NEUROLOGICAL COMPLICATIONS OF HAND, FOOT AND MOUTH DISEASE IN CHILDREN: A REVIEW

Authors

  • Jahan Shah Nanjing Medical University
  • Liu Sijun Nanjing Medical University
  • Zhao Hui Nanjing Medical University
  • Falak Zeb Nanjing Medical University
  • Ijaz UL Haq Nanjing Medical University
  • Amin Ullah Nanjing Medical University

Abstract

Background: Hand-Foot-and-Mouth disease (HFMD) is a viral illness commonly seen in young children, characterized by fever, vomiting, ulcerative lesions in oral mucosa, and vesicles on hands and feet. The early symptoms resolve but sometimes, it leads to more harsh neurological complications and even death. Therefore, the objective of this review was set to provide an overview of the symptoms, pathogenic agents, and treatment of neurological complications associated with HFMD. Methods: We reviewed literature from PubMed and Science Direct covering at least one of our objectives from inception to 4th March 2018. Result: This review represents 6 countries including China, Vietnam, Cambodia, South Korea, Taiwan, and Australia. Fifteen studies with a total of 1043 patients were included. The majority of HFMD cases with neurological complications were reported in China, predominance in boys as compared to girls, with 97% cases under 15 years of age. Meningoencephalitis and brainstem encephalitis contributed 70% of all neurological complications related to HFMD. Human Enterovirus71 genotype C, especially C4a was a causative agent associated with severe complications. Among symptoms, fever, vomiting, myoclonic jerks or seizure, headache, convulsion, and rashes were reported in almost all neurological complications. The common and supportive treatments were the administration of intravenous immunoglobulin and glucocorticoid therapies. Conclusion: Early detection and appropriate treatment of severe neurological complications can minimize the risk of adverse health outcomes. Evidence based clinical practice guidelines for early detection and treatment would be significant in the management of these devastating neurological complications.Keywords: Hand-foot-and-mouth-disease; Neurological complications; Central Nervous system disease, Aetiology; Clinical features

Author Biographies

Jahan Shah, Nanjing Medical University

Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R. China

Liu Sijun, Nanjing Medical University

Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R. China

Zhao Hui, Nanjing Medical University

Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R. China

Falak Zeb, Nanjing Medical University

Department of Food science and Nutrition, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R.China

Ijaz UL Haq, Nanjing Medical University

Department of Food science and Nutrition, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R.China

Amin Ullah, Nanjing Medical University

Department of toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu Province, P.R.China

References

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.

Chen Y, Badaruddin H, Lee VJ, Cutter J, Cook AR. The Effect of School Closure on Hand, Foot, and Mouth Disease Transmission in Singapore: A Modeling Approach. Am J Trop Med Hyg 2018;99(6):1625–32.

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.

Cao F, Huang P. Epidemiological characteristics and temporal-spatial clustering analysis of hand, foot and mouth disease in Nanchang city 2008-2012. Infect Dis (Lond) 2015;47(1):33–8.

WHO. A guide to clinical management and public health response for hand, foot and mouth disease (HFMD): Manila: WHO Regional Office for the Western Pacific.; 2011.

Chang LY, Hsiung CA, Lu CY, Lin TY, Huang FY, Lai YH, et al. Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71. Pediatr Res 2006;60(4):466–71.

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.

Fang Y, Wang S, Zhang L, Guo Z, Huang Z, Tu C, et al. Risk factors of severe hand, foot and mouth disease: a meta-analysis. Scand J Infect Dis 2014;46(7):515–22.

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(9882):2024–32.

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(9):829–37.

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(9):818–28.

Li JX, Mao QY, Liang ZL, Ji H, Zhu FC. Development of enterovirus 71 vaccines: from the lab bench to Phase III clinical trials. Expert Rev Vaccines 2014;13(5):609–18.

Mao Q, Cheng T, Zhu F, Li J, Wang Y, Li Y, et al. The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy chinese infants and children. PloS One 2013;8(11):e79599.

Sun S, Jiang L, Liang Z, Mao Q, Su W, Zhang H, et al. Evaluation of monovalent and bivalent vaccines against lethal Enterovirus 71 and Coxsackievirus A16 infection in newborn mice. Hum Vaccin Immunother 2014;10(10):2885–95.

Cai Y, Ku Z, Liu Q, Leng Q, Huang Z. A combination vaccine comprising of inactivated enterovirus 71 and coxsackievirus A16 elicits balanced protective immunity against both viruses. Vaccine 2014;32(21):2406–12.

Caine EA, Fuchs J, Das SC, Partidos CD, Osorio JE. Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice. Viruses 2015;7(11):5919–32.

Zhang C, Liu Q, Ku Z, Hu Y, Ye X, Zhang Y, et al. Coxsackievirus A16-like particles produced in Pichia pastoris elicit high-titer neutralizing antibodies and confer protection against lethal viral challenge in mice. Antiviral Res 2016;129:47–51.

Esposito S, Principi N. Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention. Eur J Clin Microbiol Infect Dis 2018;37(3):391–8.

!!! INVALID CITATION !!!

Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol 2000;17(1):23–30.

Wang JR, Tsai HP, Chen PF, Lai YJ, Yan JJ, Kiang D, et al. An outbreak of enterovirus 71 infection in Taiwan, 1998. II. Laboratory diagnosis and genetic analysis. J Clin Virol 2000;17(2):91–9.

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.

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.

Rahimi P, Roohandeh A, Sohrabi A, Mostafavi E, Bahram Ali G. Impact of Human Enterovirus 71 Genotypes in Meningoencephalitis in Iran. Jundishapur J Microbiol 2015;8(12):e27113.

Liu SL, Pan H, Liu P, Amer S, Chan TC, Zhan J, et al. Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. Rev Med Virol 2015;25(2):115–28.

Gao LD, Hu SX, Zhang H, Luo KW, Liu YZ, Xu QH, et al. Correlation analysis of EV71 detection and case severity in hand, foot, and mouth disease in the Hunan Province of China. PloS One 2014;9(6):e100003.

Yang T, Xu G, Dong H, Ye M, He T. A case-control study of risk factors for severe hand-foot-mouth disease among children in Ningbo, China, 2010-2011. Eur J Pediatr 2012;171(9):1359–64.

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.

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.

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

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(9191):1682–6.

Liu XJ, Li W, Zhang YQ, Liu YM, Liu LZ. [Clinical features and treatment of serious brainstem encephalitis caused by enterovirus 71 infection]. Zhongguo Dang Dai Er Ke Za Zhi 2009;11(12):967–9.

Xing J, Liu D, Shen S, Su Z, Zhang L, Duan Y, et al. Pathologic Studies of Fatal Encephalomyelitis in Children Caused by Enterovirus 71. Am J Clin Pathol 2016;146(1):95–106.

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(12):1226–34.

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.

McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 2002;26(1):91–107.

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(3):219–23.

Tsai JD, Kuo HT, Chen SM, Lue KH, Sheu JN. Neurological images and the predictors for neurological sequelae of epidemic herpangina/hand-foot-mouth disease with encephalomyelitis. Neuropediatrics 2014;45(2):102–8.

Chen F, Li JJ, Liu T, Wen GQ, Xiang W. Clinical and neuroimaging features of enterovirus71 related acute flaccid paralysis in patients with hand-foot-mouth disease. Asian Pac J Trop Med 2013;6(1):68–72.

Kincaid O, Lipton HL. Viral myelitis: an update. Curr Neurol Neurosci Rep 2006;6(6):469–74.

Nolan MA, Craig ME, Lahra MM, Rawlinson WD, Prager PC, Williams GD, et al. Survival after pulmonary edema due to enterovirus 71 encephalitis. Neurology 2003;60(10):1651–6.

Wolf VL, Lupo PJ, Lotze TE. Pediatric acute transverse myelitis overview and differential diagnosis. J Child Neurol 2012;27(11):1426–36.

Tian H, Yang QZ, Liang J, Dong SY, Liu ZJ, Wang LX. Clinical features and management outcomes of severe hand, foot and mouth disease. Med Princ Pract 2012;21(4):355–9.

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(7):718–23.

Published

2020-10-04

Issue

Vol. 32 No. 4 (2020): JOURNAL OF AYUB MEDICAL COLLEGE, ABBOTTABAD

Section

REVIEW ARTICLE

License

Journal of Ayub Medical College, Abbottabad is an OPEN ACCESS JOURNAL which means that all content is FREELY available without charge to all users whether registered with the journal or not. The work published by J Ayub Med Coll Abbottabad is licensed and distributed under the creative commons License  CC BY ND Attribution-NoDerivs. Material printed in this journal is OPEN to access, and are FREE for use in academic and research work with proper citation. J Ayub Med Coll Abbottabad accepts only original material for publication with the understanding that except for abstracts, no part of the data has been published or will be submitted for publication elsewhere before appearing in J Ayub Med Coll Abbottabad. The Editorial Board of J Ayub Med Coll Abbottabad makes every effort to ensure the accuracy and authenticity of material printed in J Ayub Med Coll Abbottabad. However, conclusions and statements expressed are views of the authors and do not reflect the opinion/policy of J Ayub Med Coll Abbottabad or the Editorial Board.

USERS are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This is in accordance with the BOAI definition of open access.

AUTHORS retain the rights of free downloading/unlimited e-print of full text and sharing/disseminating the article without any restriction, by any means including twitter, scholarly collaboration networks such as ResearchGate, Academia.eu, and social media sites such as Twitter, LinkedIn, Google Scholar and any other professional or academic networking site.