대한내과학회지 : 제 86 권제 3 호 2014 http://dx.doi.org/10.3904/kjm.2014.86.3.271 특집 (Special Review) - 최근국내에서발생하는신종감염병의최신지견 중증열성혈소판감소증후군 서울대학교의과대학내과학교실 김계형 오명돈 Severe Fever with Thrombocytopenia Syndrome Kye-Hyung Kim and Myoung-Don Oh Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Severe fever with thrombocytopenia syndrome (SFTS) is firstly reported in China in 2011. It is an emerging infectious disease in China, Japan and South Korea. It is caused by novel bunyavirus, called SFTS virus. The vector of SFTS is Haemaphysalis longicornis tick and domesticated animals may serve as intermediate hosts. The clinical manifestations of SFTS are fever, vomiting, diarrhea, thrombocytopenia and leukopenia. In severe cases, multiple organ failure, disseminated intravascular coagulopathy, and central nervous systems manifestation are present. The case-fatality rate is 6-30%. There is no effective antiviral therapy and supportive care is the main treatment. (Korean J Med 2014;86:271-276) Keywords: Severe fever with thrombocytopenia syndrome; Phlebovirus; Bunyavirus 서론신종감염병은전세계적으로 1940년대부터증가하고있다. 신종감염병가운데매개체가전파하는감염병은 22.8% 를차지할정도로그비중이높다. 매개체는강수량이나기온에민감하여 1990년대부터심화된기후변화로인해매개체감염병에의한신종감염병이증가하고있다 [1]. 중증열성혈소판감소증후군 (severe fever with thrombocytopenia syndrome, SFTS) 은 2011년에중국에서보고된새로운매개체감염병이다 [2]. SFTS 의주요한증상과징후는발열, 복통, 구역, 구토, 혈소판감소증및백혈구감소증이다. 중증환자는다발성장기부전이발생하며치사율은 6-30% 이다 [2-5]. 이질환은중국에이어일본에서도보고되었고 [6] 2013년에는국내에서도보고되었다 [7]. 여기서는 SFTS의원인병원체, 역학, 임상양상, 진단등에대해기술하고자한다. 본론원인병원체 SFTS의원인병원체는중증열성혈소판감소증후군바이러스 (SFTS virus, SFTSV) 이며이바이러스는버냐바이러스과 (Bunyaviridae family) 에속한다 [2]. 버냐바이러스과는세개의분절을포함한음성가닥 (negative-strand) RNA 바이러스인데, 오르토버냐바이러스 (Orthobunyavirus), 한타바이러스 Correspondence to Myoung-Don Oh, M.D. Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82-2-2072-2945, Fax: +82-2-762-9662, E-mail: mdohmd@snu.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 271 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 86, No. 3, 2014 - (Hantavirus), 나이로바이러스 (Nairovirus), 플레보바이러스 (Phlebovirus), 토스포바이러스 (Tospovirus) 를포함하는다섯개의속 (genus) 로이루어져있다 [8]. 이가운데국내에서유행하는바이러스는한타바이러스속 (Hantavirus genus) 의한탄바이러스 (Hantaan virus) 와서울바이러스 (Seoul virus) 가있다. SFTSV는플레보바이러스속 (Phlebovirus genus) 에속하며 [2], 여기에리프트밸리열바이러스 (Rift valley fever virus) 등이있다 [8]. SFTSV는지름이 80-100 nm인공모양의바이러스이다. 이바이러스는 single-stranded negative sense RNA segment인큰분절 (large (L) segment), 중간분절 (medium (M) segment) 그리고작은분절 (small (S) segment) 이렇게 3개의유전자를지니고있다 [8]. 역학 2009년 6월에중국허난성에서발생한환자에서처음으로바이러스가분리되었다 [2]. 중국에서발생한환자의남녀비는여성이 53.3% 로남성보다약간더많았으며환자의나이는중앙값이 58세로노인층에서주로발생하였다. 발생시기는 4월부터 11월까지이며대개 7-8월에집중적으로발생하고있다. 환자의직업은농업또는임업이 81.4% 를차지하였으며발생지역은허난성 (48.2%), 후베이성 (21.9%), 산둥성 (15.7%) 이대부분을차지하였다. 사망한환자의연령은 64세 ( 중앙값, 범위 38-94세 ) 로 70세이상의고령환자가주로사망하는것으로나타났다 [3]. 과거에원인이밝혀지지않았던집단발병사례를후향적으로조사한연구에서중국최초의 SFTS 사례는 2006년에발생하였다. 이사례는처음에아나플라즈마증으로추정하였으나 2012년에비로소 SFTSV가검출되어확진되었다 [9]. 일본의 SFTS는 2012년가을에야마구치현에사는 50대여성에게발병한사례에서처음으로진단되었다 [6]. 이후수행된후향적연구에서환자 11명이추가로확인되었는데, 이들가운데 6명은사망한환자였다. 사망한환자모두나이가 50세이상이었고서일본지역 ( 야마구치, 나가사키, 히로시마, 사가, 미야자키등 ) 에서보고되었다. 발생시기는 3월부터 8월까지이며 5월에가장많은환자가발생하였다. 후향적연구에서가장이른증례는 2005년에발생한환자였다 [6]. 우리나라의 SFTS는강원도춘천시에거주하던 63세여성에서처음으로확진되었다. 이환자는 2012년 8월에발열, 백혈구감소증, 혈소판감소증이발생하였으며다장기부전으로사망하였다. 환자의혈액에서 SFTSV가분리되어 2013 년 5월에보고되었다 [7]. 2013년 11월말까지질병관리본부에신고된의심환자는모두 404건이며이가운데 36명이 SFTS 로확진되었고확진환자가운데 17명이사망하였다. 발생지역은제주, 전남, 경북, 강원도등으로한반도전역에걸쳐서발생하였다 [10]. 환자들의평균연령은 69세로고령층이대부분을차지하였고농부가 75.8% 를차지하였다. 발생시기는 5월부터 10월까지이며 7월에가장많은환자가발생하였다. 감염경로 SFTS는진드기에물렸을때감염되는것으로알려져있다. 매개하는진드기는작은소참진드기 (Haemaphysalis longicornis) 이다. 꼬리소참진드기 (Rhipicephalus microplus) 도 SFTSV를매개한다고보고되었다 [2,11]. 이는유행지역의가축과환경에서채집한진드기의약 4.9% 에서 SFTSV가검출되었고검출된바이러스의핵산염기서열이환자나다른포유동물숙주에서확인된것과 95-100% 일치하였기때문이다 [2,11,12]. 중간숙주를찾기위한연구에서가축의 SFTSV 항체양성률은 3.1-69.5% 까지다양하였고바이러스혈증은 1.7-4.2% 에서확인되었다 [13]. 또한산둥성지역염소는 83% 에서항체양성률을보였다 [12]. 이들연구에서염소, 양, 돼지, 개등과같은짐승에서항체양전과바이러스혈증이확인되어이들이 SFTSV의중간숙주로지목되고있다 [12,13]. 우리나라에도작은소참진드기는널리서식하고있고 [14,15] 2011-2012년에채집한작은소참진드기에서 SFTSV가검출되었다 [16]. 환자의혈액에는 SFTSV가검출되며특히중증환자의혈액에는 SFTSV 농도가매우높으므로혈액을통해사람-사람간전파가가능하다 [9,17-20]. 발병기전 SFTS의주요징후는백혈구감소증, 혈소판감소증, 전신염증반응증후군, 응고장애, 다발성장기부전증이다. SFTS 환자들에서는 interleukin-6, interleukin-10, interferon-γ, granulocyte colony stimulating factor와같은사이토카인이높고 fibrinogen, hepcidin, phospholipase A2가상승한것이확인되었는데, 그결과전신염증반응증후군이나타나게된다 [4,21,22]. SFTS의가장큰특징인혈소판감소증의발병기전연구 - 272 -
- Kye-Hyung Kim, et al. Severe fever with thrombocytopenia syndrome - 를위해서 C57BL/6 마우스모델이수립되었다. 이동물모델에서 SFTSV RNA 는혈액, 비장, 간, 신장에서검출되었다 [23]. 비장과골수의조직병리학적변화는감염초기인 7일째부터나타나기시작하여 14일째이후점차회복되었고간과신장의변화는감염 14일째에가장심했다가 28일째에회복되었다. 바이러스증식은비장에서만검출되었는데, 특히 SFTSV 가검출된위치는비장의적색속질에있는대식세포의세포질이었다. 또한 SFTSV가혈소판에부착된것이확인되었고이러한결과로보아 SFTS 환자의혈소판감소증은 SFTSV가부착된혈소판이비장에서대식세포에탐식되어발생하는것으로추정된다 [23]. 임상소견및검사결과바이러스노출에서증상이나타날때까지의잠복기는대개 1-2주로알려져있다 [9,17-20]. 국내에서발생한 SFTS 환자의역학조사결과에따르면진드기에물린시점부터증상이나타나기까지잠복기는 4-15일이었다 [24]. 흔한증상은고열, 피로감, 두통, 근육통, 복통, 구토, 설사, 기침등비특이적인증상들이다 [2,25]. 흔한징후는혈소판감소증, 백혈구감소증, 림프절병증, 위장관출혈등이다 (Tables 1 and 2) [2,5,25]. 국내환자들도비슷한임상소견을보였다 (Table 3) [24]. SFTS의임상병기는발열기, 다장기부전기, 회복기로나눌수있다 [5]. 제1기인발열기는증상시작으로부터 1-7일간의기간으로사망환자와생존환자모두에서혈중바이러스양이 10 5-10 6 copies/ml 로높다. 이시기에는혈소판감소증, 백 Table 2. Laboratory findings of severe fever with thrombocytopenia syndrome Laboratory variables No. of patients with respective signs (%) Xu B, et al. [25] Yu XJ, et al. [2] Thrombocytopenia 234 (98.3) 69/73 (95) Leukopenia 232 (97.5) 64/74 (86) Elevated AST 234 (98.3) 53/64 (83) Elevated ALT 234 (98.3) 59/63 (94) Elevated LDH 221 (92.9) 49/51 (96) Elevated CK 166 (69.8) 25/49 (51) Elevated CK-MB NA 28/47 (60) Elevated aptt NA 56 (69) Proteinuria NA 40 (49) Hematuria NA 34 (42) Fecal occult blood NA 61 (75) AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK, creatine kinase; CK-MB, MB fraction of creatine kinase; aptt, activated partial prothrombin time; NA, not applicable. Table 1. Clinical manifestations of severe fever with thrombocytopenia syndrome Clinical symptoms No. of patients with respective symptoms (%) Liu W, et al. [27] Xu B, et al. [25] Yu XJ, et al. [2] Fever 311 (100) 232 (97.5) 81 (100) Fatigue NA 223 (93.7) 53 (65) Myalgia 257 (82.6) 165 (69.3) 32 (46) Arthralgia NA 80 (33.6) NA Headache 54 (17.4) 146 (61.3) 10 (12) Nausea 158 (50.8) 181 (76.1) 56 (69) Vomiting 114 (36.7) 153 (64.3) 56 (69) Abdominal pain NA 134 (56.3) 40 (49) Diarrhea 80 (25.7) 156 (65.6) 34 (42) Anorexia 302 (97.1) 219 (92.0) 61 (75) Cough 99 (31.8) 119 (50.0) 8 (10) Dizziness 60 (19.3) 164 (68.9) NA LN enlargement 132 (42.4) 128 (53.8) 23 (33) NA, not applicable; LN, lymph node. - 273 -
- 대한내과학회지 : 제 86 권제 3 호통권제 643 호 2014 - Table 3. Demographic and clinical characteristics of 33 Korean patients with severe fever with thrombocytopenia syndrome [24] Characteristics No. (%) Demographic features Male sex 18 (45) Age (year), median (range) 69 (28-84) Farm workers 25 (75.8) Fatal cases 15 (45.5) Clinical manifestation Incubation period (days from tick bite to 4-15 clinical symptoms) Fever 33 (100) Myalgia 16 (48.5) Gastrointestinal symptoms 28 (84.8) Vomiting 16 (48.5) Diarrhea 23 (69.7) Confusion 22 (66.7) Laboratory findings Thrombocytopenia 33 (100) Leukopenia 33 (100) Elevated AST 33 (100) Elevated ALT 31 (93.5) Elevated LDH 30 (100) a Elevated CK 24 (92.3) b AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK, creatine kinase; aptt, activated partial prothrombin time. a Total number of cases was 30. b Total number of cases was 26. 혈구감소증이나타나고아스파르테이트아미노전달효소 (aspartate aminotransferase, AST), 알라닌아미노전달효소 (alanine aminotransferase, ALT), 젖산탈수소효소 (lactase dehydrogenase, LDH), 크레아틴키나아제 (creatine kinase, CK), CK-MB가상승하기시작한다. 제2기인다장기부전기는발병 7-13일간의기간으로생존환자에서는혈중바이러스농도는감소하나사망환자에서는지속적으로바이러스농도가 10 8 copies/ml 까지증가한다. 생존환자에서는혈소판수치가회복되나사망자에서는지속적으로감소하게된다. 발병 5-9일에는활성화부분트롬보플라스틴시간 (activated partial thromboplastin time, aptt) 이지연된다. 이시기에단백뇨와혈뇨도볼수 있다. 제3기인회복기는발병 13일이후로생존환자에서는대부분의임상소견이정상으로회복된다. 그러나사망환자에서는혈중효소농도가급격히상승하게되고심한다발성장기부전과파종혈관내응고로인해사망하게된다. 이질환의치사율은초기보고에서는 30% 에이르렀지만최근중국의보고에서는 6-15% 로떨어졌다 [2,3,26]. 2013년 11월말까지발생한국내환자는 36명이며, 이가운데 17명이사망하여치사율은 47.2% (17/36) 이었다 [10]. 사망과연관된위험인자들은고령, 중추신경계이상, 출혈소견, 파종혈관내응고, 다장기부전의임상소견이동반된경우, 그리고높은혈중바이러스농도, AST, LDH, CK, CK-MB, aptt 등이다 [5,27]. 병리소견은잘기술되어있지않다. 일본에서보고된확진환자 1명의부검에서심한괴사성림프절염과림프절, 골수, 비장의혈구탐식이관찰되었다. 그외확진환자 4명의골수에서도혈구탐식이확인되었다 [6]. 그러나중국에서보고된환자 10명의골수세포흡인검사결과는정상이었고환자 4명의골수조직검사도정상인과비슷한소견이었다 [28]. 이렇게병리소견이연구에따라서서로다르므로앞으로더많은환자를대상으로한연구결과가필요하다. 진단 SFTS 진단에중요한소견은발열, 혈소판감소증, 백혈구감소증그리고진드기에노출된역학정보이다 [2,29]. 검사실진단은바이러스분리, 급성기의바이러스유전자검출, 회복기혈청의특이항체가 (IgG) 가급성기에비해 4배이상증가한경우중한가지이상을만족하면된다 [2,29]. 바이러스는급성기혈청또는전혈을베로세포 (Vero cell) 또는 DH82 세포에접종하여분리한다 [6,28]. 바이러스유전자검출은바이러스의 3개 L, M, S 분절의특정부위를검출하는역전사중합효소연쇄반응을이용한다. 2013년에중국에서개발된실시간역전사중합효소연쇄반응법 (real-time RT-PCR) 은민감도 98.6%, 특이도 99% 를가진다 [30]. 혈청검사는간접면역형광항체법, 효소결합면역흡착측정법, 미세중화법등을이용할수있다 [2]. 최근에는바이러스의 S 분절의뉴클레오캡시드단백부위를재조합한뒤항원으로이용하는방법으로이중항원샌드위치법이개발되었는데, 이검사법은사람의항체뿐만이아니라동물의항체도검출할수있다 [31]. - 274 -
- 김계형외 1 인. 중증열성혈소판감소증후군 - 감별진단 SFTS의임상소견은아나플라즈마증, 신증후군출혈열, 렙토스피라증등과비슷하여이들질환과감별이필요하다 [2]. 아나플라즈마증은참진드기 (Ixodes tick) 에의해매개되는인수공통감염병이며 SFTS와유사하게백혈구감소증과혈소판감소증이동반되지만소화기증상은흔하지않다 [32]. 이질환은최근중국과일본에서도보고되었다 [33,34]. 우리나라에서도아나플라즈마가야생동물에서검출되었고 [14,35,36] 진드기에물린뒤발생한아나플라즈마증환자도보고된바있다 [37]. 특히아나플라즈마증은독시사이클린으로치료가가능하므로 SFTS 로판단하고초기에항생제투여를하지않으면항생제로치료할수있는질환을놓칠수있다 [32]. 신증후군출혈열은초기발열기에소화기증상과복통이있다는점에서 SFTS와유사하다. 그러나얼굴, 목, 흉부의홍조, 결막충혈, 안와주위부종, 출혈및파종혈관내응고등은 SFTS의초기에는흔하지않은소견이다 [38]. 렙토스피라증도발병초기에발열, 두통, 근육통, 복통등이발생한다는점에서 SFTS와유사하다. 그러나발진이나황달과같은렙토스피라증의주증상이 SFTS에서는흔하지않다 [39]. 치료및예방 SFTSV에대한항바이러스제는아직개발되지않았다 [27]. 중국에서는 2012년부터리바비린정주를치료지침에도입하고있으나최근발표된치료결과에서는리바비린투여군과비투여군간사망률에차이는없었다 [27]. 따라서 SFTS 치료는수혈, 신대체요법등장기부전에대한보존요법이근간을이룬다. 백신은아직개발되지않았으며예방을위해서야외활동시진드기에물리지않도록주의하는것이필요하다 [16]. 결론 SFTS는중국, 일본그리고우리나라에새로이출현한진드기매개감염병이다. 주요한임상소견은발열, 백혈구감소증, 혈소판감소증, 소화기증세이며다장기부전증으로사망할수있다. 아직효과적인항바이러스제나백신은없다. 국내에서발생하는아나플라스마증, 신증후군출혈열과의감별이중요하다. 중심단어 : 중증열성혈소판감소증후군 ; 플레보바이러스 ; 버냐바이러스 REFERENCES 1. Jones KE, Patel NG, Levy MA, et al. Global trends in emerging infectious diseases. Nature 2008;451:990-993. 2. Yu XJ, Liang MF, Zhang SY, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 2011;364:1523-1532. 3. Ding F, Zhang W, Wang L, et al. Epidemiologic features of severe fever with thrombocytopenia syndrome in China, 2011-2012. Clin Infect Dis 2013;56:1682-1683. 4. Zhang YZ, He YW, Dai YA, et al. Hemorrhagic fever caused by a novel Bunyavirus in China: pathogenesis and correlates of fatal outcome. Clin Infect Dis 2012;54:527-533. 5. Gai ZT, Zhang Y, Liang MF, et al. Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J Infect Dis 2012;206:1095-1102. 6. Takahashi T, Maeda K, Suzuki T, et al. The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J Infect Dis 2013 Dec 12 [Epub]. http://dx.doi.org/10.1093/infdis/jit603. 7. Kim KH, Yi J, Kim G, et al. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis 2013; 19:1892-1894. 8. Elliott RM. Emerging viruses: the Bunyaviridae. Mol Med 1997;3:572-577. 9. Liu Y, Li Q, Hu W, et al. Person-to-person transmission of severe fever with thrombocytopenia syndrome virus. Vector Borne Zoonotic Dis 2012;12:156-160. 10. Korea Centers for Disease Control and Prevention. A current state of confirmed cases of severe fever with thrombocytopenia syndrome in Korea (Nov 28, 2013) [Internet]. Osong: Korea Centers for Disease Control and Prevention, c2013 [cited 2014 Feb 17]. Available from: http://cdc.go.kr/cdc/ intro/cdckrintro0201.jsp?menuids=home001-mnu1154 -MNU0005-MNU0011&cid=21944. 11. Zhang YZ, Zhou DJ, Qin XC, et al. The ecology, genetic diversity, and phylogeny of Huaiyangshan virus in China. J Virol 2012;86:2864-2868. 12. Zhao L, Zhai S, Wen H, et al. Severe fever with thrombocytopenia syndrome virus, Shandong Province, China. Emerg Infect Dis 2012;18:963-965. 13. Niu G, Li J, Liang M, et al. Severe fever with thrombocytopenia syndrome virus among domesticated animals, China. Emerg Infect Dis 2013;19:756-763. 14. Chae JS, Yu do H, Shringi S, et al. Microbial pathogens in ticks, rodents and a shrew in northern Gyeonggi-do near the - 275 -
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