대한영상의학회지 2010;63: 혼합성분의한약복용후발생된미만성침윤성폐질환 : 고해상 CT 및조직병리학적소견 1 김태규 김정숙 2 신은아 3 목적 : 혼합성분의한약복용후발생한미만성침윤성폐질환의고해상 CT소견및병리학적소견을알아보고자하였다. 대상과방법 : 혼합성

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1 대한영상의학회지 2010;63: 혼합성분의한약복용후발생된미만성침윤성폐질환 : 고해상 CT 및조직병리학적소견 1 김태규 김정숙 2 신은아 3 목적 : 혼합성분의한약복용후발생한미만성침윤성폐질환의고해상 CT소견및병리학적소견을알아보고자하였다. 대상과방법 : 혼합성분의한약을복용한이후기침, 호흡곤란이발생하였거나기존의기침, 호흡곤란이더심해진 8명 ( 여자 6명, 남자 2명, 31~81세 ) 을대상으로하였다. 모든환자에게흉부 X선촬영및흉부고해상 CT를시행하였고, 7명에서는방사선투시하대침절제생검및경기관지폐생검으로폐병변부위의병리조직을얻었다. 결과 : 가장흔한고해상CT 소견으로는양측성미만성간유리음영 (n=7) 이었고, 다음으로기관지주위경화 (n=5), 소엽간중격비후 (n=2) 였다. 병변은폐상부보다는폐하부, 폐주변부보다는폐중심부에주로분포하였다. 조직검사를시행한 7예의병리학적소견으로는비특이적간질성폐렴이 3명, 폐쇄성세기관지기질화폐렴이 2명, 그리고과민성폐렴, 호산구성폐렴이각각 1명이었다. 조직병리학적소견과관계없이모든환자는스테로이드치료이후임상적, 영상학적으로호전되었다. 결론 : 혼합성분의한약복용후발생한미만성침윤성폐질환의고해상CT 소견은주로양측성미만성간유리음영, 기관지주위경화로나타났으며폐하부를주로침범하는경향이있었다. 병리학적소견으로는비특이적간질성폐렴, 폐쇄성세기관지기질화폐렴, 과민성폐렴, 호산구성폐렴등다양하였다. 우리나라에서는전통적으로혼합성분의한약을복용하는환자와조직검사는시행하지않았지만, 임상적으로진단한 1 경우가많은데드물게그부작용으로기침, 호흡곤란등을호명을포함해총 8명을대상으로하였다. 여자가 6명, 남자가 2 소하는환자들이있다. 기존의여러문헌에서한약복용이후명이었으며연령은 31~81세 ( 평균 51.4세 ) 였다. 주로호소하에생긴부작용으로간독성에대해서는언급이많았으며, 최는증상은기침과호흡곤란으로, 한약복용이후에기침, 호흡근에는폐독성에관심이쏠리고있다. 하지만, 국내에서는아곤란이새로발생한환자가 4명이었고기존의기침을완화하직한약유발폐질환에대한영상학적인연구는없는것으로기위해한약을복용하였다가이후기침이더심해지면서호흡알고있다. 이에저자들은혼합성분의한약복용으로인한미곤란이발생한환자가 4명이었다. 환자들은증상이발생하거만성침윤성폐질환의고해상 CT 소견과함께조직병리학적소나악화한시점으로부터 1~1.5개월전에, 3~20일동안복합견을알아보고자하였다. 성분의한약을복용한과거력이있었다. 한약을복용한이유로는기침조절을위해서가 3명이었고, 건강증진을위한경우가 3명, 체중감량을위한경우가 2명이었다. 대상과방법모든환자는흉부 X선촬영, 흉부고해상 CT, 폐기능검사를 2005년 10월부터 2007년 6월까지, 혼합성분의한약복용시행하였다. 사용된 CT 기종은 Siemens Somatom Volume 이후조직검사에서미만성침윤성폐질환으로진단된 7명의 Zoom (Siemens medical system, Forchheim, Germany) 이었으며 2 mm의절편두께로흉곽입구에서상복부까지영상 1 인제대학교상계백병원영상의학과을얻었다. 6명의환자에서과거흉부 X선사진은정상이었으 2 이화여자대학교목동병원건진의학과 3 며 2명은과거사진이없었다. 흉부 X선촬영사진과고해상인제대학교상계백병원진단병리과이논문은 2010년 8월 30일접수하여 2010년 10 월 9일에채택되었음. CT의판독은 2명의영상의학과전문의가후향적으로분석하 519

김태규외 : 혼합성분의한약복용후발생된미만성침윤성폐질환 였으며, 고해상 CT에서주된병변의소견과그병변의분포영역에대해알아보았다.

모든환자는한약복용을중단하였고, 10일 ~4개월 ( 평균 43 일 ) 동안의스테로이드치료를받았다. 치료후면담을시행하고, 흉부 X선촬영혹은흉부고해상CT를시행하여추적관찰을하였다.

다음으로, 기관지주위경화 (peribronchial consolidation) 가나타난경우가 5명이었고, 2명에서소엽간중격비후 (interlobular septal thickening) 를나타내었다.

After one and half month, dyspnea and cough were developed. A. Chest PA shows diffuse increased haziness in both lower lung zone. B.

2 김태규외 : 혼합성분의한약복용후발생된미만성침윤성폐질환 였으며, 고해상 CT에서주된병변의소견과그병변의분포영역에대해알아보았다. 8명의환자중 5명은 16게이지의대침으로방사선투시유도하경피적폐생검술을, 2명은경기관지폐생검술을시행하여병리조직을얻어진단하였고, 나머지한명은임상적, 영상학적소견을바탕으로진단하였다. 모든환자는한약복용을중단하였고, 10일 ~4개월 ( 평균 43 일 ) 동안의스테로이드치료를받았다. 치료후면담을시행하고, 흉부 X선촬영혹은흉부고해상CT를시행하여추적관찰을하였다. 결과가장흔한흉부고해상CT 소견으로는양측성미만성간유리음영 (ground glass opacity) 으로 8명모두에서보였다. 다음으로, 기관지주위경화 (peribronchial consolidation) 가나타난경우가 5명이었고, 2명에서소엽간중격비후 (interlobular septal thickening) 를나타내었다. 8명중폐중심부에주로분포를한경우가 6명, 폐주변부에주로분포를한경우가 1명이었고중심부와주변부에골고루분포한경우가 1명이었다. 그리고폐상부 (n=2) 보다는폐하부 (n=6) 에병변이주 A B C D Fig. 1. A 51-year-old man who had taken mixed herbal medicine for general health promotion. After one and half month, dyspnea and cough were developed. A. Chest PA shows diffuse increased haziness in both lower lung zone. B. HRCT demonstrates diffuse ground glass opacities in both lower lobes. C. Fluoroguided cutting needle biopsy specimen demonstates nonspecific interstitial pneumonia pneumonia (H & E staining 400). D. On chest PA radiograph after steroid therapy, most of the opacity was cleared and patient s symptom was improved. 520

대한영상의학회지 2010;63:519-524 로존재하였다. 모든환자는폐기능검사에서제한성폐질환과함께폐쇄성폐질환의소견을나타내었다.

1), 폐쇄성세기관지기질화폐렴 (bronchiolitis obliterans organizing pneumonia) 이 2명 (Fig.

조직검사를시행하지않은나머지한명은한약복용이후에기침과호흡곤란이발생하였으며, 고해상CT소견에서양측성미만 성기관지주위경화를보여한약으로인한폐쇄성세기관지기질화폐렴의심하에한약복용을중단하고스테로이드치료를하여호전된증례였다.

고찰한약은한국, 중국, 일본등에서전통적으로많이복용해왔으며최근에는미국, 유럽등여러나라에서관심이있는약제로한약복용으로인한폐질환은 1989년 Tsukiyama 등에의 A B C D Fig. 2.

3 대한영상의학회지 2010;63: 로존재하였다. 모든환자는폐기능검사에서제한성폐질환과함께폐쇄성폐질환의소견을나타내었다. 폐생검을시행한 7명의조직병리소견으로는비특이적간질성폐렴 (nonspecific interstitial pneumonia) 이 3명 (Fig. 1), 폐쇄성세기관지기질화폐렴 (bronchiolitis obliterans organizing pneumonia) 이 2명 (Fig. 2), 과민성폐렴 (hypersensitivity pneumonitis) 과호산구성폐렴 (eosinophilic pneumonia) 이각각 1명이었다 (Fig. 3). 조직검사를시행하지않은나머지한명은한약복용이후에기침과호흡곤란이발생하였으며, 고해상CT소견에서양측성미만 성기관지주위경화를보여한약으로인한폐쇄성세기관지기질화폐렴의심하에한약복용을중단하고스테로이드치료를하여호전된증례였다. 조직병리소견과관계없이 8명모두에서한약복용중단과스테로이드치료이후임상적, 영상학적으로호전되었다 (Table 1). 고찰한약은한국, 중국, 일본등에서전통적으로많이복용해왔으며최근에는미국, 유럽등여러나라에서관심이있는약제로한약복용으로인한폐질환은 1989년 Tsukiyama 등에의 A B C D Fig. 2. A 58-year-old woman who had taken mixed herbal medicine for cough control. After one month, dyspnea and cough were progressed. A. Chest PA shows bilateral hilar and perihilar consolidation. B. HRCT shows peribronchial consolidation and ground glass opacities in both upper lobes. C. Fluoroguided cutting needle biopsy specimen demonstrates bronchiolitis obliterans organizing pneumonia (H & E staining, 100). D. Two month after steroid theraphy, chest PA was cleared with improving clinical symptom. 521

(years) Administration after Administration Dominancy Result 1 34 F Weight reduction Dyspnea Bilateral GGO and peribronchial Lower HP consolidation 2 31 F Cough control Dyspnea and Bilateral lobular

4 김태규외 : 혼합성분의한약복용후발생된미만성침윤성폐질환 Table 1. Summary of Clinical history, HRCT Finding, and Pathologic Result of Mixed Herbal Medicine Induced DILD in 8 Patients Age Purpose of Clinical Manifestation Zonal Pathologic Patient Sex HRCT finding (years) Administration after Administration Dominancy Result 1 34 F Weight reduction Dyspnea Bilateral GGO and peribronchial Lower HP consolidation 2 31 F Cough control Dyspnea and Bilateral lobular and segmental GGO Upper EP aggravating cough with intralobular septal thickening (crazy-paving appearance) 3 33 F Weight reduction Dyspnea and cough Bilateral diffuse GGO with dark Lower NSIP bronchus sign 4 48 F Cough control Dyspnea and Bilateral patchy GGO with inter-& Lower NSIP aggravating cough intralobular septal thickening (crazy-paving appearance) 5 58 F Cough control Dyspnea and Bilateral patchy GGO and patchy None BOOP aggravating cough peribronchial consolidation 6 75 M Health promotion Dyspnea Bilateral patchy peribronchial consolidation Lower BOOP 7 81 F Health promotion Dyspnea and cough Bilateral diffuse peribronchial consolidation Lower - and GGO 8 51 M Health promotion Dyspnea and cough Bilateral peribronchial GGO and Lower NSIP consolidation Note. DILD = diffuse infiltrative lung disease, HRCT = High-resolution computed tomography, GGO = ground glass opacity, HP = hypersen sitivity pneumonitis, EP = eosinophilic pneumonia, NSIP = nonspecific interstitial pneumonia, BOOP = bronchiolitis obliterans organizing pneumonia A Fig. 3. A 31-year-old women who had taken herb medicine for control of coughing. After one month, dyspnea and aggravating cough was developed. A. HRCT shows subpleural lobular ground glass opacities in both upper lobes. B. Histologic spacimen demonstrates eosinophilic pneumonia (H & E staining 400). B 522

5 대한영상의학회지 2010;63: 해처음보고되었다 (1). 일반적으로복용하는한약은한가지약제성분으로구성된것이아니라보통여러성분이혼합되어있다. Takeshita 등 (2) 은이복합한약성분중에어떤성분이폐질환을일으켰는지알기위해각각의약제성분으로유발검사를시행하였다. 한가지특정성분을투여하였을때만체온, 백혈구, C 반응단백질이상승하고, 동맥혈산소분압이감소하며, 흉부 X선촬영과 CT에서미만성간질성음영이증가하는것을확인함으로써그특정성분에의해폐질환이발생하였다는것을증명하였다. 폐질환이한약에의해유발되었다는것을증명하는또다른방법으로림프구유발검사가있다. Shiota 등 (3) 에의하면림프구유발검사에서양성으로나오면그약제를원인으로생각할수가있다. 반면에 Sakamoto 등 (4) 에의한연구에서는 5 명중 4명에서림프구자극검사를시행하였으나모두음성으로나왔으며, 림프구자극검사와관계없이 5명모두에서한약복용의병력과복용후에발생한임상증상, 영상학적검사에서의폐침윤, 여러혈액검사소견을종합하여한약유발폐질환의진단에이르렀다. 본연구에서는약제유발검사, 림프구자극검사는시행하지않았지만, 이전의정상흉부 X선촬영, 약제복용과거력, 복용이후임상증상의발생혹은악화, 영상 능부전이발생하여사망한예도보고를하였다 (14). 본연구에서는 8명모두에서한약복용을중단시키고스테로이드를사용한후임상적, 영상학적호전을보였다. 따라서한약복용이후기침혹은호흡곤란이새로발생하였거나더심해졌을때는한약유발성폐질환을의심하여약복용을즉시중단시켜야한다. 이어서흉부 X선촬영, CT를시행하여미만성침윤성폐질환의소견이있을경우스테로이드사용을고려해야할것이다. 반대로기침혹은호흡곤란을호소하는환자가영상학적혹은병리학적으로미만성침윤성폐질환의소견이있을때는한약복용의과거력을조사해보는것이필요하다. 본연구의제한점으로우선환자의수가적었다는점이다. 두번째로는약제유발검사나림프구자극검사를시행하지않았다는점이며세번째로는한약은대부분복합성분으로이루어져있는데그중어떤특정성분이폐질환을유발하였는지는알수없었다는점이다. 결론적으로혼합성분의한약복용으로유발된미만성침윤성폐질환의주된 CT 소견으로는양측성미만성간유리음영, 기관지주위폐경화이며폐상부보다는폐하부에, 폐주변부보다는폐중심부에병변이분포하는경향이있다. 또한, 조직병리학적으로는비특이적간질성폐렴, 폐쇄성세기관지-기질화폐렴, 과민성폐렴, 호산구성폐렴등을보일수있다. 학적인폐침윤, 폐조직병리, 한약복용중지와스테로이드치료후호전등의소견을종합하여진단하였다. 기관지폐포세척검사도시행할수있는데, 한약유발폐질 참 고 문 헌 환에서도일반적인약제에서와마찬가지로림프구가증가하고 1. Tsukiyama K, Tasaka Y, Nakajima M, Hino J, Nakahama C, Okimoto N, et al. A case of pneumonitis due to sho-saiko-to. Nihon CD4/CD8 비가감소를하면진단에도움을줄수있다 (2, 5, Kyobu Shikkan Gakkai Zasshi 1989;27: ). 2. Takeshita K, Saisho Y, Kitamura K, Kaburagi N, Funabiki T, 본연구에서주된고해상 CT 소견은양측성미만성간유리음영과기관지주위경화였다. 기존의문헌에서는미만성간유리음영과기관지주위경화외에도소결절, 흉막삼출, 그리고성인호흡곤란증후군이발생한경우는견인성기관지확장증이나폐구조왜곡등의소견을보고하기도하였다 (3, 4, 7). Inamura T, et al. Pneumonitis induced by ou-gon (scullcap). Intern Med 2001;40: Shiota Y, Wilson JG, Matsumoto H, Munemasa M, Okamura M, Hiyama J, et al. Adult respiratory distress syndrome induced by a Chinese medicine, Kamisyoyo-san. Intern Med 1996;35: Sakamoto O, Ichikado K, Kohrogi H, Suga M. Clinical and CT characteristics of Chinese medicine-induced acute respiratory distress syndrome. Respirology 2003;8: 기존의여러연구에서조직검사를시행하여병리소견을알아보고자한경우가있었는데주로림프구폐포염, 간질성폐 5. Heki U, Fujimura M, Ogawa H, Matsuda T, Kitagawa M. 렴, 호산구성폐렴혹은기질화폐렴등의결과였다 (2, 5, 8-10). 저자들이아는바로는조직검사에서폐쇄성세기관지-기 Pneumonitis caused by saikokeisikankyou-tou, an herbal drug. Intern Med 1997;36: Akoun GM, Cadranel JL, Milleron BJ, D Ortho MP, Mayaud CM. 질화폐렴으로나온경우는거의없는것으로알고있다. Hata Bronchoalveolar lavage cell data in 19 patients with drug-associated pneumonitis (except amiodarone). Chest 1991;99: 등 (11) 에의한연구에서는 CT에서폐쇄성세기관지-기질화폐 렴을시사하는소견이보였으나조직검사는시행하지않았다 (11). 본연구에서는 2명의병리조직에서폐포내섬유모세포 7. Akira M, Ishikawa H, Yamamoto S. Drug-induced pneumonitis: thin-section CT findings in 60 patients. Radiology 2002;224: Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, 전 (intraalveolar fibroblast plug) 을보이는폐쇄성세기관 et al. Pneumonitis during interferon and/or herbal drug therapy in 지-기질화폐렴의소견을나타내었다. patients with chronic active hepatitis. Eur Respir J 1996;9:2691- 한약유발폐질환이발생하였을때는한약복용을중지하는것이우선이다. 스테로이드를사용하지않아도증상이호전된다는보고도있으며 (2, 5) 스테로이드치료가효과있다는보고도있다 (3, 4, 8, 12). 한편, 폐부종에의해폐기능부전이발생하였을경우는스테로이드치료만으로는불충분하고기계 Kobashi Y, Nakajima M, Niki Y, Matsushima T. A case of acute eosinophilic pneumonia due to Sho-saiko-to. Nihon Kyobu Shikkan Gakkai Zasshi 1997;35: Yamawaki I, Katsura H, Taira M, Kadoriku C, Hashimoto I, Chiyotani A, et al. Six patients with pneumonitis related to blended Chinese traditional medicines. Nihon Kyobu Shikkan Gakkai Zasshi 호흡 ( 호기말양압호흡 ) 을시행하면매우효과적이라는주장 1996;34: 도있다 (13). Sato 등 (14) 은한약유발폐질환에의해폐기 523

6 김태규외 : 혼합성분의한약복용후발생된미만성침윤성폐질환 11. Hata Y, Uehara H. A case where herbal medicine sho-seiryu-to induced interstitial pneumonitis. Nihon Kokyuki Gakkai Zasshi 2005; 43: Yoshida Y. A non-cardiogenic type of pulmonary edema after administration of Chinese herbal medicine (shosaikoto) - a case report. Nihon Kokyuki Gakkai Zasshi 2003;41: Miyazaki E, Ando M, Ih K, Matsumoto T, Kaneda K, Tsuda T. Pulmonary edema associated with the Chinese medicine shosaikoto. Nihon Kokyuki Gakkai Zasshi 1998;36: Sato A, Toyoshima M, Kondo A, Ohta K, Sato H, Ohsumi A. Pneumonitis induced by the herbal medicine Sho-saiko-to in Japan. Nihon Kyobu Shikkan Gakkai Zasshi 1997;35: J Korean Soc Radiol 2010;63: Mixed Herbal Medicine Induced Diffuse Infiltrative Lung Disease: The HRCT and Histopathologic Findings 1 Tae Gyu Kim, M.D., Joung Sook Kim, M.D. 2, Eun A Shin, M.D. 3 1 Department of Radiology, Sanggye Paik Hospital, Inje University 2 Department of Health Promotion Medicine, Mokdong Hospital, Ewha Womans University 3 Department of Pathology, Sanggye Paik Hospital, Inje University Purpose: The purpose of this study was to evaluate the high-resolution CT (HRCT) and pathologic findings of mixed herbal medicine-induced diffuse interstitial lung disease. Materials and Methods: Eight patients (6 women and 2 men, age range: 31 to 81 years, mean age: 51.4 years) who presented with cough or dyspnea after taking mixed herbal medicine were included in this study. All the patients underwent plain chest radiography and HRCT. We obtained pathologic specimens from 7 patients via fluoroscopy guided large bore cutting needle biopsy and transbronchial lung biopsy. All the patients were treated with steroid therapy. Results: The most common HRCT finding was bilateral diffuse ground glass opacity (n=7), followed by peribronchial consolidation (n=5) and inter- or intralobular septal thickening (n=2). For the disease distribution, the lower lung zone was dominantly involved. The pathologic results of 7 patients were nonspecific interstitial pneumonia (n=3), bronchiolitis obliterans organizing pneumonia (n=2), hypersensitivity pneumonitis (n=1) and eosinophilic pneumonia (n=1). Irrespective of the pathologic results, all 8 patients improved clinically and radiologically after steroid treatment. Conclusion: The HRCT findings of mixed herbal medicine-induced diffuse infiltrative lung disease were mainly bilateral diffuse ground glass opacity, peribronchial consolidation and dominant involvement of the lower lung zone. Those pathologic findings were nonspecific and the differential diagnosis could include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis and eosinophilic pneumonia. Index words : Herbal Medicine Lung, Diseases Tomography, X-Ray Computed Address reprint requests to : Joung Sook Kim, M.D., Department of Health Promotion Medicine, Mokdong Hospital, Ewha Womans University, Mok-dong, Yangcheon-gu, Seoul , Korea. Tel Fax kjshpc@ewha.ac.kr 524

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¼Û±âÇõ 223 Table 1. Results of FEV 1.0, Methacholine Challenge Test, and Exercise Provocation Test in Eight Patients Who Performed PFT Pts Tests 1 2 3 4 5 6 7 8 FEV 1.0 (%pred) 66.6 88.8 120 101 90.5 95.4 91.6