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비적출술후아데노바이러스에의한혈구탐식성증후군 1 례 경북대학교의과대학소아과학교실 박숙현ㆍ이건수 A Case of Hemophagocytic Syndrome Induced by Adenovirus Infection after Splenectomy Sook Hyun Park, M.D. and Kun Soo Lee, M.D. Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea Hemophagocytic lymphohistiocytosis (HLH) is a rare but sometimes fatal disease. Its main features are prolonged fever, hepatosplenomegaly, cytopenias, and hemophagocytosis in the bone marrow, lymph nodes and other tissues. Hemophagocytic lymphohistiocytosis comprises two different conditions which are: primary, that is with a genetic etiology and secondary, associated with infections, malignancies, and autoimmune diseases. Infection associated hemophagocytic syndrome (IAHS) is caused by bacteria, parasites, fungi, but mostly viruses. A 24 year-old-male, was diagnosed with anaplastic large cell lymphoma and underwent chemotherapy for 6 years because of CNS relapse and leukemic transformation. Thrombocytopenia and splenomegaly persisted after chemotherapy. A splenectomy was done for the treatment of hypersplenism which developed after chemotherapy for anplastic large cell lymphoma, CNS relapse and leukemic transformation. We present a case of hemophagocytic syndrome induced by adenovirus infection after splenectomy. (Clin Pediatr Hematol Oncol 2009;16:49 53) Key Words: Hemophagocytic lymphohistiocytosis, Adenovirus, Anaplastic large cell lymphoma, CNS relapse, Hypersplenism, Splenectomy 책임저자 : 이건수, 대구시중구삼덕 2 가 50 번지경북대학교의과대학소아과학교실, 700-712 Tel: 053-420-5704, Fax: 053-425-6683 E-mail: kslee@knu.ac.kr 혈구탐식성림프조직구증 (hemophagocytic lymphohistiocytosis, HLH) 은발열, 범혈구감소, 응고이상, 간비종대, 골수와림프절등에서혈구포식조직구가증가된소견등이특징적으로나타나는질환이다 1,2). HLH는드물게발생하며다양한임상증상과경과를보여진단이어렵고적절한치료에도불구하고치사률이높다 3). HLH는원발성인유전성 HLH (familial hemophagocytic lymphohistiocytosis, FHLH) 와감염, 종양, 자가면역질환, 면역결핍등이원인이되는 2차적혈구탐식성림프조직구증 (secondary hemophagocytic lymphohistiocytosis, shlh) 으로나뉘는데 shlh의대표적인감염관련혈구탐식성증후군 (infection associated hemophagocytic syndrome, IAHS) 은바이러스, 특히 Epstein-Barr 바이러스, 세균, 진균등에의한감염이원인이다 1,3). 저자들은악성림프종, 중추신경계재발및백혈병전환 (leukemic transformation) 으로항암치료를시행한환아가치료종료후에도지속되는비기능항진증이있어비적출술시행후아데노바이 임상소아혈액종양제 16 권제 1 호 2009 49

50 박숙현ㆍ이건수 러스감염과관련한 IAHS 1례를보고한다. 증례환아 : 김, 24세, 남자주소 : 비적출술후 2주이상지속된고열및기침과거력 : 13세에대세포역행성림프종 (anaplastic large cell lymphoma) 진단받고항암치료시행하였다. 17세에중추신경계재발과 19세에백혈병전환을진단받고병합화학요법과방사선치료시행하였고 23세에항암치료종료하였다. 외래에서추적관찰중 22세부터발생한비종대 ( 수술당시 14 cm 촉지됨 ) 와혈소판감소를동반한비기능항진증으로 24세에비적출술을시행하였다. 가족력 : 특이사항없음. 현병력 : 본원외과에서비적출술후 1주경과하여복통이있어시행한복부전산화단층촬영에서문맥혈전증이보여항응고제복용을시작하였다. 이후 2주이상지속된 38.5 o C 이상의고열및기침으로전산화단층촬영을시행하였고다발성폐결절및림프절비대소견보여악성림프종재발의심되어소아청소년과로전과되었다. 진찰소견 : 전과당시전반적인상태는급성병색소견을보였고활력징후는혈압 113/65 mmhg, 체온 38.6 o C, 맥박 96회 / 분, 호흡수 35회 / 분이고, 산소 8 L/hr에서산소포화도는 95% 내외로유지되었다. 두경부진찰에서 1 cm 가량의 1개의오른쪽턱밑림프절이촉지되었고그외림프절비대소견은보이지않았다. 흉부청진에서심음은정상이었고양쪽폐야에서수포음이청진되었고호흡음은감소되어있었다. 복부는부드럽고만져지는종괴는없었으며간은촉지되지않았으며비장은절제상태였다. 검사소견 : 말초혈액검사에서혈색소는 9.2 g/dl, 백혈구는 3,220/μL ( 호중구 56%, 림프구 27%, 단핵구 12%), 혈소판 84,000/μL이었다. ESR은 12 mm/hr, CRP는 8.0 mg/dl이었으며 ferritin이 4,317 ng/ml이었다. 자연살해세포 (natural killer cell, NK cell) 16%, 중성지방 107 mg/dl, 섬유소원 200 mg/dl 로정상범위였다. 객담중합연쇄반응검사에서아데노바이러스가양성이었다. 방사선학적소견 : 흉부 X-ray에서양측폐에침윤이있었고 (Fig. 1), 흉부전산화단층촬영에서다발성폐결절 (Fig. 2A) 과림프절비대 (Fig. 2B) 가관찰되고양전자방출단층촬영에서양측폐에서 18 F-fluordeoxyglucose (FDG) 섭취가증가된결절은악성림프종의재발에부합하는소견으로보였다. 골수검사및폐결절조직검사소견 : 폐결절조직검사에서조직화된폐렴소견보였고골수검사에서혈구탐식세포가관찰되었다 (Fig. 3). 치료및경과 : Vancomycin 및 carbapenem, amphotericin B로 1주이상치료하였으나고열이지속되고혈구감소호전소견보이지않았으며흉부 X-ray에서침윤정도가악화되어 IAHS에준하여 dexamethasone, ectoposide, cyclosporine 병합항암화학요법을 2주간한차례시행하였다. 중추신경계의침범을시사하는소견은없어척수강내약물치료는시행하지않았다. 2주후임상적으로명확한호전소견보였고흉부전산화단층촬영에서이전에보이던다발성폐결절과림프절비 Fig. 1. Chest radiograph shows infiltration in both perihilar and peribronchial areas.

비적출술후아데노바이러스에의한혈구탐식성증후군 1 례 51 Fig. 2. (A) Chest CT shows multiple lobulated nodules with ground glass opacity, and (B) enlargement of para-aortic (filled arrow) and para-tracheal (empty arrow) lymph nodes. Fig. 3. Histologic view of his bone marrow shows stromal macrophages containing numerous red blood cells in the cytoplasm (Wright-Giemsa stain, 1,000). Fig. 4. Abdomen CT shows undulated hepatic contour probably due to capsular retraction, and a small amount of ascites. 대소견은관찰되지않아항암치료는종료하였다. 이후문맥혈전증의호전정도를파악하기위해시행한복부전산화단층촬영에서문맥혈전증은관찰되지않았으나간경화소견을보였다 (Fig. 4). 당시간기능검사에서 AST/ALT는 28/31 U/L로정상이었으나 Bilirubin (T/D) 이 5.0/2.1 mg/dl로증가되어있었다. 현재항응고제및예방적항생제복용지속하고있으며 HLH 재발소견은없는상태이다. 고찰 HLH은 1939년 Scott 등 4) 이 histiocytic medullary reticulocytosis로처음기술한이래많은연구들을거쳐 1991년 Histiocyte Society에서처음으로 HLH 의진단기준이만들어졌고 5) 1994년에는치료프로토콜인 HLH-94을소개하였다 6). 이후개정된진단기준및치료프로토콜인 HLH-2004을제시하였다 7). 2004년 Histiocyte Society가제시한진단기준은

52 박숙현ㆍ이건수 발열, 비종대, 말초혈액에서 2가지계열이상혈구감소증 ( 혈색소 <9 g/dl, 혈소판 <100 10 9 /L, 중성구 <1,000/mm), 고중성지방혈증 ( 265 mg/dl), 저섬유소원증 ( 150 mg/dl), 고페리틴혈증 ( 500 ng/ml), NK cell의기능상실또는저하, 가용성 CD 25가 2,400 U/mL 이상이거나, 골수나간, 비장, 림프절등의조직검사에서혈구탐식증의소견, 이 8가지조건중 5가지이상을만족시키는경우로규정하였다 1). 이환자의경우 1) 발열, 2) 혈구감소증, 3) 고페리틴혈증, 4) 골수조직검사에서혈구탐식증의소견으로 4가지를만족하지만임상적으로 IAHS 강력히의심되어치료를시작하였고 2주간의병합화학요법 (dexametasone, ectoposide, cyclosporine) 후호전되는양상을보였다. HLH은조직에서유해한세포를제거시키는면역반응이나이러한일련의염증반응을종료시키는제어장치의기능파괴로인해발생하게된다 2). 바이러스, 특히 Epstein-Barr 바이러스와의연관성에대한발병기전연구가활발히진행되어서특정한바이러스가 HLH을지속적으로유발하지는않으나바이러스가비특이적인유발인자로작용하여 T-세포와대식세포를자극함으로염증반응매개물질을분비하여조직에영향을미치면서증상을나타내는것으로밝혀졌다 8). 그외에도단순헤르페스바이러스, 수두대상포진바이러스, 거대세포바이러스, 후천성면역결핍바이러스, 아데노바이러스등이 IAHS의원인으로알려져있다 1-3). 이중아데노바이러스에의한 IAHS은골수이식후출혈성방광염증상이나타나는경우 9) 와치명적인폐렴을동반하는경우가보고되고있다 10,11). 원발성 HLH은상염색체열성의유전되는질환으로 50,000명중 1명의유병률을보이고일반적으로 2세미만에서 80% 이상발병하고적절한시기에치료를받지않은경우에는평균생존률이 2개월미만이다 1). 이차성 HLH은증상과임상경과가매우다양하기때문에진단을명확하게내릴수없는경우와시간이경과하면호전되는경 우들도있어유병률을정확하게파악하기힘들다 1). 상염색체열성유전으로가족력으로판단하기힘들고감염이원발성에서유발인자로작용할수있으므로원발성과이차성을감별하는것은쉽지않은데임상증상이있다면우선치료를시작하는것을추천하고있다 1,6,12). 치료에반응이좋고치료가끝난후에도재발이없다면이차성을고려할수있다 13). HLH의치료는 dexamethasone, ectoposide, cyclosporine과 methotrexate 및 corticosteroid를척수강내로주입하는병합화학요법을 8주간시행하는초기치료를시작으로이후유전적인소인이밝혀지는경우나유전적소인이없더라도증상이지속되는경우, 재발하는경우에는조혈세포이식이근본적인치료이다 1). 그외 2007년 Shin 등에의해18세성인들을대상으로 cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) 병합화학요법을시행하였고성인 HLH에게효과적인것으로보고된바있다 14). 비기능항진증은빈혈, 백혈구감소, 혈소판감소중한가지이상을만족하면서비종대를동반하는경우로정의한다. 원인으로는감염, 자가면역질환, 간내외혈관의폐쇄, 악성질환등이있고치료는비색전술, 부분적또는전체비적출술을시행한다. 본증례는항암치료종료후에도 6 개월이상비종대및혈소판감소가있어비적출술을시행하였다. 비적출술후합병증으로패혈증이가장심각하며발생빈도가 3.3 4.25% 이다 15). 대부분의경우수술후 3년이내발생하며그중 50% 가 2년이내발생하고사망률이 50% 이상이며패혈증을유발하는균주는폐렴구균, 인플루엔자균, 뇌수막구균등피막세균들이 80% 를차지한다 15). 후기합병증으로혈소판증가에따른죽상경화증도나타나는데이환자는혈소판수치가정상이었고수술후 1주이내에간문맥혈전증이관찰되었다. 그리고환자에게비적출술후발생한간병변은간경화환자의비적출술후간기능이향상되었다는보고 16) 와는상반된다.

비적출술후아데노바이러스에의한혈구탐식성증후군 1 례 53 요 13세에대세포역행성림프종 (anaplastic large cell lymphoma) 진단받고, 17세에중추신경계재발, 19세에백혈병전환과비기능항진증의병력이있는환자가비적출술을시행후면역이저하된상태에서아데노바이러스감염이있었다. 이로인해 IAHS가유발되었고병합화학요법후호전된한명의환자에게나타난일련의질환들을보고하는바이다. 약 참고문헌 1. Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48: 124-31 2. Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clinic N Am 2008;28:293-313 3. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007; 7:814-22 4. Scott R, Robb-Smith A. Histocytic medullary reticulosis. Lancet 1939;2:194-8 5. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL study group of the histiocyte society. Semin Oncol 1991;18:29-33 6. Henter JI, Aricó M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94:a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study group of the histiocyte society. Med Pediatr Oncol 1997;28:342-7 7. Kim KJ, Kim KH, Lee TJ, Chun JK, Lyu CJ, Kim DS. Clinical characteristics and prognosis factors for survival in hemophagocytic lymphohistiocytosis. Korean J Pediatr 2008;51:299-306 8. Kim SY, Yoon JY, Lee SJ, Chung NG, Jang PS, Cho B, et al. The clinical manifestation of hemophagocytic lymphohistiocytosis. Korean J Pediatric Hematol-Oncol 2003;10:244-54 9. Iyama S, Matsunaga T, Fujimi A, Murase K, Kuribayai K, Sato T, et al. Successful treatment with oral ribavrin of adenovirus-associated hemophagocytic syndrome in a stem cell transplantation recipient. Rinsho Ketsueki 2005;46:363-7 10. Morito A, Teramura T, Asazu, Mukoyama A, Imashuku S. Hemophagocytic syndrome associated with severe adenoviral pneumonia: usefulness polymerase chain reaction for diagnosis. Int J Hematol 2003;77: 295-8 11. Seidel MG, Kastner U, Minkov M, Gadner H. IVIG treatment of adenovirus infection-associated macrophage activation syndrome in a two-year-old boy. Pediatr Hematol Oncol 2003;20:445-51 12. Palazzi DL, McClain KL, Kaplan SL, Hemophagocytic syndrome in children: an important disgnostic consideration in fever of unknown origin. Clin Infect Dis 2003;36:306-12 13. Henter JI, Samuelsson-Horne A, Aricó M, Egeler RM, Elinder G, Filipovich AH, et al. Histiocyte Society. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100:2367-73 14. Shin HJ, Chung JS, Sohn SK, Choi YJ, Kim YK, Yang DH, et al. Treatment outcomes with CHOP treatment in adult patients with hemophagocytic lymphohistiocytosis. J Korean Med Sci 2008;23:439-44 15. Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin N Am 2007;21:697-710 16. Murata K, Ito K, Yoneda K, Shiraki K, Sakurai H, Ito M. Splenectomy improves liver function in patients with liver cirrhosis. Hepatogastroenterology 2008;55; 1407-11