주간건강과질병 제 10 권제 33 호 연구단신 2, Brief report 2 국내임상분리진균의자원화를통한연구인프라구축 전북대학교병원진단검사의학과조용곤 * 질병관리본부국립보건연구원감염병연구센터병원체자원관리 TF 이경민, 김미희, 황규잠 * 교신저자 :

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1 연구단신 2, Brief report 2 국내임상분리진균의자원화를통한연구인프라구축 전북대학교병원진단검사의학과조용곤 * 질병관리본부국립보건연구원감염병연구센터병원체자원관리 TF 이경민, 김미희, 황규잠 * 교신저자 : choyg@jbnu.ac.kr / 공동교신저자 : kyuhwang@nih.go.kr / Establishing a research infrastructure of pathogenic fungi resources Cho Yong Gon Department of Laboratory Medicine, Chonbuk National University Hospital Lee Kyeong Min, Kim Mi Hee, Hwang Kyu Jam Pathogen Resource TF, Center for Infectious Diseases, KNIH, KCDC Recently, it has been reported that the prevalence of fungal infection is increasing worldwide and more than one million people die from fungal infections every year, suggesting that early diagnosis and treatment methods need to be improved. It is also known that mortality from invasive fungal infections is 22.4%, showing about 50% for blood cancer patients, and 87% for allogeneic hematopoietic stem cell transplant patients. Therefore, establishing an infrastructure for research on fungal infections is considered necessary. In order to secure various fungal resources nationwide, collection system need to include resources from major domestic hospitals that have a variety of immunosuppressed patients. Additionally collection hospitals are required to identify fungi using standardized testing methods, select resources according to selection criteria, and obtain clinical and epidemiological information on patients and establish them as a database. In accordance with the law on collection and management and utilization of pathogen resources that became newly effective on February 4, 2017, establishing a specialized bank as research infrastructure to collect, manage, and distribute pathogenic fungi resources at national level should be accelerated. The bank is expected to play pivotal roles in both the improvement of diagnosis and treatment for fungal infections and the development of related health industries. 들어가는말 최근우리나라를포함하여전세계적으로진균감염의 유병률이증가추세라고보고되고있다. 특히, 진균성뇌수막염이나 혈류감염과같은침습성진균질환은환자에게치명적일수있기 때문에이러한유병률증가는심각하게받아들여지고있다. 매년 892

2 세계적으로 100만명이상이진균감염으로사망하고있지만, 현재개발된항진균제는많지않고심각한부작용을동반하는문제를갖고있다. 또한, 유전자재조합및다양한보강제 (adjuvant) 가포함된진균백신의연구가진행되고있지만상용화된제품이없는상태로새로운치료전략의개발이필요하다. 치명적인침습성진균감염의원인병원체로는 Aspergillus, Candida, Cryptococcus 등이있으며, 이러한진균병원체에의한감염은면역시스템이약한인간면역결핍바이러스 (HIV) 환자나항암치료및면역억제치료를받는환자에게는더욱치명적일수있고, 감염의위험도더높을수있다. 실제, 혈액암환자와동종조혈모세포이식환자는면역기능의저하와호중구감소증, 점막손상등의이유로침습성진균감염의고위험군으로분류하고있다. 침습성진균감염으로인한사망률은 22.4% 로높게보고되고있으며 [1], 환자의기저질환에따라크게다르지만, 혈액암환자의경우약 50%, 동종조혈모세포이식환자는약 87% 의매우높은사망률을나타낸다고알려져있다 [2]. 국내한대학병원의통계에따르면, 혈액암환자에서진균감염원인균의 81% 가 Aspergillus, 원인으로지목되고있으며, 대략 30~40% 의높은사망률을나타낸다. 인구학적특성에따라위험도가높은칸디다균의종류에차이가보고되어있는데, 고령에서는 Candida glabrata, 면역저하환자에서는 Candida krusei, 소아및신생아에서는 Candida parasilosis의위험이높은것으로나타났다 [3]. 국내의경우도전체진균감염의유병률이 2009년 6.9% 에서 2013년 7.4% 로증가한것으로보고되었다. 발생형태를구분하였을때, 피부진균증이 5.2% 로가장높았고, 칸디다증과아스페르길루스증과같은기회감염진균증이 1.7% 라고보고하였다 [4]. 2012년도 2개월간의자료분석을통해파악된국내발생주요진균감염의원인진균을종류별로살펴보면 Table 1, 2와같다 [5]. 그러나진균감염의원인병원체를주위환경에흔히존재하는진균과구분하여정확하게동정하고자원화하는것은현실적으로매우어렵기때문에, 기회감염이증가하고있는상황에서이러한환자들로부터임상적으로의의가있는진균을구별하여자원화하는것이중요하며, 이러한진균병원체를자원화하기위해서는임상정보를활용하여수집하고자원화하는체계구축이필요하다. 12% 가 Candida, 2% 가털곰팡이 (Mucormycetes), 2% 가 Fusarium, Penicillium 등의기타곰팡이, 1% 가기타효모균이었다. 이러한진균들은폐렴의원인균 (73%) 으로동정되었다. 병원검사실에서흔히분리되는 Candida 의경우다수의국가에서주요혈류감염의 Table 1. Types and frequency of molds isolated from clinical specimens of 10 university hospitals in Korea Species Number of strains Percentage of strains Aspergillus spp % Aspergillus fumigatus % Aspergillus niger % Aspergillus flavus % Aspergillus terreus % Aspergillus spp. unidentified % Trichophyton spp % Penicillium spp % Others % Total 1, % 893

3 Table 2. Types and frequency of yeasts isolated from clinical specimens of 10 university hospitals in Korea Species Number of strains Percentage of strains Candida albicans 7, % Candida tropicalis 1, % Candida parasilosis % Candida glabrata % Candida krusei % Candida famata % Candida guillerimondii % Candida lusitaniae % Candida haemulonii % Non-albicans, unidentified % Candida spp., unidentified 1, % Malassezia spp % Trichosporon spp % Cryptococcus spp % Saccharomyces cerevisiae % Kodamea spp % Others % Total 13, % 몸말 국제적인생물다양성협약 (convention on biological diversity, CBD) 에따라생물유전자원을이용해얻어지는이익을자원제공국과공유하도록하는 나고야의정서 가지난 2014년 10월 12일발효되었다. 국내에서도병원체자원에대해국가간대응을제대로할수있는법적근거로써 병원체자원의수집관리및활용촉진에관한법률 ( 이하 병원체자원법 ) 이입법, 제정되어 2017년 2월 4일자로발효되었다. 병원체자원은 보건의료의연구또는산업을위하여실제적이거나가치가있는자원 으로인간에게감염병을일으키는세균, 진균, 바이러스, 원충등의병원체및관련정보와병원체로부터유래하여자연적으로존재하는세포물질, 항원, 항체등의파생물질및관련정보가포함된다고정의하고있다. 따라서감염의대상인환자에서분리된병원체가가지고있는임상정보 및역학정보가포함되어야자원으로서가치를가지며, 이러한정보는병원체자원이미생물자원과차별화되는것으로높은가치가부여된다. 이때, 2011년제정되어시행중인 < 개인정보보호법 > 에위배되지않도록익명화처리된정보관리체계를갖추어야한다. 식별이불가능한임상정보는개인정보에해당하지않는다는점에유의하여병원체자원의수집이필요할것으로사료된다. 또한, 병원체자원법에근거하여국내병원체자원현황조사가 5년마다이루어지고, 자원의수집, 관리활용을효율적으로수행하기위해분야별병원체자원전문은행이지정, 운영될예정이다. 의진균분야는치사율이높은침습성진균자원등다양한병원체의수집이필요하지만, 일선의료기관에서는표재성피부진균의분리빈도가높기때문에, 다양한진균자원의수집및자원화를위해서는면역이정상인환자로부터저하된환자까지포함하여다양한임상상황으로부터지속적인수집을시행할수있는전국규모의 894

4 협력체계가필요하다. 국내감염병원체의수집은다양한기관에서산발적으로이루어지고있으며, 진균을보존하고분양하는기관으로는생물자원센터 (Korean collection for type culture, KCTC) 와한국미생물보존센터 (Korean culture center of microorganism, KCCM), 그리고한국의진균자원은행 (Korean collection of medical fungi, KCMF) 이있다. 이기관들이보유한진균과병원체자원법에따라지정, 운영되는진균전문은행이수집보유할진균자원은약간의차이점을가지게될것으로보인다. 의진균자원전문은행의가장큰특징으로는임상적의의가확인된원인병원체로서의진균자원을관련정보, 예를들어환자의임상정보및역학정보를함께데이터베이스화하여수집하고분양한다는점이다. 침습성진균질환에대한진단기준은 2008년발표된 EORTC/MSG(European organization for research and treatment of cancer/mycoses study group) 기준을사용하여확진 (proven) 과가능 (probable) 으로나누어분류하는데, 세부기준의내용은아래의 Table 3, 4와같다 [6]. 진균자원을수집할때, 다양한임상적특성으로진균의역학이달라질수있으므로진균분리전사용된예방적항진균제종류와환자의호중구감소증유무, 칸디다혈증의경우중심정맥카테터의사용유무, 사용된면역억제요법이나기저질환파악등의관련정보를함께수집하여연구자에게제공함으로써감염질환의치료기준개선이나항진균제내성기전연구, 치료제개발등에가치있는정보로사용될수있다. 또한, 전문은행으로서표준균주를개발하여검사실이나검사기기의정도관리나교육용참조주로제공할수있고, 다양한항원, 항체관련특성이나진균특이또는항진균제내성관련유전자분석을시행하여연구자맞춤형고부가가치자원을제공하는기능을수행할수있다. 이러한수집체계구축에있어서필수요건은다양한면역억제환자군에서분리된진균자원을전국적으로확보할수있어야하고, 이를위해서국내주요종합병원유래자원이포함되어야한다. 각병원에서는수집체계로부터표준화된검사법을사용하여진균을확인동정하고, 수집체계로부터확립된자원의선정기준에 Table 3. Criteria for proven invasive fungal disease except for endemic mycoses[6] Analysis and specimen Molds a Yeasts a Microscopic analysis: sterile material Culture Sterile material Blood Histopathologic, cytopathologic, or direct microscopic examination b of a specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage Recovery of a mold or black yeast by culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, a cranial sinus cavity specimen, and urine Blood culture that yields a mold d (e.g., Fusarium species) in the context of a compatible infectious disease process Histopathologic, cytopathologic, or direct microscopic examination b of a specimen obtained by needle aspiration or biopsy from a normally sterile site (other than mucous membranes) showing yeast cells for example, Cryptococcus species indicated by encapsulated budding yeasts or Candida species showing pseudohyphae or true hyphae c Recovery of a yeast by culture of a sample obtained by a sterile procedure (including a freshly placed [!24 h ago] drain) from a normally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process Blood culture that yields yeast (e.g., Cryptococcus or Candida species) or yeast-like fungi (e.g., Trichosporon species) Serological analysis: CSF Not applicable Cryptococcal antigen in CSF indicates disseminated cryptococcosis a If culture is available, append the identification at the genus or species level from the culture results. b Tissue and cells submitted for histopathologic or cytopathologic studies should be stained by Grocott-Gomorri methenamine silver stain or by periodic acid Schiff stain, to facilitate inspection of fungal structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should be stained with a fluorescent dye (e.g., calcofluor or blankophor). c Candida, Trichosporon, and yeast-like Geotrichum species and Blastoschizomyces capitatus may also form pseudohyphae or true hyphae. d Recovery of Aspergillus species from blood cultures invariably represents contamination

5 Table 4. Criteria for probable invasive fungal disease except for endemic mycoses[6] Host factors a Recent history of neutropenia (0.5*10 9 neutrophils/l [500 neutrophils/mm 3 ] for 110 days) temporally related to the onset of fungal disease Receipt of an allogeneic stem cell transplant Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for 13 weeks Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-a blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency) Clinical criteria b Lower respiratory tract fungal disease c The presence of 1 of the following 3 signs on CT: Dense, well-circumscribed lesions(s) with or without a halo sign Air-crescent sign Cavity Tracheobronchitis Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis Sinonasal infection Imaging showing sinusitis plus at least 1 of the following 3 signs: Acute localized pain (including pain radiating to the eye) Nasal ulcer with black eschar Extension from the paranasal sinus across bony barriers, including into the orbit CNS infection 1 of the following 2 signs: Focal lesions on imaging Meningeal enhancement on MRI or CT Disseminated candidiasis d At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks: Small, target-like abscesses (bull s-eye lesions) in liver or spleen Progressive retinal exudates on ophthalmologic examination Mycological criteria Direct test (cytology, direct microscopy, or culture) Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following: Presence of fungal elements indicating a mold Recovery by culture of a mold (e.g., Aspergillus, Fusarium, Zygomycetes, or Scedosporium species) Indirect tests (detection of antigen or cell-wall constituents) e Aspergillosis Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF Invasive fungal disease other than cryptococcosis and zygomycoses β- D -glucan detected in serum NOTE. Probable IFD requires the presence of a host factor, a clinical criterion, and a mycological criterion. Cases that meet the criteria for a host factor and a clinical criterion but for which mycological criteria are absent are considered possible IFD a Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to patients given treatment for malignant disease and to recipients of allogeneic hematopoietic stem cell and solid-organ transplants. These host factors are also applicable to patients who receive corticosteroids and other T cell suppressants as well as to patients with primary immunodeficiencies b Must be consistent with the mycological findings, if any, and must be temporally related to current episode c Every reasonable attempt should be made to exclude an alternative etiology d The presence of signs and symptoms consistent with sepsis syndrome indicates acute disseminated disease, whereas their absence denotes chronic disseminated disease e These tests are primarily applicable to aspergillosis and candidiasis and are not useful in diagnosing infections due to Cryptococcus species or Zygomycetes (e.g., Rhizopus, Mucor, or Absidia species). Detection of nucleic acid is not included, because there are as yet no validated or standardized methods 896

6 따라자원을선별하며, 선별된진균이유래한환자의임상및역학정보를정해진기준에따라확보하고데이터베이스로구축하는것이포함되어야한다. 또한, 진균감염증례를보고하는학회및연구자와의협력체계도포함되어야한다. 고빈도진균에대해서는일부수집하여기탁이이루어지고있으나, 희귀진균이나최근해외여행의증가나농수산물수입물자의증가등으로그동안국내에서보고되지않았던새로운종류의감염원인진균에대한수집은어려운실정이다. 이러한전국규모의다양한자원을수집하고자원화할수있는체계를장기적으로유지, 발전시켜야한다. 진균병원체자원은국내임상분리주가운데고빈도분리균종과 3. Oren I and Paul M. Up to date epidemiology, diagnosis and management of invasive fungal infections. Clinical Microbiology and Infection 2014;20(suppl 6): Yoon HJ, et al. Prevalence of fungal infections using National Health Insurance data from , South Korea ephih 2014;36:e 김수현, < 진단, 연구용의진균자원의개발및수집 > 질병관리본부학술연구용역과제 ( 최종보고서, 과제번호제 호 ) 2012년. 6. Pauw BD, Walsh TJ, et al. Revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (EORTC/MSG) consensus group. Clin Infect Dis 2008; 46: 저빈도또는희귀분리균종으로나누어수집및자원화하는전략으로접근하는것이필요하다. 고빈도분리진균은중복되지않는범위에서임상및역학적특성이나항진균제내성특성, 분자생물학적특성에따라다양한균주를수집하는전략이필요하고, 희귀진균은감염관련학회와의협력을통해증례보고저자로부터기탁을받는전략이마련되어야한다. 맺음말 진균분야의병원체자원전문은행의설치, 운영은체계적인수집자원화체계구축을통해전국적으로다양한진균자원의확보가가능해지고진균감염연구와진단및백신을포함한치료제의개발에필수적인국가자원인프라가구축될것으로전망된다. 참고문헌 1. McNeil MM, et al. Trends in mortality due to invasive mycotic diseases in the United States, Clin Infect Dis 2001;33: Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001;32:

편집순서 1 : 겉표지 학술연구용역사업최종결과보고서 과 국문과제명 제 영문과제명 명 주 의 ( 주의내용기재 ) 2 0 주관연구기관 : ( 글 14 point 고딕체 ) 질병관리본부 질병관리본부 - 1 -

편집순서 1 : 겉표지 학술연구용역사업최종결과보고서 과 국문과제명 제 영문과제명 명 주 의 ( 주의내용기재 ) 2 0 주관연구기관 : ( 글 14 point 고딕체 ) 질병관리본부 질병관리본부 - 1 - 주의내용 주 의 1. 이보고서는질병관리본부에서시행한학술연구용역사업의최종결 과보고서입니다. 2. 이보고서내용을발표할때에는반드시질병관리본부에서시행한 학술연구용역사업의연구결과임을밝혀야합니다.