Enterovirus 71-associated hand, foot and mouth diseases with neurologic symptoms, a university hospital experience in Korea, 2009

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1 Original article DOI: /kjp Korean J Pediatr 200;54(5) Enterovirus 7associated hand, foot and mouth diseases with neurologic symptoms, a university hospital experience in Korea, 2009 Hye Kyung Cho,.D., Na Yong Lee,.D., Hyunju Lee,.D., Hae Soon Kim,.D., Jeong Wan Seo,.D., Young i Hong,.D., Seung Joo Lee,.D., Sun Wha Lee,.D. 2, Doo Sung Cheon, Ph.D. 3, Ji Young Hong,.S. 3, Byung Hak Kang, Ph.D. 3, JongHyun Kim,.D. 3,4 and KyungHyo Kim,.D. Department of Pediatrics, Department of Radiology 2, School of edicine, Ewha Womans University, Seoul, Korea Division of Enteric and Hepatitis Viruses 3, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Korea Department of Pediatrics 4, College of edicine, The Catholic University of Korea, Seoul, Korea Received: 2 October 2009, Revised: 2 December 2009 Accepted: 4 January 200 Corresponding Author: KyungHyo Kim,.D. Department of Pediatrics, School of edicine, Ewha Womans University, 9 okdong, Yangcheongu, Seoul 570, Korea Tel: , ax: kaykim@ewha.ac.kr Copyright 200 by The Korean Pediatric Society Purpose: Handfootmouth disease (HD) is a common viral illness in children, which is usually mild and selflimiting. However, in recent epidemics of HD in Asia, enterovirus 7 (EV7) has been recognized as a causative agent with severe neurological symptoms with or without cardiopulmonary involvement. HD was epidemic in Korea in the spring of Severe cases with complications including death have been reported. The clinical characteristics in children with neurologic manifestations of EV7 were studied in Ewha Womans University okdong Hospital. ethods: Examinations for EV7 were performed from the stools, respiratory secretion or CS of children who presented neurologic symptoms associated with HD by realtime PCR. Clinical and radiologic data of the patients were collected and analyzed. Results: EV7 was isolated from the stool of 6 patients but not from respiratory secretion or CS. Among the 6 patients, meningitis (n=0) was the most common manifestation, followed by GuillainBarré syndrome (n=3), meningoencephalitis (n=2), poliomyelitislike paralytic disease (n=), and myoclonus (n=). Gene analysis showed that most of them were caused by EV7 subgenotype, which was prevalent in China in 200. Conclusion: Because EV7 causes severe complications and death in children, a surveillance system to predict upcoming outbreaks should be established and maintained and adequate public health measures are needed to control disease. Key words: Human enterovirus 7, Hand footmouth disease, Neurologic manifestation Introduction Handfootmouth disease (HD) is a common acute viral illness in children, which is usually mild and selflimiting. It is characterized by fever, oral ulcers, and vesicular exanthema on the hands, feet and buttocks. However, in recent epidemics of HD in Asia, severe cases with complications have been reported. Enterovirus 7 (EV7) has been recognized as a causative agent of HD with 639

2 640 HK Cho, et al. Enterovirus 7associated hand, foot and mouth diseases with neurologic symptoms high neurological diseases and cardiopulmonary involvement, 2). HD was epidemic in Korea in the spring of Severe cases with complications including death have been reported in HD patients, thus it has become a public health issue. On April 2009, EV7 was isolated from the stool of a patient with poliomyelitislike paralytic disease. rom that time to July 2009, we have studied EV7 as a causative agent of HD in children with neurologic manifestations who were admitted to Ewha Womans University okdong Hospital. Examinations for EV7 were performed from the stools, respiratory secretion or CS of children who presented neurologic symptoms associated with HD by realtime PCR. Although this study is about a university hospital s experience of EV7associated HD with neurologic symptoms, it is of great importance because there are few reports about EV7 infection in Korea. aterials and methods The subjects studied were 6 children hospitalized for neurologic symptoms with handfootmouth disease at Ewha Womans University okdong Hospital, Seoul, Korea from April to July, Their ages ranged from a month to eight years. Examinations for the viruses were carried out with stools, respiratory secretion or cerebrospinal fluid collected from the patients at the Division of Enteric and Hepatitis Viruses, Korea Centers of Diseases Control and Prevention. Clinical and radiologic data of the patients were collected and analyzed. EV7 was detected by realtime PCR. Viral RNA was extracted using ZR Viral RNA Kit (Zymo Research, CA, USA) according to the manufacturer s instructions. The whole genomic RNA was reversetranscribed for cdna synthesis. Amplicons of the VP genes were generated using primers as follows: forward primer SO224 (5 GCIATGYTIGGIACICAYRT3 ) and reverse primer SO222 (5 CICCIGGIGGIAYRWACAT3 ) (stpcr); and forward primer AN9 (5 CCAGCACTGACAGCAGYNGAR AYNGG3 ) and reverse primer AN (5 TACTGGACCACC TGGNGGNAYRWACAT3 ) (2 nd PCR). These PCR products were then sequenced using the ABI PRIS dye terminator cycle sequencing ready reaction kit (Perkin Elmer, Waltham, assachusetts, USA), and run on an ABI 300 sequencer (Applied Biosystems, oster City, CA, USA). Nucleotide sequences were determined by DNASTAR. Results During the four months, 6 patients were hospitalized with neurologic manifestations related with HD (Table ). Their ages ranged from a month to eight years and the mean age was 29 months. The male to female ratio was.7: (:). ever resolved in 2 to 7 days (mean, 4.5 days) and the range of peak of fever was 3.0 to 40. C (mean, 39.3 C). In most of the patients, neurologic symptoms developed between day 2 and day 3 (range, day to day 5) after the onset of fever or skin lesions. Among the 6 patients, the most frequent neurologic manifestation was meningitis (62.5%), which included definite Table. Clinical eatures of Patients with Enterovirus 7 (EV7) Associated Neurological Disease No. Sex Age (months) Clinical presentation EV7 positivity in clinical sample CS Stool CS pleocytosis (cells/mm 3 ) Daycare Attendance* Siblings infection Subgenotype of EV eningitis yoclonus GuillainBarré syndrome eningoencephalitis Poliomyelitislike paralysis eningitis eningitis eningitis, convulsion eningitis GuillainBarré syndrome eningitis eningitis eningitis GuillainBarré syndrome eningoencephalitis eningitis eningitis C Abbreviations:, not done;, untypable *Day care attendance includes daycare, kindergarten and school

3 Korean J Pediatr 200;54(5): DOI: /kjp cases with meningeal irritative symptoms and signs with CS pleocytosis (>5 cells/mm 3 ) and 2 suspected cases in whom spinal tappings were not performed. Three cases had GuillainBarré syndrome and one of them had meningoencephalitis. One patient presenting asymmetric lower limb weakness (left>right) after HD showed enhancement in the left anterior horn of the spinal cord (T level) on magnetic resonance image. EV7 were detected in the 6 patients presenting neurologic manifestations by realtime PCR. Clinical samples included stools, respiratory secretion, or cerebrospinal fluid obtained from the patients, but viruses were detected from only stools. Subgenotypes of enteroviruses were C in the poliomyelitislike paralytic disease patient, and in eleven patients presenting GuillainBarré syndrome, meningitis or myoclonus. Among the patients, only one girl presenting poliomyelitislike paralytic disease still had limping when she was running at three months after discharge, but no death or severe complication with serious disease was observed in any of the other patients. Discussion We experienced 6 patients with EV7 who presented neurologic symptoms associated with HD from April to July, ost of them were diagnosed as meningitis or meningoencephalitis, and GuillainBarré syndrome, poliomyelitislike paralytic disease and myoclonus were other clinical diseases caused by EV7. There was no mortality, and one patient with poliomyelitislike paralytic disease had sequelae. Gene analysis showed that most of them were caused by EV7 subgenotype, which was prevalent in China in 200. HD, a benign and common febrile viral disease in childhood, is caused most frequently by coxsackievirus A6 and can also be caused by EV7, other coxsackieviruses and echoviruses. It is usually a mild illness, but in outbreaks caused by EV7, high incidences of severe complications including brainstem encephalitis, acute flaccid paralysis, neurogenic pulmonary edema, pulmonary hemorrhage, shock, and rapid death have been reported especially in children under 5 years of age 3, 4). Since EV7 was discovered in California in 969, numerous outbreaks have occurred worldwide in countries of Europe, America, and Asia 59). There have been several large epidemics of EV7 infection causing high fatalities. The first report of severe epidemics of encephalitis and acute flaccid paralysis due to EV7 came from Bulgaria in 975, in which 44 deaths occurred 0). In 97, 45 patients died of neurologic diseases with HD in Hungary ). Since 997, three major epidemics have occurred in the AsiaPacific region. They were in Sarawak, alaysia in 997, Taiwan in 99, and China in 200, and 3, 7, and 26 fatal cases were reported, respectively, 2, 3). In these EV7 outbreaks, the majority of affected children had HD or herpangina, but children having only febrile illness without mucocutaneous manifestations also had neurologic complications 4). In this study, all the patients suspected to have neurologic diseases associated with EV7 had HD as a premonitory symptom, but none of them had herpangina. Approximately 0% of children with EV7associated neurological disease in Taiwan had an initial or concurrent diagnosis of herpangina 5). Neurologic disorders have been prominent in recent epidemics of EV7 disease. In the outbreaks in Taiwan in 99 and in Australia in 999, virological studies found that HD and herpangina epidemics were caused by EV7 and coxsackievirus A6 but the cases presenting with acute pulmonary edema and other neurological diseases were caused by brainstem encephalitis resulting from acute EV7 infection 4, 3, 6). Neurologic syndromes observed in EV7 include meningitis, meningoencephalomyelitis, poliomyelitislike paralytic disease, GuillainBarré syndrome, transverse myelitis, cerebellar ataxia, opsoclonusmyoclonus syndrome, benign intracranial hypertension, and brainstem encephalitis 7, 6, 7). In this study, the patients showed variable manifestations in the spectrum of neurological disease and most of them recovered without sequelae after conservative management. The more varied presentations and milder clinical manifestations are likely to reflect the contribution of immunopathological process in addition to cytopathic damage to neuronal cells 7,, 9). And, individual host genetic factors may affect clinical severity. HD with EV7associated neurological syndrome has increased continually in many countries during the last 0 years, especially in the Asia Pacific region 20, 2). In some countries, outbreaks occur in a cyclical pattern every three years, predominantly caused by strains that are distinct from previous outbreaks 22). In Singapore, since the first outbreak of HD in 970, many epidemics have occurred by predominantly circulating strain coxsackievirus A6 or EV7, and the largest one was caused by EV7 with 3,790 cases and four deaths in , 23). In 2006, Brunei reported its first major outbreak of EV7 infection. In the outbreak,,6 children were affected with three deaths resulting from severe neurologic disease 24). In the same year, an outbreak of EV7 affected approximately 4,400 children in Sarawak, alaysia 25). In the outbreak of China in 200, a total of 4,955 HD cases were reported including 26 fatal cases, mostly caused by EV7 ). Possible reasons suggested for the outbreaks were mutation of the virus with increased virulence and the presence of

4 642 HK Cho, et al. Enterovirus 7associated hand, foot and mouth diseases with neurologic symptoms host factors including the accumulation of susceptible populations and individual genetic susceptibility 26, 27). As it has been reported that some serious cases causing death or severe neurologic sequelae were associated with the EV7 infection in Korea in 2009, EV7 infection has become an important issue in public health. In 990, 993, 997 and 2000, EV7 was reported as a causative agent of aseptic meningitis and poliomyelitislike paralysis in Korea 23). Since 2003, a sentinel surveillance system for enterovirus infection has been established in Korea. According to the surveillance system, 2 cases were reported in 2003, 36 in 2004, 404 in 2005, 25 in 2006, and 742 in 200. Echoviruses and coxsackie viruses are major organisms causing aseptic meningitis. In recent epidemics in the AsiaPacific region, the predominant EV7 genotypes were various. In Sarawak during 997 and Singapore during 99, genotype B3 was most prevalent. EV7 isolated from patients in the Taiwanese epidemic during 99 belonged to genotype C2 32, 33). During the epidemics in alaysia and Singapore in 2000, the predominant EV7 genotype was B4 33). And, the EV7 outbreaks in Brunei, Sarawak and Singapore in 2006 were caused by subgenogroup B5 virus 24). EV7 in the outbreak in China during belonged to subgenotype, 20). The increasing fatality of EV7 infection in recent epidemics has been thought to be due to both endemic and epidemic circulation of the virus and its evolution. The possible occurrence of intertypic recombination of EV7 may play important roles in the emergence of various EV7 subgenotypes with varied virulence and clinical manifestations 34). EV7 isolated from 2 patients during 2000 in Korea belonged to genotype C3, which has been identified rarely in other epidemics in recent years 3, 32). As in Chinese strains in , the most frequent genotype among the EV7 strains isolated from our patients was. Interestingly, a single isolate, which was from a girl with poliomyelitislike paralysis, belonged to genotype C. Genotype C viruses were isolated from cases of uncomplicated HD in Singapore and Sarawak during 99 and in Sarawak and Western Australia during 2000, and appeared to have reduced neurovirulence 6, 33). It does not appear that a single neurovirulent genotype is associated with the severe and fatal cases as at least three distinct genotypes were isolated from fatal cases in Sarawak, Peninsular alaysia, Japan and Taiwan 7). However, further study is needed to elucidate the factors influencing the virulence of EV7. The transmission of enterovirus occurs within families, daycare centers, playgrounds and hospital nurseries. All the patients who we studied attended daycare centers including kindergartens and schools by themselves, or had siblings with HD. ore children would be congregating in a limited space, which provides a readily available reservoir for the rapid circulation of the virus 3). The fecaltooral route is considered a major transmission route for enteroviruses. Long periods of viral shedding may account for the widespread transmission of EV7 35). Chung et al 36) demonstrated that EV7 is excreted through the stool of infected patients for up to 6 weeks. Chang et al 4) presented that the culturepositive rate of throat swabs was higher than that of rectal swabs in the patients. Viruses in throat through the saliva or respiratory droplets of patients may be transmitted during the acute stage of the disease 37). Although handwashing precaution is important for the period of virus excretion through feces, it is not sufficient to limit the spread and transmission of the virus and to prevent further epidemics. Therefore, isolation of infected patients within single rooms with masks should be considered 35). Public health measures, in particular, personal and environmental hygiene must target daycare centers, kindergartens, and schools where highly susceptible children congregate. In Singapore, to stem the spread of infection, preschools where transmission persisted for more than 2 incubation periods have been recommended to close, and trigger criteria for voluntary closure were instituted in April 200. During closure, operators are to clean the centers thoroughly before they are allowed to reopen. In addition, parents are advised to ensure that their children adopt highstandard personal hygiene and to keep infected children at home until full recovery 3). In June 2009, Korea added HD and enterovirus infection to its list of nationally notifiable infectious diseases, for which all diagnosed cases must be reported within 7 days. This is expected to allow a more accurate and extensive survey of enterovirus infections nationwide and to lead to continuous collection of data about the incidence of EV7 infection and circulating viruses in Korea. In conclusion, although HD is usually a benign disease, severe neurologic and cardiopulmonary complications can be developed in cases caused by EV7. In the Korean epidemic in 2009, these complications including death were reported and most of them were caused by EV7 subgenotype. Because the outbreaks occur in a cyclical pattern, we need to establish a surveillance system to predict upcoming outbreaks and to develop adequate public health measures to control the outbreaks. References ) Yang, Ren L, Xiong Z, Li J, Xiao Y, Zhao R, et al. Enterovirus 7 outbreak in the People s Republic of China in 200. 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