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1 만성기침에서스테로이드흡입제의역할 한림대학교의과대학내과학교실, 한림대학교성심병원호흡기 알레르기내과이경훈, 장승훈, 이정화, 엄광석, 반준우, 김동규, 신태림, 박상면, 이명구, 김철홍, 현인규, 정기석 The Role of Inhaled Corticosteroid in the Management of Chronic Cough Kyung-Hun Lee, M.D., Seung Hun Jang, M.D., Jung-Hwa Lee, M.D., Kwang-Seok Eom, M.D., Joon-Woo Bahn, M.D., Dong-Gyu Kim, M.D., Tae Rim Shin, M.D., Sang Myon Park, M.D., Myung-Gu Lee, M.D., Chul-Hong Kim, M.D., In-Gyu Hyun, M.D., and Ki-Suck Jung, M.D. Division of Pulmonary, Allergy and Critical Care Medicine of Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea Background : Cough may be a consequence of bronchial hyperresponsiveness or inflammation. Empirical treatment is important in this context because it difficult to verify the obvious cause of cough using laboratory tests, Corticosteroid has a nonspecific anti-inflammatory effect, and can be used for cough management. However, its response rate has not yet been fully elucidated. This study investigated the short- term effects of inhaled corticosteroid on chronic cough Methods : Patients with chronic cough with a normal chest radiograph and a pulmonary function test were enrolled. Cases with a prior respiratory infection within 8 weeks, a history of bronchial asthma, objective wheezing on examination, subjective symptoms of gastroesophageal reflux or taking an ACE inhibitor were excluded. On the first visit, a methacholine bronchial provocation test, spontaneous sputum eosinophil count performed twice and a paranasal sinus radiograph were checked, and the patients were treated with budesonide turbuhaler 800 μg /day for ten days. The primary outcome measure was a decrease in the cough score after treatment. Results : Sixty nine chronic coughers were finally analyzed. The final diagnoses by the routine tests were as follows: bronchial asthma 13.0%, eosinophilic bronchitis 18.8%, paranasal sinusitis 23.2% and non-diagnostic cases 53.6%. The following responses to the inhaled corticosteroid were observed: definite responders, 76.8%, possible responders, 2.9% and non-responders, 20.3%. The response rate was not affected by the final diagnosis even in the non-diagnostic cases. There were minimal adverse drug related effects during the empirical treatment. Conclusion : Routine objective tests such as methacholine provocation, sputum eosinophil count and simple radiographs were notare not suitable for diagnosing chronic cough Therefore, empirical treatment is important. Short term inhaled corticosteroid is effective and can guide a further treatment plan for chronic cough. (Tuberc Respir Dis 2006; 60: ) Key words : Chronic cough, Inhaled corticosteroid, Response rate 서 기침은가장흔한호흡기증상중하나이며, 3주이상지속된만성기침의유병률은비흡연성인의 14-23% 로보고되고있다 1. 8주이상지속된기침을만성, 3-8주동안지속된기침을아급성으로세분하 론 Address for correspondence : Ki Suck Jung, M.D., Ph.D Department of Internal Medicine, Pulmonology Allergy Center, Hallym University Sacred Heart Hospital, 896 Pyungchon-dong, Dongan-gu, Anyang-si, Gyeonggi-do , Republic of Korea Phone : Fax : pulmoks@hallym.ac.kr Received : Aug Accepted : Jan 기도하지만, 아급성기침은상기도감염과관련되어있는경우를제외하면만성기침과동일한방법으로접근하는것이타당하다. 만성기침의흔한원인은호산구성기관지염, 기침변이형천식, 천식등의호산구가병리적과정에관여하는하기도질환과후비루증후군, 위-식도역류등의하기도외의질환에의한이차적기도반응에의한질환들이중요한원인으로알려져있다 2-4. 그러나이들질환은증상이서로명확하게구분되지않는경우가많아서증상에근거하여진단하는것은진단적가치가떨어지며, 최종진단은특이적치료에의하여기침이치료될때가능하다 5,6. 그러나약 20% 의환자는충분한검사와경험적치료에도불구하고원인을찾아내지못하는것으로알려 221

2 KH Lee et al. : The role of inhaled corticosteroid in chronic cough 져있다 7. 기도염증은만성기침의주요원인을차지하는천식, 비-부비동염, 위-식도역류뿐만아니라특정원인을밝히지못한특발성기침 (idiopathic cough) 에서도종종관찰된다 8,9. 임상에서여러가지검사법들의진단적한계를극복하고치료의방향설정을위하여비특이적소염제인스테로이드를사용하는경우가있으며, 저자들은만성기침환자에게경구스테로이드를단기간투여함으로써치료및진단의방향설정을비용-효과적으로달성할수있음을보고한바있다 10. 그러나만성기침에대한흡입스테로이드의효과는제한적으로알려져있어서, 만성기침의스테로이드흡입제에대한반응률을알아보고자본연구를수행하였다. 대상및방법 1. 연구대상 2003년 11월부터 2004년 7월까지한림대학교성심병원호흡기-알레르기센터를방문한만성기침환자를대상으로하였다. 만성기침은 8주이상의기침으로정의하였으며, 최근기도감염의증상이없었던 3 주이상의기침환자도연구에포함시켰다. 환자의흡연여부는고려하지않았다. 환자가내원하였을때자세한병력청취, 인후와흉부검진을시행하는동시에단순흉부방사선촬영과기본폐기능검사를시행하였다. 대상환자의선택기준은 1) 만성기침의정의에합당한경우, 2) 정상단순흉부방사선검사및정상폐기능검사, 3) 16-70세이며, 연령기준은약물투여전후증상평가의신뢰성을확보하기위한것이었다. 제외기준은 1) 최근 2년간기관지천식의진단또는치료력, 2) 청진했을때천명음의존재, 3) 위-식도역 류증상, 4) Angiotensin converting enzyme- 억제제복용, 5) 비정상단순흉부방사선또는폐기능검사, 6) 내원 3일이내에기침에대한투약이있었던경우, 7) 호흡곤란이있는경우였다. 2. 환자의처치와기침에대한평가연구기준에맞는환자를대상으로메타콜린기관지유발검사, 2회의자발객담호산구분율과부비동방사선촬영을시행하였다. 메타콜린기관지유발검사는 1999년제시된미국흉부학회의지침에따라시행하였다. 객담은전처리없이 Wright 염색을하여호산구분율을측정하였다. 치료전후기침의차이를평가하기위하여환자에게기침의심한정도를 0에서 100사이의숫자로답하게하였다. 그이후에 budesonide turbuhaler (200μg/puff) 를 1회 2puff, 1일 2회흡입하도록교육하고, 10일후에외래에서기침의변화에대하여추적관찰하였다. 이기간중에스테로이드흡입제를제외한다른약물의투여는없었다. 기침에대한재평가에는앞서사용한 1) 사이의수치적평가 (numeric cough scale) 와 2) 다음과같은계단식평가 (stepwise grading system) 가이용되었다 : 1. 최고로많이나빠졌다, 2. 매우많이나빠졌다, 3. 상당히나빠졌다, 4. 약간나빠졌다, 5. 거의같거나조금나빠졌다, 6. 변화가없었다, 7. 거의같거나조금좋아졌다, 8. 약간좋아졌다, 9. 상당히좋아졌다, 10. 매우많이좋아졌다, 11. 최고로많이좋아졌다. 대상환자들을스테로이드반응도에따라확실한스테로이드반응군, 반응추정군, 불응군으로분류하고, 각군에대한검사결과를분석하였다 (Table 1). 확실한흡입스테로이드반응군과반응추정군의합을흡입스테로이드반응군으로정의하였다. 환자가지시한객관적검사를시행하지않은경우, 흡입스테 Table 1. Degree of steroid responsiveness Degree Criteria Definite responder Improvement of cough scale 20 or grade of symptom change 9 Possible responder Improvement of cough scale =10~19 and grade of symptom change =8 Non responder Improvement of cough scale 9 or grade of symptom change 7 222

3 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 로이드투여기간중호흡기감염의임상적증거가있거나정해진추적관찰기간중병원을방문하지않은경우, 흡입스테로이드를 7일미만으로사용한경우는최종분석대상에서제외하였다. 3. 검사양성의정의시행한검사의결과는다음과같은기준을만족할때양성으로정의하였다 : 1) 메타콜린기관지유발검사 : PC20 25 mg/ml, 2) 자발객담호산구분율 3% ( 두번의검사결과중큰값 ), 3) 부비동방사선촬영 : 부비동점막의비후기관지천식의진단은다음과같은조건중하나를만족하는경우로정의하였다 : 1) 메타콜린기관지유발검사양성, 2) 환자가천명음을경험하였다고주장하면서객담호산구검사양성, 3) 과거에의사로부터천식을진단받았던병력이있으면서객담호산구양성. 호산구성기관지염은객담호산구분율이양성이면서위의천식진단기준에부합되지않는경우로, 부비동염은부비동방사선사진에서점막의비후가발견된경우로정의하였다. 상기한진단기준어디에도부합되지않는경우는진단불가증례 (non-diagnostic case) 로분류하였다. 4. 통계적분석전체대상환자및각질환군에따라흡입스테로이드에대한확실한반응군, 반응추정군, 불응군의분율을구하였다. 각질환군에따른흡입스테로이드반응률은 Chi-square test를이용하여비교하였고, 흡입스테로이드에대한반응군과불응군의약물순 응도는 Mann-Whitney U test를이용하여비교하였다. 통계분석은 SPSS version 11.0을이용하였으며, p < 0.05 일때통계적유의성이있다고판정하였다. 결과 1. 대상환자의특성총 92명의만성기침환자가연구에참여하였으나 23명은연구지침의위반으로제외되어최종 69명이분석되었다. 이들은남자 29명, 여자 40명이었고, 연령분포는 17-70세, 평균연령은 40.4 ± 13.3세였다. 분석에서제외된 23명중 10명은외래추적에서손실되었고, 4명은검사미시행, 1명은약물미사용, 3명은검사미시행및약물미사용, 3명은연구기간중추가약물복용, 2명은연구기간중새로운호흡기감염이발생하였다. 2. 최종진단및객관적검사결과최종진단결과는기관지천식 9명 (13.0%), 호산구성기관지염 13명 (18.8%), 부비동염 16명 (23.2%), 진단이불가능한증례 37명 (53.6%) 이었다. 부비동염환자 16명중 4명은기관지천식과, 2명은호산구성기관지염과동반된경우이므로부비동염단독으로진단된경우는 10명 (14.5%) 이다 (Figure 1). 69명의환자중에서객관적검사중최소 1개이상의검사에서양성인경우는 32명 (46.4%) 이고, 나머지 ( 진단불가증례 ) 37명 (53.6%) 은모든검사가정상이었다. 메타콜린기관지유발검사는 2명 (2.9%), 자발객담호산구 Table 2. Clinical characteristics and inhaled corticosteroid responsiveness of the patients* Total DR PR NR Evaluated cases, n (%) 69 (100%) 53 (76.8%) 2 (2.9%) 14 (20.3%) Age, year 40.4 ± ± ± ± 8.4 Gender, Male/Female 1 : : : 1 1 : 1.8 FVC, % predicted ± ± ± ± 7.4 FEV1, % predicted ± ± ± ± 9.7 FEV1/FVC, % 82.4 ± ± ± ± 4.8 Inhaler steroid using day 10.3 ± ± ± ± 1.2 Omitting drug, puffs 0.8 ± ± ± ± 1.2 * Values given as mean ± SD, unless otherwise indicated. Definite responder, Possible responder, Non responder 223

4 KH Lee et al. : The role of inhaled corticosteroid in chronic cough Figure 1. The distribution of diagnoses and the response rate to inhaled corticosteroid. 53.6% of the patients failed to be classified to a specific disease when sputum eosinophil count, paranasal sinus radiographs and methacholine provocation test were performed. The overall response rate to inhaled corticosteroid was around 80% in terms of cough. The response rates according to the diagnoses were not statistically different (Chi-square test, p=0.159). 분율검사는 22명 (31.9%), 부비동방사선사진은 16 명 (23.2%) 에서양성이었다. 기관지천식으로진단된 9명의환자중에서메타콜린기관지유발검사는 2명 (22.2%), 자발객담호산구분율검사는 9명 (100.0%), 부비동방사선사진은 4명 (44.4%) 에서양성이었다. 만일대상환자들에게메타콜린기관지유발검사를시행하지않았다면메타콜린기관지유발검사양성자 2명은모두호산구성기관지염으로진단이바뀌었을것이다. 그러나임상에서기관지천식과호산구성기관지염의치료과정은거의같으므로메타콜린기관지유발검사가만성기침환자를진료하는데제공하는정보는크지않다고할수있다. 3. 만성기침의흡입스테로이드에대한반응경험적흡입스테로이드투여에대한반응은확실한반응군 53명 (76.8%), 반응추정군 2명 (2.9%), 불응군 14명 (20.3%) 이었다 (Table 2). 확실한반응군과불응군사이에스테로이드흡입제사용일과사용하지않은횟수는통계적인차이가없었다 (p=0.378 and p=0.293 respectively). 최종진단에따른흡입스테로이드반응률은기관 지천식 100.0%, 호산구성기관지염 84.6%, 부비동염 87.5%( 부비동염단독진단인경우확실한반응군 90.0%), 진단불가증례 70.3%( 확실한반응군 64.9%, 반응추정군 5.4%) 이었다 (Figure 1). 호산구성기관지염환자중에서흡입스테로이드불응군 2명중 1 명은호산구성기관지염과부비동염을동시에가지고있었고갑상선기능저하증으로투약중이었다. 나머지 1명은순수한호산구성기관지염환자였다. 각진단에따른흡입스테로이드반응률의통계적차이는없었다 (p=0.159). 전체참여환자중에서 2.2% 만이치료중에새로운호흡기감염을경험하였고, 그외의어떠한부작용도나타나지않아서단기간흡입스테로이드의우수한내약성을보였다. 고찰최근보고들에의하면만성기침의기본적인기전은기도염증과관련이있다. 만성기침환자의기관지점막병리소견에서염증세포침윤과상피세포손상및기저막이두꺼워지는소견을관찰할수있다 11,12. 기도염증에의한상피세포손상으로감각신경말단의기침수용체가화학적, 기계적자극에노출되면기 224

5 Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb 침반사가나타나는것이다. 천식환자에서스테로이드는기도의염증세포침윤을억제시켜손상된섬모의재생을촉진하는것으로확인되었다 기도염증의병리과정에호산구가중요한역할을하는경우가아니라도스테로이드의비특이적항염증효과는다양한기도염증에의한기침에효과적으로작용할수있음이보고되고있다 9,16. 만성기침환자를진료하는데가장큰문제점중의하나는철저한문진과검사를시행해도정확한원인을찾지못하는경우가많다는것이다. 본연구에서일반적인검사로기침의원인을진단할수있는경우는 46.4% 의환자에불과하였으며, 나머지환자에서는경험적접근을시도할수밖에없는상황이었다. 물론기관지내시경검사나, 흉부전산화단층촬영, 24시간식도산도검사와같은검사를시행할수도있으나침습적이며비용이많이들고, 더심각한문제는이러한검사를시행해도진단율의개선은제한적이라는것이다 17,18. 이러한상황에서는가장가능성있는치료제를선택하여진단적검사를시행하는것과동시에경험적치료를시도하는것이만성기침환자에게비용-효과적이고, 빠르게진단과치료목적을달성할수있는방법이다 10. 본연구에서진단된질환에따른흡입스테로이드반응률은차이를보이지않았다. 흥미로운것은부비동염환자에서흡입스테로이드를사용했을때 90% 의반응률을보인다는것이다. 만성기침을호소하는부비동염환자에서경구스테로이드반응률은 91% 로보고된바있다 10. 이러한사실은지금까지비-부비동염에서의기침발생기전으로제시된후비루에의한기침수용체자극이기침의주된원인일가능성보다는, 이들환자에서부비동염이기관지염과동시에존재할가능성을시사한다. 즉부비동염은기도점막군 ( 부비동, 비강, 인-후두, 기관-기관지점막 ) 의범발성염증이방사선촬영이라는방식에의하여발견된것에불과할것이라는것이다. 이에대한향후추가적인연구가필요하다고생각된다. 또한진단불가증례에대한고찰이필요하다고생각된다. 본연구에이용된검사의진단적한계로인하여특정질환이진단불 가증례로분류되었을수도있지만, 지금까지특별히정의되지못한다양한원인과병리적변화를포함하는기관지염들이포함되어있을가능성이있으므로, 향후이들염증에관한세심한검증작업이필요하다고생각된다. 이들중많은환자들이흡입스테로이드치료로기침이호전되었는데, 본연구가대조군을포함하지않은한계가있으므로시간경과에따른기침의자연소실분을구분할수없어서해석에주의를요한다. 그러나통계적유의성이없다고하지만이들의스테로이드반응률이다른질환군에비하여떨어지는경향이있다는것은이들이스테로이드에반응하지않거나반응역치가높은병리과정이개입되어있는특별한질환군일가능성이있다. 본연구에흡연자가포함되어있다는점은이연구의또다른제한점일것이다. 그러나흡연자가만성기침을호소할때이들을모두흡연에의한만성기관지염으로매도하는것은바람직하지않은태도이다. 흡연성기관지염환자의일부가본연구에서진단불가증례로포함되어있을수있겠다. 그러나흡연자의기침에대한스테로이드반응률은현저히떨어지는것으로알려져있으므로이들이제외된경우라하더라도본연구에서제시된만성기침에대한흡입스테로이드반응률이저하될우려는없다고할수있다 16,19,20. 흡연과같은산화스트레스는 histone deacetylase를억제하여스테로이드의항염증작용을감소시킴으로써결과적으로스테로이드저항성을나타낸다 21. 이처럼흡연자와비흡연자의기도염증기전이서로다른양상이기때문에약의효과에영향을미친다고생각되고, 비흡연자가높은기저기침반사반응률을가지고있기때문에스테로이드치료에대한반응이더좋다고생각된다 22,23. 결론적으로만성기침환자를진료할때병력청취, 신체검진, 객관적기본검사 ( 흉부, 부비동방사선촬영, 객담호산구분율, 메타콜린기관지유발검사 ) 를시행하는동시에흡입스테로이드를단기간투여하는것은안전하고효과적이며, 검사의진단적한계를극복하고초기에진료지침을세우는방법이될수있다. 225

6 KH Lee et al. : The role of inhaled corticosteroid in chronic cough 요 연구배경 : 만성기침은정밀검사를추가하여도진단율을향상시키는데한계가있고, 확진은특이적치료에반응할때에만가능하다. 스테로이드는비특이적항염증작용을가지므로만성기침에효과적일수있다. 본연구에서는원인진단에대한진료한계를극복하기위한방법으로서, 만성기침에대한흡입스테로이드의반응률을알아보기위하여시행되었다. 방법 : 3주이상의만성기침환자를대상으로처음내원하였을때객담호산구, 메타콜린기관지유발검사, 부비동방사선촬영등의기본적인객관적검사를시행하고, 동시에 budesonide turbuhaler 800μg /day를 10일간투여하고추적방문토록하였다. 추적방문일에환자증상의개선도에따라흡입스테로이드반응군과불응군으로분류하였고검사의진단성적을조사하였으며, 각진단에따른스테로이드반응률을알아보았다. 결과 : 총 69명의만성기침환자가최종분석되었고, 흡입스테로이드의투여로증상의호전이있었던경우는 79.7% 였다. 진단된질환에따른흡입스테로이드의반응률은차이가없었다. 투여기간동안부작용은거의관찰되지않아서우수한내약성을보였다. 결론 : 만성기침환자를진료할때기본검사를시행하는동시에흡입스테로이드를단기간투여하는것은매우안전하며, 검사의진단적한계를극복하고초기에진료지침을세우는방법이될수있다. 약 참고문헌 1. Irwin RS, Rosen MJ, Braman SS. Cough. A comprehensive review. Arch Intern Med 1977;137: 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: 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: 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 : Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med 2000;343: Mello CJ, Irwin RS, Curley FJ. Predictive values of the character, timing, and complications of chronic cough in diagnosing its cause. Arch Intern Med 1996;156: 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: Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ. Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax : Lee SY, Cho JY, Shim JJ, Kim HK, Kang KH, Yoo SH, et al. Airway inflammation as an assessment of chronic nonproductive cough. Chest 2001;120: Jeon G, Jang SH, Song HG, Ha JW, Eom KS, Bahn JW, et al. Diagnostic performance of routine objective tests and cost-effective approach for chronic cough. Tuberc Respir Dis 2004;57: Boulet LP, Milot J, Boutet M, St Georges F, Laviolette M. Airway inflammation in nonasthmatic subjects with chronic cough. Am J Respir Crit Care Med 1994;149: Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without asthma. Lancet 1989;17: Lundgren R, Soderberg M, Horstedt P, Stenling R. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years of treatment with inhaled steroids. Eur Respir J 1988; 1: Jeffery PK, Godfrey RW, Adelroth E, Nelson F, Rogers A, Johansson SA. Effects of treatmenton airway inflammation and thickening of basement membrane reticular collagen in asthma. Am Rev Respir Dis 1992;145: Heino M, Karjalainen J, Ylikoski J, Laitinen A, Laitinen LA. Bronchial ciliogenesis and oral steroid treatment in patients with asthma. Br J Dis Chest 1988;82:

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Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical