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도현 필
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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2009;67:32-36 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 면역저하환자에서발생한파종성 Mycobacterium intracellulare 감염 1 예 울산대학교의과대학서울아산병원호흡기내과학교실 김선영, 오동욱, 유지희, 김동회, 노세희, 노재형, 정상수, 유동준, 심태선 Case Report A Case of Disseminated Mycobacterium intracellulare Infection in an Immunocompromised Host Sun Young Kim, M.D., Dong Wook Oh, M.D., Ji Hee Yu, M.D., Donghoi Kim, M.D., Sehui Noh, M.D., JaeHyung Roh, M.D., Sang-Su Jung, M.D., Dong-Jun Yoo, M.D., Tae Sun Shim, M.D. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea We report a case of disseminated Mycobacterium intracellulare infection in a 31-year-old man who had been diagnosed as having dermatomyositis and systemic lupus erythematosus 3-years prior. The patient developed a left pleural effusion M. intracellulare was repeatedly isolated from the pleural fluid. After antimycobacterial treatment, the patient s pleural effusion resolved, but a left knee joint effusion developed newly and M. intracellulare was cultured from the joint fluid. At present, the patient has been taking antimycobacterial medication for 15 months but his left knee joint fluid remains positive for M. intracellulare. To our knowledge, this is the second reported case of disseminated NTM infection in a non-hiv infected patient in Korea. Key Words: Mycobacterium avium complex, Disseminated infection, Immunocompromised host, Pleural effusion, Arthritis 서 비결핵항산균 (nontuberculous mycobacteria, NTM) 은자연환경에널리분포하고있으나병원성이낮다. 면역기능이정상인경우 NTM 이질환을일으키는경우는드물지만폐, 피부, 흉수염과같은국소적인부위에질환을유발할수있다 1-3. 그러나세포매개성면역저하의대표적질환인후천성면역결핍증후군 (acquired immunodeficiency syndrome, AIDS) 에서는파종성 M. avium-intracellulare complex (MAC) 질환이대표적인기회감염성질환으로알려져있다. AIDS 외에다른면역저하환자에서도 Address for correspondence: Tae Sun Shim, M.D. Division of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul , Korea Phone: , Fax: shimts@amc.seoul.kr Received: May. 28, 2009 Accepted: Jun. 22, 2009 론 다양한 NTM 감염증이보고되고있으나파종성질환의빈도는드물다 2,4. 지금까지국내에서 AIDS 가아닌면역저하환자에서 MAC에의한관절염 5, 척추염 6, 흉수 7 등이보고되었고두장기이상을침범하는파종성 MAC 감염은태반과폐가침범된 1예가보고되었다 8. 본저자들은결체조직질환으로면역억제제를복용하고있는환자에서 M. intracellulare에의한파종성감염 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 이, 남자, 31세주소 : 좌측흉막염성흉통현병력 : 내원 2주전부터발생한좌측의흉통을주소로본원에내원하였다. 흉통은흡기시나기침할때악화되었고객담, 호흡곤란등의호흡기증상이나발열, 체중감소, 야간발한등의전신적인증상은없었다. 과거력 : 3년전전신성홍반성루프스와피부근염의 32

Tuberculosis and Respiratory Diseases Vol. 67. No. 1, Jul. 2009 중첩증후군으로진단받고 corticosteroid 를지속적으로복용하는중이었으며당뇨, 고혈압, 간염및결핵력은없었다. 가족력 : 특이소견없었다. 진찰소견 : 내원시혈압 130/80 mmhg, 맥박 84회 / 분, 호흡수 20회 / 분, 체온 36.

하지에부종이나액와및서혜부림프절종대는없었고피부에발진과같은병변은관찰되지않았으며좌측상완에 Bacillus Calmette-Guerin (BCG) 흉터가있었다. 검사소견 : 입원당시말초혈액검사상백혈구 6,200/ mm 3 ( 중성구 84.6%), 혈색소 10.

2 Tuberculosis and Respiratory Diseases Vol. 67. No. 1, Jul 중첩증후군으로진단받고 corticosteroid 를지속적으로복용하는중이었으며당뇨, 고혈압, 간염및결핵력은없었다. 가족력 : 특이소견없었다. 진찰소견 : 내원시혈압 130/80 mmhg, 맥박 84회 / 분, 호흡수 20회 / 분, 체온 36.9 o C이었고의식은명료하였다. 두경부진찰상양측경부및쇄골상부에서만져지는림프절종대는없었다. 청진소견에서악설음, 천명음은들리지않았고좌측후하폐야의호흡음이감소되었다. 심음은규칙적이고심잡음은들리지않았으며복부촉진시간이나비장종대는없었고압통및반사압통도없었다. 하지에부종이나액와및서혜부림프절종대는없었고피부에발진과같은병변은관찰되지않았으며좌측상완에 Bacillus Calmette-Guerin (BCG) 흉터가있었다. 검사소견 : 입원당시말초혈액검사상백혈구 6,200/ mm 3 ( 중성구 84.6%), 혈색소 10.2 g/dl, 혈소판 118,000/ mm 3 이었고혈액화학검사는공복혈당 103 mg/dl, 뇨질소 17 mg/dl, 크레아티닌 0.7 mg/dl, 나트륨 141 mmol/l, 칼륨 4.4 mmol/l, 총단백 7.0 g/dl, 알부민 3.2 g/dl, 총빌리루빈 0.5 mg/dl, aspartate aminotransferase 36 IU/L, alanine aminotransferase 36 IU/L, alkaline phosphatase 53 IU/L, 콜레스테롤 142 mg/dl 이었으며혈액응고검사는정상범위였다. 소변검사는단백뇨 1+ 외에정상소견이었으며혈중보체는정상범위이고 HIV 항체음성이었다. 내원당시시행한혈액배양검사나객담항산균도말및배양검사에서균은배양되지않았다. 흉수검사상적혈구 150/mm 3, 백혈구 3,750/mm 3 ( 다핵구 8%, 림프 구 10%, 조직구 81%), 단백 5.5 g/dl, lactic dehydrogenase 2,597 U/L, 포도당 68 mg/dl 로삼출액소견이었다. 흉수의아데노신탈아미노효소 (adenosine deaminase, ADA) U/L 이었고항산균도말검사는양성이었으나결핵균중합효소연쇄반응 (polymerase chain reaction, PCR) 검사는음성이었다. 기관지내시경검사상정상소견이었고항산균도말및배양은모두음성이었으며이후흉수항산균배양검사에서 NTM이배양되었다. 투베르쿨린검사상경결의크기는 13 mm이었다. 방사선소견 : 단순흉부방사선촬영상새롭게발생한좌측흉수가관찰되었고 (Figure 1A) 측와위촬영에서이동성이확인되었다. 내원 2달전시행한흉부전산화단층촬영에서결체조직질환의폐침범에의한간질성폐질환소견이관찰되었으며변화가없었다. 결핵을의심할만한소견은관찰되지않았다. 임상경과 : 최초흉수검사에서 ADA가증가된림프구우세성삼출액이고항산균도말양성으로표준 4제항결핵치료시행하였다. 그러나결핵균 PCR 결과가음성이어서 NTM 가능성고려하여 ABSOLUTE TM NTM & MTB PCR 검사 (Bioseum, Seoul, Korea) 시행하였고 NTM band가검출되어항결핵치료시작 28일후부터 clarithromycin 추가하여사용하였다. 배양결과 NTN이 2회배양되었고 2균주모두 rpob 유전자의 PCR-RFLP (restriction fragment length polymorphism) 법으로 M. intracellulare으로동정되었다 6,9. M. intracellulare에의한흉수염진단하에 rifampicin (600 mg/day), ethambutol (800 mg/day), clarithromycin (1,000 mg/day), strepto- Figure 1. (A) Chest X-ray shows left pleural effusion on admission and (B) decreased left pleural effusion after 8 months. 33

SY Kim et al: Disseminated Mycobacterium intracellulare infection 에감수성을나타내었다 (MIC=2 μg/ml). 이후 amikacin (7개월째투여중 ) 을추가하였고순차적으로 isoniazid, moxifloxacin 를추가한상태로치료중이나지속적으로관절액에서균이동정되어수술을고려중이다.

3 SY Kim et al: Disseminated Mycobacterium intracellulare infection 에감수성을나타내었다 (MIC=2 μg/ml). 이후 amikacin (7개월째투여중 ) 을추가하였고순차적으로 isoniazid, moxifloxacin 를추가한상태로치료중이나지속적으로관절액에서균이동정되어수술을고려중이다. 고 찰 Figure 2. Sagittal T1-weighted enhanced fat-suppressed magnetic resonance image shows synovial thickening with well enhancement and effusion (arrow) in left knee joint; and poorly defined bone marrow signal change in medial femoral condyle and tibial plateau. These findings are consistent with septic arthritis with osteomyelitis. mycin (1 g 주 5회근육주사, 3개월 ) 으로치료하였다. 치료 8개월째흉부방사선촬영상좌측흉수는감소하였으나 (Figure 1B) 좌측무릎관절의통증및종창이새로발생하였고관절천자액검사에서백혈구 9,950/mm 3 ( 호중구 7%, 림프구 45%), 항산균도말양성이었으며 M. intracellulare가반복적으로 7회배양되었고 2회의동정검사에서모두 M. intracellulare로동정되었다. 자기공명영상에서는무릎관절의관절염및대퇴골하부와경골상부의골수염소견이관찰되었다 (Figure 2). 이후 corticosteroid 를 20 mg/day 에서 7.5 mg/day 로감량하고 rifampicin (600 mg/day), ethambutol (800 mg/day), clarithromycin (1,000 mg/day) 에 streptomycin (1 g 주 5회근육주사, 5개월 ), moxifloxacin (400 mg/day) 을추가하면서무릎관절종창은호전되고관절천자액검사에서백혈구가감소하였다. 그러나치료 15개월째좌측무릎통증이악화되어반복검사한관절천자액에서도 M. intracellulare가다시배양되었다. 이후관절경을이용한활막절제술을시행받았으며조직소견상비특징적인육아종이관찰되었으며 AFB염색은음성이었다. 수술시채취한관절액에서 M. intracellulare 가동정되었으며약제감수성검사결과 (Sensititre MAISLOW panel; TREK Diagnostic Systems, Cleveland, OH, USA) clarithromycin 파종성 NTM 질환은혈액배양에서양성을보이거나 2개이상장기를침범한경우로정의한다 4. 대부분 AIDS 환자에서발생하며 CD4 양성 T 림프구가 50/μL 이하로감소한경우에위험도가증가한다. AIDS가아닌원인으로면역기능이저하된환자에서는매우드물게파종성 NTM 질환이발생한다. 지금까지보고된증례들에서의기저원인질환은신장또는심장이식, 혈액종양, 장기간의 corticosteroid 사용, 항암화학요법등이었다 4,10. 파종성 NTM 질환의원인균은 90% 이상이 MAC이며 M. kansisii가다음으로빈도가높다. AIDS에서 MAC에의한파종성감염은폐, 림프절, 심장막, 골수, 피부나연조직, 성기, 중추신경계등을침범할수있고혈액과골수등무균적인체액에서균이동정된다 11. AIDS 환자가아닌경우침범장기는림프절이빈도가높고피부연조직, 폐, 뼈와관절순이었다 12. 국내에서보고된파종성 MAC 질환은 AIDS환자에서림프절, 폐, 골수를침범한증례가있고 13, AIDS가아닌환자에서 M. intracellulare에의한흉수염 7, 관절염 14, 척추염 6 이발생한보고는있었고임신부에서파종성감염이 1예있었으나 8 흉수와관절염이동시에발생한파종성감염의보고는없었다. 파종성질환의경우 90% 이상에서혈액배양양성이나음성인경우에는골수나간조직배양검사가적응이될수있으며림프절비대가있는경우조직검사를시행할수도있다 13. 본증례에서혈액배양은음성이었으며골수및간조직검사는시행되지않았으나무균성체액인흉수와관절액에서 M. intracellulare가동정되었으므로파종성감염으로진단할수있었다. 파종성 NTM 질환의임상증상은다양하다. 대부분발열 (80%) 을동반하며야간발한 (35%), 체중감소 (25%) 및상당수에서복통이나설사를동반한다 15. 복부압통이있는경우는있으나림프절비대는흔하지않으며심한빈혈, alkaline phosphatase 와 lactic dehydrogenase 증가가보고되고있다 16. 파종성 MAC 질환의치료는약물치료와면역상태의회복을함께고려해야하기때문에쉽지않다. AIDS 가아닌 34

4 Tuberculosis and Respiratory Diseases Vol. 67. No. 1, Jul 환자에서파종성 MAC 질환이발생한경우아직확립된치료법은없으나 AIDS 환자에서의치료를적용할수있다 10. 초기치료는 clarithromycin (1,000 mg/day) 또는 azithromycin (500 mg/day) 와 ethambutol (15 mg/kg) 을기본으로하며 rifampicin 또는 rifabutin, amikacin 을비롯한 amonoglycoside, fluoroquinolone 등을병합할수있다 4,10. 치료기간은폐질환이있을경우객담배양음전후최소 12개월더치료하여야하며혈액배양양성인경우에는면역기능회복후적어도 6 12개월더유지하는것을권장하고있다 4. AIDS 가아닌환자에서발생한파종성 NTM 감염증의치료성적에대한한보고에서사망률은 M. kansasii (100%), 신속성장균 (25%), MAC (12.5%) 순이었다 17. 본증례의경우 MAC 질환이진단된이후 corticosteroid 를감량하고감수성이확인된 clarithromycin 을포함한약제로 15개월이상투여하여흉수는호전되었으나관절염은지속되었고균이지속적으로관절액에서배양되어현재치료를지속하면서수술을기다리고있다. 요 본증례는 AIDS가아닌면역저하환자에서 M. intracellulare 에의하여관절염및흉수가발생한파종성질환의예로국내에서두번째로보고되는바이다. 약 참고문헌 1. Park SU, Koh WJ, Kwon OJ, Park HY, Jun HJ, Joo EJ, et al. Acute pneumonia and empyema caused by Mycobacterium intracellulare. Intern Med 2006;45: Koh WJ, Kwon OJ. Diagnosis and treatment of nontuberculous mycobacterial lung disease. Korean J Med 2008;74: Kim SS, Rhie EJ, Ko GJ, Choi HS, Oh HE, Kim JM, et al. A Case of Mycobacterium avium pulmonary disease with massive pleural effusion in an HIV-negative, nonimmunosuppressed patient: using PCR-restriction fragment length polymorphism assay. Infect Chemother 2004;36: Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175: Lee CW, Sung HD, Choi BM, Kim CW, Jun SJ, Min SJ. Mycobacterium Avium arthritis with extra-articular abscess in a patient with mixed connective tissue disease. Korean J Intern Med 2003;18: Jang EY, Kim MY, Kim JW, Song EH, Pack KM, Chung YP, et al. A case of vertebral osteomyelitis due to Mycobacterium intracellulare. Infect Chemother 2007; 39: Kwak SY, Bae SY, Yun WK, Kim MY, Kim YJ, Choi MK, et al. Mycobacterium intracellulare pulmonary infection accompanied with pleural effusion. Korean J Med 2008;75: Song JY, Park CW, Kee SY, Choi WS, Kang EY, Sohn JW, et al. Disseminated Mycobacterium avium complex infection in an immunocompetent pregnant woman. BMC Infect Dis 2006;6: Lee H, Park HJ, Cho SN, Bai GH, Kim SJ. Species identification of mycobacteria by PCR-restriction fragment length polymorphism of the rpob gene. J Clin Microbiol 2000;38: Inderlied CB, Kemper CA, Bermudez LE. The Mycobacterium avium complex. Clin Microbiol Rev 1993;6: Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep 2004;53: Chetchotisakd P, Kiertiburanakul S, Mootsikapun P, Assanasen S, Chaiwarith R, Anunnatsiri S. Disseminated nontuberculous mycobacterial infection in patients who are not infected with HIV in Thailand. Clin Infect Dis 2007;45: Yi SH, Choi JH, Choi MH, Shin DW, Choi JH, Kim TY, et al. Disseminated Mycobacterium avium complex infection in a patient with acquired immunodeficiency syndrome. Infect Chemother 2008;40: Park KW, Kwon HH, Chung SH, Kim KC, Choe JY, Lee YH. A case of tenosynovitis due to Mycobacterium intracellulare in a patient with rheumatoid arthritis. Infect Chemother 2007;39: Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165: Horsburgh CR Jr, Gettings J, Alexander LN, Lennox JL. Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency 35

5 SY Kim et al: Disseminated Mycobacterium intracellulare infection virus, Clin Infect Dis 2001;33: Lai CC, Lee LN, Ding LW, Yu CJ, Hsueh PR, Yang PC. Emergence of disseminated infections due to nontuberculous mycobacteria in non-hiv-infected patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan. J Infect 2006;53:

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9.Æ¯Áýb61Ç¿ÀÁ¤806~816’ J KMA Special Issue Won Jung Koh, MD O Jung Kwon, MD Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine E mail : wjkoh@smc.samsung.co.kr