주간건강과질병 제 1 권제 15 호 국내임상에서분리된세균의특성화분석에따른병원체자원화, 세브란스병원진단검사의학과김도균, 정석훈, 이경원 * 질병관리본부국립보건연구원병원체자원관리 TF 정향민, 황규잠 * 교신저자

ISSN:25-811X www.cdc.go.kr PUBLIC HEALTH WEEKLY REPORT, PHWR Vol.1 No.15 CONTENTS 358 국내임상에서분리된세균의특성화분석에따른병원체자원화, 214-216 365 간흡충감염및관리사업현황 ; 간흡충감염퇴치수준도달을위해더필요한노력은무엇인가? 372 주요통계환자감시 / 전수감시, 표본감시 병원체감시 / 인플루엔자및호흡기바이러스 급성설사질환, 엔테로바이러스

주간건강과질병 제 1 권제 15 호 국내임상에서분리된세균의특성화분석에따른병원체자원화, 214-216 세브란스병원진단검사의학과김도균, 정석훈, 이경원 * 질병관리본부국립보건연구원병원체자원관리 TF 정향민, 황규잠 * 교신저자 leekcp@yuhs.ac, 2-2228-224 공동교신저자 kyuhwang@nih.go.kr, 43-719-687 Characterized Bacteria Resources from Clinical Specimen in Korea, 214-216 Department of Laboratory Medicine, College of Medicine, Yonsei University Kim Dokyun, Jeong Seok Hoon, Lee Kyungwon Pathogen Resource TF, Center for Infectious Disease, NIH, CDC Chung Hyangmin, Hwang Kyu Jam Background: The pathogen resources bank for the clinical isolates became an important issue especially after the Nagoya Protocol in 214. However, the previous system for the bacterium-banking process had limitations including lack of detailed information about the species identification, minimal inhibitory concentration, and mode of resistance. We isolated, characterized, and deposited clinical isolates from the National Culture Collection for Pathogens (NCCP) from 214 to 216. Methodology: Survey about the stock and demand of the reference strains was given to the experts of the Korean Society of Clinical Microbiology. Referring to the result of the survey, we collected useful or rare clinical isolates in the tertiary hospitals from 214 to 216. The collected isolates were characterized in terms of identification, phenotype and genotype of resistance and toxin, and strain type. Results: We have deposited 416 strains in the bank to characterize bacteria resources. A total of 193 strains were allotted for species identification, 4 strains for antimicrobial susceptibility testing, 14 strains for toxin gene testing, 169 strains for research of epidemiology and mode of resistance. These strains would expand the resources of the National Culture Collection for Pathogen and would also be useful for future medical research and the development of identification devices. 들어가는말 임상미생물검사실및미생물연구소에서는정도관리, 교육, 연구등의목적에사용되는참조균주가중요하다. 특히 214 년에는 제 1차생물다양성협약에서법적구속력이있는 유전자원접근및이익공유에대한나고야의정서 의발효로인하여병원체자원에대한국가주권이중요한이슈로부각되었다. 또한, 항균제내성은국내 외에서지속적으로증가하고있으며 [1-3], 내성과관련된 www.cdc.go.kr 358

주간건강과질병 제 1 권제 15 호 참조균주에대한수요도점점늘어나고있다. 그람양성세균의 methicillin 내성과 vancomycin 내성, 그람음성세균의 extendedspectrum β-lactamase와 carbapenemase에의한 3, 4세대 cephalosporin과 carbapenem 내성등은특히중요하여, 최근 WHO에서도감시체계를확립하고관리를시작하는등전세계적인이슈로자리잡고있다 [4]. 국내에서도병원체에대한자원화필요성을인식하여질병관리본부에서운영중인국가병원체자원은행 (National Culture Collection for Pathogens, NCCP) 은병원체자원네트워크를구축하여국내임상분리병원체를수집, 자원화하고, 관리및분양하여보건의료연구개발의활성화에기여하고있다. 국가병원체자원은행의분양가능한보유자원은 214년 537종 2,63주대비 216년 588종 2,428주로수집및자원화건수가 17.7 % 증가하였다. 그러나국외자원은행들의보유균수와는많은차이가있어지속적으로다양한병원체자원의수집및특성분석의확대가요구되고있다. 본내용은임상미생물관련학회전문가들을대상으로참조균주의보유현황과수요를조사한후, 그에맞는임상균주를수집하고, 각균주의특성화분석결과에관한내용이다. 하였다. 그람음성막대균의특성분석에는 16S rrna 또는 rpob gene 염기서열분석을통한정확한균동정, 디스크확산법및한천희석법을통한항생제내성표현형분석, carbapenemase 유전형분석, ESBL 유전형분석, aminoglycoside 수식효소유전형분석, 독소유전자유전형분석, multilocus sequence typing (MLST) 을이용한 strain type 분석등이포함된다. 그람양성알균의경우디스크확산법및한천희석법을통한항생제내성표현형분석, meca, vana, vanb 등의주요내성유전자검출, 독소유전자검출, MLST를이용한 strain type 분석등이포함되었다. Clostridium difficile의경우균종동정및독소유전자및조절유전자의검출 (tcdc, tcdd, tcde, binary toxin 생성유전자 ) 등을검출하고 PCR ribotyping을시행하였다. 참조균주보유및수요에대한설문조사에참여한기관은총 77개기관으로, 53개의종합병원, 11개의연구기관, 5개의수탁검사실등이포함되었다. 균종별참조균주보유및필요수조사에서대부분의기관에서흔한세균의 wild type을보유하고있었으나, 균종이다양하지못하며, ESBL, carbapenemase, 독소등 특성분석이된참조균주는대부분보유하지않고있고필요기관의 몸말 저자들은정도관리용및교육용균주의수요및참조균주혹은교육용균주의보유현황과수요를파악하기위해관련학회의전문가들을대상으로설문을시행하였다. 설문조사의결과를토대로, 214년부터 216년까지총 3년간종합병원에서분리된세균성임상분리주를대상으로 1차년도에는그람음성막대균특성화및자원화, 2차년도에는그람양성알균특성화및자원화, 3차년도에는무산소성균과기타임상분리주의특성화및자원화를진행하였고, 정도관리균주선별시스템을구축하였다. 참조균주는사용목적에따라, 동정용, 항균제감수성시험용, 내성기전시험용, 독소시험용및감염역학시험용으로구분하였으며, 그용도에따라특성화분석을진행하였다. 연구기간내에개발할참조균주의목표균주수는총 38주이며, 이중 6주의 NCCP 등록을목표로 수가많아특성화분석이된많은균주들이 NCCP에등록이된다면그수요는적지않을것으로판단되었다. 설문조사결과를바탕으로 214년부터 216년까지총 416주 (1년차 144주, 2년차 135주, 3년차 137주 ) 를수집하여특성분석을시행하였다. 균주의용도별분류는균종동정용이 193주, 항균제감수성시험용이 4주, 독소유전자시험용이 14주, 역학조사용이 18주, 내성기전조사용이 33주, 내성기전및역학조사용이 118주였다 (Table 1). 균종동정용으로분리된 193주의구성은임상적으로흔히분리되는그람양성세균인 Staphylococcus 균속 12주, Streptococcus 균속 12주, Enterococcus 균속 15주, 및그람음성세균인 Pseudomonas 균속 15주, Acinsetobacter 균속이 19주, 혐기성세균인 Bacteroides 균속 14주와그람양성및음성세균의희귀균주각각 15주및 51주등이포함되었다 (Table 2, Table 3과 Table 4.). 항균제감수성시험용참조균주 4주중 18주는디스크확산법시험에사용할수있는참조균주이며, www.cdc.go.kr 359

주간건강과질병 제 1 권제 15 호 Table 1. Number of deposited bacteria according to the classification of the purpose Purpose 214 215 216 Total Species identification 39 79 75 193 Antimicrobial susceptibility testing 22 14 4 4 Toxin gene testing 3 11 14 Epidemiology 4 14 18 Mode of resistance 18 4 11 33 Epidemiology and mode of resistance 58 13 47 118 Total 144 135 137 416 Table 2. Gram-positive bacteria collected for the species identification Strain No. Name Strain No. Name 15GSB1439 Staphylococcus epidermidis 15GSU83 Enterococcus raffinosus 15GSB146 Staphylococcus haemolyticus 15GSP143 Enterococcus hirae 15GSB1478 Staphylococcus capitis 15GSB2587 Enterococcus casseliflavus 15GSB1891 Staphylococcus salivarius 14GSB977-2 Kytococcus schroeteri [5] 15GSB1995-2 Staphylococcus warneri 14GS679854-2 Corynebacterium striatum 15GSP229 Staphylococcus constellatus 14GSB519 Rhothia dentocariosa 15GSP336-2 Staphylococcus lugdunensis 15GSP167 Nocardia nova 15GSU471 Staphylococcus simulans 16GSP14 Nocardia titidiscaviarum 16GSP85 Staphylococcus pasteuri 16GSP49-2 Bergeyella zoohelcum 16GSB265 Staphylococcus pseudointermedius 16SS91 Globicatella sulfidifaciens 16SS93 Staphylococcus aureus (small colony variant) 16SS92 Lactococcus garvieae 16SS94 Staphylococcus cohnii 16SS99 Weissella viridescens 15GSR23 Streptococcus pyogenes 16SS1 Corynebacterium diphtheriae 15GSR173 Streptococcus agalactiae 16SS11 Listeria monocytogenees 15GSP363 Streptococcus dysgalactiae 16SS12 Nocardia farcinica 15GSP1-2 Streptococcus sanginosus 16SS13 Nocardia nova 15GST19 Streptococcus anginosus 16SS14 Trueperella bernardiae 15GSP114 Streptococcus dentisani 16SS15 Tsukamurella inchonensis 15GSP334 15GSB1124 16SS95 16SS96 16SS97 16SS98 Streptococcus mitis Streptococcus infantarius Streptococcus gallolyticus Streptococcus gallolyticus subsp. pasteurianus Streptococcus pyogenes (nonhemolytic variant) Streptococcus salivarius subsp. thermophilus www.cdc.go.kr 36

주간건강과질병 제 1 권제 15 호 Table 3. Gram-negative bacteria collected for the species identification Strain No. Name Strain No. Name 14P43-1 Pseudomonas mosselii GS15B32 Agrobacterium tumefaciens 14U22-2 Pseudomonas putida GS15G75 Cupriavidus basilensis 14P311 Pseudomonas stutzeri GS15T131 Ralstonia mannitolilytica 14R783 Pseudomonas plecoglossicida GS14R463 Kerstersia gyiorum 14U1436 Pseudomonas fulva GS14P62 Pasteurella multocida 14R868 Pseudomonas fulva (fluorecens) GS15P222 Pasteurella canis GS15p149 Pseudomonas oryzihabitans 15 Elizabethkingia anophelis 16 Pseudomonas otitidis [6] 15-A Elizabethkingia anophelis GS14U22-2 Pseudomonas plecoglossicida 15-B Elizabethkingia meningoseptica GS14P429 Pseudomonas stutzeri 15-C Elizabethkingia meningoseptica 16GSC295 Pseudomonas nitroreducens 15-D Elizabethkingia miricola 16GSP35 Pseudomonas hunanensis 15-E Elizabethkingia miricola 16GSP93 Pseudomonas guariconensis 15-F Elizabethkingia anophilus 16GSP223 Pseudomonas oryzihabitans GS15P31 Ochrobactrum tritici 16GSP9 Pseudomonas rhodesiae GS15P2 Nassilia varians KS21314 Acinetobacter nosocomialis GS14P66 Bordetella petrii [7] KM2131 Acinetobacter pittii GS14G59 Neisseria lactamica EUIM212S13 Acinetobacter soli GS15R617 Neisseria cinerea PS212F15 Acinetobacter oleivorans 16SS84 Campylobacter hyointestinalis [8] KB212S13 Acinetobacter bereziniae 15GSB169 Ochrobactrum anthropi IH21312 Acinetobacter gyllenbergii 15GSB142 Burkholderia multivorans DJM2137 Acinetobacter haemolyticus 15GSU175 Myroides phaeus JB213N7 Acinetobacter junii 15GST131 Ralstonia mannitolilytica KSN213N1 Acinetobacter radioresistens 16GSP261 Ralstonia pickettii GS213B1272 Acinetobacter ursingii (red brown colony) 16GSG5-3 Roseomonas sp. KSN213N16 Acinetobacter ursingii 15GSB1553 Roseomonas massiliae/mucosa EUMC21415 Acinetobacter calcoaceticus 15GSR172 Bordetella bronchiseptica IH2148 Acinetobacter genomosp. 17BJ 15GSP76 Massilia timonae GS15B2974 Acinetobacter grimontii 16GSR139 Elizabethkingia anophelis MJNS4 Acinetobacter ursingii (IMP producing) 16GSC131 Comamonas sp. 15GSB893 Acinetobacter soli 16GSR711 Ewingella americana 16GSB984 Acinetobacter guillouiae 15GSP235 Pasteurella dagmatis 16GSU157 Acinetobacter schindleri 16SS85 Capnocytophaga ochracea 16GSG24 Acinetobacter radioresistens 16SS87 Dysgonomonas capnocytophagoides 14P329-3 Neisseria cinerea 16SS88 Eikenella corrodens 14P433-1 Comamonas testosteroni 16SS89 Gordonia bronchialis 14P78-1 Shewanella haloitis 16SS9 Kerstersia sp. 14P99 Ochrobactrum galinifaecis 16SS16 Mycoplasma homonis 14P382-1 Moraxella lacunata 16GSR297 Sphingomonas echinoides 14R463-2 Kerstersia gyiorum 16GSC293 Moraxella osloensis 14U913 Stenotrophomonas maltophillia 16GSU538 Massilia timonae GS15P199-1 Rahnella aquatillis 16GSR933 Shewanella spp. GS15P42 Eikenella corrodens www.cdc.go.kr 361

주간건강과질병 제 1 권제 15 호 Table 4. Anaerobic bacteria collected for the species identification Strain No. Name Strain No. Name 2 Clostridium perfringens 16SS83 Lactobacillus rhamnosus 4 Ruminococcus gnavus 16SS84 Lactobacillus casei 15GSP21 Actinomyces neuii 1 Bacteroides fragilis 5 Actinomyces europaeus 3 Bacteroides thetaiotaomicron 6 Actinomyces odontolyticus 4 Bacteroides ovatus 15GSB2549 Actinomyces odontolyticus 5 Bacteroides uniformis 7 Eggerthella lenta 6 Bacteroides vulgatus 8 Lactobacillus casei 14-B Bacteroides faecis [9] 9 Lactobacillus gasseri 14-C Bacteroides intestinalis 9-A Bifidobacterium pseudocatenulatum 14-A Bacteroides salyersiae 1 Propionibacterium acnes GS14B315 Bacteroides massiliensis 1-A Finegoldia magna GS14C211 Bacteroides cellulosilyticus 12 Parvimonas micra 16SS7 Bacteroides cellulosilyticus 12-A Anaerococcus vaginalis 16SS71 Bacteroides faecis 14 Peptostreptococcus anaerobium 16SS72 Bacteroides intestinalis 16 Peptoniphilus indolicus 16SS73 Bacteroides saalyersiae 17 Peptoniphilus rhinitidis 7 Parabacteroides distasonis 14GSB22-2 Flavonifractor plautii 8 Prevotella intermedia 15GSB259 Clostridium subterminale 9 Fusobacterium nucleatum 16GSC61 Atopobium parvulum 1 Fusobacterium mortiferum 16SS77 Porphyromonas pogonae 11 Fusobacterium varium 16SS78 Alloscardovia omnicolens 15 Leptotrichia trevisanii 16SS79 Clostridium innocuum (vanb positive) 3 Dialister pneumosintes 16SS8 Propionibacterium avidum 16SS69 Alistipes onderdonkii 16SS81 Propionimicrobium lymphophilum 16SS74 Butyricimonas spp. 16SS82 Slackia exigua 16SS75 Odoribacter splanchnicus 균주별로디스크확산법시험 5s회를반복하여참조범위를설정하였다 ( 평균값 ± 2SD) (Table 5). 독소유전자용참조균주는 bft-1, bft-2 그리고 bft-3를독소유전자를가지고있는 Bacteroides fragilis와 sea, sec, seg, seh, sei, tst 등의독소유전자를가진 Staphylococcus aureus를포함하였다. 역학조사용참조균주는 Clostridium difficile 중임상적으로중요한 ribotype인 159, 16, 78, 27, 84, 85, 1를포함하는 14균주와다제내성과연관된 sequence type (ST) 1249, 454, 71, 739의 Acinetobacter baumannii 를 포함하였다. 내성기전시험용참조균주는그람양성세균에서 vancomycin 내성과관련된 vana 유전자와그람음성세균에서중요한내성과연관된 ESBL 유전자와 carbapenemase 유전자을가진 33주를분석하여기탁하였다. 그리고내성기전및역학조사용참조균주로 118주를확보하였는데균종별로는 A. baumannii 59주, P. aeruginosa 32주, E. coli 1주, K. pneumoniae 4주및 E. faecium이 13주였다. A. baumannii 일부는 PCR mapping으로 OXA-23 유전자를지닌 transposon을규명하였고, colistin 내성 www.cdc.go.kr 362

주간건강과질병 제 1 권제 15 호 Table 5. Reference strains for the antimicrobial susceptibility testing Strain No. Name Characteristic Stain No. Name Characteristic ISM21312* Acinetobacter baumannii Susceptible to all antibiotics tested 3-1-P113 Bacteroides fragilis Resistant to carbapenem CS2131* Acinetobacter baumannii Resistant to carbapenem 12 Neisseria gonorrhoeae Susceptible to all antibiotics tested GS211R111* Acinetobacter baumannii Resistant to carbapenem and colistin 13 Neisseria gonorrhoeae Penicillinase production PSB287* Pseudomonas aeruginosa Susceptible to all antibiotics tested 14 Neisseria gonorrhoeae High level resistant to tetracycline BDC2843* Pseudomonas aeruginosa Resistant to carbapenem 15 Neisseria gonorrhoeae Non-susceptible to cefixime and cefpodoxime AS21312* Escherichia coli Susceptible to all antibiotics tested 15-A Neisseria gonorrhoeae Resistant to Cefixime GS213U443* Escherichia coli Resistant to carbapenem (KPC-2) 16 Neisseria meningitidis Susceptible to all antibiotics tested KSS2132* Escherichia coli Resistant to carbapenem (OXA-232) 17 Campylobacter jejuni Susceptible to all antibiotics tested KS2138* Klebsiella pneumoniae Susceptible to all antibiotics tested 18 Porphyromonas sp. Susceptible to all antibiotics tested MP14* Klebsiella pneumoniae Resistant to carbapenem (KPC-2) 11 Finegoldia magna Resistant to moxacillin KSS2131* Klebsiella pneumoniae Resistant to carbapenem (OXA-232) 11-A Finegoldia magna Resistant to clindamycin YN1312* Staphylococcus aureus Susceptible to all antibiotics tested 13 Anaerococcus vaginalis Resistant to clindamycin EUIM134* Staphylococcus aureus Susceptible to methicillin 13-A Peptostreptococcus anaerobius Resistant to penicillin SB1311* Staphylococcus aureus Resistant to methicillin GS15R637 Streptococcus pneumoniae Susceptible to penicillin SS1311* Enterococcus faecalis Susceptible to all antibiotics tested SS15169 Streptococcus pneumoniae Resistant to penicillin GS135* Enterococcus faecium High level resistant to aminoglycoside INHA144 Enterococcus faecium High level resistant to Gentamicin KM149* Enterococcus faecium Resistant to vancomycin 15USP3 Pseudomonas aeruginosa Susceptible to all antibiotics tested WK136* Enterococcus faecium Susceptible to all antibiotics tested 15EUIME1 Escherichia coli Susceptible to all antibiotics tested 212-5-B6158 Bacteroides fragilis Susceptible to all antibiotics tested 15KMS15 Staphylococcus aureus Susceptible to all antibiotics tested 21-3-P152 Bacteroides fragilis Resistant to carbapenem 15IH-EFM5 Enterococcus faecium Susceptible to all antibiotics tested * These 18 strains are reference strains for antimicrobial susceptibility testing with reference interval of zone diameter. (mean ± 2 SD). www.cdc.go.kr 363

주간건강과질병 제 1 권제 15 호 A. baumannii 는 pmrcab 유전자및 LPS 유전자의염기서열을 분석하였다. P. aeruginosa 일부는전유전체염기서열분석 (whole 관련된병원체균주를지속적으로확보하고자원화할수있는 기반을마련하는것이필요할것이다. genome sequencing, WGS) 으로 carbapenemase 유전자를지닌 genomic island (PAGI) 를규명하였다. K. pneumoniae 일부는 WGS로 KPC 유전자를지닌 plasmid를규명하였고, Enterococci 일부는 vana operon과 plasmid 구조를규명하였다 (Data not shown). 세균의항균제내성은계속확산되고있으며, 특히그람음성세균에서는내성기전의확산이 clone 에의한경우가많다. OXA-23 을생성하는 A. baumannii CC92, metallo-β-lactamase 생성 Pseudomonas aeruginosa ST235, CTX-M-15 ESBL 생성 E. coli ST131 등이대표적인예이다. 그리고이들유행내성 clone 은계속바뀌는경향이있어그특성을분석하여자원은행에자원화하는노력이필요하다. 본연구는특성이분석된균주를 NCCP에공급하여 NCCP의자원을확대하고수요에맞는균주를갖추는것을목표로진행하였다. 균종동정용으로분석된 193주는임상적으로중요한균종이거나, 분리가드문균종이포함되었으며, 앞으로 matrix-associated laser desorption/ionization-time of flight mass spectrometry(maldi-tof MS) 의동정용 database 구축에도유용할것으로생각된다. 항균제감수성시험용참조균주역시임상미생물검사실에서항균제감수성내부정도관리용으로그유용성이클것으로예상되며, 독소유전자시험용, 역학조사용, 내성기전조사용으로분석된균주들역시각각의시험에서양성참조균주로사용될수있을것으로여겨진다. 맺음말 임상미생물검사실및교육기관에서참조균주에대한수요는많이증가하였지만, 특성이분석된세균자원은행은부족한상황이다. 본연구를통하여기탁된총 416주는 NCCP 병원체자원의확대에일조하였다고여겨진다. 뿐만아니라지속적으로 참고문헌 1. Hong SG, Yong D, Lee K, Kim EC, Lee WK, Jeong SH, et al. Antimicrobial resistance of clinically important bacteria isolated from hospitals located in representative provinces of Korea. Korean J Clin Microbiol 23;6:29-36. 2. Lee K, Lee MA, Lee CH, Lee J, Roh KH, Kim S, et al. Increase of ceftazidime- and fluoroquinolone-resistant Klebsiella pneumoniae and imipenem-resistant Acinetobacter spp. in Korea: analysis of KONSAR study data from 25 and 27. Yonsei Med J 21;51:91-11. 3. Shibayama K, Lee H, Kim S. Comparison of antibiotic resistance rate of medically important microorganisms between Japan and Korea. Ann Clin Microbiol 215;18:111-8. 4. World Health Organization; Global Antimicrobial Resistance Surveillance System.(http://www.who.int/antimicrobial-resistance/ global-action-plan/surveillance/glass/en/) 5. Ha J, Kim KH, Kim JO, Hong J, Jeong SH and Lee K. Bacteraemia caused by Kytococcus schroeteri in a pneumonia patient. J Med Microb Diagn 215;4:4. 6. Kim D, Hong SK, Seo YH, Kim MS, Kim HS, Yong D, et al. Two non-otic cases of POM-1 metallo-β-lactamase-producing Pseudomonas otitidis infection: Necrotizing fasciitis and panperitonitis.j Glob Antimicrob Resist. 216;7:157-158. 7. Kwon SS, Kim JO, Kim KH, Jeong SH and Lee K. Persistent Bordetella petrii infection related to bone fractures. Ann Lab Med. 216;36:7-72. 8. Kim DK, Hong SK, Kim M, Ahn JY, Yong D and Lee K. Campylobacter hyointestinalis isolated from a human stool specimen. Ann Lab Med. 215;35:657-659. 9. Lee Y, Kim HS, Yong D, Jeong SH, Lee K and Chong Y. Bacteroides faecis and Bacteroides intestinalis recovered from clinical specimens of human intestinal origin. Yonsei Med J. 215;56:292-4. 이글은 214~216년질병관리본부용역과제인 특성화세균자원은행 결과보고서를일부요약정리한내용입니다. 늘어나고있는항균제내성에대비하기위해서이와관련된 참조균주역시필요성이점점증가하고있어, 앞으로내성기전과 www.cdc.go.kr 364

주간건강과질병 제 1 권제 15 호 간흡충감염및관리사업현황 ; 간흡충감염퇴치수준도달을위해더필요한노력은무엇인가? 질병관리본부국립보건연구원면역병리센터말라리아기생충과주정원, 이명노, 신희은, 조신형 * * 교신저자 : cho4u@korea.kr, 43-719-8521 The status of Clonorchis sinensis infection in Korea: What should be done to eliminate clonorchiasis? Division of Malaria and Parasitic Diseases, Center for Immunology and Pathology, NIH, CDC Ju Jung-Won, Lee Myoung-Ro, Shin Hee-Eun, Cho Shin-Hyeong Clonorchis sinensis (Cs), or liver fluke, is a parasite that represents the highest rates of intestinal parasitic diseases in Korea. Chronic Cs infection causes abnormal liver function and induces cholangiocarcinoma. In this report, we introduce the general status and risks of Cs infection and discuss efforts to eliminate it. Human Cs infection was first discovered on September 8, 1874 at the Medical College Hospital in Calcutta, India. Cs is a foodborne parasitic disease. To prevent Cs infection, it is important to change the habit of eating raw fish from freshwater sources. In endemic areas, through intensive control program to eliminate clonorchiasis, the incidence of Cs infection has decreased. The development and application of highly sensitive and specific diagnosis would be needed to control and eliminate clonorchiasis. Praziquantel (PZQ) is the only recommended drug for clonorchiasis treatment. There is a need to develop a better drug with less side effects and less dosage. The prevalence of cholangiocarcinoma is high in Cs endemic areas, while Cs-associated cancer could develop faster and has a shorter survival period. More efforts would be needed to eliminate clonorchiasis that include: 1) development of materials for public awareness campaigns and wide distribution of these in Cs endemic areas; 2) ensuring availability of simple and accurate diagnosis method that can be applied directly in the field; and 3) development of therapeutics that can replace PZQ. 들어가는말 최근국가통계조사 (212 년, 제 8 차전국장내기생충 감염실태조사 ) 에따르면우리나라의장내기생충감염률은 2.6% 로 나타났다. 1971년최초의조사에서나타난 84.3% 의장내기생충감염양성률을 2년간의대대적인전국퇴치사업을통해 1992년 3.8% 까지크게낮춘후지금까지점진적인감소경향을유지하고있다. 2.6% 의기생충감염양성률중가장높은양성률을나타내는 www.cdc.go.kr 365

주간건강과질병 제 1 권제 15 호 것은간흡충으로제 8차전국조사에서전체감염률의 73% 를기록하였다 [1]. 이글에서는우리나라장내기생충감염률 1위인간흡충의일반적인특징및위험성등을살펴보고, 관리현황과퇴치를위해요구되는노력에대해소개하고자한다. 부검을통해담관에서뾰족하고납작한흡충을발견하였다. 간흡충에대한최초의의학적인이발견은 Lancet에 1875년 8월 21일자로보고되었다. T. Spencer Cobbold는이기생충의명칭을 Distoma sinensis 로제안하였다. 197년 Arthur Looss는이기생충의 정소가나뭇가지처럼분지되어있는특징에기인하여 Clonorchis 몸말 간흡충 (liver flukes) 은간내담도에기생하는납작한모양의기생충을통칭한다. 인간에감염되는주요간흡충은흡충류 (trematode) 중에서도 Opisthorchiidae분류군에속하며, 중국간흡충 (Clonorchis sinensis), 타이간흡충 (Opisthorchis viverrini), 고양이간흡충 (Opisthorchis felineous) 등이알려져있다. 타이간흡충은태국, 베트남남부를포함하는동남아시아에서유행하며, 고양이간흡충은러시아, 유럽일부에서유행한다. 중국간흡충의경우우리나라를포함하여베트남북부, 중국에서유행하며, 2억명이상이감염위험에노출되어있고, 약 15만명이상이감염되어있는것으로파악된다. 216년 Lancet이라는유명의학학술지에중국간흡충 (C. sinensis) 발견 14년을맞아간흡충감염증에대한리뷰논문이게재되었다 [2]. 이논문의내용을중심으로간흡충발견과생활사에대해소개하겠다. 1874년 9월 8일 2세의중국남자목수가인도캘커타에있는의과대학병원에와서심한간질환으로불과몇시간만에사망하였는데, 병리학교수인 James F. P. McConnell이 sinensis로재명명하였고지금까지학계에서부르는명칭이되었다 (Figure 1). 1975년중국후베이성에서발견된서한조시대시신의장에서간흡충충란이확인된것으로보아적어도 2천년전에도사람에게감염되어존재하였음을알수있다. 서민교수등의백제시대유적이나신라그리고조선시대의미이라를대상으로한고생물학연구를통해보여지듯이우리나라에서도 2천년이상의감염역사를가지는것으로확인된다 [3]. 최근생물정보에대한대단위분석기술의발달로 2년대들어간흡충의단백체, 전사체및유전체정보의분석이이루어져진단제, 치료제개발을위한기초자료로활발히이용되고있다 [4,5,6]. 간흡충의생활사는일본학자들에의해주로밝혀졌는데, 191년 Harujiro Kobayashi 가민물고기가 2차중간숙주로역할하는것을맨처음밝혔고, Masatomo Muto는 1918년에민물달팽이류가 1차중간숙주임을확인하였다. 질병관리본부말라리아기생충과에서는국내간흡충유행지역의강및하천을중심으로 2차중간숙주인민물고기에서간흡충피낭유충감염정도를학계전문가와함께조사해오고있다. 그결과붕어과의민물고기가주요감염원이며, 돌고기로불리는어류의경우한마리에최대 7천개이상의피낭유충이감염되어있어이를생식했을경우상당한위험을 중국서한조시대미이라에서간흡충란확인 (26 BC-AD9) 백제유적 (18 BC-AD66) Clonorchis sinensis 명명 (197) 단백체분석 (29~ ) 유전체분석 (211~) / / 간흡충발견및보고 (1874-75) 치료제 PZQ 개발 (197 년대말 ) 전사체분석 (211~) Figure 1. The Archaeological findings and major researches on Clonorchis sinensis www.cdc.go.kr 366

주간건강과질병 제 1 권제 15 호 초래할수있는수준이었다. 각민물고기의감염정도를간단하게요약하면그림 2와같다. 간흡충은감염후 26년이상생존이가능한것으로알려져있다. 최종숙주로사람을가정하고생활사를설명해보면, 사람에감염된간흡충은담도에서유약충에서성충으로발달한후충란을낳고, 충란은담즙을따라장으로이동한후분변으로배출된다. 민물달팽이의한종류인쇠우렁이가충란을먹으면장에서융모가달린유충 (miracidia) 으로부화하고, 장벽으로침투한다. 무성생식기를거쳐차례로 sporosysts, rediae 그리고꼬리가달린유충 ( 유미유충, cercariae) 으로변태한다. 감염약 95일후달팽이로부터나온유미유충은민물고기에부착하여침투한다음피부밑이나근육속에낭을만들면서약 45일안에성숙한피낭유충 (metacercariae) 으로발달한다. 감염된민물고기를사람이날것이나충분히익히지않은상태로섭취하여침투한피낭유충은위에서위액소화효소인 trypsin의자극으로탈낭을시작하고낭내단백질분해효소 (cysteine protease) 의활성을통해십이지장에서탈낭을완료한다. 낭에서빠져나온어린유충은담즙을향한 화학주성에따라팽대부 (ampulla of vater) 에서간내담관으로빠르게이동한후성충으로발달한다 (Figure 3). 감염된지약 4주후부터충란을배출하기시작하며, 산란양은숙주에따라다른데, 사람의경우매일성충한마리가약 4,개의충란을낳는것으로알려져있다. 간흡충감염에의한증상은만성적인특징을나타내는데감염정도와기간에따라임상적으로차이를나타낸다. 감염정도는분변 1그램에서관찰되는간흡충충란의수를기준으로나눌수있는데, 이를 EPG(eggs per gram) 라하며간흡충을포함한장내기생연충의감염정도를확인하는지표로쓰인다. 1,개이하를경감염, 1~3개사이를중감염그리고 3개이상을고감염으로구분한다. 이를이용해실제감염되어있는성충의수도추산해볼수있다. 간흡충 1마리가하루에낳는충란은 4,개로알려져있고, 성인 1일배변량이평균1-2 그램인점을고려하여감염정도를계산해볼수있는것이다. 2g 분변중 1g을취하여검사해서 1개의충란이관찰되었다고하면, 전체 2g에는 2만개의충란이있다고추산되고, 1마리의성충이낳는충란수를 No. of metacercariae of Clonorchis sinensis in Fresh water fish 1, 2, 3, 4, 5, 6, 7, 8, Freshwater fishes as an intermediate host of Clonorchis sinensis 7th 2nd 4th 8th 1st 6th 9th 3rd 5th 1th 칼납자루 678 긴몰개 7,68 참붕어 1,538 피라미 42 돌고기 7,75 모래무지 1,325 납지리 295 몰개 2,67 중고기 1,318 납자루 245 Figure 2. The kinds of freshwater fishes as an intermediate host of Clonorchis sinensis. (Prevention and management of tropical and endemic parasitic diseases. 216. KCDC) www.cdc.go.kr 367

주간건강과질병 제 1 권제 15 호 Figure 3. The life cycle of Clonorchis sinensis 적용하면, 약 5마리의성충이감염되어있다고할수있다. 이를통해경감염은 5마리이하, 중감염은 5 ~ 15 마리그리고고감염은 15마리이상이감염되어있다고할수있다. 이러한감염정도는구충을위한치료제복용량을정하는데중요한요소로고려되어야한다. 프라지콴텔 (Praziquantel, PZQ) 은간흡충외에도주혈흡충, 타이간흡충등흡충류와조충류에광범위하게사용되는기생충전문치료제이다. 프라지콴텔은독일에서개발되어 197년대말중국과한국에서간흡충치료를위해맨처음사용되어현재에는간흡충감염의유일한치료제로사용되고있다. 이치료제의효과는감염정도와복용기간에따라다르다. WHO에의한복용권고량은치료제인프라지콴텔을일회 25mg/kg 의양으로하루세번, 총 2일을복용 ( 총 15 mg/kg) 해야만 9% 이상구충이가능하고, 충란감소률 1% 를달성할수있다고알려져있다. 그러나이것의절반만복용할경우충란감소률은높지만, 고감염의경우치료율은크게떨어진다. 결국치료제인프라지콴텔은적절한복용량 (6kg 성인기준총9g) 이치료효율을높이지만, 상대적으로복용후전신피로감, 어지러움및메스꺼움등의부작용으로꾸준한복용이어려운점이치료제로서커다란단점이다. 이러한이유로치료제복용에만의존하는간흡충퇴치관리사업은감염률을크게낮추는것은가능하지만퇴치수준에도달하기어려운한계가있다. 최근이를대체할수있는치료제로서복용량이상대적으로적고, 부작용이적은대체약품개발이진행 www.cdc.go.kr 368

주간건강과질병 제 1 권제 15 호 되고있는데근접한것중의하나로트리벤디미딘 (tribendimidine) 이있다. 프라지콴텔의 1분의 1 복용량으로 5% 정도의치료율을나타내고부작용은상대적으로낮다. 이치료제에대한복용방법과복용량에대한연구가꾸준히진행되고있으며, 트리벤디미딘과복합처방치료의효과와안전성평가을위한대규모시험등이이루어진다면치료율을더높일수있을것으로기대된다. 간흡충감염에의한증상은감염정도 (worm burden) 와관계가있다. 감염정도가낮은환자는대개무증상을보이거나가벼운증상을나타낼뿐이지만, 감염정도가높은환자들의경우에는 의하면, 간흡충감염에의한담관암발생이전체담관암의 25% 였고암의위치는간내담관암, 간문부암, 및원위부담관암모두에서원인인자로작용하였다 [8]. 또한간흡충관련담관암 (CACC; Clonorchis sinensis associated cholangiocarcinoma) 는발생나이가상대적으로빠르고, 예후가불량하고생존기간또한짧았다 (Figure 4) 이러한결과는간흡충감염에대한보건관리가단순히구충사업에만국한될것이아니라그후속병리적인위험도를낮출수있는방향으로관리및연구사업을확대하고꾸준히전개해야할필요가있음을보여준다. 무력감, 메스꺼움, 소화불량, 두통, 현기증, 복부불만감, 설사, 복통등의비특이적인증상을나타낸다. 간흡충감염의대표적인신체증상은황달, 간비대및간이물러지는것이다. 만성간흡충감염은담석증 (cholelithiasis), 담낭염 (cholangitis) 과같은여러가지복합적인질환을야기한다. 간농양과췌장염도간흡충감염이원인이될수있는복합질환이다. 중증감염어린이들의경우발달지연등이보고되었으며, 부적응, 설사, 영양실조, 빈혈, 간비대등이관찰된다. 간흡충감염은담관암의발생과관련이있는것으로폭넓게받아들여지고있으며, 국제암연구위원회 (IARC; the International Agency for Research on Cancer) 는간흡충을 1994년발암가능인자군 (group2a) 로분류하였다가, 29년절대발암요인군 (group 1) 으로분류하였다. 이는간흡충감염에 의한간및담도의구조적이상과지속적인만성염증유발에 기인하는것으로알려져있다. 관찰된결과에의하면감염후성충은 최대 3 년정도를숙주의담관에서살수있는데완전한구충에 Figure 4. Overall survival curve according to clonorchiasis 1 yr SYR 6.% vs 49.3%, 3 yr SYR 28.3% vs 22.%, 5 yr SYR 19.2% vs 13.2% 실패할경우지속적인만성염증에노출될것이고, 유행지역에 계속거주하고날것을먹는식습관을계속유지하는경우가대부분이므로재감염또한계속이루어지게될것으로사료된다. 심지어치료제를잘복용하여완전한구충에성공하였다하더라도중감염에의해구조적으로망가진간및담도에서의병리적인진행에의한담관암과의관련위험성을배제할수없을것이다. 216년중앙암등록본부에서발표한 1999년부터 213년까지 15년간의암통계종합분석자료에의하면과거중감염이상의감염률을나타냈던곳에서담관암발생이다른지역의평균보다훨씬높았다 [7]. 또한 215년질병관리본부정책연구용역보고서에 맺음말 간흡충은식품매개그중에서도어류매개기생충이다. 질병관리본부에서는만성유행지역에대한적극적인진단과치료제제공 (active case detection & selective chemotheraphy) 을통한간흡충감염관리사업을수행하여고유행지역의감염률을지속적으로낮추어왔다. 이를통해고유행지역에서감염양상은고감염자는거의사라지고경감염과중감염자가대부분으로 www.cdc.go.kr 369

주간건강과질병 제 1 권제 15 호 나타나고있다. 간흡충감염을퇴치수준으로낮추기위해서는다음과같은다양한노력을더욱가속화시켜야하는시점이다. 1) 간흡충감염은앞서언급했듯이주로아시아국가에서일어나는데, 이지역에서는민물고기를회로생식하거나, 소금에절여먹는식문화가발달한것이감염의주요원인이다. 그러나다양한홍보와교육에도불구하고전통적인식문화에대한개선이어려운것이현실이다. 근본적인식습관개선을통한예방수준을더욱높이기위해유행지역의교육수준과문화등을고려한홍보와교육자료를개발하여유행지역주민에게실질적인교육과홍보가이루어질수있는정책수행이필요하다. 2) 최근대부분을차지하는간흡충경감염자와중감염자는표준진단법인현미경검경에서충란을직접확인하는진단에서는양성으로판정하기어려우므로보다민감하고정확하며현잔에서적용이 3. Shin D. H., et al (214). V-shaped pits in regions of ancient Baekje kingdom paleoparasitologically confirmed as likely human-waste reservoirs. Korean J Parasitol. 52(5), 569-573. 4. Yoo W.G., et al (211). Developmental transcriptomic features of the carcinogenic liver fluke, Clonorchis sinensis. PLoS Negl Trop Dis. 5(6), e128. 5. Ju J.W., et al (29) Identification of a serodiagnostic antigen, legumain, by immunoproteomic analysis of excretory-secretory products of Clonorchis sinensis adult worms. Proteomics 9(11), 366-378. 6. Wang X., et al. (211) the draft genome of the carcinogenic human liver fluke Clonorchis sinensis. Genome Biol. 12(1), R17. 7. 보건복지부, 중앙암등록본부 (216) 시군구별암발생통계및발생지도. 8. Park S. M. (215) Analysis of clinical association between clonorchiasis and cholangiocarcinoma in Korea. 질병관리본부정책연구용역사업보고서 (11-1352159-381-1). 가능한진단법개발이필요하다. 3) 간흡충치료제로사용되고있는프라지콴텔의높은복용량과부작용을낮출수있는복용법개선이나새로운치료제의발굴이간흡충감염치료사업의효과를높일수있다. 4) 간흡충감염이높았던지역에서의높은담관암발병율은간흡충치료후암발생가능성을낮추기위한관리기술과암발생조기진단기술개발을통한조치치료의필요성을제기하고있다. 이러한요구를해결하기위해서는감염환자의병리진행을보여주는생물자원의발굴과확보가필요하며이를바탕으로간흡충감염정도가어느정도부터본격적인병리증상이나타내는지, 감염정도와기간에따른담관암발생의위험도는얼마나증가하는지그리고치료후에간및담도의구조적인회복이담관암발생가능성을낮출수있는지에대한자세한연구와논의가가능해질것이다. 참고문헌 1. Korea Centers for Disease Control and Prevention. Korea Nation Institute of Health. 213. National survey of the prevalence of intestinal parasitic infections in Korea, 212. The 8th Report. Osong Chungcheongbuk-do, Korea. 2. Qian M. B., et al (216). Clonochiasis. Lancet 387, 8-81. www.cdc.go.kr 37

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status of selected infectious diseases 1.1 환자감시 / 전수감시감염병주간발생현황 (14th ) Table 1. Reported cases of national infectious diseases in Republic of Korea, ending April 8, (14th )* Group Ⅰ Group Ⅱ Group Ⅲ Group Ⅳ Classification of disease ly average Total no. of cases by year 216* 215 214 213 212 Cholera 2 4 3 Typhoid fever 5 38 3 121 121 251 156 129 Paratyphoid fever 3 17 1 56 44 37 54 58 Shigellosis 2 37 1 113 88 11 294 9 EHEC 12 14 71 111 61 58 Viral hepatitis A 116 1,45 65 4,677 1,84 1,37 867 1,197 Pertussis 2 42 1 129 25 88 36 23 Tetanus 2 24 22 23 22 17 Measles 4 14 4 18 7 442 17 3 Mumps 427 3,647 247 17,58 23,448 25,286 17,24 7,492 Rubella 2 42 1 11 11 11 18 28 Viral hepatitis B (Acute) 7 94 6 359 155 173 117 289 Japanese encephalitis 1 28 4 26 14 2 unit: no. of cases Imported cases of current : Country(no. of cases) Varicella 1,242 15,825 531 54,59 46,33 44,45 37,361 27,763 Unknown(1) Streptococcus pneumoniae 15 149 4 441 228 36 - - Malaria 2 21 3 673 699 638 445 542 Scarlet fever 521 5,174 72 11,912 7,2 5,89 3,678 968 Meningococcal meningitis 7 6 6 5 6 4 Legionellosis 3 37 128 45 3 21 25 Vibrio vulnificus sepsis 56 37 61 56 64 Murine typhus 2 2 18 15 9 19 41 Scrub typhus 23 147 4 11,17 9,513 8,13 1,365 8,64 Leptospirosis 8 117 14 58 5 28 Brucellosis 5 18 4 5 8 16 17 Rabies HFRS 6 87 2 578 384 344 527 364 Syphilis 37 448 19 1,569 1,6 1,15 799 787 CJD/vCJD 1 25 1 42 33 65 34 45 Tuberculosis 648 7,943 723 3,892 32,181 34,869 36,89 39,545 HIV/AIDS 2 22 16 1,59 1,18 1,81 1,13 868 Dengue fever 6 47 1 314 255 165 252 149 Q fever 8 46 85 27 8 11 1 West Nile fever 1 Philippines(2), Cambodia(1), India(1), Malaysia(1), Papua New Guinea(1) Lyme Borreliosis 5 15 27 9 13 11 3 Sweden(1) Melioidosis 4 4 2 2 Chikungunya fever 1 2 1 2 1 2 Philippines(1) SFTS 165 79 55 36 - MERS 185 - - - Zika virus infection 2 16 - - - - Abbreviation: EHEC= Enterohemorrhagic Escherichia coli, HFRS= Hemorrhagic fever with renal syndrome, CJD/vCJD= Creutzfeldt-Jacob Disease / variant Creutzfeldt-Jacob Disease, SFTS= Severe fever with thrombocytopenia syndrome, MERS-CoV= Middle East Respiratory Syndrome Coronavirus. Cum: Cumulative counts from 1st to current in a year. * The reported data for year 216, are provisional but the data from 212 to 215 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. The reported surveillance data excluded Hansen s disease and no incidence data such as Diphtheria, Poliomyelitis, Haemophilus influenzae type b, Epidemic typhus, Anthrax, Plague, Yellow fever, Viral hemorrhagic fever, Smallpox, Severe Acute Respiratory Syndrome, Animal influenza infection in humans, Novel Influenza, Tularemia, Newly emerging infectious disease syndrome and Tick-borne Encephalitis. Data on scarlet fever included both cases of confirmed and suspected since September 27, 212. 문의 : (43) 719-7112 www.cdc.go.kr 372

Table 2. Reported cases of national infectious diseases in Republic of Korea, ending April 8, (14th )* unit: no. of cases Provinces Cholera Typhoid fever Paratyphoid fever Shigellosis Enterohemorrhagic Escherichia coli Viral hepatitis A Pertussis Tetanus Total 2 5 38 43 3 17 12 2 37 34 12 3 116 1,45 615 2 42 52 2 1 Seoul 1 9 1 4 3 8 6 2 1 29 286 113 9 4 Busan 1 1 1 1 1 4 3 1 32 38 1 Daegu 3 2 1 2 1 1 1 23 8 1 1 19 Incheon 2 2 1 2 6 11 128 77 3 2 Gwangju 2 1 1 1 1 1 1 2 21 2 2 Daejeon 1 2 1 1 7 82 2 19 Ulsan 1 2 12 9 2 Sejong 1 2 1 1 16 1 Gyonggi 1 8 2 6 2 11 7 4 1 31 429 195 13 2 Gangwon 1 1 1 5 33 15 Chungbuk 1 1 1 1 1 1 3 24 1 Chungnam 2 3 2 1 2 11 14 24 1 1 Jeonbuk 1 2 2 1 4 86 28 1 3 Jeonnam 1 2 2 2 8 56 17 3 1 Gyeongbuk 2 1 1 3 1 26 1 2 1 1 Gyeongnam 1 1 2 9 1 1 2 1 1 2 27 12 2 1 1 Jeju 1 1 1 1 15 3 Cum: Cumulative counts from 1st to current in a year * The reported data for year 216, are provisional but the data from 211 to 215 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 373

Table 2. Reported cases of national infectious diseases in Republic of Korea, ending April 8, (14th )* unit: no. of cases Provinces Measles Mumps Rubella Viral hepatitis B (Acute) Japanese encephalitis Varicella Malaria Scarlet fever Total 4 14 2 427 3,647 2,82 2 42 5 7 94 59 1 1,242 15,825 9,536 2 21 25 521 5,174 687 Seoul 1 4 1 48 362 292 5 1 4 21 8 1 133 1,458 955 9 4 43 527 97 Busan 1 29 193 22 3 2 1 8 96 974 848 1 28 398 77 Daegu 12 96 88 3 4 1 74 924 639 2 146 49 Incheon 1 12 144 162 4 7 84 929 626 2 2 4 21 222 44 Gwangju 26 287 24 2 1 1 51 455 263 1 16 245 32 Daejeon 2 9 91 156 2 4 2 23 372 226 27 157 3 Ulsan 15 114 11 3 2 26 518 343 1 1 13 175 32 Sejong 3 24 8 3 26 28 1 1 4 26 1 Gyonggi 3 7 9 111 875 583 1 2 2 26 11 336 4,489 2,558 4 1 211 1,619 27 Gangwon 19 235 96 1 1 5 2 22 38 54 1 1 4 37 16 Chungbuk 1 11 92 53 1 2 5 1 14 228 223 1 5 83 18 Chungnam 1 14 152 9 2 2 2 36 674 378 1 1 27 299 4 Jeonbuk 18 13 38 1 5 6 744 352 1 11 16 45 Jeonnam 5 3 29 158 2 58 77 368 1 2 225 25 Gyeongbuk 1 18 199 77 1 6 5 3 66 917 332 1 24 335 63 Gyeongnam 1 46 46 155 1 4 4 11 1,325 64 41 434 8 Jeju 6 38 69 1 27 46 235 6 86 11 Cum: Cumulative counts from 1st to current in a year * The reported data for year 216, are provisional but the data from 211 to 215 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. Data on scarlet fever included both cases of confirmed and suspected since September 27, 212. www.cdc.go.kr 374

Table 2. Reported cases of national infectious diseases in Republic of Korea, ending April 8, (14th )* unit: no. of cases Provinces Meningococcal meningitis Legionellosis Vibrio vulnificus sepsis Murine typhus Scrub typhus Leptospirosis Brucellosis Hemorrhagic fever with renal syndrome Total 7 1 3 37 5 2 2 2 23 147 83 8 3 5 18 6 87 49 Seoul 1 1 11 2 1 2 12 3 2 3 3 3 Busan 2 1 9 6 1 3 1 Daegu 4 2 2 1 Incheon 4 1 3 1 1 2 Gwangju 3 1 1 2 Daejeon 1 4 4 1 1 Ulsan 1 1 3 3 2 1 1 1 Sejong 1 1 Gyonggi 1 6 1 1 1 8 1 1 1 1 3 2 36 15 Gangwon 1 1 2 1 3 2 4 5 Chungbuk 2 5 1 1 2 1 4 3 Chungnam 1 2 2 4 15 4 1 3 1 6 3 Jeonbuk 1 1 7 9 2 1 8 3 Jeonnam 1 1 5 3 14 2 1 6 3 Gyeongbuk 1 1 1 11 4 1 3 1 6 Gyeongnam 1 1 6 32 14 1 1 2 3 Jeju 1 1 3 1 Cum: Cumulative counts from 1st to current in a year * The reported data for year 216, are provisional but the data from 211 to 215 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. Calculated by averaging the cumulative counts from 1st to current, for a total of 5 preceding years www.cdc.go.kr 375

Table 2. Reported cases of national infectious diseases in Republic of Korea, ending April 8, (14th )* unit: no. of cases Syphilis CJD/vCJD Dengue fever Q fever Lyme Borreliosis SFTS Zika virus infection Tuberculosis Provinces 3-year 3-year Total 37 448 22 1 25 11 6 47 25 8 46 3 5 15 2-648 7,943 9,18 Seoul 12 148 32 3 2 2 17 9 1 4 7-123 1,449 1,852 Busan 2 24 14 1 1 1-31 526 697 Daegu 3 15 8 4 1 3 2 1 1-33 382 472 Incheon 2 36 17 1 1 2 1 1 1-35 437 471 Gwangju 2 14 7 1 1 1 1-13 213 244 Daejeon 2 11 4 1 1-23 19 214 Ulsan 2 3 2 1-11 153 19 Sejong 4 1-4 23 2 Gyonggi 9 112 53 6 2 2 13 6 2 9 2 1-139 1,698 1,833 Gangwon 1 8 8 3 1 3-26 321 368 Chungbuk 3 5 3 2 2 1 12-23 251 271 Chungnam 9 8 1 1 1 2 5 1 1 2-21 373 374 Jeonbuk 1 7 6 1 2-3 312 341 Jeonnam 1 1 4 1 1 1 1-38 43 435 Gyeongbuk 17 9 1 3 1 4 1 1-39 57 631 Gyeongnam 14 15 1 1 1 2 2 6 1-49 521 595 Jeju 2 14 9 1-1 121 1 Cum: Cumulative counts from 1st to current in a year * The reported data for year 216, are provisional but the data from 211 to 215 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. 5(3)-year average is mean value calculated by cumulative counts from 1st to current for 5(3) preceding years. www.cdc.go.kr 376

1.2 환자감시 / 표본감시감염병주간발생현황 (14th ) 1. Influenza, Republic of Korea, ending April 8, (14th ) 년도제 14 주인플루엔자의사환자분율은외래환자 1, 명당 16.7 명으로지난주 (13.6) 대비증가 216- 절기유행기준은 8.9 명 (/1,) 인플루엔자유행주의보발령 : 216 년 12 월 8 일 ( 목 ) 1 9 8 7 ILI per 1, 6 5 4 3 2 1 36 38 4 42 44 46 48 5 52 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 32 34 216-215-216 214-215 213-214 Figure 1. The ly proportion of Influenza-Like Illness per 1, outpatients, 213-214 to 216- flu seasons 2. Hand, Foot and Mouth Disease(HFMD), Republic of Korea, ending April 8, (14th ) 년도제 14 주수족구병의사환자분율은외래환자 1, 명당.8 명으로지난주 (.4) 대비증가 수족구병은 29 년 6 월법정감염병으로지정되어표본감시체계로운영 55. 5. 45. 4. 수족구병환자분율 (%) 35. 3. 25. 2. 15. 1. 5. 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 216 215 214 213 Figure 2. The status of HFMD sentinel surveillance, 213- www.cdc.go.kr 377

3. Ophthalmologic, Republic of Korea, ending April 8, (14th ) 년도제 14 주유행성각결막염의외래환자 1, 명당분율은 15.5 명으로지난주 16.8 명보다감소하였음 동기간급성출혈성결막염의환자분율은.5 명으로지난주.2 명보다증가하였음 6 5 1, 명당외래환자수 4 3 2 1 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 214 215 216 Figure 3. The ly proportion of Epidemic keratoconjunctivitis per 1, outpatients 5 4 1, 명당외래환자수 3 2 1 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 214 215 216 Figure 4. The ly proportion of Acute hemorrhagic conjunctivitis per 1, outpatients www.cdc.go.kr 378

4. Reported cases of national sentinel surveillance disease in the Republic of Korea, ending April 8, (14th ) unit: no. of cases/sentinels Viral hepatitis Sexually Transmitted Diseases Hepatitis C Gonorrhea Chlamydia Genital herpes Condyloma acuminata Total 1.7 1.2 13.8 1.4 4.1 4.7 2.6 11.6 8.3 2.3 11.8 9. 1.6 8.2 6.4 Cum: Cumulative counts from 1st to current in a year According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. 문의 : (43)719-7118, 7132, 6917 자세히보기 : 질병관리본부 정책 / 사업 감염병감시 표본감시주간소식지 1.3 수인성및식품매개감염병집단발생주간현황 (14th ) Waterborne & Foodborne disease outbreaks, Republic of Korea, ending April 8, (14th ) 년도제 14 주에집단발생이 11 건이발생하였으며누적발생건수는 18 건 ( 환례수 898 명 ) 이발생함 35 3 25 2 15 1 5 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 년도 216 년도 4 년평균발생건수 (11-14 년 ) Figure 5. Number of Waterborne & Foodborne disease outbreaks reported by, 216- www.cdc.go.kr 379

2.1 병원체감시 / 인플루엔자및호흡기바이러스주간감시현황 (14th ) 1. Influenza, Republic of Korea, ending April 8, (14th ) 제 14 주에의뢰된호흡기검체 291 건중인플루엔자바이러스 44 건 (15.1%)[A(H3N2) 형 3 건, B 형 41 건 ] No. of Positive 2 18 16 14 12 1 8 6 4 2 1. 9. 8. 7. 6. 5. 4. 3. 2. 1. Percent positive(%) 36 38 4 42 44 46 48 5 52 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 32 34 A/H3N2 A(not subtyped) A/H1N1pdm9 B percent positive Figure 6. The ly proportion of Influenza-Like Illness per 1, outpatients, 216- flu seasons 2. Respiratory viruses, Republic of Korea, ending April 8, (14th ) 년도제14 주호흡기검체에대한유전자검사결과 76.3% 의호흡기바이러스가검출되었음 ( 최근 4주평균 294 개의호흡기검체에대한유전자검사결과를나타내고있음 ) 주별통계는잠정통계이므로변동가능 216- () Weekly total Detection rate (%) HAdV HPIV HRSV IFV HCoV HRV HBoV HMPV 11 57.8 1.7 3.5 3.1 6.9 6.9 19. 2.4 14.2 12 64.9 1.7 2.4 2.7 9.6 4.8 23.4.7 19.6 13 63.4 2.9 3.9 1.3 15.4 2.9 2.6 1. 15.4 14 76.3 3.8 3.1 1. 15.1 4.1 26.1 3.4 19.6 59. 3. 2. 3.7 15.2 7.3 15.7 1. 11. 216 59. 6.3 6. 4.6 15.9 5.5 15. 1.6 4.1 - HAdV : human Adenovirus, HPIV : human Parainfluenza virus, HRSV : human Respiratory syncytial virus, IFV : Influenza virus, HCoV : human Coronavirus, HRV : human Rhinovirus, HBoV : human Bocavirus, HMPV : human Metapneumovirus : the rate of detected cases between Jan. 1. - Apr. 8., (Average No. of detected cases is 294 in last 4 s) 216 : the rate of detected cases between Dec. 27. 215 - Dec. 31. 216. 자세히보기 : 질병관리본부 알림 주간질병감시정보 www.cdc.go.kr 38

2.2 병원체감시 / 급성설사질환실험실표본주간감시현황 (13th ) Acute gastroenteritis causing virus No. of sample No. of detection (Detection rate, %) Group A Rotavirus Norovirus Enteric Adenovirus Astrovirus Total 1 82 14 (17.1) 15 (18.3) (.) (.) 29 (35.4) 11 96 3 (31.3) 13 (13.5) 1 (1.) 2 (2.1) 46 (47.9) 12 84 34 (4.5) 2 (23.8) 1 (1.2) 3 (3.6) 58 (69.) 13 6 18 (3.) 15 (25.) (.) 1 (1.7) 34 (56.7) 845 18 (21.3) 197 (23.3) 13 (1.5) 16 (1.9) 46 (48.) * The samples were collected from children <5 years of sporadic acute gastroenteritis > in Korea. Acute gastroenteritis causing bacteria Week No. of Sample Salmonella Pathogenic spp. E.coli Shigella spp. No. of isolation (Isolation rate, %) V.parahaem V. cholerae Campylobacter C.perfringens S. aureus B. cereus Total olyticus spp. 1 188 1 (.53) 1 (.53) () () () 2 (1.6) 4 (2.13) 1 (.53) 3 (1.6) 12 (6.38) 11 155 3 (1.94) 1 (.65) () () () 3 (1.94) 1 (.65) 4 (2.58) 1 (.65) 13 (8.39) 12 19 1 (.53) 1 (.53) () () () 5 (2.63) 1 (.53) 2 (1.5) 2 (1.5) 12 (6.32) 13 18 2 (1.11) 3 (1.67) () () () () 4 (2.22) 2 (1.11) 1 (.56) 12 (6.67) 2,115 23 (1.9) 27 (1.28) 2 (.9) 1 (.5) () 15 (.71) 34 (1.61) 32 (1.51) 25 (1.18) 159 (7.52) * Bacterial Pathogens ; Salmonella spp., E. coli (EHEC, ETEC, EPEC, EIEC), Shigella spp., Vibrio parahaemolyticus, Vibrio cholerae, Campylobacter spp., Clostridium perfringens, Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Yersinia enterocolitica. * hospital participating in Laboratory surveillance in 216 (7 hospitals) 자세히보기 : 질병관리본부 알림 주간질병감시정보 www.cdc.go.kr 381

2.3 병원체감시 / 엔테로바이러스실험실주간감시현황 (13th ) The detection rate of Enterovirus in enterovirus sentinel surveillance, Republic of Korea, ending April 1, (13th ) 년도제 13 주실험실표본감시결과엔테로바이러스검출건수는 2 건이며, 년도누적발생건수는 2 건임 Aseptic meningitis 8 6 4 2 1 5 9 13 17 21 25 29 33 37 41 45 49 53 216 Enterovirus detection rate (%) Enterovirus detection rate (%) Figure 7. Detection rate of enterovirus in Aseptic meningitis patients from 216 to HFMD and Herpangina 25 2 15 1 5 1 5 9 13 17 21 25 29 33 37 41 45 49 53 216 Enterovirus detection rate (%) Enterovirus detection rate (%) HFMD with Complications Figure 8. Detection rate of enterovirus in HFMD and Herpangina patients from 216 to 1 9 8 7 6 5 4 3 2 1 1 5 9 13 17 21 25 29 33 37 41 45 49 53 216 Enterovirus detection rate (%) Enterovirus detection rate (%) Figure 9. Detection rate of enterovirus in HFMD with Complications patients from 216 to www.cdc.go.kr 382

주요통계이해하기 <Table 1> 은지난 5년간발생한법정감염병과 년해당주발생현황을비교한표로, 는 년해당주의신고건수를나타내며, 은 년 1주부터해당주까지의누계건수, 그리고 ly average 는지난 5년 (211-215 년 ) 해당주의신고건수와이전 2주, 이후 2주의신고건수 ( 총 25주 ) 평균으로계산된다. 그러므로 과 ly average 의신고건수를비교하면해당주단위시점과예년의신고수준을비교해볼수있다. Total no. of cases by year 는지난 5년간해당감염병현황을나타내는확정통계이며연도별현황을비교해볼수있다. 예 ) 년 12 주의 ly average(5 년간주평균 ) 는 211 년부터 215 년의 1 주부터 14 주까지의신고건수를 총 25 주로나눈값으로구해진다. * ly average(5 년주평균 )=(X1 + X2 + + X25)/25 1주 11주 12주 13주 14주 215년 해당주 214년 X1 X2 X3 X4 X5 213년 X6 X7 X8 X9 X1 212년 X11 X12 X13 X14 X15 211년 X16 X17 X18 X19 X2 21년 X21 X22 X23 X24 X25 <Table 2> 는 17 개시 도별로구분한법정감염병보고현황을보여주고있으며, 각감염병별로 Cum, average 와 Cum, 을비교해보면최근까지의누적신고건수에대한이전 5년동안해당주까지의평균신고건수와비교가가능하다. Cum, average 는지난 5년 (211-215 년 ) 동안의동기간신고누계평균으로계산된다. <Table 3> 은표본감시감염병에대한신고현황으로, 최근발생양상을신속하게파악하는데도움이된다.

발간등록번호 11-1351159-2-3 주간건강과질병, PHWR 은질병관리본부에서시행되는조사사업을통해생성된감시및연구자료를기반으로근거중심의건강및질병관련정보를제공하고자최선을다할것이며, 제공되는정보는질병관리본부의특정의사와는무관함을알립니다. 본간행물에서제공되는감염병통계는 감염병의예방및관리에관한법률 에의거, 국가감염병감시체계를통해신고된자료를기반으로집계된것으로집계된당해년도자료는의사환자단계에서신고된것이며확진결과시혹은다른병으로확인될경우수정될수있는잠정통계임을알립니다. 주간건강과질병, PHWR 은질병관리본부홈페이지를통해주간단위로게시되고있으며, 정기적구독을원하시는분은 kcdcnids@korea.kr로신청가능합니다. 이메일을통해보내지는본간행물의정기적구독요청시구독자의성명, 연락처, 직업및이메일주소가요구됨을알려드립니다. 주간건강과질병 발간관련문의 : kcdcnids@korea.kr/ 43-719-7116/7125 창 발 간 : 28 년 4 월 4 일 행 : 년 4 월 13 일 발행인 : 정기석 편집인 : 정은경 편집위원 : 최영실, 김기순, 최병선, 조신형, 조성범, 김봉조, 구수경, 김용우, 이동한, 조은희, 오윤희, 김희숙, 박윤진 편 집 : 질병관리본부감염병관리센터감염병관리과 충북청주시흥덕구오송읍오송생명 2 로 187 오송보건의료행정타운 ( 우 )28159 Tel. (43) 719-7116/7125 Fax. (43) 719-7139