DOI: 10.4046/trd.2009.66.5.374 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2009;66:374-379 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 장천공이동반된 Churg-Strauss 증후군 1 예 Case Report 순천향대학교의과대학 1 내과학교실, 2 영상의학교실, 3 병리학교실, 4 외과학교실박정훈 1, 정윤석 1, 김양기 1, 이영목 1, 황정화 2, 김기업 1, 김동원 3, 어수택 1, 김재준 4 A Case of Churg-Strauss Syndrome with Interstinal Perforation Jung Hoon Park, M.D. 1, Yun Seok Jung, M.D. 1, Yang Ki Kim, M.D. 1, Young Mok Lee, M.D. 1, Jung Hwa Hwang, M.D. 2, Ki-Up Kim, M.D. 1, Dong Won Kim, M.D. 3, Soo-Taek Uh, M.D. 1, Jea Jun Kim, M.D. 4 Departments of 1 Internal Medicine, 2 Radiology, 3 Pathology, 4 Surgery, School of Medicine, Soonchunhyang University, Seoul, Korea Churg-Strauss syndrome (CSS) or allergic granulomatous angiitis is a rare syndrome that is characterized by hypereosinophilic systemic necrotizing vasculitis affecting small- to medium-sized arteries and veins. In general, it occurs in individuals with pre-existing allergic asthma. When CSS appears in patients, it has the following characteristics: eosinophilia of more than 10% in peripheral blood, paranasal sinusitis, pulmonary infiltrates, histological proof of vasculitis with extravascular eosinophils, and mononeuritis multiplex or polyneuropathy. Therapeutic trials dedicated to Churg-Strauss syndrome have been limited due to the rarity of this disorder and the difficulty in making a histological diagnosis. Proper treatment of patients with CSS is not widely known. In this case study, we report on our experience with an unusual patient case, characterized by purpura and a perforation of the small intestine after inadequate steroid therapy. Key Words: Churg-Strauss syndrome, Asthma, Intestinal perforation, Eosinophilic infiltration 서 Churg-Strauss 증후군 (Churg-Strauss Syndrome) 또는알레르기육아종증은기관지천식, 부비동염, 말초혈액의호산구증가, 말초신경병증, 이동성폐침윤및혈관밖육아종형성을특징으로하는전신성혈관염이다 1. 이질환은특발성으로발생한다고알려져있으나최근항중성구세포질항체 (anit-neutrophil cytoplasmic antibody, ANCA) 와의관련성이알려지면서자가면역질환으로추정되고있다 2. Churg- Strauss 증후군은폐, 심장, 소화기, 근육신경계, 피부, 신장등의다양한장기를침범할수있으며, Address for correspondence: Ki-Up Kim, M.D., Ph.D. Department of Internal Medicine, School of Medicine, Soonchunhyang University, 22, Hannam-dong, Yongsangu, Seoul 143-740, Korea Phone: 82-2-709-9027, Fax: 82-2-792-5812 E-mail: kukim@hosp.sch.ac.kr Received: Mar. 11, 2009 Accepted: May. 7, 2009 론 폐와피부다음으로세번째로흔히침범하는장기가소화기이다 3. 소화기증상으로복통과설사가가장흔히관찰되며, 식도궤양, 급성담낭염, 충수돌기염, 허혈성대장염, 소장점막등의궤양등다양한형태로나타날수있다. 소장과대장, 또는식도, 담낭및대장을동시에침범한예가드물게보고되었으며, 장천공 (intestinal perforation) 을동반할수있다 4. 우리나라에서도 1998년처음보고된후추가로 3예가더보고되었다 4-8. 알레르기성천식으로치료중이던젊은남자에서전신에발생한자반, 호산구증가증으로 Churg-Strauss 증후군으로진단후부신피질호르몬제로치료중발생한장천공을경험하였기에보고한다. 증례환자 : 25세, 남자주소 : 일주일간의근육통과상, 하지의자반증현병력 : 2년전기관지천식, 알레르기성비염, 상악동 374
Tuberculosis and Respiratory Diseases Vol. 66. No. 5, May 2009 부비동염을진단후천식조절흡입제및속효성기관지확장제로증상조절중호전과악화가반복되었다. 1개월전기침, 흰색의객담과 MRC (Medical Research Council) Grade 3의호흡곤란으로내원하여말초혈액내호산구증가 (10%), 흉부전산화단층촬영에서양폐의침윤성병변이있어기관지폐포세척술로호산구의증가 (21%) 를확인하여호산구성폐렴으로치료받은병력이있었다. 환자는내원일주일전부터전신근육통과사지의말단부터중심부로진행하는자반이발생하여입원하였다. 과거력 : 6년전결핵진단및완치판정받았다. 가족력 : 특이사항없었다. 사회력 : 판매직으로 5갑년의흡연력과간헐적인음주력이외특이사항없었다. Figure 1. Chest radiography from 25 years old patient shows bilateral pleural effusion, patchy consolidation and increased interstitial marking of right lower lung field. 신체검사소견 : 내원하였을때, 혈압 136/84 mmhg, 맥박분당 92회, 호흡수분당 24회, 체온 37.6 o C다. 급성병색이었으나의식은명료하였고심박동수는규칙적이었으며, 심잡음은들리지않았다. 흉부및복부진찰소견에서이상소견은관찰되지않았다. 신경학적이상소견은관찰되지않았으나등과양팔과양다리에서자반이관찰되었으며, 환자의피부는스치기만해도심한통증을호소하였다. 검사소견 : 말초혈액검사에서백혈구 5,200/mm 3 ( 호중구 53%, 호산구 17%, 림프구 16%), 혈소판 283,000/μL, C-반응단백 20 mg/dl, 총 Ig E 1,474 IU/mL 이었으며, 신기능및간기능검사는정상범위였다. 입원시동맥혈가스분석검사에서 ph 7.467, PaCO 2 40.6 mmhg, PaO 2 63.0 mmhg, Bicarbonate 28.7 meq/l, 산소포화도 93.3% 였다. 항핵항체 (antinuclear antibody) 및 ANCA는음성이었다. 영상의학소견 : 단순흉부방사선사진에서양측의흉수가관찰되며우측폐하부에서폐경화와증가된간질음영이관찰되었다 (Figure 1). 흉부전산화단층촬영에서기관지확장과기관지벽의비후가관찰되며다양한크기의다발성반점형경화가양측폐에서보였다 (Figure 2). 심장검사소견 : 심전도검사에서이상이없었고, 심장초음파검사에서심기능의이상은없었다. 비즙및객담세포검사, 폐활량검사 : 호흡기분비물에대한세포검사는비즙내호산구 13.3%, 객담내호산구 39.3% 로증가되어있었다. 폐활량검사는노력성폐활량 (forced vitial capacity, FVC) 38%, 1초간노력성호기량 (forced expiratory volume of 1 second, FEV 1 ) 46%, 노력성폐활량대 1초간노력성호기량비 (FEV 1 /FVC) 95% 였다. 피부조직병리검사소견 : 표피의과각화및적혈구의혈관밖유출이있었으며, 진피의표층부및심층부에섬유소의침착 (deposition of fibrin) 과다발성으로세정맥과 Figure 2. Computed tomography from the presented patient, there are multiple, variable-sized, nodules, or nodular airspace consolidation in both lungs (A). At lower area of lung shows mild bronchial dilatation, bronchial wall thickening and tiny centrilobular branching opacities (B). 375
JH Park et al: Churg-Strauss syndrome with intestinal perforation Figure 3. Photography from purpura, which was stained by hematoxylin and eosin (H&E), shows epidermal hyperkeratosis and extravasated erythrocytes beneath of epidermis (arrow, A, 40). Magnified pictures from same patient shows leukocytoclastic vasculitis with granulma formation at the perivenular area of dermal area (B, 100), and marked neutrophils and eosinophils were infiltrated at dermal area (C, 200). Figure 4. Colonoscopic findings from the presented patient who had abdominal pain and diarrhea, shows multiple ulceration and mucosal edema. Findings of biopsy are eosinophilic infiltration and edema at the small and medium sized vessels. 혈관주위로호중구와호산구의침윤이있어백혈구파괴성혈관염 (leukocytoclastic vasculitis) 및호산구침윤 (eosinophilic infiltration) 의소견이었다 (Figure 3). 임상경과 : 병력과영상의학적소견, 혈중호산구증가, 자반에서시행한피부조직병리검사에서다발성의호산구성혈관염소견으로 Churg-Strauss 증후군으로진단하였으며고용량메틸프레드니솔론 (250 mg/day) 투여를하였다. 내원 3일째부터사지통증의소실을포함한증상의호전을보여감량중, 7일째지속되는복통과설사가있어대장내시경을하였다. 대장내시경에서장전체에부종과다수의궤양이관찰되어 (Figure 4) 조직검사를하였으며대장의작은혈관과중간크기의혈관주위의호산구침윤이관찰되어 Churg-Strauss 증후군의소화기계침범을확인하였다. 고용량메틸프레드니솔론 (250 mg/day) 치료를다시시작하여증상의호전을보여빠르게감량하여경구용스테로이드 30 mg으로전환하여퇴원하였다. 외래에서 2주동안프레드니솔론 10 mg으로감량하면서유지하던중오심, 구토, 급성경련성복통, 압통및반발압통을호소하였고, 복부단순촬영에서횡경막하자유공기 (subphrenic free air) 를확인하여장천공에의한복막염으로개복술을시행하였다. 수술장소견은다발성괴사를동반한자반성병변이소장에전반적으로산재되어있어분절절제및문합을하였으며대장의이상은관찰되지않았다. 절제된소장의조직병리검사에서소장점막과혈관주위로호산구의침윤이관찰되었다 (Figure 5). 수술후고용량메틸프레드니솔론다시투여하였으며약 2개월후증상이호전되어퇴원후메틸프레드니솔론 8 mg을유지하며경과관찰중이다. 고찰 1951 년 Churg 와 Strauss 가조직내호산구침윤, 괴사성 376
Tuberculosis and Respiratory Diseases Vol. 66. No. 5, May 2009 Figure 5. Specimen from resected small intestine were combined with ulcerated area, perivascular infiltration of inflammatory cells and fibrin thrombus and fibronoid necrosis (A, H&E stain, 40; B, H&E stain, 100). Magnified finding of perivascular area showed marked infiltration of eosinophils and neutrophils which were compatible with eosinophilic leukocytoclastic vasculitis (C, H&E stain, 200). Some other area showed granulation tissue with hemorrhage (not shown). 혈관염및혈관외조직의육아종형성등의 3가지병리학적특징을가지며기관지천식과말초혈액의호산구증가증을보인환자를처음기술하면서 Churg-Strauss 증후군으로불리게되었다 1. 역학과원인에대해서현재까지명확하게밝혀지지않았다. 최근항중성구세포질항체와의관련성, 알레르기성특징, T 림프구및면역반응이확인되면서자가면역성질환의하나로알려져있으며, Vaglio 등이 HLA-DR B4와의관련성에대해서제시하면서유전과의관련성이밝혀졌다 2,9. Churg-Strauss 증후군의임상양상은세단계로나눠지며, 첫단계인전구기는 20 30 대에아토비성질환, 알레르기성비염, 천식으로나타나며수년간지속될수있으며, 두번째단계는호산구증가증과조직침윤이특징적으로나타나는호산구침윤단계로말초혈액에서호산구증가가보이고, 여러장기, 특히폐나소화기계에침윤이관찰된다. 세번째단계는혈관염단계로 30 40대에발현되며, 생명을위협할정도로중간및작은혈관에전신적으로혈관염이발생하고, 때때로혈관내외로육아종이나타난다. 혈관염단계는발열, 체중감소, 피로감등의비특이적인증상이선행한다 10. 본환자에서는약 2년간알레르기성비염, 부비동염, 그리고천식으로치료받은병력으로보아전구기가지나면서혈액내호산구증가및소화기및피부의호산구침윤단계로진행된것으로판단되었다. Churg-Strauss 증후군은다양한분류체계가보고되고 있다. 이중미국류마티스학회에서는 6가지의기준을제시했다 11. 천식, 호산구혈증 (>10%), 단일또는다발성신경병증, 이동하는또는일시적인폐음영, 급성또는만성부비동염, 조직에서호산구축척을보이는혈관이포함된생검이다. 이중 4가지이상을만족할경우진단에 85% 의민감성, 99.7% 의특이성을보인다. 본증례에서는천식과부비동염, 호산구혈증 (12%), 방사선학적폐음영, 호산구축척을보이는혈관이포함된생검소견을보여진단에합당한소견이다. Churg-Strauss 증후군에서소화기증상은호흡기, 피부증상에이어세번째로흔하다. Churg 과 Strauss 는 1951 년 13예의증례보고에서 12예가복통, 설사가있었으며, 1예는소화성궤양에의한천공으로사망하였다고보고하였으며 1, 이후연구에서소화기침범은 37 62% 에서복통을비롯한설사, 장출혈로나타나며심한복통이동반된경우에는장폐쇄, 허혈성장염, 궤양및장천공의가능성을고려해야한다 7,10,12. 이질환의위장관침범의병리학적특징은혈관염으로나타난장간막허혈에의해이차적으로발생하는궤양과호산구의위장벽침윤으로특징적인조직병리소견은괴사성혈관염, 호산구의조직침윤및혈관외육아종의형성이다 13,14. 이중창자간막혈관염 (mesenteric vasculitis) 에의한창자간막허혈로궤양, 출혈, 장천공등을유발하게된다. 본증례의경우복통, 설사, 오심, 구토증상으로대장내시경을시행하였고, 전반적인점막부종, 홍반성변화, 다발성궤양이관찰되었 377
JH Park et al: Churg-Strauss syndrome with intestinal perforation 으며, 병리조직검사에서호산구의침윤을동반한혈관염소견을보여고용량스테로이드로치료를시작하여증상의호전으로스테로이드를감량하여투약하던중복통및자유공기음영으로장천공이의심되어시행한개복술에서소장괴사에의한천공으로확인되었다. 병리조직검사에서호산구침윤을동반한혈관염소견을보여혈관염에의한허혈로인해천공이발생되었을것으로추정할수있었다. 또한이전의보고는주로대장을침범한궤양성대장염의보고와장천공의경우소장에국한된보고가있었으나본증례의경우대장의침범과소장을동시에침범이확인된예였다. Churg-Strauss 증후군의일차적치료는전신적부신피질호르몬제이다. 천식이있을때는흡입성부신피질호르몬제로같이치료해야한다. 전신적부신피질호르몬제는 0.5 1.5 mg/kg 용량으로 6 12주또는병이완전히사라질때까지유지한다. 치료반응에대한감시나재발은호산구수나적혈구침강속도를확인하면서알수있다. 성공적인치료후에발생하는재발은드물지만치료의조기중단은재발을유발할수있다. 본증례에서는임상적으로 Churg-Strauss 증후군이확인되었으나환자의경과가예상보다좋은것으로판단되어조기에스테로이드를감량하였으나이에의한악화로인한장천공이유발되었을것으로판단되었다. 조절이되지않는환자는면역억제제, 또는고용량정맥면역글로불린에반응할수있다 12. 기타치료법으로부실피질호르몬제와인터페론알파조합치료, 또는혈장교환술이있다. 예후는명확하게알려지지않았으나부신피질호르몬제치료후 1년생존율이 90%, 5년생존율이 62% 로알려져있으며치료후의미있는사망률의감소를보였다 12. Guillevin 등 15 은 Churg-Strauss 증후군환자에서나쁜예후를나타내는인자로하루 1 g 초과의단백뇨, 신장기능이상 ( 혈청크레아티닌 1.4 이상 ), 심장침범, 중추신경계의침범및소화기계침범등을제시하였다. Churg-Strauss 증후군환자들의가장흔한사망원인은심장의침범이지만소화관침범을동반한경우예후가좋지않다. 사망환자의 8% 에서장간막경색, 장천공, 장폐색등의소화관침범이원인이었다 12. 따라서 Churg-Strauss 증후군을진단받은환자에서소화기증상을호소하는경우소화관침범여부에대한검사를시행하는것이좋을것으로판단되며, 충분한기간의치료또는증상이완전히소실될때까지치료가필요하다. 요 천식조절중이던환자에서임상증상과조직검사를바탕으로진단된 Churg-Strauss 증후군을진단하고치료중발생한장천공을경험하였기에문헌고찰과함께보고하는바이다. 약 참고문헌 1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951;27: 277-301. 2. Keogh KA, Specks U. Churg-Strauss syndrome: update on clinical, laboratory and therapeutic aspects. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:3-12. 3. Kurita M, Niwa Y, Hamada E, Hata Y, Oshima M, Mutoh H, et al. Churg-Strauss syndrome (allergic granulomatous angiitis) with multiple perforating ulcers of the small intestine, multiple ulcers of the colon, and mononeuritis multiplex. J Gastroenterol 1994;29:208-13. 4. Jung SH, Kim KH, Nam SM, Park HC, Chu HK, Whang IS, et al. A case of Churg-Strauss syndrome with manifestations of esophageal ulcer, acute acalculous cholecystitis and ischemic colitis. Korean J Med 1993;45: 369-75. 5. Kim JH, Yoon KY, Shin YM. Churg-Strauss syndrome with multiple small bowel perforation. J Korean Surg Soc 1998;54:148-52. 6. Kim YB, Choi SW, Park IS, Han JY, Hur YS, Chu YC. Churg-Strauss syndrome with perforating ulcers of the colon. J Korean Med Sci 2000;15:585-8. 7. Oh MJ, Ji SH, Lim DH, Min TH, Lee BJ, Choi DC, et al. A case of intestinal perforation in Churg-Strauss syndrome patient. Korean J Med 2004;67:208-12. 8. Lee YK, Choi KW, Lee CY, Kim Hs, Kim KH, Kim YH. A case of Churg-Strauss syndrome associated with small bowel perforation following high dose systemic steroid intravenous injection. Korean J Dermatol 2008;46:950-4. 9. Vaglio A, Martorana D, Maggiore U, Grasselli C, Zanetti A, Pesci A, et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum 2007;56:3159-66. 10. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984;63:65-81. 11. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, 378
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