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Outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 in a Juku in Fengtai District, Beijing, China, 2015

Outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 in a Juku in Fengtai... An outbreak of hand, foot, and mouth disease (HFMD) that occurred in a Juku in Fengtai District, Beijing, China, in 2015 was monitored by the China Information System for Disease Control and Prevention. Epidemiological investiga‑ tion showed that 11 cases occurred from two classes in the preschool art training department in the Juku. Coxsacki‑ evirus A6 (CV‑ A6) was identified as the causative pathogen of the outbreak via sequences analysis of products of real‑ time reverse‑ transcription polymerase chain reaction (RT‑ PCR) and nested RT‑ PCR. Phylogenetic analysis showed that CV‑ A6 strains isolated in this study clustered with epidemic strains isolated in China since 2013. The outbreak ended quickly with effective measures. This event indicates that continuous surveillance of HFMD etiological agents other than enterovirus 71 and coxsackievirus A16 is necessary. Keywords: Coxsackievirus A6, HFMD, Outbreak (CV-A6) has rapidly replaced the original circulating Background strains EV-A71 and CV-A16, becoming the predomi- Hand, foot, and mouth disease (HFMD) is character- nant etiological agent of HFMD in some areas in China ized by mild febrile illness and vesicular exanthema on (Han et  al. 2014; Lu et  al. 2014). CV-A6 is classified hands, feet and mouth. HFMD is a virus-induced infec- as human enterovirus A in the family Picornaviridae, tious disease affecting mainly infants and children, typ - genus Enterovirus, and is an etiological agent of mild ically causing outbreaks in kindergartens and primary herpangina or HFMD (Mirand et  al. 2012; Osterback schools. Severe cases can also involve serious complica- et al. 2009; Sinclair et al. 2014; Wei et al. 2011). CV-A6 tions, such as encephalitis, meningitis, or death. HMFD has also been reported to cause outbreaks worldwide is considered a substantial public health threat, and (Feder et  al. 2014; Puenpa et  al. 2013; Fujimoto et  al. ranked first among category C infectious diseases by 2012; He et al. 2013). the Ministry of Health of the People’s Republic of China in 2008. The predominant causative agents of HFMD Methods are enterovirus 71 (EV-A71) and coxsackievirus A16 Study design (CV-A16); additionally, other CVA, CVB, and some An HFMD outbreak associated with CV-A6 in a Juku echoviruses have been reported to cause HFMD (He in Fengtai District, Beijing, China was monitored by the et  al. 2013). Since 2012, a newly emerged enterovirus China Information System for Disease Control and Pre- vention, From July 17–22. The outbreak was investigated *Correspondence: 13611367235@163.com; zhenglishu2000@sina.com immediately after it was reported to Fengtai District Jin‑ Song Li and Xiao‑ Gen Dong contributed equally to this work Center for Disease Control and Prevention (CDC) of Bei- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Diseases Control and Prevention, China CDC, 100 Ying‑Xin St., jing on July 19 2015. Two investigators comprehensively Xi‑Cheng District, Beijing 100052, China recorded the entire investigation and completed all of the Fengtai District Center for Diseases Control and Prevention of Beijing, 3 relevant documents appropriately. Xi An St., Feng‑Tai District, Beijing 100071, China © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li et al. SpringerPlus (2016) 5:1650 Page 2 of 4 Samples and laboratory investigation 9 cases (81.8  %) exhibited herpangina, and 10 (90.9  %) Samples were collected from the cases, close contacts cases exhibited mild fever (<38.5  °C). There were no and environmental surface in the classroom. Twelve severe cases and no patients had serious complications. pharyngeal swabs were collected from two teachers, two parents of the sick children, and eight sick children, in Viral pathogens of this outbreak addition to five swab samples that were obtained from Four pharyngeal swab samples and three stool samples desks and a hand wash basin in the classroom. Addition- which were from six sick children and one close contact ally, three stool samples were collected from the other were positive for enterovirus, but negative for EV-A71 three sick children. and CV-A16. The samples from the other close contacts, Suspensions of rectal swabs and swabs of environ- the surface of the classroom and other five sick children ment surfaces were prepared by adding 1 ml phosphate- were negative to enterovirus with real-time PCR. Six buffered saline (PBS; pH 7.2) and briefly vortexing. fragments were amplified from two cases, one parent’s Suspensions of faecal samples were prepared by vortex- pharyngeal swab, and three stool samples. Sequences ing 0.2 g of faeces with 800 µl PBS for 3 min followed by were genotyped as CV-A6 using NCBI BLAST and phy- centrifugation at 13,000  rpm for 10  min. Viral RNA was logenetic analyses. extracted using the QIAamp Viral RNA Mini Kit (QIA- GEN, Hilden, Germany). All samples were tested for Nucleotide sequence similarity and phylogenetic analysis the presence of enterovirus, EV-A71 and CV-A16 by Six CV-A6 clinical isolates shared 99–100  % and 100  % real-time RT-PCR using a real-time TaqMan reverse- nucleotide and amino acid homology with other clinical transcription polymerase chain reaction (RT-PCR) isolates in China after 2013, respectively, but only 82 and kit from Jiangsu Shuoshi Bio-Tech Co., Ltd. (Hang- 84  % homology to CV-A6 prototype strain Gdula. Four zhou, China). cDNA from enterovirus-positive samples distinct lineages (ABCD) were revealed by phylogenetic was synthesized using primer OL68-1 (GGTAA(C/T) analysis; lineage A was divided into two sublineages A1 TTCCACCACCA(A/T/G/C)CC). The resultant frag - and A2 (Fig. 1). ments, which included the partial 5′ untranslated region, The phylogenetic analysis showed CV-A6 had con - VP2, and complete VP4, were amplified by nest RT-PCR tinuously evolved and spread to other areas. In lineage with primers OL68-1 and MD91 (CCTCCGGCCCCT A, most strains of sublineage A2 were detected in Japan GAATGCGGCTAAT), followed by nest pair primers before 2009 and a few from China and Finland, whereas OL68-1 and EVP4 (CTACTTTGGGTGTCCGTGTT), sublineage A1 was a recent epidemic strain that first as previously reported (Ishiko et al. 2002). The fragments appeared in 2008–2009. CV-A6 was detected in more were sequenced using the ABI 3730 system (Applied Bio- areas with a detection rate that markedly increased in systems, Foster City, CA, USA). the past 2 years. In Japan, lineages A, B and D were iso- lated at different years, however, lineages B and D were Nucleotide sequence similarity and phylogenetic analysis only isolated in Japan before 2000. Lineage B comprised Virus genotype and nucleotide sequence similarities were strains isolated in 1997, whereas sublineage A2 was iso- analysed by Blastn online. Phylogenetic analysis based on lated in Japan before 2003 and then detected in other the complete VP4 fragments of the most reference strains areas in 2008–2011. Only two strains of prototype strain of CV-A6 in GenBank was conducted with the neighbor- Gdula from the United States and Japan comprised lin- joining method using the MEGA5.0 software program. eage C. Strains from this study clustered with epidemic strains isolated in 2013–2014 from China and other areas Results comprising sublineage A1. Epidemiological investigation A 5-year-old boy, who attended the preschool art training Control measures of the outbreak in a Juku in Fengtai District, Beijing, China, had a fever CV-A6 is primarily transmitted via the fecal–oral route (38.4  °C) on July 17, and red vesicular lesions appeared by contaminated hands, toys, or food. After the Fengtai the next day. From July 17–22, 11 cases in the Juku were Center for Disease Control and Prevention confirmed the reported by different hospitals to the China Information outbreak with the China Information System for Disease System for Disease Control and Prevention. Three cases Control and Prevention on July 19, normal control meas- were reported on July 17, and 4 cases each were reported ures were taken, such as hand washing and classroom on July 18 and 19. The 11 cases, which included 5 girls disinfection. Health education was also intensified in this and 6 boys, were from two classes that shared noontime Juku. Classes in the preschool art training department rest in the same room. Nine (81.8  %) cases exhibited were suspended for 14 days starting July 21, and the chil- vesicular exanthema on hands, feet and in the mouth, dren were continuously monitored for any new cases. No Li et al. SpringerPlus (2016) 5:1650 Page 3 of 4 Fig. 1 Phylogenetic analysis of CV‑A6 complete VP4 nucleotide sequences phylogenetic analysis was performed and the tree was constructed using the neighbor‑joining algorithm implemented in the MEGA version 5.0 software program with 1000 bootstrap pseudoreplicates. The numbers on the branches indicate the bootstrap values, excluding those <70 % for clarity. CV‑A16 (accession no. KM382148.1) was used as an outgroup con‑ trol. Black dots show CV‑A6 strains isolated in this study. GenBank numbers of reference sequences are shown. a Phylogenetic analysis of the most reference strains of CV‑A6. b Phylogenetic analysis of the subtree A1 new case was reported up to August 7, indicating that the District in the past few years. But we have no the data outbreak had ended. of CV-A6 associated with the sporadic cases in Fengtai District. So more enterovirus need to be monitored in Discussion the HFMD cases. HFMD outbreaks caused by enteroviruses except for Following the approval and application of EV-A71 EV-A71 and CV-A16 have recently increased world- vaccines in China, the etiological agents of HFMD are wide (Osterback et  al. 2009; Wei et  al. 2011). Sporadic anticipated to change significantly in Fengtai District. cases of CV-A6 infection are becoming more frequent, Further investigation is needed to clarify significant especially in China (Han et  al. 2014; Lu et  al. 2014; changes in HFMD etiological agents other than EV-A71 Hu et  al. 2015; Bian et  al. 2015). It was also recently and CV-A16. Our phylogenetic analysis of the CV-A6 reported as the major etiological agent in Changchun, also show that the virus is undergoing rapid evolution north China. In 2013, CV-A6 replaced EV-A71 and in recent years, becoming the main pathogen of HFMD, CV-A16 as the main causative agent of HFMD, with a and spreading to other places where without the CV-A6 detection rate of 43.1  %, in the suburban areas of Bei- report. Thus, a more comprehensive monitoring system jing. (Han et  al. 2014; Hongyan et  al. 2014). This is for HMFD and CV-A6 is needed to understand the evo- the first HFMD outbreak caused by CV-A6 in Fengtai lution of CV-A6. Li et al. SpringerPlus (2016) 5:1650 Page 4 of 4 Received: 12 June 2016 Accepted: 12 September 2016 China Information System for Disease Control and Prevention is a powerful tool to detect outbreaks, and additional infectious diseases should be included in this system to implement early intervention measures for epi- demics or outbreaks. Clinicians should strengthen the References training to report the cases of infectious diseases, so that Bian L, Wang Y, Yao X et al (2015) Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev the control measures can be carried out at the early stage Anti Infect Ther. 13:1061–1071 of the outbreaks which are critical to end the outbreaks Feder HM Jr, Bennett N, Modlin JF (2014) Atypical hand, foot, and mouth as early as possible. disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 14:83–86 Fujimoto T, Iizuka S, Enomoto M et al (2012) Hand, foot, and mouth disease Conclusions caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis 18:337–339 This HFMD outbreak in a juku in Beijing, China, was Han JF, Xu S, Zhang Y et al (2014) Hand, foot, and mouth disease outbreak caused by coxsackievirus A6, China, 2013. J Infect 69(3):303–305 caused by CV-A6. Measures, such as a sensitive surveil- He SJ, Han JF, Ding XX et al (2013a) Characterization of enterovirus 71 and lance system, early identification of the pathogen and coxsackievirus A16 isolated in hand, foot, and mouth disease patients in timely intervention, are keys to controlling outbreaks of Guangdong, 2010. Int J Infect Dis. 17:e1025–e1030 He YQ, Chen L, Xu WB et al (2013b) Emergence, circulation, and spatiotem‑ disease caused by CV-A6. To control the outbreak at the poral phylogenetic analysis of coxsackievirus a6‑ and coxsackievirus early stage, more types of diseases should be monitored a10‑associated hand, foot, and mouth disease infections from 2008 to by China Information System for Disease Control and 2012 in Shenzhen, China. J Clin Microbiol. 51:3560–3566 Hongyan G, Chengjie M, Qiaozhi Y et al (2014) Hand, foot and mouth Prevention. disease caused by coxsackievirus A6, Beijing, 2013. Pediatr Infect Dis J. 33:1302–1303 Nucleotide sequence accession numbers Hu YQ, Xie GC, Li DD et al (2015) Prevalence of coxsackievirus A6 and enterovi‑ rus 71 in hand, foot and mouth disease in Nanjing, China in 2013. Pediatr Partial sequences of CV-A6 have been deposited under Infect Dis J. 34:951–957 accession numbers: KX061468–KX061473. Ishiko H, Shimada Y, Yonaha M et al (2002) Molecular diagnosis of human enteroviruses by phylogeny‑based classification by use of the VP4 Authors’ contributions sequence. J Infect Dis 185:744–754 JSL identified the pathogens causing this outbreak, performed the genetic Lu J, Zeng H, Zheng H et al (2014) Hand, foot and mouth disease in Guang‑ analysis, and drafted the manuscript; XGD identified the pathogens causing dong, China, in 2013: new trends in the continuing epidemic. Clin this outbreak; MQ collected the samples and undertook the epidemiological Microbiol Infect 20:O442–O445 investigation; HRF, RXL and JYY conducted the epidemiological investiga‑ Mirand A, Henquell C, Archimbaud C et al (2012) Outbreak of hand, foot and tion and outbreak control; JJZ participated in the design of the study; LSZ mouth disease/herpangina associated with coxsackievirus A6 and A10 participated in the design of the study, revised and edited the manuscript. All infections in 2010, France: a large citywide, prospective observational authors read and approved the final manuscript. study. Clin Microbiol Infect 18:E110–E118 Osterback R, Vuorinen T, Linna M et al (2009) Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 15:1485–1488 Acknowledgements Puenpa J, Chieochansin T, Linsuwanon P et al (2013) Hand, foot, and mouth We thank the staff of the juku who helped with this study. The study was disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis funded by the China Megaproject for infectious diseases (2014ZX10004‑002, 19:641–643 2015ZX10004‑203) from the Ministry of Science and Technology and the Sinclair C, Gaunt E, Simmonds P et al (2014) Atypical hand, foot, and mouth Ministry of Health. disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Euro Surveill 19:20745 Competing interests Wei SH, Huang YP, Liu MC et al (2011) An outbreak of coxsackievirus A6 hand, The authors declare that they have no competing interests. foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis 11:346 Compliance with ethical standards Informed consent to both participate and to publish was obtained from the children’s parents or from the study subjects themselves. Our research has been approved by the ethics committee of Fengtai District Center for Diseases Control and Prevention of Beijing. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png SpringerPlus Springer Journals

Outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 in a Juku in Fengtai District, Beijing, China, 2015

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Springer Journals
Copyright
Copyright © 2016 by The Author(s)
Subject
Science, Humanities and Social Sciences, multidisciplinary; Science, Humanities and Social Sciences, multidisciplinary
eISSN
2193-1801
DOI
10.1186/s40064-016-3307-x
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Abstract

An outbreak of hand, foot, and mouth disease (HFMD) that occurred in a Juku in Fengtai District, Beijing, China, in 2015 was monitored by the China Information System for Disease Control and Prevention. Epidemiological investiga‑ tion showed that 11 cases occurred from two classes in the preschool art training department in the Juku. Coxsacki‑ evirus A6 (CV‑ A6) was identified as the causative pathogen of the outbreak via sequences analysis of products of real‑ time reverse‑ transcription polymerase chain reaction (RT‑ PCR) and nested RT‑ PCR. Phylogenetic analysis showed that CV‑ A6 strains isolated in this study clustered with epidemic strains isolated in China since 2013. The outbreak ended quickly with effective measures. This event indicates that continuous surveillance of HFMD etiological agents other than enterovirus 71 and coxsackievirus A16 is necessary. Keywords: Coxsackievirus A6, HFMD, Outbreak (CV-A6) has rapidly replaced the original circulating Background strains EV-A71 and CV-A16, becoming the predomi- Hand, foot, and mouth disease (HFMD) is character- nant etiological agent of HFMD in some areas in China ized by mild febrile illness and vesicular exanthema on (Han et  al. 2014; Lu et  al. 2014). CV-A6 is classified hands, feet and mouth. HFMD is a virus-induced infec- as human enterovirus A in the family Picornaviridae, tious disease affecting mainly infants and children, typ - genus Enterovirus, and is an etiological agent of mild ically causing outbreaks in kindergartens and primary herpangina or HFMD (Mirand et  al. 2012; Osterback schools. Severe cases can also involve serious complica- et al. 2009; Sinclair et al. 2014; Wei et al. 2011). CV-A6 tions, such as encephalitis, meningitis, or death. HMFD has also been reported to cause outbreaks worldwide is considered a substantial public health threat, and (Feder et  al. 2014; Puenpa et  al. 2013; Fujimoto et  al. ranked first among category C infectious diseases by 2012; He et al. 2013). the Ministry of Health of the People’s Republic of China in 2008. The predominant causative agents of HFMD Methods are enterovirus 71 (EV-A71) and coxsackievirus A16 Study design (CV-A16); additionally, other CVA, CVB, and some An HFMD outbreak associated with CV-A6 in a Juku echoviruses have been reported to cause HFMD (He in Fengtai District, Beijing, China was monitored by the et  al. 2013). Since 2012, a newly emerged enterovirus China Information System for Disease Control and Pre- vention, From July 17–22. The outbreak was investigated *Correspondence: 13611367235@163.com; zhenglishu2000@sina.com immediately after it was reported to Fengtai District Jin‑ Song Li and Xiao‑ Gen Dong contributed equally to this work Center for Disease Control and Prevention (CDC) of Bei- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Diseases Control and Prevention, China CDC, 100 Ying‑Xin St., jing on July 19 2015. Two investigators comprehensively Xi‑Cheng District, Beijing 100052, China recorded the entire investigation and completed all of the Fengtai District Center for Diseases Control and Prevention of Beijing, 3 relevant documents appropriately. Xi An St., Feng‑Tai District, Beijing 100071, China © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li et al. SpringerPlus (2016) 5:1650 Page 2 of 4 Samples and laboratory investigation 9 cases (81.8  %) exhibited herpangina, and 10 (90.9  %) Samples were collected from the cases, close contacts cases exhibited mild fever (<38.5  °C). There were no and environmental surface in the classroom. Twelve severe cases and no patients had serious complications. pharyngeal swabs were collected from two teachers, two parents of the sick children, and eight sick children, in Viral pathogens of this outbreak addition to five swab samples that were obtained from Four pharyngeal swab samples and three stool samples desks and a hand wash basin in the classroom. Addition- which were from six sick children and one close contact ally, three stool samples were collected from the other were positive for enterovirus, but negative for EV-A71 three sick children. and CV-A16. The samples from the other close contacts, Suspensions of rectal swabs and swabs of environ- the surface of the classroom and other five sick children ment surfaces were prepared by adding 1 ml phosphate- were negative to enterovirus with real-time PCR. Six buffered saline (PBS; pH 7.2) and briefly vortexing. fragments were amplified from two cases, one parent’s Suspensions of faecal samples were prepared by vortex- pharyngeal swab, and three stool samples. Sequences ing 0.2 g of faeces with 800 µl PBS for 3 min followed by were genotyped as CV-A6 using NCBI BLAST and phy- centrifugation at 13,000  rpm for 10  min. Viral RNA was logenetic analyses. extracted using the QIAamp Viral RNA Mini Kit (QIA- GEN, Hilden, Germany). All samples were tested for Nucleotide sequence similarity and phylogenetic analysis the presence of enterovirus, EV-A71 and CV-A16 by Six CV-A6 clinical isolates shared 99–100  % and 100  % real-time RT-PCR using a real-time TaqMan reverse- nucleotide and amino acid homology with other clinical transcription polymerase chain reaction (RT-PCR) isolates in China after 2013, respectively, but only 82 and kit from Jiangsu Shuoshi Bio-Tech Co., Ltd. (Hang- 84  % homology to CV-A6 prototype strain Gdula. Four zhou, China). cDNA from enterovirus-positive samples distinct lineages (ABCD) were revealed by phylogenetic was synthesized using primer OL68-1 (GGTAA(C/T) analysis; lineage A was divided into two sublineages A1 TTCCACCACCA(A/T/G/C)CC). The resultant frag - and A2 (Fig. 1). ments, which included the partial 5′ untranslated region, The phylogenetic analysis showed CV-A6 had con - VP2, and complete VP4, were amplified by nest RT-PCR tinuously evolved and spread to other areas. In lineage with primers OL68-1 and MD91 (CCTCCGGCCCCT A, most strains of sublineage A2 were detected in Japan GAATGCGGCTAAT), followed by nest pair primers before 2009 and a few from China and Finland, whereas OL68-1 and EVP4 (CTACTTTGGGTGTCCGTGTT), sublineage A1 was a recent epidemic strain that first as previously reported (Ishiko et al. 2002). The fragments appeared in 2008–2009. CV-A6 was detected in more were sequenced using the ABI 3730 system (Applied Bio- areas with a detection rate that markedly increased in systems, Foster City, CA, USA). the past 2 years. In Japan, lineages A, B and D were iso- lated at different years, however, lineages B and D were Nucleotide sequence similarity and phylogenetic analysis only isolated in Japan before 2000. Lineage B comprised Virus genotype and nucleotide sequence similarities were strains isolated in 1997, whereas sublineage A2 was iso- analysed by Blastn online. Phylogenetic analysis based on lated in Japan before 2003 and then detected in other the complete VP4 fragments of the most reference strains areas in 2008–2011. Only two strains of prototype strain of CV-A6 in GenBank was conducted with the neighbor- Gdula from the United States and Japan comprised lin- joining method using the MEGA5.0 software program. eage C. Strains from this study clustered with epidemic strains isolated in 2013–2014 from China and other areas Results comprising sublineage A1. Epidemiological investigation A 5-year-old boy, who attended the preschool art training Control measures of the outbreak in a Juku in Fengtai District, Beijing, China, had a fever CV-A6 is primarily transmitted via the fecal–oral route (38.4  °C) on July 17, and red vesicular lesions appeared by contaminated hands, toys, or food. After the Fengtai the next day. From July 17–22, 11 cases in the Juku were Center for Disease Control and Prevention confirmed the reported by different hospitals to the China Information outbreak with the China Information System for Disease System for Disease Control and Prevention. Three cases Control and Prevention on July 19, normal control meas- were reported on July 17, and 4 cases each were reported ures were taken, such as hand washing and classroom on July 18 and 19. The 11 cases, which included 5 girls disinfection. Health education was also intensified in this and 6 boys, were from two classes that shared noontime Juku. Classes in the preschool art training department rest in the same room. Nine (81.8  %) cases exhibited were suspended for 14 days starting July 21, and the chil- vesicular exanthema on hands, feet and in the mouth, dren were continuously monitored for any new cases. No Li et al. SpringerPlus (2016) 5:1650 Page 3 of 4 Fig. 1 Phylogenetic analysis of CV‑A6 complete VP4 nucleotide sequences phylogenetic analysis was performed and the tree was constructed using the neighbor‑joining algorithm implemented in the MEGA version 5.0 software program with 1000 bootstrap pseudoreplicates. The numbers on the branches indicate the bootstrap values, excluding those <70 % for clarity. CV‑A16 (accession no. KM382148.1) was used as an outgroup con‑ trol. Black dots show CV‑A6 strains isolated in this study. GenBank numbers of reference sequences are shown. a Phylogenetic analysis of the most reference strains of CV‑A6. b Phylogenetic analysis of the subtree A1 new case was reported up to August 7, indicating that the District in the past few years. But we have no the data outbreak had ended. of CV-A6 associated with the sporadic cases in Fengtai District. So more enterovirus need to be monitored in Discussion the HFMD cases. HFMD outbreaks caused by enteroviruses except for Following the approval and application of EV-A71 EV-A71 and CV-A16 have recently increased world- vaccines in China, the etiological agents of HFMD are wide (Osterback et  al. 2009; Wei et  al. 2011). Sporadic anticipated to change significantly in Fengtai District. cases of CV-A6 infection are becoming more frequent, Further investigation is needed to clarify significant especially in China (Han et  al. 2014; Lu et  al. 2014; changes in HFMD etiological agents other than EV-A71 Hu et  al. 2015; Bian et  al. 2015). It was also recently and CV-A16. Our phylogenetic analysis of the CV-A6 reported as the major etiological agent in Changchun, also show that the virus is undergoing rapid evolution north China. In 2013, CV-A6 replaced EV-A71 and in recent years, becoming the main pathogen of HFMD, CV-A16 as the main causative agent of HFMD, with a and spreading to other places where without the CV-A6 detection rate of 43.1  %, in the suburban areas of Bei- report. Thus, a more comprehensive monitoring system jing. (Han et  al. 2014; Hongyan et  al. 2014). This is for HMFD and CV-A6 is needed to understand the evo- the first HFMD outbreak caused by CV-A6 in Fengtai lution of CV-A6. Li et al. SpringerPlus (2016) 5:1650 Page 4 of 4 Received: 12 June 2016 Accepted: 12 September 2016 China Information System for Disease Control and Prevention is a powerful tool to detect outbreaks, and additional infectious diseases should be included in this system to implement early intervention measures for epi- demics or outbreaks. Clinicians should strengthen the References training to report the cases of infectious diseases, so that Bian L, Wang Y, Yao X et al (2015) Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev the control measures can be carried out at the early stage Anti Infect Ther. 13:1061–1071 of the outbreaks which are critical to end the outbreaks Feder HM Jr, Bennett N, Modlin JF (2014) Atypical hand, foot, and mouth as early as possible. disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 14:83–86 Fujimoto T, Iizuka S, Enomoto M et al (2012) Hand, foot, and mouth disease Conclusions caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis 18:337–339 This HFMD outbreak in a juku in Beijing, China, was Han JF, Xu S, Zhang Y et al (2014) Hand, foot, and mouth disease outbreak caused by coxsackievirus A6, China, 2013. J Infect 69(3):303–305 caused by CV-A6. Measures, such as a sensitive surveil- He SJ, Han JF, Ding XX et al (2013a) Characterization of enterovirus 71 and lance system, early identification of the pathogen and coxsackievirus A16 isolated in hand, foot, and mouth disease patients in timely intervention, are keys to controlling outbreaks of Guangdong, 2010. Int J Infect Dis. 17:e1025–e1030 He YQ, Chen L, Xu WB et al (2013b) Emergence, circulation, and spatiotem‑ disease caused by CV-A6. To control the outbreak at the poral phylogenetic analysis of coxsackievirus a6‑ and coxsackievirus early stage, more types of diseases should be monitored a10‑associated hand, foot, and mouth disease infections from 2008 to by China Information System for Disease Control and 2012 in Shenzhen, China. J Clin Microbiol. 51:3560–3566 Hongyan G, Chengjie M, Qiaozhi Y et al (2014) Hand, foot and mouth Prevention. disease caused by coxsackievirus A6, Beijing, 2013. Pediatr Infect Dis J. 33:1302–1303 Nucleotide sequence accession numbers Hu YQ, Xie GC, Li DD et al (2015) Prevalence of coxsackievirus A6 and enterovi‑ rus 71 in hand, foot and mouth disease in Nanjing, China in 2013. Pediatr Partial sequences of CV-A6 have been deposited under Infect Dis J. 34:951–957 accession numbers: KX061468–KX061473. Ishiko H, Shimada Y, Yonaha M et al (2002) Molecular diagnosis of human enteroviruses by phylogeny‑based classification by use of the VP4 Authors’ contributions sequence. J Infect Dis 185:744–754 JSL identified the pathogens causing this outbreak, performed the genetic Lu J, Zeng H, Zheng H et al (2014) Hand, foot and mouth disease in Guang‑ analysis, and drafted the manuscript; XGD identified the pathogens causing dong, China, in 2013: new trends in the continuing epidemic. Clin this outbreak; MQ collected the samples and undertook the epidemiological Microbiol Infect 20:O442–O445 investigation; HRF, RXL and JYY conducted the epidemiological investiga‑ Mirand A, Henquell C, Archimbaud C et al (2012) Outbreak of hand, foot and tion and outbreak control; JJZ participated in the design of the study; LSZ mouth disease/herpangina associated with coxsackievirus A6 and A10 participated in the design of the study, revised and edited the manuscript. All infections in 2010, France: a large citywide, prospective observational authors read and approved the final manuscript. study. Clin Microbiol Infect 18:E110–E118 Osterback R, Vuorinen T, Linna M et al (2009) Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 15:1485–1488 Acknowledgements Puenpa J, Chieochansin T, Linsuwanon P et al (2013) Hand, foot, and mouth We thank the staff of the juku who helped with this study. The study was disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis funded by the China Megaproject for infectious diseases (2014ZX10004‑002, 19:641–643 2015ZX10004‑203) from the Ministry of Science and Technology and the Sinclair C, Gaunt E, Simmonds P et al (2014) Atypical hand, foot, and mouth Ministry of Health. disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Euro Surveill 19:20745 Competing interests Wei SH, Huang YP, Liu MC et al (2011) An outbreak of coxsackievirus A6 hand, The authors declare that they have no competing interests. foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis 11:346 Compliance with ethical standards Informed consent to both participate and to publish was obtained from the children’s parents or from the study subjects themselves. Our research has been approved by the ethics committee of Fengtai District Center for Diseases Control and Prevention of Beijing.

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Published: Sep 23, 2016

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