Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Enterovirus 71 infection and neurological complications

  • Lee, Kyung Yeon (Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine)
  • Received : 2015.08.15
  • Accepted : 2015.10.14
  • Published : 2016.10.15
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Abstract

Since the outbreak of the enterovirus 71 (EV71) infection in Malaysia in 1997, large epidemics of EV71 have occurred in the Asia-Pacific region. Many children and infants have died from serious neurological complications during these epidemics, and EV71 infection has become a serious public health problem in these areas. EV71 infection causes hand, foot and mouth disease (HFMD) in children, and usually resolves spontaneously. However, EV71 occasionally involves the central nervous system (CNS), and induces diverse neurological complications such as brainstem encephalitis, aseptic meningitis, and acute flaccid paralysis. Among those complications, brainstem encephalitis is the most critical neurological manifestation because it can cause neurogenic pulmonary hemorrhage/edema leading to death. The characteristic clinical symptoms such as myoclonus and ataxia, cerebrospinal fluid (CSF) pleocytosis, and brainstem lesions on magnetic resonance imaging, in conjunction with the skin rash of HFMD and the isolation of EV71 from a stool, throat-swab, or CSF sample are typical findings indicating CNS involvement of EV71 infection. Treatment with intravenous immunoglobulin and milrinone are recommended in cases with severe neurological complications from EV71 infection, such as brainstem encephalitis. Despite the recent discovery of receptors for EV71 in human cells, such as the scavenger receptor B2 and P-selection glycoprotein ligand 1, it is not known why EV71 infection predominantly involves the brainstem. Recently, 3 companies in China have completed phase III clinical trials of EV71 vaccines. However, the promotion and approval of these vaccines in various countries are problems yet to be resolved.

Keywords

References

  1. McMinn PC. The emergence of enterovirus 71 as a major cause of acute neurological disease in young children of the Asia-Pacific region. J Pediatr Infect Dis 2006;l:17-23.
  2. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol 2010;9:1097-105. https://doi.org/10.1016/S1474-4422(10)70209-X
  3. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 1974;129:304-9. https://doi.org/10.1093/infdis/129.3.304
  4. 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;60:329-40. https://doi.org/10.1007/BF01317504
  5. 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;71:217-27. https://doi.org/10.1007/BF01314873
  6. 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;31:678-83. https://doi.org/10.1086/314032
  7. Shih SR, Ho MS, Lin KH, Wu SL, Chen YT, Wu CN, et al. Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. Virus Res 2000;68:127-36. https://doi.org/10.1016/S0168-1702(00)00162-3
  8. 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;341:929-35. https://doi.org/10.1056/NEJM199909233411301
  9. cMinn 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;32:236-42. https://doi.org/10.1086/318454
  10. Zeng M, El Khatib NF, Tu S, Ren P, Xu S, Zhu Q, et al. Seroepidemiology of Enterovirus 71 infection prior to the 2011 season in children in Shanghai. J Clin Virol 2012;53:285-9. https://doi.org/10.1016/j.jcv.2011.12.025
  11. Yip CC, Lau SK, Woo PC, Yuen KY. Human enterovirus 71 epidemics: what's next? Emerg Health Threats J 2013;6:19780. https://doi.org/10.3402/ehtj.v6i0.19780
  12. 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:e1076-81. https://doi.org/10.1016/j.ijid.2010.07.006
  13. Thoa le PK, Chiang PS, Khanh TH, Luo ST, Dan TN, Wang YF, et al. Genetic and antigenic characterization of enterovirus 71 in Ho Chi Minh City, Vietnam, 2011. PLoS One 2013;8:e69895. https://doi.org/10.1371/journal.pone.0069895
  14. Seiff A. Cambodia unravels cause of mystery illness. Lancet 2012;380:206. https://doi.org/10.1016/S0140-6736(12)61201-X
  15. 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;198:1685-91. https://doi.org/10.1086/592988
  16. van der Sanden S, Koopmans M, Uslu G, van der Avoort H; Dutch Working Group for Clinical Virology. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol 2009;47: 2826-33. https://doi.org/10.1128/JCM.00507-09
  17. Mirand A, Schuffenecker I, Henquell C, Billaud G, Jugie G, Falcon D, et al. Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries. J Gen Virol 2010;91(Pt 9):2263-77. https://doi.org/10.1099/vir.0.021741-0
  18. Witso E, Palacios G, Ronningen KS, Cinek O, Janowitz D, Rewers M, et al. Asymptomatic circulation of HEV71 in Norway. Virus Res 2007;123:19-29. https://doi.org/10.1016/j.virusres.2006.07.015
  19. 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: 3192-200. https://doi.org/10.1128/JCM.00628-08
  20. Kapusinszky B, Szomor KN, Farkas A, Takacs M, Berencsi G. Detection of non-polio enteroviruses in Hungary 2000-2008 and molecular epidemiology of enterovirus 71, coxsackievirus A16, and echovirus 30. Virus Genes 2010;40:163-73. https://doi.org/10.1007/s11262-009-0440-4
  21. Siafakas N, Attilakos A, Vourli S, Stefos E, Meletiadis J, Nikolaidou P, et al. Molecular detection and identification of enteroviruses in children admitted to a university hospital in Greece. Mol Cell Probes 2011;25:249-54. https://doi.org/10.1016/j.mcp.2011.06.001
  22. Ryu WS, Kang B, Hong J, Hwang S, Kim J, Cheon DS. Clinical and etiological characteristics of enterovirus 71-related diseases during a recent 2-year period in Korea. J Clin Microbiol 2010;48:2490-4. https://doi.org/10.1128/JCM.02369-09
  23. Choi CS, Choi YJ, Choi UY, Han JW, Jeong DC, Kim HH, et al. Clinical manifestations of CNS infections caused by enterovirus type 71. Korean J Pediatr 2011;54:11-6. https://doi.org/10.3345/kjp.2011.54.1.11
  24. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther 2009;7:735-42. https://doi.org/10.1586/eri.09.45
  25. Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, et al. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 1999;354:1682-6. https://doi.org/10.1016/S0140-6736(99)04434-7
  26. Chang LY, Hsia SH, Wu CT, Huang YC, Lin KL, Fang TY, et al. Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002. Pediatr Infect Dis J 2004;23:327-32. https://doi.org/10.1097/00006454-200404000-00010
  27. Chong P, Liu CC, Chow YH, Chou AH, Klein M. Review of enterovirus 71 vaccines. Clin Infect Dis 2015;60:797-803. https://doi.org/10.1093/cid/ciu852
  28. 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:e244-52. https://doi.org/10.1542/peds.2006-3331
  29. 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;29:184-90. https://doi.org/10.1086/520149
  30. Hu Y, Jiang L, Peng HL. Clinical analysis of 134 children with nervous system damage caused by enterovirus 71 infection. Pediatr Infect Dis J 2015;34:718-23. https://doi.org/10.1097/INF.0000000000000711
  31. Lee KY, Lee YJ, Kim TH, Cheon DS, Nam SO. Clinico-radiological spectrum in enterovirus 71 infection involving the central nervous system in children. J Clin Neurosci 2014;21:416-20. https://doi.org/10.1016/j.jocn.2013.04.032
  32. Wang SM, Liu CC. Update of enterovirus 71 infection: epidemiology, pathogenesis and vaccine. Expert Rev Anti Infect Ther 2014; 12:447-56. https://doi.org/10.1586/14787210.2014.895666
  33. Chang LY, Tsao KC, Hsia SH, Shih SR, Huang CG, Chan WK, et al. Transmission and clinical features of enterovirus 71 infections in household contacts in Taiwan. JAMA 2004;291:222-7. https://doi.org/10.1001/jama.291.2.222
  34. Lee MS, Chang LY. Development of enterovirus 71 vaccines. Expert Rev Vaccines 2010;9:149-56. https://doi.org/10.1586/erv.09.152
  35. Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 2009;15:798-801. https://doi.org/10.1038/nm.1992
  36. Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 2009;15:794-7. https://doi.org/10.1038/nm.1961
  37. Lin TY, Chang LY, Hsia SH, Huang YC, Chiu CH, Hsueh C, et al. The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis 2002;34 Suppl 2:S52-7. https://doi.org/10.1086/338819
  38. Huang MC, Wang SM, Hsu YW, Lin HC, Chi CY, Liu CC. Long-term cognitive and motor deficits after enterovirus 71 brainstem encephalitis in children. Pediatrics 2006;118:e1785-8. https://doi.org/10.1542/peds.2006-1547
  39. Lee KY, Yeh HR. Continuous myocloni and tonic spasms in a 2-month-old infant with enterovirus 71 brain stem encephalitis. Neuropediatrics 2015;46:52-5.
  40. Cho HK, Lee NY, Lee H, Kim HS, Seo JW, Hong YM, et al. Enterovirus 71-associated hand, foot and mouth diseases with neurologic symptoms, a university hospital experience in Korea, 2009. Korean J Pediatr 2010;53:639-43. https://doi.org/10.3345/kjp.2010.53.5.639
  41. Shen WC, Chiu HH, Chow KC, Tsai CH. MR imaging findings of enteroviral encephaloymelitis: an outbreak in Taiwan. AJNR Am J Neuroradiol 1999;20:1889-95.
  42. Jang S, Suh SI, Ha SM, Byeon JH, Eun BL, Lee YH, et al. Enterovirus 71-related encephalomyelitis: usual and unusual magnetic resonance imaging findings. Neuroradiology 2012;54:239-45. https://doi.org/10.1007/s00234-011-0921-8
  43. Li J, Chen F, Liu T, Wang L. MRI findings of neurological complications in hand-foot-mouth disease by enterovirus 71 infection. Int J Neurosci 2012;122:338-44. https://doi.org/10.3109/00207454.2012.657379
  44. Zeng H, Wen F, Gan Y, Huang W. MRI and associated clinical characteristics of EV71-induced brainstem encephalitis in children with hand-foot-mouth disease. Neuroradiology 2012;54:623-30. https://doi.org/10.1007/s00234-011-0979-3
  45. Lian ZY, Huang B, He SR, Liang CH, Guo YX. Diffusion-weighted imaging in the diagnosis of enterovirus 71 encephalitis. Acta Radiol 2012;53:208-13. https://doi.org/10.1258/ar.2011.110407
  46. 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;91:632-5. https://doi.org/10.1111/j.1651-2227.2002.tb03292.x
  47. 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;36:269-74. https://doi.org/10.1086/345905
  48. Wang SM, Lei HY, Su LY, Wu JM, Yu CK, Wang JR, et al. Cerebrospinal fluid cytokines in enterovirus 71 brain stem encephalitis and echovirus meningitis infections of varying severity. Clin Microbiol Infect 2007;13:677-82. https://doi.org/10.1111/j.1469-0691.2007.01729.x
  49. Yamayoshi S, Fujii K, Koike S. Receptors for enterovirus 71. Emerg Microbes Infect 2014;3:e53. https://doi.org/10.1038/emi.2014.49
  50. Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 2004;85(Pt 1):69-77. https://doi.org/10.1099/vir.0.19423-0
  51. Chung PW, Huang YC, Chang LY, Lin TY, Ning HC. Duration of enterovirus shedding in stool. J Microbiol Immunol Infect 2001; 34:167-70.
  52. Kung YA, Hung CT, Liu YC, Shih SR. Update on the development of enterovirus 71 vaccines. Expert Opin Biol Ther 2014;14:1455-64. https://doi.org/10.1517/14712598.2014.935330
  53. Shipley JB, Tolman D, Hastillo A, Hess ML. Milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci 1996;311:286-91. https://doi.org/10.1016/S0002-9629(15)41723-9
  54. Gong M, Lin XZ, Lu GT, Zheng LJ. Preoperative inhalation of milrinone attenuates inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass. Med Princ Pract 2012;21: 30-5. https://doi.org/10.1159/000332411
  55. Chi CY, Khanh TH, Thoa le PK, Tseng FC, Wang SM, Thinh le Q, et al. Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med 2013;41:1754-60. https://doi.org/10.1097/CCM.0b013e31828a2a85
  56. Wang SM, Lei HY, Huang MC, Wu JM, Chen CT, Wang JN, et al. Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol 2005;39: 219-23. https://doi.org/10.1002/ppul.20157
  57. Chang LY, Huang LM, Gau SS, Wu YY, Hsia SH, Fan TY, et al. Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med 2007;356:1226-34. https://doi.org/10.1056/NEJMoa065954
  58. Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2013;381: 2024-32. https://doi.org/10.1016/S0140-6736(13)61049-1
  59. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014; 370:829-37. https://doi.org/10.1056/NEJMoa1303224
  60. Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med 2014;370:818-28. https://doi.org/10.1056/NEJMoa1304923

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