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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2009;66: CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 동종조혈모세포이식후비분류성간질성폐렴으로사망한 1 예 1 고려대학교안산병원내과, 2 병리과, 3 성균관대학교의과대학삼성서울병원병리과, 4 고려대학교안산병원흉부외과 정기환 1, 성화정 1, 이주한 2, 한정호 3, 신철 1, 박형주 4, 김제형 1 A Case of Nonclassifiable Interstitial Pneumonia after Allogeneic Hematopoietic Stem Cell Transplantation Ki Hwan Jung, M.D. 1, Hwa Jung Sung, M.D. 1, Ju-Han Lee, M.D. 2, Joungho Han, M.D. 3, Chol Shin, M.D. 1, Hyung Joo Park, M.D. 4, Je Hyeong Kim, M.D. 1 Departments of 1 Internal Medicine, 2 Pathology, Korea University Ansan Hospital, Ansan, 3 Department of Pathology, Saumsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 4 Department of Thoracic and Cardiovascular Surgery, Korea University Ansan Hospital, Ansan, Korea Despite the improvements in supportive care, early and late hematopoietic stem cell transplantation-related complications still remain a significant cause of morbidity and mortality. Pulmonary complications occur in 40 60% of patients who undergo allogeneic hematopoietic stem cell transplantation. Late-onset noninfectious pulmonary complications can occur months and even years after transplantation. Interstital lung disease has also been reported to be a late post-transplant complication. Exposure to cytotoxic drugs and/or irradiation has been implicated as a cause of pulmonary toxicity including pulmonary fibrosis. We report a case of an 18-year-old female with non-classifiable interstitial pneumonia that manifested eight and a half years after allogeneic hematopoietic stem cell transplantation. The condition worsened rapidly and the patient eventually died. Key Words: Hematopoietic stem cell transplantation, Interstitial lung disease, Pneumothorax 서 조혈모세포이식 (hematopoietic stem cell transplantation) 후발생하는폐합병증의빈도는약 40 60% 로, 이식과관련된이환율및사망률을증가시킨다 1,2. 초기에는감염성질환, 미만성폐포출혈및폐부종등이발생하고, 후기에는비감염성질환으로만성이식편대숙주질환 (graft versus host disease, GVHD) 과관련된폐쇄세기관지염 (bronchiolitis obliterans, BO), 특발성기질화폐렴 Address for correspondence: Je Hyeong Kim, M.D. Division of Pulmonary, Sleep and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, 516, Gojan-1-dong, Danwon-gu, Ansan , Korea Phone: , Fax: chepraxis@korea.ac.kr Received: Dec. 23, 2008 Accepted: Jan. 19, 2009 론 (cryptogenic organizing pneumonia, COP) 등이주로발생한다 3. 드물게알킬화제 (alkylating agent), 시클로포스파미드 (cyclophosphamide) 등의화학요법제 (chemotherapeutic agent) 와방사선조사와관련된직접폐손상에의한간질성폐질환이발생한다 4,5. 최근효과적인예방적항생제치료에의해조혈모세포이식후감염성폐질환의발생이감소하면서, 비감염성폐질환의빈도는상대적으로증가하는추세이다 6. 저자들은동종조혈모세포이식을시행받은지약 8년 6개월후에호흡곤란및저산소혈증으로내원한 18세여자환자에서, 폐조직생검을통해비분류성간질성폐질환 (nonclassifiable interstitial pneumonia, NCIP) 을진단하였으나, 전신스테로이드치료에도호전되지않고진행하여재발성의기흉을동반한호흡부전으로사망한 1예를경험하였기에보고한다. 122

Tuberculosis and Respiratory Diseases Vol. 66. No. 2, Feb. 2009 증례환자 : 정OO, 18세, 여자주소 : 흉부불편감및호흡곤란현병력 : 환자는약 2주전부터발생한흉부불편감과, 수일전부터점차악화되는운동시호흡곤란을주소로응급실로내원하였다. 기침, 객담등의호흡기증상과열감및오한을호소하였다.

그러나퇴원 3일후, 다시심한호흡곤란및흉통이발생하여시행한단순흉부촬영및전산화단층촬영에서이전에관찰되었던기낭의파열과심한기흉이있어, 흉관삽관술및파열된제일큰크기의기낭에대한쐐기절제술 (we dge resection) 을시행하였고, 수술후에도반복되는기흉이있어흉막유착술을시행하였다.

키 151 cm, 체중 30 kg으로악액질및만성병색을띠었고, 청색증소견을보였으나곤봉지는없었다. 흉부진찰상전폐야에서거친호흡음과좌중하폐야에서악설음이청진되었다. 방사선및검사실소견 : 내원후시행한단순흉부촬영 (Figure 1A) 에서척추측만증과좌하폐야의혼탁음영소견을보였다. 대기중동맥혈가스분석에서 ph 7.41, PaCO 2 40.2 mmhg, PaO 2 63.

2 Tuberculosis and Respiratory Diseases Vol. 66. No. 2, Feb 증례환자 : 정OO, 18세, 여자주소 : 흉부불편감및호흡곤란현병력 : 환자는약 2주전부터발생한흉부불편감과, 수일전부터점차악화되는운동시호흡곤란을주소로응급실로내원하였다. 기침, 객담등의호흡기증상과열감및오한을호소하였다. 과거력 : 환자는 8년 6개월전복통을주소로본원에내원하여재생불량빈혈 (aplastic anemia) 을진단받고, 동종조혈모세포이식을시행한병력이있었다. 내원 2년 6개월전갑자기발생한흉통으로내원하여, 우하폐엽의기낭 (air cysts) 및양측상엽의기포 (blebs) 을동반한기흉을진단받고, 흉관삽관술치료후호전되어퇴원하였다. 그러나퇴원 3일후, 다시심한호흡곤란및흉통이발생하여시행한단순흉부촬영및전산화단층촬영에서이전에관찰되었던기낭의파열과심한기흉이있어, 흉관삽관술및파열된제일큰크기의기낭에대한쐐기절제술 (we dge resection) 을시행하였고, 수술후에도반복되는기흉이있어흉막유착술을시행하였다. 쐐기절제술병변에대한조직병리소견에서는폐실질의기낭변화를동반한만성염증및중피세포과증식의병리소견을보였다. 환자는흉막유착술후퇴원하였고, 더이상외래로내원하지않아단순흉부촬영및폐기능검사등의추적검사는시행하지못했다. 진찰소견 : 내원당시환자는분당 20회, 혈압은 110/70 mmhg로안정적이었고, 열감을호소하였으나체온은 37.4 o C였다. 키 151 cm, 체중 30 kg으로악액질및만성병색을띠었고, 청색증소견을보였으나곤봉지는없었다. 흉부진찰상전폐야에서거친호흡음과좌중하폐야에서악설음이청진되었다. 방사선및검사실소견 : 내원후시행한단순흉부촬영 (Figure 1A) 에서척추측만증과좌하폐야의혼탁음영소견을보였다. 대기중동맥혈가스분석에서 ph 7.41, PaCO mmhg, PaO mmhg, HCO mmol/l, SaO % 로저산소혈증을보였고, 말초혈액검사에서백혈구 12,840/μl ( 호중구 80.5%, 림프구 12.9%, 단핵구 3.4%, 호산구 1.2%), 혈색소 14.6 g/dl, 혈소판 263,000/ μl로경도의백혈구증가증을보였다. 객담에대한항산균도말검사및세균배양검사는음성이었다. 단순흉부촬영에서보이는병변의정도에비해심한저산소혈증과과거의기흉등의병력을고려하여시행한고해상흉부전산화단층촬영 (high resolution computed tomography, HRCT) 에서는과거의검사와비교하여, 새로발생된좌하폐엽의소엽사이막비후 (interlobular septal thickening) 및폐실질의경화를동반한간유리혼탁화 (ground glass opacification, GGO) 음영과양측상엽의망상결절형침윤 (reticulonodular opacity) 및우하폐엽기낭의악화소견이관찰되었다 (Figure 2). 폐기능검사는호흡곤란으로인해전폐용적및확산능은검사하지못했고, 기관지확장제후폐활량측정 (post-bronchodilator spirometry) 에서 FEV L (16%), FVC 0.46 L (16%), FEV 1 /FVC 97% 로 Figure 1. Chest radiograph on admission (A) showed reticulonodular opacities on both upper lung zones and patchy opacities with consolidation on left mid to lower lung zone. After 2 months (B), recurrent pneumothoraxes were developed and progressive bilateral haziness worsened until 5 months after admission (C), resulting in death. 123

KH Jung et al: Nonclassifiable interstitial pneumonia after allogeneic hematopoietic stem cell transplantation Figure 2.

consolidation on left lower lobe (B) and aggravated air cysts on right lower lobe (C). Figure 3.

fibrosis. Subpleural and peribronchiolar collagen type fibrosis with some lymphocytic infiltration was seen (H&E stain, A: 200, B: 400).

하지만약 1주일간의치료에도불구하고, 임상양상및방사선학적인호전의소견이없었다. 감염성폐질환의가능성이적다고판단되어, 좌하폐엽의간유리상음영병소및방사선학적으로비교적정상인좌상폐엽에대한비디오흉강경수술하폐생검을시행하였다.

상기조직병리소견들은기존에보고된일반적인간질성폐질환의아형에일치하지않아, 골수이식후지연형으로발생하는 비감염성폐합병증 (late-onset noninfectious pulmonary complication, LONIPC) 중의하나인비분류성간질성폐렴

3 KH Jung et al: Nonclassifiable interstitial pneumonia after allogeneic hematopoietic stem cell transplantation Figure 2. High resolution computed tomography of chest on admission showed reticulonodular opacities on both upper lobes (A), ground glass opacity with consolidation on left lower lobe (B) and aggravated air cysts on right lower lobe (C). Figure 3. Histopathology of the resected left lower lobe revealed chronic inflammation with alveolar macrophages in alveolar space and focal interstitial fibrosis. Subpleural and peribronchiolar collagen type fibrosis with some lymphocytic infiltration was seen (H&E stain, A: 200, B: 400). 심한제한성장애를보였다. 치료및경과 : 환자가열감및객담을호소하고, 백혈구증가증및방사선검사상의폐경화를동반한국소적 GGO 소견으로미루어보아, 지역사회폐렴의가능성을판단하고, 항생제치료를시행하였다. 하지만약 1주일간의치료에도불구하고, 임상양상및방사선학적인호전의소견이없었다. 감염성폐질환의가능성이적다고판단되어, 좌하폐엽의간유리상음영병소및방사선학적으로비교적정상인좌상폐엽에대한비디오흉강경수술하폐생검을시행하였다. 조직병리소견상좌하폐엽의병소에서는폐포내폐포대식세포의침윤및국소적인간질성섬유화를동반한만성염증이관찰되었고, 좌상폐엽에서는폐기종, 림프구의침윤, 간질성섬유화및폐포대식세포의응집을동반한만성염증소견이관찰되었다 (Figure 3). 상기조직병리소견들은기존에보고된일반적인간질성폐질환의아형에일치하지않아, 골수이식후지연형으로발생하는 비감염성폐합병증 (late-onset noninfectious pulmonary complication, LONIPC) 중의하나인비분류성간질성폐렴 (nonclassifiable interstitial pneumonia, NCIP) 으로진단하였다. 결합조직병 (connective tissue disease) 과연관된간질성폐질환의가능성에대한혈청학적검사는모두정상이었다. 진단이후환자는반복적인기흉을동반한진행성의호흡곤란이심해지는임상양상을보여 (Figure 1B), 전신스테로이드를이용한항염증치료를시행하였음에도불구하고, 임상및방사선학적으로악화되어 (Figure 1C), 내원 5개월만에사망하였다. 고찰조혈모세포이식이급성백혈병, 골수이형성증후군, 재생불량빈혈등의기존혈액질환이외에다발성골수종, 고형암등의치료에도광범위하게시행되면서, 조혈모세 124

4 Tuberculosis and Respiratory Diseases Vol. 66. No. 2, Feb 포이식을시행받는환자의수가증가하는추세이다 7. 조혈모세포이식과관련된감염성및비감염성폐합병증은, 전체수여자의약 40 60% 에서발생하고, 이식후사망의약 50% 에서관련되어있으며 2,4, 최근국내보고에의하면전체수여자의약 25% 에서폐합병증이발생하고, 이중약 30% 의환자들이사망하는것으로알려졌다 8. 폐합병증은이식후면역재구성 (immune reconstitution) 상태가변화하는특정시기에따라특징적인발생양상을보인다 1,9. 일반적으로이식후 30일까지는지속적인호중구감소증으로인해, 세균과거대세포바이러스 (cytomegalovirus, CMV) 감염등의바이러스및침습적진균감염등의감염성합병증이발생하고, 비감염성으로는폐부종, 미만성폐포출혈 (diffuse alveolar hemorrhage, DAH) 등이발생한다. 이식후 30일부터 100일까지는호중구감소증은회복되고체액면역및세포매개면역의저하가있는시기로, 바이러스감염이외에 Pneu mocystis jirovecii (P. jirovecii) 등에의한감염성폐질환과, 급격히진행하는전격성경과를보여약 60 80% 의환자가사망하는특발성폐렴증후군 (idiopathic pneumonia syndrome, IPS) 이흔하게발생한다. 이식후 100일후부터는만성이식편대숙주질환 (graft versus host disease, GVHD) 과관련된 LONIPC 인 BO 6,8,10, COP 및지연폐독성증후군 (delayed pulmonary toxicity syndrome) 등이발생한다 7. 또한, 골수이식과정중에사용하는시클로포스파미드등의폐독성이있는항암제및방사선치료에의한직접적인폐손상도보고된바있다 5. 본증례의환자는처음호흡곤란및기흉이발생하고방사선학적검사에서기낭을동반한폐병변이발견되었을당시, 이미조혈모세포이식후약 6년이지난상태였고, 금번내원당시방사선소견에서기존병변의악화를동반한항생제치료에반응하지않는새로운간질성침윤이발생하여 LONIPC 의발생을고려할수있었다 9. 내원시주로호흡곤란을호소하여, 처음에는조혈모세포이식후약 6 10% 에서발생하고만성적폐쇄성환기장애를일으키는 BO의가능성을고려했으나, 발생시기가일반적으로알려져있는이식후약 3 24 개월과맞지않고, 폐기능검사에서 BO에서나타내는전형적인폐쇄성장애가아닌제한성장애를보여 BO의가능성은임상적으로배제하였다. 단순흉부촬영및 HRCT 에서폐경화를동반한 GGO 소견을보여 COP 등조혈모세포이식과관련한간질성폐렴의가능성을고려하였고 11,12, 확진을위해비디오흉강경하폐생검을시행하였다. 병리조직소견상방사선 학적으로 GGO를보인좌하폐엽의병소에서는폐포내폐포대식세포의침윤및국소적인간질성섬유화를동반한만성염증이관찰되었고, 방사선학적으로특이소견이없던좌상폐엽에서도폐기종, 림프구의침윤, 간질성섬유화및폐포대식세포의응집을동반한만성염증이관찰되었다. 이소견들은일반적인간질성폐렴의아형에해당하지않는소견으로, 조혈모세포이식후발생하는 LONIPC 중의하나인 NCIP로진단하였다. 최근까지도조혈모세포이식후비감염성폐합병증에대한명확한진단기준및분류가확립되지않아혼란스러운면이있기는하지만 6, NCIP는이식후지연형으로발생하는폐합병증으로, Palmas 등 3 의보고에의하면조혈모세포이식을받은 179 명중 18명에서 LONIPC 가발생하였고, 이중에서 8명이분류되지않는 NCIP 으로진단되었으며, 이중 5명이스테로이드치료에도불구하고호전이없었다. NCIP 등의 LONIPC 가주로이식후 100 일이후에지연형으로발생하고, 일단발병하게되면이식후 1년까지의사망률을증가시킨다. 하지만, 이식후수년이상장기간동안폐합병증의발생및경과를추적한연구는매우제한적이다 2,13. 본증례의환자의경우일반적으로 LONIPC 가발생하는시기보다매우늦은시기인이식후약 6년후에호흡곤란등의임상증상과방사선학적변화가발생하였고, 이후추적관찰하지못해약 2년 6개월동안의단순흉부촬영및폐기능검사의변화는확인하지못했지만, 약 2년 6개월후에기존병변의악화및추가병변의발생으로인한폐기능의감소로사망하여, 기존에보고된 NCIP 보고들과다르게훨씬더지연형의임상경과를보였다. 따라서, 과거와비교하여조혈모세포이식이주요한치료법으로서시행빈도가증가하고, 감염성합병증에대한치료법및전반적인지지적치료법이발달하여환자들의사망률이감소하고생존기간이증가하는임상적현실을고려했을때, 아직은발병기전이명확하지않고, 발생할경우치명적일수있는 LONIPC 에대한임상적인관심과연구가필요할것으로판단된다. 요약조혈모세포이식후 1년이내에발생하는폐합병증의진단및분류는확립되어있으나, 수년이상장기간생존자에게서발생하는폐합병증에대해서는잘알려져있지않다. 저자들은 8년전동종조혈모세포이식을시행받고, 호흡곤란을주소로내원한 18세여자환자에서, 폐조직 125

5 KH Jung et al: Nonclassifiable interstitial pneumonia after allogeneic hematopoietic stem cell transplantation 생검을통해비분류성간질성폐렴을진단하였으나, 스테로이드치료에도불구하고급격한악화를보여호흡부전으로사망한 1예를경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Yen KT, Lee AS, Krowka MJ, Burger CD. Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment. Clin Chest Med 2004;25: Eikenberry M, Bartakova H, Defor T, Haddad IY, Ramsay NK, Blazar BR, et al. Natural history of pulmonary complications in children after bone marrow transplantation. Biol Blood Marrow Transplant 2005; 11: Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998;100: Michelson PH, Goyal R, Kurland G. Pulmonary complications of haematopoietic cell transplantation in children. Paediatr Respir Rev 2007;8: Yabe M, Yabe H, Hattori K, Morimoto T, Hinohara T, Takakura I, et al. Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997;19: Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2007;13: Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2004; 170: Lim DH, Lee J, Lee HG, Park BB, Peck KR, Oh WS, et al. Pulmonary complications after hematopoietic stem cell transplantation. J Korean Med Sci 2006; 21: Khurshid I, Anderson LC. Non-infectious pulmonary complications after bone marrow transplantation. Postgrad Med J 2002;78: Ahn CM, Hwang SY, Byun MK, Lee JH, Chung WY, Moon JW, et al. Recurrent secondary pneumothorax caused by bronchiolitis obliterans due to chronic graft versus host disease in a patient with chronic myelogenous leukemia after allogenic bone marrow transplantation. Tuberc Respir Dis 2004;57: Gosselin MV, Adams RH. Pulmonary complications in bone marrow transplantation. J Thorac Imaging 2002; 17: Wah TM, Moss HA, Robertson RJ, Barnard DL. Pulmonary complications following bone marrow transplantation. Br J Radiol 2003;76: Griese M, Rampf U, Hofmann D, Führer M, Reinhardt D, Bender-Götze C. Pulmonary complications after bone marrow transplantation in children: twenty-four years of experience in a single pediatric center. Pediatr Pulmonol 2000;30:

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<30372EC1F5B7CA D B1E8BEE7BCF62E687770> 대한내과학회지 : 제 77 권제 6 호 2009 증례 08-311 조혈모세포이식후에만성이식편대숙주반응과동반된종격동기종 1예 고신대학교의과대학복음병원내과 이호섭 신성훈 김양수 A case of pneumomediastinum combined with chronic graft-versus-host disease following allogeneic hematopoietic