KOREA CENTER FOR KOREA CENTER FOR DISEASE DISEASE CONTROL&PERVENTION CONTROL&PREVENTION 주간건강과질병 KOREA CENTER FOR DISEASE CONTROL&PREVENTION www.cdc.go.kr ISSN:2005-811X. 8. 28. 제 7 권제 35 호 기생충감염에의한숙주면역조절의중요성 Effect of Parasite Infection on the Regulation of Host Immune Response 질병관리본부국립보건연구원면역병리센터말라리아기생충과 정영일, 이상은 Abstract Parasites employ various strategies to evade effective host immune response that thwarts infection. Although immune evasion has been developed to favor parasite establishment within the host, certain immune-escaping strategies might, quite paradoxically, be also beneficial for the host. Regulatory B cells, regulatory T cells, and alternatively activated macrophages have been identified as key components of the immune regulatory network functioning during helminth infections. These immune regulatory cells expand during parasite infection and may promote the development of chronic infection and parasites survival as well as influence unrelated immune-driven pathology such as allergy and autoimmune diseases. Meanwhile, there are increasing evidences which indicate that modulation of immune response induced by parasite infection negatively affects the resistance to major global microbial pathogens, including Mycobacterium tuberculosis, human immunodeficiency virus (HIV), and Plasmodium species that cause malaria. In addition, anti-helminth treatments may have a substantial effect on vaccine efficacy. Thus, it is important to determine how and as to what extent do helminths interfere with the successful control of specific concurrent co-infections. This review briefly analyzes some of the current data related to the regulatory cells derived from parasites that contribute to the down regulation of the immune response of the host. CONTENTS 761 기생충감염에의한숙주면역조절의중요성 767 원인불명병원체분석법의해외동향 773 한국성인의콜레스테롤수준 (2008-2012) 777 주요통계 : 수족구병의사환자분율 / 유행성각결막염, 급성출혈성결막염발생분율 / 인플루엔자의사환자분율 / 지정감염병
762 제 7 권제 35 호 Ⅰ. 들어가는말 장내기생충은아주오랜시간동안숙주인인간과함께공존해오면서다양한면역조절기전들을진화시켜왔다. 이들기생충들에감염되면숙주면역체계는이에대항하기위해강력한 TH2 면역반응을작동하게된다. 그러나기생충의입장에서는이러한숙주면역계의공격으로부터살아남아야하고, 이를위해숙주면역체계를교란시키는다양한면역회피기전을진화시켜왔다. 대표적인면역회피전략으로숙주의염증반응을제어할수있는면역조절세포를활성화시키는것이다. 기생충감염에의해유도되는면역조절세포로서는조절 T 세포 (CD4 + CD25 + FoxP3 + T cell), 조절 B 세포 (IL-10 + -producing CD1d high CD5 + CD19 + B cell), 그리고대체적활성화대식세포 (Alternatively activated macrophage) 가대표적이다. 흥미롭게도기생충감염에의해유도된면역세포들은알레르기 (allergy) 나자가면역질환 (autommune diseases) 과같이과도한염증반응이원인이되는면역질환과만나게되면방관자효과 (bystander effect) 로서의도하지않은이들질환의발병과진행을억제하게된다. 이러한이유에서기생충감염에의한면역질환의억제기전은지난 10년간기생충연구에서큰화두가되고있다. 비록다양한연구결과가쏟아져나오면서많은논쟁을야기하고있지만, 그럼에도불구하고, 실제임상적적용에서기생충을이용한생물치료가새로운자가면역치료법으로각광을받고있는점은기생충이우리면역체계에서큰영향력을나타내고있음을부인할수없는부분이다. 한편, 기생충에의한숙주면역반응의조절은또다른측면에서중요한의미를갖는다. 즉, 기생충감염이다른병원체감염에유의적인영향을미치는것이다. 전세계적으로문제가되는주요감염성병원체인 Mycobacterium tuberculosis, human immunodeficiency virus(hiv) 와 Plasmodium 종 (species) 의경우, 이들질병의유행지역과기생충의유행지역이묘하게겹치는것을발견할수있는데, 최근수행된역학조사와다양한실험모델을이용한연구결과들은기생충감염이이들병원체에대한감수성을증가시킨다는것을확인시켜주고있다. 본원고는기생충감염으로인한면역반응조절이숙주에미치는영향을중심으로두가지시각에서고찰해보고자한다. 즉, 알레르기나자가면역질환과같은면역질환을억제할수있는 이로운면역반응의유도기전과이를활용한자가면역질환치료요법을소개하고, 이와는상반된개념으로기생충감염이다른감염성병원체에대한숙주의감수성에미치는영향에대해기술하고자한다. Ⅱ. 몸말 기생충감염에의한숙주면역반응조절기전만성적으로장내기생충에감염된환자의말초혈액내 T 세포를분리하여기생충항원으로자극시켜도세포는이에크게반응하지않는다. 뿐만아니라, 기생충이외의항원에대해서도대조군에비해세포의활성화정도가훨씬떨어지는것으로나타난다. 이는기생충감염기간동안앞서기술한 3가지면역조절세포가중심이되어면역조절네트워크가활성화됨에따른결과로이해되고있다. 기생충감염에의해조절 T 세포의개체수가크게증가하는것은놀라운사실이아니다. 윤충 (helminth) 에서원충 (protozoan parasite) 에이르기까지다양한종의기생충감염에서이들세포가활성화되고개체수가증가되는것이확인되었으며, 동물모델을이용하여이들세포를인위적으로제거시켰을때, 기생충감염에대한숙주의저항성은현저히증가하고, 기생충충체부하 (worm burden) 는크게감소되는것을확인할수있다. 이렇듯, 조절 T 세포는기생충이갖는숙주면역회피기전에중심이되는면역조절세포이다. 한편, IL-10 을분비하는조절 B 세포는자가면역질환의발병과진행을조절하는데중요한역할을수행하는면역조절세포로처음알려졌다. 최근기생충과관련된연구결과에서도이러한조절 B 세포가기생충감염기간동안그개체수가높은수준으로증가되는것으로확인되었다. 기생충에의한알레르기와자가면역질환억제기전에있어서조절 B 세포의중요성역시최근동물실험통해확인되었다. 즉, 이들세포를인위적으로제거하거나기능을차단하였을때, 기생충감염에의해유발된알레르기염증반응의억제효과가함께소실되었으며, 반대로입양면역 (adaptive transfer) 을통해이들세포를인위적으로이식했을때, 염증반응에대한억제력이복원되는것이확인되었다 [1]. 또한조절 B 세포는조절 T 세포의분화와활성을유지하는데깊이관여하는것으로알려져있다.
주간건강과질병 763 마지막으로대체적활성화대식세포역시기생충감염동안활성화되는특징을나타내는데, 이들세포는조절 T 세포의분화를촉진시키며, 면역조절과과도한염증반응으로인해손상된조직을회복시키는데중요한 arginase 1을활성화시키는역할을수행한다 [2]. 그러나기생충감염이어떤식으로세포들을자극하여면역조절세포로의분화와증식을유도하는지에대한구체적인기전에대해서는아직명확하게밝혀지지않고있다. 따라서이러한면역조절네트워크를촉진시킬수있는기생충유래의면역조절분자는어떤것이있는지규명하는것이앞으로무엇보다도중요하다. 대표적으로장내에기생하는선충의일종인 Heligmosomoides polygyrus bakeri의분비물질중에서찾은 TGF-β-like ligand는조절 T 세포의분화를강하게유도할수있는것으로확인되었다 [3]. 이밖에도사상충에의해분비되는 ES-62 단백질의 N-type glycan에부착된 phosphorylcholine 이염증반응억제에관여하는것으로확인되었다. 기생충유래의면역조절물질을발굴하는것만큼중요한것은이들물질들이갖는작동기전에대해규명하는것이다. 현재까지이러한기생충유래면역조절물질에대한명확한작동기전에대한연구는많이미흡한실정이기에기생충을활용한생물치료요법개발을위해서는앞으로많은연구가필요할것으로사료된다. 기생충을이용한자가면역질환의치료요법의효과지난 50여년동안의산업화과정을지나면서면역계이상에기인하는다양한면역질환들이선진국을중심으로폭발적인증가추세를나타내고있다. 그러나열약한위생환경으로인해기생충감염이유행하는지역에서는알레르기와자가면역질환의유병률이현저히낮은결과를보인다. 이러한역학조사연구결과뿐만아니라, 실험동물모델을통해확인된다양한자가면역질환들 ( 뇌수막염, 제1형당뇨, 궤양성대장염, 및관절염등 ) 에서기생충감염에의한억제효과는새로운면역질환들에대한생물치료요법으로서기생충의가치를일깨워주는근거가되고있다. 기생충을임상치료에적용한대표적인사례로돼지편충 (Trichuris suis) 의알을이용한염증성장질환치료요법이있다. 염증성장질환은궤양성대장염 (ulcerative colitis) 과 크론병 (Crohn's disease) 으로잘알려져있으며, 장점막에만성적으로염증및면역반응이초래되어지속적인조직손상을일으키는면역질환이다. 현재까지명확한병태생리는알려져있진않지만, 환경적요인, 유전적요인또는세균감염의한면역조절기능의결함등이단독또는복합적인행태로관여되는것으로이해되고있다. 또한, 치료에있어서도단순히염증부위를외과적수술을통해절제하거나, 스테로이드계열의약물치료를통해증상을완화시키는정도에서만이뤄질뿐완치방법을찾지못하고있는실정이다. 이러한상황에서기생충을이용한생물치료요법의탁월한효과는이들질환으로고통받는환자들에게큰희망을안겨주고있다. T. suis는돼지의장내에서기생하는편충으로서사람에게서기생하는편충과유사하지만, 숙주특이성으로인해인체내에서는오랫동안생존하지못할뿐만아니라, 개체수도증가하지않으며전염되지않고일정시간경과후에는인체내에서자연스럽게사라지는특징을갖는다. 가축농장에서종사하는대다수사람들은 T. suis 에빈번히노출되어있지만, 이들에게큰해를입히지않는다. 이러한점들이기생충이갖는잠재적유해성에도불구하고, 돼지편충충란을임상적으로활용할수있는기준을제공해주었다. 실제크론병과궤양성대장염환자를대상으로살아있는돼지편충의충란을투여한결과는놀라울정도로질병치료에효과를보여주었으며, 이러한치료효과는다수의임상연구결과를통해확인되었다. 즉, 크론병환자를대상으로 2,500 개의 T. suis 충란 (ova) 을구강투여하고 6주간모니터링한결과, 이들환자들의크론병활동지수 (Crohn's Disease Activity Index, CDAI) 가 150 이하로현저히떨어진것을확인하였다 [4]. CDAI는의학적인증상들과크론병치료등급으로결정된표준지표로서 150 이하의 CDAI지수는질환진행이다소진정되었다는것을의미한다. 복용후약 8주후에는다시 CDAI지수가상승하는것이관찰되는데, 이는장내에서부화한돼지편충이 8주전후로해서점차이들환자의대장에서사라진것과연관되어나타난결과로해석되고있다. 이후 16주부터재투여시, 다시 CDAI 지수가낮아지는것을확인할수있다 (Figure 1). 궤양성대장염환자의경우, 더욱강력한치료효과를보이는데, 궤양성대장염의활동성을나타내는대장염활동지수 (Simple Clinical Colotis Activity Index, SCCAI) 가충란투여후, 지속적으로감소되는것이
764 제 7 권제 35 호 확인되었다 (Figure 1). 이러한 T. suis 충란을이용한염증성장질환에대한치료효과는플라시보효과로인해나타나는것이아니며, 2주마다 2,500개이상의충란을복용하여도합병증을유발하지않는것으로보고되었다. 그리고기존치료약제인 Prednisone, Azathioprine, 6-mercaptopurine 에대해서도서로영향을미치지않는것으로확인되었다. 염증성장질환에대한생물치료제로서돼지편충충란의활용은이미독일등외국제약회사에서무균돼지를숙주로하여생산및제품화하였으며, FDA의승인을기다리고있다. 전세계적으로염증성장질환환자가급속도로증가되는추세에비추어볼때기생충충란등기생충유래물질을이용한 이남아프리카에는이들감염성병원체의유병률이심각한수준에이른것을확인할수있다. 물론여기에는사회적요인, 제도적요인, 지리적요인, 의료보건시설의빈약함등다양한요인들이복합적으로영향을미칠수있으므로, 전적으로기생충감염에의한것이라고단정하기에는어려움이있으나, 최근의연구결과에따르면, 기생충감염에의해숙주의면역반응변화를가져오고, 그결과, 결핵, HIV, 및말라리아와같은병원체감염에대한감수성에영향을주었을가능성이높음을시사해준다. 이와관련해서이집트에서수행된사례조절연구 (case-control study) 는결핵에대한감수성이장내기생충감염과유의적인 약제개발은그경제성과시장성측면에서무한한잠재력을가질 연관성을갖는것을잘보여주고있다. 즉, 감염된장내 것으로사료된다. 기생충의종 (species) 수가많은사람일수록결핵에함께감염된 경우가많은것으로나타났다. 또다른연구에서는, 나이, 성, 기생충감염으로인한다른감염성병원체의동시감염 (Co-infection) 의효과앞서기술한것처럼기생충감염으로인한면역반응조절이숙주에게반드시이로움만제공하는것은아니다. 기생충감염은다른감염성병원체에대한감수성 (susceptibility) 에도큰영향을주는것으로알려져있다. 전세계적으로결핵등과같은감염성병원체와기생충감염유행지역을살펴보면재미있게도많은지역에서일치하는것을알수있다 (Figure 2). Figure 2 에서도알수있듯이, 기생충감염률이높은사하라 지역이동일한집단을대상을조사한결과, 결핵감염과동시에기생충에도감염된환자의비율이가장높은것으로나타났다 [5]. 이렇듯, 기생충과결핵에동시감염되어있는환자가많은이유는기생충감염에의해유도된숙주면역조절기전이결핵감염에대한인체면역반응에도관여하기때문이다. 다수의토양매개성기생충의유충은폐를통해이동하여착생하는과정동안, 폐의면역반응을조절하여 M. tuberculosis의감염이용이한환경을유도하는것으로이해되고있다. 한편, 아메리카구충 (Necator americanus) 에감염된환자들을 Crohn's disease Ulcerative colitis Treatment & Observation Maintenance Treatment & Observation Maintenance CDAI ( ) 350 300 250 200 150 100 = Ova + REMISSION SCCAI ( ) 10 9 8 7 6 5 4 3 2 = Ova + REMISSION 0 0 2 4 6 8 10 12 16 19 22 25 28 Time (Weeks) 0 2 4 6 8 10 13 16 19 22 25 28 Time (Weeks) Figure 1. Response profiles of a Crohn s disease patient and an ulcerative colitis patient treated with T. suis ova therapy. These ova were obtained from specific pathogen free pigs. Standard viral and bacterial culture were performed on aliquots of ova to assure that they contained no pathogens. Remission was defined as a decrease in CDAI to less than 150 and in SSCAI to less than 4 [4]
주간건강과질병 765 대상으로조사한연구자료에의하면기생충감염으로인해유도되는강력한 TH2면역반응과조절 T 세포의활성화가기생충이착생하는장점막조직주변뿐만아니라, 전신적으로활성화되어있는것을확인할수있다. 이는기생충에의해유도된면역반응조절효과가기생충이감염된지점으로부터떨어진부위에서의병원균에대한면역반응까지영향력을미칠수있음을간접적으로시사해준다. 이밖에도기생충에동시감염된결핵환자에서분리한말초혈액단핵세포 (Peripheral Blood Mononuclear Cells, PBMCs) 를 mycobacteria로자극했을때, 기생충에노출되지않은결핵환자의말초혈액단핵세포에비해 IFN-γ 생성은낮은반면, 항염증싸이토카인인 IL-10 생성이크게증가되는것으로확인되었다 [6]. 여기에조절 T 세포를인위적으로제거하게되면 IFN-γ 의생성이유의적으로증가되는데, 이는조절 T 세포가 IFN-γ 의생성을직접적으로억제하는것을의미한다. 또한, 항기생충치료를통해기생충제거한후, 잠복감염된결핵환자의말초혈액단핵세포는기생충제거전보다 mycobacteria 특이적면역반응에대해호전된양상을나타내었는데, 이는기생충과결핵이혼합감염된지역에서기생충의제거가활동성결핵으로진행될수있는위험을크게감소시킬수있음을시사해준다. 기생충감염은 BCG 백신효능에있어서도큰영향을미치는것으로확인되었다. BCG 백신전, 기생충을제거한집단에서는그러지않은대조군에비해강한 IFN-γ 반응과낮은 TGF-β 생성을나타내었다 [7]. 이는기생충에감염된사람에서 BCG에대해빈약한면역원성을보이는원인이기생충에의해유도된 TGF-β 생성의증가에기인하는것으로이해되고있다 [7]. 이러한점은동물모델을이용한실험에서도확인되었다. 즉, BCG 접종에의해형성된 M. tuberculosis 감염에대한저항성이만손주혈흡충 (Schistosoma mansoni) 을동시감염시킨마우스에서는유의적으로감소되는것이확인되었다 [8]. 한편, HIV는결핵및말라리아와더불어세계보건을위협하는가장위험하고강력한감염성질환중하나로, 현재전세계에서약 3,300만명이감염돼있는것으로추산되고있고, 이감염자들중 2,200만명이상이사하라이남아프리카에집중해있는것으로파악되고있다. HIV의유행지역역시 기생충유행지역과긴밀하게중복되는경향을나타내고있는데, 이러한두질환간의상관관계를잘설명해주는것이탄자니아에서수행된역학연구결과이다. 즉, 비뇨생식기주혈흡충증 (urogenital schistosomiasis) 을보이는여성이그렇지않은여성에비해 HIV 감염률이 3배이상높은양상을나타내었다 [9]. 이는기생충의감염이 HIV에대한감수성을증가시킨다는중요한근거가될수있다. 또한, 혈관내기생충에감염된임산부가감염되지않은임산부에비해태아에게 HIV가전이되는것이 7배이상높게나타난다는사실을통해기생충의동시감염이 HIV의모계전송 (mother-to-child transmission) 의위험도를절대적으로높이는것으로확인되었다. 이러한주요원인은기생충항원에의한 in utero T cell priming에기인하는것으로, 임신과정중에기생충항원에감작된태아의제대혈단핵구세포 (Cord Blood Mononuclear Cell, CBMC) 는 proviral genetranscription pathway 의활성화가강하게일어나는특징을나타내며, HIV 감염에용이한환경이조성되어 HIV 감염에대한감수성이더욱크게나타나는것으로밝혀졌다 [10]. Ⅲ. 맺는말 지금까지기생충감염에의한숙주면역반응조절기전의특성과이러한기생충감염이유도하는면역반응조절을이용한새로운자가면역질환치료법의개발과효과, 그리고기생충감염으로인한면역반응의변화가다른감염성병원체에대한인체의감수성에미치는영향에대하여간략히기술하였다. 기생충은숙주의면역체계에많은영향을주면서오랜시간동안공존하며진화해왔다. 인체와함께한역사만큼이나그들이갖는숙수면역체계에서의역할을간과해서는안될일이다. 어쩌면현시대에치료가어려운난치성질환이나원인불명의질환이기생충과깊은연관성을가질지는체계적이고심도있는연구를통하지않고서는누구도모를일이다. 자가면역질환치료에돼지편충충란의효과가임상실험을통해검증되고제품화되어 FDA 승인을기다리고있듯이, 기생충을활용한면역조절제개발을위해면역억제효과가탁월한기생충유래의면역조절물질을발굴하고이들의
766 제 7 권제 35 호 parasitology 167: 1-11. 4. Summers RW, Elliott DE, Qadir K, Urban JF, Thompson R, et al. 2003. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. The American journal of gastroenterology 98: 2034-2041. 5. Tristão-Sá R, Ribeiro-Rodrigues R, Johnson LT, Pereira FEL, Dietze R. 2002. Intestinal nematodes and pulmonary tuberculosis. Revista da Sociedade Brasileira de Medicina Tropical 35: 533-535. Figure 2. World map showing the geographic distribution of coinfection with helminths together with tuberculosis, malaria and/or HIV infection of adults [11] 면역조절기전을연구하는것이무엇보다중요하다하겠다. 또한 논란이되고있지만, 기생충감염이결핵및말라리아와같은 다른감염성병원체에대한감염의위험을증가시키고, 해당 감염성병원체에대한백신의보호효과를저해할수있는지에 대한체계적인연구도필요하다고하겠다. 이러한이유에서 기생충감염과숙주의면역조절기전에대한보다심도있는 연구는공중보건을위협하는감염성질환을관리하고 통제하는데또하나의역할을할것으로사료된다. 6. Resende Co T, Hirsch CS, Toossi Z, Dietze R, Ribeiro Rodrigues R. 2007. Intestinal helminth co infection has a negative impact on both anti Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy. Clinical & Experimental Immunology 147: 45-52. 7. Elias D, Britton S, Aseffa A, Engers H, Akuffo H. 2008. Poor immunogenicity of BCG in helminth infected population is associated with increased in vitro TGF-β production. Vaccine 26: 3897-3902. 8. Elias D, Akuffo H, Pawlowski A, Haile M, Schön T, et al. 2005. Schistosoma mansoni infection reduces the protective efficacy of BCG vaccination against virulent Mycobacterium tuberculosis. Vaccine 23: 1326-1334. IV. 참고문헌 1. Hussaarts L, van der Vlugt LE, Yazdanbakhsh M, Smits HH. 2011. Regulatory B-cell induction by helminths: implications for allergic disease. Journal of Allergy and Clinical Immunology 128: 733-739. 2. Broadhurst MJ, Leung JM, Lim K, Girgis NM, Gundra UM, et al. 2012. Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoiddependent type-2 immunity to helminth infection in mice. PLoS pathogens 8: e1002883. 3. Hewitson JP, Grainger JR, Maizels RM. 2009. Helminth 9. Downs JA, Mguta C, Kaatano GM, Mitchell KB, Bang H, et al. 2011. Urogenital schistosomiasis in women of reproductive age in Tanzania's Lake Victoria region. The American journal of tropical medicine and hygiene 84: 364-369. 10. Steiner KL, Malhotra I, Mungai PL, Muchiri EM, Dent AE, et al. 2012. In utero activation of fetal memory T cells alters host regulatory gene expression and affects HIV susceptibility. Virology 425: 23-30. 11. Salgame P, Yap GS, Gause WC. 2013. Effect of helminthinduced immunity on infections with microbial pathogens. Nature immunology 14: 1118-1126. immunoregulation: the role of parasite secreted proteins in modulating host immunity. Molecular and biochemical
주간건강과질병 767 원인불명병원체분석법의해외동향 Identification of Viral Pathogens in Diseases of Unknown Causes Abroad 질병관리본부국립보건연구원감염병센터호흡기바이러스과 이한샘, 이준우 Abstract Background : Novel emerging infectious diseases have increased due to climate change, environmental pollution, and globalization. Rapid identification of the etiologic agent is imperative for the prevention of diseases from spreading in public health. Thus, the purpose of this report is to survey the rapid identification systems, including the recently developing molecular techniques, to identify the causative agent in cases of unknown infectious illness or outbreaks worldwide. event : The recent case reports that identified the emerging infectious diseases were searched by using online search programs (PubMed, Google, etc.). Moreover, through the websites of the CDC (USA) and Robert Koch Institute (Germany), their own systems to identify the undiagnosed disease outbreaks were introduced. Results : This report describes several events in which virus identification is carried out through cell culture/virus isolation, electron microscopy, polymerase chain reaction, and next-generation sequencing. Other useful laboratory methods for diagnosis of an unknown virus include serologic testing; Immunofluorescence assay and immunohistochemistry assays. Conclusions : As molecular diagnostic techniques are being developed in scope and magnitude, it is critical to retain and use classical techniques as well as new molecular techniques. The rapid combination of cell culture/electron microscopy analysis and new molecular methods including next-generation sequencing is an unbiased approach to the identification of unrecognized pathogen. In addition, the collaboration among clinicians, epidemiologists, microbiologists, electron microscopists, and laboratorians who use different technologies is crucial for the successful investigations of diseases of unknown origin. 동물간의공통적으로감염되는사례가있기에신종호흡기바이러스의대두는국가보건차원에서더욱관심을가져야한다. 대표적인사례로는 2002년에서 2003년에유행하였던중증급성호흡기증후군코로나바이러스 (Severe Acute Respiratory Syndrome coronavirus, SARS-CoV), 2008년에서 2009년에유행했던신종인플루엔자바이러스그리고최근 2012년부터현재까지중동지역에서유행하고있는중동호흡기증후군코로나바이러스 (Middle East Respiratory Syndrome coronavirus, MERS-CoV) 가있다. 이러한신종바이러스출현에대응하기위해서각국에서는원인불명감염증이의심되는환자의검체로부터신속히병원체를탐지하는조직체계를구성하여운영하고있다. 미국의경우질병관리본부 (Centers for Disease Control and Prevention, CDC) 산하에 Division of High-Consequence Pathogens and Pathology (DHCPP)[1] 를설립하여운영하고있으며, 독일의경우로버트코흐연구소 (Robert Koch institute, RKI) 산하에 Zentrum f r Biologische Gefahren und Spezielle Pathogens (ZBS)[2] 를설립하여신종병원체에대해대응하고있다. 이에본문에서는원인불명병원체의대응체계에대한국외사례들과원인병원체규명에사용되는최신면역분자유전학적분석법을소개하고자한다. Ⅰ. 들어가는말 최근신종병원체들이새롭게나타나국가보건차원에서위협이되고있으며병원체의증가원인으로는기후변화, 환경오염, 해외유동인구수의증가등으로보고있다. 특히호흡기바이러스의경우, 공기감염으로빠르게전파되고, 사람과 II. 몸말 중증급성호흡기증후군병원체 (SARS) 사례 2002 년부터중국광동에서시작된중증급성호흡기증후군은짧은시간동안전세계로퍼졌으며, 치사율이 9.6% 에이르러심각한공포를조성하였다. 따라서미국 CDC에서는
768 제 7 권제 35 호 원인병원체의확인을위해미국, 홍콩, 싱가포르, 대만, 태국, 캐나다등에서확보한 19명의환자혈청, 혈액, 조직등을활용하여분석하였다. 이들검체로부터각종호흡기바이러스들 ( 인플루엔자바이러스 (Influenzavirus) A와 B, 파라믹소바이러스아과 (Paramyxovirinae), 뉴모바이러스아과 (Pneumovirinae), 아데노바이러스종 (Mastadenoviridae), 헤르페스바이러스종 (Herpetoviridae), 피코나바이러스종 (Picornaviridae), 한타바이러스 (hantaviruses), 아레나바이러스 (arenaviruses)) 검출을위한유전자진단법 (Polymerase chain reaction, PCR) 과세균들 (yersinia, mycoplasma, chlamydia, legionella, Coxiella burnetii, spotted fever and typhus group rickettsiae) 에대한유전자진단법을실시하였으나이러한방법으로는원인병원체를규명할수없어전형적인세포배양동정법으로원인병원체분리를실시하였다. 환자의혈청, 혈액, 인후도말등의검체와사후주요장기조직들로부터얻은샘플을활용하여다양한세포들 (Vero E6, NCI-H292, MDCK, LLC-MK2, B95-8 세포 ) 에접종한후, 세포병변을 2주간관찰하였다. 그결과 19명의환자중 46세환자의인후도말샘플이접종된 Vero-E6와 NCI-H292 에서병변효과가나타났으며, 이를고정후전자현미경을사용한 형태학적분석을실시하여원인병원체가사람코로나바이러스계통임을확인하였다 (Figure 1). 그후, 전체코로나바이러스 (Pan-coronavirus) 를검출을할수있는유전자진단법을신속하게구축하였고, 이를활용하여사스코로나바이러스의염기서열을규명할수있었다. 또한환자로부터분리된사스코로나바이러스가감염된 Vero-E6세포를활용한항원슬라이드를제작하였으며, 이를실제중증급성호흡기증후군환자와정상인의혈청으로면역형광분석 (Immunofluorescence assay, IFA) 에사용하였다. 마지막으로면역조직화학분석법 (Immunohistochemistry, IHC) 을사용하여다른사람코로나바이러스 (OC43, 229E) 와교차반응분석을실시하였다. 이외에도미국 CDC에서는앞서언급한전형적인분석법외에차세대염기서열분석법 (Next-generation sequencing, NGS) 을통한원인병원체분석연구를수행하고있다. 이와같이미국 CDC의 Division of High-Consequence Pathogens and Pathology(DHCPP, http://www.cdc.gov /ncezid/dhcpp/) 는원인을모르는죽음이나원인불명감염성질환그리고신종고위험병원체를체계적으로탐지하는전문화된시스템을구축하고있다. Figure 1. A) Cell culture isolate of severe acute respiratory syndrome coronavirus, in which virions are seen in the cisternae of the budding compartment (arrow). Also present are an inclusion of viral nucleocapsids (arrowhead) and double-membrane vesicles (asterisk). Scale bar = 100 nm. B) Coronavirus particles in cytoplasmic vesicles that appear to migrate to the cell surface. Virions are seen lining the cell membrane (arrow), a characteristic feature of this virus. Scale bar = 500 nm. [4]
주간건강과질병 769 중동호흡기증후군병원체 (MERS) 사례 2012년 6월, 사우디아라비아의 Jeddah에있는병원에 60세의성인환자가호흡기증상 ( 폐렴, 발열, 호흡곤란 ) 으로입원하였다 [5]. 이환자로부터채취된객담과혈액을네덜란드의에라스무스 (Erasmus) 대학내 ViroScience 연구실로운송한후, 대학연구자들은환자의객담을 LLC-MK2와 Vero 세포에각각접종하여병변효과를관찰하였다. 또한객담에서상피세포를분리하여이를활용하여항원슬라이드를제작하고, 인플루엔자바이러스 A/B, 파라인플루엔자바이러스 type 1-3, 아데노바이러스, 호흡기세포융합바이러스 (R espi rat or y syncytial virus) 등의항체와면역형광분석을실시하였으나모든검사결과는음성으로판정되었다. 이후병원체의유전물질 (DNA/RNA) 을추출하여파라믹소바이러스, 코로나바이러스, 엔테로바이러스, 아데노바이러스에대한유전자진단법을실시하였다. 다행히전체코로나바이러스유전자진단법에서유전자증폭반응이일어났고, 이증폭산물을통해일부염기서열을알아내었다. 그런후, Roche 사의 454 GS FLX를이용한분리된바이러스전장분석의성공으로신종전염병인중동호흡기증후군의원인병원체를동정할수있게하였다 [5]. 통하여 orthorpoxvirus 계통임을규명하였고우두바이러스가동물로부터사람에게공통감염되었음을확인하였다 (Figure 2). 로버트코흐연구소는산하에 ZBS 센터를운영하고있으며, 이를통하여원인불명병원체에의한감염을신속히규명하고있다 (Figure 3). ZBS 센터는총 6개부서로조직되어있고, 기존에알려진바이러스나세균감염을진단하는감염병센터 (Department 1) 와협력하여운영되고있다. Department 1에서동정하지못한병원체의경우, ZBS 센터가주관하여규명연구를실시하게된다. 6개 ZBS 부서의역할은 ZBS1이차세대 사람감염우두바이러스 (Cowpoxvirus) 사례독일로버트코흐연구소는바이러스분리배양과전자현미경분석법을통해동물에게감염되는우두바이러스 (Cowpoxvirus, CPXV) 가사람에게감염될수있음을확인하였다 [6]. 2008년독일 Krefeld시주변에사는네명의사람과 Landau시의 동물원근로자에게심각한피부병변이발생하였다. 의사들은이피부병변증상을수두바이러스 (poxvirus) 계열의병원체에감염되었을것으로의심하였고, 이후로버트코흐연구소에서환자의피부조직에서분리한바이러스를전자현미경을사용하여형태학적분석을실시하여수두바이러스계통임을확인하였다. 또한수두바이러스항체를이용한면역조직화학분석법과유전자진단법을통해이피부질환의원인병원체가우두바이러스임을규명하였다. 이에전장염기서열분석을통해이바이러스를 CPXV HumKre08/1라고명명하였다. 또한 Krefeld 시의한동물원에서 13 마리몽구스가심한피부병변을보였으며, 이들로부터얻은피부조직을전자현미경분석을 Figure 2. Histopathological and electron microscopical examination. (A) Multiple circumscribed, elevated, pale red, plaque-like foci in the lung of mongoose (B) HE-stained skin lesion of mongoose showing multiple eosinophilic intracytoplasmic inclusion bodies (arrows) and mild ballooning degeneration of epidermal cells associated with focal severe necrotizing dermatitis with neutrophilic and lymphoplasmacellular infiltrates, (C) HE-stained liver section of mongoose showing severe necrosis with hemorrhage and mild inflammatory infiltration and degenerating hepatocytes with multiple intracytoplasmic inclusion bodies (arrow), (D) HE-stained lung section of mongoose showing a bronchiolus with markedly hyperplastic epithelium and focal obliterating proliferation undergoing necrosis. Negative-stain electron microscopy revealing typical orthopoxvirus-like particles in skin lesion material of mongoose (E) and jaguarundi (F) [6]
770 제 7 권제 35 호 Figure 3. ZBS scope of work chart [2] 염기서열분석법및유전자진단법 (PCR, RT-PCR, real-time PCR) 과항원-항체반응을기반으로하여전문적으로조사하며, ZBS4가전자현미경분석을전담하고있다. 고위험에속한세균조사는 ZBS2가전담하며, 생물학적독소 ( 단백질, 지질, 당 ) 에대한조사는 ZBS3과 ZBS6이담당하고있다. ZBS5는고위험병원체의관리를위해생물안전레벨 4 연구실 (Biosafety level-4 lab) 을주관하고있다. 차세대염기서열분석법 (NGS) 을활용한사례병원체분리의고전적인동정법에는바이러스배양및전자현미경을통한형태학적분석동정법이있으나, 최근에는차세대염기서열분석법을활용한방안이모색되고있다. 차세대염기서열분석법의장점은방대한양의염기서열데이터를신속하고효과적으로분석할수있다는것이다. 그러나컴퓨터알고리즘을잘구성하여분석해야하는단점이있다. 예를들어, ZBS1은원인불명병원체의전장유전체확보와검출을위해염기서열을분석하는로버트코흐연구소의 Center Sequencing 연구실의지원을받고있다. 이연구실에서는 Roche/454 FLXT, Ion Torrent PGM, Illumina HiSeq 1500 을보유하고 있어병원체의유전자게놈분석, Metagenomics, RNA Sequencing, Ultra-deep sequencing 등의업무를수행하고있다. 이런최신 NGS 기술및분석을통해서 Schmallenberg 바이러스 [7], Lloviu 바이러스 [8], Base-Congo 바이러스 [9] 등이발견되기도하였다. 원인미상병원체에감염된환자조직샘플로부터병원체동정을위해 NGS를수행하는체계는 Figure 4의모식도와같다 (Figure 4)[10]. NGS를수행하여획득한방대한양의염기서열정보들을맵핑 (mapping) 또는 de novo assembly 방식을통해 400-500 bp 이상의염기서열데이터를형성시킨후, 미국 National Center for Biotechnology (NCBI) 의 Genbank 데이터와비교분석하여새로운종의염기서열을규명하게된다. 맨처음분류는포유동물유전자, 곰팡이유전자, 세균유전자, 바이러스유전자군으로분류하며, 그후세균및바이러스종, 식물바이러스종, 포유동물의바이러스종으로나누어분석을실시한다. 마지막으로사람과동물에게감염가능한포유동물바이러스들을다시분류하여재분석한다.
주간건강과질병 771 Figure 4. A flow-chart describing the entire process from sample collection through the various data-analysis steps. Step 1 and 2 illustrate sample collection, preparation and sequencing while step 3 through 6 illustrate in silico efforts [10] Ⅲ. 맺는말 본문에서는신 변종감염병의원인병원체를신속히규명한해외연구사례들과이때활용된병원체분리및배양기술, 전자현미경을통한형태학적분석법, 그리고차세대염기서열분석법 (NGS) 등의동정기술에관하여소개하였다. 전형적인세포배양을통한병원체분류법은사람보카바이러스처럼일반적으로사용되는세포주에서배양이안되는병원체의경우, 동정할수없고, 다양한세포의배양및유지에많은노동력이요구된다. 뿐만아니라, 실험수행자의기술에의존적이라는단점도있다. 더구나질병에걸린환자가처음방문하게되는지역병원과보건소에서는검체채취및운송등의어려움이있다. 체외세포배양조건 (In vitro cell culture) 에서는병원체의복제가이루어지지않는경우도있어세포병변을관찰하기힘들며, 신선한검체임에도불구하고병원체의분리율이낮게나오기도한다. 실제 SARS의경우, 초기 19명환자에서 5명의검체에서만바이러스가분리되었다 [4]. 전자현미경을활용한형태학적분석법은실제로병원체를직접관찰할수있어초기병원체동정에큰도움이됨에도 불구하고, 많은양의샘플들을처리할수없는단점이있으며, 일부는형태학적으로구분이힘들어항체를이용한새로운형태의분석법이개발되고있다. 또한전문적으로병원체와세포의병변을판별할수있는경험과지식을갖춘숙련된연구자가요구된다 [12]. RT-PCR, 실시간 PCR 등을포함한유전자진단법은세포배양이불필요하며전체진단과정을표준화할수있는장점이있어병원체규명에가장많이사용되고있으나, 진단프라이머제작시기존에알려진병원체의염기서열을활용해야하기때문에미지의병원체검출에는한계가있다. 즉, 신 변종병원체는기존에알려진염기서열과상동성이높지않기때문에유전자증폭반응에필수적인프라이머가작용하지않아검출이안되는단점이있을수있다. 그에반해 NGS법은염기서열에비의존적인 SISPA (Sequence-independent, single primer amplification) 유전자진단법을사용하므로전장염기서열분석이나새로운종의병원체들을동정할수있다. 그러나동정된바이러스가질환의직접적원인인지판단하기어렵다. 그러므로원인병원체의명확한규명을위해면역형광검색법과같은면역분자학적인
772 제 7 권제 35 호 방법이수반되어야한다. 결론적으로, 원인불명병원체의신속한규명을위해서는임상의의신속한인지, 면역-분자학적방법을활용한최신병원체탐지기술의지속적인개발, 이러한동정법들을전문적으로수행및분석할수있는전문인력양성뿐만아니라, 학계및감염병관련부서간의긴밀한공동협력등이매우필요하다. 9. Grard G, Fair J. N., Lee D., et al. 2012. A novel rhadovirus associated with acute hemorrhagic fever in central Africa. PLos Pathog. Vol 8. e1002924. 10. Lysholm, F., Wetterbom A., Lindau C., et al. 2012. Characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing. Vol. 7, No. 2, e30875. 11. van Regenmortel M.H. V, Fauquet C.M, Bishop D.H.L, Carstens E.B., IV. 참고문헌 1. http://www.cdc.gov/ncezid/dhcpp/ 2. http://www.rki.de/en/content/institute/departmentsunits/ CenterBioSafety/CenterBioSaf ety_node.html;jsessionid=1afaed7 E567775EF93B94A9B6A9E4ACD.2_cid372 3. Goldsmith, C. S, Ksiazek, T. G., Rollin, P. E, et al. 2013. Cell culture Estes M.K., Lemon S.M, et al. 2000. Virus taxonomy: classification and nomenclature of viruses, 7th Report of the International Committee on Taxonomy of Viruses. San Diego: Academic Press. 12. Hazelton R. P and Gelderblom, R. H. 2003. Electron microscopy for rapid diagnosis of infectious agents in emergent situations. Emerging Infectious Diseases. Vol. 9, No. 3, p294-303.7. and electron microscopy for identifying viruses in diseases of unknown cause, Emerging Infectious Disease. Vol. 19, No. 6, p886-891. 4. Ksiazek T. G., Erdman D., Goldsmith C. S,, et al. 2003. A novel coronavirus associated with severe acute respiratory syndrome, N. Engl. J. Med. Vol. 348, No. 20, p1953-1966. 5. Zaki, A.M, Boheemen, V, S, Besterbroer, M. T. et al. 2012. Isolation of a Novel Coronavirus from a man with Pneumonia in Saudi Arabia. N. Engl. J. Med. Vol. 367, p1814-1820. 6. Kurth A., Straube M., Kuczka A., et al. 2009. Cowpox Virus Outbreak in Banded Mongooses (Mungos mungo) and Jaguarundis (Herpailurus yagouaroundi) with a Time-Delayed Infection to Humans. PLoS ONE. Vol. 4, No. 9, e6883. 7. Gibbens N. 2012. Schmallenberg virus: a novel viral disease in northern Europe. Vet. Rec. Vol. 170, No. 58. http:dx.doi.org/ 10.1136/vr.e292 8. Negredo A., Palacious G, Vazquez-Moron S, et al. 2011. Doscovery of an ebolavirus-like filovirus in Europe. PLos Pathog. Vol 7. e1002304.
주간건강과질병 773 한국성인의콜레스테롤수준 (2008-2012) Status of Cholesterol Level Among Adults in Korea, 2008-2012 질병관리본부질병예방센터건강영양조사과 김윤아 Abstract In 2012, an estimated 15.4% of adults aged 30 and above had high total cholesterol. The percentage with high total cholesterol was higher in women (18.2%) than in men (12.5%). From 2008 through 2012, the percentage of adults aged 30 and above with high total cholesterol increased by 33.0 percent. During 2008 2012, 44.8% of adults aged 30 years with high total cholesterol were aware of the diagnosis, 34.1% were taking medication to lower their cholesterol, and 27.0% had their cholesterol under control. 콜레스테롤 (cholesterol) 은혈액내에순환하고있는지방의일종으로, 인체가정상적으로기능하는데있어필수적인물질이지만과다한콜레스테롤은동맥혈관벽에축적되어죽상동맥경화증 (atherosclerosis) 을유발하고나아가심혈관질환의발생위험을높인다 [1]. 일반적으로혈중총콜레스테롤 (Total cholesterol, TC) 이 240mg / dl이상인사람은관상동맥질환 (coronary artery diseases) 의고위험군으로분류되지만, 임상적으로는콜레스테롤의구성성분인지단백 (lipoprotien) 을분석하여보다세분화된접근법을취하고있다. 예를들어, 저밀도지단백 (Low density lipoprotein, LDL) 은죽상동맥경화증을유발하는역할을하는데비해고밀도지단백 (High density lipoprotein, HDL) 은축적된콜레스테롤을제거하는역할을하기때문에 LDL이 160mg / dl이상이거나 HDL이 40mg / dl미만, 중성지방 (Triglyceride, TG) 이 200mg / dl이상인경우도고위험군으로분류하고이상지질혈증 (dyslipidemia) 으로진단하고있다 [2]. 이글에서는국민건강영양조사자료를이용하여최근 5년간 (2008-2012) 우리나라성인의콜레스테롤수준과이에따른심혈관질환고위험군현황을살펴보고자한다. 2012년이상지질혈증유병률현황 (Prevalence of dyslipidemia among Korean adults, 2012) 만 30세이상성인에서고콜레스테롤혈증 ( 총콜레스테롤 240mg/dL 이상또는콜레스테롤강하제복용 ) 유병률은 15.4% 이며, 남자 (12.5%) 에비해여자 (18.2%) 가높았다. 연령이증가할수록유병률도함께증가하는경향을보이며특히여성에서 50대이후급격한증가를보였다 (Figure 1). 저콜레스테롤혈증 (H DL콜레스테롤 40mg/d L 미만 ) 의유병률은 19.9% 이며, 고콜레스테롤과반대로여자 (14.3%) 보다남자 (25.7%) 가높았다. 연령과함께유병률도증가하는경향을보이나 50대이후에는비교적유사한수준으로유지하는것으로나타났다 (Figure 2). 고중성지방혈증 ( 중성지방 200mg/dL 이상 ) 유병률은 17.1% 이며, 여자 (13.1%) 에비해남자 (21.4%) 가높았다. 30대부터 50대까지점진적으로증가하는경향을보이다가남녀모두 50대에가장높은유병률을나타냈고 60대이후에는감소하는경향을보였다 (Figure 3). 콜레스테롤유병률추이 (Trends in prevalence of high total cholesterol, 2008-2012) 콜레스테롤유병률 ( 표준화 ) 은 2008년 10.9% 에서 2012년 14.5% 로 3.6%p(33.0%) 증가하였다. 전연령군에서증가추세를보였며, 30-40대에비해 50세이상의인구집단에서큰폭으로증가를보였다. 특히, 여성의경우 50대이후연령군에서가파른증가를나타냈다 (Figure 4). 콜레스테롤관리수준 (Cholesterol management status in 2008-2012) 고콜레스테롤혈증유병자중의사로부터진단을받은사람의비율은 44.8% 였으며, 남자 (42.0%) 에비해여자 (46.9%) 가다소높았다. 혈중콜레스테롤수치를낮추기위해약물치료를
774 제 7 권제 35 호 Figure 1. Percentage of adults aged 30 and over with high total cholesterol in Korea, 2012 NOTES: High total cholesterol is serum total cholesterol of 240 mg/dl or currently taking medication to lower cholesterol. Figure 2. Percentage of adults aged 30 and over with low HDL cholesterol in Korea, 2012 NOTES: Low HDL cholesterol is serum high-density lipoprotein (HDL) cholesterol less than 40mg/dL.
주간건강과질병 775 Figure 3. Percentage of adults aged 30 and over with high triglyceride in Korea, 2012 NOTES: High glyceride is serum glyceride of 200mg/dL Figure 4. Trends in percentage of adults aged 30 and over with high total cholesterol in korea, 2008 2012 NOTES: High total cholesterol is serum total cholesterol of 240 mg/dl or currently taking medication to lower cholesterol. Estimates were age adjusted by the direct method to the projected population from 2005 by Statistics Korea.
776 제 7 권제 35 호 받고있는사람은 34.1% 였으며, 남자 (31.9%) 보다여자 (35.9%) 가높았다. 혈중총콜레스테롤수치가 200mg/dL 미만으로조절되고있는사람은 27.0% 이며, 남자 (25.6%) 보다여자 (28.0%) 가높았다. 약물치료를받고있는치료자에서조절률은 77.6% 로성별, 연령군별로모두유사한수준을보였다 [3]. 남녀모두 30-40대의인지율, 치료율과조절률은매우낮았으며, 50대이후는인지율과치료율이향상되어조절률도더불어증가하였다 (Figure 5). 결론적으로, 고콜레스테롤혈증 (hypercholesterolemia) 은우리나라국민의주요사망원인인심뇌혈관질환 ( 심장질환, 뇌졸중 ) 의위험요인 (risk factor) 이다. 그간정부와전문가, 시민단체들은심뇌혈관질환을예방하고적절하게관리하기위한노력을지속하여왔으며특히, 한국지질동맥경화학회 (Korean Society of Lipidology and Atherosclerosis) 는매년 9월 4일을 콜레스테롤의날 로지정하고, 콜레스테롤의 새로운콜레스테롤치료가이드라인 (2013) 에서는 LDL 또는 TG 수치자체보다는 10년내심혈관질환이발생할위험도를평가하여일차예방을위한스타틴 (statin) 약물치료기준을제시하였다. 위험도예측에포함된요인은연령 (age), 성별 (sex), 인종 (race), 총콜레스테롤 (TC), HDL 수축기혈압 (systolic blood pressure, SBP), 혈압약복용 (taking antihypertensive drug), 당뇨병 (diabetics), 흡연 (smoking) 등으로결과적으로는콜레스테롤수치를기준으로했을때보다치료대상범위가확대되었다. 물론이가이드라인은아시아인을별도로고려하고있지않아이를국내환자들에게적용하기위해서는상당한연구와자료의축적이필요하겠지만, 현재우리나라국민의콜레스테롤관리수준은만족스러운상태로보기어렵기때문에보다적극적인대책과노력이필요하다고할것이다. < 참고문헌 > 위험성과예방관리법을전국민에게널리알리기위한캠페인을 벌이고있다. 그럼에도불구하고 2008년부터 2012년까지최근 5년간만 30세이상성인의고콜레스테롤유병률은지속적으로증가하는추세를보이고있다. 2012년현재성인 6명중 1명이고콜레스테롤혈증유병자이며, 이들중혈중콜레스테롤이적절한수준으로조절되고있는사람은 4명중 1명에불과하다. 최근미국심장학회 (American College of Cardiology, ACC) 와미국심장협회 (American Heart Association, AHA) 에서발표한 1. Ross, R. 1999. Atherosclerosis-An Inflammatory Disease. N EngJ Med. 340:115-1126. 2. National Cholesterol Education Program, National Heart, lung and blood institute, National Institutes of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 2002. NIH Publication. 3. 질병관리본부. 2013. 2012 국민건강통계 ( 국민건강영양조사제5기 3차년도 ). Figure 5. Cholesterol management status in 2008-2012 (pooled-sample data) NOTES: 1) Awareness: Having been diagnosed with hypercholesterolemia by a doctor among those with high total cholesterol. 2) Treatment: ly taking medication to lower cholesterol for 20 or more days per month among those with high total cholesterol. 3) Controlled: Serum total cholesterol <200mg/dL among those with high total cholesterol.
주간건강과질병 777 Satus of Selected National Infectious Diseases Surveillance 1. Hand, Foot and Mouth Disease(HFMD) Republic of Korea, ending August 23, (34th Week)* 년도제 34 주수족구병의사환자분율은외래환자 1,000 명당 8.4 명이며, 2013 년동기간수족구병의사환자분율 6.3 명보다높음. 잠정통계이므로변동가능함 수족구병은 2009 년 6 월법정감염병으로지정되어표본감시체계로운영되고있음. No. of HFMD per 1,000 consultation 40 30 20 10 0 1 5 9 13 17 21 25 29 33 37 41 45 49 53 2013 2012 2011 Figure 1. The status of HFMD sentinel surveillance, 2011-2. Ophthalmologic, Republic of Korea, ending August 23, (34th ) 년도제34주유행성각결막염의외래환자 1,000 명당분율은 23.8 명으로지난주 21.7 명보다증가하였음 동기간급성출혈성결막염의환자분율은 2.6 명으로지난주 2.9 명보다감소하였음 주별통계는잠정통계이므로변동가능 80 40 15 45.7 50.7 30 EKC per 1,000 60 40 20 30 20 10 Case//sentinel AHC per 1,000 12 9 6 3 24 18 12 6 Case//sentinel 0 0 0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 0 2013(36~) Case//sentinel(1~35) 10years average 2013(36~) 2013 Case//sentinel(1~35) 2007, 2012 2003~2013 Figure 1. The mean of outpatients to Epidemic keratoconjunctivitis for a Figure 2. The mean of outpatients to Acute hemorrhagic conjunctivitis for a 3. Influenza, Republic of Korea, ending August 23, (34th ) 년도제 34 주인플루엔자의사환자분율은외래환자 1,000 명당 1.3 명으로지난주 (1.7) 보다감소하였으며유행판단기준 (12.1/1,000 명 ) 보다낮은수준임.5.1 일자인플루엔자유행주의보해제 인플루엔자표본감시체계가변경됨에따라 2013- 절기유행기준은 12.1 명 (/1,000) 으로변경 ILI per 1,000 (2013- season) 80 70 60 50 40 30 20 10 baseline(12.1) 25 20 15 10 5 ILI per 1,000 (Past seasons) 0 0 2013-2012-2013 2011-2012 2010-2011 Figure 1. The ly proportion of Influenza-Like Iliness per 1,000 outpatients, 2010-2011 to 2013- seasons
778 년제 34 주 (8.17.-8.23.) Table 1. Reported cases of national infectious diseases in Republic of Korea, ending August 23, (34th Week)* Classification of disease Group Ⅰ Group Ⅱ Group Ⅲ Group Ⅳ ly average Total no. of cases by year 2013 2012 2011 2010 2009 Cholera - - - 3-3 8 - Typhoid fever 3 201 3 156 129 148 133 168 China(1) Paratyphoid fever 2 25 2 54 58 56 55 36 Imported cases of current : Country(no. of cases) Shigellosis 4 67 4 294 90 171 228 180 Philippines(2) EHEC 3 93 3 61 58 71 56 62 Viral hepatitis A 21 984 41 867 1,197 5,521 - - Pertussis 2 51 1 36 230 97 27 66 Tetanus 1 20 1 22 17 19 14 17 Measles 7 556 1 107 3 42 114 17 Philippines(1) Mumps 469 14,505 138 17,024 7,492 6,137 6,094 6,399 Rubella 4 40 1 18 28 53 43 36 Viral hepatitis B ** 107 3,124 75 3,394 2,753 1,428 - - Japanese encephalitis 1 2-14 20 3 26 6 Varicella 360 25,705 283 37,361 27,763 36,249 24,400 25,197 Malaria 27 445 49 445 542 826 1,772 1,345 Scarlet fever 60 3,871 10 3,678 968 406 106 127 Meningococcal meningitis 0 2-6 4 7 12 3 Legionellosis 2 17 1 21 25 28 30 24 Vibrio vulnificus sepsis 4 14 3 56 64 51 73 24 Murine typhus 0 5-19 41 23 54 29 Scrub typhus 16 259 5 10,365 8,604 5,151 5,671 4,995 Leptospirosis 3 8 1 50 28 49 66 62 Brucellosis 1 10-16 17 19 31 24 Rabies 0 0 - - - - - - HFRS 4 100 4 527 364 370 473 334 Syphilis 27 619 18 799 787 965 - - CJD/vCJD 2 36-34 45 29 - - Tuberculosis 827 24,224 766 36,089 39,545 39,557 36,305 35,845 HIV/AIDS 21 638 15 1,013 868 888 773 768 Dengue fever 6 110 6 252 149 72 125 59 Q fever 0 7-11 10 8 13 14 West Nile fever 0 0 - - 1 - - - Lyme Borreliosis 0 8-11 3 2 - - Melioidosis 0 1-2 - 1 - - Chikungunya fever 0 0-2 - - - - SFTS 7 48-36 - - - - unit: no. of cases Cambodia(1), Malaysia(1), Philippines(3), Southeast Asia(1) 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. Cum: Cumulative counts from 1st to current in a year. * The reported data for year are provisional data but the data for years 2009, 2010, 2011, 2012 and 2013 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, Haemophilus influenzae type b, Poliomyelitis, Epidemic typhus, Anthrax, Plague, Yellow fever, Viral hemorrhagic fever, Smallpox, Botulism, Severe Acute Respiratory Syndrome, Animal influenza infection in humans, Novel Influenza, Tularemia, Newly emerging infectious disease syndrome and Tick-borne Encephalitis. Surveillance system for Viral hepatitis A, Viral hepatitis B, Syphilis, CJD/vCJD, West Nile fever was changed from Sentinel Surveillance System to National Infectious Disease Surveillance System as of December 30, 2010. Calculated by summing the incidence counts for the current, the 2 s preceding the current, and the 2 s following the current, for a total of 5 preceding years (For Viral hepatitis A, Viral hepatitis B, Syphilis, CJD/vCJD, West Nile fever, Lyme Borreliosis, Melioidosis, this calculation only used 3-year data (2011, 2012, 2013) because of being designated as of December 30, 2010. ** Data on viral hepatitis B included acute viral hepatitis B, HBsAg positive maternity and perinatal hepatitis B virus infection. Data on scarlet fever included both cases of confirmed and suspected since September 27, 2012.
주간건강과질병 779 Table 2. Reported cases of national infectious diseases in Republic of Korea, ending August 23, (34th Week)* unit: no. of cases Provinces Cholera Typhoid fever Paratyphoid fever Shigellosis Enterohemorrhagic Escherichia coli Viral hepatitis A Pertussis Tetanus average Total - - 1 3 201 101 2 25 31 4 67 96 3 93 43 21 984 2,036 2 51 62 1 20 9 Seoul - - 1-30 20-3 8 1 12 19-12 7 3 190 391-15 5 1 2 1 Busan - - - - 6 9 1 2 2-4 10-3 2-20 86-1 2-3 1 Daegu - - - - 6 6 - - 1-2 3-27 3-16 19-1 - - 1 - Incheon - - - - 10 3-3 3 1 27 7-8 2 2 88 317 2 7 5-1 - Gwangju - - - - 13 2-1 2 - - 3-6 8-45 60-1 2 - - - Daejeon - - - - 10 1 - - 1 - - 1-1 1-16 61-3 - - - - Ulsan - - - - - 2-2 - - - 2-13 2-13 19 - - - - - - Sejong - - - - - - - - - - - - - - - - 1 1 - - - - - - Gyonggi - - - 1 26 19-7 6-9 21 1 9 4 10 358 667-6 5-2 1 Gangwon - - - - 2 2 - - 1 - - 2 - - - 1 31 74-1 1-2 1 Chungbuk - - - - - 3-2 1 - - 2 - - 1 1 18 68 - - - - 1 1 Chungnam - - - - 14 4 1 2 1-1 6-2 4 2 51 70-2 3 - - 1 Jeonbuk - - - 1 9 1-1 1-4 2 - - 2 2 57 91 - - - - - - Jeonnam - - - - 7 2-1 1-2 7 1 7 3-33 44-2 35-3 - Gyeongbuk - - - 1 11 7-1 1-1 3 - - 2-22 28-9 1-3 1 Gyeongnam - - - - 56 20 - - 2 2 2 8 1 2 1-19 34-1 2-2 2 Jeju - - - - 1 - - - - - 3 - - 3 1-6 6-2 1 - - - Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional data but the data for years 2009, 2010, 2011, 2012 and 2013 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. Viral hepatitis A data on sentinel surveillance system changed to National Infectious Disease Surveillance System as of December 30, 2010 average is mean value calculated by cumulative counts from 1st to current for 5 preceding years.
780 년제 34 주 (8.17.-8.23.) Table 2. Reported cases of national infectious diseases in Republic of Korea, ending August 23, (34th Week)* unit: no. of cases Measles Mumps Rubella Viral hepatitis B Japanese encephalitis Varicella Malaria Scarlet fever Provinces 4-year average Total 7 556 50 469 14,505 4,881 4 40 29 107 3,124 1,446 1 2-360 25,705 19,466 27 445 673 60 3,871 597 Seoul 2 127 1 28 1,496 621-3 4 11 301 114 - - - 38 2,174 1,821 4 65 88 7 385 73 Busan - 21 1 46 1,525 239-4 4 6 253 249 - - - 31 1,993 1,932-11 16 4 388 42 Daegu - 15-11 423 249-1 3 6 180 73 - - - 49 1,898 1,635 2 8 10 2 269 36 Incheon - 68 20 20 650 643 1 1 1 9 265 135 - - - 24 1,668 1,618 11 99 99-124 41 Gwangju - 3 1 105 1,629 85-1 - 7 159 85 - - - 6 572 480-3 5 3 104 33 Daejeon 2 28-5 317 358-1 - - 19 7 - - - 16 719 383 - - 7 3 106 4 Ulsan 1 8-7 344 195-1 1 6 152 75 - - - 13 658 770-3 5 1 83 17 Sejong - - - 1 33 12 - - 1 1 8 1 - - - - 24 32 - - - - 5 3 Gyonggi 2 177 4 75 2,670 1,139 1 13 6 39 813 267-1 - 92 7,829 4,681 8 209 315 20 1,036 163 Gangwon - 3-15 507 279 - - 1 2 118 84 1 1-12 909 1,653-11 75 1 81 7 Chungbuk - 9-4 227 136-2 1 2 89 38 - - - 4 453 588-5 8 1 34 16 Chungnam - 15-16 573 172-3 - - 107 29 - - - 9 1,408 587 2 6 7 6 191 24 Jeonbuk - 4 1 77 1,963 77-1 1 1 117 47 - - - 12 1,286 419-8 8 1 218 35 Jeonnam - 44 1 27 836 73 - - 1 3 167 59 - - - 25 1,012 595-1 6 1 146 4 Gyeongbuk - 27-3 385 185 1 8 2 4 85 71 - - - 4 1,071 698-6 11 4 274 63 Gyeongnam - 6 21 24 693 237 1 1 2 9 270 97 - - - 19 1,394 948-8 11 6 358 30 Jeju - 1-5 234 181 - - 1 1 21 15 - - - 6 637 626-2 2-69 6 Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional data but the data for years 2009, 2010, 2011, 2012 and 2013 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. Viral hepatitis B data on sentinel surveillance system changed to National Infectious Disease Surveillance System as of December 30, 2010 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, 2012.
주간건강과질병 781 Table 2. Reported cases of national infectious diseases in Republic of Korea, ending August 23, (34th Week)* unit: no. of cases Provinces Meningococcal meningitis Legionellosis Vibrio vulnificus sepsis Murine typhus Scrub typhus Leptospirosis Brucellosis Rabies Total - 2 4 2 17 18 4 14 9-5 10 16 259 175 3 8 4 1 10 17 - - - Seoul - 1 1-3 5 - - 1-1 3-7 12 - - 1 - - - - - - Busan - - - - 3 2 1 1 1 - - 1 1 12 12 - - - - - - - - - Daegu - - - - - - - - - - 1 - - 6 4 - - - - 1 1 - - - Incheon - - 1 - - - - 2 - - 1 1 1 5 9 - - - - - - - - - Gwangju - - - - - - - - - - - - - 5 2 - - - - - - - - - Daejeon - - - - 2 - - - - - - - - 6 6-1 - 1 3 1 - - - Ulsan - - - - - - - 1 - - - - 1 5 3 - - - - - 1 - - - Sejong - - - - - - - - - - - - - 1 1 - - - - - - - - - Gyonggi - 1 1-3 3 1 1 1-1 2 1 27 29 2 5 1 - - 1 - - - Gangwon - - - 1 3 3 - - - - - - - 4 6 - - - - 1 1 - - - Chungbuk - - - - - 1 - - - - - 1-4 4 - - - - 1 1 - - - Chungnam - - 1 1 1 1 - - 1-1 1 3 15 15 - - 1 - - 2 - - - Jeonbuk - - - - - 1-1 1 - - - 1 41 22 - - - - 1 3 - - - Jeonnam - - - - - - 2 7 2 - - - 6 74 17 1 1 - - - 1 - - - Gyeongbuk - - - - 1 1 - - - - - 1 1 16 11 - - 1-2 2 - - - Gyeongnam - - - - 1 1-1 2 - - - 1 26 19-1 - - - 2 - - - Jeju - - - - - - - - - - - - - 5 3 - - - - 1 1 - - - Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional data but the data for years 2009, 2010, 2011, 2012 and 2013 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
782 년제 34 주 (8.17.-8.23.) Table 2. Reported cases of national infectious diseases in Republic of Korea, ending August 23, (34th Week)* unit: no. of cases Provinces Hemorrhagic fever with renal syndrome Syphilis CJD/vCJD Dengue fever Q fever Lyme Borreliosis Melioidosis Tuberculosis 3-year average 3-year average 3-year average 3-year average Total 4 100 121 27 619 520 2 36 28 6 110 68-7 6-8 1-1 - 827 24,224 25,076 Seoul 1 5 9 3 106 77-5 7 2 25 21 - - 2-1 1-1 - 158 4,917 5,157 Busan - 2 5-36 44-2 2-9 5 - - - - 1 - - - - 52 1,811 2,097 Daegu - - 1 3 38 18-5 2 2 7 2 - - - - 1 - - - - 44 1,239 1,373 Incheon - 2 5 3 41 60-3 1-5 4 - - - - - - - - - 48 1,278 1,283 Gwangju - - 1-6 19 - - 1-2 - - - - - - - - - - 13 560 630 Daejeon - 3 2 1 15 10 - - 1-5 3-1 - - - - - - - 22 585 626 Ulsan - - 1-21 6-1 - - 1 1 - - - - - - - - - 23 514 574 Sejong - 1 - - 1 - - - - - - - - - - - - - - - - 3 49 51 Gyonggi - 28 38 13 171 121-7 6 2 33 17 - - 2-2 - - - - 195 4,957 4,669 Gangwon 1 17 11-19 21 1 2 1-1 1 - - - - 1 - - - - 28 1,077 891 Chungbuk 1 10 8-24 14-1 1-1 2 - - 1 - - - - - - 12 680 781 Chungnam - 4 9 3 30 13-2 2-2 2-2 1 - - - - - - 47 1,052 1,015 Jeonbuk - 10 7-11 18 - - 1 - - 3 - - - - - - - - - 37 868 981 Jeonnam 1 11 7 1 7 13-1 1-4 1-1 - - - - - - - 32 1,119 1,155 Gyeongbuk - 4 14-39 22-5 1-8 1-2 - - 1 - - - - 63 1,708 1,779 Gyeongnam - 2 3-40 42 1 2 1-7 4-1 - - 1 - - - - 43 1,562 1,740 Jeju - 1 - - 14 22 - - - - - 1 - - - - - - - - - 7 248 305 Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional data but the data for years 2009, 2010, 2011, 2012 and 2013 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. Syphilis, CJD/vCJD data on sentinel surveillance system changed to National Infectious Disease Surveillance System as of December 30, 2010 average is mean value calculated by cumulative counts from 1st to current for 5 preceding years.
주간건강과질병 783 Table 3. Reported cases of national sentinel surveillance disease in Republic of Korea, ending AUGUST 9, (32th Week)* unit: no. of cases Viral hepatitis Sexually Transmitted Diseases Hepatitis C Gonorrhea Chlamydia Genital herpes Condyloma acuminata Total 2.6 25.8 28.1 1.8 6.9 8.6 2.2 15.1 16.6 2.7 18.4 15.3 2.4 11.1 8.8 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. 주요통계이해하기 <Table 1> 은지난 5년간발생한법정감염병과 년해당주발생현황을비교한표로, 는 년해당주의신고건수를나타내며, 은 년 1주부터해당주까지의누계건수, 그리고 ly average 는지난 5년 (2009-2013 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 2009 년부터 2013 년의 10 주부터 14 주까지의신고건수를 총 25 주로나눈값으로구해진다. * ly average(5 년주평균 )=(X1 + X2 + + X25)/25 10주 11주 12주 13주 14주 년 해당주 2013년 X1 X2 X3 X4 X5 2012년 X6 X7 X8 X9 X10 2011년 X11 X12 X13 X14 X15 2010년 X16 X17 X18 X19 X20 2009년 X21 X22 X23 X24 X25 <Table 2> 는 17 개시 도별로구분한법정감염병보고현황을보여주고있으며, 각감염병별로 Cum, average 와 Cum, 를비교해보면최근까지의누적신고건수에대한이전 5년동안해당주까지의평균신고건수와비교가가능하다. Cum, average 는지난 5년 (2009-2013 년 ) 동안의동기간신고누계평균으로계산된다. <Table 3> 은주요표본감시감염병에대한신고현황으로, 최근발생양상을신속하게파악하는데도움이된다.
발간등록번호 11-1351159-000002-03 PUBLIC HEALTH WEEKLY REPORT, 주간건강과질병 PHWR ISSN:2005-811X PHWR Vol.7 NO.35 www.cdc.go.kr 주간건강과질병, PHWR 은질병관리본부가보유한감시, 조사사업및연구자료에대한종합, 분석을통한근거에기반하여건강과질병관련정보를제공하고자최선을다할것이며, 제공되는원고의내용은질병관리본부의입장과는무관함을알립니다. 주간건강과질병에서제공되는감염병통계는 감염병의예방및관리에관한법률 에의거하여국가감염병감시체계를통해신고된자료를기반으로집계된것이며, 당해년도자료는의사환자단계에서신고된것으로확진결과가나오거나다른병으로확인된경우수정및변동가능한잠정통계입니다. 동간행물은인터넷 (http://www.cdc.go.kr) 에주간단위로게시되며이메일을통해정기적인구독을원하시는분은이름, 이메일, 주소, 연락처, 직업을간단히기입하여 oxsi@korea.kr로신청하여주시기바랍니다. 주간건강과질병에대하여궁금하신사항은 oxsi@korea.kr로문의하여주시기바랍니다. 창 발 간 : 2008 년 4 월 4 일 행 : 년 8 월 28 일 발행인 : 양병국편집인 : 정충현편집위원 : 윤승기, 최혜련, 박영준, 김윤아, 최영실, 김기순, 정경태, 최병선, 조신형, 조성범, 김봉조, 구수경, 김용우, 조은희, 박선희, 유석현, 조승희, 최수영 편 집 : 질병관리본부감염병관리센터감염병감시과 충북청원군오송읍오송생명 2 로 187 오송보건의료행정타운 ( 우 )363-951 Tel. (043)719-7166, 7176 Fax. (043)719-7189 http://www.cdc.go.kr