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1 대한내과학회지 : 제 87 권제 4 호 Azacitidine 치료후폐손상이발생한골수형성이상증후군 1 예 울산대학교의과대학내과학교실 김호철ㆍ김상형ㆍ안지환ㆍ권혜미ㆍ최종한ㆍ김태형ㆍ이제환 Azacitidine-Induced Lung Injury in a Patient with Myelodysplastic Syndrome Ho Cheol Kim, Sang Hyung Kim, Jee Hwan Ahn, Hye Mi Kwon, Jong Han Choi, Tae Hyung Kim, and Je-Hwan Lee Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea In randomized phase 3 clinical trials azacitidine has been shown to prolong survival in patients with higher-risk myelodysplastic syndrome (MDS). Therefore, azacitidine therapy should be considered for treating MDS patients with higher-risk disease. A 78- year-old male was administered the first cycle of azacitidine treatment for higher-risk MDS. On day three of chemotherapy he complained of fever and dyspnea, and radiographic findings revealed bilateral perihilar-peribronchial infiltration and a small amount of pleural effusion. Considering the possibility of pneumonia, intravenous broad-spectrum antibiotics were administered and azacitidine therapy was discontinued. Upon improvement of the patient s subjective symptoms and radiographic abnormalities, azacitidine therapy was resumed. However, fever and dyspnea developed again upon recommencement of azacitidine therapy. A diagnosis was made of azacitidine-induced lung injury and corticosteroid treatment was administered. Although lung injury is a rare complication induced by azacitidine, physicians should be aware of this life-threatening side effect. (Korean J Med 2014;87: ) Keywords: Myelodysplastic Syndrome; Azacitidine; Lung injury 서론골수형성이상증후군 (Myelodysplastic syndrome, MDS) 은골수내조혈세포의형성이상으로인하여말초혈액에서의혈구감소및형태학적이상을초래하는악성혈액질환이며급성골수성백혈병으로이행될수있다 [1]. Azacitidine은 cytidine의피리미딘뉴클레오시드유사체로 핵안에서인산화가되어활성화가된다. 이약제는세포에서 DNA 메틸화에관여하는 DNA methytransferase (DMT) 에결합하여작용을억제함으로써 DNA 저메틸화를일으키거나골수에작용해세포독성을일으켜골수형성이상증후군의치료제로작용한다. 일련의 3상임상시험들에서 azacitidine 치료를통하여고위험군의 MDS 환자들의생존기간을유의하게향상시킬수있음이입증되었고, 이러한결과로미국식 Received: Revised: Accepted: Correspondence to Je-Hwan Lee, M.D., Ph.D. Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-Gu, Seoul , Korea Tel: , Fax: , jhlee3@amc.seoul.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

- Ho Cheol Kim, et al. Azacitidine Lung Injury - 품의약품안정청의승인을받았으며, 고위험군의 MDS 환자들에서는 azacitidine 치료가우선적으로고려되어야한다 [2]. 표준요법은 75 mg/m 2 를 7일간피하주사하고, 4주마다반복하는것인데대부분의부작용은골수억제에따른혈액학적독성이다.

2 - Ho Cheol Kim, et al. Azacitidine Lung Injury - 품의약품안정청의승인을받았으며, 고위험군의 MDS 환자들에서는 azacitidine 치료가우선적으로고려되어야한다 [2]. 표준요법은 75 mg/m 2 를 7일간피하주사하고, 4주마다반복하는것인데대부분의부작용은골수억제에따른혈액학적독성이다. Azacitidine에의한폐손상은현재까지 6예에서만보고될정도로매우드물며특히국내에서는보고되지않았다 [3-8]. 저자들은골수형성이상증후군으로진단받고 azacitidine으로치료를하던중폐손상을보였던 78세남자환자를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 78세남자주소 : 1일전부터시작된발열현병력 : 3개월전부터운동시호흡곤란을주소로내원하였고말초혈액검사상범혈구감소증을보여골수검사를시행하였고골수형성이상증후군 ( 아형 : refractory anemia with excess blast-2, RAEB-2) 으로진단되었다. 외래에서 azacitidine 요법 ( 하루 75 mg/m 2 를피하로 7일연속투여 ) 을시작하였는데, 치료 2일째부터발열및운동시호흡곤란증세가발생하여응급실로내원하였다. 과거력 : 골수형성이상증후군이외의병력은없었고, 먼지나다른약물등알레르겐에대한노출력은없었다. 흡연및음주는하지않았다. 진찰소견 : 내원당시혈압 78/48 mmhg, 맥박 118회 / 분, 호흡수 18회 / 분, 체온 39.3 였다. 외관상급성병색을보였 으나의식은명료하였다. 두경부의이상소견은관찰되지않았고, 흉부청진상양측폐야에폐음감소및수포음이청진되었다. 복부진찰에서는특이소견은없었다. 검사실소견 : 말초혈액검사상백혈구 2,800/mm 3 ( 호중구 48.6%, 림프구 25.0%, 단핵구 24.3%, 호산구 1.0%), 혈색소 7.4 g/dl, 혈소판 12,000/mm 3 였다. 혈액응고검사상 PT 13.8 sec ( 정상치 sec), INR 1.21, aptt 31.0 sec ( 정상치 sec) 이었으며일반생화학검사에서 aspartate aminotransferase 32 IU/L, alanine transaminase 42 IU/L, alkaline phosphatase 87 IU/L, lactate dehydrogenase 414 IU/L였다. C 반응단백은 7.94 mg/dl로상승되어있었다. 소변검사상혈뇨및단백뇨는관찰되지않았다. 내원 2주전에시행한골수검사에서세포충실도가 15% 이고골수아세포 (myeloblast) 가 11.0% 였으며 MDS RAEB-2 로진단되었다. MDS 진단당시백혈구 1,000/mm 3 ( 호중구 43.0%, 림프구 49.0%, 단핵구 4.0%, 호산구 1.0%, 골수아세포는측정되지않았다.), 혈색소 9.3 g/dl, 혈소판 54,000/mm 3 였다. 방사선소견 : 흉부단순방사선촬영및흉부전산화단층촬영에서양측소량의흉수및양측폐문부를따라기관지주위폐침윤이관찰되었다 (Fig. 1). 치료및임상경과 : 고열및호흡곤란이외에기침, 가래등의증상이없었으나면역저하환자임을고려하여폐렴으로진단하에 azacitidine의중단및광범위항생제 (ceftriaxone 및 moxifloxacin) 의투여를시작하였다. 항생제투여후 2일이지났으나여전히 38.0 의발열과호흡곤란증상이지속되었다. 혈액배양검사는음성이었고, 객담배양검사에서 Candida albicans가동정되어 fluconazole을추가투여하였다. Figure 1. Initial chest X-ray and chest computed tomography (CT) reveal both pleural effusion and bilateral infiltration

- 대한내과학회지 : 제 87 권제 4 호통권제 650 호 2014 - A B Figure 2. Chest X-ray shows peribronchial infiltration of the right lower lung field and pleural effusion (A), and improved state (B).

Azacitidine에의한폐손상으로진단하고즉시 azacitidine의투여를중단하였고스테로이드 ( 메틸프레드니솔론하루 20 mg) 를투여하였다. 스테로이드투여 2일째부터환자의임상증상및흉부단순방사선촬영은빠르게호전되었다 (Fig. 2B).

3 - 대한내과학회지 : 제 87 권제 4 호통권제 650 호 A B Figure 2. Chest X-ray shows peribronchial infiltration of the right lower lung field and pleural effusion (A), and improved state (B). 입원후 1주일에호흡곤란증상및흉부방사선소견이호전되는양상을보여, 입원 10일째 azacitidine 치료를재개하였다. Azacitidine 을다시투여한지 3일후에 38.4 C의발열과호흡곤란증상이다시발생하였고, 흉부단순방사선촬영상오른쪽폐야의폐침윤악화및양측흉수가새롭게발생하였다 (Fig. 2A). 혈액배양및객담배양검사에서동정되는균은없었다. Azacitidine에의한폐손상으로진단하고즉시 azacitidine의투여를중단하였고스테로이드 ( 메틸프레드니솔론하루 20 mg) 를투여하였다. 스테로이드투여 2일째부터환자의임상증상및흉부단순방사선촬영은빠르게호전되었다 (Fig. 2B). 고찰 Azacitidine 과관련된부작용은골수억제 ( 백혈구감소증, 빈혈, 혈소판감소증 ) 및위장관계부작용 ( 구역감, 구토, 설사, 변비등 ) 이흔하며, 간독성및신독성에대한보고도있다 [2]. Azacitidine과관련된폐손상은매우드물게보고되고있으며 (Table 1), 특히국내에서의보고는없다. 간혹골수형성이상증후군자체에의해서도폐침범이일어날수있으나주로기질화폐렴의소견으로나타나며특히골수형성이상증후군의진행에따라폐손상이동반되는것으로알려져있다 [8]. 본증례의환자에서객담배양검사상동정된 Candida albicans는구강내상재균으로항생제투여를하는입원환자의 55% 까지에서동정된다는보고가있으며, Candida albicans에의한폐렴의발생빈도는매우낮은것으로알려져있다 [9]. 본증례의환자에서는 azacitidine 투여후발열및호흡곤란이발생하였고흉부단순방사선촬영의변화가일어났으며 azacitidine 중단후호전되었으나재투여시증상및흉부단순방사선촬영의변화가다시발생하였다는점으로볼때골수형성이상증후군자체또는 Candida albicans가원인일가능성보다는 azacitidine에의한폐손상의가능성이높다. 약물유해반응을평가하는 Naranjo 지표에따르면, 본증례에서 azacitidine은 상당히관련이있음 (probable) 에해당하였다 [10]. Azacitidine에의한폐손상이일어나는기전에대하여 DNA 저메틸화이외에직접적인세포독성이나다른기전에의한다는보고가있다. Cytidine 유사체인항암제 gemcitabine

4 - 김호철외 6 인. Azacitidine 폐손상 1 예 - Table 1. Azacitidine-induced lung injury: summary of cases in the literature Case Report (ref.) Age/ Gender Country Symptom onset Symptom Chest CT findings Pathological findings 1 Adams et al. [5] 2 Hueser & Patel [6] 3 Sekhri et al. [7] 4 Nair et al. [8] 5 Pillai et al. [9] 6 Hayashi M. et al. [10] 71/M USA Not available Fever 55/F USA 5 day Fever, dyspnea 56/M USA 1 wk Fever, 76/M USA 2 wk Fever, 74/F UK 5 day Fever, 74/M Japan 2 day Fever, Interstitial opacity, alveolar shadow pneumonitis, interstitial and alveolar fibrosis Therapy None Outcome Death Interstitial opacity NA Steroid Improvement Airspace disease, nodular opacity Infiltration, ground-glass opacity (GGO), lymph node (LN) enlargement Reticulonodular shadow, GGO, pleural effusion Infiltration, GGO, Pleural effusion, LN enlargement pneumonia, bronchocentric granuloma pneumonia, eosinophilic pneumonia Steroid Steroid Remission Improvement NA Steroid Remission NA Steroid Remission 은직접적인세포독성에의해모세혈관내피세포의손상을일으켜폐손상을일으키는것으로알려져있는데, gemcitabine과 azacitidine은분자구조가유사하여폐손상에있어서비슷한기전을가질것이라는추측이있다. 이외에도 azacitidine에의한폐손상이제1형알레르기반응또는면역글로불린 E와관련된과민반응에의한것이라는보고도있는데, 증상발생시간이짧고약물투여중단시빠른시간안에호전된다는점은이주장을뒷받침한다 [6]. Azacitidine에의한폐손상에대한치료는대증요법과함께스테로이드를투여하는것이며이전에보고된증례들에서도스테로이드치료후대부분의경우에서임상양상이호전되었다 (Table 1). Azacitidine에의한폐손상은흔하지는않으나, 발생할경우매우심각한결과를초래할수있으므로, azacitidine 치료를시행하는의사들의주의를요한다. 요 저자들은골수형성이상증후군환자에서 azacitidine 치료시행후에발생한폐손상을경험하였기에문헌고찰과함께보고하는바이다. 약 중심단어 : 골수형성이상증후군 ; Azacitidine; 폐손상 REFERENCES 1. Choi CW. The NCCN clinical practice guidelines and best supportive care for the myelodysplastic syndromes. Korean J Med 2009;76: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10: Adams CD, Szumita PM, Baroletti SA, Lilly CM. Azacitidine-induced interstitial and alveolar fibrosis in a patient with myelodysplastic syndrome. Pharmacotherapy 2005;25:

5 - The Korean Journal of Medicine: Vol. 87, No. 4, Hueser CN, Patel AJ. Azacitidine-associated hyperthermia and interstitial pneumonitis in a patient with myelodysplastic syndrome. Pharmacotherapy 2007;27: Sekhri A, Palaniswamy C, Kurmayagari K, Kalra A, Selvaraj DR. Interstitial lung disease associated with azacitidine use: a case report. Am J Ther 2012;19:e Nair GB, Charles M, Ogden L, Spiegler P. Eosinophilic pneumonia associated with azacitidine in a patient with myelodysplastic syndrome. Respir Care 2012;57: Pillai AR, Sadik W, Jones PA, Thachil J. Interstitial pneumonitis: an important differential diagnosis for pulmonary sepsis in haematology patients. Leuk Res 2012;36:e Hayashi M, Takayasu H, Tada M, et al. Azacitidine-induced pneumonitis in a patient with myelodysplastic syndrome: first case report in Japan. Intern Med 2012;51: Meersseman W, Lagrou K, Spriet I, et al. Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med 2009;35: Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:

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