FOCUSED ISSUE OF THIS MONTH pissn 1975-8456 / eissn 2093-5951 https://doi.org/10.5124/jkma.2017.60.6.475 국내진드기매개질환의현황과전망 설형 김동민 조선대학교의과대학내과학교실 Present state and future of tick-borne infectious diseases in Korea Hyoung Sul, MD Dong-Min Kim, MD Department of Internal Medicine, Chosun University School of Medicine, Gwangju, Korea The incidence of vector-borne infectious diseases is increasing due to developments in diagnostic techniques, as well as due to economic, environmental, and ecological factors such as global warming, increased rainfall, globalization, and urbanization. Tick-borne infectious diseases occurring in Korea include severe fever with thrombocytopenia syndrome, Lyme disease, anaplasmosis, and Japanese spotted fever. Various skin lesions, such as erythema migrans, tick bite sites, rash, and eschar, are associated with tick-borne infectious diseases. It is necessary to remove ticks immediately to prevent transmission of these tick-borne infectious diseases. Especially for conditions such as Lyme disease, at least 24 to 48 hours of tick attachment to the host is required for transmission of the causative pathogens to the host. Tick-borne diseases are acquired after outdoor activities and have nonspecific symptoms such as fever, headache, and chills, which make them difficult to identify without a diagnostic test. Rapid diagnosis and early treatment can reduce the otherwise significant morbidity and mortality associated with these conditions; therefore, therapy should not be delayed until laboratory confirmation is received. Key Words: Tick-borne diseases; Scrub typhus; Lyme disease; Rickettsia infections 서론 전세계적으로지구온난화가가속화되며기온이올라가고 강수량및강수강도가증가되고있다. 우리나라에서또한사 계절중여름이길어지고있으며, 강수일수는 14% 감소하였 으나, 강수강도가 18% 증가하여연강수량은 7% 증가하였다 [1]. 기후변화가매개체감염병에미치는영향에대해서는 아직까지논란이있으나. 지구온난화에의한기온및강수량 Received: April 20, 2017 Accepted: May 2, 2017 Corresponding author: Dong-Min Kim E-mail: drongkim@chosun.ac.kr Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 의증가는쥐와같은척추동물의먹이의증가, 따뜻한겨울이쥐의생존에유리할뿐아니라, 진드기의생존율, 산란율, 활동률을증가시키고, 진드기의개체수가증가함에따라진드기매개질환의발생률에영향을줄수있다 [2,3]. 그러나매개체감염병의증가에대해단지기후변화하나로설명하기는힘들며, 최근의진단법개발분야에서큰발전등으로인한과거에진단하지못한매개체감염병의진단율의향상도기여하였으리라생각된다. 또한전세계가글로벌화되며국가간자유로운이동이가능하게되어새로운매개체와병원균을접할수있는기회가많아졌고, 도시화로인한토지이용의변화, 사회기반시설의변화등사회경제적, 환경적, 생태학적측면의다양한영향을고려해야할것이다 [4,5]. 절지동물매개질환으로몸이에의해전파되는발진티프스, 쥐벼룩에의해전파되는페스트, 발진열이있고, 참진드기 국내진드기매개질환 475
Table 1. Causative agents, vectors, and clinical characteristics of tick-borne diseases Disease Major causative agents Major vectors Signs or symptoms Diagnosis Treatment Lyme disease Borelia burgdorferi sensu lato (B. burgdorferi sensu stricto, B. afzelii, B. garinii) Ixodes scapularis I. ricinus I. persulcatus I. nipponensis I. granulatus Anaplasmosis Anaplasma phagocytophilum I. scapularis I. nipponensis Ehrlichiosis Ehrlichia chaffeensis Amblyomma americanum SFTS SFTS virus Haemaphysalis longicornis Japanese spotted fever Rickettsia japonica Haemaphysalis spp. Ixodes spp. Dermacentor spp. Rickettsialpox Rickettsia akari Liponyssoides sanguineus (mouse mite) Erythema migrans, fatigue, myalgia, fever, chill, arthralgia Fever, chill, headache, myalgia Fever, chill, headache, myalgia Fever, chill, Gastrointestinal symptoms (abdominal pain, diarrhea, nausea, vomiting), headache, myalgia Fever, headache, myalgia, maculopapular rash, petechiae, eschar Fever, headache, myalgia, vesiculr rash, eschar ELISA,, confirmed by Western blotting Microscopic detection of morula IHC detection in skin biopy IHC detection in skin biopy IHC detection in skin biopy Amoxicillin Chloramphenicol Rifampin Chloramphenicol Rifampin ELISA, enzyme-linked immunosorbent assay;, immunofluorescence assay;, polymerase chain reaction; SFTS, severe fever with thrombocytopenia syndrome; IHC, immunohistochemistry assay;. 180 Lyme disease SFTS Scrub typhus 14,000 환으로쯔쯔가무시병, 리케차폭스 (Ric- No. of Lyme disease and SFTS 160 140 120 100 80 60 40 20 12,000 10,000 8,000 6,000 4,000 2,000 No. of scrup typhus kettialpox) 등이있다. 전세계적으로진드기매개질환의발생률이점차증가하고있으며, 이는국내에서도마찬가지이다 (Figure 1). 본논문에서는참진드기매개질환에대해알아보고자한다. 0 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 0 라임병 Year Figure 1. Incidence of mite and tick-borne diseases reported to Korea Centers for Disease Control and Prevention in South Korea. SFTS, severe fever with thrombocytopenia syndrome. 라임병은북아메리카, 유럽, 아시아에 서주로발생되는매개체관련질환으 매개질환으로라임병 (Lyme disease), 중증열성혈소판감소증후군 (severe fever with thrombocytopenia syndrome, SFTS), 아나플라즈마증 (Anaplasmosis), 에를리키아증 (Ehrlichiasis), Q열, 야생토끼병 ( 야토병, Tularemia), 일본홍반열, 바베시아증 (Babesiosis) 등이있으며, 털진드기매개질 로 10-30 μm길이, 0.2-0.25 μm두께의스피로헤타세균인 Borrelia species 균에감염된진드기가사람을물때감염된다 [6]. 라임병을일으키는 Borrelia species는대략 20종으로구성된그룹인 Borrelia burgdorferi sensu lato complex 이며, B. burgdorferi sensu stricto, B. afzelii, B. garinii, 476 대한의사협회지
Sul H Kim DM Tick-borne infectious diseases in Korea 유하고있으나약충과성충이가장흔한매개체이다. 참진드기는크기가작기때문에대개환자는진드기물림을기억하지못하나, 진드기흡혈에의해 Borrelia species가인체내로침투하며, 3-32일간의잠복기후흡혈부위에서이동홍반 (erythema A B migrans) 을형성하며, 국소적으로증식을시작하고독감유사증상을보인다. 이동홍반은붉은반점이나구진으로시작되며서서히퍼져커다란하나의윤상병변을형성하며이것의바깥테두리경계는분명하며부분적으로중심부위가깨끗하다 (1기, 국소적감염 ). 수일에서수주이내에 B. burgdorferi 는혈행 C Figure 2. (A) Dorsal view of Ixodes nipponensis. (B) Ventral view of I. nipponensis. (C) Dorsal view of Haemaphysalis longicornis. (D) Ventral view of H. longicornis. D 성으로여러다른부위로퍼져나가파종 성감염을일으키며, 이차적인다발성윤 상피부병변과발열, 오한, 피로감, 권태 B. valaisiana와 B. lusitaniae 등이보고되었다 [7]. 아시아에서는대부분 B. garinii 또는 B. afzelii가원인균이다. Borrelia species 들은주로 Ixodes species의참진드기에의해전파되며, 유럽에서는 Ixodes ricinus와 I. persulcatus 가주요진드기매개체로보고되었고, 북아메리카에서는 I. scapularis, 일본에서는 I. nipponensis, 중국에서는 I. persulcatus 등이보고되었다 [8]. 진드기개체수가증가하고활동이왕성한봄, 초여름에라임병이많이발생하는것으로알려져있다. 국내에서는 1993년진드기로부터라임병병원체가처음분리되었으며, 2010년 12월제4군법정감염병으로지정되었다. 우리나라에서주요매개종으로여겨지는산림참진드기 (I. persulcatus) 는강원산간에주로분포하며, 일본참진드기 (I. nipponensis) 는전국적인분포를하는것으로알려져있고 (Figure 2), 남방참진드기 (I. granulatus) 는주로전라남도쪽에존재한다 [9]. 참진드기는야생쥐, 다람쥐, 개, 사슴, 사람등의포유류와조류, 파충류등에기생할수있다. 참진드기는유충, 약충, 성충세단계모두에서라임병원체를보 감, 근육통, 관절통등의심한전신증상을호소한다. 치료를받지않은환자에서도전신증상은대개수주이내에사라지나, 초기증상의호전이후에적절한치료를받지않은 50% 이상의환자는라임병의합병증을갖게된다. 주된합병증은심장 ( 심장염, 부정맥, 고도방실차단, 심부전등 ), 신경계 ( 뇌수막염, 뇌염, 뇌신경염, 다발성단신경염, 척수염등 ), 관절침범등이며간, 비장, 근육, 연부조직, 안구등의다발성장기를침범한증례들이보고되었다 (2기, 파종성감염 )[10-13]. 파종성감염이후라임병의염증성병변은대개저절로호전되지만, 적절한치료를받지않았다면수개월또는수년후에만성감염의형태로재발하게된다. 후기지속감염은주로중추신경 ( 라임뇌병증 ), 관절, 피부 ( 만성위축성선단피부염 ) 를침범한다 (3기, 후기지속감염 ). 라임병을확진하려면감염조직에서원인병원체 (Borrelia species) 를분리하는것이지만실제임상에서원인균분리가가능한경우는매우드물며대개혈청학적검사를통해서진단하게된다. 감염초기수주이내에형성되는 IgM 항체는편모항원에대한특이항체이고, 시간이경과하면서 국내진드기매개질환 477
병원체의다른항원에대한항체를형성하며 3-6주째에최고조에이른다. 대개 IgM 항체는급성감염 6개월후에기저치수준으로감소하게되지만드물게장기간높게유지되기도한다. IgG 항체도동일한항원에대한특이항체로 IgM 항체보다수주일늦게형성되기시작하며 24개월이상점진적인상승을보인다. 그러나혈청학적검사의민감도나특이도는높지못하며, 20-30% 가급성기에항체가검출되며 70% 가 2-4주후회복기에항체양전화를보이나조기항생제치료가양전률을낮출수있다. 혈청학적검사법으로면역형광법 (immunofluorescence assay, ) 과효소면역측정법 (enzyme-linked immunosorbent assay, ELISA) 이있는데, ELISA가민감도, 객관성, 재현성이높고자동화가가능하므로 보다많이사용된다. 항체검사상양성또는보류판정을보이는경우웨스턴블롯검사로최종확인을해야한다. 발병 4주이내인경우는 IgM과 IgG 모두에대하여웨스턴블롯검사를시행해야한다. 피부조직, 관절액, 혈액, 뇌척수액검체를이용해 Borrelia species에대한중합효소연쇄반응 (polymerase chain reaction, ) 검사를통해서도진단할수있으나아직일반적으로사용되지는않고있다 [14,15]. 초기국소적 / 파종성감염에대해서는경구항생제치료가가능하며, 심장염, 신경계침범, 불응성관절염등의임상양상을보이는환자에대해서는주사용항생제치료가권장된다. 발병초기에는항생제치료에대한반응이좋지만진행된후기지속감염환자의경우는항생제치료에도불구하고호전이없을수있다. 이초기라임병의치료제로선호되며, 이는라임병을전파하는진드기에의해동시에전파될수있는아나플라즈마증등에도효과적이기때문이다. 9세미만의소아와임신중인환자에서는가능하면 doxycycline 처방을피해야하며, 소아라임병환자에게는하루 amoxicillin 30-40 mg/kg을 3회로나누어분복하게한다. 아나플라즈마증 아나플라즈마증및에를리키아증은세포내병원체인 Anaplasma phagocytophilum와 Ehrlichia chaffeensis 가주요원인병원체인진드기매개감염질환이다 [16-18]. 아나플라즈마증은미국에서는주로 I. scapularis 진드기에의해매개되어 A. phagocytophilum이과립구성백혈구를감염시키고, 에흐리키아증은주로 Amblyomma americanum 진드기에의해매개되며 E. chaffeensis가단핵구성백혈구를감염시킨다. 우리나라에서 A. phagocytophilum와 E. chaffeensis는 Haemaphysalis longicornis, I. nipponensis, I. persulcatus 등진드기와등줄쥐, 족제비, 사슴과같은야생동물에서검출되었으며 [19-23], 우리나라에서환자발생은 2014 년최초로아나플라즈마증환자가보고되었다 [24]. 진드기에물린후, 5-11일이지나면고열과불쾌감, 근육통, 두통등비특이적인임상증상이나타나며 [25,26], 젊은성인의경우경미한증상이나타나지만고령이거나면역저하자의경우에는혈소판및백혈구감소증, 간기능효소수치상승및심각한증상이발생할수있다. 아나플라즈마증의급성기에는림프구감소증이나미성숙백혈구를동반한백혈구감소증, 혈소판감소증이나타나며이러한혈액학적이상소견은주로발병첫주에나타나고항생제투여없이도호전될수있다. 미국중서부와북동부에서발생한 144명의아나플라즈마증환자를대상으로연구한결과 [26], 아나플라즈마증발병첫 9일간의급성기의혈액소견에서혈소판수의평균이 66x10 9 /L로혈소판감소증이가장흔하게관찰되었으며, 그외빌리루빈상승없이중등도의간수치상승및 lactate dehydrogenase 상승또한흔하게관찰되었다. 아나플라즈마증은말초혈액도말검사에서세포질내봉입체 (morula, 상실배 ) 를관찰하여진단하거나, A. phagocytophilum를배양또는 을이용하여진단할수있다. 혈청학적검사법으로 를이용하여진단한다. 배양으로확인된아나플라즈마증환자의 95% 이상에서 A. phagocytophilum 에대한항체는증상발생후평균 11일정도에관찰되었으며, 평균약 15일경에최고치에도달하였다. 대부분의환자에서감염후수개월뒤 1:640 이상의항체역가를여전히보였고 1년후에약반수에서항체가검출되었다 [27]. 단 를이용하여진단할때는 E. chaffeensis와 A. phagocytophilum 간교차반 478 대한의사협회지
Sul H Kim DM Tick-borne infectious diseases in Korea 응이있을수있으므로주의하여야한다. 한연구에따르면 12명의아나플라즈마증환자중 2명이사망하였으며나머지 10명은 doxycycline을투여한지 48시간이내에열이내리며빠르게회복되었다 [28]. 또다른연구에서는 18명의아나플라즈마증환자모두 doxycycline을투여한후 48시간이내열이내리며회복되었다. 아나플라즈마증및에를리키아증환자의치료약제로 doxycycline을 10일동안투여하거나해열후 3-5일간더투여하는것을권장하다 [29]. 이치료기간은 B. burgdorferi와동반감염시에도효과적일수있다. Tetracycline 계열약제에과민증또는알러지가있는경우에는 rifampin 300 mg을 2회 / 일, 7-10일간투여할수있으나, 이경우약의효과에대해증례보고수준으로추가적인연구가필요하다 [30]. 한역학조사특징을보고한연구에의하면 SFTS 사망률이 32.6% 였으며, SFTS는전국적으로발생하였다. 산악과구릉지역을중심으로, 즉강원, 경기의북부지역및제주도지역이주요발생지역으로, 서부와서남부의평야지대에서는발생률이상대적으로낮았으며, SFTS 발생빈도는매년증가하고있다 [38]. SFTS 진단은발열, 혈소판감소증, 백혈구감소증, 진드기에노출된역학정보가중요하다. 실험실진단은바이러스분리, 급성기바이러스유전자검출, 회복기혈청의항체가 (IgG) 가 4배이상상승한경우중한가지이상을만족하면확진할수있다 [31]. 현재 SFTSV에대한항바이러스제또는백신은아직개발되지않은상태이며 [39], 야외활동시진드기에물리지않도록예방하는것이필요하다 [40]. 중증열성혈소판감소증후군 홍반열군리케차감염증 SFTS의원인병원체는버냐바이러스과 (Bunyaviridae family) 에속하는중증열성혈소판감소증후군바이러스 (SFTS virus, SFTSV) 이다 [31]. SFTSV는 single-stranded negative sense RNA segment인큰분절, 중간분절, 작은분절, 이렇게 3개의유전자를가진다 [32]. SFTS는 2009년중국허난성에서발병한환자에서바이러스가처음분리되었고 [31], 일본의경우 2012년야마구치현에서처음사례가보고되었다 [33]. 우리나라의 SFTS는 2012년강원도춘천시에거주하던환자에서발열, 백혈구감소증, 혈소판감소증등의증상이발생하여다장기부전으로사망한사례가첫증례로보고되었다 [34]. SFTS의감염경로는주로작은소참진드기 (H. longicornis) (Figure 2) 가매개하여바이러스에감염되는것으로알려져있다 [31,35]. 바이러스에노출된후 4-15일의잠복기를거치며, 고열, 피로감, 두통, 근육통, 복통, 구토, 설사, 기침등비특이적인증상들이나타난다 [31,36]. 또한혈소판감소증, 백혈구감소증, 림프절비대, 위장관출혈등의징후가특징이다 [31,36,37]. 우리나라의 2013-2015년사이 172명의 SFTS 사례에대 홍반열군리케차감염증 (spotted fever group rickettsial diseases) 은홍반열군의리케차 (Rickettsia spp.) 에의해감염되며, 참진드기와털진드기등절지동물에의해매개되는리케차질환이다. 발생지역에따라질환명이불리는경우가많으며, 로키산홍반열 (Rocky mountain spotted fever), 퀸즐랜드진드기티푸스 (Queensland tick typhus), 아프리카진드기열 (Aftrican tick bite fever), 일본홍반열 (Japanese spotted fever), 지중해홍반열 (Mediterranean spotted fever) 등이여기에속한다. 리케차폭스 (Rickettsialpox) 의경우털진드기에의해전파되고, Rickettsia felis의경우고양이벼룩에의해전파되는것을제외하고는거의모든홍반열군의리케차균들은참진드기에의해전파된다. 홍반열군의리케차균들은두개의주요표면외막단백인 OmpA 와 OmpB 로종을구분할수있다. 우리나라에서보고된홍반열군리케차감염증은리케차폭스와일본홍반열이있는데리케차폭스의원인균은 R. akari이며, 일본홍반열은 R. japonica가원인균이다. 국내에서는 1957년처음으로들쥐에서홍반열군의리케차인 R. akari를분리하였으며, 이후가시들피참진드기 (H. bispinosa) 에서 R. japonica와 국내진드기매개질환 479
R. rickettsii를 을통해확인하였다. 또한사람에서홍반열군의리케차균을분리한것은 2006년이처음으로 R. japonica가분리되었다 [41]. 대부분의홍반열은봄, 이른여름에흔히발생하며진드기에노출후 2-14일경 ( 대부분 5-7일 ) 에발열, 두통, 근육통, 구역, 구토등의비특이적인증상으로시작된다. 로키산홍반열의발진은주로손목, 발목에서시작하여중심부및손바닥, 발바닥으로퍼지는양상으로나타나며리케차폭스의발진은초기에반점구진상발진으로시작하여수일에거쳐수포양상으로변하는양상으로수두로오인되기쉽다. 일본홍반열은대부분갑작스럽게발병하며 90% 에서진드기에물려생긴가피가있으며발진은거의모든환자에서생기는데처음엔쌀알크기의반점홍반성발진으로시작하여대개는 3-4일후점출혈발진으로변한다. 쯔쯔가무시병과다르게국소림프절증은잘동반되지않는다. 야외활동력과함께가피와발진등임상소견을보이는경우의심해볼수있으며, 진단에가장흔히사용되는검사법은 과혈청학적검사법이며, 홍반열군특이유전자를 을통해확인하거나 를이용하여급성기와회복기혈청검사를시행하여항체역가가 4배이상상승하는경우진단할수있다 [42]. 감염이후항체가생성되는데 7-10일이소요되므로감염첫주항체검사가음성이라고해서질병을배제해서는안된다. 발진이나가피가있을경우발진이나가피부위피부생검을시행하여 이나면역조직화학염색 (Immunohistochemistry) 을시행하여진단할수있으며, 이는항생제투여후민감도가감소되므로가급적항생제치료전시행해야한다. 홍반열군의선택적치료제는 doxycycline 으로 100 mg을 12시간간격으로 5-7일간투여한다. 진드기매개질병의동시감염 하나의진드기는서로다른감염성병원체를동시에가지고있을수있으며, 한번의 tick bite로여러가지병원체의전파가가능하다 [43]. I. scapularis는아나플라즈마증, 에를리키아증, 라임병, 혹은바베시아증을전파할수 있다. 라임병환자의 23% 가바베시아증이동반되었고 [44], 10-30% 가아나플라즈마증이나에를리키아증이동반되었다. 동시감염은더욱심한증상을일으키는것으로알려져있다 [43,45]. 그러므로라임병이나아나플라즈마증환자를진료할때다른진드기매개질환의가능성을염두에두어야하며, 라임병의경우치료시아나플라즈마증의동시감염을고려하여다른항생제보다는아나플라즈마증에효과가있는 tetracycline 계열항생제투여를고려하는게좋다. 진드기제거및진드기매개질병의예방 라임병의경우는진드기매개질병을전파하기위해서는진드기와접촉이적어도 24-48시간필요하기때문에원인병원체의전파가능성을줄일수있도록진드기를빨리제거해야한다 [46]. 진드기제거는포셉을사용하고, 포셉을돌리면서진드기를제거하면몸통만제거되고진드기의구기가부러져피부에남을수있으므로, 포셉으로진드기의몸체를피부에최대한가깝게잡아서수직으로힘을줘서제거하여야한다. 구기가피부에남으면깨끗한포셉으로남아있는구기를제거해야한다 [47]. 진드기매개질병을예방하기위해서는진드기의주요서식지인풀숲이나나무가우거진지역을피해야하고, 진드기기피제를사용하는것이바람직하다. 야외활동시긴팔, 긴바지, 모자, 목수건, 토시, 장갑, 양말, 장화등작업복을구비하고야외활동후에도평상복과분리세탁, 목욕등으로철저한관리가필요하다. 라임병등매개체감염병발생위험지역에서야외활동을하는경우는반바지, 반팔옷, 샌들등을피하고식약청에서허가받은곤충기피제를사용해야한다. DEET (N,Ndiethyl-m-toluamide) 성분을포함한기피제는 2-3시간동안효과가있으며바짓단, 소매, 양말, 신발그리고눈과입주변을제외한피부에제한적으로처리하고권장량이상의농도가피부에직접닿지않도록주의해야한다 [40]. Permethrin이들어있는기피제는피부에직접닿지않고의복에만처리해야한다. 사용하기전날처리하였다가입 480 대한의사협회지
Sul H Kim DM Tick-borne infectious diseases in Korea 는것이좋고반드시완전히말린다음에입어야한다. 예방목적의항생제투여와관련해서, 진드기에물린경우에 24-72시간동안진드기가달라붙어있어야스피로헤타가진드기내장에서침샘을통해사람에게전파되므로 24시간이내에제거하였다면그것만으로충분하나, 라임병유행지역에서 36시간이상진드기부착이확인되었으며, 충혈된약충이나성충이발견되었다면진드기를제거하고나서경구 doxycycline 200 mg을 1회투여하는것을추천한다 [48]. 결론 전세계적으로진드기매개질환의발생률이점차증가하고있다. 발열과함께두통, 오심, 구토등비특이적인증상이있으면서, 진드기노출위험이있는야외활동력과함께발진, 가피, 진드기물린부위등의임상소견을보이는환자의경우진드기매개질환을반드시의심해보아야한다. 진단을위해서혈액을이용한진드기매개질환특이유전자를타깃으로한 을시행하거나급성기및회복기의혈청학적검사를시행하여항체가상승을통해진단하여야한다. 대부분의진드기매개질환이신속히초기에진단하여치료한경우완치되는경우가많으므로실험실검사확진을위해치료가지연되어서는안된다. 또한하나의진드기가여러진드기매개감염병원체를가지고있을수있으며한번의진드기교상으로진드기매개감염병이동시감염이가능하므로동시감염에대한임상양상관찰및진단이필요할수있다. Acknowledgement This study was supported by research funds from Chousn University Hospital 2016. 찾아보기말 : 진드기매개병 ; 쯔쯔가무시병 ; 라임병 ; 리케차병 ORCID Hyoung Sul, http://orcid.org/0000-0001-9305-4814 Dong-Min Kim, http://orcid.org/0000-0001-6373-0922 REFERENCES 1. National Institute of Meteorological Research. Climate change of Korea: present state and future. Seogwipo: National Institute of Meteorological Research; 2009. 2. Kim SH, Jang JY. Correlations between climate change-related infectious diseases and meteorological factors in Korea. J Prev Med Public Health 2010;43:436-444. 3. Rossati A. Global warming and its health impact. Int J Occup Environ Med 2017;8:7-20. 4. Medlock JM, Leach SA. Effect of climate change on vectorborne disease risk in the UK. Lancet Infect Dis 2015;15:721-730. 5. Randolph SE. To what extent has climate change contributed to the recent epidemiology of tick-borne diseases? Vet Parasitol 2010;167:92-94. 6. Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH Jr. Updates on Borrelia burgdorferi sensu lato complex with respect to public health. Ticks Tick Borne Dis 2011;2:123-128. 7. Noh Y, Kim SY, Lee YS, Kim DW, Kwon T, Hwang KJ. Wholegenome sequence of Borrelia garinii strain 935T isolated from Ixodes persulcatus in South Korea. Genome Announc 2014 Dec [Epub]. https://doi.org/10.1128/genomea.01298-14. 8. Picken RN, Strle F, Picken MM, Ruzic-Sabljic E, Maraspin V, Lotric-Furlan S, Cimperman J. Identification of three species of Borrelia burgdorferi sensu lato (B. burgdorferi sensu stricto, B. garinii, and B. afzelii) among isolates from acrodermatitis chronica atrophicans lesions. J Invest Dermatol 1998;110:211-214. 9. Shim JC, Youn YH, Kim JR. The investigation of Ixodidae. Rep Natl Inst Health 1994;31:149-155. 10. Blaut-Jurkowska J, Olszowska M, Kaznica-Wiatr M, Podolec P. Lyme carditis. Pol Merkur Lekarski 2015;39:111-115. 11. Santino I, Longobardi V. Clinical and serological features of patients with suspected Lyme borreliosis. Int J Immunopathol Pharmacol 2011;24:797-801. 12. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012;379:461-473. 13. Stanek G, Strle F. Lyme borreliosis. Lancet 2003;362:1639-1647. 14. Sroka-Oleksiak A, Ufir K, Salamon D, Bulanda M, Gosiewski T. Nested- real time as alternative molecular tool for detection of Borrelia burgdorferi compared to the classical serological diagnosis of the blood. Med Dosw Mikrobiol 2016; 68:47-56. 15. Moore A, Nelson C, Molins C, Mead P, Schriefer M. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of lyme disease, United States. Emerg Infect Dis 2016 Jul [Epub]. https://doi.org/10.3201/eid2207.151694. 16. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, Mudde AH, Dofferhoff TS, Richter C, Smilde TJ, Krabbe PF, Oyen WJ, 국내진드기매개질환 481
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