파울러자유아메바감염에의한원발성아메바성뇌수막염의최근동향 Status of Primary Amoebic Meningoencephalitis Caused by Naegleria fowleri Infection Abstract Background: Naegleria fowleri is a free-living protozoan parasite and causative agent of an acute and lethal primary amoebic meningoencephalitis (PAM), which is an acute, fulminant, necrotizing, and hemorrhagic meningoencephalitis that leads to death in approximately seven days. Here, we introduce the current status of N. fowleri in the literature. Current status: N. fowleri cases have been reported in healthy individuals, who had a history of swimming in freshwater, lakes or pools, bathing in hot spring spa, nasal irrigation, or ritual ablution. The mortality rate owing to PAM is alarming and it remains over 95% despite the advances in antimicrobial chemotherapy and supportive care. Over the past 50 years, only 3 people have survived from the attack of this merciless pathogen. In epidemiological types, 7 types have been detected in Europe, 3 types in USA, 1 type in Oceania (Australia, New Zealand) and Japan, 2 types in mainland Asia (India, China and Thailand). Because there were two cases of acanthamoeba meningoencephalitis in Korea, a meningoencephalitis with amoebic infection should be not excluded in the clinical field. Prospective future: PAM caused by N. fowleri infection in tropical and subtropical regions may break out continuously and sporadically, and its risk also increases with climate change. In Korea, the surveillance focusing on the free-living amoeba is necessary to be performed in the natural environment for public health. In addition, the best method of preventing N. fowleri infection is to avoid water-based activities in warm freshwater environments in foreign countries, and minimize contaminated tap or freshwater entering the nose. 질병관리본부국립보건연구원면역병리센터말라리아 기생충과이상은, 박미연 1) 들어가는말 자유생활아메바 (free-living amoeba) 는호수, 수영장, 수돗물과같은물이나흙또는먼지등광범위한자연환경에서자유생활을하는아메바를의미하는데, 이중사람에게감염되어질병을일으키는대표적인아메바로는파울러자유아메바 (Naegleria fowleri) 와가시아메바 (Ac a nth a moeba culbertsoni, A. polyphaga, A. castellani) 가있다. 특히파울러자유아메바는사람, 마우스및실험동물감염시에치명적인원발성아메바성뇌수막염 (Primary amoebic meningoencephalitis, PAM) 을유발하여사망에이르게하는 병원성이매우높은원충이다 [1]. 최근미국에서물놀이를한청소년 3명의생명을앗아가며, CNN을통해 뇌를먹는아메바 (brain-eating amoeba) 로국내및전세계에공포감을심어준파울러자유아메바는미국뿐아니라, 베트남에서도수영을하던청년이사망한사례가있으며, 파키스탄에서는 13명의환자가집단으로발생해전원사망하는등파울러자유아메바에감염되어뇌수막염이발생한대부분의환자들이사망하는것으로알려져있다 [2,3]. 가까운일본의경우에는 1996년파울러자유아메바에의한아메바성뇌수막염이처음보고되었고 [4], 실제환경표본조사결과, 온천및공장배수등에서파울러자유아메바가검출되기도 1) 교신저자 (miyeoun@korea.kr/043-719-8520) 186 www.cdc.go.kr
Vol. 8 No. 9 PUBLIC HEALTH WEEKLY REPORT, KCDC 하였다 [5]. 우리나라의경우에는 1976 년과 1998년가시아메바에의한뇌수막염으로사망한보고가있지만 [6,7], 아직까지파울러자유아메바감염에의한증례는보고된바없다. 이에본원고에서는파울러자유아메바에대한최근국내외현황을소개하고질병관리본부국립보건연구원말라리아기생충과의국가기생충질환관리에대해재조명해보고자한다. 1. 따뜻한강이나호수및연못등지에서의수영및수상스포츠와같은레져활동을하는경우 ( 특히여름철수온이많이올라가있을경우에위험함. 전세계사례 ) 2. 비염치료에많이사용하고있는코세척기 (neti pot) 를통해아메바가포함된깨끗하지않은물이나수돗물을사용하여직접비강안으로영양형이감염되는경우 [8] 몸말 일반적으로자유아메바는영양형의형태에서는환경변화에민감한반면, 포낭형은환경에더잘적응한다고알려져있으며, 특히열에강하여온천수나열증이있는인체내또는 46 에서도배양이가능하다. 자유아메바의영향형은 7-35 μm의크기로아메바형또는편모형, 두가지형태이며, 편모형일때에는분열증식을하지않으나편모가없어지고아메바형이되면분열증식을한다 (Figure 1). 이러한생활사를보이는자유아메바의인체감염은대부분담수에서수영한적이있는건강한어린이나젊은이에게서주로발생하고있다. 지금까지의증례보고및 연구결과에따른파울러자유아메바의감염경로는다음과 같다 (Figure 2). Figure 1. Life-cycle and infection route of free-living amoeba Figure 2. Variable routes and a warning sign of Naegleria fowleri infection[9] www.cdc.go.kr 187
3. 동남아및아프리카등에서깨끗하게관리하지하지않은오염된물에서수영하는경우 [2] 4. 오염된상수도나깨끗하지않은물로목욕하거나코를씻는경우 [3] 원발성아메바성뇌수막염 (PAM) 환자의사망률은 95% 이상으로알려져있는데, 그이유는질병의진행정도가매우빠르고, 초기에신속정확한진단이어려우며, 현재까지적절한치료제또는치료법이없기때문이다. 현재임상적진단방법은뇌척수액및뇌조직생검에서현미경을이용해직접아메바를관찰하거나실험실에서배양하는방법에의존하고있기때문에진단이지연되어치료시기가늦어지고, 특히파울러자유아메바에의한질병관련지식이부족하고세균성뇌수막염과의구분을위한임상적특징이뚜렷하지않기때문에치료시기를놓치거나적절하지못한치료제를사용하는경우, 환자의생존률이 5% 미만으로매우낮아진다 [10]. 최근대만의경우, 75 세의남자가 PAM 증상으로사망하였는데, 이환자의뇌척수액에서파울러자유아메바의영양형을현미경과 PCR을통해확인하였다 [11]. 또한파키스탄에서는 17개월동안 13건의 PAM 감염사례가발생하였는데, 상수도물을이용해목욕을한뒤감염이되었고모든환자의뇌척수액검체에서아메바가배양양성반응을 나타냈으며, 3건에서 PCR 검사양성이었다 [3]. 전세계적으로파울러자유아메바감염에의한뇌수막염은산발적으로발생하고있는데 (Figure 3)[12], 지금까지환자와물에서검출된파울러자유아메바의유전형은모두 8가지로보고되고있다 (Table 1)[2]. 이들유전형에따른병원성의차이는알려지지않았으나, genotype 2형, 3형, 5형이가장많은분포를나타냈다. 이러한파울러자유아메바의유전형분석은환자가어디서감염되었는지를추적할수있게도움을줄수있지만, 아이러니하게도한장소에서여러가지유전형이발견될수있고시간이지나면서유전형이바뀔수있기때문에역학적인부분에서한계가있을수있다. 현재까지파울러자유아메바감염에대한치료제로알려진약제는, 항진균제인 Amphotericin B가사용되고있지만, 아메바성뇌수막염에감염된전체환자중 7명의환자에서만이 Amphotericin B 또는다른약제들 (miconazole, rifampin) 과혼합사용하여성공적으로치료된바있다 [13]. Amphotericin B는고질소혈증 (azotemia) 이나저칼륨혈증 (hypokalemia) 같은신장기능장애를초래하거나, 종종빈혈, 오한, 발열, 구토, 어지럼증을동반하므로사용에제한이따르며, 또한극히일부환자들만이 Amphotericin B를통해서치료가되었기때문에 Figure 3. Map showing the distribution of reported primary amoebic meningoencephalitis(pam) caused by N. fowleri infection in worldwide[11] 188 www.cdc.go.kr
Vol. 8 No. 9 PUBLIC HEALTH WEEKLY REPORT, KCDC Table 1. Distribution of N. fowleri genotypes[11] *Asia(mainland): 태국, 인도, 홍콩등 약제의효율성이나특이성에대해서확신을가질수없는 실정이다. 아메바검출을위한표준화된환경조사법을개발하였다 [16]. 그러나실제임상및환경조사에적용하기위해서는정량적및 정성적평가와함께관련전문의들과의토의가이루어져야할 맺는말 지금까지의증례보고를통해파울러자유아메바에의한원발성아메바성뇌수막염은 1965년처음보고된이후현재까지약 320건의증례가보고되었으며, 이중약 98% 가 것이다. 더불어 1976 년이래국내에서도가시아메바성뇌수막염환자보고사례가있기때문에앞으로뇌수막염환자에대한원인규명시아메바감염에대한감별진단도수행되어야할것이다. 향후말라리아기생충과에서는효율적인국가기생충질환예방관리에대한과학적근거마련을위해파울러자유아메바의감염실태조사등관련연구를지속적으로수행해나갈것이다. 사망하였다. 미국의경우, 1965 년부터 2010 년까지총 111 건이 파울러자유아메바에의한아메바성뇌수막염으로보고되었는데 [12], 특히아리조나주에서물놀이를많이하는호수등을조사한바에따르면, 파울러자유아메바가겨울에더많은검출률을보이지만, PAM 환자는여름에주로발생하는이유는겨울보다여름에보다다양한물놀이를하기때문이라고보고하기도하였다 [14,15]. 지금까지우리나라에서는관련조사가수행되지않았지만, 일본, 대만, 인도, 파키스탄, 태국등동남아시아국가에서도발생하고있고, 또한우리나라도지구온난화의영향으로점차아열대성기후로변하고있기때문에파울러자유아메바의자연환경내분포에대한실태조사가필요할것으로사료된다. 이에말라리아기생충과에서는 2014년정책연구용역 ( 과제명 : 파울러자유아메바의진단및환경조사법구축 ) 을통해신속하고간편한 nested PCR 검사법을구축하였으며, 호수등자연환경에서의 참고문헌 1. Barnett ND, Kaplan RJ. Hopkin RJ, Saubolle MA, Rudinsky MF. 1996. Primary amoebic menigoencephalitis with Naegleria fowleri: clinical review. Pediatr Neurol. 15: 230-234. 2. Phu NH, Hoang Mai NT, Nghia HD, Chau TT, Loc PP, Thai le H, Phuong TM, Thai CQ, Man DN, Van Vinh Chau N, Nga TV, Campbell J, Baker S, Whitehorn J. 2013. Fatal consequences of freshwater pearl diving. Lancet. 381(9861): 176. 3. Shakoor S, Beg MA, Mahmood SF, Bandea R, Sriram R, Noman F, Ali F, Visvesvara GS, Zafar A. 2011. Primary amebic meningoencephalitis caused by Naegleria fowleri, Karachi, Pakistan. Emerg Infect Dis. 17(2): 258-261. 4. Sugita Y, Fujii T, Hayashi I, Aoki T, Yokoyama T, Morimatsu M, www.cdc.go.kr 189
Fukuma T, Takamiya Y. 1999. Primary amebic meningoencephalitis due to Naegleria fowleri: an autopsy case in Japan. Pathol Int. 49(5): 468-470. 및환경조사법구축 (2014-E54001-00) 5. Kuroki T, Yagita K, Yabuuchi E, Agata K, Ishima T, Katsube Y, Endo T. 1998. Isolation of Legionella and free-living amoebae at hot spring spas in Kanagawa, Japan. Kansenshogaku Zasshi. 71(10): 1050-1055. 6. Ringsted J, Jager BV, Suk D, Visvesvara GS. 1976. Probable acanthamoeba meningoencephalitis in a Korean child. Am J Clin Pathol. 66: 723-730. 7. Im K and Kim DS. 1998. Acanthamoebiasis in Korea: two new cases with clinical cases review. Yonsei Med J. 39(5): 478-484. 8. CDC. Notes from the field: primary amebic meningoencephalitis associated with ritual nasal rinsing-st. Thomas, U.S. Virgin islands, 2012. MMWR Morb Mortal Wkly Rep 2013; 62(45): 903. 9. Siddiqui R, Khan NA. 2014. Primary amoebic meningoencephalitis caused by Naegleria fowleri: An old enemy presenting new challenges. PLoS NTD. 8: 1-8. 10. da Rocha-Azevedo B, Tanowitz HB, Marciano-Cabral F. 2009. Diagnosis of infections caused by pathogenic freeliving amoebae. Interdiscip Perspect Infect Dis. 251406, http://dx.doi.org/10.1155/2009/251406. 11. Su MY, Lee MS, Shyn LY, Lin WC, Hsiao PC, Wang CP, Ji DD, Chen KM, Lai SC. 2013. A fatal case of Naegleria fowleri meningoencephalitis in Taiwan. Korean J Parasitol. 51(2): 203-206. 12. De Jonckheere JF. 2011. Origin and evolution of the worldwide distributed pathogenic amoeboflagellate Naegleria fowleri. Infect Genet Evol. 11: 1520-1528. 13. CDC. Investigational drug available directly from CDC for the treatment of infections with free-living amebae. MMWR Morb Mortal Wkly Rep 2013; 62(33): 666. 14. Sifuentes LY, Choate BL, Gerba CP, Bright KR. 2014. The occurrence of Naegleria fowleri in recreational water in Arizona. J Environ Sci Health, Part A. 49: 1322-1330. 15. Centers for Disease Control. Naegleria fowleri-primary Amebic Meningoencephalitis (PAM). Author: Atlanta, GA, 2013. Available at www.cdc.gov /parasites /Naegleria /graphs.html. 16. 질병관리본부. 2014. 정책연구용역과제 파울러자유아메바의진단 190 www.cdc.go.kr