대한내과학회지 : 제 89 권제 4 호 2015 http://dx.doi.org/10.3904/kjm.2015.89.4.452 궤양성대장염으로 Infliximab 치료중인환자에서발생한 Mycobacterium gordonae 폐질환 1예 단국대학교의과대학단국대학교병원 1 내과, 2 병리과 최지성 1 배종욱 1 이상원 1 최규호 1 신정은 1 명나혜 2 박재석 1 A Case of Mycobacterium gordonae Pulmonary Disease in a Patient with Ulcerative Colitis Treated with Infliximab Ji Sung Choi 1, Jong Wook Bae 1, Sang Won Lee 1, Gyu Ho Choi 1, Jeong Eun Shin 1, Na-Hye Myung 2, and Jae Seuk Park 1 Departments of 1 Internal Medicine and 2 Pathology, Dankook University Hospital, Dankook University Medical College, Cheonan, Korea Tumor necrosis factor-α (TNF-α) is a key component of the host defense against mycobacterial infection. Mycobacterium gordonae (M. gordonae) is one of the least virulent mycobacteria, and is generally considered non-pathogenic if detected from a clinical specimen. Here, we report a rare case of pulmonary M. gordonae infection in a patient with ulcerative colitis who had been treated with infliximab, a TNF-α antagonist. M. gordonae infection was treated successfully with clarithromycin, rifampin, and ethambutol. We believe this to be the first report of M. gordonae pulmonary disease associated with TNF-α antagonist treatment. (Korean J Med 2015;89:452-456) Keywords: Mycobacterium gordonae; Ulcerative colitis; Infliximab; Tumor necrosis factor-alpha 서론종양괴사인자-알파 (tumor necrosis factor-alpha, TNF-α) 길항제들은류마티스관절염, 건선, 염증성장질환과같은다양한염증성질환의치료제로이용되고있다 [1]. TNF-α 는결핵균뿐만아니라비결핵항산균 (nontuberculous mycobacteria) 에대한인체의면역학적방어기전에서중요한역할을하므로 TNF-α 길항제치료를받고있는환자에서비결핵항산균폐 질환이발생할위험성이증가한다 [2,3] Mycobacterium gordonae (M. gordonae) 는독성이낮아객담에서검출되면비결핵항산균폐질환의가능성이낮고대표적인오염균으로간주되고있다 [4]. 저자들은 TNF-α 길항제로치료중인궤양성대장염환자에서 M. gordonae 폐질환으로진단되어적절한약물치료후호전된증례를경험하였기에문헌고찰과함께보고하는바이다. Received: 2015. 4. 30 Revised: 2015. 6. 3 Accepted: 2015. 6. 16 Correspondence to Jae Seuk Park, M.D., Ph.D. Department of Internal Medicine, Dankook University Hospital, Dankook University Medical College, 201 Manghyang-ro, Dongnam-gu, Cheonan 31116, Korea Tel: +82-41-550-3055, Fax: +82-41-556-3256, E-mail: jspark@dankook.ac.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 452 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Ji Sung Choi, et al. Mycobacterium gordonae pulmonary disease - 증례환자 : 39세여자주소 : 흉부영상소견이상현병력 : 환자는 5년전궤양성대장염으로진단받고 mesalamine, azathioprine, prednisolone 등을투여하면서추적관찰중궤양성대장염이악화되어 8개월전부터 TNF-α 길항제인 infliximab (remicade) 치료 (5 mg/kg) 를시작하였다. Infliximab 치료시작당시흉부 X-선소견은정상이었고 (Fig. 1A), 인터페론감마분비검사 (interferon-gamma releasing assay, Quanti- FERON-TB Gold) 는음성이었다. Infliximab 투여후대장염증이호전되어정기적으로 infliximab 투여받으면서경과관 찰중 (8개월에걸쳐 6차 infliximab 투여후 ) 시행한흉부 X- 선검사에서좌하엽에경화성병변 (consolidation) 이관찰되어 (Fig. 1B) 원인검사를위해입원하였다. 입원당시발열, 기침, 객담과같은호흡기증상은없었다. 과거력 : 궤양성대장염치료이외에특이과거력은없었다. 사회력 : 음주나흡연은하지않았다. 이학적소견 : 내원시체중은 48 kg, 키는 155 cm, 신체활력징후는혈압 114/80 mmhg, 맥박수 96회 / 분, 호흡수 20회 / 분, 체온은 36.5 였다. 흉부청진상심음은정상이었으며천명이나수포음은청진되지않았다. 복부는편평하고부드러웠으며, 간이나비장의종대는없었다. 검사실소견 : 입원당시말초혈액검사에서백혈구 5,290/ A B C Figure 1. Chest X-ray at the start of infliximab treatment (A), and after 8 months (B) and 10 months (C) of treatment. Panel A shows normal radiologic findings, whereas panels B and C show consolidation in the left lower lung (arrow). Anti-mycobacterial treatment for Mycobacterium gordonae infection was initiated after 10 months of infliximab treatment. A B Figure 2. Chest computed tomography (CT) upon admission (after 8 months of infliximab treatment) showed consolidation in the left lower lobe posterior segment along the bronchovascular bundle (arrow) (A). Contrast-enhanced CT revealed a focal low-density region (arrow) (B). - 453 -
- 대한내과학회지 : 제 89 권제 4 호통권제 662 호 2015 - mm 3 ( 호중구 70.9%, 림프구 14.0%), 혈색소 9.4 g/dl, 혈소판 358,000/mm 3, 혈청생화학검사에서혈청총단백 5.2 g/dl, 알부민 2.9 g/dl, AST/ALT 21/10 U/L, 총빌리루빈 0.26 mg/dl, 혈액요소질소 14.9 mg/dl, Cr 0.43 mg/dl, LDH 251 U/L, C-reactive protein 1.56 mg/dl였다. 소변검사상특이소견은없었다. 인터페론감마분비검사를다시시행했는데음성이었다. 객담항산균도말및배양검사는음성이었다. 방사선소견 : 흉부 X-선검사 (Fig. 1B) 및흉부전산화단층촬영 (Fig. 2) 에서좌하엽에폐경화 (consolidation) 소견이관찰되었다. 기관지내시경검사 : 기관지내병변은없었고좌하엽 posterior basal segment에서기관지폐포세척 (bronchoalveolar lavage) 을시행하였다. 기관지폐포세척액세포진검사에서암세포는관찰되지않았고, 항산균도말검사는음성이었고결핵균핵산증폭검사에서결핵균은검출되지않았다. 경피세침흡인검사 (percutaneous fine needle aspiration): 좌측폐병변에대해경피세침흡인을시행하여시행한병리검사에서괴사성병변을동반한상피양세포들과림프구의집합체가관찰되었다 (Fig. 3). 조직에대한항산균도말검사는음성이었고, 핵산증폭검사에서결핵균은음성이었고비결핵항산균은양성이었다. 치료및경과 : 폐세포병리소견상비결핵항산균에의한폐병변의가능성이크지만호흡기증상이없고균동정이되 지않았기때문에폐병변에대한치료를시행하지않고항산균배양검사결과를기다렸다. 이후기관지폐포세척액에대한액체배지와고체배지에서비결핵항산균이배양되었다. 폐조직에대한항산균배양검사에서는배양되지않았다. 기관지폐포세척액에서배양된비결핵항산균에대해균동정검사를시행하였는데 M. gordonae가동정되었다. 결핵연구원에 Table 1. Antibiotic susceptibility data for isolated Mycobacterium gordonae Antibiotics Test concentrations (mcg/ml) MIC (mcg/ml) Amikacin 1-128 32 Cefoxitin 2-256 > 256 Ciprofloxacin 0.125-16 > 16 Clarithromycin 0.5-64 1 Doxycycline 0.25-32 > 32 Imipenem 0.5-64 > 64 Moxifloxacin 0.125-16 4 Rifampicin 0.125-16 8 Sulfamethoxazole/trimethoprim 0.25/4.75-32/608 8/152 Tobramycin 0.25-32 8 Ethambutol 0.25-32 16 Linezolid 2-64 32 MIC, minimal inhibitory concentration. A B C Figure 3. Fine needle aspiration cytology of the lung lesion showed relatively loose aggregates of epithelioid histiocytes admixed with scattered lymphocytes in a background of necrotic material (arrow) (A, B) (Papanicolaou stain, 400). Immunohistochemical staining for CD68, a histiocytic marker, showed that cells were mostly composed of histiocytic inflammatory cells (C) ( 200). - 454 -
- 최지성외 6 인. M. gordonae 폐질환 - A B Figure 4. Chest X-ray after 2 months (A) and 12 months (B) of anti-mycobacterial treatment for Mycobacterium gordonae pulmonary infection. Panel A shows partial resolution of the lesion observed in the left lower lung (arrow). Panel B shows complete resolution of the lesion. 의뢰하여동정된 M. gordonae의약제감수성검사를시행하였다 (Table 1). 폐병변이처음관찰된지 2개월후에시행한흉부 X-선에서좌하엽경화성병변이지속적으로관찰되어 (Fig. 1C) M. gordonae 폐질환으로진단하고약제감수성검사에서감수성을보인 clarithromycin, rifampin, ethambutol로치료를시작하였다. 치료시작후병변이지속적으로감소하였고 (Fig. 4) 치료시작 1개월과 3개월후에 2차례추구객담항산균도말및배양검사를시행하였는데모두음성이었다. 1년간약물치료후 M. gordonae 폐질환치료를종결하였다. 치료종결 6개월에시행한흉부 X-선소견에서재발의증거가없었으며 infliximab 5 mg/kg로 6주간격으로투약하면서증상및내시경적관해를유지하고있다. 고찰궤양성대장염은호전과악화를반복하는만성염증성장질환으로그원인은정확히알려져있지않다. TNF-α 가장관염증의중요한매개체이며 TNF-α 길항제들이스테로이드나면역억제제에비해우수한증상호전과점막치유효과를보이는것이밝혀짐에따라스테로이드나 azathioprine 과같은면역억제제사용으로관해나호전을보이지않는중등도이상의궤양성대장염환자에서 TNF-α 길항제들의사용이증 가하고있다 [5]. TNF-α는육아종의형성등결핵균에대한인체의면역학적방어기전에서중요한역할을하는데 TNF-α 길항제가이과정을억제하므로결핵균에감염된사람에서 TNF-α 길항제치료를받을경우결핵이발생할위험성이증가한다 [2]. 그러므로 TNF-α 길항제사용전에활동성결핵여부를확인하고결핵이없을경우결핵감염검사를시행하고잠복결핵감염으로진단되면잠복결핵감염치료를시행하도록권고하고있다 [5]. 본증례의환자도 TNF-α 길항제를사용하기전에흉부 X-선검사와인터페론감마분비검사를시행하여폐결핵이없고잠복결핵감염상태가아님을확인하였다. TNF-α 길항제는결핵균뿐만아니라비결핵항산균에대한방어기전도억제하므로 TNF-α 길항제치료를받는환자에서비결핵항산균폐질환이발생또한증가하는것으로알려져있다 [6]. 비결핵항산균은균종에따라독성 (virulence) 이다른데, mycobacterium avium complex (MAC), M. kansasii, M. abscessus 등은상대적으로독성이높아객담에서검출되면비결핵항산균폐질환의가능성이크지만, M. gordonae는독성이낮아폐병변을일으키는경우가거의없으며객담에서 M. gordonae 가검출되면대표적인오염균으로간주되어왔다 [4,7]. 그러나기관지폐포세척액또는폐조직생검에서 M. gordonae가 - 455 -
- The Korean Journal of Medicine: Vol. 89, No. 4, 2015 - 검출되거나객담의경우 M. gordonae가반복해서검출되고폐병변을일으킬수있는다른원인이없을때 M. gordonae 폐질환 (true infection) 을의심해볼수있으며 [7], 사람면역결핍바이러스 (human immunodeficiency virus) 감염, 스테로이드치료, 장기이식환자와같은면역억제환자들뿐만아니라정상면역인에서도 M. gordonae가병을일으킬수있다는보고들이있다 [8,9]. TNF-α 길항제로치료중인환자들에서발생한비결핵항산균폐질환의원인균을분석한국내외의연구들에서도대부분 MAC이원인균이었으며 M. gordonae가원인균인경우는없었다 [3,10]. 그러나본증례는 TNF-α 길항제를사용중인환자에서도 M. gordonae가폐질환을일으킬수있음을보여주고있다. M. gordonae 폐질환의흉부방사선소견은폐결절, 공동, 폐침윤 (infiltration), 기관지확장, 폐경화 (consolidation) 등다양한소견을보일수있다고알려져있으며 [9], 본증례에서는폐경화소견을보였다 (Fig. 2). M. gordonae 감염의치료약제와치료기간은아직정립되지않는데시험관에서항균력이있는 clarithromycin, rifampin, ethambutol, fluoroquinolone 등이경험적으로사용되고있다 [7]. 본증례에서도배양된 M. gordonae에대한약제감수성검사에서감수성을보이는 clarithromycin, rifampin, ethambutol로치료하였고치료에좋은반응을보였다. 치료기간또한문헌마다 9개월에서 22개월까지다양한데본증례에서는 12개월간약물치료로적절히치료되었다 [8]. 본증례는 TNF-α 길항제를사용중인환자에서발생한 M. gordonae 폐질환으로적절한약물치료로완치된첫번째증례보고이다. 그러므로임상검체에서 M. gordonae가검출되더라도오염균으로보고감별진단에서배제하지말고 M. gordonae 감염병의가능성을고려하여야할것으로사료된다. 요약 TNF-α는항산균에대한인체의면역학적방어기전에서중요한역할을한다. Mycobacterium gordonae는독성이낮아임상검체에서검출되면대부분오염균으로간주되고있다. 저자들은 TNF-α 길항제로치료중인궤양성대장염환자에서 M. gordonae 폐질환으로진단되어적절한약물치료후 호전된증례를경험하였기에문헌고찰과함께보고하는바이다. 중심단어 : Mycobacterium gordonae; 궤양성대장염 ; Infliximab; 종양괴사인자-알파 REFERENCES 1. Gisbert JP, González-Lama Y, MatéJ. Systematic review: Infliximab therapy in ulcerative colitis. Aliment Pharmacol Ther 2007;25:19-37. 2. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-1104. 3. Yoo JW, Jo KW, Kang BH, et al. Mycobacterial diseases developed during anti-tumour necrosis factor-α therapy. Eur Respir J 2014;44:1289-1295. 4. Koh WJ, Kwon OJ, Jeon K, et al. Clinical significance of nontuberculous mycobacteria isolated from respiratory specimens in Korea. Chest 2006;129:341-348. 5. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012; 10:391-399.e1. 6. Winthrop KL, Yamashita S, Beekmann SE, Polgreen PM; Infectious Diseases Society of America Emerging Infections Network. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis 2008;46:1738-1740. 7. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. 8. Weinberger M, Berg SL, Feuerstein IM, Pizzo PA, Witebsky FG. Disseminated infection with Mycobacterium gordonae: report of a case and critical review of the literature. Clin Infect Dis 1992;14:1229-1239. 9. Mazumder SA, Hicks A, Norwood J. Mycobacterium gordonae pulmonary infection in an immunocompetent adult. N Am J Med Sci 2010;2:205-207. 10. Mori S, Tokuda H, Sakai F, et al. Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterialdisease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. Mod Rheumatol 2012;22:727-737. - 456 -