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1 대한내과학회지 : 제 77 권제 6 호 2009 증례 조혈모세포이식후에만성이식편대숙주반응과동반된종격동기종 1예 고신대학교의과대학복음병원내과 이호섭 신성훈 김양수 A case of pneumomediastinum combined with chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation Ho Sup Lee, M.D., Seong Hoon Shin, M.D., and Yang Soo Kim, M.D. Department of Internal Medicine, Kosin University College of Medicine, Gospel Hospital, Busan, Korea Pulmonary complications are very common after allogeneic stem cell transplantation and are sometimes serious. Late-onset noninfectious pulmonary complications of chronic graft-versus-host disease (GVHD) after allogeneic stem cell transplantation include bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia. Especially, bronchiolitis obliterans is correlated with GVHD. If they occur simultaneously, serious pulmonary and subcutaneous complications such as pneumomediastinum, subcutaneous emphysema, and pneumothorax can occur. We present the case of a 19-year-old man who had pneumomediastinum, subcutaneous emphysema, and pneumothorax with GVHD after allogeneic stem cell transplantation. (Korean J Med 77: , 2009) Key Words: Pneumomediastinum; Allogeneic stem cell transplantation; Graft-versus-host disease; Bronchiolitis obliterans 서론조혈모세포이식이후에발생하는호흡기계부작용은많은빈도에서관찰되며, 사망에이르게할정도로치명적인경우도있다 1-3). 그러나그중에서비감염성호흡기계부작용 (Late-onset noninfectious pulmonary complications, LONIPC) 으로폐색성모세기관지염 (bronchiolitis obliterans, BO) 과기질화폐렴을동반한폐색성모세기관지염 (Bronchiolitis Obliterans Organizing Pneumonia, BOOP) 이대표적이라할수있는데, 이는만성이식편대숙주반응 (graft versus host disease, GVHD) 과관련이있는경우가많고, 특히이런경우에서종격동기종과피하기종등이발병하기도한다 3-5). 그외에도 GVHD 자체가종격동기종이나피하기종의원인이될수있으며, 약물도원인이될수있다. 하지만아직까지정확한원인이나기전이밝혀진것은없다 5). 저자들은조혈모세포이식이후에만성이식편대숙주병과동반되어나타난종격동기종과피하기종의드문 1예를경험하였기에문헌고찰과함께보고하는바이다. Received: Accepted: Correspondence to Yang Soo Kim, M.D., Department of Internal Medicine, Kosin University College of Medicine, 34 Amnam-dong, Suh-gu, Busan , Korea yas@ns.kosinmed.or.kr

- The Korean Journal of Medicine: Vol. 77, No. 6, 2009 - Table 1. Results of pulmonary function tests Measurement Before the onset of dyspnea After the onset of dyspnea FVC (L) 4.05 (69%) 1.

2 - The Korean Journal of Medicine: Vol. 77, No. 6, Table 1. Results of pulmonary function tests Measurement Before the onset of dyspnea After the onset of dyspnea FVC (L) 4.05 (69%) 1.70 (29%) FEV 1 (L) 3.54 (72%) 1.50 (30%) FEV 1/FVC (%) FEV 25~75% (L/sec) 3.97 (76%) 1.72 (33%) 증 례 환자 : 나, 19세, 남자주소 : 동종조혈모세포이식후 9개월째서서히진행된호흡곤란현병력 : 환자는반복되는오심과구토증세로병원방문후혈액검사상에서이상소견발견되어골수검사시행후급성림프구성백혈병으로진단되었고, 이후 VPDL (vincristine, prednisolone, daunorubicin, L-asparginase) 로관해유도항암요법을시행하였다. 이후두차례의공고항암요법시행이후에환자의형제로부터조직적합성항원이일치하는말초혈액조혈모세포를수집하여환자에게주입함으로써동종조혈모세포이식을시행하였다. 당시조혈모세포이식의전처치로 BuCy (busulfan, cyclophosphamide) 를사용하였고, 이후저자들은환자에게완벽한생착이이루어진것을확인하였다. 조혈모세포이식후 9개월째에환자는간기능검사수치가상승하고, 피부발진이양측다리와몸통에나타나기시작하여만성이식편대숙주반응으로진단하고복용중이던 cyclosporine을 tacrolimus 로전환하고, 스테로이드를추가하였다. 그럼에도불구하고, 서서히진행된호흡곤란을호소하였고, 당시입술과구강점막, 몸통, 양측팔과다리에피부발진이있었고, 호흡곤란이심한상태였으며, 체온은정상이었다. 과거력 : 선천성청각장애가있었으며, 사시가있어수술한병력이있었다. 가족력 : 특이소견없었다. 진찰소견 : 혈압은 120/80 mmhg, 맥박 92회 / 분, 호흡수 35회 / 분, 체온 36.8 였다. 의식은명료하였고, 입술과구강점막, 몸통, 양측팔과다리에피부발진이있었다. 청진상양측폐의호흡음이감소되어있었고, 좌측쇄골상부에피하기종이촉지되었다. 환자의피부발진은동종조혈모세포이식후 7개월째부터 Figure 1. Plain chest radiograph showing subcutaneous emphysema in the left supraclavicular area, lung parenchymal infiltration in both lower lung fields, and air density in both upper lung fields. 나타나기시작하였고, 흉부, 등그리고안면부에분포하여체표면적의약 25~50% 정도를차지하였고, 구강점막에태선모양병변이관찰되었다 ( 사진미제공 ). 설사는관찰되지않았다. 검사소견 : 내원시환자의간기능검사상총빌리루빈이 2.5 mg/dl로확인되었고, 폐기능검사상심한폐쇄성기류장애를보였고, 폐기능검사결과는표 1에나타내었다. 방사선소견 : 흉부방사선상좌측쇄골상부에피하기종이관찰되고, 양측폐하부에폐실질침윤소견과양측폐상부에공기음영이관찰되었다 ( 그림 1). 흉부컴퓨터단층촬영상양측폐하에미만성의폐포음영이감소된양상이관찰되고, 세기관지확장이관찰되었다. 좌측쇄골상부에피하기종과, 심한종격동기종이관찰되었다 ( 그림 2). 환자는내원시시행한폐기능검사와흉부컴퓨터단층촬영결과상폐색성모세기관지염이의심되었으나, 환자의폐기능검사상심한폐쇄성기류장애가있었던것과폐생검시종격동기종및기흉의악화가능성이예상되어폐생검은시행하지못하였다. 치료및경과 : 현재까지보고된바에따르면증례와같은질환에대한표준화된치료방법은아직알려진바가없으나, 면역억제치료가가장최선의치료방법으로알려져있

- Ho Sup Lee, et al. Pneumomediastinum combined with chronic graft-versus-host disease - A B C D Figure 2.

pneumothorax. 다. 그래서저자들은환자에게기존에복용중이던 tacrolimus를계속유지하면서고용량스테로이드를정맥주사하였다. 그리고침상안정시키고, 산소를공급하며치료하였다.

고찰조혈모세포이식이후에발생하는감염성또는비감염성호흡기계부작용은 40~60% 에서발생하고이식관련사망의 10~40% 를차지한다. 특히조혈모세포이식후 3개월에발생하는비감염성호흡기계부작용은이식관련사망의중요한 원인이된다 1,2). 특히폐색성모세기관지염은비감염성호흡기계부작용중의하나로서 GVHD와관련되어나타나는경우치명적이어서사망률이 50~55% 에이른다 3).

3 - Ho Sup Lee, et al. Pneumomediastinum combined with chronic graft-versus-host disease - A B C D Figure 2. Computed tomography (CT) images showing decreased attenuation in both lower lungs and bronchial dilatation, subcutaneous emphysema in the supraclavicular area, and extensive pneumomediastinum and pneumothorax. 다. 그래서저자들은환자에게기존에복용중이던 tacrolimus를계속유지하면서고용량스테로이드를정맥주사하였다. 그리고침상안정시키고, 산소를공급하며치료하였다. 환자는치료경과 45일만에촬영한흉부컴퓨터단층촬영상, 진단당시시행했던사진과비교하였을때, 좌측쇄골상부에서관찰되던피하기종이감소한소견외에종격동기종과미만성폐포음영의감소소견은관찰되지않았다 ( 그림 3). 면역억제치료이후환자의호흡곤란의증상은경미하게호전되는양상을보였으나, 치료 52일째부터갑자기기침과각혈이발생하였고, 폐기종발생 53일만에사망하였다. 고찰조혈모세포이식이후에발생하는감염성또는비감염성호흡기계부작용은 40~60% 에서발생하고이식관련사망의 10~40% 를차지한다. 특히조혈모세포이식후 3개월에발생하는비감염성호흡기계부작용은이식관련사망의중요한 원인이된다 1,2). 특히폐색성모세기관지염은비감염성호흡기계부작용중의하나로서 GVHD와관련되어나타나는경우치명적이어서사망률이 50~55% 에이른다 3). 한편, 조혈모세포이식이후에발생하는비감염성호흡기계부작용은 GVHD와밀접한관련이있으며, GVHD는호흡기계부작용의중요한위험인자가된다는것이밝혀져있다 1,4). 그리고 GVHD와관련하여비감염성호흡기계부작용을일으키는원인들로는폐색성모세기관지염, 기질화폐렴을동반한폐색성모세기관지염, 미만성폐포손상 (diffuse alveolar damage, DAD), 림프구성간질성폐렴 (lymphocytic interstitial pneumonia, LIP) 그리고달리분류되지않은간질성폐렴 (nonclassifiable interstitial pneumonia, NCIP) 이있다고알려져있고, 이들은조혈모세포이식후발생하는자발적인종격동기종, 피하기종, 폐실질기종그리고기흉의가장흔한원인이된다고알려져있다. 한편이차성종격동기종, 기흉의원인으로는진균감염, 기관지-흉막누공그리고기관지또는식도의천공이원인이된다고알려져있다 3,4)

- 대한내과학회지 : 제 77 권제 6 호통권제 592 호 2009 - A B C Figure 3.

lung attenuation and bronchial dilatation in both lower lungs, pneumomediastinum, and pneumothorax are similar to the previous scan.

종격동기종의발생기전은아직까지명확하게밝혀진것은없지만, 폐색성모세기관지염과기질화폐렴을동반한폐색성모세기관지염, 림프구성간질성폐렴등의비감염성호흡기계부작용과바이러스, 세균등에의한감염성원인에의해폐포가파열되고,

보통골수이식후 8~12개월이후에발생하고, 진단은폐생검을통해서조직학적확진을할수있으나폐기능검사에서 폐용적이감소하여심한폐쇄성기류장애를보이면서방사선학적검사상세기관지의확장소견이보이면진단에도움이된다 5).

4 - 대한내과학회지 : 제 77 권제 6 호통권제 592 호 A B C Figure 3. Computed tomography (CT) images showing decreased subcutaneous emphysema in the supraclavicular area compared with the previous scan, whereas the decreased lung attenuation and bronchial dilatation in both lower lungs, pneumomediastinum, and pneumothorax are similar to the previous scan. D GVHD와관련된비감염성호흡기계부작용의원인으로는조혈모세포이식이후에발생하는 GVHD와 GVHD를예방하기위해사용하는 methotrexate와 prednisone-cyclosporine 의병합요법이주된원인이될수있다. 조혈모세포이식전처치로사용되는 Busulfan 도원인이될수있다 4-6). 종격동기종의발생기전은아직까지명확하게밝혀진것은없지만, 폐색성모세기관지염과기질화폐렴을동반한폐색성모세기관지염, 림프구성간질성폐렴등의비감염성호흡기계부작용과바이러스, 세균등에의한감염성원인에의해폐포가파열되고, 그로인해발생한가스가기관지혈관의외피막을따라종격동안으로운반되어종격동기종이발생한다는이론으로이런기전을 Macklin 효과라고한다 3). 폐색성모세기관지염은비감염성호흡기계부작용의하나로동종조혈모세포이식이후에만성 GVHD와동반되어나타나는경우가많고, 자가조혈모세포이식에서는드물다. 보통골수이식후 8~12개월이후에발생하고, 진단은폐생검을통해서조직학적확진을할수있으나폐기능검사에서 폐용적이감소하여심한폐쇄성기류장애를보이면서방사선학적검사상세기관지의확장소견이보이면진단에도움이된다 5). 조혈모세포이식이후에발생한폐색성모세기관지염의치료로는 cyclosporine 또는 prednisone을사용하여면역억제를증가시키는것이도움이될수있고, thalidomide를사용하여폐기능을향상시켰다는보고도있었다 5). Hill 등에의하면조혈모세포이식후자발적으로발생한종격동기종환자 7명중 4명이생존하여사망률 43.5% 였다고보고한바있다 7). 그러나 Vogel 등에의한보고에서는여섯명중두명만이생존하여 Hill 등의보고에서보다낮은생존율을보였다. 그리고그들은조혈모세포이식의전처치의종류, 호흡기합병증의종류및중증도에따라다른생존율을보일수있다고보고했다 3). 마지막으로현재까지국내와국외에서보고된조혈모세포이식이후에발생한만성 GVHD와동반되어종격동기종과피하기종이발생한사례들을표 2에서비교하였다. 본증

5 - 이호섭외 2 인. 만성이식편대숙주반응과동반된종격동기종 - Table 2. Comparison of the clinical presentation of patients with late-onset noninfectious pulmonary complications (LONIPC) after allogeneic stem cell transplantation Case No * Age/sex Diagnosis GVHD Conditioning regimen Onset time after BMT FVC (L) or FEV 1 (L) predx postdx LONIPC Outcome 1 5) 43/M NHL yes BEAM 7 months PM, SE, PT, PC died 2 2) 13/F AML yes TBI, mel 7 months Not checked SE, PM, survived 3 8) 6/F ALL yes TBI, mel, cyt 7 months FEV 1/FVC PM, SE, PT, PC survived 4 9) 51/M NHL yes TBI, CyATG 2 months Not checked PM, SE, PT died 5 6) 42/M CML yes BuCy 3 months PM, SE survived 6 10) 27/F CML yes BuCy 5 months Severe obstruction PM, SE died 7 11) 28/M CML yes BuCy 4 months PM, SE, survived 8 18/M ALL yes BuCy 9 months PM, SE, PT, PC died GVHD, graft-versus-host disease; BMT, bone marrow transplantation; predx, before diagnosis; postdx, after diagnosis; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; NHL, non-hodgkin s lymphoma; BEAM, BCNU, etoposide, ara-c, and melphalan; PM, pneumomediastinum; SE, subcutaneous emphysema; PT, pneumothorax; PC, pneumopericardium; TBI, total body irradiation; mel, melphalan; cyt, cytarabine; CyATG, cyclophosphamide and antithymoglobulin; BuCy, busulfan and cyclophosphamide. * Reference number; 8, the case in this article. 례환자의경우와유사한임상양상을보였고, 병변의발생부위도유사하였다. 그러나저자들이경험한환자의경우면역억제치료및산소공급등의보존적치료이후에결국사망하였지만, 다른문헌들의보고에서는환자들이경험한질환의경중의차이가있겠지만, 생존한경우도있었다 2,3,5,6,8-11). 요약조혈모세포이식을시행한이후에호흡기계부작용은다수에서발생한다고보고되고있으며, 그중에서도만성 GVHD 와병발하는비감염성호흡기계부작용에는폐색성모세기관지염, 기질화폐렴을동반한폐색성모세기관지염등이있다. 그중에서폐색성모세기관지염은만성 GVHD와관련이깊고, 이들이동시에발생하는경우종격동기종과피하기종등의치명적인부작용들이나타날수있다. 저자들은조혈모세포이식이후에만성 GVHD와병발하여발생한비감염성호흡기계부작용중의하나인종격동기종과피하기종의드문 1예를경험하였기에보고하는바이다. 중심단어 : 종격동기종, 동종조혈모세포이식, 만성이식편대숙주반응, 폐색성모세기관지염 REFERENCES 1) Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ, Litzow MR. Late onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 100: , ) Kudoh T, Suzuki N, Oda T, Watanabe J, Haseyama K, Katoh S, Mizue N, Chiba S. Pneumomediastinum, subcutaneous emphysema, and pulmonary fibrosis in a patient with idiopathic pneumonia syndrome after bone marrow transplantation. Pediatr Hematol Oncol 17: , ) Vogel M, Brodoefel H, Bethge W, Faul C, Hartmann J, Schimmel H, Wehrmann M, Claussen CD, Horger M. Spontaneous thoracic air leakage syndrome in patients following allogeneic hematopoietic stem cell transplantation causes, CT follow up and patient outcome. Eur J Radiol 60: , ) Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y, Nishimura M. Late onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft versus host disease and with the graftversus leukemia effect. Blood 102: , ) Kumar S, Tefferi A. Spontaneous pneumomediastinum and subcutaneous emphysema complicating bronchiolitis obliterans after allogeneic bone marrow transplantation: case report and review of literature. Ann Hematol 80: ,

6 - The Korean Journal of Medicine: Vol. 77, No. 6, ) Galanis E, Litzow MR, Tefferi A, Scott JP. Spontaneous pneumomediastinum in a patient with bronchiolitis obliterans after bone marrow transplantation. Bone Marrow Transplant 20: , ) Hill G, Helenglass G, Powles R, Perren T, Selby P. Mediastinal emphysema in marrow transplant recipients. Bone Marrow Transplant 2: , ) Adjaoud D, Dauger S, Yakouben K, Aizenfisz S, Bensaid P, Lescoeur B, Baruchel A. Reversible severe air leak syndrome in a child with bronchiolitis obliterans after allogeneic stem cell transplantation. Eur J Pediatr 165: , ) Tanvetyanon T, Toor AA, Stiff PJ. Post transplant air leak syndrome. Br J Haematol 126:758, ) Lee NR, Lee TH, Song EK, Kwak JY, Yim CY. Recurrent pneumomediastinum and subcutaneous emphysema complicating chronic graft versus host disease after allogeneic bone marrow transplantation. Korean J Hematol 41:61-65, ) Lee BH, Lee JJ, Lee YK, Ahn JS, Kim YK, Hwang HI, Park MR, Cho SH, Chung IK, Kim HJ. Spontaneous pneumomediastinum and subcutaneous emphysema secondary to bronchiolitis obliterans in a patient undergoing allogeneic bone marrow transplantation. Korean J Hematopoietic Stem Cell Transplant 7: ,

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical