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1 Clinical Pediatric Hematology-Oncology Volume 22 ㆍ Number 2 ㆍ October 2015 ORIGINAL ARTICLE 소아청소년환자에서의동종조혈모세포이식후발생한폐쇄성세기관지염증후군의임상적특성 임주연ㆍ한승민ㆍ김효선ㆍ한정우ㆍ유철주 연세대학교의과대학소아과학교실 Bronchiolitis Obliterans Syndrome after Allogenic Hematopoietic Stem Cell Transplantation in Pediatric Patients Ju Yeon Lim, M.D., Seung Min Hahn, M.D., Hyo Sun Kim, M.D., Jung Woo Han, M.D. and Chuhl Joo Lyu, M.D., Ph.D. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea Background: Bronchiolitis obliterans syndrome (BOS) is a life-threatening lung complication after allogenic hematopoietic stem cell transplantation (HSCT). As long-term survival following allogenic HSCT has improved, the number of BOS patients has been steadily increased. However, the survival and treatment of BOS have not improved significantly for decades. Identification of risk factors of BOS would improve the clinical outcome of allogenic HSCT recipients. Methods: We retrospectively investigated medical records of 147 allogenic HSCT recipients between 2005 and 2014 in Yonsei Cancer Center. Risk factors for BOS were analyzed with Chi-square test, logistic regression analysis, and the Student s t-test. Results: BOS occurred to 23 patients (15.6%). Pulmonary function test (PFT) results before transplantation were similar in all patients, but patients with BOS had a significant decrease in forced expiratory volume in one second (FEV1) after transplantation compared with controls (68.4±26.4% vs. 91.6±21.0%, P<0.05). Acute graft-versus-host disease (GVHD) (OR 5.98, P=0.009) and peripheral blood as sources of stem cell (OR 4.00, P=0.031) increased risk for BOS, respectively. On the other hand, previously reported risk factors, such as age of donors and recipients, pulmonary infection within 100 days after allogenic HSCT and deference of immunosuppressant were not associated with increased the incidence of BOS in our study. Conclusion: We report here the result of a single-center study on the incidence, clinical factors, and outcome of BOS after allogenic HSCT. BOS is an important cause of post-transplantation morbidity and mortality. Risk reduction can be achieved by better prevention and control of BOS. Key Words: Bronchiolitis obliterans syndrome, Hematopoietic stem cell transplantation, Graft versus host disease pissn / eissn Clin Pediatr Hematol Oncol 2015;22: Received on September 15, 2015 Revised on September 30, 2015 Accepted on October 13, 2015 Corresponding Author: Chuhl Joo Lyu Department of Pediatrics, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: Fax: cj@yuhs.ac 127
2 Ju Yeon Lim, et al 서 론 동종조혈모세포이식 (hematopoietic stem cell transplantation, HSCT) 은악성혈액질환에서선택할수있는근치적치료방법으로, 최근 20년간다양한질환에서시행되고있으며그건수가해마다증가하고있다. 하지만보존적치료방법의발전에도불구하고, 이식과관련된합병증과사망률증가는여전히의료계에서주요관심사가되고있다 [1]. 특히호흡기계합병증은 HSCT 후사망과관련된주요한원인으로알려져있고, 40-60% 의환자에서발생하는것으로알려져있다 [2]. 다른호흡기계합병증에비해상대적으로흔하지않지만, 폐쇄성세기관지염증후군 (Bronchiolitis obliterans syndrome, BOS) 은 HSCT 후이환율을증가시키고, 생존율을감소시키는중요한호흡기계합병증이다 [3,4]. BOS는이식후발생하는감염이동반되지않은소기도의비가역적폐쇄성폐질환으로 1982 년에 Roca 등에 [5] 의해처음으로보고되었으며, 이후발생률이증가하여 2-26% HSCT 환자에서발생하는것으로다수의보고를통해알려져있다 [6-8]. 다양한치료방법에도불구하고 BOS의사망률은매우높아, 21% 에서 100% 에달하는것으로보고되었으며, 최근 20년간치료성공률이나, 생존율이크게증가하지않고있다 [3,4,9-12]. HSCT 후발생하는 BOS의병인은정확히밝혀진바가없으며, 조직검사를통해병리학적확진해야하는것으로알려져있었고, 진단기준이명확하지않았었다. 그러나, 최근진단기준을단일화하려는노력으로 2014년 NIH (National Institute of Health) 에서새로운기준을제시하여조직학적확인이없이도폐기능검사 (pulmonary function test, PFT) 혹은영상학적방법을통해확진가능한것으로변경되었다 (Table 1)[13]. BOS는호흡기계증상이없고, 흉부 X선촬영에서특이소견없는경우에도발병하는경우도있으며, 임상양상또한다양하여조기에진단하거나치료를시작하기어려움이있다 [10]. 따라서정기적인 PFT의중요성이대두되고있으며이식전후 PFT를기준으로하여 BOS의진단및발병과관련된임상적특성에대한연구가필요할것으로생각된다. 기존의연구에서급, 만성이식편대숙주반응 (graft-versus-host disease, GVHD) 의유무, 조혈모세포 (stem cell) 의종류, 이식전처치 (conditioning), 면역억제제의종류등의차이가 BOS의발생에영향을주는것으로보고되었으나 [3,4,14-16], 국내에서는몇몇사례보고외의전, 후향적연구는부족한실정이다. 따라서본연구는최근 10년간연세암병원에서동종 HSCT를받은환자들을대상으로 PFT, 폐전산화단층촬영 (computed tomography, CT) 을통한 BOS의진단및발병위험요인, 임상적인특징, 예후및사망률에관해비교분석해보고자하였다. 1) 대상환자 Table 1. Bronchiolitis obliterans syndrome diagnostic criteria FEV1<75% FEV1/FVC <0.7 Absence of infection Air trapping on CT RV>120% Confirmed by lung biopsy 대상및방법 연세암병원소아혈액종양과에서 2005년 1월부터 2014년 12월까지동종 HSCT를받았던환자들의의무기록을후향적으로분석하였고연세의료원의학연구윤리심의위원회의승인을받았다. 연구기간에 HSCT를받은환자는총 151명이었으며그중추적관찰이불가능하였던 4명을제외한 147명 ( 남성 90명, 여성 57명 ) 이분석대상이되었다. 이들을대상으로진단당시나이, 이식당시나이, 조혈모세포의종류, 이식전처치, T세포의수, 면역억제제의종류, 급성 GVHD의유무등에따른 BOS의발생과예후의차이를비교분석하였다. 2) 진단기준 BOS의진단은 2014 NIH criteria를기준으로했으며, 급성및만성 GVHD의진단또한같은기준에따라판단하였으며 (1) 1초내 forced expiratory volume (FEV1) 이예측치의 75% 이하이거나 2년내에 10% 이상의 FEV1 감소가있으면서 albuterol 사용후에도 75% 이상으로회복되지않을것. (2) FEV1/ FVC (functional vital capacity) 가 0.7 이하이거나 predicted FEV1<75% (+albuterol) FEV/VC<0.7 Or The 5 th percentile of predicted Absence of infection One supportive of BOS: Air trapping or small airway thickening or bronchiectasis on CT Or RV or RV/TLC>120% Diagnostic feature of chronic GVHD of the lungs in the presence if another distinctive manifestation of chronic GVHD FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; VC, vital capacity (forced vital capacity or slow vital capacity, whichever is greater); CT, computed tomography; BOS, bronchiolitis obliterans syndrome; RV, residual volume; TLC, total lung capacity; GVHD, Graft versus Host Disease. The 5 th percentile of predicted is equivalent to the lower value of predicted confidence interval. 128 Vol. 22, No. 2, October 2015
3 Clinical Factors of Bronchiolitis Obliterans Syndrome confidence interval의최저값이예측치의 5% 이하일것. (3) 감염의증거가없을것. (4) 다른만성 GVHD의임상증상이있을것, 네가지를모두만족하며추가적으로 CT (computed tomography) 에서 air trapping이보이거나 PFT에서 residual volume이 120% 이상일경우보조적진단기준이될수있다. 또한 biopsy를통해확진하는것이필수요소가아닌것으로바뀌었다 (Table 1)[13]. 급성 GVHD는이식후 100일이내에피부, 위장관, 간등의장기에발생한경우진단하였고, 만성 GVHD는 100일이후에피부, 위장관, 간, 눈, 호흡기, 생식기등에발생한거부반응으로진단하였다 [13]. 3) 검사 (1) 폐기능검사 2008년이후모든 HSCT 환자들은 (n=117) 이식전 3개월이내, 이식후 3개월이후부터매 3개월마다 PFT를추적하였으며, 2008년이전의환자들은 (n=30) 정기적검사를시행하지않아 BOS 진단과관련된통계에서는제외되었다. PFT는 spirometer를통해 FEV1 (Forced expiratory volume in one second), FVC (Forced vital capacity), RV (Residual volume), VC (Vital capacity) 등을구하고 BOS 진단에는 FEV1, FEV1/FVC 값을이용하였다. (2) 영상검사 PFT결과가 BOS 진단기준에부합하거나, PFT 결과가정상범주이더라도비가역적인폐쇄성폐질환의임상양상을보일때, 발열이동반되지않는호흡기계증상이지속될경우고해상도폐 CT를시행하였고, 검사상기관지확장증 (bronchiectasis) 또는공기포획 (air trapping) 의특징적소견이보일때진단의보조적근거로사용하였다 [17]. 4) 고용량스테로이드치료본원에서의고용량스테로이드치료는 Methylprednisolone를사용하여 30 mg/kg ( 최대 1,000 mg) 정맥투여하였고, 첫달에는 3일연속으로투여하고이후 6개월간매달 1회씩시행하며이후 PFT는매달, chest CT는 3개월마다시행하였다. 또한보조적으로흡입형스테로이드제제를매일투여하도록하였다. 5) 통계분석 BOS의위험요인정의를위해연속형변수에대해서는 Independent sample T-test, 범주형변수에대해서는 Chi square test, univariate binary logistic regression analysis를이용하여군간의차이를살펴보았다. 각항목은 T세포수를제외하고는모두범주형변수로처리하였으며, 나이는 10세기준, 조혈모세포원은 Bone marrow, peripheral blood, cord blood로구분하였고이식전처치는 TBI (Total body irradiation) 가포함된경우와그렇지않은경우로나누었다. 면역억제제는 cyclosporine 혹은 tacrolimus가포함된군으로각각나누었고, 면역억제제중단시기는 3개월이하, 3-6개월, 6개월이상으로구분하였으며, 이식후 100일까지호흡기계감염유, 무로나누어분석하였다. BOS의유무로발생군과대조군으로나누어생존율및중앙생존기간을비교분석하였고 BOS를진단받은환자들중각각의차이점에따른 ( 이식당시나이, 이식전처치, 고용량스테로이드치료유무 ) 생존율, 중앙생존기간의차이를 Kaplan-Meier method로구하고, 그차이를 log-rank test를이용해비교분석하였다. 통계학적분석에는 IBM SPSS statistics version 22.0 (SPSS Inc., Chicago, IL, USA) 를이용하였으며 P-value가 0.05 미만인경우를통계학적으로유의하다고판단하였다. 결과 1) 환자특성및 BOS의발생률본연구의대상환자는총 147명으로평균연령은 9.6±6.3 세이었고, 남자는 90명 (61.2%) 여자는 57명 (38.8%) 였다. 그중백혈병 (leukemia) 환자는 90명 (61.2%), 재생불량빈혈 (aplastic anemia) 20명 (13.6%), 림프종 (lymphoma) 11명 (7.5%), 기타질환이 26명 (17.7%) 였고이식된조혈모세포의종류로는말초혈액이 76명 (51.7%), 골수가 63명 (42.9%), 제대혈이 8명 (5.4%) 이었다. 초기에투여된면역억제제의종류는 cyclosporin이 62명으로전체의 42.2% 였으며 tacrolimus가 85명으로전체의 57.8% 에해당되었고이식전처치로전신방사선조사 (total body irradiation, TBI) 가포함된경우가 57명으로 38.8% 를차지하였다. BOS가진단된환자는총 23명으로전체의 15.6% 에해당되었으며평균연령은 9.9±5.5세였으며, 이식부터진단까지의평균기간은 9.8±6.5개월이었다. 진단명은급성림프구성백혈병이 13명 (56.5%), 급성골수성백혈병이 5명 (21.7%) 이었고이식된조혈모세포의종류는말초혈액이 19명 (82.6%) 였으며공여자는비혈연공여자가 20명으로전체의 87% 로확인되었다. 이식부터 BOS가발병하기까지의평균기간은 8.3±6.4개월이었다. 이식후 3개월째 PFT에서 Forced expiratory volume in 1 Clin Pediatr Hematol Oncol 129
4 Ju Yeon Lim, et al second (FEV1) 의평균값은 BOS 환자군이 68.4±26.4 liter, 대조군은 91.6±21 liter로통계적으로유의한차이를보였다 (P<0.01) (Table 2). 2) BOS의위험인자 BOS 환자군중 14명이 10세이상으로전체 10세이상환자의 22.6% 에해당되었고 (P=0.048), 이식된조혈모세포종류로는말초혈액이 19명으로전체말초혈액이식환자의 25% (P= 0.005) 에해당되어통계적으로유의미한차이를보였다. 그러나이식전처치중 TBI가포함된환자중 BOS가진단된환자는 13.3% (12/90), TBI가포함되지않은경우는 19.3% (11/57) 으로통계적으로유의한차이를보이지않았다 (P=0.332). 이식된 T세포의값은평균 19.4±13.2 ( 10 7 )/kg으로대조군 13.2±10.1 ( 10 7 )/kg과통계적으로유의한차이를보였다. (P=0.027). 면역억제제의경우 tacrolimus를투여한환자군중 BOS가발병한환자는 22.4% (19/85), cyclosporin을투여한 Table 2. Comparison of Pulmonary function test result between bronchiolitis oblierans syndrome and control group in pre and post hematopoietic stem cell transplantation BOS (+) BOS ( ) t P-value Pre FEV ± ± Pre FEV1/FVC 105.1± ± Post FEV1 68.4± ± <0.01 (D+ 3 month) Post FEV1/FVC 96.3± ± (D+ 3 month) Dx FEV1 49.8±18.6 Dx FEV1/FVC 89.1±21.6 Dx FEV1, forced expiratory volume in 1 second at diagnosis; FVC, forced vital capacity. Table 3. Risk factors of Bronchiolitis obliterans syndrome by Chi square test Clinical factors BOS (+) BOS ( ) Odd Ratio P-value Age at diagnosis (years) <10 9 (10.6%) 76 (89.4%) 1 >10 14 (22.6%) 48 (77.4%) HSCT age (years) <10 9 (11.8%) 67 (88.2%) 1 >10 14 (19.7%) 57 (80.3%) Gender Male 15 (16.7%) 75 (83.3%) Female 8 (14.0%) 49 (86.0%) 1 Stem cell source BM 4 (6.3%) 59 (93.7%) PB 19 (25.0%) 57 (75.0%) CB 0 (0.0%) 8 (100.0%) Conditioning regimen TBI 11 (19.3%) 46 (80.7%) Non-TBI 12 (13.3%) 78 (86.7%) GVHD prophylaxis Cyclosporin 4 (6.5%) 58 (93.5%) 1 GVHD prophylaxis Tacrolimus 19 (22.4%) 66 (77.6%) agvhd (+) 21 (21.0%) 79 (79.0%) agvhd Pulmonary infection (After HSCT<D+100) Pulmonary infection (After HSCT<D+100) ( ) 2 (4.3%) 45 (95.7%) 1 ( ) 18 (16.6%) 90 (83.4%) 1 (+) 5 (12.8%) 34 (87.2%) Fungal 1 (11.1%) 8 (88.9%) Viral 0 (0.0%) 16 (100.0%) Bacterial 4 (28.6%) 10 (71.4%) BOS, bronchiolitis obliterans syndrome; BM, bone marrow; PB, peripheral blood; CB, cord blood; TBI, total body irradiation; agvhd, acute Graft-versus-Host disease; HSCT, hematopoietic stem cell transplantation. 130 Vol. 22, No. 2, October 2015
5 Clinical Factors of Bronchiolitis Obliterans Syndrome 환자군에서는 6.5% (4/62) 으로통계적으로유의한차이를보였고 (P=0.01), 급성 GVHD가발생했던환자중 BOS에진단된환자는전체급성 GVHD 환자중에 21% (21/100) (P=0.01) 로급성 GVHD가동반되지않았던환자에비해통계적으로유의하게 BOS가진단된확률이높았다 (P=0.01) (Table 3). Univariate logistic regression test 에서이식된 T세포의수가많을수록 OR 1.05 (P=0.035), 조혈모세포의종류는말초혈액일경우 OR 4.92 (P=0.006), 면역억제제로 Tacrolimus를사용했을경우 OR (P=0.014) 로통계적으로유의하게 BOS에걸릴확률이높았다. 또한급성 GVHD가있었던환자들이없던환자들에비해 BOS에진단될확률이 5.98배높은것으로확인되었다 (P=0.019) (Table 4). 그러나결과중 P-value 0.25 이하의항목들의 multivariate logistic regression test에서는급성 GVHD가있었던환자들만이유의미하게 BOS에진단될확률이높은것을확인하였다 (P=0.034) (Table 5). Table 4. Risk factors of Bronchiolitis obliterans syndrome by univariate logistic regression analysis Odd ratio CI (95%) P-value Age (Diagnosis) <10 1 > T-cell (N=101) Source BM 1 PB CB HLA type (N=63) Full match 1 Mismatch A DR Type of GVHD prophylaxis Cyclosporin 1 Tacrolimus Immunosuppressant Tapering off duration <3 mo mo >6 mo Acute GVHD ( ) 1 (+) Pulmonary infection ( ) 1 (After HSCT<D+100) (+) BM, bone marrow; PB, peripheral blood; CB, cord blood; Age Dx, age at diagnosis; GVHD, Graft-versus-Host disease. Table 5. Risk factors of Bronchiolitis obliterans syndrome by multivariate logistic regression analysis Odd ratio CI (95%) P-value Age (Diagnosis) <10 > T-cell (N=101) Source BM PB CB Type of GVHD prophylaxis Cyclosporin Tacrolimus Immunosuppressant Tapering off duration Acute GVHD <3 mo 3-6 mo >6 mo ( ) (+) Clin Pediatr Hematol Oncol 131
6 Ju Yeon Lim, et al 3) 폐기능검사 BOS 진단당시 FEV1의평균값은 49.8±18.6, FEV1/FVC (forced vital capacity) 의평균값은 89.2±21.6이었고, 가장폐기능이저하되었을때 FEV1의평균값은 44.9±27.16, FEV1/ FVC의평균값은 78.1±27.7이었다 (Table 2). 4) 예후및생존율 (1) 예후 BOS 환자군의평균생존율은 31.9%, 대조군의평균생존 율은 53.1% 로통계적으로유의한차이를보이지는않았다 (P=0.63) (Fig. 1). (2) BOS 환자군에서예후에영향을주는인자전체 BOS 환자중 10세미만인환자의평균생존율은 61.0%, 10세이상은 21.0% 였으나통계적으로유의한차이를보이지는않았지만 (corrected P=0.07), TBI가포함된이식전처치를받은환자의평균생존율은 23.9% 로그렇지않은경우 38.6% 에비해낮았으며통계적으로유의미한차이를보였다 (Corrected P=0.04). 치료목적으로고용량스테로이드요법 Fig. 1. Survival rate after HSCT (Hematopoietic stem cell transplantation). BOS, Bronchiolitis obliterans syndrome. Fig. 3. Comparison of survival rate according to the conditioning regimen between including total body irradiation and control group in bronchiolitis obliterans syndrome. TBI, Total body irradiation. Fig. 2. Comparison of survival rate according to the age at hematopoietic stem cell transplantation between <10 years and >10 years age subgroups in bronchiolitis obliterans syndrome. BOS, Bronchiolitis obliterans syndrome; HSCT, Hematopoietic Stem Cell Transplantation. Fig. 4. Comparison of survival rate according to treatment between including steroids pulse treatment and control group in bronchiolitis obliterans syndrome. Steroid pulse tx, steroid pulse treatment. 132 Vol. 22, No. 2, October 2015
7 Clinical Factors of Bronchiolitis Obliterans Syndrome 을시행받은환자의평균생존율은 37.5% 로대조군 48.27% 에비해오히려낮은생존율을보였지만통계적으로의미있는차이를보이지는않았다 (corrected P=0.15) (Fig. 2-4). 5) 사망원인전체 147명의환자중 66명 (44.9%) 이생존하였고사망원인으로는감염이 64% (42/147), 기저질병의악화가 16.6% (11/147), BOS의악화가 9% (6/147) 순이었다. 총 BOS 환자 23명중 11명 (47.8%) 이사망하였고, 사망원인으로는 BOS의악화가 6명 (54.5%), 감염이 3명 (27.3%), 기저질병의악화가 2명 (18.2%) 으로확인되었다. 고찰 GVHD는동종 HSCT 후흔하게발생하는합병증이다 [18]. 그중폐와관련된합병증인 BOS의경우상대적으로이환율과사망률이높아원인, 위험요인과치료에대한관심이높은실정이다. 말초조혈모세포이식이확대되면서생착까지의기간이짧아지고이는초기감염합병증을감소시켰지만상대적으로 BOS와같은비감염성호흡기계합병증이증가하고있는것으로보여진다. BOS의발병기전에대해아직정립된사항은없지만, 급성및만성 GVHD에서면역관련세포및다양한 cytokine들의역할에대해서논란이되고있으며, 공여자의 T세포가폐실질손상에영향을줄가능성이있다는의견이다수있다. 그러나, T세포를 immunomodulation 했을경우에도 GVHD는발생하므로 B세포와도연관되어있을가능성도대두되고있어이러한 alloimmunity와의관련성에대한정립이필요한상태이다 [20,21]. 기존의연구에서는만성 GVHD 과거력, 고연령공여자와수혜자, 낮은이식전 FEV1/FVC, 남성, HLA 불일치, Methotrexate를포함한면역억제제사용, TBI, Busulfan이포함된이식전처치, 이식후 100일이내에호흡기계합병증의과거력이있을경우등이 BOS의위험요인으로작용한다고보고되었다 [8,9,22,23]. 본연구에서는 2008년이후로 BOS가진단된환자들을대상으로하여추적기간이짧아서 5년생존율대신 3년생존율을측정했으며그값은 53.7% 였고, 중앙생존기간은 41.1개월이었다. BOS의위험인자로는 univariate analysis 시에는진단시나이, 급성 GVHD의과거력, 이식시주입된 T세포의수, 면역억제제의종류, 조혈모세포의종류등이통계적으로유의미하였지만 multivariate analysis 시에는급성 GVHD의 유무만이통계적으로의미있는차이를보였다. HLA 불일치정도, TBI 유무등의차이는통계적으로유의미하게 BOS의발생률을증가시키지는않았다. 기존의연구결과에서만성 GVHD가 BOS의발생과통계적으로의미있는연관관계가있다고보고되었으나 [4], 본연구에서는만성 GVHD에 BOS가포함되어기록되어있어통계에서제외하였다. 의료의발전에도 BOS의발병률과그로인한사망률이감소하지않고있어 BOS의발병원인과위험요인에대한중요성이날로커지고있는가운데, 본연구에서는소아 HSCT 환자들의임상적특징과위험요인에대한단일기관에서의지속적인연구로 BOS의예방과치료에대한밑바탕이될가능성을제시하고있다. 이번연구를통해 BOS는다양한면역과관련된기전, 이식전처치, 면역억제제나스테로이드등과같은치료로인한독성등다양한원인이복합적으로영향을주는것을생각해볼수있고, 이를기반으로앞으로전, 후향적연구가지속된다면예방및치료에대한보다효과적이고구체적인결과를얻을수있을것이다. BOS는진단되기전까지증상이없거나흉부방사선촬영에서정상소견을보일수있어본연구에서처럼이식후에정기적인 PFT를시행하는것이조기진단및치료성공률상승에도움이될수있을것으로생각된다. Williams 등의사례보고에서와같이이식후증상이없어경과관찰하던중 1년만에시행한 PFT에서폐기능이이식전보다 50% 감소한사례를여러보고에서확인할수있다 [24]. Chien 등의연구에서이식후 1년동안정기적인 PFT를통해추적관찰을하는것에대한중요성이언급되는데, 이는이식후첫 1년동안 FEV1이급격히저하될경우사망률이상승하기때문이다 [25]. 따라서정기적인 PFT 및추적관찰이매우중요하며, 앞선연구에서흡입형스테로이드나 macrolides 계열의항생제가 BOS의예방및치료에도움이된다는보고가있어 [26] 조기치료를시작했을때예후의변화에대한추가적인연구가필요하겠다. 그러나본연구는후향적인자료수집으로인해 GVHD의정도, 이식된조혈모세포의수, HLA 일치정도, 공여자에대한정보가부족했던한계점이있었다. 또한 2008년부터이식전, 그리고이식후 3, 6, 9, 12개월에정기적으로 PFT를시행하였기에 2008년이전환자들의데이터는비교가불가능하였으며, 따라서최근에 BOS의진단율이높아져생존기간이 1년미만인경우가많아생존율을확인하는데오차가발생했을가능성이있어향후지속적인연구가필요하겠다. 요약하면, 본연구에서는소아환자들에서동종 HSCT 후 BOS의발생위험요인과예후에대해보고하였고, multivariate analysis를바탕으로하였을때통계적으로유의한결과 Clin Pediatr Hematol Oncol 133
8 Ju Yeon Lim, et al 는급성 GVHD 과거력이있었던경우한가지였다. 그러나, 진단시나이, 이식시주입된 T세포의수, 면역억제제의종류, 말초조혈모세포이식등도 univariate analysis 시의미있는결과를보여결국은다양한이식전후의요인과관련이될가능성이높을것으로예측되어, 관련된지속적이며대규모의연구가필요할것이다. References 1. Patriarca F, Skert C, Sperotto A, et al. Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation. Bone Marrow Transplant 2004;33: Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow transplantation. Chest 1996;109: Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003;9: Santo Tomas LH, Loberiza FR Jr, Klein JP, et al. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stemcell transplantation for leukemia. Chest 2005;128: Roca J, Grañeña A, Rodriguez-Roisin R, Alvarez P, Agusti- Vidal A, Rozman C. Fatal airway disease in an adult with chronic graft-versus-host disease. Thorax 1982;37: 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: Au BK, Au MA, Chien JW. Bronchiolitis obliterans syndrome epidemiology after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011;17: Gazourian L, Rogers AJ, Ibanga R, et al. Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Am J Hematol 2014;89: Paz HL, Crilley P, Topolsky DL, Coll WX, Patchefsky A, Brodsky I. Bronchiolitis obliterans after bone marrow transplantation: the effect of preconditioning. Respiration 1993;60: Alonso Riofrío R, Villa Asensi JR, Sequeiros González A, Díaz Pérez MA, González Vicent M, Madero López L. Obstructive lung disease after allogenic stem cell transplantation in children. An Pediatr (Barc) 2004;61: Philit F, Wiesendanger T, Archimbaud E, Mornex JF, Brune J, Cordier JF. Post-transplant obstructive lung disease ("bronchiolitis obliterans"): a clinical comparative study of bone marrow and lung transplant patients. Eur Respir J 1995;8: Kim SH, Kook H, Kim SY, et al. Fatal bronchiolitis obliterans with very severe subcutaneous emphysema and pneumomediastinum after unrelated BMT. Korean J Pediatr Hematol Oncol 2003;10: Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21: e Duncker C, Dohr D, Harsdorf S, et al. Non-infectious lung complications are closely associated with chronic graft-versus-host disease: a single center study of incidence, risk factors and outcome. Bone Marrow Transplant 2000;25: Sakaida E, Nakaseko C, Harima A, et al. Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graftversus-host disease and with the graft-versus-leukemia effect. Blood 2003;102: Miflin G, Russell NH, Hutchinson RM, et al. Allogeneic peripheral blood stem cell transplantation for haematological malignancies-an analysis of kinetics of engraftment and GVHD risk. Bone Marrow Transplant 1997;19: Gunn ML, Godwin JD, Kanne JP, Flowers ME, Chien JW. High-resolution CT findings of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. J Thorac Imaging 2008;23: Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versushost disease and other late complications of bone marrow transplantation. Semin Hematol 1991;28: Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;28: Sengsayadeth SM, Srivastava S, Jagasia M, Savani BN. Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012;18: Forslöw U, Mattsson J, Gustafsson T, Remberger M. Donor lymphocyte infusion may reduce the incidence of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2011;17: Clark JG, Schwartz DA, Flournoy N, Sullivan KM, Crawford SW, Thomas ED. Risk factors for airflow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987;107: Crawford SW, Clark JG. Bronchiolitis associated with bone marrow transplantation. Clin Chest Med 1993;14: Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA 2009;302: Vol. 22, No. 2, October 2015
9 Clinical Factors of Bronchiolitis Obliterans Syndrome 25. Chien JW, Martin PJ, Flowers ME, Nichols WG, Clark JG. Implications of early airflow decline after myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2004;33: Khalid M, Al Saghir A, Saleemi S, et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J 2005;25: Clin Pediatr Hematol Oncol 135
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