Original Article DOI: /ic Infect Chemother 2010;42(6): Infection & Chemotherapy 급성백혈병환자에서발생한침습성폐진균증에대한외과적절제술의치료결과 김시현 1 최수

Original Article DOI: 10.3947/ic.2010.42.6.383 Infect Chemother 2010;42(6):383-390 Infection & Chemotherapy 급성백혈병환자에서발생한침습성폐진균증에대한외과적절제술의치료결과 김시현 1 최수미 1 이동건 1 박재길 2 권재철 1 박선희 1 김희제 1 이석 1 엄기성 1 최정현 1 유진홍 1 민우성 1 가톨릭대학교의과대학내과학교실 1, 흉부외과학교실 2 Outcome of Surgical Resection for Invasive Pulmonary Fungal Diseases in Patients with Acute Leukemia Background: In patients with hematologic diseases, surgical resection can be recommended for definite diagnosis, curative treatment, and prevention of complications or redevelopment of invasive pulmonary fungal diseases (IPFD). The purpose of this study was to investigate the outcome of surgical resection for IPFD in patients planned to undergo subsequent chemotherapy (CTx) or hematopoietic stem cell transplantation (HSCT) for acute leukemia. Materials and Methods: We reviewed the medical records of adult patients with acute leukemia who underwent surgical resection for IPFD which developed during the neutropenic period after CTx. Results: From January 2004 through August 2008, a total of 15 patients (8 males and 7 females with median age of 49 years) underwent surgical resection. All patients were treated by elective surgical resection of residual IPFD lesion before subsequent CTx or HSCT. The median diameter of the main lesion was 66 mm (range, 33-98 mm). Pericardial adhesion due to local invasion of pulmonary lesion was observed in one patient. Lobectomy was performed in 13 cases, lobectomy with wedge resection in 1 case, and segmentectomy with wedge resection in 1 case. Air leakage was complicated in 2 patients. Thirty-day mortality after surgical resection was 0%. After subsequent CTx or HSCT, IPFD redeveloped in 5 patients. However, the overall mortality was not different between the groups with or without the redevelopment of IPFD. Also, mortality attributable to IPFD was only 6% (1/15) during the overall follow-up period (median 184 days, range 58-1,251 days). Conclusions: In patients planned to receive subsequent CTx or HSCT for acute leukemia, surgical resection combined with medical therapy for IPFD could be considered for those who have significant residual lesion. Further study will be needed to determine whether surgical resection can shorten the duration of medical treatment and improve survival outcome. Key Words: Invasive pulmonary fungal diseases, Thoracic surgery, Acute leukemia, Chemotherapy, Hematopoietic stem cell transplantation Si-Hyun Kim 1, Su-Mi Choi 1, Dong-Gun Lee 1, Jae Kil Park 2, Jae-Cheol Kwon 1, Sun Hee Park 1, Hee-Je Kim 1, Seok Lee 1, Ki-Seong Eom 1, Jung-Hyun Choi 1, Jin-Hong Yoo 1, and Woo-Sung Min 1 Departments of 1 Internal Medicine and 2 Thoracic and Cardiovascular Surgery, The Catholic University of Korea, College of Medicine, Seoul, Korea Copyright 2010 by The Korean Society of Infectious Diseases Korean Society for Chemotherapy Submitted: June 17, 2010 Revised: October 13, 2010 Accepted: October 14, 2010 Correspondence to Su-Mi Choi, M.D., PhD. Department of Internal Medicine, Yeouido St. Mary s Hospital, The Catholic University of Korea, #62 Yeouidodong, Yeongdeungpo-gu, Seoul 150-173, Korea Tel: +82-2-3779-1376, Fax: +82-2-780-3132 E-mail: sumichoi@catholic.ac.kr www.icjournal.org

384 SH Kim, et al. Outcome of surgical resection for invasive pulmonary fungal diseases www.icjournal.org 서론 급성백혈병은관해유도화학요법후공고요법을거쳐완전관해에이르게한뒤, 공여자가있을경우조혈모세포이식을시행하여완치가가능한질환이다 [1]. 혈액종양환자에서가장흔한진균증은아스페르길루스종을포함한사상진균 (mold) 에의한폐감염이다 [2-5]. 최근 galactomannan antigen, β-d-glucan 등의검사법을통한조기진단과새로운항진균제사용으로침습성아스페르길루스증의치료성적이향상되고있다 [6, 7]. 그러나화학요법중침습성진균증 (invasive fungal disease) 의발생은연이은화학요법이나조혈모세포이식을지연시키거나진행하더라도침습성진균증의재발가능성때문에환자의치료방향과예후에큰영향을미치게된다. 이에대한대안으로외과적절제술의유용성에대한연구들이몇몇보고되었으나아직국내데이터는부족한실정이다 [8-14]. 본연구자들은화학요법중발생한침습성폐진균증 (invasive pulmonary fungal disease) 으로수술적절제를시행했던급성백혈병환자들의수술전, 후임상적특징및연이은화학요법이나조혈모세포이식후경과를조사하여수술적절제의장기치료성적을알아보고자하였다. 대상및방법 1. 대상환자와침습성폐진균증에대한예방및진단급성백혈병으로가톨릭조혈모세포이식센터에입원한 18 세이상의성인환자중 2004 년 1월부터 2008 년 8월까지방사선학적, 조직학적, 미생물학적검사결과등을종합하여임상적으로침습성폐진균증을진단받고외과적절제를시행받은환자를대상으로전산화의무기록을후향적으로조사하였다. 본연구는여의도성모병원임상연구심의위원회 (institutional review board) 의승인후진행되었다 ( 승인번호 ; SC10RISI0074). 화학요법또는조혈모세포이식을시행받은모든환자에게항암제또는전처치약제투여시작일부터예방적으로 ciprofloxacin (500 mg/ 일 ) 과 fluconazole (FCZ, 100 mg/ 일 ) 또는 itraconazole (ICZ) 경구액 (5 mg/kg/ 일 ) 을투여하였고, 절대호중구수가 3일연속 500/ mm 3 이상으로회복되거나발열또는감염으로주사용항생제를투여하게될경우예방적항생제사용을중단하였다. 호중구감소는말초혈액의절대호중구수가 500/mm 3 미만인경우또는 1,000/mm 3 미만이면서 2일이내 500/mm 3 미만으로감소할것으로예측되는경우로, 발열은구강에서한번측정한체온이 38.3 이상이거나 38 이상의체온이 1시간이상지속되는경우로정의하였다 [15]. 침습성진균감염이의심되기시작한시점에서환자가호소한증상을초기증상으로정의하였고, 방사선학적소견은흉부전산화단층촬영 (CT scan) 결과에따라기술하였다. 침습성폐진균증발생일은항생제에반응하지않는호중구감소성발열과함께흉통이나기침등의호흡기증상이발생한시점이나호흡기증상이없더라도지속적인호중구감소성발열과함께 단순흉부 X- 선사진에서새로운침윤이관찰된시점중선행한날로정의하였다. 진균학적검사는모든호흡기검체에서시행한진균배양검사와세포검사, 혈청 galactomannan assay (Platelia Aspergillus GM-EIA, Bio-Rad, Korea) 결과를조사하였다. 혈청 galactomannan assay는흡광도지수가 2회연속 0.5이상이거나한번이라도 0.7 이상인경우를양성으로판정하였고 [16-18], 침습성폐진균증은 European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) 의정의에따라 확진 (proven), 거의틀림없는 (probable), 가능한 (possible) 으로분류하였다 [19, 20]. 2. 침습성폐진균증에대한항진균요법과수술적치료전략 호중구감소성발열이 5 일이상지속되는경우경험적항진균제 로 amphotericin B deoxycholate (AMB, 1 mg/kg 하루 1 번 ) 또는 itraconazole 주사제 (ICZV, 200 mg 하루 2 번씩 2 일간투여후, 200 mg 하루 1번 ) 를투여하였고, 침습성폐진균증이의심되면반응을평가하여초기항진균제에부적응이나치료실패를보일경우 caspofungin (CSFG, 70 mg 하루 1번투여후, 50 mg 하루 1번 ) 또는 voriconazole 주사제 (VCZV, 6 mg/kg 하루 2번투여후, 4 mg/kg 하루 2번 ) 로변경하였다. 접합균증 (zygomycosis) 이의심되거나배양결과에서확인된경우에는 liposomal amphotericin B (L-AMB, 3-5 mg/kg 하루 1번 ) 로변경하였다. 주사제는환자가호중구감소에서회복되고임상증상및방사선소견이호전중이면서위장관흡수에장애가없다고판단될경우경구 ICZ 또는 voriconazole (VCZ) 로전환하였다. 경구항진균제요법은침습성폐진균증관련증상이나방사선학적소견이남아있어 ( 부분호전 ) 치료목적으로투여한경우는 유지요법 으로, 증상이나방사선학적소견이완전호전되었으나연이은골수억제치료시재발방 Neutropenia Invasive pulmonary fungal diseases (IPFD) Cure of IPFD IV antifungal therapy Central lesion involving pulmonary artery Emergency surgical resection Before recovery of neutropenia Prevention of massive hemoptysis Persistent IPFD lesion on CT scan Peripheral lesion Recovery of neutropenia Persistent IPFD lesion in a significant size and planned to treat with subsequent CTx or HSCT Elective surgery Resection of residual mass and achievement of definite diagnosis Figure 1. Tentative strategy of considering surgical management for invasive pulmonary fungal diseases (IPFD) in patients who have hematologic diseases and are planned to receive subsequent chemotherapy (CTx) or hematopoietic stem cell transplantation (HSCT) at catholic HSCT center.

www.icjournal.org DOI: 10.3947/ic.2010.42.6.383 Infect Chemother 2010;42(6):383-390 385 지를목적으로투여된경우는 2차예방 으로표현하였다. 현재연구자들의병원에서는침습성폐진균증에대해수술적치료를고려하는전략은폐병변이폐동맥을포함한큰혈관이나심장 ( 또는심막 ) 을침범하여대량객혈, 출혈또는심장눌림증의위험이있는경우응급수술을고려하고, 폐말단부위병변인경우항진균요법을유지하면서치료반응을관찰하여호중구감소에서회복된후에도잔존병변크기가상당하여계획하고있는연이은화학요법이나조혈모세포이식을지연시킬수밖에없는환자에서는계획된수술적절제를고려하고있다 (Fig. 1). 외과적절제와관련하여수술적응증, 방법, 수술후합병증유무, 추가입원기간등을조사하였고, 수술후조직병리검사와진균배양검사결과를토대로침습성진균증의범주를재분류하여수술전, 후의차이를분석하였다. 조직병리소견에서 Gomori methenamine silver 또는 periodic acid-schiff 염색시격벽이있고예각의분지를형성하는유리질의균사가관찰되는경우아스페르길루스증을시사하는소견이나, 아스페르길루스종외에 Penicillium, Fusarium, Scedosporium 등의사상진균감염가능성을배제할수없으므로배양검사에서진균이동정되지않으면침습성폐사상진균증확진예 (proven invasive pulmonary mold disease) 로정의하였다 [20]. 그러나논문전반에서조직학적으로사상진균이확인되지않은예까지포함하여포괄적인의미에서침습성폐진균증으로표현하였다. 수술후급성백혈병에대한치료로화학요법이나조혈모세포이식을시행한경우침습성폐진균증의재발또는재감염여부와마지막추적시생존여부를확인하였고, 사망한경우사망원인을조사하였다. 원칙적으로재발 (relapse) 과재감염 (reinfection) 은구분되어야하나실제임상에서원인진균이동정되는빈도가낮고, 동정되더라도그것이같은균주인지확인이거의불가능하기에재발생 (redevelopment) 으로표현하였다. 3. 통계분석 SPSS 12.0 (SPSS Korea, ( 주 ) 데이터솔루션, 서울, 한국 ) 을사용하여, 연속변수에대해서는 Mann-Whitney U test, 비연속변수에대해서는 Fisher s exact test 를이용하였다. 침습성폐진균증이재발생한군과재발생하지않은군의생존분석은 Kaplan Meier 분석을이용하였고, Log-rank 법으로두군간의생존율을비교하였다. P값은 0.05 미만인경우통계학적으로유의한것으로판정하였다. 결과 1. 환자의특징과침습성폐진균증의임상소견급성백혈병에대한화학요법중침습성폐진균증에대해수술적절제술을시행받은환자는총 15 명이었고, 남자 8명 (53%), 여자 7명 (47%), 나이는 49세 ( 중앙값, 범위 31-61 세 ) 였다. 기저질환은급성골수성백혈병 12 명 (80%), 급성림프구성백혈병 3명 (20%) 이었다. 침습성폐진균증은 8명에서관해유도화학요법, 5명에서공고화학요법, 2명 에서재관해유도화학요법중발생하였다 (Table 1). 이들에서화학요법시호중구감소기간은 18 일 ( 중앙값, 범위 7-74 일 ) 이었고, 침습성폐진균증발생일은화학요법시작일로부터 16 일 ( 중앙값, 범위 9-46 일 ) 이었다. 임상증상으로 11 명 (73%) 에서광범위경험적항생제투여에도 5일이상지속되는호중구감소성발열이관찰되었다. 1명을제외한모든환자가적어도 1가지이상의호흡기증상을호소하였는데, 흉통이 12 명 (80%) 에서관찰되어가장빈번하였고, 기침 (53%), 객혈 (20%), 호흡곤란 (13%) 순이었다 (Table 2). 흉부 CT scan 은모든환자에서절대호중구수가 1,000/mm 3 이상회복된후시행되었고, 이는침습성폐진균증발생일로부터 8일 ( 중앙값, 범위 0-17 일 ) 째였다. 수술전 CT에서는흉막- 기저쐐기모양 (47%) 이가장흔하였고, 그외결절 (33%), 경화 (13%), 공기 -초승달징후 (7%) 가관찰되었다. 가장큰주병변의지름은 66 mm ( 중앙값, 범위 33-98 mm) 였고, 5명 (33%) 에서는양측폐야에다발성병변이관찰되었다. 흉수와심장막유착을보인환자는각각 6명 (40%) 과 1명 (7%) 이었다. 5명 (33%) 에서혈청 galactomannan 양성이었고, 첫양성결과가침습성폐진균증발생일보다 7일 ( 중앙값, 범위 39일전-8 일후 ) 앞서있었다. 모든환자에서수술전객담진균배양검사가시행되었으나동정된진균은없었고, 1명에서진단 18 일째기관지경술을시행하였으나기관지폐포세척액의진균배양과세포검사에서진균이동정되거나균사가관찰되지는않았다. 기관지폐포세척액에서 galactomannan assay 는시행하지않았다. 수술전 EORTC/MSG 정의에따른분류는 5명이 거의틀림없는, 10 명이 가능한 에해당되었다. 1차항진균제로는 13 명 (87%) 에서 AMB, 2명 (13%) 에서 ICZV 이투여되었다. AMB를투여한 13명중 3명은침습성폐진균증의진행으로, 2명은약제부작용 ( 각각신독성과주입관련반응 ) 으로 CSFG 이나 VCZV 로변경하였다. ICZV 를투여한 2명은모두침습성폐진균증이진행하여각각 AMB, CSFG 으로변경하였다. 항진균제주사제투여기간은 18 일 ( 중앙값, 범위 6-101 일 ) 이었고, 이차예방을위한시기를제외한경구제를포함한총항진균제투여기간은 64일 ( 중앙값, 범위 15-144 일 ) 이었다. Table 1. Demographic Characteristics of the Patients Who Underwent Surgical Resection for Invasive Pulmonary Fungal Diseases Characteristics No. (%) of patients (n=15) Male sex 8 (53) Age, median years (range) 49 (31-61) Underlying disease AML 12 (80) ALL 3 (20) Treatment of underlying disease Induction CTx 8 (53) Consolidation CTx 5 (33) Reinduction CTx 2 (13) Duration of neutropenia, median days (range) 18 (7-74) Onset of IPFD after CTx, median days (range) 16 (9-46) AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CTx, chemotherapy; IPFD, invasive pulmonary fungal diseases.

386 SH Kim, et al. Outcome of surgical resection for invasive pulmonary fungal diseases www.icjournal.org Table 2. Clinical Characteristics of Patients Who Underwent Surgical Resection for Invasive Pulmonary Fungal Diseases No. Age/ Sex Dx/CTx Clinical Features Radiologic Findings a Mycological Exam. Initial symptoms Duration of neutropenia, days Pattern of infiltrate Bilateral No. of involved lobe Halo Pleural effusion Diameter b, mm Category of IPFD Culture GM Preop. Postop. 1 49/M AML/Induction Chest pain, fever 28 Nodule N 1 + - 46 - - Possible Proven + 2 39/F AML/Induction Chest pain, cough 26 Wedge-shape N 2 + + 62 - - Possible Possible - 3 38/M AML/Induction Fever 16 Wedge-shape N 1 - + 60 - + Probable Proven + 4 49/F ALL/Induction Chest pain 24 Wedge-shape N 1 + - 51 - + Probable Proven + 5 46/F AML/Reinduction Chest pain, cough 19 Nodule N 1 - - 33 - + Probable Proven + 6 53/M AML/Reinduction Cough, fever 18 Nodule Y 3 + - 45 - - Possible Proven + 7 39/M AML/Consolidation Chest pain, cough, fever 74 Wedge-shape N 1 - - 78 - + Probable Probable - 8 58/M AML/Consolidation Chest pain, cough, fever 17 Wedge-shape Y 2 + - 85 - + Probable Probable - 9 50/F AML/Induction Chest pain, cough, fever, hemoptysis 14 Nodule N 1 + + 66 - - Possible Proven + 10 53/F AML/Consolidation Chest pain, cough, fever 15 Wedge-shape N 1 - + 66 - - Possible Proven + 11 52/M ALL/Consolidation Chest pain, fever 7 Nodule N 1 + - 42 - - Possible Proven + 12 31/F ALL/Induction Cough, fever 14 Consolidation N 1 - - 89 - - Possible Proven + 13 46/M AML/Induction Chest pain, fever 19 Nodule with air-crescent Y 3 + - 70 - - Possible Proven + 14 61/F AML/Consolidation Chest pain, cough, dyspnea, hemoptysis 15 Wedge-shape Y 3 + + 75 - - Possible Proven + 15 40/M AML/Induction Chest pain, fever 18 Consolidation Y 3 + + 98 - - Possible Possible - Dx, diagnosis; CTx, chemotherapy; Exam., examination; IPFD, invasive pulmonary fungal diseases; GM, galactomannan; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; N, no; Y, yes. a Radiologic findings were based on chest CT scan. b Diameter was measured at the largest main lesion. Stepup 2. 수술적절제와수술후임상경과 15 명모두연이은화학요법이나조혈모세포이식전에잔존병변의제거를목적으로계획된수술을시행받았다. 폐양측에다발성병변을보였던 5명은항진균제치료에부분호전을보였으나, Table 2에제시된바와같이주병변의크기가상당하여항진균요법만으로는연이은화학요법이나이식을수주내로시행하기어렵다는판단하에수술을시행받았고, 5명중 3명에서다음치료전에완전호전을보였다. 수술시기는침습성폐진균증발생 26일 ( 중앙값, 범위 17-112 일 ) 째시행하였다. 수술시절대호중구수는 7,353/mm 3 ( 중앙값, 범위 1,969-31,040/mm 3 ), 혈소판수는 118,000/mm 3 ( 중앙값, 범위 48,000-666,000/mm 3 ) 이었다. 폐엽절제술이 13명, 폐엽절제술과쐐기절제술, 구역절제술과쐐기절제술이각각 1명에서시행되었다. 수술관련합병증으로 2명에서공기누출이발생하였으나, 가슴관을삽입하여각각 14 일, 25일간배출후영구후유증없이호전되었다. 11 명에서수술후절제조직으로진균배양검사를시행하였으나진균이배양된경우는없었다. 조직병리검사결과 11 명에서아스페르길루스증에합당한소견이관찰되었고, 3명에서기질화폐렴, 1명에서골화가동반된국소괴사조직소견이관찰되었다. 조직병리소견을추가하여침습성진균증의범주를재분류하였을때, 11 명에서범주가향상되었다. 특히 8명은 가능한 에서 확진된 침습성폐사상진균증으로분류되었다. 수술후연이은화학요법이나이식을시행받은환자는 14 명으로, 5 명은 1회이상의화학요법, 4명은화학요법후조혈모세포이식, 5명은조혈모세포이식을시행받았다 (Table 3). 나머지한명 (patient No. 14) 은조혈모세포이식을위해입원하였으나기저질환의재발이확인되어이식이취소되었다. 수술후연이은화학요법또는이식까지의기간은 46일 ( 중앙값, 범위 20-112 일 ) 이었다. 두명 (patient No. 6, 8) 을제외한모든환자에서연이은화학요법또는이식당시침습성폐진균증이완전호전을보였고, 2차예방을위해 10 명에서 ICZ 경구액이, FCZ 과 VCZ 이각각 1명에게투여되었다. 부분호전을보인 2명에서는유지치료를위해 ICZ 경구액과 VCZ 이각각투여되었다. 연이은치료후 35.7% (5/14) 에서침습성폐진균증이재발생하였고, 그중 4명은수술적절제와항진균요법으로완전호전을보였던경우이고, 1명은부분호전을보였던경우였다. 연이은치료후침습성폐진균증이재발생한군 (5명 ) 과재발생하지않은군 (9명 ) 사이의폐병변의크기 (46 mm 대 66 mm, P=0.583), 총항진균제투여기간 (115 일대 82일, P=0.226), 발생후수술까지의기간 (44 일대 26일, P=0.275), 수술후연이은화학요법또는이식까지기간 (51 일대 33일, P=0.156) 등에통계적으로유의한차이는없었다 (Table 4). 다만수술전양측폐야에다발성병변을보였던 4명중 3명 (75%) 에서, 편측병변을보였던 10 명중 2명 (20%) 에서침습성폐진균증이재발생하여수술전다발성병변인환자에서더흔히재발생하는경향을보였다 (P=0.095). 그러나침습성폐진균증이재발생한군과재발생하지않은군의생존율에는차이가없었다 (P=0.730). 침습성폐진균증진단후마지막추적관찰까지기간은 184 일 ( 중앙값, 범위 58-1,251 일 ) 이었고, 수술후 30일사망률은 0%, 마지막추적

www.icjournal.org DOI: 10.3947/ic.2010.42.6.383 Infect Chemother 2010;42(6):383-390 387 Table 3. Subsequent Myelosuppressive Treatment for Acute Leukemia and Long Term Outcome No. Interval from op. to subsequent myelosuppressive Tx Subsequent myelosuppressive Tx Status of IPFD a Antifungal drug for secondary prophylaxis or maintenance Tx. Redevelop. of IPFD Duration of follow-up, days b Outcome 1 34 CTx CR ICZ Y 170 Survival 2 30 CTx + HSCT CR ICZ N 453 Survival 3 31 CTx + HSCT CR ICZ N 1003 Survival 4 73 CTx CR VCZ N 168 Died of fulminant CDAD 5 25 HSCT CR ICZ N 125 Died of DAH 6 112 CTx PR VCZ Y 169 Died of bacterial sepsis 7 53 CTx CR FCZ N 140 Died of DAH 8 53 HSCT PR ICZ N 560 Survival 9 20 CTx + HSCT CR ICZ N 699 Survival 10 33 HSCT CR ICZ N 1288 Survival 11 51 HSCT CR ICZ Y 156 Died of redeveloped IPFD 12 51 CTx + HSCT CR ICZ N 208 Survival 13 41 CTx CR ICZ Y 605 Survival 14 - ND CR - N 101 Died of relapsed leukemia 15 102 HSCT CR ICZ Y 652 Survival op, operation; Tx, treatment; IPFD, invasive pulmonary fungal diseases; Redevelop., redevelopment; CTx, chemotherapy; CR, complete response; ICZ, itraconazole; Y, yes; HSCT, hematopoietic stem cell transplantation; N, no; VCZ, voriconazole; CDAD, Clostridium difficile-associated disease; DAH, diffuse alveolar hemorrhage; PR, partial response; FCZ, fluconazole; ND, not done. a At the time of subsequent CTx or HSCT. b Duration of follow-up was defined as the number of days from operation to last contact. Table 4. Comparison between Patients according to the Redevelopment of Invasive Pulmonary Fungal Disease During Subsequent Myelosuppressive Treatment No. (%) of patients Redevelopment of IPFD or median (range) Y (n=5) N (n=9) P Male sex 5 (100) 3 (33) 0.031 Age, years 49 (40-53) 46 (31-58) NS Underlying disease NS AML 4 (80) 7 (78) ALL 1 (20) 2 (22) Treatment of underlying disease NS Induction CTx 3 (60) 5 (56) Consolidation CTx 1 (20) 3 (33) Reinduction CTx 1 (20) 1 (11) Duration of neutropenia (days) 18 (7-28) 17 (14-74) NS Radiologic findings Bilateral lesions 3 (60) 1 (11) 0.095 Diameter (mm) 46 (42-98) 66 (33-89) NS Central necrosis 3 (60) 7 (78) NS Pleural effusion 1 (20) 4 (44) NS Interval from onset of IPFD to op. (days) 44 (17-112) 26 (20-42) NS Postop. complication 2 (40) 1 (11) NS Interval from op. to subsequent myelosuppressive 51 (34-112) Tx (days) 33 (20-73) NS Status of IPFD at subsequent myelosuppressive Tx NS CR 4 (80) 8 (89) PR 1 (20) 1 (11) Duration of total antifungal therapy (days) 115 (39-162) 82 (22-221) NS Survival 3 (60) 6 (67) NS IPFD, invasive pulmonary fungal diseases; Y, yes; N, no; NS, not significant; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CTx, chemotherapy; op., operation; postop., postoperative; Tx, treatment; CR, complete response; PR, partial response. 기간까지전체사망률은 40% (6/15) 였다. 이중 1명만이침습성폐진균증과관련하여사망하였는데, 환자 (patient No. 11) 는수술후동종조혈모세포이식을시행받고급성이식편대숙주병에대한면역억제치료중다시발생한침습성폐진균증으로수술후 156 일 ( 이식후 88일 ) 에급성호흡부전으로사망한예였다 (Table 3). 고찰 본연구에서는 15 명의침습성폐진균증의심환자에서연이은화학요법또는조혈모세포이식전완치를목적으로호중구감소증이회복된후계획된수술적절제가시행되었다. 이중심장막유착을보인 1명의환자는응급수술의적응증이었으나, 환자의전신상태가불량하여호중구감소에서회복된후수술을시행하였다. 수술후조직검사결과로는 73.3% (11/15) 에서 EORTC/MSG 정의에근거한범주가향상된반면조직배양에서동정된진균이없었던것은수술전이미상당한기간동안투여된항진균제의효과로생각된다. 수술후치명적인합병증은발생하지않았고, 수술후 30일사망률은 0% 였다. 침습성폐진균증은 86.7% (13/15) 에서다음치료전완전호전을보였으나, 급성백혈병에대한추가적치료를받은환자의 35.7% (5/14) 에서침습성폐진균증이재발생하였다. 그러나최종추적기간까지침습성폐진균증관련사망률은단지 6.7% (1/15) 였다. 다만연이은화학요법또는이식시수술전다발성병변인환자에서재발생이더흔한경향을보여, 이러한환자에서수술적절제를고려할때에는각환자의임상조건과방사선학적소견에근거한개별적접근이필요하겠다. 침습성폐진균증에대한수술적치료는그시기나적응증에대한지침이아직명확히정해져있지않다. 주로원인이불확실한병변에대

388 SH Kim, et al. Outcome of surgical resection for invasive pulmonary fungal diseases www.icjournal.org 한확진이나국소적병변에대한완치를목적으로시행되며, 부가적으로병변이주요혈관이나심막에인접해있어출혈의위험이높거나지속적인객혈이나흉벽침범소견이동반된경우에고려될수있다 [21-24]. 침습성폐진균증은혈관폐쇄로인한이차적인폐경색증과폐분리증으로발생하는데, 추후공동 (cavitation) 이생기면이러한허혈성병변내로는항진균제도달이어렵고지속적인공동내진균성장으로재발의병원소로작용할수있으므로수술적제거가효율적일수있다 [25-27]. Brodoefel 등에따르면 CT scan 소견에근거하여침습성폐아스페르길루스증의병변크기를추적한결과, 항진균요법만으로병변크기가반으로줄어드는데는 31 일, 완전호전까지는 85.5 일이소요되었다 [26]. Zhang 등의연구에서도침습성진균감염에대해항진균요법만시행한군에서는이식전에평균 11 주의항진균제가투여된반면, 항진균요법과수술적제거를동시에시행한군에서는연이은치료를 4 주가까이앞당길수있었다 [28]. 물론연구에포함된환자의기저질환과일차치료약제에도차이가있어직접적인비교는어렵겠지만, 본연구결과 86.7% 의환자에서 46일째완전호전을보여기존연구와유사한성적을보였다. 이제까지의보고에의하면대량출혈의위험이높을경우호중구감소상태일지라도응급수술이시행된예들이있었으나, 수술후합병증이나폐진균증의급속한진행으로인한사망예가호중구감소에서호전된후계획된수술을시행한경우보다많았던것으로보인다 [10, 11, 14, 22, 23, 29]. 화학요법직후의혈액종양환자에서수술을고려할때에는출혈, 감염 ( 농흉 ), 사강형성등수술관련합병증외에도불량한전신상태, 전신마취에따른부작용에대한부담과폐절제에따른수술후폐기능까지고려해야한다. 그럼에도불구하고항진균요법만시행한군에서의침습성폐아스페르길루스증에의한사망률이 41% 였던데반해, 항진균요법과수술적절제를병행함으로써이를 14% 까지줄이고전체생존율을더높였다는연구결과가있다 [8, 30, 31]. 또한계획된수술의경우낮은합병증과사망률을보이며, 추가적인화학요법을시행받은환자들에서국소적인감염억제효과도보고된바있다 [9, 13, 32]. 그러나이러한연구결과들은모두그표본수가작고후향적인연구이기때문에수술적절제가항진균제치료기간을의미있게단축시키고연이은화학요법치료후재발을감소시켜장기생존율을높일수있는지여부는아직분명치않다. 본연구역시항진균요법만시행한군과의비교- 대조군연구가아니므로상대적으로전신상태가더좋은환자들이수술을시행받아장기예후에서향상된결과를보였을수있다. 또한수술을고려한대상도침습성폐진균증잔존병변의크기가비교적큰경우에한정되어시행한후향적연구이며, 표본수도작아재발생의위험요인에관한다변량분석등충분한분석을시행할수없었다는제한점이있다. 국내에서도본원의전체혈액종양환자중폐아스페르길루스증에대해수술을시행한 14 예를보고한논문이있었다 [33]. 그러나과거연구의경우기저질환이이질적이어서연이은화학요법제의형태가다양했을뿐만아니라, 추적기간이길지않았고혈액종양환자에서적용되는침습성진균감염에대한 EORTC/MSG 분류를적용하지않았다. 본연구는국내에서처음으로침습성폐진균증에대한수술적절제후연 이은화학요법또는조혈모세포이식까지의장기추적관찰을통해수술적치료의결과를조사하였다는의의가있다. 결론적으로본연구결과침습성폐진균증잔존병변의크기가상당한경우연이은화학요법또는조혈모세포이식을받아야하는급성백혈병환자에서기저질환이재발하기전에다음치료를계속할수있도록수술적절제를고려할수있을것으로생각된다. 본연구를통해잠정적인수술적치료의전략과장기추적결과를제시함으로써유사한환자를진료하는감염관련전문가들에게참고자료가되었으면한다. 추가적으로수술적치료가항진균요법의기간을줄일수있을지, 항진균요법만시행한군과비교하여재발을줄이고사망률을줄일수있는지에관한잘계획된전향적연구가필요하겠다. References 1. Hoffman R, Benz EJ Jr., Shattil SJ, Furie B, Silberstein LE, McGlave P, Heslop H. Hematology: Basic Principles and Practice. 5th ed. Philadelphia: Churchill Livingstone; 2008. 2. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100:4358-66. 3. Martino R, Subirà M. Invasive fungal infections in hematology: new trends. Ann Hematol 2002;81:233-43. 4. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78:123-38. 5. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997;175:1459-66. 6. Baddley JW, Andes DR, Marr KA, Kontoyiannis DP, Alexander BD, Kauffman CA, Oster RA, Anaissie EJ, Walsh TJ, Schuster MG, Wingard JR, Patterson TF, Ito JI, Williams OD, Chiller T, Pappas PG. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis 2010;50: 1559-67. 7. Maertens J, Theunissen K, Verhoef G, Verschakelen J, Lagrou K, Verbeken E, Wilmer A, Verhaegen J, Boogaerts M, Van Eldere J. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005;41:1242-50. 8. Habicht JM, Matt P, Passweg JR, Reichenberger F, Gratwohl A, Zerkowski HR, Tamm M. Invasive pulmonary fungal infection in hematologic patients: is resection effective? Hematol J 2001;2:250-6. 9. Moreau P, Zahar JR, Milpied N, Baron O, Mahé B, Wu D, Germaud P, Despins P, Delajartre AY, Harousseau JL. Localized invasive pulmonary aspergillosis in patients with neutropenia. Effectiveness of surgical resection. Cancer 1993;72:3223-6.

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