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VIRO-TypeNed is a collaborative molecular surveillance platform facilitated through a web-based database. Genetic data in combination with epidemiological, clinical and patient data are shared between clinical and public health laboratories, as part of the surveillance underpinning poliovirus eradication. We analysed the combination of data submitted from 2010 to 2014 to understand circulation patterns of non-polio enteroviruses (NPEV) of public health relevance. Two epidemiological patterns were observed based on VIRO-TypeNed data and classical surveillance data dating back to 1996: (i) endemic cyclic, characterised by predictable upsurges/outbreaks every two to four years, and (ii) epidemic, where rare virus types caused upsurges/outbreaks. Genetic analysis suggests continuous temporal displacement of virus lineages due to the accumulation of (silent) genetic changes. Non-synonymous changes in the antigenic B/C loop suggest antigenic diversification, which may affect population susceptibility. Infections were frequently detected at an age under three months and at an older, parenting age (25–49 years) pointing to a distinct role of immunity in the circulation patterns. Upsurges were detected in the summer and winter which can promote increased transmissibility underlying new (cyclic) upsurges and requires close monitoring. The combination of data provide a better understanding of NPEV circulation required to control and curtail upsurges and outbreaks.


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  1. The picornavirus pages. Enterovirus. Pirbright; The Pirbright Institute. [Accessed: 14 Sep 2016]. Available from: http://www.picornaviridae.com/enterovirus/enterovirus.htm
  2. Abzug MJ. Presentation, diagnosis, and management of enterovirus infections in neonates. Paediatr Drugs. 2004;6(1):1-10.  https://doi.org/10.2165/00148581-200406010-00001  PMID: 14969566 
  3. Grist NR, Bell EJ, Assaad F. Enteroviruses in human disease. Prog Med Virol. 1978;24:114-57. PMID: 360295 
  4. Mohle-Boetani JC, Matkin C, Pallansch M, Helfand R, Fenstersheib M, Blanding JA, et al. Viral meningitis in child care center staff and parents: an outbreak of echovirus 30 infections. Public Health Rep. 1999;114(3):249-56.  https://doi.org/10.1093/phr/114.3.249  PMID: 10476994 
  5. Hawkes MT, Vaudry W. Nonpolio enterovirus infection in the neonate and young infant. Paediatr Child Health. 2005;10(7):383-8. PMID: 19668644 
  6. Fuchs I, Golan A, Borer A, Shemer-Avni Y, Dagan R, Greenberg D. Proactive approach to containment of enterovirus infection in the nursery. Clin Pediatr (Phila). 2013;52(7):639-44.  https://doi.org/10.1177/0009922813484087  PMID: 23572447 
  7. Verma NA, Zheng XT, Harris MU, Cadichon SB, Melin-Aldana H, Khetsuriani N, et al. Outbreak of life-threatening coxsackievirus B1 myocarditis in neonates. Clin Infect Dis. 2009;49(5):759-63.  https://doi.org/10.1086/605089  PMID: 19622042 
  8. Modlin JF. Fatal echovirus 11 disease in premature neonates. Pediatrics. 1980;66(5):775-80. PMID: 7432883 
  9. Gear JH, Measroch V. Coxsackievirus infections of the newborn. Prog Med Virol. 1973;15:42-62. PMID: 4572439 
  10. Freund MW, Kleinveld G, Krediet TG, van Loon AM, Verboon-Maciolek MA. Prognosis for neonates with enterovirus myocarditis. Arch Dis Child Fetal Neonatal Ed. 2010;95(3):F206-12.  https://doi.org/10.1136/adc.2009.165183  PMID: 20444813 
  11. Kaplan MH, Klein SW, McPhee J, Harper RG. Group B coxsackievirus infections in infants younger than three months of age: a serious childhood illness. Rev Infect Dis. 1983;5(6):1019-32.  https://doi.org/10.1093/clinids/5.6.1019  PMID: 6318288 
  12. Wildenbeest JG, van den Broek PJ, Benschop KS, Koen G, Wierenga PC, Vossen AC, et al. Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility. Antivir Ther. 2012;17(3):459-66.  https://doi.org/10.3851/IMP1936  PMID: 22293148 
  13. Benschop KS, van der Avoort HG, Duizer E, Koopmans MP. Antivirals against enteroviruses: a critical review from a public-health perspective. Antivir Ther. 2015;20(2):121-30.  https://doi.org/10.3851/IMP2939  PMID: 25643052 
  14. Simmonds P, Welch J. Frequency and dynamics of recombination within different species of human enteroviruses. J Virol. 2006;80(1):483-93.  https://doi.org/10.1128/JVI.80.1.483-493.2006  PMID: 16352572 
  15. Lukashev AN, Lashkevich VA, Ivanova OE, Koroleva GA, Hinkkanen AE, Ilonen J. Recombination in circulating enteroviruses. J Virol. 2003;77(19):10423-31.  https://doi.org/10.1128/JVI.77.19.10423-10431.2003  PMID: 12970427 
  16. Lukashev AN. Role of recombination in evolution of enteroviruses. Rev Med Virol. 2005;15(3):157-67.  https://doi.org/10.1002/rmv.457  PMID: 15578739 
  17. McWilliam Leitch EC, Cabrerizo M, Cardosa J, Harvala H, Ivanova OE, Kroes AC, et al. Evolutionary dynamics and temporal/geographical correlates of recombination in the human enterovirus echovirus types 9, 11, and 30. J Virol. 2010;84(18):9292-300.  https://doi.org/10.1128/JVI.00783-10  PMID: 20610722 
  18. Savolainen C, Hovi T, Mulders MN. Molecular epidemiology of echovirus 30 in Europe: succession of dominant sublineages within a single major genotype. Arch Virol. 2001;146(3):521-37.  https://doi.org/10.1007/s007050170160  PMID: 11338388 
  19. Harvala H, Kalimo H, Bergelson J, Stanway G, Hyypiä T. Tissue tropism of recombinant coxsackieviruses in an adult mouse model. J Gen Virol. 2005;86(Pt 7):1897-907.  https://doi.org/10.1099/vir.0.80603-0  PMID: 15958668 
  20. Harvala H, Kalimo H, Dahllund L, Santti J, Hughes P, Hyypiä T, et al. Mapping of tissue tropism determinants in coxsackievirus genomes. J Gen Virol. 2002;83(Pt 7):1697-706.  https://doi.org/10.1099/0022-1317-83-7-1697  PMID: 12075089 
  21. Harvala H, Kalimo H, Stanway G, Hyypiä T. Pathogenesis of coxsackievirus A9 in mice: role of the viral arginine-glycine-aspartic acid motif. J Gen Virol. 2003;84(Pt 9):2375-9.  https://doi.org/10.1099/vir.0.19246-0  PMID: 12917458 
  22. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010;9(11):1097-105.  https://doi.org/10.1016/S1474-4422(10)70209-X  PMID: 20965438 
  23. Sun LM, Zheng HY, Zheng HZ, Guo X, He JF, Guan DW, et al. An enterovirus 71 epidemic in Guangdong Province of China, 2008: epidemiological, clinical, and virogenic manifestations. Jpn J Infect Dis. 2011;64(1):13-8. PMID: 21266750 
  24. Meijer A, Benschop KS, Donker GA, van der Avoort HG. Continued seasonal circulation of enterovirus D68 in the Netherlands, 2011-2014. Euro Surveill. 2014;19(42):20935.  https://doi.org/10.2807/1560-7917.ES2014.19.42.20935  PMID: 25358039 
  25. Esposito S, Zampiero A, Ruggiero L, Madini B, Niesters H, Principi N. Enterovirus D68-associated community-acquired pneumonia in children living in Milan, Italy. J Clin Virol. 2015;68:94-6.  https://doi.org/10.1016/j.jcv.2015.05.017  PMID: 26071345 
  26. Farrell JJ, Ikladios O, Wylie KM, O’Rourke LM, Lowery KS, Cromwell JS, et al. Enterovirus D68-associated acute respiratory distress syndrome in adult, United States, 2014. Emerg Infect Dis. 2015;21(5):914-6.  https://doi.org/10.3201/eid2105.142033  PMID: 25897542 
  27. Lang M, Mirand A, Savy N, Henquell C, Maridet S, Perignon R, et al. Acute flaccid paralysis following enterovirus D68 associated pneumonia, France, 2014. Euro Surveill. 2014;19(44):20952.  https://doi.org/10.2807/1560-7917.ES2014.19.44.20952  PMID: 25394254 
  28. Midgley SE, Christiansen CB, Poulsen MW, Hansen CH, Fischer TK. Emergence of enterovirus D68 in Denmark, June 2014 to February 2015. Euro Surveill. 2015;20(17):21105.  https://doi.org/10.2807/1560-7917.ES2015.20.17.21105  PMID: 25955773 
  29. Pfeiffer HC, Bragstad K, Skram MK, Dahl H, Knudsen PK, Chawla MS, et al. Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014. Euro Surveill. 2015;20(10):21062.  https://doi.org/10.2807/1560-7917.ES2015.20.10.21062  PMID: 25788251 
  30. Poelman R, Schuffenecker I, Van Leer-Buter C, Josset L, Niesters HG, Lina B, et al. European surveillance for enterovirus D68 during the emerging North-American outbreak in 2014. J Clin Virol. 2015;71:1-9.  https://doi.org/10.1016/j.jcv.2015.07.296  PMID: 26364237 
  31. Janes VA, Minnaar R, Koen G, van Eijk H, Dijkman-de Haan K, Pajkrt D, et al. Presence of human non-polio enterovirus and parechovirus genotypes in an Amsterdam hospital in 2007 to 2011 compared to national and international published surveillance data: a comprehensive review. Euro Surveill. 2014;19(46):20964.  https://doi.org/10.2807/1560-7917.ES2014.19.46.20964  PMID: 25425513 
  32. van der Sanden SM, Koopmans MP, van der Avoort HG. Detection of human enteroviruses and parechoviruses as part of the national enterovirus surveillance in the Netherlands, 1996-2011. Eur J Clin Microbiol Infect Dis. 2013;32(12):1525-31.  https://doi.org/10.1007/s10096-013-1906-9  PMID: 23780695 
  33. Niesters HG, Rossen JW, van der Avoort H, Baas D, Benschop K, Claas EC, et al. Laboratory-based surveillance in the molecular era: the TYPENED model, a joint data-sharing platform for clinical and public health laboratories. Euro Surveill. 2013;18(4):20387. PMID: 23369392 
  34. Benschop K, Molenkamp R, van der Ham A, Wolthers K, Beld M. Rapid detection of human parechoviruses in clinical samples by real-time PCR. J Clin Virol. 2008;41(2):69-74.  https://doi.org/10.1016/j.jcv.2007.10.004  PMID: 18354819 
  35. Poelman R, Schölvinck EH, Borger R, Niesters HG, van Leer-Buter C. The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses. J Clin Virol. 2015;62:1-5.  https://doi.org/10.1016/j.jcv.2014.11.011  PMID: 25542461 
  36. Benschop K, Minnaar R, Koen G, van Eijk H, Dijkman K, Westerhuis B, et al. Detection of human enterovirus and human parechovirus (HPeV) genotypes from clinical stool samples: polymerase chain reaction and direct molecular typing, culture characteristics, and serotyping. Diagn Microbiol Infect Dis. 2010;68(2):166-73.  https://doi.org/10.1016/j.diagmicrobio.2010.05.016  PMID: 20846590 
  37. Beld M, Minnaar R, Weel J, Sol C, Damen M, van der Avoort H, et al. Highly sensitive assay for detection of enterovirus in clinical specimens by reverse transcription-PCR with an armored RNA internal control. J Clin Microbiol. 2004;42(7):3059-64.  https://doi.org/10.1128/JCM.42.7.3059-3064.2004  PMID: 15243060 
  38. Benschop K, Thomas X, Serpenti C, Molenkamp R, Wolthers K. High prevalence of human Parechovirus (HPeV) genotypes in the Amsterdam region and identification of specific HPeV variants by direct genotyping of stool samples. J Clin Microbiol. 2008;46(12):3965-70.  https://doi.org/10.1128/JCM.01379-08  PMID: 18945833 
  39. Oberste MS, Maher K, Flemister MR, Marchetti G, Kilpatrick DR, Pallansch MA. Comparison of classic and molecular approaches for the identification of untypeable enteroviruses. J Clin Microbiol. 2000;38(3):1170-4. PMID: 10699015 
  40. Oberste MS, Maher K, Kilpatrick DR, Flemister MR, Brown BA, Pallansch MA. Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol. 1999;37(5):1288-93. PMID: 10203472 
  41. Kroneman A, Vennema H, Deforche K, van der Avoort H, Peñaranda S, Oberste MS, et al. An automated genotyping tool for enteroviruses and noroviruses. J Clin Virol. 2011;51(2):121-5.  https://doi.org/10.1016/j.jcv.2011.03.006  PMID: 21514213 
  42. Nix WA, Oberste MS, Pallansch MA. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol. 2006;44(8):2698-704.  https://doi.org/10.1128/JCM.00542-06  PMID: 16891480 
  43. Harvala H, McLeish N, Kondracka J, McIntyre CL, McWilliam Leitch EC, Templeton K, et al. Comparison of human parechovirus and enterovirus detection frequencies in cerebrospinal fluid samples collected over a 5-year period in edinburgh: HPeV type 3 identified as the most common picornavirus type. J Med Virol. 2011;83(5):889-96.  https://doi.org/10.1002/jmv.22023  PMID: 21412796 
  44. Page GS, Mosser AG, Hogle JM, Filman DJ, Rueckert RR, Chow M. Three-dimensional structure of poliovirus serotype 1 neutralizing determinants. J Virol. 1988;62(5):1781-94. PMID: 2451757 
  45. Simmonds P. SSE: a nucleotide and amino acid sequence analysis platform. BMC Res Notes. 2012;5(1):50.  https://doi.org/10.1186/1756-0500-5-50  PMID: 22264264 
  46. Kumar S, Tamura K, Nei M. MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform. 2004;5(2):150-63.  https://doi.org/10.1093/bib/5.2.150  PMID: 15260895 
  47. Benschop KS, Williams CH, Wolthers KC, Stanway G, Simmonds P. Widespread recombination within human parechoviruses: analysis of temporal dynamics and constraints. J Gen Virol. 2008;89(Pt 4):1030-5.  https://doi.org/10.1099/vir.0.83498-0  PMID: 18343846 
  48. McWilliam Leitch EC, Bendig J, Cabrerizo M, Cardosa J, Hyypiä T, Ivanova OE, et al. Transmission networks and population turnover of echovirus 30. J Virol. 2009;83(5):2109-18.  https://doi.org/10.1128/JVI.02109-08  PMID: 19091869 
  49. Tokarz R, Firth C, Madhi SA, Howie SR, Wu W, Sall AA, et al. Worldwide emergence of multiple clades of enterovirus 68. J Gen Virol. 2012;93(Pt 9):1952-8.  https://doi.org/10.1099/vir.0.043935-0  PMID: 22694903 
  50. Meijer A, van der Sanden S, Snijders BE, Jaramillo-Gutierrez G, Bont L, van der Ent CK, et al. Emergence and epidemic occurrence of enterovirus 68 respiratory infections in The Netherlands in 2010. Virology. 2012;423(1):49-57.  https://doi.org/10.1016/j.virol.2011.11.021  PMID: 22177700 
  51. Cordey S, Petty TJ, Schibler M, Martinez Y, Gerlach D, van Belle S, et al. Identification of site-specific adaptations conferring increased neural cell tropism during human enterovirus 71 infection. PLoS Pathog. 2012;8(7):e1002826.  https://doi.org/10.1371/journal.ppat.1002826  PMID: 22910880 
  52. Baek K, Yeo S, Lee B, Park K, Song J, Yu J, et al. Epidemics of enterovirus infection in Chungnam Korea, 2008 and 2009. Virol J. 2011;8(1):297.  https://doi.org/10.1186/1743-422X-8-297  PMID: 21668960 
  53. Savolainen-Kopra C, Paananen A, Blomqvist S, Klemola P, Simonen ML, Lappalainen M, et al. A large Finnish echovirus 30 outbreak was preceded by silent circulation of the same genotype. Virus Genes. 2011;42(1):28-36.  https://doi.org/10.1007/s11262-010-0536-x  PMID: 20960045 
  54. Rahamat-Langendoen J, Riezebos-Brilman A, Borger R, van der Heide R, Brandenburg A, Schölvinck E, et al. Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections. J Clin Virol. 2011;52(2):103-6.  https://doi.org/10.1016/j.jcv.2011.06.019  PMID: 21802981 
  55. Ayscue P, Van Haren K, Sheriff H, Waubant E, Waldron P, Yagi S, et al. Acute flaccid paralysis with anterior myelitis - California, June 2012-June 2014. MMWR Morb Mortal Wkly Rep. 2014;63(40):903-6. PMID: 25299608 
  56. Khan F. Enterovirus D68: acute respiratory illness and the 2014 outbreak. Emerg Med Clin North Am. 2015;33(2):e19-32.  https://doi.org/10.1016/j.emc.2014.12.011  PMID: 26065305 
  57. Midgley CM, Jackson MA, Selvarangan R, Turabelidze G, Obringer E, Johnson D, et al. Severe respiratory illness associated with enterovirus D68 - Missouri and Illinois, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(36):798-9. PMID: 25211545 
  58. Nougairede A, Bessaud M, Thiberville SD, Piorkowski G, Ninove L, Zandotti C, et al. Widespread circulation of a new echovirus 30 variant causing aseptic meningitis and non-specific viral illness, South-East France, 2013. J Clin Virol. 2014;61(1):118-24.  https://doi.org/10.1016/j.jcv.2014.05.022  PMID: 24973284 
  59. Milia MG, Cerutti F, Gregori G, Burdino E, Allice T, Ruggiero T, et al. Recent outbreak of aseptic meningitis in Italy due to Echovirus 30 and phylogenetic relationship with other European circulating strains. J Clin Virol. 2013;58(3):579-83.  https://doi.org/10.1016/j.jcv.2013.08.023  PMID: 24051044 
  60. Ramirez-Fort MK, Downing C, Doan HQ, Benoist F, Oberste MS, Khan F, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60(4):381-6.  https://doi.org/10.1016/j.jcv.2014.04.023  PMID: 24932735 
  61. Rabenau HF, Richter M, Doerr HW. Hand, foot and mouth disease: seroprevalence of Coxsackie A16 and Enterovirus 71 in Germany. Med Microbiol Immunol (Berl). 2010;199(1):45-51.  https://doi.org/10.1007/s00430-009-0133-6  PMID: 19941005 
  62. McPhee F, Zell R, Reimann BY, Hofschneider PH, Kandolf R. Characterization of the N-terminal part of the neutralizing antigenic site I of coxsackievirus B4 by mutation analysis of antigen chimeras. Virus Res. 1994;34(2):139-51.  https://doi.org/10.1016/0168-1702(94)90096-5  PMID: 7531922 
  63. Westerhuis BM, Koen G, Wildenbeest JG, Pajkrt D, de Jong MD, Benschop KS, et al. Specific cell tropism and neutralization of human parechovirus types 1 and 3: implications for pathogenesis and therapy development. J Gen Virol. 2012;93(Pt 11):2363-70.  https://doi.org/10.1099/vir.0.043323-0  PMID: 22837420 
  64. Yarmolskaya MS, Shumilina EY, Ivanova OE, Drexler JF, Lukashev AN. Molecular epidemiology of echoviruses 11 and 30 in Russia: different properties of genotypes within an enterovirus serotype. Infect Genet Evol. 2015;30:244-8.  https://doi.org/10.1016/j.meegid.2014.12.033  PMID: 25562123 
  65. Moeller JL. Aseptic meningitis: a seasonal concern. Phys Sportsmed. 1997;25(7):34-42.  https://doi.org/10.3810/psm.1997.07.1472  PMID: 20086919 
  66. David JM, Ravel A, Nesbitt A, Pintar K, Pollari F. Assessing multiple foodborne, waterborne and environmental exposures of healthy people to potential enteric pathogen sources: effect of age, gender, season, and recall period. Epidemiol Infect. 2014;142(1):28-39. PMID: 23731678 
  67. Pallansch MA, Oberste MS. Enterovirus 71 encephalitis: a new vaccine on the horizon? Lancet. 2013;381(9871):976-7.  https://doi.org/10.1016/S0140-6736(13)60286-X  PMID: 23668563 
  68. Oberste MS, Moore D, Anderson B, Pallansch MA, Pevear DC, Collett MS. In vitro antiviral activity of V-073 against polioviruses. Antimicrob Agents Chemother. 2009;53(10):4501-3.  https://doi.org/10.1128/AAC.00671-09  PMID: 19635956 
  69. Thibaut HJ, De Palma AM, Neyts J. Combating enterovirus replication: state-of-the-art on antiviral research. Biochem Pharmacol. 2012;83(2):185-92.  https://doi.org/10.1016/j.bcp.2011.08.016  PMID: 21889497 

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