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Abstract

Hand, foot, and mouth disease (HFMD) is caused by multiple viruses in the genus Enterovirus, which include the well-known polioviruses (PVs), coxsackieviruses A and B (CV-A and CV-B), and enteric cytopathic human orphan (ECHO) viruses. The genome of EVs is single-stranded, positive-sense RNA. The open reading frame (ORF) region in EVs genome encodes structural proteins that further formed EV capsids. EVs are among the fastest evolving viruses with high genetic variability. Thus, the classification of EVs is initially based on clinical manifestations of their infection, subsequent serological characteristics, and differences in the nucleotide sequences up to the modern era. Currently, the genus Enterovirus consists of 3 human RV species (RV-A, -B and -C), 4 human EV species (HEV-A, -B, -C, and -D), and 6 animal EVs. The major pathogens (EV-A71, CV-A16, CV-A6, CV-A10, etc.) causing HFMD are included in the species of EV-A. The HFMD outbreaks were alternatively caused by infections with CV-A16 and EV-A71 ever since 1990s; however, the pathogenicity of HFMD changed greatly in the past decade, with new pathogens being identified continuously. Rapid diagnosis and genotyping of EV infection are through virus isolation and culture, serological assays, PCR identification or supplementary analysis, such as microarray.

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References

  1. Dalldorf G, Sickles GM. An unidentified, filtrable agent isolated from the feces of children with paralysis. Science. 1948;108(2794):61–2.

    Article  CAS  PubMed  Google Scholar 

  2. Melnick JL, Shaw EW, Curnen EC. A virus isolated from patients diagnosed as non-paralytic poliomyelitis or aseptic meningitis. Proc Soc Exp Biol Med. 1949;71(3):344–9.

    Article  CAS  PubMed  Google Scholar 

  3. Godman GC, Bunting H, Melnick JL. The histopathology of Coxsackie virus infection in mice. I. Morphologic observations with four different viral types. Am J Pathol. 1952;28(2):223–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Enders JF, Weller TH, Robbins FC. Cultivation of the Lansing strain of poliomyelitis virus in cultures of various human embryonic tissues. Science. 1949;109(2822):85–7.

    Article  CAS  PubMed  Google Scholar 

  5. Author. ENTERIC cytopathogenic human orphan (ECHO) viruses. Science. 1955;122(3181):1187–8.

    Article  Google Scholar 

  6. Koonin EV, Wolf YI, Nagasaki K, Dolja VV. The Big Bang of picorna-like virus evolution antedates the radiation of eukaryotic supergroups. Nat Rev Microbiol. 2008;6(12):925–39.

    Article  CAS  PubMed  Google Scholar 

  7. Agol VI, Gmyl AP. Viral security proteins: counteracting host defences. Nat Rev Microbiol. 2010;8(12):867–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lei X, Cui S, Zhao Z, Wang J. Etiology, pathogenesis, antivirals and vaccines of hand, foot, and mouth disease. Natl Sci Rev. 2015;2(3):268–84.

    Article  CAS  Google Scholar 

  9. Sanjuan R. From molecular genetics to phylodynamics: evolutionary relevance of mutation rates across viruses. PLoS Pathog. 2012;8(5):e1002685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lukashev AN, Vakulenko YA. Molecular evolution of types in non-polio enteroviruses. J Gen Virol. 2017;98(12):2968–81.

    Article  CAS  PubMed  Google Scholar 

  11. Domingo E, Sheldon J, Perales C. Viral quasispecies evolution. Microbiol Mol Biol Rev. 2012;76(2):159–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature. 2006;439(7074):344–8.

    Article  CAS  PubMed  Google Scholar 

  13. Huang SW, Huang YH, Tsai HP, Kuo PH, Wang SM, Liu CC, et al. A selective bottleneck shapes the evolutionary mutant spectra of enterovirus A71 during viral dissemination in humans. J Virol. 2017;91:23.

    Article  Google Scholar 

  14. Lukashev AN, Shumilina EY, Belalov IS, Ivanova OE, Eremeeva TP, Reznik VI, et al. Recombination strategies and evolutionary dynamics of the human enterovirus A global gene pool. J Gen Virol. 2014;95(4):868–73.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lukashev AN, Lashkevich VA, Ivanova OE, Koroleva GA, Hinkkanen AE, Ilonen J. Recombination in circulating Human enterovirus B: independent evolution of structural and non-structural genome regions. J Gen Virol. 2005;86(Pt 12):3281–90.

    Article  CAS  PubMed  Google Scholar 

  17. Blomqvist S, Bruu AL, Stenvik M, Hovi T. Characterization of a recombinant type 3/type 2 poliovirus isolated from a healthy vaccinee and containing a chimeric capsid protein VP1. J Gen Virol. 2003;84(Pt 3):573–80.

    Article  CAS  PubMed  Google Scholar 

  18. Martin J, Samoilovich E, Dunn G, Lackenby A, Feldman E, Heath A, et al. Isolation of an intertypic poliovirus capsid recombinant from a child with vaccine-associated paralytic poliomyelitis. J Virol. 2002;76(21):10921–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lukashev AN. Role of recombination in evolution of enteroviruses. Rev Med Virol. 2005;15(3):157–67.

    Article  CAS  PubMed  Google Scholar 

  20. Lauring AS, Andino R. Quasispecies theory and the behavior of RNA viruses. PLoS Pathog. 2010;6(7):e1001005.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pfeiffer JK, Kirkegaard K. Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice. PLoS Pathog. 2005;1(2):e11.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gnadig NF, Beaucourt S, Campagnola G, Borderia AV, Sanz-Ramos M, Gong P, et al. Coxsackievirus B3 mutator strains are attenuated in vivo. Proc Natl Acad Sci U S A. 2012;109(34):E2294–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meng T, Kwang J. Attenuation of human enterovirus 71 high-replication-fidelity variants in AG129 mice. J Virol. 2014;88(10):5803–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xiao Y, Rouzine IM, Bianco S, Acevedo A, Goldstein EF, Farkov M, et al. RNA Recombination enhances adaptability and is required for virus spread and virulence. Cell Host Microbe. 2016;19(4):493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xiao Y, Dolan PT, Goldstein EF, Li M, Farkov M, Brodsky L, et al. Poliovirus intrahost evolution is required to overcome tissue-specific innate immune responses. Nat Commun. 2017;8(1):375.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kitamura N, Semler BL, Rothberg PG, Larsen GR, Adler CJ, Dorner AJ, et al. Primary structure, gene organization and polypeptide expression of poliovirus RNA. Nature. 1981;291(5816):547–53.

    Article  CAS  PubMed  Google Scholar 

  27. Laine P, Savolainen C, Blomqvist S, Hovi T. Phylogenetic analysis of human rhinovirus capsid protein VP1 and 2A protease coding sequences confirms shared genus-like relationships with human enteroviruses. J Gen Virol. 2005;86(3):697–706.

    Article  CAS  PubMed  Google Scholar 

  28. Stanway G, Hughes PJ, Mountford RC, Minor PD, Almond JW. The complete nucleotide sequence of a common cold virus: human rhinovirus 14. Nucleic Acids Res. 1984;12(20):7859–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. King AM, Adams MJ, Carstens EB, Lefkowitz EJ. Virus taxonomy. Ninth report of the International Committee on Taxonomy of Viruses. 2012.

    Google Scholar 

  30. Adams MJ, Carstens E. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2012). Arch Virol. 2012;157(7):1411–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Adams M, Lefkowitz E, King A, Carstens E. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2014). Arch Virol. 2014;159(10):2831–41.

    Article  CAS  PubMed  Google Scholar 

  32. Adams M, Lefkowitz E, King A, Bamford D, Breitbart M, Davison A, et al. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2015). Cham: Springer; 2015.

    Book  Google Scholar 

  33. Adams MJ, Lefkowitz EJ, King AM, Harrach B, Harrison RL, Knowles NJ, et al. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2016). Arch Virol. 2016;161(10):2921–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mombo IM, Lukashev AN, Bleicker T, Brunink S, Berthet N, Maganga GD, et al. African Non-human primates host diverse enteroviruses. PLoS One. 2017;12(1):e0169067.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Oberste MS, Feeroz MM, Maher K, Nix WA, Engel GA, Begum S, et al. Naturally acquired picornavirus infections in primates at the Dhaka zoo. J Virol. 2013;87(1):572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jiang P, Faase JA, Toyoda H, Paul A, Wimmer E, Gorbalenya AE. Evidence for emergence of diverse polioviruses from C-cluster coxsackie A viruses and implications for global poliovirus eradication. Proc Natl Acad Sci U S A. 2007;104(22):9457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arden KE, McErlean P, Nissen MD, Sloots TP, Mackay IM. Frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections. J Med Virol. 2006;78(9):1232–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McErlean P, Shackelton LA, Lambert SB, Nissen MD, Sloots TP, Mackay IM. Characterisation of a newly identified human rhinovirus, HRV-QPM, discovered in infants with bronchiolitis. J Clin Virol. 2007;39(2):67–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lamson D, Renwick N, Kapoor V, Liu Z, Palacios G, Ju J, et al. MassTag polymerase-chain-reaction detection of respiratory pathogens, including a new rhinovirus genotype, that caused influenza-like illness in New York State during 2004-2005. J Infect Dis. 2006;194(10):1398–402.

    Article  CAS  PubMed  Google Scholar 

  42. Lau SK, Yip CC, Tsoi HW, Lee RA, So LY, Lau YL, et al. Clinical features and complete genome characterization of a distinct human rhinovirus (HRV) genetic cluster, probably representing a previously undetected HRV species, HRV-C, associated with acute respiratory illness in children. J Clin Microbiol. 2007;45(11):3655–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee WM, Kiesner C, Pappas T, Lee I, Grindle K, Jartti T, et al. A diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants. PLoS One. 2007;2(10):e966.

    Article  PubMed  PubMed Central  Google Scholar 

  44. McErlean P, Shackelton LA, Andrews E, Webster DR, Lambert SB, Nissen MD, et al. Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C). PLoS One. 2008;3(4):e1847.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, et al. Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity. J Infect Dis. 2007;196(6):817–25.

    Article  CAS  PubMed  Google Scholar 

  46. Robinson CR, Doane FW, Rhodes AJ. Report of an outbreak of febrile illness with pharyngeal lesions and exanthem: Toronto, summer 1957; isolation of group A Coxsackie virus. Can Med Assoc J. 1958;79(8):615–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Alsop J, Flewett TH, Foster JR. “Hand-foot-and-mouth disease” in Birmingham in 1959. Br Med J. 1960;2(5214):1708–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Flewett TH, Warin RP, Clarke SK. ‘Hand, foot, and mouth disease’ associated with Coxsackie A5 virus. J Clin Pathol. 1963;16:53–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Duff MF. Hand-foot-and-mouth syndrome in humans: coxsackie A10 infections in New Zealand. Br Med J. 1968;2(5606):661–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chumakov M, Voroshilova M, Shindarov L, Lavrova I, Gracheva L, Koroleva G, et al. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol. 1979;60(3-4):329–40.

    Article  CAS  PubMed  Google Scholar 

  51. Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol. 1982;71(3):217–27.

    Article  CAS  PubMed  Google Scholar 

  52. Ishimaru Y, Nakano S, Yamaoka K, Takami S. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child. 1980;55(8):583–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. Lancet Infect Dis. 2014;14(4):308–18.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Centers for Disease C, Prevention. Deaths among children during an outbreak of hand, foot, and mouth disease–Taiwan, Republic of China, April-July 1998. MMWR Morb Mortal Wkly Rep. 1998;47(30):629–32.

    Google Scholar 

  55. Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341(13):929–35.

    Article  CAS  PubMed  Google Scholar 

  56. Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31(3):678–83.

    Article  CAS  PubMed  Google Scholar 

  57. McMinn P, Stratov I, Nagarajan L, Davis S. Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis. 2001;32(2):236–42.

    Article  CAS  PubMed  Google Scholar 

  58. Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9(1):78–85.

    Article  PubMed  PubMed Central  Google Scholar 

  59. AbuBakar S, Sam IC, Yusof J, Lim MK, Misbah S, MatRahim N, et al. Enterovirus 71 outbreak, Brunei. Emerg Infect Dis. 2009;15(1):79–82.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Khanh TH, Sabanathan S, Thanh TT, Thoa le PK, Thuong TC, Hang V, et al. Enterovirus 71-associated hand, foot, and mouth disease, Southern Vietnam, 2011. Emerg Infect Dis. 2012;18(12):2002–5.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Galassi FM, Habicht ME, Ruhli FJ. Poliomyelitis in Ancient Egypt? Neurol Sci. 2017;38(2):375.

    Article  PubMed  Google Scholar 

  62. Horstmann DM. The poliomyelitis story: a scientific hegira. Yale J Biol Med. 1985;58(2):79–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. De Jesus NH. Epidemics to eradication: the modern history of poliomyelitis. Virol J. 2007;4:70.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Ritchie W, Russell B. Paralytic poliomyelitis. Med J. 1949;1:465–71.

    Article  Google Scholar 

  65. Schaefer J, Shaw EB. Poliomyelitis in pregnancy. Calif Med. 1949;70(1):16–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Poliomyelitis (polio). Available from: https://www.who.int/health-topics/poliomyelitis.

  67. GPEI – Global Polio Eradication Initiative. Available from: https://polioeradication.org/.

  68. Vogelsang TM. The occurrence of Bamble Disease (epidemic pleurodynia) in Norway. Med Hist. 1967;11(1):86–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leendertse M, van Vugt M, Benschop KS, van Dijk K, Minnaar RP, van Eijk HW, et al. Pleurodynia caused by an echovirus 1 brought back from the tropics. J Clin Virol. 2013;58(2):490–3.

    Article  PubMed  Google Scholar 

  70. Jacobson LM, Redd JT, Schneider E, Lu X, Chern SW, Oberste MS, et al. Outbreak of lower respiratory tract illness associated with human enterovirus 68 among American Indian children. Pediatr Infect Dis J. 2012;31(3):309–12.

    Article  PubMed  Google Scholar 

  71. Rotbart HA. Enteroviral infections of the central nervous system. Clin Infect Dis. 1995;20(4):971–81.

    Article  CAS  PubMed  Google Scholar 

  72. Lee BE, Davies HD. Aseptic meningitis. Curr Opin Infect Dis. 2007;20(3):272–7.

    Article  PubMed  Google Scholar 

  73. Cui A, Yu D, Zhu Z, Meng L, Li H, Liu J, et al. An outbreak of aseptic meningitis caused by coxsackievirus A9 in Gansu, the People’s Republic of China. Virol J. 2010;7:72.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Irani DN. Aseptic meningitis and viral myelitis. Neurol Clin. 2008;26(3):635–55.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Fowlkes AL, Honarmand S, Glaser C, Yagi S, Schnurr D, Oberste MS, et al. Enterovirus-associated encephalitis in the California encephalitis project, 1998-2005. J Infect Dis. 2008;198(11):1685–91.

    Article  PubMed  Google Scholar 

  76. Zhang L, Yan J, Ojcius DM, Lv H, Miao Z, Chen Y, et al. Novel and predominant pathogen responsible for the enterovirus-associated encephalitis in eastern China. PLoS One. 2013;8(12):e85023.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 1999;341(13):936–42.

    Article  CAS  PubMed  Google Scholar 

  78. Zuckerman MA, Sheaff M, Martin JE, Gabriel CM. Fatal case of echovirus type 9 encephalitis. J Clin Pathol. 1993;46(9):865–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti-Infect Ther. 2009;7(6):735–42.

    Article  PubMed  Google Scholar 

  80. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 1974;129(3):304–9.

    Article  CAS  PubMed  Google Scholar 

  81. Bible JM, Pantelidis P, Chan PK, Tong CY. Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol. 2007;17(6):371–9.

    Article  CAS  PubMed  Google Scholar 

  82. Modlin JF. Enterovirus deja vu. N Engl J Med. 2007;356(12):1204–5.

    Article  CAS  PubMed  Google Scholar 

  83. Qiu J. Enterovirus 71 infection: a new threat to global public health? Lancet Neurol. 2008;7(10):868–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Qiu J. Viral outbreak in China tests government efforts. Nature. 2009;458(7238):554–5.

    Article  CAS  PubMed  Google Scholar 

  85. Bouchard MJ, Lam DH, Racaniello VR. Determinants of attenuation and temperature sensitivity in the type 1 poliovirus Sabin vaccine. J Virol. 1995;69(8):4972–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cameron-Wilson CL, Pandolfino YA, Zhang HY, Pozzeto B, Archard LC. Nucleotide sequence of an attenuated mutant of coxsackievirus B3 compared with the cardiovirulent wildtype: assessment of candidate mutations by analysis of a revertant to cardiovirulence. Clin Diagn Virol. 1998;9(2-3):99–105.

    Article  CAS  PubMed  Google Scholar 

  87. Halim S, Ramsingh AI. A point mutation in VP1 of coxsackievirus B4 alters antigenicity. Virology. 2000;269(1):86–94.

    Article  CAS  PubMed  Google Scholar 

  88. Brown BA, Oberste MS, Alexander JP Jr, Kennett ML, Pallansch MA. Molecular epidemiology and evolution of enterovirus 71 strains isolated from 1970 to 1998. J Virol. 1999;73(12):9969–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McMinn P, Lindsay K, Perera D, Chan HM, Chan KP, Cardosa MJ. Phylogenetic analysis of enterovirus 71 strains isolated during linked epidemics in Malaysia, Singapore, and Western Australia. J Virol. 2001;75(16):7732–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cardosa MJ, Perera D, Brown BA, Cheon D, Chan HM, Chan KP, et al. 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. 2003;9(4):461–8.

    Article  PubMed  Google Scholar 

  91. Shimizu H, Utama A, Onnimala N, Li C, Li-Bi Z, Yu-Jie M, et al. Molecular epidemiology of enterovirus 71 infection in the Western Pacific Region. Pediatr Int. 2004;46(2):231–5.

    Article  PubMed  Google Scholar 

  92. Mizuta K, Abiko C, Murata T, Matsuzaki Y, Itagaki T, Sanjoh K, et al. Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003. J Clin Microbiol. 2005;43(12):6171–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Van Tu P, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC, et al. Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis. 2007;13(11):1733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. van der Sanden S, Koopmans M, Uslu G, van der Avoort H, Dutch Working Group for Clinical V. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol. 2009;47(9):2826–33.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Bible JM, Iturriza-Gomara M, Megson B, Brown D, Pantelidis P, Earl P, et al. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J Clin Microbiol. 2008;46(10):3192–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Diedrich S, Weinbrecht A, Schreier E. Seroprevalence and molecular epidemiology of enterovirus 71 in Germany. Arch Virol. 2009;154(7):1139–42.

    Article  CAS  PubMed  Google Scholar 

  97. Schuffenecker I, Mirand A, Antona D, Henquell C, Chomel JJ, Archimbaud C, et al. Epidemiology of human enterovirus 71 infections in France, 2000-2009. J Clin Virol. 2011;50(1):50–6.

    Article  PubMed  Google Scholar 

  98. Iwai M, Masaki A, Hasegawa S, Obara M, Horimoto E, Nakamura K, et al. Genetic changes of coxsackievirus A16 and enterovirus 71 isolated from hand, foot, and mouth disease patients in Toyama, Japan between 1981 and 2007. Jpn J Infect Dis. 2009;62(4):254–9.

    Article  CAS  PubMed  Google Scholar 

  99. Herrero LJ, Lee CS, Hurrelbrink RJ, Chua BH, Chua KB, McMinn PC. Molecular epidemiology of enterovirus 71 in peninsular Malaysia, 1997-2000. Arch Virol. 2003;148(7):1369–85.

    Article  CAS  PubMed  Google Scholar 

  100. Lin TY, Twu SJ, Ho MS, Chang LY, Lee CY. Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg Infect Dis. 2003;9(3):291–3.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Ap M, Rais F, Abdullah MA, Zamri LA, Ali HM, Kassim FM, et al. Molecular epidemiology of human enterovirus71 (HEV71) strains isolated in Peninsular Malaysia and Sabah from year 2001 to 2009. J Gen Mol Virol. 2011;3(1):18–26.

    Google Scholar 

  102. Wu TN, Tsai SF, Li SF, Lee TF, Huang TM, Wang ML, et al. Sentinel surveillance for enterovirus 71, Taiwan, 1998. Emerg Infect Dis. 1999;5(3):458–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang Y, Tan XJ, Wang HY, Yan DM, Zhu SL, Wang DY, et al. An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. J Clin Virol. 2009;44(4):262–7.

    Article  PubMed  Google Scholar 

  104. Zhang Y, Zhu Z, Yang W, Ren J, Tan X, Wang Y, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J. 2010;7:94.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Tee KK, Lam TT, Chan YF, Bible JM, Kamarulzaman A, Tong CY, et al. Evolutionary genetics of human enterovirus 71: origin, population dynamics, natural selection, and seasonal periodicity of the VP1 gene. J Virol. 2010;84(7):3339–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Komatsu H, Shimizu Y, Takeuchi Y, Ishiko H, Takada H. Outbreak of severe neurologic involvement associated with Enterovirus 71 infection. Pediatr Neurol. 1999;20(1):17–23.

    Article  CAS  PubMed  Google Scholar 

  107. Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, et al. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis. 1999;29(1):184–90.

    Article  CAS  PubMed  Google Scholar 

  108. Hagiwara A, Tagaya I, Yoneyama T. Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. Intervirology. 1978;9(1):60–3.

    Article  CAS  PubMed  Google Scholar 

  109. Gromeier M, Wimmer E, Gorbalenya AE. Genetics, pathogenesis and evolution of picornaviruses. In: Origin and evolution of viruses. Amsterdam: Elsevier; 1999. p. 287–343.

    Chapter  Google Scholar 

  110. Shimizu H, Utama A, Yoshii K, Yoshida H, Yoneyama T, Sinniah M, et al. Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997-1998. Jpn J Infect Dis. 1999;52(1):12–5.

    Article  CAS  PubMed  Google Scholar 

  111. Tagaya I, Tachibana K. Epidemic of hand, foot and mouth disease in Japan, 1972-1973: difference in epidemiologic and virologic features from the previous one. Jpn J Med Sci Biol. 1975;28(4):231–4.

    Article  CAS  PubMed  Google Scholar 

  112. Poyry T, Hyypia T, Horsnell C, Kinnunen L, Hovi T, Stanway G. Molecular analysis of coxsackievirus A16 reveals a new genetic group of enteroviruses. Virology. 1994;202(2):982–7.

    Article  CAS  PubMed  Google Scholar 

  113. Hogle JM, Chow M, Filman DJ. Three-dimensional structure of poliovirus at 2.9 A resolution. Science. 1985;229(4720):1358–65.

    Article  CAS  PubMed  Google Scholar 

  114. Aswathyraj S, Arunkumar G, Alidjinou EK, Hober D. Hand, foot and mouth disease (HFMD): emerging epidemiology and the need for a vaccine strategy. Med Microbiol Immunol. 2016;205(5):397–407.

    Article  CAS  PubMed  Google Scholar 

  115. Sickles GM, Mutterer M, Feorino P, Plager H. Recently classified types of Coxsackie virus, group A; behavior in tissue culture. Proc Soc Exp Biol Med. 1955;90(2):529–31.

    Article  CAS  PubMed  Google Scholar 

  116. Ferson MJ, Bell SM. Outbreak of Coxsackievirus A16 hand, foot, and mouth disease in a child day-care center. Am J Public Health. 1991;81(12):1675–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bendig JW, Fleming DM. Epidemiological, virological, and clinical features of an epidemic of hand, foot, and mouth disease in England and Wales. Commun Dis Rep CDR Rev. 1996;6(6):R81–6.

    CAS  PubMed  Google Scholar 

  118. Chang LY. Enterovirus 71 in Taiwan. Pediatr Neonatol. 2008;49(4):103–12.

    Article  PubMed  Google Scholar 

  119. Ang LW, Koh BK, Chan KP, Chua LT, James L, Goh KT. Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. Ann Acad Med Singap. 2009;38(2):106–12.

    Article  PubMed  Google Scholar 

  120. Kar BR, Dwibedi B, Kar SK. An outbreak of hand, foot and mouth disease in Bhubaneswar, Odisha. Indian Pediatr. 2013;50(1):139–42.

    Article  PubMed  Google Scholar 

  121. Zhu J, Luo Z, Wang J, Xu Z, Chen H, Fan D, et al. Phylogenetic analysis of Enterovirus 71 circulating in Beijing, China from 2007 to 2009. PLoS One. 2013;8(2):e56318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zou XN, Zhang XZ, Wang B, Qiu YT. Etiologic and epidemiologic analysis of hand, foot, and mouth disease in Guangzhou city: a review of 4,753 cases. Braz J Infect Dis. 2012;16(5):457–65.

    Article  PubMed  Google Scholar 

  123. Mao Q, Wang Y, Yao X, Bian L, Wu X, Xu M, et al. Coxsackievirus A16: epidemiology, diagnosis, and vaccine. Hum Vaccin Immunother. 2014;10(2):360–7.

    Article  PubMed  Google Scholar 

  124. Sun T, Liu Y, Zhang Y, Zhou L. Molecular phylogeny of coxsackievirus A16. J Clin Microbiol. 2014;52(10):3829–30.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Fu X, Wan Z, Li Y, Hu Y, Jin X, Zhang C. National epidemiology and evolutionary history of four hand, foot and mouth disease-related enteroviruses in China from 2008 to 2016. Virol Sin. 2020;35(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  126. Chen X, Tan X, Li J, Jin Y, Gong L, Hong M, et al. Molecular epidemiology of coxsackievirus A16: intratype and prevalent intertype recombination identified. PLoS One. 2013;8(12):e82861.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina WM, et al. Comparative genetic analysis of VP4, VP1 and 3D gene regions of enterovirus 71 and coxsackievirus A16 circulating in Malaysia between 1997-2008. Trop Biomed. 2012;29(3):451–66.

    CAS  PubMed  Google Scholar 

  128. Noisumdaeng P, Korkusol A, Prasertsopon J, Sangsiriwut K, Chokephaibulkit K, Mungaomklang A, et al. Longitudinal study on enterovirus A71 and coxsackievirus A16 genotype/subgenotype replacements in hand, foot and mouth disease patients in Thailand, 2000-2017. Int J Infect Dis. 2019;80:84–91.

    Article  PubMed  Google Scholar 

  129. Zhao K, Han X, Wang G, Hu W, Zhang W, Yu XF. Circulating coxsackievirus A16 identified as recombinant type A human enterovirus, China. Emerg Infect Dis. 2011;17(8):1537–40.

    PubMed  PubMed Central  Google Scholar 

  130. Zhang Y, Wang D, Yan D, Zhu S, Liu J, Wang H, et al. Molecular evidence of persistent epidemic and evolution of subgenotype B1 coxsackievirus A16-associated hand, foot, and mouth disease in China. J Clin Microbiol. 2010;48(2):619–22.

    Article  CAS  PubMed  Google Scholar 

  131. Chen L, Yao XJ, Xu SJ, Yang H, Wu CL, Lu J, et al. Molecular surveillance of coxsackievirus A16 reveals the emergence of a new clade in mainland China. Arch Virol. 2019;164(3):867–74.

    Article  CAS  PubMed  Google Scholar 

  132. Zhang M, Zhao Y, Zhang H, Lin K, Liu H, Zhang J, et al. Molecular characterization of Coxsackievirus A16 strains isolated from children with severe hand, foot, and mouth disease in Yunnan, Southwest China, during 2009-2015. J Med Virol. 2019;91(1):155–60.

    Article  CAS  PubMed  Google Scholar 

  133. Sun Z, Zhang G, Guo P, Liu J, Gao Q, Xu X, et al. Epidemiological characterizations, pathogen spectrum and molecular characteristics of Coxsackievirus A16 from patients with HFMD in Yantai, Shandong, China between 2011 and 2015. Hum Vaccin Immunother. 2017;13(8):1831–8.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zhao G, Zhang X, Wang C, Wang G, Li F. Characterization of VP1 sequence of Coxsackievirus A16 isolates by Bayesian evolutionary method. Virol J. 2016;13:130.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Palani S, Nagarajan M, Biswas AK, Maile A, Paluru V. B1c genetic subtype of coxsackievirus A16 associated with hand, foot and mouth disease in Andaman Islands, India. Trans R Soc Trop Med Hyg. 2016;110(7):421–3.

    Article  PubMed  Google Scholar 

  136. Hassel C, Mirand A, Farkas A, Diedrich S, Huemer HP, Peigue-Lafeuille H, et al. Phylogeography of coxsackievirus A16 reveals global transmission pathways and recent emergence and spread of a recombinant genogroup. J Virol. 2017;91:18.

    Article  Google Scholar 

  137. Wang J, Teng Z, Chu W, Fang F, Cui X, Guo X, et al. The emergence and spread of one coxsackievirus A16 genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016. Emerg Microbes Infect. 2018;7(1):131.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Bentley K, Evans DJ. Mechanisms and consequences of positive-strand RNA virus recombination. J Gen Virol. 2018;99(10):1345–56.

    Article  CAS  PubMed  Google Scholar 

  139. Qiu J, Yan H, Cheng N, Lu X, Hu X, Liang L, et al. The clinical and epidemiological study of children with hand, foot, and mouth disease in Hunan, China from 2013 to 2017. Sci Rep. 2019;9(1):11662.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Koh WM, Bogich T, Siegel K, Jin J, Chong EY, Tan CY, et al. The epidemiology of hand, foot and mouth disease in Asia: a systematic review and analysis. Pediatr Infect Dis J. 2016;35(10):285–300.

    Article  Google Scholar 

  141. Yi L, Zeng H, Zheng H, Peng J, Guo X, Liu L, et al. Molecular surveillance of coxsackievirus A16 in southern China, 2008-2019. Arch Virol. 2021;166(6):1653–9.

    Article  CAS  PubMed  Google Scholar 

  142. Wright HT Jr, Landing BH, Lennette EH, Mc AR. Fatal infection in an infant associated with Coxsackie virus group A, type 16. N Engl J Med. 1963;268:1041–4.

    Article  PubMed  Google Scholar 

  143. Goldberg MF, Mc AA. Myocarditis possibly due to Coxsackie group A, type 16, virus. J Pediatr. 1963;62:762–5.

    Article  CAS  PubMed  Google Scholar 

  144. Wang CY, Li LF, Wu MH, Lee CY, Huang LM. Fatal coxsackievirus A16 infection. Pediatr Infect Dis J. 2004;23(3):275–6.

    Article  PubMed  Google Scholar 

  145. Legay F, Leveque N, Gacouin A, Tattevin P, Bouet J, Thomas R, et al. Fatal coxsackievirus A-16 pneumonitis in adult. Emerg Infect Dis. 2007;13(7):1084–6.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Goto K, Sanefuji M, Kusuhara K, Nishimura Y, Shimizu H, Kira R, et al. Rhombencephalitis and coxsackievirus A16. Emerg Infect Dis. 2009;15(10):1689–91.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Xu W, Liu CF, Yan L, Li JJ, Wang LJ, Qi Y, et al. Distribution of enteroviruses in hospitalized children with hand, foot and mouth disease and relationship between pathogens and nervous system complications. Virol J. 2012;9:8.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Cai K, Wang Y, Guo Z, Yu H, Li H, Zhang L, et al. Clinical characteristics and managements of severe hand, foot and mouth disease caused by enterovirus A71 and coxsackievirus A16 in Shanghai, China. BMC Infect Dis. 2019;19(1):285.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Zhu Z, Zhu S, Guo X, Wang J, Wang D, Yan D, et al. Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008. Virol J. 2010;7:300.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Li W, Yi L, Su J, Lu J, Zeng H, Guan D, et al. Seroepidemiology of human enterovirus71 and coxsackievirusA16 among children in Guangdong province, China. BMC Infect Dis. 2013;13:322.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Zhang HM, Li CR, Liu YJ, Liu WL, Fu D, Xu LM, et al. To investigate pathogen of hand, foot and mouth disease in Shenzhen in 2008. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2009;23(5):334–6.

    PubMed  Google Scholar 

  152. Pan H, Zhu YF, Qi X, Zhang YJ, Li L, Deng F, et al. Analysis on the epidemiological and genetic characteristics of enterovirus type 71 and Coxsackie A16 virus infection in Jiangsu, China. Zhonghua Liu Xing Bing Xue Za Zhi. 2009;30(4):339–43.

    CAS  PubMed  Google Scholar 

  153. Huang W, Zhou SF, Zhang F. Genetic analysis and etiology study of hand-foot-mouth disease in surveillance hospitals of Hunan Province during the period of 2008–2010. Practical Preventive Medicine 2011.

    Google Scholar 

  154. Jia L, Zhao CS, Zhang L, Li S, Zhang DT, Liu BW, et al. Comparisons of epidemiological and clinical characteristics in children with hand-foot-mouth disease caused by Enterovirus 71 and Coxsackievirus A16. Zhongguo Dang Dai Er Ke Za Zhi. 2011;13(8):635–7.

    PubMed  Google Scholar 

  155. Rong-Xia YE, Zhang YL, Pan KN, Tong YX. Significance of enterovirus 71 and coxsackievirus 16 pathogens detection in preventing epidemics of hand, foot and mouth disease. Chin J Nosocomiol. 2011.

    Google Scholar 

  156. Zhang W, Wang YG, Yang ZH, Pang BD, Zhang YL. Severe hand-foot-and-mouth disease caused by mixed infection of enterovirus 71 and coxsackie A16: reports of 6 cases. Chin General Pract. 2011;14:3341–33.

    Google Scholar 

  157. Yip CC, Lau SK, Zhou B, Zhang MX, Tsoi HW, Chan KH, et al. Emergence of enterovirus 71 “double-recombinant” strains belonging to a novel genotype D originating from southern China: first evidence for combination of intratypic and intertypic recombination events in EV71. Arch Virol. 2010;155(9):1413–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jarvis TC, Kirkegaard K. Poliovirus RNA recombination: mechanistic studies in the absence of selection. EMBO J. 1992;11(8):3135–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kirkegaard K, Baltimore D. The mechanism of RNA recombination in poliovirus. Cell. 1986;47(3):433–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lukashev AN, Lashkevich VA, Ivanova OE, Koroleva GA, Hinkkanen AE, Ilonen J. Recombination in circulating enteroviruses. J Virol. 2003;77(19):10423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Santti J, Harvala H, Kinnunen L, Hyypia T. Molecular epidemiology and evolution of coxsackievirus A9. J Gen Virol. 2000;81(Pt 5):1361–72.

    CAS  PubMed  Google Scholar 

  162. Huang SC, Hsu YW, Wang HC, Huang SW, Kiang D, Tsai HP, et al. Appearance of intratypic recombination of enterovirus 71 in Taiwan from 2002 to 2005. Virus Res. 2008;131(2):250–9.

    Article  CAS  PubMed  Google Scholar 

  163. Noisumdaeng P, Sangsiriwut K, Prasertsopon J, Klinmalai C, Payungporn S, Mungaomklang A, et al. Complete genome analysis demonstrates multiple introductions of enterovirus 71 and coxsackievirus A16 recombinant strains into Thailand during the past decade. Emerg Microbes Infect. 2018;7(1):214.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Abubakar S, Chee HY, Shafee N, Chua KB, Lam SK. Molecular detection of enteroviruses from an outbreak of hand, foot and mouth disease in Malaysia in 1997. Scand J Infect Dis. 1999;31(4):331–5.

    Article  CAS  PubMed  Google Scholar 

  165. Chua BH, McMinn PC, Lam SK, Chua KB. Comparison of the complete nucleotide sequences of echovirus 7 strain UMMC and the prototype (Wallace) strain demonstrates significant genetic drift over time. J Gen Virol. 2001;82(Pt 11):2629–39.

    Article  CAS  PubMed  Google Scholar 

  166. Hooi PS, Chua BH, Lee CS, Lam SK, Chua KB. Hand, foot and mouth disease: University Malaya Medical Centre experience. Med J Malaysia. 2002;57(1):88–91.

    CAS  PubMed  Google Scholar 

  167. Moreira RC, Castrignano SB, Carmona Rde C, Gomes FM, Saes SG, Oliveira RS, et al. An exanthematic disease epidemic associated with coxsackievirus B3 infection in a day care center. Rev Inst Med Trop Sao Paulo. 1995;37(3):235–8.

    Article  CAS  PubMed  Google Scholar 

  168. Russo DH, Luchs A, Machado BC, Carmona Rde C, Timenetsky MC. Echovirus 4 associated to hand, foot and mouth disease. Rev Inst Med Trop Sao Paulo. 2006;48(4):197–9.

    Article  PubMed  Google Scholar 

  169. Zhu Z, Xu WB, Xu AQ, Wang HY, Zhang Y, Song LZ, et al. Molecular epidemiological analysis of echovirus 19 isolated from an outbreak associated with hand, foot, and mouth disease (HFMD) in Shandong Province of China. Biomed Environ Sci. 2007;20(4):321–8.

    CAS  PubMed  Google Scholar 

  170. Grist NR, Bell EJ, Assaad F. Enteroviruses in human disease. Prog Med Virol. 1978;24:114–57.

    CAS  PubMed  Google Scholar 

  171. Yamashita T, Ito M, Taniguchi A, Sakae K. Prevalence of coxsackievirus A5, A6, and A10 in patients with herpangina in Aichi Prefecture, 2005. Jpn J Infect Dis. 2005;58(6):390–1.

    Article  PubMed  Google Scholar 

  172. Cabral LA, Almeida JD, de Oliveira ML, Meza AC. Hand, foot, and mouth disease: a case report. Quintessence Int. 1998;29(3):194–6.

    CAS  PubMed  Google Scholar 

  173. Kamahora T, Itagaki A, Hattori N, Tsuchie H, Kurimura T. Oligonucleotide fingerprint analysis of coxsackievirus A10 isolated in Japan. J Gen Virol. 1985;66(12):2627–34.

    Article  CAS  PubMed  Google Scholar 

  174. Blomqvist S, Klemola P, Kaijalainen S, Paananen A, Simonen ML, Vuorinen T, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  175. Mirand A, Henquell C, Archimbaud C, Ughetto S, Antona D, Bailly JL, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 and A10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18(5):E110–8.

    Article  CAS  PubMed  Google Scholar 

  176. Hubiche T, Schuffenecker I, Boralevi F, Leaute-Labreze C, Bornebusch L, Chiaverini C, et al. Dermatological spectrum of hand, foot and mouth disease from classical to generalized exanthema. Pediatr Infect Dis J. 2014;33(4):e92–8.

    Article  PubMed  Google Scholar 

  177. Cabrerizo M, Tarrago D, Munoz-Almagro C, Del Amo E, Dominguez-Gil M, Eiros JM, et al. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20(3):O150–6.

    Article  CAS  PubMed  Google Scholar 

  178. Lynch MD, Sears A, Cookson H, Lew T, Laftah Z, Orrin L, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40(5):525–8.

    Article  CAS  PubMed  Google Scholar 

  179. Montes M, Artieda J, Pineiro LD, Gastesi M, Diez-Nieves I, Cilla G. Hand, foot, and mouth disease outbreak and coxsackievirus A6, northern Spain, 2011. Emerg Infect Dis. 2013;19(4):676.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Sinclair C, Gaunt E, Simmonds P, Broomfield D, Nwafor N, Wellington L, et al. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Euro Surveill. 2014;19(12):20745.

    Article  CAS  PubMed  Google Scholar 

  181. Wei SH, Huang YP, Liu MC, Tsou TP, Lin HC, Lin TL, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Lu QB, Zhang XA, Wo Y, Xu HM, Li XJ, Wang XJ, et al. Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7(12):e52073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Fujimoto T, Iizuka S, Enomoto M, Abe K, Yamashita K, Hanaoka N, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18(2):337–9.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998-2005. Pediatrics. 2007;120(2):e244–52.

    Article  PubMed  Google Scholar 

  185. Puenpa J, Theamboonlers A, Korkong S, Linsuwanon P, Thongmee C, Chatproedprai S, et al. Molecular characterization and complete genome analysis of human enterovirus 71 and coxsackievirus A16 from children with hand, foot and mouth disease in Thailand during 2008-2011. Arch Virol. 2011;156(11):2007–13.

    Article  CAS  PubMed  Google Scholar 

  186. Ben-Chetrit E, Wiener-Well Y, Shulman LM, Cohen MJ, Elinav H, Sofer D, et al. Coxsackievirus A6-related hand foot and mouth disease: skin manifestations in a cluster of adult patients. J Clin Virol. 2014;59(3):201–3.

    Article  PubMed  Google Scholar 

  187. Di B, Zhang Y, Xie H, Li X, Chen C, Ding P, et al. Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guangzhou, 2010-2012. Virol J. 2014;11:157.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Gopalkrishna V, Patil PR, Patil GP, Chitambar SD. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61(3):420–5.

    Article  CAS  PubMed  Google Scholar 

  189. Han JF, Xu S, Zhang Y, Zhu SY, Wu DL, Yang XD, et al. Hand, foot, and mouth disease outbreak caused by coxsackievirus A6, China, 2013. J Infect. 2014;69(3):303–5.

    Article  PubMed  Google Scholar 

  190. Hongyan G, Chengjie M, Qiaozhi Y, Wenhao H, Juan L, Lin P, et al. Hand, foot and mouth disease caused by coxsackievirus A6, Beijing, 2013. Pediatr Infect Dis J. 2014;33(12):1302–3.

    Article  PubMed  Google Scholar 

  191. Lo SH, Huang YC, Huang CG, Tsao KC, Li WC, Hsieh YC, et al. Clinical and epidemiologic features of Coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44(4):252–7.

    Article  CAS  PubMed  Google Scholar 

  192. Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14(12):e1076–81.

    Article  PubMed  Google Scholar 

  193. Zeng H, Lu J, Zheng H, Yi L, Guo X, Liu L, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guangdong, China. Sci Rep. 2015;5:10550.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Zha J, Ma Z. Epidemiological and genetic analysis concerning the coxsackievirus A6 related endemic outbreak of hand-foot-mouth disease in Taizhou, China, during 2013. J Med Virol. 2015;87(12):2000–8.

    Article  CAS  PubMed  Google Scholar 

  195. 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.

    Article  PubMed  Google Scholar 

  196. Fonseca MC, Sarmiento L, Resik S, Martinez Y, Hung LH, Morier L, et al. Coxsackievirus A6 and enterovirus 71 causing hand, foot and mouth disease in Cuba, 2011-2013. Arch Virol. 2014;159(9):2451–5.

    Article  CAS  PubMed  Google Scholar 

  197. Hayman R, Shepherd M, Tarring C, Best E. Outbreak of variant hand-foot-and-mouth disease caused by coxsackievirus A6 in Auckland, New Zealand. J Paediatr Child Health. 2014;50(10):751–5.

    Article  PubMed  Google Scholar 

  198. Lott JP, Liu K, Landry ML, Nix WA, Oberste MS, Bolognia J, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69(5):736–41.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Mathes EF, Oza V, Frieden IJ, Cordoro KM, Yagi S, Howard R, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132(1):e149–57.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Yang Q, Ding J, Cao J, Huang Q, Hong C, Yang B. Epidemiological and etiological characteristics of hand, foot, and mouth disease in Wuhan, China from 2012 to 2013: outbreaks of coxsackieviruses A10. J Med Virol. 2015;87(6):954–60.

    Article  PubMed  Google Scholar 

  201. Bracho MA, Gonzalez-Candelas F, Valero A, Cordoba J, Salazar A. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17(12):2223–31.

    Article  PubMed  PubMed Central  Google Scholar 

  202. He YQ, Chen L, Xu WB, Yang H, Wang HZ, Zong WP, et al. Emergence, circulation, and spatiotemporal phylogenetic analysis of coxsackievirus a6- and coxsackievirus a10-associated hand, foot, and mouth disease infections from 2008 to 2012 in Shenzhen, China. J Clin Microbiol. 2013;51(11):3560–6.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Tian H, Zhang Y, Sun Q, Zhu S, Li X, Pan Z, et al. Prevalence of multiple enteroviruses associated with hand, foot, and mouth disease in Shijiazhuang City, Hebei province, China: outbreaks of coxsackieviruses a10 and b3. PLoS One. 2014;9(1):e84233.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Osterback R, Vuorinen T, Linna M, Susi P, Hyypia T, Waris M. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15(9):1485–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Davia JL, Bel PH, Ninet VZ, Bracho MA, Gonzalez-Candelas F, Salazar A, et al. Onychomadesis outbreak in Valencia, Spain associated with hand, foot, and mouth disease caused by enteroviruses. Pediatr Dermatol. 2011;28(1):1–5.

    Article  PubMed  Google Scholar 

  206. Pallansch MA. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In: Fields virology. Philadelphia: Lippincott Williams & Wilkins; 2001.

    Google Scholar 

  207. 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.

    Article  PubMed  Google Scholar 

  208. Nasri D, Bouslama L, Pillet S, Bourlet T, Aouni M, Pozzetto B. Basic rationale, current methods and future directions for molecular typing of human enterovirus. Expert Rev Mol Diagn. 2007;7(4):419–34.

    Article  CAS  PubMed  Google Scholar 

  209. Yu N, Guo M, He SJ, Pan YX, Chen XX, Ding XX, et al. Evaluation of human enterovirus 71 and coxsackievirus A16 specific immunoglobulin M antibodies for diagnosis of hand-foot-and-mouth disease. Virol J. 2012;9:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Xu F, He D, He S, Wu B, Guan L, Niu J, et al. Development of an IgM-capture ELISA for Coxsackievirus A16 infection. J Virol Methods. 2011;171(1):107–10.

    Article  CAS  PubMed  Google Scholar 

  211. de Crom SC, Obihara CC, van Loon AM, Argilagos-Alvarez AA, Peeters MF, van Furth AM, et al. Detection of enterovirus RNA in cerebrospinal fluid: comparison of two molecular assays. J Virol Methods. 2012;179(1):104–7.

    Article  PubMed  Google Scholar 

  212. Guney C, Ozkaya E, Yapar M, Gumus I, Kubar A, Doganci L. Laboratory diagnosis of enteroviral infections of the central nervous system by using a nested RT-polymerase chain reaction (PCR) assay. Diagn Microbiol Infect Dis. 2003;47(4):557–62.

    Article  CAS  PubMed  Google Scholar 

  213. Watkins-Riedel T, Woegerbauer M, Hollemann D, Hufnagl P. Rapid diagnosis of enterovirus infections by real-time PCR on the light cycler using the TaqMan format. Diagn Microbiol Infect Dis. 2002;42(2):99–105.

    Article  CAS  PubMed  Google Scholar 

  214. Perera D, Podin Y, Akin W, Tan CS, Cardosa MJ. Incorrect identification of recent Asian strains of Coxsackievirus A16 as human enterovirus 71: improved primers for the specific detection of human enterovirus 71 by RT PCR. BMC Infect Dis. 2004;4:11.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Chen TC, Chen GW, Hsiung CA, Yang JY, Shih SR, Lai YK, et al. Combining multiplex reverse transcription-PCR and a diagnostic microarray to detect and differentiate enterovirus 71 and coxsackievirus A16. J Clin Microbiol. 2006;44(6):2212–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Xiao XL, He YQ, Yu YG, Yang H, Chen G, Li HF, et al. Simultaneous detection of human enterovirus 71 and coxsackievirus A16 in clinical specimens by multiplex real-time PCR with an internal amplification control. Arch Virol. 2009;154(1):121–5.

    Article  CAS  PubMed  Google Scholar 

  217. Tan EL, Chow VT, Quak SH, Yeo WC, Poh CL. Development of multiplex real-time hybridization probe reverse transcriptase polymerase chain reaction for specific detection and differentiation of Enterovirus 71 and Coxsackievirus A16. Diagn Microbiol Infect Dis. 2008;61(3):294–301.

    Article  CAS  PubMed  Google Scholar 

  218. Thao NT, Ngoc NT, Tu PV, Thuy TT, Cardosa MJ, McMinn PC, et al. Development of a multiplex polymerase chain reaction assay for simultaneous identification of human enterovirus 71 and coxsackievirus A16. J Virol Methods. 2010;170(1-2):134–9.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Cello J, Strannegard O, Svennerholm B. A study of the cellular immune response to enteroviruses in humans: identification of cross-reactive T cell epitopes on the structural proteins of enteroviruses. J Gen Virol. 1996;77(9):2097–108.

    Article  CAS  PubMed  Google Scholar 

  220. Chung YC, Ho MS, Wu JC, Chen WJ, Huang JH, Chou ST, et al. Immunization with virus-like particles of enterovirus 71 elicits potent immune responses and protects mice against lethal challenge. Vaccine. 2008;26(15):1855–62.

    Article  CAS  PubMed  Google Scholar 

  221. Harkonen T, Paananen A, Lankinen H, Hovi T, Vaarala O, Roivainen M. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. J Med Virol. 2003;69(3):426–40.

    Article  CAS  PubMed  Google Scholar 

  222. Khong WX, Foo DG, Trasti SL, Tan EL, Alonso S. Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol. 2011;85(7):3067–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy. Acta Paediatr. 2002;91(6):632–5.

    Article  CAS  PubMed  Google Scholar 

  224. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis. 2003;36(3):269–74.

    Article  CAS  PubMed  Google Scholar 

  225. Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis. 2003;188(4):564–70.

    Article  CAS  PubMed  Google Scholar 

  226. Singh S, Chow VT, Phoon MC, Chan KP, Poh CL. Direct detection of enterovirus 71 (EV71) in clinical specimens from a hand, foot, and mouth disease outbreak in Singapore by reverse transcription-PCR with universal enterovirus and EV71-specific primers. J Clin Microbiol. 2002;40(8):2823–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Noisumdaeng P, Sangsiriwut K, Prasertsopon J, Klinmalai C, Payungporn S, Mungaomklang A, et al. Complete genome analysis demonstrates multiple introductions of enterovirus 71 and coxsackievirus A16 recombinant strains into Thailand during the past decade. Emerg Microbes Infect. 2018;7(1):214.

    Article  PubMed  PubMed Central  Google Scholar 

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Li, D. (2024). Etiology of HFMD. In: Xu, X., Che, Y., Li, Q. (eds) Molecular Biology of Hand-Foot-Mouth Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-99-9660-5_2

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