Case report Infect Chemother 2011;43(4): pissn eissn Infection & Chemotherapy 급성

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1 Case report Infect Chemother 2011;43(4): pissn eissn Infection & Chemotherapy 급성골수성백혈병환자에서발생한아스페르길루스및 Enterococcus faecium 간농양 : 증례보고및문헌고찰 홍경욱 권재철 전현지 이동건 김희제 민우성가톨릭대학교의과대학내과학교실 Liver Abscess by Aspergillus and Enterococcus faecium in a Patient with Acute Myeloid Leukemia: A Case Report and Literature Review We report a case of liver abscess caused by Aspergillus and Enterococcus faecium in a patient with acute myeloid leukemia. As far as we know, this is the first case of hepatic aspergillosis in Korea. After remission induction chemotherapy, the female patient presented with abdominal pain and was found to have liver abscess. The patient was treated with antibiotics against E. faecium, which was isolated from the abscess drainage. However, the therapeutic response was unsatisfactory and a left lateral sectionectomy of the liver was conducted after 21 days of treatment. The liver tissue showed typical pathologic findings of aspergillosis and voriconazole was administered. Allogeneic hematopoietic stem cell transplantation was performed successfully after 4 months. The possibility of aspergillosis should be considered when an immunocompromised patient with hepatic abscess poorly responds to the use of broad spectrum antibiotics. Kyung-Wook Hong, Jae-Cheol Kwon, Hyun Ji Chun, Dong-Gun Lee, Hee-Je Kim, and Woo-Sung Min Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Key Words: Aspergillosis, Enterococcus, Liver abscess, Acute myeloid leukemia 서론 아스페르길루스증은주로면역저하환자에서발생하는기회감염이며, 혈액종양환자에서항암화학치료나동종조혈모세포이식후호중구감소증이지속될때흔히발생한다. 급성백혈병환자의아스페르길루스증발생율은 5-24% 로알려져있으며, Lin 등의문헌고찰에따르면사망율은약 60% 이다 [1]. 급성골수성백혈병환자에서아스페르길루스증이생겼을때기여사망율이 38% 였다는보고도있다 [2]. 간아스페르길루스증의보고는많지않으며, 지금까지외국에서 17 예가보고되었고, 국내에서는아직보고가없었다 [3-12]. 그리고아스페르길루스증은대부분호흡기를통해감염되어혈류를통해파급되는데, 폐병변이동반되지않은원발성간아스페르길루스증은더욱드물어서지금까지외국에서 6예가보고되었다 [3, 8-12]. 저자들은급성골수성백혈병으로관해유도항암치료후완전관해가된환자에서 Enterococcus faecium 및아스페르길루스간농양을진단, 치료하여호전된사례를경험하였기에문헌고찰과함께보고하고자한다. Copyright 2011 by The Korean Society of Infectious Diseases Korean Society for Chemotherapy Submitted: April 19, 2011 Revised: June 3, 2011 Accepted: June 3, 2011 Correspondence to Dong-Gun Lee, M.D., Ph.D. Department of Internal Medicine, Seoul St. Mary s Hospital, #505, Banpo-dong, Seocho-gu, Seoul , Korea Tel: , Fax: symonlee@catholic.ac.kr

378 KW Hong, et al. Liver Abscess by Aspergillus and E. faecium in an AML Patient 증례 41세여자가내원당일시작된배꼽주위복통과구토가있어서응급실로내원하였다. 환자는내원 45일전급성골수성백혈병을진단받고, 관해유도항암요법 (idarubicin, enocitabine) 을투여받은후 1주전퇴원하였다.

2 378 KW Hong, et al. Liver Abscess by Aspergillus and E. faecium in an AML Patient 증례 41세여자가내원당일시작된배꼽주위복통과구토가있어서응급실로내원하였다. 환자는내원 45일전급성골수성백혈병을진단받고, 관해유도항암요법 (idarubicin, enocitabine) 을투여받은후 1주전퇴원하였다. 관해유도항암요법중혈청갈락토만난항원검사 (galactomannan, GM, Platelia Aspergillus EIA, Bio-Rad, Korea) 가 0.54 로증가한적이있으나가래, 발열등의증상이없고, 이후 3일간격의추적검사결과지속적으로음성이어서 amphotericin B deoxycholate 등의항진균제치료없이경과관찰하였던병력이있었다. 당시항암치료 2주후호중구감소성발열로 E. faecium 과 Clostridium ramosum 균혈증이동반되어 teicoplanin (400 mg/ 일 ), imipenem/cilastatin sodium (2 g/ 일 ) 을투여받았다. 항생제투여후바로해열되어항진균제는투여하지않았고, 동반된증상, 징후가없어혈액배양검사결과가음전되고 2주간항생제투여한후퇴원했으며, 호중구감소증은 20일간지속된후에회복되었다. 환자는항암치료시작 2일전부터 fluconazole (100 mg/ 일 ) 을예방요법으로복용하였고내원 1주전퇴원하면서중지했었다. 활력징후는혈압 126/88 mmhg, 맥박 102 회 / 분, 호흡수 20회 / 분, 체온 36.8 였다. 신체검진에서복부압통, 반동압통은없었으며, 경부, 흉부및사지검사에서특이소견없었다. 말초혈액검사에서백혈구 7,300/mm 3 ( 호중구 60.6%), 혈색소 11.8 g/dl, 혈소판 444,000/mm 3 이었다. 생화학검사에서적혈구침강속도 50 mm/hr, C- 반응성단백 0.83 mg/dl ( 정상 ), 아스파르테이트아미노전이효소 / 알라닌아미노전이효소 23/29 IU/L, 알칼리인산분해효소 72 IU/L ( 정상 ), 총빌리루빈 / 직접빌리루빈 1.7/1.5 mg/dl, 크레아틴활성효소 / 젖산염탈수소효소 9/485 IU/L, 혈액요소질소 / 크레아티닌 14.6/0.5 mg/dl 이었으며, 혈액응고검사에서프로트롬빈시간 (INR) 1.20, D-이량체 7.06 μg/ml ( 정상 1.3) 였다. 골수검사는완전관해상태였다. 흉부방사선검사에서소량의양측흉막삼출이관찰되었고, 복부전산화단층촬영에서간좌엽에 7.5 cm 크기의테두리조영을보이는저음영종괴가관찰되어간농양으로진단하였다 (Fig. 1). 초음파유도경피적농양배액술을시행한결과농이배출되었고, 혈액배양검사후 cefoperazone/sulbactam (4 g/ 일 ) 을처방하였다. 내원 5일째간농양배액에서 E. faecium 이동정되었으며, 진균배양검사에서는배양된진균이없었다. 혈액배양검사와요배양검사는음성이었다. E. faeicum 은 ampicillin 내성, glycopeptide 감수성이었다. Teicoplanin (400 mg/ 일 ) 을추가하였고, cefoperazone/sulbactam 은 2주간투여하고중단하였다. 내원 12일째배액관으로나오는양이적어재시행한복부전산화단층촬영에서간농양의크기가 6 cm 정도로약간줄었지만큰차이가없고, 배액관의위치를재조정했으나점성이높아서배농이잘되지않아 21일째좌외측간절제술을시행하였다. 수술후 6일째에검사한복부전산화단층촬영에서더이상농양이관찰되지않는것을확인한후 teicoplanin 을중단하였고, 총 25일간투여하였다. 입원후시행한 6회의혈청 GM은모두 0.5 이하였다. 조직검사는괴사된간조직에진균덩이가있으며, Grocott-Gomori methenamine silver 및 Periodic Acid Schiff 염색에서예각의가지를이루는유격균사가관찰되어서아스페르길루스증소견에합당하였다. 간농양안쪽의괴사된부위에는많은균사가있고, 혈관을침범하고있는양상이관찰되었으나, 농양벽밖의간실질에서는균사가보이지않았다 (Fig. 2). 간절제술시에얻은조직으로는배양검사를시행하지못하였고, 배액된간농양진균배양검사결과가음성이어서 2008 년 European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) 에서정의한 거의틀림없는 (probable) 침습성진균질환으로진단하였다 [13]. 병변은수술로제거되었으나조직검사결과를확인한후정주로 voriconazole 6mg/kg bid 를투여하였고, 1일후경구 voriconazole (400 mg/ 일 ) 로변경하여 2주간투여한후 7 일간공고항암요법을시행했으며호중구감소성발열등의감염합병증은없었다. Voriconazole (400 mg/ 일 ) 을계속유지하면서 2개월후동종조혈모세포이식을성공적으로시행받았고, 이식 1개월후인현재까지문제없이외래에서경과관찰중이다. Voriconazole 최저농도는 2-3 μg/ml 으로유지되었고, CYP2C19 genotyping 은 CYP2C19 *1/*1, homozygous extensive metabolizer 이었다. 고찰 Figure 1. Abdominal CT scan shows a 7.5 cm -size large abscess with thick wall at left lateral section of the liver, indicated by an arrow. 급성백혈병환자의항암치료가발전하면서생존율이증가했으나, 장기간의호중구감소증등으로진균감염의위험이커졌다 [2]. 또한 azole 계항진균제예방요법이널리사용되면서균사형진균감염증이증가되었는데, Leventakos 등은백혈병환자의진균감염중 58% 가아스페르길루스증이라고보고했다 [14]. 지금까지보고된간아스페르길루스증환자들의임상적특징을정리하였다 [3-12] (Table 1). 국내에서는아직보고된증례가없었고, 외국에서총 17 예가보고되었다. 간농양으로나타난경우는 7예이고, 본증례와같이간에만농양을형성한환자는 4명이었다. 1명을제외하고는면역기능저하가있는기저질환이있었고, 혈액질환이 12명 (70.6%) 으로가장많았다. 11 명 (64.7%) 에서 2개이상의장기를침범했으며, 초기부터 voriconazole 을사용한환자는 3명이었

http://dx.doi.org/10.3947/ic.2011.43.4.377 Infect Chemother 2011;43(4):377-381 379 A B Figure 2. Pathologic findings of the liver abscess in case patient.

(B) Fungi suspicious of aspergillus species with Y-shaped branching of septated hyphae are scattered within liver abscess (Grocott-Gomori methenamine silver stain, x400). Table 1.

3 Infect Chemother 2011;43(4): A B Figure 2. Pathologic findings of the liver abscess in case patient. (A) Abscess formation (left upper) is observed (hematoxylin & eosin stain, x200). (B) Fungi suspicious of aspergillus species with Y-shaped branching of septated hyphae are scattered within liver abscess (Grocott-Gomori methenamine silver stain, x400). Table 1. List of the Cases of Hepatic Aspergillus Age/Sex Underlying Disease Involvement Abscess Formation Diagnosis Treatment Course Year/Ref. 45/M Acute monoblastic Leukemia Liver Yes Biopsy {Micafungin+AMB} VCZ Cured 2010 [3] 11/- AML Liver, spleen No Biopsy, Culture AMB Cured 2008 [3] 41/M Liver and kidney transplantation Hepatic, renal artery No Biopsy not treated Died 2008 [4] 27/F None, Necrotizine fasciitis Liver, blood, abdominal wall Yes Culture CASF+VCZ Cured 2007 [5] 39/M AIDS Liver, lung, BM No Culture VCZ Cured 2007 [6] 46/F ALL Disseminated No Biopsy, Culture AMB {VCZ+CASF} Died 2006 [3] 53/F NHL Liver, spleen Yes Biopsy VCZ Cured 2006[ 7] 37/F AML Liver No Biopsy {CASF+AMB} VCZ Cured 2005 [8] 13/F Acute undifferentiated leukemia Disseminated Yes Biopsy AMB VCZ Cured 2003 [3] 66/M Aplastic anemia Liver Yes Culture AMB Died 2003 [9] 13/M AML Liver, spleen No Biopsy {AMB+ITZ} VCZ Died 2001 [3] 13/M CVI Liver Yes Culture AMB+ITZ Cured 2001 [10] 55/F Liver transplantation Liver Yes Culture ITZ Cured 1996 [11] 43/F Aplastic anemia Liver Yes Biopsy, Culture AMB Died 1991 [12] 31/M Acute progranulocytic Leukemia Liver, lung, leg No Biopsy AMB Cured 1975 [3] 33/F AML Disseminated No Autopsy AMB Died 1975 [3] 44/M AML Disseminated No Autopsy not treated Died 1960 [3] AMB, amphotericin B dexoxycholate; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CASF, caspofungin; CVI, common variable immunodeficiency; ITZ, itraconazole; NHL, non-hodgkin s lymphoma; VCZ, voriconazole. 다. 총 7명 (41.2%) 이사망했는데이중 5명은 2개이상의장기가침범되었던환자였다. 본증례와같이간에다른세균이복합감염된예는없었다. 환자는내원 1개월전관해유도항암치료중혈청 GM 0.54 였고, 11 일째에호중구감소증이시작되었으며, 20일째에발열이시작되고 E. faeicum, C. ramosum 균혈증이확인된과거력이있다. 항생제를투여후바로해열되었으며, 호중구감소증에서도회복되고복통등의증상이없어서퇴원하였다. 이때복부전산화단층촬영을검사했다면간농양을확인할수있었을지모르고조기진단, 치료할수있었을것이다. 그리고혈청 GM이호중구감소증발생 8일전에 1회만양성으로나오고, 이후호중구감소증기간과그이후에지속적으로음성이었으며, 항생제투여후해열된것으로보아호중구감소증시기의발열은균혈증에의 한것이었을가능성이높겠다. 아스페르길루스는포자에의해서매개되는감염으로호흡기계를가장흔히침범하지만, 파종성감염이되었을때는혈류를통해서심부기관을감염시킬수있으며, 드물게위장관에집락화되어있다가점막손상등이있을때문맥을통해서간농양을만들수도있다 [2]. Hori 등은침습성아스페르길루스증환자 107 명을부검한결과 97% 에서폐아스페르길루스증이동반되어있었으며, 간을침범한경우는 15% 였으나모두폐병변을동반한파종아스페르길루스증이었다고보고했다 [15]. 본환자에서호흡기증상이없고, 단순흉부방사선검사에서소량의양측흉막삼출이관찰되었으나흉부전산화단층촬영을하지않았기때문에폐병변이동반되지않았다고확신하기는어렵다. 그러나호중구감소성발열전에혈청 GM 양성이었는데, 만약이시기에폐아스페르길루스증

4 380 KW Hong, et al. Liver Abscess by Aspergillus and E. faecium in an AML Patient 이있었고혈류를통해간으로파급된것이라면효과적인항진균제투여없이호중구감소성발열에서회복되지는못했을것이다. E. faeicum, C. ramosum 균혈증이있었다가항생제투여와함께호중구감소증에서회복되면서균혈증은음전되었으나이후간문맥을통해 E. faeicum 등이농양을형성하면서집락화되어있던아스페르길루스가같이유입된것일가능성이높겠다. 본환자에서아스페르길루스증발생의위험인자로작용한것은급성골수성백혈병및고강도항암치료에의한장기간의호중구감소증, 균혈증과광범위항생제사용력, fluconazole 예방요법등이다 [16]. 이증례를통해서강조되는점은면역저하환자에서간농양이있고항생제에반응이없을때진균감염의가능성을염두에두어야하며, 정확한진단과치료를위해서경피적농양배액술외에수술적치료도고려할수있다는것이다. 아스페르길루스증은조직소견이나생리적무균부위에서의배양결과로확인할수있으며, 호중구감소증의정도나항진균제사용이혈청 GM 결과에영향을줄수있다 [17, 18]. 본환자는내원 5주전혈청 GM 1회양성결과후에지속적으로음성으로나왔었고, 경피적농양배액술을통해서원인세균이동정되었으나, 감수성있는항생제를투여함에도호전이늦어수술적절제술을시행한결과조직검사에서아스페르길루스증을진단할수있었다. 그리고간농양의크기가 7.5 cm로컸지만수술적절제를함으로써점성이높아잘배액되지않는간농양을제거할수있었다 [19]. 미국감염학회의아스페르길루스증치료지침에서도간아스페르길루스증의초치료는내과적치료가원칙이나, 담도폐쇄가있거나내과적치료에반응하지않을때는수술적치료를고려하고있다 [20]. 본환자는수술조직검사결과간농양벽외측에균사가보이지는않았으나이를폐아스페르길루스종과마찬가지로치료할수는없었다. 간아스페르길루스증이라는점자체가파종아스페르길루스증의가능성을배제할수없으며, 조직검사에서도농양내균사가혈관을침범하는양상이보였기때문이다. 또한동종조혈모세포이식후면역억제제를장기간복용할예정이었기때문에재발의가능성등을고려해서침습성폐아스페르길루스증에준해서장기간항진균제치료를하는것이합당할것으로판단하였다 [20]. 결론적으로, 면역저하환자에서발생한간농양이배농과광범위항생제치료에반응하지않는경우, 진균감염의가능성을의심해야하며적극적으로조직검사를시행하는것이진단에도움을줄수있겠다. Acknowledgement 본연구는가톨릭대학교서울성모병원임상연구심사위원회의심의를거쳤습니다.( 과제번호 KC11RISI0234, 2011 년 4월 11 일 ) References 1. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001;32: Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, Pastore D, Picardi M, Bonini A, Chierichini A, Fanci R, Caramatti C, Invernizzi R, Mattei D, Mitra ME, Melillo L, Aversa F, Van Lint MT, Falcucci P, Valentini CG, Girmenia C, Nosari A. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Hae matologica 2006;91: Yamada R, Horikawa K, Ishihara S, Hoshino K, Kawaguchi T, Iyama K, Mitsuya H, Asou N. Successful treatment of Aspergillus liver abscesses in a patient with acute monoblastic leukemia using combination antifungal therapy including micafungin as a key drug. Int J Hematol 2010;91: Zhan HX, Lv Y, Zhang Y, Liu C, Wang B, Jiang YY, Liu XM. Hepatic and renal artery rupture due to Aspergillus and Mucor mixed infection after combined liver and kidney transplantation: a case report. Transplant Proc 2008;40: Rieder J, Lechner M, Lass-Floerl C, Rieger M, Lorenz I, Piza H, Bonatti H. Successful management of Aspergillus liver abscess in a patient with necrotizing fasciitis. Dig Dis Sci 2007; 52: Scott CJ, Lambert JS, Taylor CB, Poulton MB. Invasive Aspergillus fumigatus associated with liver and bone in volve ment in a patient with AIDS. Int J Infect Dis 2007;11: van der Velden WJ, Blijlevens NM, Klont RR, Donnelly JP, Verweij PE. Primary hepatic invasive aspergillosis with progression after rituximab therapy for a post transplantation lymphoproliferative disorder. Ann Hematol 2006;85: Marotta G, Tozzi M, Sammassimo S, Defina M, Raspadori D, Gozzetti A, Lauria F. Complete resolution of hepatic aspergillosis after non-myeloablative hematopoietic stem cell transplantation in a patient with acute myeloid leukemia. Hematology 2005;10: Lee TY, Yang SS, Chen GH, Hwang WL, Lin YH, Hwang JI. Hepatic abscess caused by Aspergillus fumigatus infection following splenectomy and immunosuppressive therapy. J Formos Med Assoc 2003;102: Trachana M, Roilides E, Gompakis N, Kanellopoulou K, Mpantouraki M, Kanakoudi-Tsakalidou F. Case report. Hepatic abscesses due to Aspergillus terreus in an immunodeficient child. Mycoses 2001;44: Mazza D, Gugenheim J, Toouli J, Mouiel J. Survival of a liver graft recipient treated for an aspergillar liver abscess. Clin Infect Dis 1996;23: Ow C, Maldjian C, Shires GT 3rd, Markisz J, Kazam E. CT, US, and MR imaging of hepatic aspergilloma. J Comput Assist Tomogr 1991;15: De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J,

5 Infect Chemother 2011;43(4): Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Muñoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Coopera tive Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46: Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010;50: Hori A, Kami M, Kishi Y, Machida U, Matsumura T, Kashima T. Clinical significance of extra-pulmonary involvement of invasive aspergillosis: a retrospective autopsy-based study of 107 patients. J Hosp Infect 2002;50: Sparrelid E, Hägglund H, Remberger M, Ringdén O, Lönnqvist B, Ljungman P, Andersson J. Bacteraemia during the aplastic phase after allogeneic bone marrow transplantation is associated with early death from invasive fungal infection. Bone Marrow Transplant 1998;22: Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs 2007;67: Marr KA, Leisenring W. Design issues in studies evaluating diagnostic tests for aspergillosis. Clin Infect Dis 2005;41 (Suppl 6):S Tan YM, Chung AY, Chow PK, Cheow PC, Wong WK, Ooi LL, Soo KC. An appraisal of surgical and percutaneous drainage for pyogenic liver abscesses larger than 5 cm. Ann Surg 2005; 241: Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, Patterson TF; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46:

Case Report DOI: /ic Infect Chemother 2011;43(1):76-81 pissn eissn Infection & Chemotherapy 침습성기관 - 기관지아스페르길루스

Case Report DOI: /ic Infect Chemother 2011;43(1):76-81 pissn eissn Infection & Chemotherapy 침습성기관 - 기관지아스페르길루스 Case Report DOI: 10.3947/ic.2011.43.1.76 Infect Chemother 2011;43(1):76-81 pissn 2093-2340 eissn 2092-6448 Infection & Chemotherapy 침습성기관 - 기관지아스페르길루스증 : 증례보고및국내문헌고찰 최재기 노진희 이보희 윤재승 김시현 권재철 홍지형 이국진 박선희