DOI: 10.4046/trd.2009.67.5.422 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2009;67:422-429 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. Original Article 만성특발성기침에대한흡입스테로이드의치료효과 1 한림대학교의과대학내과학교실, 2 한림대학교성심병원호흡기 - 알레르기내과, 3 한강성심병원호흡기 - 알레르기내과 한보람 1,2, 장승훈 1,2, 김유진 1,2, 박성훈 1,2, 황용일 1,2, 김동규 1,2, 김철홍 1,3, 현인규 1,3, 정기석 1,2 The Efficacy of Inhaled Corticosteroid on Chronic Idiopathic Cough Boram Han, M.D. 1,2, Seung Hun Jang, M.D. 1,2, Yu Jin Kim, M.D. 1,2, Sunghoon Park, M.D. 1,2, Yong Il Hwang, M.D. 1,2, Dong-Gyu Kim, M.D. 1,2, Cheol-Hong Kim, M.D. 1,3, In-Gyu Hyun, M.D. 1,3, Ki-Suck Jung, M.D. 1,2 1 Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Division of Pulmonary, Allergy, and Critical Care Medicine, 2 Hallym University Sacred Heart Hospital, Anyang, 3 Hangang Sacred Heart Hospital, Seoul, Korea Background: The discomfort caused by chronic cough, that is persistent for more than 3 weeks, causes a number of patients to seek medical attention. However, the underlying disorder often remains undetermined despite thorough examinations, and is considered to be idiopathic. This study compared the efficacy of inhaled corticosteroid with conventional cough suppressants on chronic idiopathic cough. Methods: Eligible patients with chronic idiopathic cough were randomly assigned to either the inhaled fluticasone group or the codeine plus levodropropizine oral administration group. The subjects in each group took their planned medication for 2 weeks. After the trial, comparative analyses of outcomes were performed in terms of the remnant cough (%) at the end of treatment, drug compliance, and adverse drug events. Results: Seventy-seven patients were enrolled in this randomized trial; 38 to the inhaled fluticasone group and 39 to the codeine plus levodropropizine group. The remnant cough was 41.0±35.8% in the inhaled fluticasone group, and 32.4±32.0% in the codeine+levodropropizine group (p=0.288). Drug compliance was 95.4±7.4% and 81.8±18.6% in the inhaled fluticasone and the codeine+levodropropizine group, respectively (p<0.001). Nine patients had adverse drug events in the codeine+levodropropizine group compared to one in the inhaled fluticasone group (p<0.001). Conclusion: Short-term inhaled corticosteroid is not inferior to conventional antitussive agents in controlling chronic idiopathic cough without significant adverse events. Key Words: Cough; Antitussive Agents; Corticosteroid 서 기침은임상에서흔히접하는증상중의하나로서 1,2, 3 주이상지속된만성기침의경우유병률이 3 40% 까지보고되고있다 2,3. 만성기침은삶의질을저하시킬뿐아 Address for correspondence: Seung Hun Jang, M.D. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 896, Pyeongan-dong, Dongan-gu, Anyang 431-070, Korea Phone: 82-31-380-3718, Fax: 82-31-381-3973 E-mail: chestor@hallym.or.kr Received: Aug. 24, 2009 Accepted: Sep. 24, 2009 론 니라 4,5, 특정호흡기질환과관련된증상의하나로나타날수있기때문에이에맞는적절한치료가필요하다 6. 기침의원인을찾기위해서일반적으로병력청취, 신체검진, 흉부및부비동방사선촬영, 폐기능검사및기관지유발검사, 유도객담내염증세포분율검사등을시행하며, 흉부전산화단층촬영이나기관지내시경검사는만성기침의원인을밝히는데에큰도움을주지못하는것으로알려져있다. 선행연구에따르면계통적접근을통해만성기침의원인을 78 100% 까지찾아낼수있으며 7-14, 천식, 상기도기침증후군, 위식도역류가비흡연자만성기침의가장흔한원인으로알려져있다 7-9,11,13,14. 기침원인에대한최종진단은특정진단을의심하고그에맞는치 422
Tuberculosis and Respiratory Diseases Vol. 67. No. 5, Nov. 2009 료에의해기침이소실될때확진할수있다. 그러나일부환자에서는다양하고체계적인검사를통해서도기침의원인이밝혀지지않는데, 이런경우만성특발성기침으로분류된다. 천식, 상기도기침증후군, 위식도역류, 호산구성기관지염및안지오텐신전환효소억제제에의한기침의경우, 기도염증이동반된다고보고되고있으며 12,15, 몇가지연구에서는원인이밝혀지지않은만성기침환자의기도에서도조직학적염증이존재한다고보고한바있다 16-19. 임상에서만성특발성기침치료로비특이적소염제인스테로이드를경험적으로투여하기도하는데, 선행연구에서는흡입용스테로이드가기침감소에유의한효과를보인다고보고하였다 19-22. 일반적으로만성특발성기침에대해서는의사의판단에따라진해제등의대증적치료가주축을이룬다 23. 만성특발성기침에서도비특이적인기관지염증이관찰된다면, 스테로이드를사용하여기도염증을줄임으로써기침경감효과를얻을수있을것이며, 앞서기술한만성특발성기침에서의스테로이드효과가그증거가될수있겠다. 조사한바에의하면아직까지만성특발성기침치료에있어서흡입스테로이드와기존진해제의효과를비교한연구가없었다. 따라서이연구는만성특발성기침에서이들약제의효과를비교하고자하였다. 대상및방법 1. 연구대상 3주이상지속된기침을주소로한림대학교성심병원호흡기-알레르기내과를방문한환자들을대상으로복용약제를포함한자세한병력청취와신체검진을비롯하여흉부및부비동단순방사선촬영, 유도객담내염증세포분율, 폐기능검사와메타콜린기관지유발검사를기본선별검사로시행하였다. 18세이상, 정상방사선소견및정상폐기능을보이고메타콜린기관지유발검사에서기도과민반응이없으며, 비흡연자, 이전에천명음을경험하지않았던자, 유도객담내호산구분율이 1% 이하인자들을연구대상자로하였다. 비흡연자는평생 100개비미만의흡연으로정의하였다. 제외기준으로는천식의병력, 천명음을경험하였거나청진시천명음이확인된경우, 위-식도역류의주관적증상이있거나, 발열이나인후통, 화농성비루와같은호흡기감염증상이최근 8주내있었던경우, 안지오텐신전환효소억제제를복용하는 경우, 기침에영향을줄수있는항히스타민제또는진해제를검사시작 3일이내에복용한경우로하였다. 2. 메타콜린기관지유발검사본검사전에히스타민을이용한피부단자시험을통해항히스타민에노출되었던자를배제하였으며, 메타콜린기관지유발검사는선량계를이용한 5회폐활량흡입법으로시행하였다 24. 기본폐기능검사를실시한후에 0.625, 1.25, 2.5, 12.5, 25 mg/ml 로농축한메타콜린분무액을압축기 (Pulmo-Aide 5650D; DeVibliss Health Care, Somerset, PA, USA) 와연무기 (DeVibliss 646; De- Vibliss Health Care) 를이용해흡입하였다. 대상자들은 KoKo-MSM analog micro-dosimeter (nspire Health Inc., Louisville, CO, USA) 로정량화한메타콜린을천천히 5초간흡입한후그대로 5초간숨을멈추는방식을 5회반복하였으며, 흡입 30초, 90초후에각각 1초간노력성호기량 (forced expiratory volume at one second, FEV 1 ) 을측정해가장높은측정값을분석자료로이용하였다. 메타콜린유발검사는 FEV 1 이기저치의 20% 이상감소하거나마지막농도인 25 mg/ml에도달하였을때중단하였다. FEV 1 이 20% 감소하는메타콜린의농도 (PC 20 ) 가 25 mg/ ml 이하일경우기도과민성이있다고평가하였다. 3. 유도객담내의세포수측정기저 FEV 1 을측정한후대상자들의입을물로헹구고마른거즈로닦도록하였다. 4.5% 고장성식염수분무액 15 ml를 5분간흡입한후다시물로입을헹구고 50 ml falcon tube에객담을배출하도록하였다. 이와같은과정을 3 4회반복하여모은객담을동량의 0.15% dithiothreitol 과섞어인산완충식염수에서 30분간용해하고 100 μm 여과기를통해여과한후 4 o C 온도에서 5분간 2,000 rpm으로원심분리하였다. 부유물질을조심스럽게제거하고인산완충식염수로재부유한후, cytospin을이용하여슬라이드를제작하고 Wright 염색처리하여 300개이상의비편평세포를세는중에탐식구, 호중구, 림프구및호산구세포분율을조사하였다. 4. 연구설계연구선택기준을만족하는대상자들을성별로층화한후 fluticasone propionate (FLT) 흡입군과 codeine phosphate (CD)+levodropropizine (LDP) 경구복용군으로무작위배정하였다. 치료를시작하기전두군은기침의 423
BR Han et al: Inhaled corticosteroid on chronic idiopathic cough 빈도와강도및양상, 동반증상을묻는설문지를작성하였다. 기침의빈도는하루중드물게기침을하는경우, 매일하지만매시간은아닌경우, 매시간하는경우, 거의하루종일하는경우로구분하여각각 1점에서 4점까지부여하였으며, 기침의강도는일상생활에지장이없는경우, 약간의지장이있는경우, 상당한지장이있는경우, 기침때문에일하기힘든경우로나누어 1점에서 4점까지부여하였다. FLT군은 fluticasone propionate 250 μg 을디스커스형흡입기로하루두차례흡입하고, CD/LDP 군은 codeine 20 mg과 levodropropizine 60 mg을하루세차례복용하도록하였다. 투약은대조위약군이없는개방형연구형식으로진행되었으며검사기간동안호흡기증상에영향을미칠수있는기타모든약제들은금지하였다. 2주간의치료후잔여기침분율, 투약순응도, 약물유해반응을조사하였다. 정해진때에진료를하지못한경우에는전화조사를통해결과를확인하였다. 잔여기침분율 (%) 은치료전기침정도를 100% 로하여치료후의상대적인값을 0 100% 로측정하였다. 1차결과변수는각군의잔여기침분율로하였으며, 2차결과변수는치료종결시점에잔여기침분율이 50% 이하가되는자들로정의한치료반응군의비율과각군의약물유해반응들로하였다. 투약순응도는처음예정되었던용량에대한실제복용한용량의비율로계산하였다. 양군간잔여기침분율의차이가 20 이상일때의미있다고하였고, 각군의대상자수는잔여기침분율의표준편차를 30, 예상탈락자비율을 5%, α-error 를 0.05, 검정력을 80% 로하여계산하였고, 신뢰성을갖는차이를입증하기위해서는각군당 38명의대상자가필요하였다. 본연구는한림대학교성심병원기관윤리위원회의승인을받았으며, 모든피험자들로부터동의서를받았다. ( 양측검정 ) 일때통계적유의성을인정하였다. 결과 1. 대상자특성 2004년 11월부터 2007년 7월까지한림대학교성심병원호흡기-알레르기내과를방문한만성기침환자들을대상으로앞서기술한인정기준을만족하는총 77명의환자에서 CD/LDP 군에 39명, FLT군에 38명을성별층화하여무작위배정하였다. 임상시험기간중에 CD/LDP 군에서 2명의추적관찰실패와 2명의시험중단 ( 약물부작용 1 명, 호흡기감염 1명 ) 이발생하여모두 35명이시험을완료하였으며, FLT군에서는 3명의추적관찰실패, 1명의시험중단 ( 시험기간중금지약물임의복용 ) 으로모두 34명이시험을완료하였다 (Figure 1). 각군별대상자들의기본특성을 Table 1에기술하였다. CD/LDP 군과 FLT군의중앙연령 ( 범위 ) 은각각 36세 (23 59세), 36세 (18 74 세 ) 였으며 (p=0.529), 남 : 녀성비는두군모두약 1: 3.5였다. 기침유병기간의중앙값은 CD/LDP 군에서 8주 (95% 신뢰구간, 6 10주 ), FLT군에서 10주 (95% 신뢰구간, 8 12 주 ) 를보였다 (p=0.824). 임상시험전기침의빈도와강도, 기본폐기능검사결과, 객담내염증세포분율, 비염증상, 만성기침또는알레르기의과거력, 만성기침의가족력모두두군간유의한차이가없었다. 2. 치료효과 2주간의치료를마친후측정한잔여기침분율은 CD/ LDP군에서 32.4±32.0%, FLT군에서 41.0±35.8% 였다 5. 통계분석 각군간기본특성들의차이는연속형자료는 t-test를, 범주형자료는 chi-square test를사용하여분석하였으며, 분석대상자수가 30명미만인경우에는 Mann-Whitney U test 또는 Kruskal-Wallis test를이용하였다. 연령과기침유병기간의중앙값은 Kaplan-Meier method를이용해계산, log-rank test 를통해비교하였다. 각군의유해반응들을열거하고그빈도를기술하였다. Intention-to-treat analysis 원칙에따라추적관찰에실패하여잔여기침분율에대한어떠한자료도수집되지못한경우를제외한모든피험자를대상으로분석하였으며, p-value<0.05 Figure 1. Trial profile. 424
Tuberculosis and Respiratory Diseases Vol. 67. No. 5, Nov. 2009 Table 1. Baseline patient characteristics Codeine+Levodropropizine Fluticasone p-value Case, n 39 38 Median age, yr (range) 36 (23 59) 36 (18 74) 0.529 Gender, male:female 1:3.6 1:3.4 0.900 Median duration of cough, wk (range) 8 (3 1,040) 10 (3 520) 0.824 3 8 wk, n (%) 21 (53.8%) 16 (42.1%) 9 12 wk, n (%) 9 (23.1%) 9 (23.7%) 13 wk, n (%) 9 (23.1%) 13 (34.2%) Grade of cough frequency (grade 1 4) 2.7±0.9 2.6±0.8 0.551 Grade of cough severity (grade 1 4) 2.0±0.8 2.1±0.8 0.865 Lung function FEV 1, % predicted 108.8±11.4 108.4±15.1 0.882 FEV 1/FVC, % 86.4±6.0 85.6±5.8 0.216 Differential cell count in induced sputum Macrophages, % 51.0±35.7% 50.4±38.1% 0.951 Lymphocytes, % 3.9±4.3% 3.2±3.0% 0.472 Neutrophils, % 44.8±33.6% 46.0±36.1% 0.899 Rhinitis*, n (%) 10 (25.6%) 12 (31.6%) 0.495 Previous history of allergy, n (%) 14 (35.8%) 13 (34.2%) 0.286 Previous history of chronic cough, n (%) 26 (66.7%) 21 (55.3%) 0.192 Family history of chronic cough, n (%) 11 (28.2%) 11 (28.9%) 0.709 Data are presented as mean±sd if they are not indicated. *Rhinitis was defined when more than two symptoms of rhinorrhea, sneezing, nasal stuffiness, and itching sense were present at the time of enrollment. Figure 2. Remnant cough after two-week treatment. Remnant cough (% baseline) were 32.4±32.0% in the codeine+levodropropizine group and 41.0±35.8% in the fluticasone group (p=0.288). Dashed lines represent the mean. (p=0.288) (Figure 2). 치료반응군 ( 잔여기침분율 50% 인자 ) 의비율은 CD/LDP 군에서 74.4%, FLT군에서 60.5% 였다 (p=0.432). 투약순응도는 CD/LDP 군에서 81.8± 18.6%, FLT군에서 95.4±7.4% 으로유의한차이가있었는 데 (p<0.001), 투약순응도가치료효과에영향을주었는지를확인하기위해투약순응도를치료반응상태에따라구분하여재분석하였다. 먼저 CD/LDP 군중치료반응군의투약순응도는 80.2±20.3%, 비반응군의투약순응도는 87.7±9.7% 로나타났으며 (p=0.323), FLT군내치료반응군과비반응군의투약순응도는각각 96.0±6.2%, 94.3±9.6% 로나타났다 (p=0.547). 이를통해두군모두에서투약순응도가치료효과에미치는영향이그다지크지않다는것을확인할수있었다. 단지 CD/LDP 군에서상대적으로낮은투약순응도를보이는것은약제복용의번거로움이나약물유해반응에대한우려때문일것으로추측된다. 3. 임상적요인들과치료효과와의관계치료효과에영향을줄수있다고예상되는여러임상요인들을분석해보았으나단지한가지요인만이치료효과와관련이있는것으로나타났다. 담배연기에의해기침이악화되는경우에는진해제가 fluticasone 보다치료효과가좋았다 (Table 2). 이를통해대부분의임상적요소들은보다우수한치료효과를위한약제를선택하는데 425
BR Han et al: Inhaled corticosteroid on chronic idiopathic cough Table 2. Clinical factors and remnant cough in each group Remnant cough (%) Codeine+Levodropropizine Fluticasone p-value Duration of cough 3 8 wk 29.1±32.1 33.6±30.9 0.589 9 12 wk 21.9±23.0 40.7±40.9 0.422 13 wk 50.0±35.7 49.6±39.2 1.000 p-value 0.154 0.437 History of chronic Present 30.2±31.9 42.9±32.6 0.159 cough Absent 37.1±33.2 38.9±39.9 0.982 p-value 0.514 0.608 History of allergy Present 35.6±32.8 51.4±44.7 0.421 Absent 31.4±32.3 39.2±34.7 0.386 p-value 0.789 0.394 Aggravating factor Cold air Yes 32.6±33.4 41.3±37.1 0.329 of cough No 31.4±39.6 39.6±32.9 0.746 p-value 0.984 0.709 Dry air Yes 35.5±33.2 52.8±38.1 0.152 No 29.1±31.4 29.8±30.5 0.774 p-value 0.501 0.059 Talking Yes 40.5±34.8 45.5±35.2 0.648 No 25.5±28.5 34.1±36.9 0.526 p-value 0.177 0.311 Dust Yes 34.4±34.6 44.2±34.7 0.252 No 27.6±25.7 32.8±39.0 0.859 p-value 0.676 0.248 Irritant odor Yes 38.8±39.7 47.5±45.0 0.554 No 31.6±31.6 40.1±35.3 0.315 p-value 0.640 0.549 Smoke Yes 29.0±31.6 50.3±34.1 0.031 No 39.6±33.1 29.9±35.7 0.424 p-value 0.327 0.063 Exercise Yes 56.2±44.7 40.0±20.0 0.604 No 27.8±27.6 41.1±37.2 0.169 p-value 0.115 0.813 Diurnal variation Present 29.2±30.8 42.1±38.8 0.325 Absent 39.9±35.1 37.8±26.8 0.818 p-value 0.472 0.955 Seasonal variation Present 36.3±34.9 41.8±37.7 0.615 Absent 23.2±22.8 36.0±24.1 0.253 p-value 0.340 0.943 Familial history of Present 33.6±40.4 44.8±43.1 0.731 chronic cough Absent 31.9±28.7 39.7±33.8 0.367 p-value 0.894 0.970 Rhinitis Present 35.5±27.9 47.3±35.1 0.443 Absent 31.3±33.8 37.7±36.5 0.531 p-value 0.480 0.236 도움을주지못하였음을알수있었다. 4. 약물유해반응 시험중발견된약물유해반응은 Table 3 과같다. 유해 반응의종류는두군에서매우다른양상으로나타났다. CD/LDP 군의피험자한명만이중등도의어지러움으로시험을중단하였으며, 유해반응을보였던피험자들은특별한치료없이모두자연히회복되었다. CD/LDP 군에서 426
Tuberculosis and Respiratory Diseases Vol. 67. No. 5, Nov. 2009 Table 3. Summary of adverse events Adverse Codeine+Levodropropizine Fluticasone events (n=37) (n=35) Epigastric pain, n (%) 2 (5.4%) 0 (0.0%) Dizziness, n (%) 1 (2.7%) 0 (0.0%) Drowsiness, n (%) 3 (8.1%) 0 (0.0%) Headache, n (%) 2 (5.4%) 0 (0.0%) Nausea, n (%) 1 (2.7%) 0 (0.0%) Hoarseness, n (%) 0 (0.0%) 1 (2.9%) Respiratory infection, n (%) 1 (2.7%) 0 (0.0%) Total, n (%) 9 (24.3%)* 1 (2.9%) *One patient simultaneously had drowsiness and headache. 는모두 9명 (24.3%) 의피험자가, FLT군에서는 1명 (2.9%) 의피험자가유해반응을보였다 (p<0.001). 고 만성기침의원인을파악하기위해서는체계적인계통적접근과, 의심되는원인에대한특이적치료에대한반응평가가필요하다. 계통적접근의흐름은진료지침마다차이가있지만공통적으로권고하는내용은폐실질질환유무를확인하고안지오텐신전환효소억제제와같이잘알려져있는원인을고려할것, 그리고만성기침의가장흔한원인으로알려져있는상기도기침증후군, 천식, 위-식도역류질환을확인하는것이다. Irwin 등 7 이만성기침의원인을찾기위해해부학적접근방법을제안한이래로많은수의유사한연구가시행되었고상당히높은진단과치료성공률을보여주었다 7-16. 그러나이러한진단적접근과경험적치료에도불구하고약 30% 에이르는상당수의기침에서원인이밝혀지지않고있으며, 최근연구에서원인불명의만성기침이증가하고있다고보고하였다 25. 만성특발성기침은다양한병리기전들과연관되어있어그원인은고가의다양한검사를통해서도분명히밝히기어렵다. 더욱이흉부및부비동단순방사선촬영이나기본폐기능검사와는달리메타콜린기관지유발검사나유도객담내세포분율측정, 흉부전산화단층촬영, 기관지내시경등은전문화된의료기관이아니면쉽게시행할수없기때문에임상에서는종종만성특발성기침의대증적치료로비특이적인진해제를처방하게된다 23. 수십년간기침의기전에대한많은연구결과가보고되었으며, 그중몇몇연구에서는특발성을포함한여러원인의만성기침이기도염증과관련있다고보고하였다. 찰 이러한증거는만성기침환자의기관지조직검사또는기관지분비물에서염증매개물질의농도증가등을통해서증명되었다 16-19. 스테로이드는비특이적소염제로여러염증성질환의치료목적으로폭넓게사용되고있는데, 염증세포들이주로림프구와호산구로구성되어있다면스테로이드의항염증효과는더욱커질것이다. 스테로이드는만성기침에서가끔사용되어왔으며, 만성기침에서스테로이드의치료효과는몇몇연구에서입증된바있다 20-22. 그러나만성특발성기침에서기존진해제와비교하여스테로이드의치료효과가어느정도인지는알수없었다. 기도염증이만성특발성기침원인의일부를차지한다면, 스테로이드는기도염증을치료함으로써기침을호전시키는합당한치료제가될수있을것이다. 따라서본연구는흡입용스테로이드인 fluticasone 과비특이적인진해제의진해효과를비교한점에서특이하다고할수있을것이다. 만성특발성기침은여러종류의치료에도쉽게호전되지않는경향을보이기때문에, 진해제군의환자에게는기침의표준치료제라할수있는강력한중추성진해제인 codeine 에말초성진해제인 levodropropizine 을추가하였다. 본연구결과에서중등도용량의흡입용 fluticasone 이매우강력한조합의진해제에비해만성특발성기침을조절하는데다소효과가떨어지는것처럼보이나그차이는통계적으로의미있는정도가아니었다. 특히본연구에서 PC 20 25 이상, 객담내호산구비율 1% 이하로일반적인천식환자를배제하는경우보다엄격한기준을사용하였는데, 이는경미한기관지천식, 호산구성기관지염, 기관지과민증등을모두배제함으로써보다만성특발성기침환자에적합한대상자들을선정하여흡입스테로이드효과가과장되게나타나는것을방지하였다. 본연구결과는스테로이드반응성기도염증이만성특발성기침병인의일부일것이라는사실을시사하고있으며, 흡입용 fluticasone 은투약순응도나약물유해반응측면에서본다면오히려일부환자들에게는더욱유용할것이다. 따라서치료효과, 복약의편의성, 약제부작용등을모두고려하여흡입용 fluticasone 은만성특발성기침치료의하나로고려될수있을것이다. 담배연기에의해악화되는기침외에는흡입스테로이드와진해제의유효성이대비되는다른임상적요소를확인할수없었기때문에, 치료해보지않은상태에서는스테로이드치료대상환자를선별하기어려우나, 여러가지약물로경험적치료를하면서스테로이드반응군을찾을수있을것으로생각된 427
BR Han et al: Inhaled corticosteroid on chronic idiopathic cough 다. 이러한접근법은만성기침환자들의상당수에서이후에도만성기침이재발되는경향이있기때문에향후에도사용될수있는적절한약물을찾는다는면에서유용할것으로생각된다. 본연구의단점은위약대조군없이진행되었기때문에비록짧은기간이었으나상당수의기침이치료하지않아도저절로좋아지면서일부는약물에의한치료반응군으로평가됐을가능성도있을것이다. 그러나흡입용스테로이드와진해제는이미특발성기침에서도그효과가인정되고있고, 본연구진행기관이 3차의료기관으로서 1, 2차의료기관으로부터전원된환자들이많기때문에임상시험용위약대조군을설정하는것은기관윤리위원회승인에장애가될수있었다. 또한맹검법을사용하지않은개방형태의연구로서의한계점을가진다. 그리고환자를선별하는과정에서환자의주관적위-식도역류증상만으로이에의한기침환자가배제되었다고하기는어려울것이나, 위-식도역류에의한기침을배제하는절대적진단법이없다는제한점이있는데다국내에서위-식도역류에의한기침이전체만성기침에서차지하는비율이 10% 이하로서구사회에비하면매우적으므로이러한환자들이섞여있을가능성은높지않다. 본연구에서임상시험양군의의미있는잔여기침분율의차이를 20으로설정하였는데, 이는이견이있을수있는연구자들의주관적결정이다. 이차이를더작게설정했을경우에요구되는임상시험대상환자는증가하게되며, 두군의치료효과는의미있는차이를보였을수도있다. 그러나본연구를시행한기관의연구수행능력을고려하였을때, 잔여기침분율차이 20 이하를유의한차이로통계적으로검증하는것은불가능하였다. 결론적으로본연구는만성특발성기침에서비특이적소염제인흡입용 fluticasone 을단기간사용할때의진해효과는강력한진해제복합요법과비교하여유의한차이가없으며, 오히려투약순응도나약물유해반응에있어서장점이있다는것을확인하였다. 그러므로흡입용 fluticasone 은만성특발성기침의치료방법으로고려될수있을것이다. 참고문헌 1. Irwin RS, Rosen MJ, Braman SS. Cough. A comprehensive review. Arch Intern Med 1977;137:1186-91. 2. Barbee RA, Halonen M, Kaltenborn WT, Burrows B. A longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE. Chest 1991; 99:20-6. 3. Morice AH, Kastelik JA. Chronic cough in adults. Thorax 2003;58:901-7. 4. French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med 1998;158:1657-61. 5. Kuzniar TJ, Morgenthaler TI, Afessa B, Lim KG. Chronic cough from the patient's perspective. Mayo Clin Proc 2007;82:56-60. 6. Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med 2000;343:1715-21. 7. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis 1981;123:413-7. 8. Poe RH, Harder RV, Israel RH, Kallay MC. Chronic persistent cough. Experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest 1989;95: 723-8. 9. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640-7. 10. O'Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med 1994;150:374-80. 11. McGarvey LP, Heaney LG, Lawson JT, Johnston BT, Scally CM, Ennis M, et al. Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998;53: 738-43. 12. Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160: 406-10. 13. Palombini BC, Villanova CA, Araujo E, Gastal OL, Alt DC, Stolz DP, et al. A pathogenic triad in chronic cough: asthma, postnasal drip syndrome, and gastroesophageal reflux disease. Chest 1999;116:279-84. 14. Kastelik JA, Aziz I, Ojoo JC, Thompson RH, Redington AE, Morice AH. Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J 2005;25:235-43. 15. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibi- 428
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