만성폐쇄성폐질환환자에서기관지확장제의사용에따른단독폐용적반응 (isolated volume response) 과 GOLD 분류와의관계 고려대학교의과대학내과학교실허규영, 이승현, 정진용, 김세중, 이경주, 이은주, 정혜철, 이승룡, 이상엽, 김제형, 신철, 심재정, 인광호, 강경호, 유세화 Isolated Volume Response to a Bronchodilator and GOLD Classification in Patients with COPD Gyu Young Hur, M.D., Seung Hyeun Lee, M.D., Jin Yong Jung, M.D., Se Joong Kim, M.D., Kyoung Ju Lee, M.D., Eun Joo Lee, M.D., Hye Cheol Jung, M.D., Sung Yong Lee, M.D., Sang Yeub Lee, M.D., Je Hyeung Kim, M.D., Chol Shin, M.D., Jae Jeong Shim, M.D., Kwang Ho In, M.D., Kyung Ho Kang, M.D., Se Hwa Yoo, M.D. Department of Internal Medicine, Korea University Medical Center Background : Chronic obstructive lung disease is characterized by smoke-related, gradually progressive, fixed airflow obstructions. However, some studies suggested that a reversible bronchial obstruction is common in chronic obstructive lung disease. Such reversibility persists despite the continued treatment with aerosolized bronchodilators and it appears to be related to the diminution in symptoms. The isolated volume response to a bronchodilator is defined as a remarkable increase in the FVC in response to the administration of a bronchodilator whereas the FEV 1 remains unchanged. This has been suggested in patients with severe emphysema. Therefore, the aim of this study was to determine the relationship between the response to a bronchodilator and the severity of an airflow obstruction in COPD patients using the GOLD classification. Methods : This study examined 124 patients with an airway obstruction. The patients underwent spirometry, and the severity of the airflow obstruction was classified by GOLD. The response groups were categorized by an improvement in the FVC or FEV 1 > 12%, and each group was analyzed. Results : Most subjects were men with a mean age of 65.9±8.5 years. The mean smoking history was 41.26±20.1 pack years. The isolated volume response group had relatively low FEV 1 and FVC values compared with the other groups. (p<0.001) Conclusion : In this study, an isolated volume response to a bronchodilator is a characteristic of a severe airway obstruction, which is observed in patient with a relatively poorer baseline lung function. (Tuberc Respir Dis 2005; 59: 23-29) Key words : COPD, Bronchodilator, GOLD, Isolated volume response 서 만성폐쇄성폐질환은기관지천식에비해흡연과연관되어있으며서서히진행하는고정된기류제한을특징으로하는만성질환이다. 기류폐쇄의가역성은일반적으로폐기능검사상기관지확장제흡입후 1초간노력성호기량 (1-s forced expiratory volume: FEV 1 ) 론 Address for correspondence : Jae Jeong Shim, M.D Department of internal medicine, Korea University, Seoul, Korea #97, Guro-dong, Guro-gu, Seoul, Korea Phone : 82-2-818-6639 Fax : 92-2-830-2208 E-mail : jaejshim@kumc.or.kr Received : Apr. 4. 2005 Accepted : Jun. 15. 2005 의증가여부로정의된다. 그러나여러연구에서기류폐쇄의가역성은기관지천식뿐만아니라만성폐쇄성폐질환환자에서도흔히관찰되며, 지속적으로흡입성기관지확장제로치료하였을때에도이러한가역성을보이며, 증상의경감과도관련이있는것으로생각된다. 1,2 또한최근에는만성폐쇄성폐질환환자에서기관지확장제의사용이운동능력의향상에도도움을준다는연구결과도있었다 3. 일부중증도이상의만성폐쇄성폐질환환자에서는기관지확장제를사용하였을때 1초간노력성호기량의변화없이노력성폐활량 (forced vital capacity: FVC) 이현저히증가되는양상을볼수있으며, 이를단독폐용적반응 (isolated volume response) 이라고한다 4,5. 이러한단독폐용적반응은기관지확장의증 23
GY Hur, et al.: Isolated volume response to a bronchodilator in COPD 거로받아들여지고있으나, 그기전은아직명확히밝혀지지않고있다 6. 지금까지만성폐쇄성폐질환환자의중증도를파악하기위해기관지확장제를사용한뒤폐용적의변화를확인하는연구들은있었으나, 4,7,8 기관지확장제의반응정도와질환의중증도의상관관계에대한연구는없었다. 따라서이번연구는만성폐쇄성폐질환환자에서 GOLD 분류법에따른기류폐쇄의정도와기관지확장제의반응정도와의상관성에대한분석을시행하였다. 대상및방법임상적으로만성폐쇄성폐질환이의심되어고려대학교의료원에서폐기능검사를시행받은환자들을선별하였으며, 시행한폐기능검사상 1초간노력성호기량의노력성폐활량에대한비 (FEV 1 /FVC) 가 0.7 이하로기류제한이있는경우를대상으로하였다. 기관지천식을배제하기위하여기관지확장제투여후 1초간노력성호기량의변화가 15% 이상, 절대값의변화가 200ml 이상인경우는제외하였다 9. 또한흉부방사선사진상결핵이나기관지확장증등이상소견이있는경우도제외하였다. 폐기능검사장비는 Vmax229 (SensorMedics, Yorba Linda, CA, US) 를사용하였으며, 기관지확장제반응을확인하기위해서는속효성베타항진제인살부타몰 (salbutamol) 을사용하였고, 사용 30분뒤폐기능검사를다시시행하였다. 대상환자는폐기능검사결과에따라 GOLD 분류 법으로중증도를분류하였으며 10, 기관지확장제반응여부에따라네가지군으로분류하였다. 먼저기관지확장제사용후 1초간노력성호기량의향상없이노력성폐활량만증가하는경우단독폐용적반응군 (is olated volume ) 로정의하였고, 노력성폐활량의변화없이 1초간노력성호기량만증가하는경우는단독기류반응군 (isolated flow ), 1초간노력성호기량과노력성폐활량모두증가하는경우는기류-용적반응군 (flow-volume ), 1 초간노력성호기량과노력성폐활량모두증가하지않는경우는비반응군 (non ) 으로정의하였다. 4 기관지확장제사용후 1초간노력성호기량및노력성폐활량수치의증가는미국흉부학회기준에따라 12% 이상향상되었을때증가된것으로정의하였다 9,11. 통계처리를위해서는 SPSS 10.0(SPSS Inc. Chicago, IL, US) 통계패키지를사용하였으며, 각군간비교를위해서 Student s t-test, χ 2 -test 및 Oneway ANOVA 를사용하였으며사후분석을위하여 Tukey 및 Dunnet 을사용하였다. 결과환자특성대상환자는모두 124명으로, 남자가 111명, 여자 13 명이었으며, 평균연령은 65.89±8.43 세였다. 흡연자는 122명으로, 평균흡연력은 41.33±20.07 갑년이었다. 폐기능검사후기관지확장제반응여부에따라비반응군 Table 1. Baseline characteristics of each group Variables Non FEV 1 FVC FEV 1-FVC N 87 14 11 12 Age, yr 65.26 ± 0.82 69.92 ± 10.27 68.00 ± 8.56 63.92 ± 6.92 Smoking, PY 41.15 ± 19.93 42.30 ± 26.25 45.45 ± 18.63 37.08 ± 16.84 FEV 1, liters 1.70 ± 0.55 1.29 ± 0.45 1.00 ± 0.31 1.02 ± 0.23 % of predicted 66.90 ± 19.13 50.38 ± 14.27 40.27 ± 14.12 39.25 ± 13.03 FVC, liters 3.07 ± 0.76 2.68 ± 0.56 2.46 ± 0.56 2.50 ± 0.53 % of predicted 85.39 ± 16.57 73.62 ± 10.99 67.73 ± 14.85 65.67 ± 9.59 Values are means ± SD (standard deviation). FEV 1, forced expiratory volumes in 1s; FVC forced vital capacity 24
Tuberculosis and Respiratory Diseases Vol. 59. No. 1, Jul. 2005 Table 2. Comparisons of the baseline lung function between the and non- Variables Any Non p Age, yr 67.33 ± 8.88 65.26 ± 8.27 NS Smoking, PY 41.52 ± 20.90 41.15 ± 19.93 NS FVC, Liters 2.82 ± 0.64 3.16 ± 0.72 <0.001 % of predicted 77.54 ± 12.34 86.80 ± 16.78 <0.001 Absolute change of FVC 0.306 ± 0.173 0.082 ± 0.26 <0.001 FEV 1, Liters 1.11 ± 0.37 1.70 ± 0.55 <0.001 % of predicted 43.58 ± 14.40 66.90 ± 19.14 <0.001 Absolute change of FEV 1 0.120 ± 0.066 0.052 ± 0.078 <0.001 FEF 25-75%, L/sec 0.46 ± 0.23 0.82 ± 0.38 <0.001 PEF, L/sec 3.25 ± 1.11 4.29 ± 1.57 <0.001 FEF 25%, L/sec 1.11 ± 0.70 2.43 ± 1.42 <0.001 FEF 50%, L/sec 0.54 ± 0.30 1.00 ± 0.49 <0.001 FIF 50%, L/sec 2.53 ± 1.01 2.89 ± 1.10 NS FEF 50/FIF 50 0.26 ± 0.16 0.37 ± 0.19 <0.001 Values are means ± SD (standard deviation). FEV 1, forced expiratory volumes in 1s; FVC, vital capacity; FEF 25-75%, maximal mid expiratory flow; FEF 25%, FEF 50% and FEF 75%, forced expiratory flows at 25%, 50% and 75%; PEF, peak expiratory flow; FIF 50, forced inspiratory flow at 50% of control FVC. (non responsers), 단독기류반응군 (FEV 1 ), 단독용적반응군 (FVC ), 기류-용적반응군 (FEV 1 -FVC ) 의 4군으로분류하였다. 각군은비반응군 90명, 단독기류반응군 11명, 단독용적반응군 12명, 기류-용적반응군 11명이었으며, 각군간의연령, 흡연력은통계적으로유의한차이를보이지않았다 (Table 1). 각군간의비교각군간의특성을비교하기위하여, 단독기류반응군, 단독용적반응군과기류-용적반응군을반응군 (any responsers) 으로다시분류하였고, 반응군과비반응군의특성을비교하였다 (Table 2). 기관지확장제에반응을보였던반응군이기관지확장제에반응을 보이지않았던비반응군에비해노력성폐활량, 1초간노력성호기량, 노력성중간호기량 (FEF 25-75% ) 등의폐기능검사수치들이통계적으로유의한수준으로낮았다 (p<0.001). 폐기능검사결과에따라각대상환자들을 GOLD 분류법에의해분류하였고 (Table 3), 반응군이비반응군에비해 GOLD 단계의중증도가더높은소견을보였다 (p<0.001). 기저폐기능검사결과에서각군간의기저노력성폐활량수치및 1초간노력성호기량수치를비교하면 Table 3. GOLD classification and the bronchodilator Any Non GOLD stage <0.001 Ⅰ 1 27 Ⅱ 17 44 Ⅲ 15 15 Ⅳ 4 1 Total 37 87 p Figure 1. Comparison of the mean baseline FVC value between each group. Compared with the baseline FVC value in the four groups, the value of the non group was significantly lower than in the other groups. (p=0.002) * : p<0.05 compared with non (by post hoc) 25
GY Hur, et al.: Isolated volume response to a bronchodilator in COPD Figure 2. Comparison of the mean baseline FEV 1 value between each group. Compared with four groups of baseline FEV 1 value, the value of non group is significantly lower than others. (p<0.001) * : p<0.001 compared with Non (by post hoc) : p<0.05 compared with Non resonders (by post hoc) Table 4. Comparison of the GOLD classification between the FEV 1 and FVC FEV 1 FVC GOLD stage <0.05 Ⅰ 1 0 Ⅱ 9 4 Ⅲ 4 4 Ⅳ 0 3 Total 14 11 (Figure 1, 2), 비반응군의노력성폐활량및 1초간노력성호기량값은다른군과유의한차이를보이고있으며, 사후분석을통해단독용적반응군과기류-용적반응군이비반응군보다기저폐기능검사수치가통계적으로의미있게낮은것을보여준다. 다시단독기류반응군 (isolated flow response) 과단독용적반응군 (isolated volume response) 간의 GOLD 단계의상관관계를살펴보면 (Table 4), 단독용적반응군에서 GOLD 단계의중증도가더높은환자들의분포가유의하게많은것을보여준다 (p<0.05). 고 만성폐쇄성폐질환은전술한바와같이기관지천식과달리폐기능검사상기도의가역성이없는경우 찰 p (not fully reversible) 로정의되고있다 12. 미국흉부학회및유럽흉부학회의지침서등에의하면기관지확장제반응이 12% 이상인경우를기도의가역성이있다고정의하며 9, 11, 실제임상적으로만성폐쇄성폐질환과기관지천식을감별진단하는데사용하기도한다. 그러나기관지천식뿐만아니라만성폐쇄성폐질환환자에서도기관지확장제에대한반응을보일수있으며지속적인기관지확장제치료를통해환자의증상이경감되는것을경험하기도한다 1. 그러나만성폐쇄성폐질환환자의중증도를가장잘반영한다고알려진 1초간노력성호기량의변화는환자의운동능력의변화와그대로일치하지는않는다 7,13,14. 따라서고식적인폐기능검사를통한기관지확장제투여후 1초간노력성호기량의변화측정만으로만성폐쇄성폐질환환자의기류폐쇄정도를판단하는데는많은어려움이있으며, 그리하여지금까지만성폐쇄성폐질환환자의폐기능정도를정확히반영하는다른요인에대한연구들이있어왔다. Ramsdell 등은 4 241명을대상으로기관지확장여부를확인하는변수를찾기위하여본연구와같이네가지군으로나누었고, 체적변동기록법 (body plethysmography) 을통해측정한폐활량 (vital capacity: VC), 기능성잔기용량 (functional residual capacity: FRC) 등정적폐용적의변화가기관지확장을가장잘반영한다고하였으며, Girard 5 등은단독폐용적반응을보이는경우, 1 초간노력성호기량의변화뿐만아니라노력성폐활량도기관지확장반응을평가하는데사용될수있으며, 3초간노력성호기량및 6초간노력성호기량을측정하여이값도증가된다면명백한기관지확장이라고증명할수있다고하였다. 또한 Biring 등은 15 만성폐쇄성폐질환환자에서미국흉부학회기준보다노력성흡기폐활량 (forced inspiratory vital capacity: FIVC) 을통하여기도의가역성여부를더욱정확하게밝힐수있다고하였다. Newton등은 7 폐의심한과팽창을보이는환자에서폐용적을측정하여기관지확장반응을정확히예측할수있다고하였으며, O Donnell 등은 16 유사한연구를통하여폐기종이심한환자일수록폐용적에대한기관지확장반응이더크며, 이는기능성잔기량중흡기용량 (inspiratory capacity: IC) 26
Tuberculosis and Respiratory Diseases Vol. 59. No. 1, Jul. 2005 의변화가가장크다고밝혔다. Smith 등도 17 기도의가역성을보다정확하게예측하기위하여체적변동기록법을이용하였으며, 국내에서는 Park등이 8 17명의환자를대상으로하여이를증명하였다. 한편, 만성폐쇄성폐질환에서의기관지확장제반응에대한연구는지금까지꾸준히진행되어왔으며, 기관지확장제를투여하였을때 FVC만증가되는단독폐용적반응은기관지확장의불변의진리로받아들여지고있으나 9,18 그기전은아직정확히밝혀지지않고있다. Verbeken 등 19 에의하면증가된기종성공기공간 (emphysematous airspace) 이주변의소기관을압박하여폐포의팽창시에기도의직경에변화를일으킨다는공간경쟁 (space competition) 이론을설명한바있다. 또한 Cerveri 등 6 은용적반응군과기류반응군으로나누어폐기능검사및고해상도컴퓨터단층촬영을시행하였으며, 용적반응군에서전폐용적에서의탄력반동 (elastic recoil) 이낮고, 폐기종범위가 40% 이상높음을증명하였다. 따라서용적반응을보이는것이폐기종이 40% 이상인심한만성폐쇄성폐질환환자의특징이될수있다고설명하였으며, 또한폐의과팽창을반영하는다른폐기능측정법을이용하였을때고해상도컴퓨터단층촬영못지않게폐기종의정도를잘반영할수있다고하였다 20. Ayres 등 1 은만성폐쇄성폐질환환자에서, Pare 등 21 은기관지천식환자에서기관지확장제를투여한뒤반응을비교하였으며, 모두기관지확장제투여후기류우세반응은대기도저항의호전을반영하고, 용적우세반응은말초기도의확장을반영한다고하였다. 이중용적우세반응을보이는경우에는기저말초기도저항을가지므로기저폐기능검사소견이더욱불량하다고설명하였다 12. 이번연구는만성폐쇄성폐질환으로진단된환자를대상으로간단한폐활량검사및기관지확장제투여후폐활량검사를시행하여질환의중증도와비교한것으로, GOLD 분류에의한중증도와폐기능검사상기관지확장제투여효과간의상관관계를살펴보고자하였다. 시행한폐기능검사결과에따라단독용적반응군, 단독기류반응군, 양측모두반응을보이는기류-용적반응군, 모두반응을보이지않는비반응군으로나누었고, 전체 124명의대상환자중에서 각각 11명, 14명, 12명, 87명으로분류되었다. 각군의환자들의기저폐기능검사수치를분석하여 GOLD 단계와비교한결과용적혹은기류반응을보이는반응군 (any ) 에서비반응군 (non-) 에비해통계적으로유의하게 GOLD 단계의중증도가더높았다 (Table 2). 각군의 GOLD 단계분포를살펴보면단독용적반응군과기류-용적반응군에서 GOLD 단계의중증도가더높은환자들이분포하며, 단독기류반응군보다단독용적반응군의 GOLD단계의중증도가더높아, 단독기류반응군보다단독용적반응군이기저폐기능정도가더낮음을보여주었다 (Table 3, 4). 또한각군의기저노력성폐활량, 1초간노력성호기량의평균값을비교해보면, 비반응군이다른군보다노력성폐활량, 1초간노력성호기량의평균값이높은것을알수있었으며, 사후분석을통해단독용적반응군과기류-용적반응군의평균값이비반응군에비해유의하게낮은것이증명되었다 (Figure 1, 2). 이는앞서 Sciurba 등의연구결과와같이단독폐용적반응을보일수록말초기도저항을보인다는사실을토대로, 이번연구결과에서도용적반응및기류-용적반응을보이는환자군에서기저폐기능검사수치가더낮고, GOLD 단계의중증도도더높다는점을보여주고있다. 이번연구는 124명이라는비교적다수의환자군을대상으로하여기관지확장제반응과 GOLD 단계간의관계를비교한것이다. 여기에서, 단순폐활량검사및기관지확장제투여후반응여부로만성폐쇄성폐질환환자의중증도를추측할수있고, 기관지확장제에대한단독용적반응은심한기류제한의특징이될수있으며, 이러한환자들이상대적으로더나쁜기저폐기능검사수치를가지고있음을보여주고있다. 따라서이러한용적반응및기류반응을보이는환자들에게는지속적으로기관지확장제를사용함으로써환자의증상호전을기대해볼수있으며, 폐용적측정을위한체적변동기록법등검사를시행하지않고도환자의폐기능정도를추측하는데도움을줄수있을것으로기대된다. 또한이번연구를바탕으로기관지확장제투여에따른단독폐용적반응의기전에대한향후더많은연구들이필요하리라사료된다. 27
GY Hur, et al.: Isolated volume response to a bronchodilator in COPD 요 약 참고문헌 배경 : 만성폐쇄성폐질환은기관지천식과달리, 흡연과연관이있으며, 서서히진행하는고정된기류제한을특징으로한다. 그러나여러연구에서기류폐쇄의가역성은만성폐쇄성폐질환환자에서도흔히관찰되며, 지속적으로흡입성기관지확장제로치료하였을때에도이러한가역성이보여, 증상의경감과도관련이있는것으로생각된다. 지금까지기관지확장제의반응정도와질환의중증도를확인하는연구는없었으며, 이번연구는만성폐쇄성폐질환환자에서기류폐쇄의정도와기관지확장제의반응정도의상관성을 GOLD 분류법을통해분석하였다. 방법 : 만성폐쇄성폐질환환자들로 1초간노력성호기량의노력성폐활량에대한비 (FEV 1 /FVC) 가 0.7 이하인경우를대상으로하여 GOLD 분류법과기관지확장제반응여부에따라분류하였다. 기관지확장제사용후 1초간노력성호기량, 노력성폐활량의변화정도에따라단독용적반응군, 단독기류반응군, 기류-용적반응군, 비반응군으로나누어분석하였다. 결과 : 대상환자는모두 124명으로, 평균연령은 65.89±8.43 세였다. 기관지확장제에반응을보였던반응군이기관지확장제에반응을보이지않았던비반응군에비해폐기능검사수치들이통계적으로유의한수준으로낮았으며, 반응군이비반응군에비해 GOLD 단계의중증도가더높은소견을보였다. 결론기관지확장제에대한단독용적반응은심한기류제한의특징이될수있으며, 이러한환자들이상대적으로기도폐쇄정도가더심하며, 기저폐기능검사수치도의미있게낮아만성폐쇄성폐질환환자에있어서폐기능정도를추측하는데도움을줄수있을것으로기대된다. 1. Ayres SM, Griesbach SJ, Reimold F, Evans RG. Br onchial component in chronic obstructive lung disease. Am J Med 1974;57:183-91. 2. Hanania NA, Kalberg C, Yates J, Emmett A, Hor stman D, Knobil K. The bronchodilator response to salmeterol is maintained with regular, long-term use in patients with COPD. Pulm Pharmacol Ther 2005; 18:19-22. 3. O'Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to ex ercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86-94. 4. Ramsdell JW, Tisi GM. Determination of broncho dilation in the clinical pulmonary function labor atory: role of changes in static lung volumes. Chest 1979;76:622-8. 5. Girard WM, Light RW. Should the FVC be consider ed in evaluating response to bronchodilator? Chest 1983;84:87-9. 6. Cerveri I, Pellegrino R, Dore R, Corsico A, Fulgoni P, van de Woestijne KP, et al. Mechanisms for isolated volume response to a bronchodilator in patients with COPD. J Appl Physiol 2000;88:1989-95. 7. Newton MF, O'Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large po pulation of patients with severe hyperinflation. Chest 2002;121:1042-50. 8. Park HP, Park HS, Lee SW, Seo YW, Lee JE, Seo CK, et al. Change of lung volumes in chronic obstr uctive pulmonary disease patients with improvement of airflow limitation after treatment. Tuberc Respir Dis 2004;57:143-7. 9. American Thoracic Society. Lung function testing: selection of reference values and interpretative strat egies. Am Rev Respir Dis 1991;144:1202-18. 10. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, mana gement, and prevention of chronic obstructive pul monary disease. Am J Respir Crit Care Med 2001; 163:1256-76. 11. Sourk RL, Nugent KM. Bronchodilator testing: con fidence intervals derived from placebo inhalations. Am Rev Respir Dis 1983;128:153-7. 12. Sciurba FC. Physiologic similarities and differences between COPD and asthma. Chest 2004;126(2 Suppl): 117S-24S. 13. O'Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during 28
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