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Breastfeeding, previous Epstein-Barr virus infection, Enterovirus 71 infection, and rural residence are associated with the severity of hand, foot, and mouth disease

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Abstract

Severe hand, foot, and mouth disease (HFMD) is likely to develop critical complications such as brainstem encephalitis, acute pulmonary edema, and circulatory failure, which cause child mortality during outbreaks. This study aims to investigate factors that predict the severity of HFMD. One hundred sixteen in-patient children with severe HFMD and 202 with mild HFMD were retrospectively enrolled. Potential factors were collected for each child including sex, age, residence, modes of delivery, birth weight, virus types causing HFMD, and virus exposure history. Univariate and multivariable logistic regression were used to determine which factors were associated with HFMD severity. In the univariate analysis, breastfeeding (OR 0.514, 95 % CI 0.309–0.856), rural residence (OR 1.971, 95 % CI 1.239–3.137), current Enterovirus 71 (EV71) infection (OR 2.539, 95 % CI 1.504–4.287), and previous Epstein-Barr virus (EBV) exposure (OR 3.136, 95 % CI 1.863–5.278) were each associated with the severity of HFMD. In the multivariate model, breastfeeding (OR 0.570, 95 % CI 0.332–0.980), rural residence (OR 1.973, 95 % CI 1.202–3.237), current EV71 infection (OR 2.290, 95 % CI 1.315–3.987), and previous EBV exposure (OR 2.550, 95 % CI 1.470–4.422) remained independently associated with the severity of HFMD. In conclusion, previous EBV exposure, EV71 infection, and rural residence are risk factors for severe HFMD; breastfeeding is a protective factor.

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References

  1. Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B (2004) Epstein-Barr virus in pediatric multiple sclerosis. JAMA 291(15):1875–1879. doi:10.1001/jama.291.15.1875

    Article  PubMed  CAS  Google Scholar 

  2. Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286(24):3083–3088

    Article  PubMed  CAS  Google Scholar 

  3. Bible JM, Pantelidis P, Chan PK, Tong CY (2007) Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol 17(6):371–379. doi:10.1002/rmv.538

    Article  PubMed  CAS  Google Scholar 

  4. Bray PF, Luka J, Culp KW, Schlight JP (1992) Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 42(9):1798–1804

    Article  PubMed  CAS  Google Scholar 

  5. Chang LY, Lin TY, Huang YC, Tsao KC, Shih SR, Kuo ML, Ning HC, Chung PW, Kang CM (1999) Comparison of enterovirus 71 and coxsackie-virus A16 clinical illnesses during the Taiwan enterovirus epidemic, 1998. Pediatr Infect Dis J 18(12):1092–1096

    Article  PubMed  CAS  Google Scholar 

  6. Choi CS, Choi YJ, Choi UY, Han JW, Jeong DC, Kim HH, Kim JH, Kang JH (2011) Clinical manifestations of CNS infections caused by enterovirus type 71. Korean J Pediatr 54(1):11–16. doi:10.3345/kjp.2011.54.1.11

    Article  PubMed  Google Scholar 

  7. Chong CY, Chan KP, Shah VA, Ng WY, Lau G, Teo TE, Lai SH, Ling AE (2003) Hand, foot and mouth disease in Singapore: a comparison of fatal and non-fatal cases. Acta Paediatr 92(10):1163–1169

    Article  PubMed  CAS  Google Scholar 

  8. Field CJ (2005) The immunological components of human milk and their effect on immune development in infants. J Nutr 135(1):1–4

    PubMed  CAS  Google Scholar 

  9. Frank AL, Taber LH, Glezen WP, Kasel GL, Wells CR, Paredes A (1982) Breast-feeding and respiratory virus infection. Pediatrics 70(2):239–245

    PubMed  CAS  Google Scholar 

  10. Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M (1988) Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 7(7):484–488

    Article  PubMed  CAS  Google Scholar 

  11. Hamosh M (2001) Bioactive factors in human milk. Pediatr Clin North Am 48(1):69–86

    Article  PubMed  CAS  Google Scholar 

  12. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF (1999) Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341(13):936–942. doi:10.1056/nejm199909233411302

    Article  PubMed  CAS  Google Scholar 

  13. James DC, Dobson B (2005) Position of the American Dietetic Association: promoting and supporting breastfeeding. J Am Diet Assoc 105(5):810–818. doi:10.1016/j.jada.2005.03.015

    Article  PubMed  Google Scholar 

  14. James JA, Neas BR, Moser KL, Hall T, Bruner GR, Sestak AL, Harley JB (2001) Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum 44(5):1122–1126. doi:10.1002/1529-0131(200105)44:5<1122::aid-anr193>3.0.co;2-d

    Article  PubMed  CAS  Google Scholar 

  15. Jenista JA, Powell KR, Menegus MA (1984) Epidemiology of neonatal enterovirus infection. J Pediatr 104(5):685–690

    Article  PubMed  CAS  Google Scholar 

  16. Kramer MS, Kakuma R (2002) Optimal duration of exclusive breastfeeding. Cochrane Database Syst Rev 1:CD003517. doi:10.1002/14651858.cd003517

  17. Kushner D, Caldwell BD (1996) Hand-foot-and-mouth disease. J Am Podiatr Med Assoc 86(6):257–259

    PubMed  CAS  Google Scholar 

  18. Lee MS, Lin TY, Chiang PS, Li WC, Luo ST, Tsao KC, Liou GY, Huang ML, Hsia SH, Huang YC, Chang SC (2010) An investigation of epidemic enterovirus 71 infection in Taiwan, 2008: clinical, virologic, and serologic features. Pediatr Infect Dis J 29(11):1030–1034. doi:10.1097/INF.0b013e3181e52945

    PubMed  Google Scholar 

  19. Lee BY, Wateska AR, Bailey RR, Tai JH, Bacon KM, Smith KJ (2010) Forecasting the economic value of an enterovirus 71 (EV71) vaccine. Vaccine 28(49):7731–7736. doi:10.1016/j.vaccine.2010.09.065

    Article  PubMed  Google Scholar 

  20. Libster R, Bugna Hortoneda J, Laham FR, Casellas JM, Israele V, Polack NR, Delgado MF, Klein MI, Polack FP (2009) Breastfeeding prevents severe disease in full term female infants with acute respiratory infection. Pediatr Infect Dis J 28(2):131–134. doi:10.1097/INF.0b013e31818a8a82

    Article  PubMed  Google Scholar 

  21. Liu MY, Liu W, Luo J, Liu Y, Zhu Y, Berman H, Wu J (2011) Characterization of an outbreak of hand, foot, and mouth disease in Nanchang, China in 2010. PLoS One 6(9):e25287. doi:10.1371/journal.pone.0025287

    Article  PubMed  CAS  Google Scholar 

  22. Long HM, Taylor GS, Rickinson AB (2011) Immune defence against EBV and EBV-associated disease. Curr Opin Immunol 23(2):258–264. doi:10.1016/j.coi.2010.12.014

    Article  PubMed  CAS  Google Scholar 

  23. Mao LX, Wu B, Bao WX, Han FA, Xu L, Ge QJ, Yang J, Yuan ZH, Miao CH, Huang XX, Zhang C, Xu H (2010) Epidemiology of hand, foot, and mouth disease and genotype characterization of enterovirus 71 in Jiangsu, China. J Clin Virol 49(2):100–104. doi:10.1016/j.jcv.2010.07.009

    Article  PubMed  Google Scholar 

  24. Masucci MG, Ernberg I (1994) Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol 2(4):125–130

    Article  PubMed  CAS  Google Scholar 

  25. McAulay KA, Higgins CD, Macsween KF, Lake A, Jarrett RF, Robertson FL, Williams H, Crawford DH (2007) HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 117(10):3042–3048. doi:10.1172/jci32377

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. McMinn P, Stratov I, Nagarajan L, Davis S (2001) Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis 32(2):236–242. doi:10.1086/318454

    Article  PubMed  CAS  Google Scholar 

  28. Melnick JL (1984) Enterovirus type 71 infections: a varied clinical pattern sometimes mimicking paralytic poliomyelitis. Rev Infect Dis 6(Suppl 2):S387–390

    Article  PubMed  Google Scholar 

  29. Ministry of Health of the People’s Republic of China (2010) Hand, foot and mouth disease clinic guide (2010 edition). Available :http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohyzs/s3586/201004/46884.htm. (in Chinese) Accessed 19 January 2012.

  30. Ni H, Yi B, Yin J, Fang T, He T, Du Y, Wang J, Zhang H, Xie L, Ding Y, Gu W, Zhang S, Han Y, Dong H, Su T, Xu G, Cao G (2012) Epidemiological and etiological characteristics of hand, foot, and mouth disease in Ningbo, China, 2008–2011. J Clin Virol 54(4):342–348. doi:10.1016/j.jcv.2012.04.021

    Article  PubMed  Google Scholar 

  31. Nishimura T, Suzue J, Kaji H (2009) Breastfeeding reduces the severity of respiratory syncytial virus infection among young infants: a multi-center prospective study. Pediatr Int 51(6):812–816. doi:10.1111/j.1442-200X.2009.02877.x

    Article  PubMed  Google Scholar 

  32. Papenburg J, Hamelin ME, Ouhoummane N, Carbonneau J, Ouakki M, Raymond F, Robitaille L, Corbeil J, Caouette G, Frenette L, De Serres G, Boivin G (2012) Comparison of risk factors for human metapneumovirus and respiratory syncytial virus disease severity in young children. J Infect Dis 206(2):178–189. doi:10.1093/infdis/jis333

    Article  PubMed  Google Scholar 

  33. Qiu J (2008) Enterovirus 71 infection: a new threat to global public health? Lancet Neurol 7(10):868–869. doi:10.1016/s1474-4422(08)70207-2

    Article  PubMed  Google Scholar 

  34. Quigley MA, Kelly YJ, Sacker A (2007) Breastfeeding and hospitalization for diarrheal and respiratory infection in the United Kingdom Millennium Cohort Study. Pediatrics 119(4):e837–842. doi:10.1542/peds.2006-2256

    Article  PubMed  Google Scholar 

  35. Richardson HB Jr, Leibovitz A (1965) “Hand, foot, and mouth disease”in children; an epidemic associated with Coxsackie virus a-16. J Pediatr 67:6–12

    Article  PubMed  Google Scholar 

  36. Sadeharju K, Knip M, Virtanen SM, Savilahti E, Tauriainen S, Koskela P, Akerblom HK, Hyoty H (2007) Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics 119(5):941–946. doi:10.1542/peds.2006-0780

    Article  PubMed  Google Scholar 

  37. Shen GP, Pan QH, Hong MH, Qin HD, Xu YF, Chen LZ, Feng QS, Jorgensen TJ, Shugart YY, Zeng YX, Jia WH (2011) Human genetic variants of homologous recombination repair genes first found to be associated with Epstein-Barr virus antibody titers in healthy Cantonese. Int J Cancer 129(6):1459–1466. doi:10.1002/ijc.25759

    Article  PubMed  CAS  Google Scholar 

  38. Shibata D, Weiss LM (1992) Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol 140(4):769–774

    PubMed  CAS  Google Scholar 

  39. Simon KC, O’Reilly EJ, Munger KL, Finerty S, Morgan AJ, Ascherio A (2012) Epstein-Barr virus neutralizing antibody levels and risk of multiple sclerosis. Mult Scler 18(8):1185–1187. doi:10.1177/1352458511433920

    Article  PubMed  Google Scholar 

  40. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH (2010) Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10(11):778–790. doi:10.1016/s1473-3099(10)70194-8

    Article  PubMed  Google Scholar 

  41. Sun LM, Zheng HY, Zheng HZ, Guo X, He JF, Guan DW, Kang M, Liu Z, Ke CW, Li JS, Liu L, Guo RN, Yoshida H, Lin JY (2011) An enterovirus 71 epidemic in Guangdong Province of China, 2008: epidemiological, clinical, and virogenic manifestations. Jpn J Infect Dis 64(1):13–18

    PubMed  Google Scholar 

  42. Tan X, Huang X, Zhu S, Chen H, Yu Q, Wang H, Huo X, Zhou J, Wu Y, Yan D, Zhang Y, Wang D, Cui A, An H, Xu W (2011) The persistent circulation of enterovirus 71 in People’s Republic of China: causing emerging nationwide epidemics since 2008. PLoS One 6(9):e25662. doi:10.1371/journal.pone.0025662

    Article  PubMed  CAS  Google Scholar 

  43. Tee KK, Lam TT, Chan YF, Bible JM, Kamarulzaman A, Tong CY, Takebe Y, Pybus OG (2010) Evolutionary genetics of human enterovirus 71: origin, population dynamics, natural selection, and seasonal periodicity of the VP1 gene. J Virol 84(7):3339–3350. doi:10.1128/jvi.01019-09

    Article  PubMed  CAS  Google Scholar 

  44. The Centre for Health Protection of Hong Kong (2007) Management of hand foot mouth disease (HFMD) in Health Care Settings. Available at: http://www.chp.gov.hk/en/sas4/101/110/104.html. Accessed May, 2007

  45. Thorley-Lawson DA (2001) Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1(1):75–82. doi:10.1038/35095584

    Article  PubMed  CAS  Google Scholar 

  46. Tiewsoh K, Lodha R, Pandey RM, Broor S, Kalaivani M, Kabra SK (2009) Factors determining the outcome of children hospitalized with severe pneumonia. BMC Pediatr 9:15. doi:10.1186/1471-2431-9-15

    Article  PubMed  Google Scholar 

  47. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA, Host A, Kuitunen M, Olsen SF, Skerfving S, Sundell J, Wille S (2003) Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 58(9):833–843

    Article  PubMed  Google Scholar 

  48. Vennemann MM, Bajanowski T, Brinkmann B, Jorch G, Yucesan K, Sauerland C, Mitchell EA (2009) Does breastfeeding reduce the risk of sudden infant death syndrome? Pediatrics 123(3):e406–410. doi:10.1542/peds.2008-2145

    Article  PubMed  CAS  Google Scholar 

  49. Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, Yang YJ, Lin SJ, Yeh TF (1999) Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis 29(1):184–190. doi:10.1086/520149

    Article  PubMed  CAS  Google Scholar 

  50. Witso E, Cinek O, Aldrin M, Grinde B, Rasmussen T, Wetlesen T, Ronningen KS (2010) Predictors of sub-clinical enterovirus infections in infants: a prospective cohort study. Int J Epidemiol 39(2):459–468. doi:10.1093/ije/dyp333

    Article  PubMed  Google Scholar 

  51. Wong SS, Yip CC, Lau SK, Yuen KY (2010) Human enterovirus 71 and hand, foot and mouth disease. Epidemiol Infect 138(8):1071–1089. doi:10.1017/s0950268809991555

    Article  PubMed  CAS  Google Scholar 

  52. World Health Organization (2008) Breastfeeding. Available at: www. who. Int/topics/breastfeeding/en. Accessed November 1,2008

  53. Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, Chow VT (2010) 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 14(12):e1076–1081. doi:10.1016/j.ijid.2010.07.006

    Article  PubMed  Google Scholar 

  54. Xu QH, Gao LD, Huang W, Hu SX, Zhang F, Deng ZH, Liu FQ, Zhou SF, Zeng G, Yang H (2011) Risk factors of death cases of hand-foot-and-mouth disease in Hunan province. Zhonghua Yu Fang Yi Xue Za Zhi 45(10):904–908

    PubMed  Google Scholar 

  55. Yang F, Ren L, Xiong Z, Li J, Xiao Y, Zhao R, He Y, Bu G, Zhou S, Wang J, Qi J (2009) Enterovirus 71 outbreak in the People’s Republic of China in 2008. J Clin Microbiol 47(7):2351–2352. doi:10.1128/jcm.00563-09

    Article  PubMed  Google Scholar 

  56. Zhang Y, Tan XJ, Wang HY, Yan DM, Zhu SL, Wang DY, Ji F, Wang XJ, Gao YJ, Chen L, An HQ, Li DX, Wang SW, Xu AQ, Wang ZJ, Xu WB (2009) An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. J Clin Virol 44(4):262–267. doi:10.1016/j.jcv.2009.02.002

    Article  PubMed  Google Scholar 

  57. Zhu Q, Li Y, Li N, Han Q, Liu Z, Li Z, Qiu J, Zhang G, Li F, Tian N (2012) Prolonged exclusive breastfeeding, autumn birth and increased gestational age are associated with lower risk of fever in children with hand, foot, and mouth disease. Eur J Clin Microbiol Infect Dis 31(9):2197–2202. doi:10.1007/s10096-012-1555-4

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the doctors of the Department of Infectious Diseases of Second Affiliated Hospital of Medical College of Xi’an Jiaotong University and Xi’an Children’s Hospital for their fervent help in data collection.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Infectious Diseases, Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, No. 157, Xiwu Road, Xi’an, Shaanxi, 710004, China

    Yaping Li, Shuangsuo Dang, Wenjun Wang, Xiaoli Jia, Ning Gao & Mei Li

  2. Department of Epidemiology and Biostatistics, Xi’an Jiaotong University College of Medicine, No. 76, Yanta West Road, Xi’an, Shaanxi, 710061, China

    Yaping Li, Shuangsuo Dang, Wenjun Wang, Xiaoli Jia, Ning Gao & Mei Li

  3. Department of Infectious Diseases, Xi’an Children’s Hospital, Xi’an, Shaanxi, 710003, China

    Huiling Deng & Jun Wang

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  1. Yaping Li
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Li, Y., Dang, S., Deng, H. et al. Breastfeeding, previous Epstein-Barr virus infection, Enterovirus 71 infection, and rural residence are associated with the severity of hand, foot, and mouth disease. Eur J Pediatr 172, 661–666 (2013). https://doi.org/10.1007/s00431-013-1939-1

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