing medical records. We evaluated the spirometry test, a 6-min walk distance test, and obtained the MMRC dyspnea scale, the Korean version of the CAT, and the BODE index at the time of visit. To assess the usefulness of the CAT, correlations between the CAT and other methods were evaluated. Results: The mean age of patients was 68.3±8.6 years and 95% of patients were male. There was a significant correlation between the CAT score and FEV 1 % (r= 0.323, p=0.012), the frequency of acute exacerbation (r=0.292, p=0.024), the MMRC dyspnea scale (r=0.554, p<0.001), the BODE index (r=0.380, p=0.003), and 6 MWD (r= 0.372, p=0.004). The mean CAT score increased according to the GOLD stage (stage 1, 10.7±4.5; stage 2, 13.1±7.9; stage 3, 16.3±6.2; stage 4, 16.5±14.8; p=0.746). Conclusion: The CAT was shown to be useful for the assessment of COPD severity. Therefore, the CAT is an easily applied and simple method for assessing COPD severity in an outpatient clinic. Key Words: Body Mass Index; Pulmonary Disease, Chronic Obstructive; Disease Progression; Quality of Life 서 만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 은점차진행하는비가역적인기류제한을특징으로하는질환으로전세계적으로유병률과사망률 Address for correspondence: Jong Deog Lee, M.D., Ph.D. Division of Pulmonology and Allergy, Department of Internal Medicine, Gyeongsang National University College of Medicine, 92, Chilam-dong, Jinju 660-751, Korea Phone: 82-55-750-8611, Fax: 82-55-758-9122 E-mail: ljd8611@empal.com Received: Jul. 14, 2011 Accepted: Sep. 6, 2011 론 이점차증가하고있는주요한호흡기질환이다 1. 만성폐쇄성폐질환환자는그자연경과중급성악화를겪기도하지만많은수의환자는외래진료를통한추적관찰이의료진과의주요접촉이된다. 따라서만성폐쇄성폐질환을치료하는데있어서진료실에서단시간내에환자의상태를평가하고이후추적하는것이중요한데, 현재까지는주로기류제한의정도를평가하는폐활량검사가이용되어왔다 2. 이러한폐활량검사는객관적이고반복시행이가능하며특히 1초노력성호기량 (forced expiratory volume in one second, FEV 1 ) 의감소정도는 COPD 의진행과사망률을예측할수있는지표가된다는 271
YE Kim et al: The usefulness of the chronic obstructive pulmonary disease assessment test 점에서장점을가지나, 호흡곤란등환자가느끼는증상과의연관성이비교적약하고 3, 폐기능의변화가환자가느끼는건강상의악화를반영하지못한다는점에서이를보완할만한대체평가수단의필요성이대두된다. 최근단순폐기능뿐만아니라환자의삶의질, 증상, 기능적운동능력등여러가지측면에서복합적으로평가하는것이 COPD 환자의상태를더잘반영한다는점이보고된후 MMRC호흡곤란점수 (modified medical research council dyspnea scale), 체질량지수 (body mass index, BMI), 6분도보검사 (6 minute walk distance) 를이용한 BODE (BMI, degree of obstruction, dyspnea, exercise capacity) 지수등이개발되었고특히 BODE index 는COPD 환자의사망률을예측하는데폐기능검사보다더유용하다고알려져있다 4. COPD 환자에서폐기능의감소는기능적운동능력을감소시키고일상생활에서의작업수행능력을떨어뜨리며나아가우울증등의문제를초래함으로인해결국삶의질까지떨어뜨리게된다. 감소된폐기능의정도를알아낼뿐만아니라삶의질저하에대한평가가해당환자에대한 COPD 의영향을평가하는데중요한요소가되는것은바로이러한호흡곤란악순환의고리가존재하기때문이다 5. COPD 환자의삶의질을평가하는데는그동안세인트조지호흡기설문 (Saint George's respiratory questionnaire, SGRQ) 이주로사용되었으나복잡하고다소긴시간이소요되어진료실에서평가도구로사용하기에는번거로움이있었다. 최근 COPD 환자의삶의질평가도구로만성폐쇄성폐질환평가테스트 (COPD assessment test, CAT) 라는평가도구가개발되었고 6, 한국인 COPD 환자의평가에있어 CAT 한국어판에대한타당도및신뢰도에대한고무적인연구결과가보고된바있다 7. 본연구는이러한 CAT 한국어판과다른평가방법들과의비교를통하여 CAT 검사가 COPD 외래환자의평가에적절히적용될수있는지를확인하고자시행되었다. 대상및방법 1. 연구 2010년 3월부터 2010년 10월까지경상대학교병원호흡기내과외래에방문한안정된상태의만성폐쇄성폐질환환자들을대상으로하였다. 만성폐쇄성폐질환의진단은 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 진단기준에따라기관지확장제투여후의 1초간 노력성호기량 (forced expiratory volume in one second, FEV 1 ) 의노력성폐활량 (force vital capacity, FV) 에대한비 (FEV 1 /FVC) 가정상예측치의 70% 미만인경우로하였으며 FEV 1 추정정상치에따라중증도를평가하였다. 연구포함기준과제외기준은아래에제시한바와같다. 1) 연구대상포함기준 : 10년이상의흡연력이있는흡연자또는전흡연자, 나이가 40세이상이고 80세이하인경우, COPD 진단을받았고 FEV 1 /FVC ratio가 70% 미만인경우, 기관지천식이동반되지않은경우, 그리고흉부 x-선상심한기관지확장증이나결핵성파괴폐등다른구조적폐질환이없는경우로하였다. 2) 연구대상제외기준 : 스스로설문지를작성할수없는경우, 최근 3개월이내 COPD 급성악화가있었던경우, 6분도보검사가불가능한경우, 환자의건강상태가단기간내에변동이있을것으로예상이되는타장기의급성질환을가지고있는경우, 연구결과에영향을줄수있는조절되지않는질환을가지고있는경우 ( 만성신부전, 울혈성심부전, 악성종양, 간경화등 ) 는제외하였다. 2. 연구방법전향적단면연구로서환자가외래에방문하였을때 CAT 한국어판, MMRC 호흡곤란점수에대하여정보를얻었고, 추가적으로폐기능검사, 6분도보검사를시행하였고이를바탕으로 BODE 지수를산출하였다. 또한지난 1 년간급성악화의횟수를조사하였다. 1) 의무기록검토와병력청취 : 각환자들의나이, 성별, 체질량지수, 흡연여부및흡연량, 지난 1년간보고된급성악화의횟수에대하여조사하였다. 2) COPD 급성악화의정의 : COPD 급성악화는 COPD 로치료받던환자가기침, 호흡곤란, 객담의양또는객담양상의변화등호흡기증상의급격한악화가 2일이상지속되고예정되지않는병원방문및스테로이드투여등치료의조정이필요한경우로정의하였다 1. 3) MMRC 호흡곤란점수 : MMRC 호흡곤란점수는호흡곤란의정도를평가하는방법으로 0 4점까지의점수로나타내었다 4. 4) CAT 한국어판설문 : CAT 설문은 COPD 환자의삶의질을평가하는도구로총 8개의항목으로구성되어있고, 각항목은 0점에서 5점까지점수로평가하여총점을 0점에서 40점까지갖게된다 6. 본연구에서는 GlaxoSmith- Kline사 (Hertfordshire SG1 2NY, UK) 에서개발한한국어판 CAT 설문을사용하였다. 272
Tuberculosis and Respiratory Diseases Vol. 71. No. 4, Oct. 2011 5) 폐기능검사 : 모든환자들에게폐활량측정기 (Master Screen Body, Viasys Healthcare, Jaeger, Germany) 를사용하여 FEV 1 (% predicted) 과 FVC를측정하였다. 6) 6분도보검사 : COPD 환자의기능적운동능력에대한평가로 6분도보검사 (m) 를측정하였는데 8 단단하고평탄한외래복도를 20미터단위로표시한후연구대상자에게 6분동안걷게하여그거리를연구원이미터단위로측정하였다. 7) BODE지수계산 : BODE 지수는 FEV 1 (% predicted), 6분도보거리 (m), MMRC 호흡곤란점수, 체질량지수 (BMI, kg/m 2 ) 의 4개항목으로구성되어있다. FEV 1 (% predicted), 6분도보거리 (m), MMRC 호흡곤란점수는 0점에서 3점까지, 체질량지수는 0점에서 1점까지점수로평가하여총점 0 10점까지점수로평가하였다 4. 8) 통계분석 : 각각의값은평균 ± 표준편차로표시하였다. CAT 의타당도를평가하기위해 COPD 환자에대한평가방법으로시행중인폐기능검사, 6분도보거리, 지난 1년간급성악화횟수, MMRC 호흡곤란점수, BODE 지수와 CAT의관계를단순상관분석 (Pearson's correlation) 을이용해조사하였다. 통계분석은 SAS for Window version 18.0 (SPSS Inc., Chicago, IL, USA) 을이용하였고 p<0.05인경우통계학적으로유의한것으로판단하였다. 9) 기관윤리위원회심의 : 본연구는사전에경상대학교병원임상연구심의위원회 (Institutional Review Board, IRB) 의심의를승인받아시행되었다. 결과 1. 대상환자특성연구에포함된환자는총 60명으로, 평균나이는 68.3± 8.6 세였으며남자가 57명, 여자가 3명이었다. 전체환자의지난 1년간급성악화빈도는 1.7±2.6회였고, 평균체질량지수는 22.2±3.5 kg/m 2 였다. 폐기능검사결과 FEV 1 (% predicted) 은 58.5±22.4% 였고 FEV 1 /FVC (%) 는 48.4 ±11.5% 였다. 흡연량은 40.1±24.3갑년이었다 (Table 1). 2. 연구대상환자의 COPD중증도 GOLD stage로구분했을때 stage 1에해당하는환자는 11명 (18.3%), stage 2는 24명 (40.4%), stage 3는 23명 (38.3%), stage 4는 2명 (3.3%) 으로중등증및중증 COPD 에해당하는환자의비율이높았다. 대상환자의 6분도보 Table 1. The baseline characteristics of study population Characteristics Age, yr M:W BMI, kg/m 2 Smoking history, PY Smoking status, n (%) Ex-smoker Current smoker Frequency of exacerbation during last year FEV 1, % predicted FEV 1/FVC, % GOLD stage, n (%) 1 2 3 4 6 MWD, m MMRC dyspnea scale BODE index CAT Mean±SD 68.3±8.6 57:3 22.2±3.5 40.1±24.3 48 (75.0) 12 (20.0) 1.7±2.6 58.5±22.4 48.4±11.5 11 (18.3) 24 (40.0) 23 (38.3) 2 (3.3) 424.4±123.3 1.3±1.1 2.7±2.7 14.0±7.1 BMI: body-mass index; PY: pack-years; FEV 1: forced expiratory volume in one second; FVC: forced vital capacity GOLD: global initiative for chronic obstructive lung disease; MMRC: modified medical research council dyspnea scale; 6 MWD: 6-minute walk distance; BODE: body mass index, degree of obstruction, dyspnea, exercise capacity; SD: standard deviation. 거리는 424.4±123.3 m였고, MMRC 호흡곤란점수는 1.3±1.1이었으며 BODE 지수는 2.7±2.7, CAT점수는 14.0±7.1이었다. 3. CAT 와다른방법들과의상관성 1) CAT점수와폐기능검사와의상관성 : CAT점수가높을수록 FEV 1 (%) 은낮게나타나 CAT 점수와 FEV 1 (% predicted) 간에는유의한음의상관관계를보였다 (r= 0.323, p=0.012; Figure 1). GOLD stage에따라 stage 1에서 4까지나눈후각군의평균 CAT 수치를조사하였을때각각 10.7±4.5, 13.1±7.9, 16.3±6.2, 16.5±14.8로중증도가심해질수록 CAT 점수도증가하는경향을보였으나통계학적인유의성은없었다 (p=0.746). 2) CAT점수와 COPD 급성악화빈도와의상관성 : COPD 급성악화의빈도가높은환자일수록 CAT점수가높게조사되어급성악화의빈도와 CAT점수는통계학적으로유의한양의상관관계를보였다 (r=0.292, p=0.024; Figure 2). 273
YE Kim et al: The usefulness of the chronic obstructive pulmonary disease assessment test Figure 1. Correlation between COPD assessment test (CAT) and FEV 1 (% predicted) (r= 0.323, p=0.012). COPD: chronic obstructive pulmonary disease; FEV 1 : forced expiratory volume in one second. Figure 3. Correlation between COPD assessment test (CAT) and MMRC dyspnea scale (r=0.554, p<0.001). COPD: chronic obstructive pulmonary disease; MMRC: modified medical research council dyspnea scale. Figure 2. Correlation between COPD assessment test (CAT) and frequency of acute exacerbation (r=0.292, p=0.024). COPD: chronic obstructive pulmonary disease. Figure 4. Correlation between COPD assessment test (CAT) and 6 MWD (m) (r= 0.372, p=0.004). COPD: chronic obstructive pulmonary disease. 3) CAT점수와 MMRC 호흡곤란점수 : CAT점수와 MMRC 호흡곤란점수와의상관분석에서유의한상관성을보였다 (r=0.554, p<0.001; Figure 3). MMRC 호흡곤란점수에따른평균 CAT점수를비교해보았을때, MMRC 호흡곤란점수가 0점에서 5점으로높을수록평균 CAT점수도유의하게증가하였다 (MMRC 0, 8.8±3.9; MMRC 1, 13.6±6.9; MMRC 2, 16.6±6.8; MMRC 3, 18.1±6.2; MMRC 4, 26.5±0.7; p<0.001). 4) CAT점수와 6분도보거리와의상관성 : 6분도보거리가짧을수록 CAT 점수가증가하였는데두지표간에는통계학적으로유의한음의상관관계가있었다 (r= 0.372, p=0.004; Figure 4). 5) BODE 지수와의상관성 : CAT점수와 BODE 지수와의상관분석에서도유의한상관성을보였다 (r=0.380, p= 0.003; Figure 5). 고찰본연구를통해저자등은 COPD환자의삶의질을간단히평가할수있는도구로개발된 CAT 한국어판설문평가가현재 COPD 환자의평가와추적관찰에활용되고있는폐기능검사, 급성악화의빈도, MMRC 호흡곤란점수, 274
Tuberculosis and Respiratory Diseases Vol. 71. No. 4, Oct. 2011 Figure 5. Correlation between COPD assessment test (CAT) and BODE index (r=0.380, p=0.003). COPD: chronic obstructive pulmonary disease; BODE: body mass index, degree of obstruction, dyspnea, exercise capacity. BODE 지수, 6분도보거리등다른평가도구들과유의한상관성이있음을확인하였다. 이는이러한잣대가 COPD 환자의삶의질과관련이높음을보여준이전의연구들과도일치한결과를보여주었다 9,10. COPD 환자를평가하는데폐기능검사나 6분도보거리검사, MMRC 호흡곤란점수및 BODE 지수등은수치화할수있어상당히객관적이라는장점을가지고있다. 이로인해그동안 COPD 환자의치료에서중요한평가지표로사용되어왔다. COPD 환자에서삶의질은환자스스로평가하는만족의정도또는환자의작업능력, 질환으로인한환자의고충및감정상태등과직접적인연관이있기때문에이러한삶의질을평가하는것은환자에대한 COPD 의전체적인영향을알아보는데중요한요소가된다 5. 그동안삶의질을평가하기위한도구로널리사용되었던 SGRQ와폐기능검사결과와의상관성이보고되었고 11, 한국어판 SGRQ의타당도와신뢰도도입증되어있지만, SGRQ는 50개항목으로구성되어있어복잡하고시간이소요되어실제환자진료특히외래환자진료에적용하는데는제약이있었다. 반면, CAT는 8개항목으로구성된간단한설문을통해 COPD 환자의삶의질을평가하는도구로문항이간략하여고령의환자에서도작성하기쉽고, 소요시간도짧아서실제진료실에서유용성이높고, 반복적인설문을통해환자의경과를관찰을하는데에도도움이될것으로예측된다. COPD에서 FEV 1 (%) 을측정하는것은 COPD 로인한 기류제한의정도를정량화하는데필수적이고 1, FEV 1 (%) 의감소의속도는질병의진행과사망률을예측할수있어 COPD 환자를평가하는데중요한척도이다 12. 따라서 COPD 환자를평가할수있는새로운잣대를만들고자할때 FEV 1 (%) 과의상관관계를보여주는것은그잣대의유용성및타당성에대한점수를매기는데있어필수적인항목이된다. 처음으로 CAT 한국어판의타당도와신뢰도를평가한연구에서는폐활량 (FVC, % pred) 과의상관성을평가하였는데, 지표간의약한상관성을보여주는데그쳤고 7, 본연구에서는 CAT 한국어판과 FEV 1 (%) 검사와의유의한상관성을확인할수있었다. COPD 의급성악화는폐기능감소를촉진시켜질병의진행에악영향을미치고운동능력을저하시키며삶의질을떨어뜨려, 유병률및사망률을증가시키고의료비로인한경제적부담을가중시키는등 COPD 환자의경과에중요한역할을한다 13,14. 따라서급성악화를예방하는것은 COPD 치료에서중요한부분으로생각되며, COPD 의급성악화빈도자체도 COPD 환자를평가하는지표로의미가있다. 본연구에서비록상관계수가낮기는했지만, 급성악화의빈도와 CAT 점수간의유의한상관관계를확인할수있었다. 운동능력의감소는만성폐질환의주요한특징으로운동능력을평가하는것은예후와치료의반응을예측하는데이용될수있다. 6분도보거리검사는기능적운동능력을평가하는표준화된검사방법으로 8,15, 이전연구에서폐기능및삶의질과상관성이있음이이미밝혀져있다 10,16. 본연구에서도 CAT 한국어판과 6분도보거리와의상관성을확인하였다. 환자가느끼는호흡곤란은환자가질환으로인해느끼는불편감및작업능력과밀접한관계가있으므로 COPD 환자를관찰하는데있어중요한지표이며, 이전여러연구들에서폐기능에따른중증도분류보다호흡곤란의정도에따라분류하는것이 COPD 환자의삶의질과사망률을평가하는데더유용하다는결과를보여주었다 17,18. 본연구에서는호흡곤란을평가하기위해 MMRC 호흡곤란점수를사용하였고 CAT 한국어판과 MMRC 호흡곤란점수와의유의한상관관계를확인할수있었다. 최근 COPD 환자에서사망률을예측하는도구로폐기능검사를반영하는 GOLD분류를사용하는것보다다면성분류체계인 BODE 지수를사용하는것이더정확하다는보고가있었고 4, BODE지수와 COPD 환자를평가하는다른방법들과의상관성도보고되었다 19,20. 또한장기적으로 275
YE Kim et al: The usefulness of the chronic obstructive pulmonary disease assessment test BODE지수의변화를평가하는것으로심한 COPD환자에서사망률을예측할수있다는연구도있었다 21,22. 그러나 4개의항목각각에대한평가를진료할때마다적용하기는어려워만성폐쇄성폐질환환자를모니터하는데적용하기에는제약이있다. 본연구의결과다면성분류체계인 BODE 지수와 CAT점수간에유의한상관성을확인할수있었다. 최근영상학적인검사장비의개발및보급이활발해지면서, 흉부전산화단층촬영검사를시행하는경우가보편화되었고, 이에따라여러연구들에서 COPD 평가방법으로흉부전산화단층촬영을통한폐기종의정도 (emphysema index), 총폐용적 (total lung capacity, TLV), 기관지벽두께의시각적반정량측정 (visual semi-quantitative estimation of bronchial wall thickness, VBT) 등에대한연구결과가보고된바있다 23-25. 향후 CAT점수와이러한영상학적평가방법들과의상관성및동맥혈가스검사, 염증지표등생화학적검사를통한평가방법과의상관성에대한연구를시행한다면그유용성을더욱입증할수있을것으로생각된다. COPD 는이질적인 (heterogeneous) 질환으로다면적인평가가필요한것으로이해되고있으며, 따라서 COPD 환자를평가하기위한여러가지방법들이연구되고있다. 본연구결과, 삶의질을평가하는간단한도구로개발된 CAT설문은 COPD 환자의증상, 기능적운동능력, 폐기능, 사망률을예측하는데사용되는다른평가도구들과유의한상관성이있는것을확인할수있었고향후안정상태의만성폐쇄성폐질환외래환자를진료하는데있어간단한평가도구로활용할수있을것으로생각된다. 참고문헌 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management, and prevention of COPD. [place unknown]: GOLD; c2010 [cited 2011 Sep 30]. Available from: http:// www.goldcopd.org/guidelines/guidelines-global-strategyfor-diagnosis-management.html. 2. Mannino DM, Reichert MM, Davis KJ. Lung function decline and outcomes in an adult population. Am J Respir Crit Care Med 2006;173:985-90. 3. Wolkove N, Dajczman E, Colacone A, Kreisman H. The relationship between pulmonary function and dyspnea in obstructive lung disease. Chest 1989;96:1247-51. 4. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005-12. 5. Havlucu Y, Çelik P, Dinç G, Şakar A, Yorgancioğlu A. Assessment of quality of life in chronic obstructive pulmonary disease. Turkish Respir J 2005;6:78-83. 6. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34:648-54. 7. Lee S, Lee JS, Song JW, Choi CM, Shim TS, Kim TB, et al. Validation of the Korean version of chronic obstructive pulmonary disease assessment test (CAT) and Dyspnea-12 questionnaire. Tuberc Respir Dis 2010;69: 171-6. 8. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7. 9. Farkas J, Kosnik M, Zaletel-Kragelj L, Flezar M, Suskovic S, Lainscak M. Distribution of self-rated health and association with clinical parameters in patients with chronic obstructive pulmonary disease. Wien Klin Wochenschr 2009;121:297-302. 10. Sanchez FF, Faganello MM, Tanni SE, Lucheta PA, Padovani CR, Godoy I. Relationship between disease severity and quality of life in patients with chronic obstructive pulmonary disease. Braz J Med Biol Res 2008; 41:860-5. 11.Weatherall M, Marsh S, Shirtcliffe P, Williams M, Travers J, Beasley R. Quality of life measured by the St George's Respiratory Questionnaire and spirometry. Eur Respir J 2009;33:1025-30. 12. Burrows B. Predictors of loss of lung function and mortality in obstructive lung diseases. Eur Respir Rev 1991;1:340-5. 13. Kanner RE, Anthonisen NR, Connett JE; Lung Health Study Research Group. Lower respiratory illnesses promote FEV 1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med 2001;164:358-64. 14. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-52. 15.Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric 276
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