주간건강과질병 제 11 권제 33 호 연구논문, Research article HIV/AIDS 치료제개발현황 질병관리본부국립보건연구원감염병연구센터바이러스질환연구과윤철희, 이소림, 김기순 * * 교신저자 : An o

Transcription

1 pissn X eissn PUBLIC HEALTH WEEKLY REPORT, PHWR Vol.11, No.33 CONTENTS 182 HIV/AIDS 치료제개발현황 193 라싸열의실험실진단및특성 199 통계단신 (QuickStats) 칼슘섭취현황 111 주요감염병통계환자감시 : 전수감시, 표본감시 병원체감시 : 인플루엔자및호흡기바이러스 급성설사질환, 엔테로바이러스 매개체감시 : 말라리아매개모기, 일본뇌염매개모기

2 주간건강과질병 제 11 권제 33 호 연구논문, Research article HIV/AIDS 치료제개발현황 질병관리본부국립보건연구원감염병연구센터바이러스질환연구과윤철희, 이소림, 김기순 * * 교신저자 : tigerkis@nih.go.kr, An overview regarding development of therapeutic drugs against HIV/AIDS Yoon Cheol-Hee, Lee Sorim, Kim Kisoon Division of Viral Disease Research, Center for Infectious Disease Research, KNIH, KCDC Background: anti-human immunodeficiency virus (anti-hiv) drugs can reduce HIV-associated morbidity, prolong survival, and prevent HIV transmission. However, the drug resistance is an emerging problem worldwide, because of chronic therapy without interruption during patient s life span. To overcome the drug-resistance, development of anti-hiv drugs is continued with finding new therapeutic targets that are essential for HIV replication. status: The discovery of HIV as the causative agent of acquired immune deficiency syndrome (AIDS) and an increasing understanding of the viral replication cycle have been instrumental in research of anti-hiv drug. Anti-HIV drug discovery has been focused on targeted inhibition of HIV using specific pharmacological agents. Since the approval of Zidovudine (AZT) in 1987, over 3 anti-hiv drugs belonging to six distinct classes based on their biological function and resistance profiles are being used: (1) nucleoside-analog reverse transcriptase inhibitors (NRTIs), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (3) integrase inhibitors (INSTIs), (4) protease inhibitors (PIs), (5) fusion inhibitors, and (6) co-receptor antagonists. Additionally, several anti-hiv drugs are being developed, such as long active drugs, humanized antibody, and prodrug metabolized to active form in patients. In this review, we will outline the developmental history of anti-hiv drugs with their basic principles and limitations due to drug resistance. Future perspective: Anti-HIV drugs are being developed to overcome the drug resistance, adverse effects, and limited adherence shown in earlier drugs. ly, reverse transcriptase, protease, and integrase inhibitors are available for patient care. Although several anti-hiv drugs are effective for patient treatment, researchers have to continue discovering new therapeutic targets before resistance to current drugs emerges. Furthermore, research and development focused on agents that target persistent HIV reservoirs should be strengthened, which may lead to prolonged drug-free remission and HIV cure. Keywords: Human immunodeficiency virus (HIV), anti-hiv drug, Therapeutic target, Drug resistance 182

3 주간건강과질병 제 11 권제 33 호 들어가는말 1981년미국질병통제예방센터 (Centers for Disease Control and Prevention, CDC) 는동성연애자및마약사용자집단에서치명적인감염질환이발생했다고보고하였다. 이질병은환자의면역상태를결핍시켜카포시육종및뉴모시스티스카리니폐렴, 림프종등을유발하게하였으며, 결국환자를사망케하는것이특징이었다. 처음이질병을보이는집단이주로남성동성연애자였기에 치료제로써개발되었다. 이후비뉴클레이시드역전사효소저해제, 단백분해효소저해제, 바이러스침입저해제및바이러스통합효소저해제들이순서대로개발되었다. 최근에는기존약물의효과를개선시키거나새로운패러다임의 HIV 치료제개발이계속진행되고있다. 이글에서는이들약제들의개발과정및그작용기전등을살펴보고, 나아가최근개발되고있는항바이러스제들을살펴봄으로써미래의 HIV/acquired immune deficiency syndrome(aids) 치료제개발방향을제시해보고자한다. 처음에는남성동성연애자관련면역결핍증 (Gay-related immunodeficiency syndrome, GRID) 으로불리었다. 1983년프랑스파스퇴르연구소의뤽몽따니에그룹에서림프종환자의림프절에서레트로바이러스한종이분리되었고, 후에이바이러스가 human immunodeficiency virus(hiv) 로밝혀졌다. 이후많은연구를통해이바이러스의생활사가밝혀지게되면서치료제및진단기술이신속히개발될수있었다. HIV의가장큰특징은역전사과정으로이과정을차단하는치료제개발전략이가장먼저적용되었고 1987년뉴클레오시드계열역전사효소저해제인 Zidovudine(azidothymidine, AZT) 이최초의 HIV 몸말 1983년 HIV 발견이후 HIV의생활사가밝혀졌으며, 이들연구결과를토대로 HIV 증식을저해하는치료제가개발되어왔다. HIV는 CD4+ 세포의수용체 CD4와보조수용체 (CCR5, CXCR4) 에결합한후숙주세포안으로침투한다. 침투한후바이러스 RNA 게놈은역전사효소에의해 DNA로변형된후핵으로이동하여숙주세포의염색체에통합효소 (integrase) 에의해삽입이 Figure 1. Stages of the HIV-1 life cycle that are targeted by antiretroviral drugs[2] Nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (InSTIs) and allosteric integrase inhibitors (ALLINIs)

4 주간건강과질병 제 11 권제 33 호 Figure 2. FDA-approved individual antiretroviral drugs and drug combinations[3] 된다. 삽입된바이러스 DNA(provirus) 는바이러스전사인자 Tat(Trans-activator of Transcription) 와숙주의여러인자들의도움을받아바이러스의 mrna가발현된다. 발현된바이러스 mrna의일부는자손바이러스의게놈이되고, 일부 mrna는바이러스의외막단백질 (gp12, gp41) 과비리온형성에필요한여러단백질로번역되어숙주세포막을싸고세포밖으로나가게된다. 이때비리온내에서바이러스단백분해효소 (protease) 에의해바이러스가성숙 (maturation) 되어비로소감염력이있는바이러스로변모한뒤인접한다른세포에재감염되어새로운 바이러스생활사가시작된다 (Figure 1)[2]. 이러한바이러스의생활사에서꼭필요한단계는항-HIV 약제개발을위한타겟으로선정되었으며, 현재이들중 5가지단계를각각차단하는항-HIV 약제약 3여종이개발되었다. 항-HIV 약제개발의타겟으로사용된 5가지단계는보조수용체 CCR5와의결합단계, 바이러스막과숙주세포막의융합단계, 바이러스 DNA 합성 ( 역전사 ) 단계, 바이러스 DNA의숙주세포염색체로의통합단계그리고마지막으로바이러스성숙단계 (maturation) 이다. 1987년최초역전사효소저해제 Zidovudine 부터최근의통합효소 184

5 주간건강과질병 제 11 권제 33 호 Table 1. Nucleoside reverse transcriptase inhibitors, NRTIs Generic name Brand name FDA approval date Zidovudine (ZDV) Retrovir 1987 Didanosine (ddi) Videx 1991 Zalcitabine (ddc) Hivid 1992 Stavudine (d4t) Zerit 1994 Lamivydine (3TC) Epivir 1995 Abacavir (ABC) Ziagen 1998 Tenofovir disoproxil fumarate (TDF) Viread 21 Emtricitabine (FTC) Emtriva 23 Tenofovir alafenamide fumarate (TAF) Vemlidy 216 Figure 3. Nucleoside reverse transcriptase inhibitors, X-ray crystal structure of HIV-1 NRTI[4] 저해제 Elvitegravir 까지각단계를저해하는 3 여종의 HIV 저해제등 6 종류로분류된다 [2,3,4]. 치료제들이개발되어환자치료에이용되고있다 [2,3](Figure 2). 현재까지개발된 HIV 치료제는작용기전및화학적형태로 역전사효소저해제 ( 뉴클레오사이드계열, 비뉴클레오사이드계열 ), 단백분해효소저해제, 통합효소저해제, CCR5 길항제, 막융합 1. 역전사효소저해제 (Reverse transcriptase inhibitors, RTIs) 185

6 주간건강과질병 제 11 권제 33 호 Table 2. Non-nucleoside reverse transcriptase inhibitors, NNRTIs Generic name Brand name FDA approval date Nevirapine (NVP) Viramune 1996 Delavirdine (DEL) Rescriptor 1997 Efavirenz (EFV) Sustiva 1998 Etravirine (ETR) Intelence 28 Extended-release Nevirapine Viramune XR 211 Rilpivirine (RPV) Edurant 211 Figure 4. Non-nucleoside reverse transcriptase inhibitors, X-ray crystal structure of HIV-1 RT and action mode of NNRTI[4] 1987 년최초의 HIV 치료제로뉴클레오시드계열역전사효소 개발되면서최근까지 NNRTI 는계속개발되고있다. 저해제 (Nucleoside reverse transcriptase inhibitor, NRTI) 계열의 Zidobudine(3'-azido 3'-deoxythymidine, AZT) 이개발된이후뉴클레오시드계열의다양한역전사효소저해제들이속속들이개발되었다. 이후뉴클레오시드계열약제에대한내성이증가되면서 1996년비뉴클레오사이드역전사효소저해제 (Non nucleoside reverse-transcriptase inhibitor, NNRTI) 인 nevirapine(nvp) 이 가 ) 뉴클레오시드계열역전사효소저해제 (Nucleoside reverse-transcriptase inhibitors, NRTIs) NRTIs는미 FDA에서최초로승인된항-HIV 약물군이다. 이들은주로전구체로복용하며, 이후숙주세포에들어가인산화되어뉴클레오티드형태로변환되면서약물로써활성을 186

7 주간건강과질병 제 11 권제 33 호 Table 3. Protease inhibitors Generic name Brand name FDA approval date Saquinavir (SQV) Invirase 1995 Ritonavir (RTV) Norvir 1996 Indinavir (IDV) Crixivan 1996 Nelfinavir (NFV) Viracept 1997 Amprenavir (APV) Agenerase 1999 Atazanavir (ATV) Reyataz 23 Fosamprenavir (FPV) Lexiva 23 Tipranavir (TPV) Aptivus 25 Darunavir (DRV) Prezista 26 Figure 5. Protease inhibitors, the crystal structure of HIV-1 protease and action mode of PI[4] 갖게된다. 현재까지개발된 NRTI 는 8 종이며최근엔 Tenofovir 의 약리활성을증가시킨 Tenofovir alafenamide fumarate(taf) 가 뉴클레오티드와의 3-5 인산에스터결합을차단함으로써 DNA 합성을종료시키는작용기전이있다 (Figure 3)[4]. 개발사용되고있다 (Table 1). 이들은공통적으로뉴클레오시드의 당분자의 3-OH( 수산화기 ) 가없기때문에바이러스의 DNA 합성과정에서 DNA 가닥에껴들어가 DNA 체인의다음에오는 나 ) 비뉴클레오시드역전사효소억제제 (Non-nucleoside reverse-transcriptase inhibitors, NNRTIs) 187

8 주간건강과질병 제 11 권제 33 호 Figure 6. Peptide sequences of enfuvirtide and its action mode[5] NNTRIs는 NRTIs와다르게바이러스 DNA합성종료자로서역할하지않고, 역전사효소의활성부위근처의소수성낭 (hygrophobic pocket) 에직접결합하여효소의구조를변화시킴으로써효소작용을억제한다 (Figure 4)[4]. 따라서기존의 NRTIs와의교차내성은없다. 최근까지도개발되고있는역전사효소저해제이며, 이들약물을단독투여하면 HIV가내성획득에취약하고, 다른 NNRTIs에대한교차내성이있다. 따라서이약제는다른계열의항-HIV 약제와함께투여한다. 현재까지승인된약제는 6종이있다 (Table 2). 2. 단백분해효소억제제 (Protease inhibitors, PIs) 199년대중반이후다양한 HIV의단백분해효소저해제들 (PIs) 이개발되었다. HIV의단백분해효소는감염력이없는 중요한효소이다. 따라서단백분해효소저해제는 HIV 신약분야에서매력적인타겟으로각광받았다. 이러한단백분해효소저해제가개발된초기에는이효소가바이러스증식에매우중요한역할을하며, 크기도 11 kda로매우작기때문에내성발생이적을것으로기대하였다. 그러나 PIs로치료한환자들에서내성돌연변이가매우높은빈도로발생하였으며, 특히모든 PIs는효소의활성부위에결합하는유사한화학구조를가지고있기때문에교차내성에취약한단점이있는것으로밝혀졌다. 따라서현재 PIs들은 3가지항-HIV 약제를투여하는 칵테일요법 에만주로사용된다. 또한 PIs를오래사용하면지방의체내분포가변하고지질대사에이상이나타난다는단점이있다. 따라서 26년 Darunavir 이후더이상신규 PI는개발되지않고있다 [4]. 3. 막융합억제제 (Membrane fusion inhibitor) 비리온 (virion) 에함유되어있는 Gag 와 Gag-Pol 의전구체 단백질을절단시켜감염력이있는성숙된바이러스로변화시켜주는 1997 년 crystal 구조연구에서 HIV 의막융합단백질 gp41 의 188

9 주간건강과질병 제 11 권제 33 호 Figure 7. Chemical structure of CCR5 antagonist (Maraviroc)[4] 바이러스막외부 2개의도메인 (heptad repeats, HRs) 을구성하는각각 3개의헬릭스가상호결합하면서 6개의 coiled-coil 구조 (sixhelix bundle) 를이루며바이러스막과세포막이서로융합되는것이밝혀지면서, 이과정을차단하는펩타이드가개발되었다 (Figure 6). 이는 23 년 Enfuvirtide(T-2, Fuzeon) 라는이름으로미식약청 (Food and Drug Administration, FDA) 의승인을받아주로기존약물로치료가어려운환자를대상으로주사제로써처방되고있다 [5]. 4. CCR5 길항제 (Antagonist) 5. 통합효소 DNA가닥전달저해제 (Integrase strand transfer inhibitors, INSTIs) 역전사가종료되면바이러스 DNA는숙주의염색체에끼어들어가프로바이러스 (provirus) 가된다. 그때부터비로소바이러스는자신의유전자를발현하고자신의후손을만들어낼수있다. 이렇게바이러스 DNA가숙주의염색체에삽입될때필요한것이통합효소 (integrase) 이며, 이는바이러스의생활사의핵심적인단계를책임지고있다. 이통합효소는가장최근개발된 항 -HIV 약물의타겟이다. 통합효소는 3 -OH 그룹을절단하고 Maraviroc(MVC, brand name Selzentry) 은 HIV의보조수용체인 CCR5 길항제로 27년개발된소분자약물이다 (Figure 7). 이는 CCR5 보조수용체의소수성낭 (pocket) 에결합하여그구조를변형시켜바이러스의막단백질 gp12의 V3 loop가 CCR5에결합하는것을방해하여바이러스의숙주세포침투를막는다. 이약제는숙주의보조수용체를타겟으로함에도바이러스단백질에직접결합하여작용하는다른항-HIV 약물과는다른내성기전을이용해내성을획득할수있음이알려졌다. 이약제에대한내성획득기전으로는바이러스의 gp12의 CCR5 대신 CXCR4로의감염경로변형, Maraviroc 보다강한 CCR5와의결합력강화, 이후바이러스의 DNA가닥을숙주염색체로전달해통합하는일련의작용을한다. 그중통합효소저해제들은바이러스 DNA가닥을전달하는기능을타겟으로하여개발되었고, 이들을통합효소 DNA가닥전달저해제 (INSTI) 로부른다. 27년 Raltegravir(RAL) 가가장먼저통합효소저해제로개발되었고, 이후 213년 Dolutegravir(DTG), 214년 Elvitegravir(ETG) 가순차적으로개발되었다 (Table 4). 이들은통합효소의활성부위 (active site) 와바이러스 DNA가결합하기위해필요한 2개의마그네슘이온과결합하여통합효소의활성부위와 DNA와의결합을차단한다 (Figure 8)[4,7]. Maraviroc-CCR5 복합체를인식해침투하는능력을획득하는경우 등이다 [4,6]. 6. 최근개발되고있는 HIV/AIDS 신약 189

10 주간건강과질병 제 11 권제 33 호 Figure 8. Integrase strand transfer inhibitors, the crystal structure of virus integrase and action mode of INSTI[4,7] 가 ) 장시간작용약물 : Cabotegravir(CAB) + Ripivirine (RPV) 환자몸에서장시간작용하는항바이러스제로는 약보다환자의편리함을증가시켜주는것으로보고되었다. 장시간 작용하는약물이개발되면환자는몇달에한번씩만복용하면 됨으로환자의삶의질을매우높일수있을것으로기대한다 [8]. Cabotegravir 와 Ripivirine 이있다. 현재개발중인통합효소저해제 Cabotegravir(CAB, GSK744) 는반감기가최대 4일이며나노파티클형태인 nanosuspension 은 21~5 일이며, 최장 9일에 1회복용으로도바이러스의증식을효과적으로억제할수있다. Ripivirine(RPV) 은이미개발된비뉴클레오시드계열역전사효소저해제 (NNTRI) 로 25 mg 알약의반감기가최대 5일이고장시간작용하는 nanosuspension은반감기가최대 9일까지가능하다. 최근무작위 2b상임상시험결과둘의약물을혼합하여복용시최대 8주 (56일) 간격으로복용한환자의 94% 에서혈중바이러스의농도를 5 copies/ml 이하로유지할수있어기존매일먹는 나 ) Bictegravir(BIC) Bictegravir(BIC) 는통합효소저해제로개발되었으며, 이는 2종의역전사효소저해제와함께 3중복합제 BIC/FTC/TAF 형태로임상3상연구를거쳐 년미 FDA에서승인되었다. 이 3중복합처방제는임상연구에서 Dolutegravir(DTG) 가포함된 3중복합제 DTG/FTC/TAF 와유사한바이러스증식억제효능을보였으며, 약물역효과는오히려덜한것으로밝혀졌다. 또한 BIC는내성발생이적고, DTG에서보이는내성돌연변이에대해서도효과가높은것으로밝혀졌다. 이의반감기는 18시간이다 [9]. 19

11 주간건강과질병 제 11 권제 33 호 Table 4. Integrase strand transfer inhibitors, INSTIs Generic Name Brand Name FDA Approval Date Raltgravir (RAL) Isentress 27 Dolutegravir (DOL) Tivicay 213 Elvitegraivr (ELV) Vitekta 214 다 ) Doravirine(MK-1439) 차세대비뉴클레오시드계열역전사효소저해제 (NNRTI) 로최근임상3상연구를진행하였다. Doravirine은다른항-HIV 약물들과병용사용시약물간상호간섭작용이거의없었으며, 다른항-HIV 약물에서나타나는악성콜레스테롤저밀도지방단백질 (LDL) 등의수치가비교그룹보다감소하였으며, 중추신경계 (CNS) 부작용도거의없었다. 보강연구결과여부에따라 FDA 승인이주목된다 [1]. 치료제들이개발되고있다. HIV에한번감염되면완치되지않고평생약을복용해야한다. 이렇듯 HIV가완전히제거되지않는상황에서지속적으로약물에접한바이러스와이를회피하기위한내성돌연변이가축적되어더이상그약물로는제압되지않는새로운바이러스로재탄생하게된다. 내성획득력이뛰어난 HIV에대항하기위해인류는뉴클레오시드계열역전사효소저해제이후다양한치료타겟을개발해그를차단할수있는약물개발에 힘을쏟고있다. 199 년대중반에는바이러스의완숙을억제하는 라 ) Fostemsavir(BMS-66368) Fostemsavir(FTR) 는체내에서 Temsavir(TMR) 로대사되어바이러스의 gp12에결합하여보조수용체 CCR5, CXCR4와의결합을차단함으로써 HIV의숙주세포침입을억제한다. 이는다른종류의항레트로바이러스약물과교차저항이없었다 [11]. 단백분해효소저해제 Saquinavir 등이개발되었고, 뉴클레오시드계열의역전사효소저해제의높은내성발생빈도와교차내성을극복하기위한비뉴클레오시드역전사효소 Nevirapine 등이개발되었다. 2가지이상의치료타겟이개발되면서내성발생을최소하기위해 3가지이상의치료타겟약물을동시에처방하는 다중항레트로바이러스약물치료법 (Combination Anti-Retroviral 마 ) Ibalizumab(Trogarzo) Ibalizumab은숙주세포의 CD4에높은친화도로결합하는인간화면역글로불린 G4 단클론항체이다. 이는 CCR5와 CXCR4 친화성바이러스모두숙주세포로의침입을저해하며기존의항레트로바이러스치료제와교차저항이없었다. 년 3월미 FDA에서다제내성 HIV를치료하기위해사용허가가났고매 14일마다정맥주사로치료하며, 다른항레트로약제와병용사용을권고하고있다 [12,13]. Therapy, cart) 이일반적인 HIV/AIDS 치료방법으로자리잡게되었다. 그럼에도불구하고바이러스는완전히사라지지않고지속적으로약물에노출되면서다제내성이발생하는등내성문제는계속되고있다. 2년대들어와서는내성을극복하기위해새로운치료타겟을찾기시작했고, 23년바이러스의침투과정을타겟으로하는 Enfuviritide가개발되었으며, 몇년후 27년에는 CCR5 길항제 Maraviroc이개발되기도하였다. 이들약물또한다양한형태의내성을유발시키면서, 더강력한 HIV 치료제개발이필요하게되었다. 그중바이러스의핵산을숙주의 맺는말 1983 년 HIV 가처음발견되고 4 년만인 1987 년최초의 HIV 치료제인 Zidovudine 이개발된이후 3 년동안 3 여종의 HIV 염색체안으로삽입시키는통합효소가새로운치료타겟으로각광받게되었고, 27년최초의통합효소저해제인 Raltegravir 가개발되었다. 이후 213년 Dolutegravir, 214년 Elvitegravir, 그리고가장최근인 년복합제제의원료약제로 Bictegravir가개발되었다. HIV와인류의싸움은더욱치열해지고있으며, 191

12 주간건강과질병 제 11 권제 33 호 최근에는매일먹는약에대한불편함을덜기위해통합효소저해제기반의장시간작용제가개발되고있다. 또한 년기존의약물과는전혀다른형태인인간화항체 Ibalizumab이개발성공하기도하였다. 항HIV 약물은계속개발되고있지만 HIV를근본적으로완치하기위해선바이러스가잠복감염된세포를찾아내어선택적으로괴사시켜야한다. 그러나아직까지잠복감염세포의특이표지인자조차발견되지않고있다. 또한현재가장각광받고있는통합효소저해제들은기존약물의화학구조를기반으로하여개발되었기에조만간또다른형태의내성이발생할것으로예상된다. 따라서우리는미래에발생할항HIV 약물의내성문제를미리예측하고, 새로운치료타겟을찾아야할것이다. 이와더불어숙주세포에숨어있는 HIV를완전히환자몸으로부터 217;39: Paul E Sax, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US ): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 217;39: Molina JM, et al. Conference on Retroviruses and Opportunistic Infections Abstract 45LB 11. Lalezari J, et al. Attachment inhibitor prodrug BMS in ARVexperienced subjects: 24 analysis. Conference on Retroviruses and Opportunistic Infections Abstract Medscape March 6 "FDA Approves Ibalizumab for Multidrug- Resistant HIV-1" Lewis S, et al. Conference on Retroviruses and Opportunistic Infections Abstract 449LB. 제거시킬수있는완치기술개발에도더많은열정을쏟아부어야 인류와 HIV 와의싸움에서인류의승리로결판날것이다. 참고문헌 1. F. Barre-Sinoussi, et al. Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS). Science. 1983;22: Sarah B, et al. A mechanistic theory to explain the efficacy of antiretroviral therapy. Nature. 214;12: Tomas Cihlar and Marshall Fordyce status and prospects of HIV treatment. Opinion in Virology. 216;18: Eric J. Arts and Daria J. Hazuda. HIV-1 Antiretroviral Drug Therapy. Cold Spring Harb Perspect Med. 212;2:a Lalezari JP, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drugresistant HIV infection in North and South America. N Engl J Med. 23;348: Kondru R, et al. Molecular interactions of CCR5 with major classes of small-molecule anti-hiv CCR5 antagonists. Mol Pharmacol. 28;73: Hare S, et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci. 21;17: David A Margolis, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96- results of a randomized, open-label, phase 2b, non-inferiority trial. Lancet

13 주간건강과질병 제 11 권제 33 호 연구단신, Brief report 라싸열의실험실진단및특성 질병관리본부감염병분석센터고위험병원체분석과김진원, 김유리, 강병학, 이기은 * * 교신저자 : gerhie@korea.kr, Lassa fever diagnostics Kim Jin-Won, Kim Yu-ri, Kang Byung Hak, Rhie Gi-eun Division of High-risk Pathogens, Center for Laboratory Control of Infectious Diseases, KCDC Lassa fever is an acute viral hemorrhagic illness caused by Lassa virus. Lassa fever is endemic in the West African countries including Nigeria, Guinea, Sierra Leone, Liberia, Mali, and Côte d Ivoire. There have also been reports of imported cases through international travel and repatriation in Europe and North America. Lassa fever usually presents within 6 to 21 days after infection. The initial symptoms are nonspecific illness with fever, malaise, headache, anorexia, and weakness. The differential diagnosis of Lassa fever can hardly be distinguished based on clinical symptoms from other endemic febrile illnesses. After the onset of illness, treatment with antiviral drugs during the early stages and supportive care are available. Laboratory diagnosis plays an important role in the differential diagnosis of Lassa fever because it is difficult to diagnose based on clinical symptoms. Keyword: Lassa virus, Lassa fever, Laboratory diagnosis, Clinical symptoms 들어가는말 라싸열은라싸바이러스에의해발병하는급성바이러스성출혈열이다. 라싸바이러스는아레나바이러스과 (Arenaviridae) 에속하는단일가닥 RNA 바이러스로, L segment 와 S segment 의두개유전자를가지고있다. 1969년나이지리아동북부라싸마을에서발생한출혈열환자에서원인바이러스가분리되어라싸바이러스로명명되었다 [1]. 라싸열의주요유행국가는나이지리아, 기니, 시에라리온, 라이베리아, 베냉등서아프리카지역 (Figure 1) 으로, 최근나이지리아에서발생한라싸열은지난 217년 11월에발생하여 년 4월현재까지유행하고있으며 년에만 21개주에서 413명의환자가보고되었다 ( 년 4월 15일기준, WHO). 아프리카이외지역에서발생사례는라싸열유행지역에서귀국한후에발병하여확인된경우로유럽, 북미등지에서사례보고가있었으며, 라싸열이처음알려진 1969년이후약 3여건에이른다 [2]. 라싸열은고위험군에속하는에볼라바이러스병, 마버그열등의바이러스성출혈열중에서국외유입사례가가장많이보고된질병이다 [3]. 라싸열의매개체는서아프리카지역에서서식하는들쥐 (Mastomys natalensis) 로, 감염된들쥐는특별한증상없이침, 소변, 분변, 호흡기분비물, 혈액등을통해바이러스를배출하는 193

14 주간건강과질병 제 11 권제 33 호 Figure 1. Geographic distribution of Lassa fever in West African affected countries, (Source: WHO, 숙주역할을한다. 또한감염환자의체액및분비물을통하여사람간의전파도가능하다. 들쥐의배설물과직접접촉, 에어로졸의흡입, 섭취, 감염환자의체액등을통해서감염이발생하면발열, 무력감, 두통, 근육통, 오심, 구토, 소화불량등의증상과함께발병한다. 발병초기에리바비린등의항바이러스제투여가효과가있는것으로알려져있으며, 증상에대한대증요법을적용한다. 라싸열의초기증상은말라리아등열대성풍토병및에볼라등고위험군출혈열과유사하여임상증상만으로정확한진단이어렵다. 따라서조기진단을통한신속한치료및대응을위한실험실진단이필수적이다. 이단신에서는라싸열실험실진단법과특성에대하여소개하고자한다. 라싸열은보통 2~21일의잠복기를거치며 3주이내에임상증상이나타난다. 초기에는열, 피로감, 두통, 인후통, 근육통, 기침, 흉통, 복통, 메스꺼움, 구토, 설사등의비특이적인증상이나타난다. 감염된사람의 8% 에서증상이없거나경미한증상을보이며, 약 2% 에서비정상적인출혈, 전립선부종, 호흡곤란, 저혈압, 단백뇨, 혈장염, 청각장애, 뇌증, 다발성장기부전등의증상을보이며병이진행된다 [4]. 치사율은대개 15% 정도로알려져있지만, 216년에는 5% 라고보고되었다 [5]. 회복된사람은청력을손실하거나신경계후유증을겪기도한다 [5,6]. 라싸열에대한치료는환자의증상에대한대증요법을중심으로하며, RNA의합성을저해하는항바이러스제인리바비린을 처방하기도한다. 리바비린을라싸열초기에적용할경우효과가 몸말 임상증상및치료 있는것으로알려져있으며, 발병 6일이내의환자에적용할경우사망위험이 5% 미만으로낮아지지만, 이후에는효과가감소하는것으로보고되었다 [7]. 최근연구에서는리바비린과같은계열항바이러스제인파비피라비르가영장류에서라싸바이러스감염을억제하는효과가있음을확인하였다 [8]. 숙주세포의유전자 194

15 주간건강과질병 제 11 권제 33 호 Figure 2. A transmission electron micrograph (TEM) of a number of Lassa virus virions adjacent to some cell debris (Source: CDC, Public Health Image Library, Credit: C. S. Goldsmith) 합성에도영향을주는리바비린과달리파비피라비르는바이러스의유전자복제과정에만작용하며향후임상시험에서의효과가검증된다면라싸열치료에적용할수있을것으로기대된다. 라싸열진단의특징 라싸열의초기증상이비특이적이고, 발생지역에서유행하는말라리아, 뎅기열, 황열과같은풍토병이나인플루엔자등의열병, 에볼라등의출혈열과유사하기때문에감별진단이필수적이다. 특히라싸열유행지역에서는실험실진단시설과시약의한계로경험에의존하여말라리아나세균감염으로진단하여치료중환자가호전되지않을경우라싸열을의심하는사례가발생한다. 이러한진단지연으로인해환자의격리가늦어지고가족및의료종사자에게전염될가능성이증가하며항바이러스요법을적용할시기를놓치게되어치료효과가감소하게된다. 특히라싸열유행지역에서발생한 214년서아프리카에볼라바이러스병유행은적절한진단의필요성을더욱보여주고있다. 한연구에서는에볼라바이러스병이유행하기수년전부터시에라리온의라싸열진단실험실에서급성발열성질환으로검사한검체를분석한결과, 6~7% 에서라싸열과말라리아는음성이었으나에볼라와마버그바이러스감염이의심되는혈청학적증거가발견되었다고한다 [9]. 따라서급성발열성질환의원인을명확하게파악하여대응하기위해서는상황에적합한유효하고신속한진단검사가필요하다. 라싸바이러스는에볼라바이러스와같은미생물제4위험군에속하는고위험병원체로생물안전 4등급시설 (Biosafety level 4, BL4) 에서취급하는것을권장한다 [1]. 라싸열감염환자의체액과분비물을통한사람간의전파가가능하므로의심검체를취급할때에도감염의위험성을충분히인지하고적절한방법으로취급해야한다. WHO에서도라싸바이러스감염의심검체를취급할때에볼라바이러스취급에관한가이드라인에따라 BL4 수준의시설사용을권장한다 [11]. 하지만전세계적으로 BL4를사용할수있는경우가제한적이므로 BL4 수준의시설을사용할수없는경우에한하여 WHO에서제시하는생물안전규정을준수하는조건으로더낮은등급의실험실에서검체를취급할수있도록허용하고있다 [11,12]. 그러나라싸바이러스를배양하는등직접적으로취급하는경우에는 BL4 수준의실험실안전을준수해야한다. 라싸열의심검체의전처리 195

16 주간건강과질병 제 11 권제 33 호 Table 1. Selected assays for detecting Lassa virus Assay type a Traget b Reference Standard RT-PCR GPC gene Demby et al.,1994 Ölschläger et al., 21 L-gene Vieth et al., 27 Real-time RT-PCR SYBR R green GPC gene Drosten et al., 22 Safronetz et al., 21 TagMan R Chemistry NP, GPC gene Trombley et al., 21 IFA Ag capture Irradiated virus Bausch et al., 2 RDT Ag capture rnp Matthew et al.,, ELISA Ag capture rnp Saijo et al., 27 IgM Irradiated virus Bausch et al., 2 rgpc, rnp Satterly et al., 216 IgG Irradiated virus Bausch et al., 2 rnp rnp Saijo et al., 27 O'Hearn et al., 216 a IFA, indirect fluorescent-antibody test; RDT, rapid diagnostic test b rnp, recombinant nucleoprotein; rgpc, recombinant glycoprotein complex 실험실검사를위하여검체를불활화하는방법으로는여러가지방법이있지만, 검사방법이나목적에따라적절한방법을선택하여사용하는것이좋다. 가장일반적으로사용하는방법은구아니딘염을포함한용액을이용한화학적불활화로 TRIzol, Triton X-1, Buffer AVL, 에탄올을사용한다 [13,14]. 혈액검체의경우 56~6 에서열처리하여불활화하기도하며, 검체의종류에따라서열처리만으로불활화가완전하게이루어지지않을수있으므로화학적불활화와함께사용하기도한다 [12]. 바이러스배양 걸리는시간이길고 BL4 시설을필수적으로갖추어야하지만, 라싸바이러스유전자형과무관하게적용이가능하며, 바이러스검출과특성규명에활용할수있다는장점이있다. 바이러스유전자검출 Real-time RT-PCR의경우높은특이도와민감도로감염병진단에널리사용하는방법이며, 라싸바이러스진단에도가장많이사용하는표준방법이다. 세포에서바이러스를분리배양하는것에비하여더욱신속하게검체에서바이러스유무를확인할수있으며, 검체에서핵산을추출하는과정에자동화기기를사용할경우다량 최근에는바이러스유전자를검출하는실시간역전사핵산증폭기법 (real-time RT-PCR) 이나면역학적검사법이널리사용되지만, 바이러스분리배양은여전히골드스탠더드로남아있다. 의심검체를원숭이신장세포의한종류인 Vero E6 세포에접종하여세포변성이나타나면양성이라고볼수있으며 [15], RT-PCR 항원검출검사, 전자현미경검사등으로검증한다. 라싸열환자혈액, 인후도찰물, 소변, 뇌척수액등을배양에사용할수있다. 바이러스배양은유전자검출이나면역학적검사법에비하여결과를얻는데 검체를신속하게처리할수있다. 정량적 real-time RT-PCR 기법을적용할경우, 별도의과정없이검체의바이러스총량을확인할수있으며실험에사용한프라이머종류와바이러스유전자형에따라서 1,237~4,29 RNA copies/ml 의검출한계를보인다 [15]. 라싸바이러스유전체는 L segment 와 S segment로이루어져있는데, 각각유전자는유전자형에따라 32% 와 25% 의유전적변이를보이며유전자형은지역에따라다르게나타난다 [16]. 유전적다양성은유전자검출법의민감도와특이도에영향을줄수 196

17 주간건강과질병 제 11 권제 33 호 있으므로상대적으로유전자변이가적은 S segment 를중심으로개발되고있으며 S segment 부위를진단에활용하고있다. 항원및항체검출 항원검출방법은주로바이러스혈증이나타나는발병초기부터일주일사이의혈액검체에적용할수있다. 특히, 항원검출용신속진단키트의경우특별한검사장비가필요하지않으며, 수십분이내에진단이가능하므로현장에서적용가능한진단방법이다. 항원검출법은유전자검출법에비하여민감도가떨어지는것으로알려져있지만, 최근연구에서는라싸바이러스의핵산단백질특이단클론항체를이용한신속진단키트 (rapid diagnostic test, RDT) 에서 real-time RT-PCR을이용한유전자검출법대비 9% 이상의민감도를보였으며음성사례의상당수는회복기혈청이거나증상이경미한경우임을확인하였다 [17]. 항체검출방법은 enzyme-linked immunosorbent 있는방법이지만, 진단까지소요되는시간이길고, BL4를필요로하는단점이있다. 바이러스유전자검출법은가장널리쓰이는진단법으로, 민감도가높고, 불활화된검체를 BSL-2 조건에서처리하여신속하게바이러스유전자를검출할수있는장점이있지만, 바이러스의유전적다양성으로인한위음성의가능성이있다. 혈액에서바이러스항원을검출하는방법은현장적용이가능하고진단에소요되는시간이짧으며발병초기바이러스혈증이나타나는기간에적용가능하지만상대적으로민감도가떨어진다는단점이있다. 라싸바이러스특이 IgM이나 IgG를검출하는방법은발병초기의신속한진단에적용하기는어렵지만바이러스혈증이후의진단, 급성기와회복기혈청비교를통한재감염사례등을확인하는데활용할수있다. 다양한라싸열진단법중에모든사례에적용할수있는이상적인방법한가지를고르기는어렵지만각진단법의특성을이해하고상황에따라선택적으로적용한다면의심사례발생시신속하고적절한대응이가능할것으로사료된다. assay(elisa) 또는 indirect immunofluorescence assay(ifa) 를 사용하여라싸바이러스특이 IgM이나 IgG를검출한다. 라싸바이러스특이 IgM은일부환자에서는발병 4일이내에검출되기도하지만보통감염후 2주정도부터검출된다 [18]. 라싸열유행지역에서는최근발열증상이없었던건강한사람을대상으로한검사에서도 28% 가 IgM 양성으로나타나기도하고, IgG의경우증상발현후평균 25.6일에검출되며역가가수십년동안지속되기도하므로, 항체가측정만으로현재의감염여부를판단하기에는어려움이있다 [15]. 맺는말 발병초기의비특이적인임상증상과라싸바이러스의높은유전적다양성, 고위험병원체취급을위한 BL4 시설의필요로인해라싸열진단에는여러가지제약이있다. 바이러스배양은진단에있어서골드스탠더드이며유전자형에무관하게적용할수 참고문헌 1. Frame JD, Baldwin JM Jr, Gocke DJ, Troup JM. Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. Am J Trop Med Hyg. 197;19: Beeching NJ, Fletcher TE, Hill DR, Thomson GL. Travellers and viral haemorrhagic fevers: what are the risks? Int J Antimicrob Agents. 21;36:S Macher AM, Wolfe MS. Historical Lassa fever reports and 3-year clinical update. Emerg Infect Dis. 26;12: Centers for Disease Control and Prevention. Lassa fever. Centers for Disease Control and Prevention, Atlanta, GA. accessed 31 July. 5. World Health Organization WHO Target Product Profile for Lassa virus Vaccine. 6. Ogbu O, Ajuluchukwu E, Uneke CJ. Lassa fever in West African. J Vector Borne Dis. 27;44: McCormick JB. King IJ, Webb PA, Scribner CL, Craven RB, Johnsoson KM, Elliott, Belmont-Williams R. Lassa fever. Effective therapy with rivavirin. N Engl J Med. 1986;314:

18 주간건강과질병 제 11 권제 33 호 8. Rosenke K, Feldmann H, Westover JB, Hanley PW, Martellaro C, Feldmann F, Saturday G, Lovaglio J, Scott DP, Furuta Y, Komeno T, Gowen BB, Safronetz D. Use of Flavipiravir to treat lassa virus infecion in macaques. Emerg Infect Dis. ;24(9). 9. O'Hearn AE, Voorhees MA, Fetterer DP, Wauquier N, Coomber MR, Bangura J, Fair JN, Gonzalez JP, Schoepp RJ. Serosurveillance of viral pathogens circulating in West Africa. Virol J. 216;13: 질병관리본부 실험실생물안전지침. ( 정부간행물발간등록번호 ). 11. World Health Organization Interim guideline: laboratory diagnosis of Ebola virus disease. World Health Organization, Geneva, Switzerland. 12. Pan American Health Organization, World Health Organization General procedures for inactivation of potentially infectious samples with Ebola virus and other highly pathogenic viral agents. Regional Office for the Americas of the World Health Organization, Washington. 13. Haddock E, Feldmann F, Feldmann H. Effective chemical inactivation of Ebola virus. Emerg Infect Dis. 216;22: Smither SJ, Weller SA, Phelps A, Eastaugh L, Ngugi S, O'Brien LM, Steward J, Lonsdale SG, Lever MS. Buffer AVL alone does not inactivate Ebola virus in a representative clinical sample type. J Clin Microbiol. 215;53: Raabe V, Koehler J. Laboratory Diagnosis of Lassa Fever. J Clin Microbiol : Andersen KG, Shapiro BJ, Matranga CB, et al. Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus. Cell. 215;164: Boisen ML, Hartnett JN, Shaffer JG, et al. Field validation of recombinant antigen immunoassays for diagnosis of Lassa fever. Sci Rep. ;8: Bausch DG, Rollin PE, Demby AH, et al. Diagnosis and clinical virology of Lassa fever as evaluated by enzyme-linked immunosorbent assay, indirect fluorescent-antibody test, and virus isolation. J Clin Microbiol. 2;38:

19 통계단신, QuickStats 주간건강과질병 제 11 권제 33 호 칼슘섭취현황 Trends in calcium intake and major food sources, [ 정의 ] 칼슘권장섭취량대비섭취비율 : 칼슘권장섭취량에대한섭취량비율의평균권장섭취량 : 215 한국인영양소섭취기준 ( 보건복지부, 215) 남자의칼슘섭취수준은권장섭취량의 68%, 여자는 57% 로 (216 년 ), 남녀모두상당히낮고여자가더심각. 채소류와우유류는칼슘의 주요급원식품군으로, 우유섭취증가와함께칼슘섭취문제가해소될것으로기대했으나 21 년이후답보수준이며, 채소류섭취량이 감소할것으로예상되어칼슘부족우려됨 ( 그림 A, 자세한결과는 216 국민건강통계 참조 ). Calcium deficiency is the traditional nutrition problem in Korea. In both of men and women, the ratios of calcium intake compared to the recommended nutrient intake were lower than 7%. Because the consumption of vegetable and milk, the major sources of calcium intake, was not improved, calcium deficiency could be more severe (Figure A). Calcium intake to recommended nutrient intake (%) Year Men Women Figure A. Change in intakes of calcium, vegetable and milk, Intake of vegetable (g) Intake of milk/milk products (g) Year Men Women Year * Source: Korea National Health and Nutrition Examination Survey * The ages of subjects were 1 year or over. * Percentage of calcium intake to recommended nutrient intake (RNI) is the ratio of calcium intake compared to the recommended intake of respective sex and age group. * RNI was from the Dietary Reference Intakes for Koreans, 215 by the Ministry of Health and Welfare. * The mean and standard error was calculated using direct standardization method based on 5 population projection. Men Women Source: Korea Health Statistics 216: Korea National Health and Nutrition Examination Survey (KNHANES Ⅶ-1), Reported by: Division of Health and Nutrition Survey, Korea Centers for Disease Control and Prevention 199

20 주간건강과질병 제 11 권제 33 호 11

21 주요감염병통계, Statistics of selected infectious diseases 1.1 환자감시 : 전수감시감염병주간발생현황 (32nd Week) Table 1. Reported cases of national infectious diseases in Republic of Korea, ending August 11, (32nd Week)* Category Ⅰ Category Ⅱ Category Ⅲ Category Ⅳ Classification of disease ly average Total no. of cases by year Imported cases of current : Country (no. of cases) Cholera Typhoid fever Paratyphoid fever Cambodia(1) Shigellosis India(5), Philippines(5), Malaysia(1) EHEC Viral hepatitis A 44 1, ,419 4,679 1,84 1, Pertussis Tetanus Measles Mumps , ,924 17,57 23,448 25,286 17,24 Rubella Viral hepatitis B (Acute) Japanese encephalitis Varicella 1,583 57, ,92 54,6 46,33 44,45 37,361 Haemophilus influenza 2 3 type b Streptococcus pneumoniae Malaria Scarlet fever , ,838 11,911 7,2 5,89 3,678 Meningococcal meningitis Legionellosis Vibrio vulnificus sepsis Murine typhus Myanmar(1) Scrub typhus 53 1, ,528 11,15 9,513 8,13 1,365 Leptospirosis Brucellosis Rabies HFRS Syphilis 28 1, ,148 1,569 1,6 1, CJD/vCJD Tuberculosis , ,161 3,892 32,181 34,869 36,89 HIV/AIDS ,9 1,62 1,18 1,81 1,13 Viral hepatitis C 25 7,28-6, Russia(1) VRSA CRE 234 6,811-5, Unit: No. of cases Dengue fever Indonesia(3), Thailand(3), Myanmar(2), Vietnam(2), Taiwan(1), Laos(1), Uganda(1), Cambodia(1), Philippines(1) Q fever West Nile fever Lyme Borreliosis Melioidosis Chikungunya fever Philippines(2), Myanmar(1), Vietnam(1), Uganda(1), Indonesia(1) SFTS MERS Zika virus infection Maldives(1), Myanmar(1), Vietnam(1), Indonesia(1), Thailand(1), Philippines(1) Abbreviation: EHEC= Enterohemorrhagic Escherichia coli, HFRS= Hemorrhagic fever with renal syndrome, CJD/vCJD= Creutzfeldt-Jacob Disease / variant Creutzfeldt-Jacob Disease, VRSA= Vancomycin-resistant Staphylococcus aureus, CRE= Carbapenem-resistant Enterobacteriaceae, 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 217, are provisional but the data from 213 to 216 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, 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)

22 Table 2. Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Diseases of Category Ⅰ Unit: No. of cases Reporting area Cholera Typhoid fever Paratyphoid fever Shigellosis Overall Seoul Busan Daegu Incheon Gwangju Daejeon Ulsan Sejong 2 1 Gyonggi Gangwon Chungbuk Chungnam Jeonbuk Jeonnam Gyeongbuk Gyeongnam Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

23 Table 2. (Continued) Reported cases of infectious diseases by geography, s ending August 11, (32nd Week)* Unit: No. of cases Diseases of Category Ⅰ Diseases of Category Ⅱ Reporting area Enterohemorrhagic Escherichia coli Viral hepatitis A Pertussis Tetanus Overall ,714 1, Seoul Busan Daegu Incheon Gwangju Daejeon Ulsan Sejong Gyonggi Gangwon Chungbuk Chungnam Jeonbuk Jeonnam Gyeongbuk Gyeongnam Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

24 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Diseases of Category Ⅱ Unit: No. of cases Reporting area Measles Mumps Rubella Viral hepatitis B (Acute) Overall ,98 11, Seoul ,627 1, Busan Daegu Incheon Gwangju Daejeon Ulsan Sejong Gyonggi ,672 2, Gangwon Chungbuk Chungnam Jeonbuk , Jeonnam Gyeongbuk Gyeongnam ,175 1, Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

25 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Unit: No. of cases Diseases of Category Ⅱ Diseases of Category Ⅲ Reporting area Japanese encephalitis Varicella Malaria Scarlet fever Overall 1,583 57,693 29, ,29 6,434 Seoul 189 6,181 3, , Busan 18 3,279 1, , Daegu 67 3,8 1, Incheon 86 2,413 1, Gwangju 65 1, Daejeon 36 1, Ulsan 24 1, Sejong Gyonggi ,24 8, ,317 1,927 Gangwon 3 1,59 1, Chungbuk 48 2, Chungnam 48 1,89 1, Jeonbuk 79 2,528 1, Jeonnam 72 2,32 1, Gyeongbuk 86 2,715 1, Gyeongnam 145 5,4 2, Jeju 5 2, Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

26 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Diseases of Category Ⅲ Unit: No. of cases Reporting area Meningococcal meningitis Legionellosis Vibrio vulnificus sepsis Murine typhus Overall Seoul Busan Daegu Incheon Gwangju 1 1 Daejeon 1 4 Ulsan 3 1 Sejong Gyonggi Gangwon 7 3 Chungbuk 11 2 Chungnam Jeonbuk Jeonnam Gyeongbuk 21 2 Gyeongnam Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

27 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Diseases of Category Ⅲ Unit: No. of cases Reporting area Scrub typhus Leptospirosis Brucellosis Hemorrhagic fever with renal syndrome Overall 53 1, Seoul Busan Daegu Incheon Gwangju Daejeon Ulsan Sejong Gyonggi Gangwon Chungbuk Chungnam Jeonbuk Jeonnam Gyeongbuk Gyeongnam Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

28 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Unit: No. of cases Diseases of Category Ⅲ Diseases of Category Ⅳ Reporting area Syphilis CJD/vCJD Tuberculosis Dengue fever Overall 28 1, ,338 2, Seoul ,62 3, Busan ,156 1, Daegu , Incheon , Gwangju Daejeon Ulsan Sejong Gyonggi ,741 4, Gangwon Chungbuk Chungnam Jeonbuk Jeonnam , Gyeongbuk ,196 1, Gyeongnam ,175 1, Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

29 Table 2. (Continued) Reported cases of infectious diseases by geography, ending August 11, (32nd Week)* Diseases of Category Ⅳ Unit: No. of cases Reporting area Q fever Lyme Borreliosis SFTS Zika virus infection 3-year 3-year Overall Seoul Busan Daegu Incheon Gwangju Daejeon Ulsan Sejong 1 - Gyonggi Gangwon Chungbuk Chungnam Jeonbuk Jeonnam Gyeongbuk Gyeongnam Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year are provisional but the data from 213 to 217 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

30 1.2 환자감시 : 표본감시감염병주간발생현황 (32nd ) 1. Influenza, Republic of Korea, s ending August 11, (32nd ) 년도제 32 주인플루엔자표본감시 ( 전국 2 개표본감시기관 ) 결과, 의사환자분율은외래환자 1, 명당 2.7 명으로지난주 (4.5 명 ) 대비감소 217- 절기유행기준은 6.6 명 (/1,) ILI per 1, Figure 1. Weekly proportion of influenza-like illness per 1, outpatients, to 217- flu seasons 2. Hand, Foot and Mouth Disease(HFMD), Republic of Korea, s ending August 11, (32nd ) 년도 32 주차수족구병표본감시 ( 전국 95 개의료기관 ) 결과, 의사환자분율은외래환자 1, 명당 18.8 명으로전주 (26.2 명 ) 대비감소 수족구병은 29 년 6 월법정감염병으로지정되어표본감시체계로운영 No. of outpatients / 1, Figure 2. Weekly proportion of hand, foot and mouth disease per 1, outpatients,

31 3. Ophthalmologic infectious disease, Republic of Korea, s ending August 11, (32nd ) 년도 32 주차유행성각결막염표본감시 ( 전국 92 개의료기관 ) 결과, 외래환자 1, 명당분율은 34.1 명으로전주 28.5 명대비증가 동기간급성출혈성결막염의환자분율은.8 명으로전주.8 명대비동일 6 5 No. of outpatients / 1, Figure 3. Weekly proportion of epidemic keratoconjunctivitis per 1, outpatients 5 4 No. of outpatients / 1, Figure 4. Weekly proportion of acute hemorrhagic conjunctivitis per 1, outpatients

32 4. Sexually Transmitted Diseases, Republic of Korea, s ending August 11, (32nd ) 년도제 32 주성매개감염병표본감시기관 ( 전국보건소및의료기관 592 개참여 ) 에서신고기관당성기단순포진 2.8 건, 첨규콘딜롬 2.5 건, 클라미디아감염증 1.9 건, 임질 1.3 건발생을신고함. 제 32 주차신고의료기관수 : 임질 14 개, 클라미디아 43 개, 성기단순포진 31 개, 첨규콘딜롬 19 개 Unit: No. of cases/sentinels Gonorrhea Chlamydia Genital herpes Condyloma acuminata 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) , 7132 자세히보기 : 질병관리본부 정책 / 사업 감염병감시 표본감시주간소식지 1.3 수인성및식품매개감염병집단발생주간현황 (32nd ) Waterborne and foodborne disease outbreaks, Republic of Korea, s ending August 11, (32nd ) 년도제 32 주에집단발생이 9 건 ( 사례수 168 명 ) 이발생하였으며누적발생건수는 383 건 ( 사례수 6,312 명 ) 이발생함 No. of outbreaks Average no. of cases in last 5 years( ) Figure 5. Number of waterborne and foodborne disease outbreaks reported by,

33 2.1 병원체감시 : 인플루엔자및호흡기바이러스주간감시현황 (32nd ) 1. Influenza viruses, Republic of Korea, s ending August 11, (32nd ) 년도제 32 주에전국 52 개감시사업참여의료기관에서의뢰된호흡기검체 141 건중양성 1 건. (A(H1N1)pdm9 1 건 ) No. of positives A(H3N2) A(not subtyped) A(H1N1)pdm9 B Percent positive Percent positives (%) Figure 6. Number of specimens positive for influenza by subtype, to 217- flu season 2. Respiratory viruses, Republic of Korea, s ending August 11, (32nd ) 년도제 32 주호흡기검체 (141 건 ) 에대한유전자검사결과 31.9% 의호흡기바이러스가검출되었음. ( 최근 4 주평균 152 개의호흡기검체에대한유전자검사결과를나타내고있음 ) 주별통계는잠정통계이므로변동가능 () Weekly total Detection rate (%) No. of samples Detection rate (%) HAdV HPIV HRSV IFV HCoV HRV HBoV HMPV , 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 July August. 11., (Average No. of detected cases is 152 last 4 s) 217 : the rate of detected cases between January December 자세히보기 : 질병관리본부 알림 주간질병감시정보

34 2.2 병원체감시 : 급성설사질환실험실표본주간감시현황 (31st ) Acute gastroenteritis-causing viruses and bacteria, Republic of Korea, s ending August 4, (31st ) 년도제31주실험실표본감시 (17 개시 도보건환경연구원및 7개의료기관 ) 급성설사질환유발바이러스검출건수는 4건 (9.1%), 세균검출건수는 47건 (22.4%) 이었음. Acute gastroenteritis-causing viruses Week No. of sample No. of detection (Detection rate, %) Group A Rotavirus Norovirus Enteric Adenovirus Astrovirus Total (.) 6 (9.) 3 (4.5) 3 (4.5) 12 (17.9) (2.7) 3 (4.1) 1 (1.4) 2 (2.7) 8 (11.) (4.3) 2 (2.9) 5 (7.2) 2 (2.9) 12 (17.4) (2.3) 2 (4.5) (.) 1 (2.3) 4 (9.1) 2, (9.9) 295 (13.5) 72 (3.3) 38 (1.7) 622 (28.5) * 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 (5.2) 19 (9.9) () () () 8 (4.2) 2 (1.) 6 (3.1) 6 (3.1) 51 (26.7) (3.8) 2 (1.9) () () () 4 (2.2) 1 (.5) 3 (1.6) 2 (1.1) 38 (2.7) (2.9) 17 (7.) () 1 (.4) () 7 (2.9) 4 (1.7) 5 (2.1) 5 (2.1) 46 (19.) (6.2) 2 (9.5) () 2 (1.) () 4 (1.9) 2 (1.) 1 (.5) 5 (2.4) 47 (22.4) 5, (2.7) 22 (3.8) 2 (.3) 6 (.1) () 56 (1.) 67 (1.2) 96 (1.7) 95 (1.7) 697 (12.2) * 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 (7 hospitals) 자세히보기 : 질병관리본부 알림 주간질병감시정보

35 2.3 병원체감시 : 엔테로바이러스실험실주간감시현황 (31st ) Enterovirus, Republic of Korea, s ending August 4, (31st ) 년도제 31 주실험실표본감시 (1 개시 도보건환경연구원, 전국 53 개참여병원 ) 결과, 엔테로바이러스검출률 5.%(28 건양성 /56 검체 ), 년누적양성률 32.%(412 건양성 /1,289 검체 ) 임. - 무균성수막염 6 건 ( 년누적 85 건 ), 수족구병및포진성구협염 6 건 ( 년누적 213 건 ), 합병증동반수족구 1 건 ( 년누적 12 건 ), 기타 15 건 ( 년누적 12 건 ) 임. ( 엔테로바이러스감시사업전산망이전에따라 31 주차로집계된검사건수감소 ) Aseptic meningitis 8 No. of cases Enterovirus detection cases 217 Enterovirus detection cases Figure 7. Detection cases of enterovirus in aseptic meningitis patients from 217 to HFMD and Herpangina No. of cases Enterovirus detection cases 217 Enterovirus detection cases Figure 8. Detection cases of enterovirus in HFMD and herpangina patients from 217 to HFMD with Complications No. of cases Enterovirus detection cases 217 Enterovirus detection cases Figure 9. Detection cases of enterovirus in HFMD with complications patients from 217 to

36 3.1 매개체감시 / 말라리아매개모기주간감시현황 (31st ) Vector surveillance: Malaria vector mosquitoes, Republic of Korea, ending August 4, (31st ) 년도제 31 주말라리아매개모기주간발생현황 (3 개시 도, 총 2 개채집지점 ) - 전체모기 : 평균 21 개체로평년 54 개체대비 33 개체 (61.1%) 감소및전년 15 개체대비 6 개체 (4.%) 증가 - 말라리아매개모기 : 평균 7 개체로평년 21 개체대비 14 개체 (66.7%) 감소및전년 5 개체대비 2 개체 (4.%) 증가 7 6 No. of mosquitoes Week Total Mosquitoes(Average) Malaria Vector Mosquitoes(Average) Total Mosquitoes Malaria Vector Mosquitoes Total Mosquitoes Malaria Vector Mosquitoes Figure 1. Weekly incidences of malaria vector mosquitoes in 3.2 매개체감시 / 일본뇌염매개모기주간감시현황 (31st ) Vector surveillance: Japanese encephalitis vector mosquitoes, Republic of Korea, ending August 4, (31st ) 년 31 주일본뇌염매개모기주간발생현황 : 1 개시 도보건환경연구원 ( 총 1 개지점 ) - 전체모기 : 평균 1,366 개체로평년 85 개체대비 561 개체 (69.7%) 증가및전년 538 개체대비 828 개체 (153.9%) 증가 - 일본뇌염매개모기 (Japanese encephalitis vector, JEV) : 평균 32 개체로평년 121 개체대비 89 개체 (73.6%) 감소및전년 84 개체대비 52 개체 (61.9%) 감소 No. of mosquitoes 3, 2, 1,8 1,6 1,4 1,2 1, Week Total Mosquitoes (Average) JEV Vector Mosquitoes (Average) Total Mosquitoes JEV Vector Mosquitoes Total Mosquitoes JEV Vector Mosquitoes Figure 11. Weekly incidences of Japanese encephalitis vector mosquitoes in 자세히보기 : 질병관리본부 민원 / 정부 3. 사전정보공개

37 주요통계이해하기 < 통계표 1> 은지난 5년간발생한법정감염병과 년해당주발생현황을비교한표로, 금주환자수 ( ) 는 년해당주의신고건수를나타내며, 년누계환자수 ( ) 는 년 1주부터해당주까지의누계건수, 그리고 5년주평균환자수 ( ly average) 는지난 5년 ( 년 ) 해당주의신고건수와이전 2주, 이후 2주의신고건수 ( 총 25주 ) 평균으로계산된다. 그러므로금주환자수 ( ) 와 5년주평균환자수 ( ly average) 의신고건수를비교하면해당주단위시점과예년의신고수준을비교해볼수있다. 연도별환자수 (Total no. of cases by year) 는지난 5년간해당감염병현황을나타내는확정통계이며연도별현황을비교해볼수있다. 예 ) 년 12 주의 5 년주평균환자수 ( ly average) 는 213 년부터 217 년의 1 주부터 14 주까지의신고건수를 총 25 주로나눈값으로구해진다. * 5 년주평균환자수 ( ly average)=(x1 + X2 + + X25)/25 1주 11주 12주 13주 14주 년 해당주 217년 X1 X2 X3 X4 X5 216년 X6 X7 X8 X9 X1 215년 X11 X12 X13 X14 X15 214년 X16 X17 X18 X19 X2 213년 X21 X22 X23 X24 X25 < 통계표 2> 는 17 개시 도별로구분한법정감염병보고현황을보여주고있으며, 각감염병별로최근 5년누계평균환자수 (Cum, average) 와 년누계환자수 (Cum, ) 를비교해보면최근까지의누적신고건수에대한이전 5년동안해당주까지의평균신고건수와비교가가능하다. 최근 5년누계평균환자수 (Cum, average) 는지난 5년 ( 년 ) 동안의동기간신고누계평균으로계산된다. 기타표본감시감염병에대한신고현황그림과통계는최근발생양상을신속하게파악하는데도움이된다.

38 발간등록번호 주간건강과질병, PHWR 은질병관리본부에서시행되는조사사업을통해생성된감시 및연구자료를기반으로근거중심의건강및질병관련정보를제공하고자최선을다할 것이며, 제공되는정보는질병관리본부의특정의사와는무관함을알립니다. 본간행물에서제공되는감염병통계는 감염병의예방및관리에관한법률 에의거, 국가감염병감시체계를통해신고된자료를기반으로집계된것으로집계된당해년도자료는의사환자단계에서신고된것이며확진결과시혹은다른병으로확인될경우수정될수있는잠정통계임을알립니다. 주간건강과질병, PHWR 은질병관리본부홈페이지를통해주간단위로게시되고있으며, 정기적구독을원하시는분은 이메일을통해보내지는본간행물의정기적구독요청시구독자의성명, 연락처, 직업및이메일주소가요구됨을알려드립니다. 주간건강과질병 발간관련문의 : kcdc215@korea.kr/ /33 창 발 간 : 28 년 4 월 4 일 행 : 년 8 월 16 일 발행인 : 정은경 편집인 : 박도준 편집위원 : 최영실, 김기순, 최병선, 조신형, 조성범, 김봉조, 구수경, 김용우, 이동한, 조은희, 이은규, 윤여란, 신영림, 김청식, 전경아, 권효진 편 집 : 질병관리본부유전체센터의과학지식관리과 충북청주시흥덕구오송읍오송생명2로 187 오송보건의료행정타운 ( 우 )28159 Tel. (43) /33 Fax. (43)