주간건강과질병 제 8 권제 24 호 2012-2014 년국내급성이완성마비환자실험실모니터링결과 Surveillance of Acute Flaccid Paralysis (AFP) in the Republic of Korea during 2012 to 2014 Abstract Background: Acute flaccid paralysis (AFP) is described as the sudden onset of weakness and limping in one or more limbs in children and mainly caused by poliovirus infection. AFP surveillance is conducted by the World Health Organization (WHO) to continue poliomyelitis eradication. This study aimed to investigate clinical and etiological characterization of paralysis cases through a nationwide AFP surveillance during the period 2012-2014. Methods: The AFP surveillance was conducted by reporting and laboratory testing according to the WHO recommendations. Results: In 265 total cases of AFP between 2012 and 2014, none was confirmed as poliomyelitis. In 2014, the non-polio AFP rate was 1.24% in 2012, 1.11% in 2013 and 1.22% (non-polio AFP cases per 100,000 children aged below 15years). The patients aged below 5 years accounted for the largest proportion (57.9%) of the cases. The analysis of the temporal distribution showed that occurrences were distributed randomly throughout the year, with the highest occurrence from May to July (101 cases; 38.11%). The major clinical manifestation of AFP was meningoencephalitis (98 cases; 37.0%) and the Guillain-Barré Syndrome (36 cases; 13.6%). Non-polio enterovirus (NPEV) infection was diagnosed in 122 patients (40.04%), and the major genotype was Enterovirus 71 (76 cases; 62.3%). The present study demonstrated that while patients with AFP were not infected with wild poliovirus, they tested highly positive for Enterovirus. Conclusions: The AFP surveillance systems complied with WHO-specified epidemiological and laboratory performance standards. Therefore, this surveillance significantly improved our knowledge about epidemic characteristics and clinical symptoms associated with AFP. 질병관리본부국립보건연구원감염병센터백신연구과윤영실, 이준우, 이상원 1) 들어가는말 급성이완성마비 (Acute Flaccid Paralysis, AFP) 란하나이상의팔혹은다리에갑작스럽게근육의긴장도가약화되거나상실되면서나타나는마비증상을의미한다. 영유아및소아에서의급성이완성마비는일반적으로폴리오바이러스 (Poliovirus, PV) 감염에의해발생하기때문에, 우선적으로바이러스감염을확인하는것이필요하다. 폴리오바이러스는피코나바이러스과 (Family Picornaviridae), 엔테로바이러스속 (Genus Enterovirus) 에속하는바이러스로, 크게 3개의혈청형 (type 1, 2, 3) 으로분류되며, 소아마비를유발한다 [1]. 폴리오예방접종은두종류의백신을사용하고있다. 그중하나는 1961년부터약독화된 Sabin PV균주를사용한구강투여백신 (Oral Polio Vaccine, OPV) 이며, 다른하나는주사용불활화백신인 Salk formalin-inactivated polio vaccine (IPV) 이다. 이두백신을활용한예방접종의활성화는폴리오박멸을추진하는데중추적역할을하였다 [2]. 우리나라는 1962년도에 IPV 백신, 1965년도에 OPV 백신을 1) 교신저자 (043-719-8150/ epilsw@korea.kr) 548 www.cdc.go.kr
Vol. 8 No. 24 PUBLIC HEALTH WEEKLY REPORT, KCDC 도입하였으며, OPV의백신접종후발생한이상반응등의문제로 2004년이후국내에서는 IPV만접종되고있다. 국내폴리오바이러스감염환자발생은 1983년도보고된 5명을마지막으로야생폴리오바이러스 (wild poliovirus) 검출사례는없으며, 이러한결과를바탕으로 2000년폴리오박멸을선언하여세계보건기구인증폴리오퇴치국지위를획득하였다. 세계보건기구 (WHO) 에의하면폴리오박멸은철저한예방접종과급성이완성마비환자감시에의해가능하다 [3]. 폴리오퇴치계획은 1988년부터시작되었으며, 현재야생폴리오바이러스혈청형 type 2는전세계적으로박멸이되었으나, 혈청형 type 1과 3은아프가니스탄, 나이지리아, 파키스탄등의소수국가에서아직까지도발생하고있는실정이다 [4]. 따라서이미박멸된국가라할지라도폴리오발생국가로부터유입되어재발생될위험이있다. 실례로 2011 년파키스탄에서발생했던야생폴리오바이러스 type 1이중국에서분리된보고가있다. 따라서야생폴리오바이러스의해외유입을막기위한실험실감시가지속적으로필요한실정이다 [5]. 질병관리본부국립보건연구원백신연구과는 1998년이후현재까지세계보건기구서태평양사무소와의협력을통해폴리오국내발생감시를지속적으로수행하여폴리오박멸국지위를유지하고있다. 이에본글은 2012년부터 2014년까지국내에서발생한급성이완성마비환자의폴리오바이러스감염여부를확인한실험실감시결과를공유하고, 급성이완성마비 (AFP) 감시사업을홍보함으로써해외에서유입되는야생폴리오바이러스를조기에탐지하여국내발생및확산을예방하고자한다. 환자 256명으로부터발병 2주이내에채취한 2개의분변검체 (24-48 시간간격 ) 와정보를수집하여실시하였다. 검체전처리는분변검체에 10ml PBS와 1ml chloroform 을처리하여 5분동안강하게흔들어원심분리하여상층액을분리한후필터링한다. 필터링된검체는세계보건기구에서권고한두가지세포주 (L20B cell와 RD cell) 에접종하여바이러스분리배양을실시한다. 검체가접종된세포에병변이발생할경우다음과같이혈청학적검사를실시하였으며, 혈청학적검사는 National Institute of Public Health and the Environment (RIVM) 에서공여한표준항혈청을사용한다. 중화시험에사용한표준항혈청은폴리오바이러스 type 1, 2, 3형을감별할수있는폴리오 pool (polio1+2+3, 1+2, 2+3, 1+3, 1, 2, 3) 과콕사키바이러스 B (CB) pool (B1-6) 및콕사키바이러스 A (CA) 와에코바이러스 (E) 를감별할수있는 7개의 pool (A-G) 로구성되며, 세포병변효과를관찰하는중화시험을수행하여혈청형을동정한다. 또한엔테로바이러스의유전자적진단검사를위해검체로부터핵산을추출하고, 실시간역전사융합효소반응 (real time RT-PCR) 을수행한다. 바이러스의유전자형확인을위해바이러스의외형을구성하고있는구조단백질인 VP1의염기서열을분석하고, 증폭된산물의염기서열을기존에보고된바이러스표준주와비교하여일치도가가장높은유전자형을찾아검증한다. 세포배양을통해동정된바이러스형과일치하는지확인하고, 혈청학적검사로동정되지않는엔테로바이러스는유전자형을검증한다. WHO에서는 AFP 감시사업의민감도를평가하는지표로 non-polio AFP rate 1 이상을기준으로하고있는데, non-afp rate 란 15 세미만아동 100,000 명당 AFP 1 건을보고하는것을의미한다. 몸말 본조사는 AFP 실험실감시사업을통해 2012 년부터 2014 년까지 3 년간전국의료기관으로부터급성이완성마비증상이있는 본감시사업에서는 2002년부터 2011년 0.1-0.8 로다소낮은수준이었지만, 2012 년부터는 1 이상의값을나타내 WHO에서권고하는감시사업의민감도를충족하였다 (Table 1). AFP는 24-48시간간격으로 2번의분변검체를채취해야하는데 www.cdc.go.kr 549
주간건강과질병 제 8 권제 24 호 Table 1. Annual incidence rate of non-polio acute flaccid paralysis (AFP) Year population Non-polio AFP cases Annual incidence rate per 100,000* AFP cases with adequate stool samples AFP cases with adequate stool samples (%) 2002 9,860,001 20 0.20 19 95.0 2003 9,718,733 23 0.23 20 87.0 2004 9,632,613 37 0.39 37 100.0 2005 9,240,016 16 0.17 16 100 2006 9,026,009 33 0.37 28 84.8 2007 8,733,709 26 0.30 22 84.6 2008 8,408,098 8 0.10 8 100.0 2009 8,309,872 20 0.24 20 100.0 2010 7,975,374 70 0.89 67 95.7 2011 7,770,912 32 0.42 29 90.6 2012 7,559,063 94 1.24 84 89.0 2013 7,370,118 83 1.11 78 94.0 2014 7,198,984 88 1.22 76 86.0 * Mean annual incidence rate per 100,000: In order to estimate the mean annual incidence rate of non-polio AFP per 100,000 individuals, the cases of non-polio AFP were considered as the numerator and the relevant population as the denominator 70 60 No. of AFP cases 50 40 30 20 2012 2013 2014 10 0 <1 1-5 6-10 11-15 >15 Age Figure 1. Distribution of acute flaccid paralysis (AFP) cases by age groups from 2012 to 2014 이러한검체채취기준을준수한적정검체건수는전체 504 건으로 91.6% 였다 (Table 1). AFP 환자의연령분포 (Figure 1) 는 5 세미만의영유아에서 가장큰비율 (57.9%) 을차지했으며, 그다음으로는 6-10 (18.8%) 세, 10-15 (15.4%) 세의소아로나타났다. 265 명의 AFP 환자중 122 명 (46.0%) 에서엔테로바이러스가 550 www.cdc.go.kr
Vol. 8 No. 24 PUBLIC HEALTH WEEKLY REPORT, KCDC Table 2. Enterovirus genotypes according to the diagnosis of the AFP patients from 2012 to 2014 CA2 CA4 CA5 CA6 CA10 CA16 CB3 CB5 E6 E7 E30 EV71 EV(UT) Total meningoencephalitis 0 0 0 2 2 1 0 3 1 0 1 35 6 51 GBS 0 0 0 0 0 1 1 0 0 0 0 5 1 8 ADEM 0 1 0 1 0 0 1 0 0 0 0 3 0 6 transverse myelitis 1 0 0 0 0 1 0 1 0 0 0 6 2 11 encephalitis 1 0 1 0 0 0 0 0 0 0 2 7 1 12 poliomyelitis 0 0 0 0 0 0 0 0 0 0 0 1 0 1 other 1 1 0 1 0 1 0 2 0 2 2 13 2 25 HFMD 0 0 0 0 0 0 0 0 0 0 0 3 0 3 meningitis 0 1 0 0 0 0 0 1 0 0 0 3 0 5 Total 3 3 1 4 2 4 2 7 1 2 5 76 12 122 Abbreviation: NPEV= non-polio enterovirus, CA= Coxsackievirus A, CB= Coxsackievirus B, E= Echovirus, GBS= Guillain-Barré Syndrome, UT=untypable 20 18 16 No. of AFP cases 14 12 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 Month 2012 2013 2014 Figure 2. Number of acute flaccid paralysis (AFP) cases by month from 2012 to 2014 검출되었으며, EV71이 76 (62.3%) 건으로가장큰비중을차지하였고그외에 CB5가 7건, E30, CA6, CA16 은각 5건, 4건, 4건이검출되었다 (Table 2). AFP 환자의임상적특징 (Figure 3) 은전체 265 건중뇌수막염 (meningoencephalitis) 이가장많은 98건 (37.0%) 이었고, 이중엔테로바이러스양성은 51건으로 CA6, CA10, CA16, CB5, E6, E30, EV71, EV (UT) 가검출되었다 (Figure 3, Table 2). 그다음으로는길랑-바레증후군 (Guillain-Barré Syndrome) 이 36건 (13.6%) 으로이중엔테로바이러스는 CA16, CB3, CB5, EV71, EV (UT) 가검출되었다. 그외에뇌염 (encephalitis), 횡단성척추염 (transverse myelitis), 급성파종성뇌척수염 (Acute Demyelinating Encephalomyelitis, ADEM) 도 www.cdc.go.kr 551
주간건강과질병 제 8 권제 24 호 No, AFP cases 40 35 30 25 20 15 10 5 0 2012 2013 2014 Diagnosis Figure 3. Distribution of acute flaccid paralysis (AFP) cases by clinical manifestation from 2012 to 2014 각각 20 건 (7.5%), 19 건 (7.2%), 18 건 (6.8%) 로나타났다 (Figure 3, Table 2). 마비를일으키는기전에대한연구가추가적으로필요하다. 향후에도본과에서는폴리오국가표준실험실운영을통하여 지속적인국내발생감시를실시하여폴리오박멸국가지위를 유지할계획이다. 맺는말 본보고서에는 2012-2014 년 AFP 환자감시현황과그결과를정리하여바이러스학적데이터, 임상및실험적정보가기술되어있다. 15세미만에서 non-polio AFP 를진단하는것이폴리오박멸인증에중요한기준이기때문에 [9], 질병관리본부국립보건연구원백신연구과에서 2012-2014 년동안 non-polio AFP rate가 >1의비율을보여준것은현재적절한 AFP 감시체계를유지하고있음을의미한다. 그러나 AFP 보고는모든병원에서의무적으로시행하는것이아니다. 따라서보다신뢰도높은자료를산출하기위해서는의료진의자발적인참여가중요하다. 본감시사업결과, 국내의 AFP 환자는야생폴리오바이러스에의해발생한것이아니라주로 non-polio enterovirus (NPEV) 에감염된것으로나타났다. 따라서 NPEV의역학적인조사와 참고문헌 1. Savolainen-Kopra C, Blomqvist S. 2010. Mechanisms of genetic variation in polioviruses. Rev Med Virol. 20(6):358-371. 2. Dowdle WR, De Gourville E, Kew OM, Pallansch MA, Wood DJ. 2003. Polio eradication: the OPV paradox. Rev Med Virol. 13(5):277-91. 3. CDC. 2004. Global Polio Eradication Initiative Strategic Plan. MMWR. 53(5):107-8. 4. The Global Polio Eradication Initiative. 2012. Polio this week. http://polioeradication.org/dataandmonitoring/poliothisweek. aspx. 5. WHO. 2011. Confirmed international spread of wild poliovirus from Pakistan. Wkly. Epidemiol. Rec. 86:437-444. 552 www.cdc.go.kr
Vol. 8 No. 24 PUBLIC HEALTH WEEKLY REPORT, KCDC 6. Lam RMK, Tsang THF, Chan KY, Lau YL, Lim WL, Lam TH, Leung NK. 2005. Surveillance of acute flaccid paralysis in Hong Kong: 1997 to 2002. Hong Kong Med J. 11(3):164-73. 7. Cardosa MJ, Perera D, Brown BA, Cheon DS, Chan HM, Chan KP, Cho H, McMinn P. 2003. Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-pacific region: comparative analysis of the VP1 and VP4 genes. Emerg Infect Dis. 9(4):461-8. 8. Saeed M, Zaidi SZ, Naeem A, Masroor M, Sharif S, Shaukat S, Angez M, Khan A. 2007. Epidemiology and clinical findings associated with enteroviral acute flaccid paralysis in Pakistan. BMC Infect Dis. 15(7):6. 9. Hull BP, Dowdle WR. 1997. Poliovirus surveillance: building the global polio laboratory network. J Infect Dis. 175(Suppl 1):S113 S116. www.cdc.go.kr 553