Enteroviruses (EVs) are major pathogens in young infants. These viruses were traditionally classified into the following four subgenera: polio, coxsackie A and B, and echoviruses. Now that poliomyelitis seems to be controlled in most parts of the world, coxsackie and echoviruses are gaining more attention because (i) the structural and pathophysiological similarities and (ii) the consequent possibilities in translational medicine. Enteroviruses are transmitted mainly by oral and fecal–oral routes; the clinical manifestations include a viral prodrome including fever, feeding intolerance, and lethargy, which may be followed by exanthema; aseptic meningitis and encephalitis; pleurodynia; myopericarditis; and multi-system organ failure. Laboratory diagnosis is largely based on reverse transcriptase–polymerase chain reaction, cell culture, and serology. Prevention and treatment can be achieved using vaccination, and administration of immunoglobulins and antiviral drugs. In this article, we have reviewed the properties of these viruses, their clinical manifestations, and currently available methods of detection, treatment, and prognosis.
Baggen J, Thibaut HJ, Strating J, et al. The life cycle of non-polio enteroviruses and how to target it. Nat Rev Microbiol 2018;16(6): 368–381. DOI: 10.1038/s41579-018-0005-4.
Hawkes MT, Vaudry W. Nonpolio enterovirus infection in the neonate and young infant. Paediatr Child Health 2005;10(7):383–388. PMID: 19668644.
Horstmann DM. Enterovirus infections: Etiologic, epidemiologic and clinical aspects. Calif Med 1965;103:1–8. PMID: 14336786.
Oberste MS, Maher K, Williams AJ, et al. Species-specific RT-PCR amplification of human enteroviruses: A tool for rapid species identification of uncharacterized enteroviruses. J Gen Virol 2006;87 (Pt. 1):119–128. DOI: 10.1099/vir.0.81179-0.
Oberste MS, Maher K, Kilpatrick DR, et al. Molecular evolution of the human enteroviruses: Correlation of serotype with VP1 sequence and application to picornavirus classification. J Virol 1999;73(3):1941–1948. DOI: 10.1128/JVI.73.3.1941-1948.1999.
National Collaborating Centre for Infectious Diseases C. EV-D68. University of Mannitoba. Available at: https://nccid.ca/debrief/ev-d68/ Accessed on: 23 August 2022.
Tapparel C, Siegrist F, Petty TJ, et al. Picornavirus and enterovirus diversity with associated human diseases. Infect Genet Evol 2013;14:282–293. DOI: 10.1016/j.meegid.2012.10.016.
Pons–Salort M, Parker EP, Grassly NC. The epidemiology of non-polio enteroviruses: Recent advances and outstanding questions. Curr Opin Infect Dis 2015;28(5):479–487. DOI: 10.1097/QCO.000000000 0000187.
Jiang P, Liu Y, Ma HC, et al. Picornavirus morphogenesis. Microbiol Mol Biol Rev 2014;78(3):418–437. DOI: 10.1128/MMBR.00012-14.
Payne S. Introduction to RNA viruses. Viruses 2017:97–105. DOI: 10.1016/B978-0-12-803109-4.00010-6.
Laitinen OH, Svedin E, Kapell S, et al. Enteroviral proteases: Structure, host interactions and pathogenicity. Rev Med Virol Jul 2016;26(4): 251–267. DOI: 10.1002/rmv.1883.
Groppelli E, Levy HC, Sun E, et al. Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes. PLoS Pathog 2017;13(2):e1006197. DOI: 10.1371/journal.ppat.1006197.
Wells AI, Coyne CB. Enteroviruses: A gut–wrenching game of entry, detection, and evasion. Viruses 2019;11(5):460. DOI: 10.3390/v11050460.
Stone VM, Hankaniemi MM, Laitinen OH, et al. A hexavalent coxsackievirus B vaccine is highly immunogenic and has a strong protective capacity in mice and nonhuman primates. Sci Adv 2020;6(19):eaaz2433. DOI: 10.1126/sciadv.aaz2433.
Lugo D, Krogstad P. Enteroviruses in the early 21st century: New manifestations and challenges. Curr Opin Pediatr 2016;28(1):107–113. DOI: 10.1097/MOP.0000000000000303.
Olchawa–Czech A, Ptak K, Szymonska I, et al. Severe enterovirus infections in infants <3 months of age and the importance of medical history. J Mother Child 2021;24(3):37–44. DOI: 10.34763/jmotherandchild.20202403.2022.d-20-00007.
Bopegamage S. Enterovirus infections: Pivoting role of the adaptive immune response. Virulence 2016;7(5):495–497. DOI: 10.1080/21505 594.2016.1175701.
Rodriguez–Lazaro D, Cook N, Ruggeri FM, et al. Virus hazards from food, water and other contaminated environments. FEMS Microbiol Rev 2012;36(4):786–814. DOI: 10.1111/j.1574-6976.2011.00306.x.
Tiwari S, Dhole TN. Assessment of enteroviruses from sewage water and clinical samples during eradication phase of polio in North India. Virol J 2018;15(1):157. DOI: 10.1186/s12985-018-1075-7.
Keswick BH, Gerba CP, Goyal SM. Occurrence of enteroviruses in community swimming pools. Am J Public Health. 1981;71(9): 1026–1030. DOI: 10.2105/ajph.71.9.1026.
Imamura T, Oshitani H. Global reemergence of enterovirus D68 as an important pathogen for acute respiratory infections. Rev Med Virol 2015;25(2):102–114. DOI: 10.1002/rmv.1820.
Noor A, Krilov LR. Enterovirus Infections. Pediatr Rev 2016;37(12): 505–515. DOI: 10.1542/pir.2016-0103.
Chang LY, Tsao KC, Hsia SH, et al. Transmission and clinical features of enterovirus 71 infections in household contacts in Taiwan. JAMA 2004;291(2):222–227. DOI: 10.1001/jama.291.2.222.
Yen M, Tsao H, Huang Y, et al. Viral load in blood is correlated with disease severity of neonatal coxsackievirus B3 infection: Early diagnosis and predicting isease severity is possible in severe neonatal enterovirus infection. Clin Infect Dis 2007;44(10):e78–e81. DOI: 10.1086/515399.
Moore M, Kaplan MH, McPhee J, et al. Epidemiologic, clinical, and laboratory features of coxsackie B1–B5 infections in the United States, 1970–1979. Public Health Rep 1984;99(5):515–522. PMID: 6091168.
Modlin JF, Polk BF, Horton P, et al. Perinatal echovirus infection: Risk of transmission during a community outbreak. N Engl J Med 1981;305(7):368–371. DOI: 10.1056/NEJM198108133050703.
Hendry E, Hatanaka H, Fry E, et al. The crystal structure of coxsackievirus A9: New insights into the uncoating mechanisms of enteroviruses. Structure 1999;7(12):1527–1538. DOI: 10.1016/s0969-2126(00)88343-4.
Selinka HC, Wolde A, Sauter M, et al. Virus–receptor interactions of coxsackie B viruses and their putative influence on cardiotropism. Med Microbiol Immunol 2004;193(2–3):127–131. DOI: 10.1007/s00430-003-0193-y.
Nelsen–Salz B, Eggers HJ, Zimmermann H. Integrin α(v)β3 (vitronectin receptor) is a candidate receptor for the virulent echovirus 9 strain Barty. J Gen Virol 1999;80(Pt. 9):2311–2313. DOI: 10.1099/0022-1317-80-9-2311.
Jokinen J, White DJ, Salmela M, et al. Molecular mechanism of α2β1 integrin interaction with human echovirus 1. EMBO J 2010;29(1):196–208. DOI: 10.1038/emboj.2009.326.
Morosky S, Wells AI, Lemon K, et al. The neonatal Fc receptor is a pan-echovirus receptor. Proc Natl Acad Sci U S A 2019;116(9):3758–3763. DOI: 10.1073/pnas.1817341116.
Gong X, Zhou J, Zhu W, et al. Excessive proinflammatory cytokine and chemokine responses of human monocyte-derived macrophages to enterovirus 71 infection. BMC Infect Dis 2012;12:224. DOI: 10.1186/1471-2334-12-224.
Wei X, Yang J, Gao L, et al. The transfer and decay of maternal antibodies against enterovirus A71, and dynamics of antibodies due to later natural infections in Chinese infants: A longitudinal, paired mother–neonate cohort study. Lancet Infect Dis S2021;21(3):418–426. DOI: 10.1016/S1473-3099(20)30480-1.
Chen B, Yang Y, Xu X, et al. Epidemiological characteristics of hand, foot, and mouth disease in China: A meta-analysis. Medicine (Baltimore) 2021;100(20):e25930. DOI: 10.1097/MD.0000000000025930.
Alexander JP Jr, Baden L, Pallansch MA, et al. Enterovirus 71 infections and neurologic disease–United States, 1977–1991. J Infect Dis. 1994;169(4):905–908. DOI: 10.1093/infdis/169.4.905.
Lum LC, Wong KT, Lam SK, et al. Fatal enterovirus 71 encephalomyelitis. J Pediatr 1998;133(6):795–798. DOI: 10.1016/s0022-3476(98)70155-6.
Feder HM Jr, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: A vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis 2014;14(1):83–86. DOI: 10.1016/S1473-3099(13) 70264-0.
Stewart CL, Chu EY, Introcaso CE, et al. Coxsackievirus A6-induced hand–foot–mouth disease. JAMA Dermatol 2013;149(12):1419–1421. DOI: 10.1001/jamadermatol.2013.6777.
Davia JL, Bel PH, Ninet VZ, et al. Onychomadesis outbreak in Valencia, Spain associated with hand, foot, and mouth disease caused by enteroviruses. Pediatr Dermatol. 2011;28(1):1–5. DOI: 10.1111/j.1525-1470.2010.01161.x.
Zhang J, Liu H, Zhao Y, et al. Identification of a new recombinant strain of echovirus 33 from children with hand, foot, and mouth disease complicated by meningitis in Yunnan, China. Virol J 2019;16(1):63. DOI: 10.1186/s12985-019-1164-2.
Bian L, Gao F, Mao Q, et al. Hand, foot, and mouth disease associated with coxsackievirus A10: more serious than it seems. Expert Rev Anti Infect Ther 2019;17(4):233–242. DOI: 10.1080/14787210.2019.1585242.
Li W, Gao HH, Zhang Q, et al. Large outbreak of herpangina in children caused by enterovirus in summer of 2015 in Hangzhou, China. Sci Rep 2016;6:35388. DOI: 10.1038/srep35388.
Sabin AB, Krumbiegel ER, Wigand R. ECHO type 9 virus disease. AMA J Dis Child 1958;96(2):197–219. DOI: 10.1001/archpedi.1958. 02060060199011.
Bell EJ, Ross CA, Grist NR. ECHO 9 infection in pregnant women with suspected rubella. J Clin Pathol 1975;28(4):267–269. DOI: 10.1136/jcp.28.4.267.
Neva FA. A second outbreak of Boston exanthem disease in Pittsburgh during 1954. N Engl J Med 1956;254(18):838–843. DOI: 10.1056/NEJM195605032541806.
Frothingham TE. ECHO virus type 9 associated with three cases simulating meningococcemia. N Engl J Med 1958;259(10):484–485. DOI: 10.1056/NEJM195809042591007.
Emer JJ, Bernardo SG, Kovalerchik O, et al. Urticaria multiforme. J Clin Aesthet Dermatol 2013;6(3):34–39.
Nagai T, Hanaoka N, Katano H, et al. A fatal case of acute encephalopathy in a child due to coxsackievirus A2 infection: A case report. BMC Infect Dis 2021;21(1):1167. DOI: 10.1186/s12879-021-06858-2.
Dalwai A, Ahmad S, Pacsa A, et al. Echovirus type 9 is an important cause of viral encephalitis among infants and young children in Kuwait. J Clin Virol 2009;44(1):48–51. DOI: 10.1016/j.jcv.2008. 10.007.
Dancea AB. Myocarditis in infants and children: A review for the paediatrician. Paediatr Child Health 2001;6(8):543–545. DOI: 10.1093/pch/6.8.543.
Kaplan MH, Klein SW, McPhee J, et al. Group B coxsackievirus infections in infants younger than three months of age: A serious childhood illness. Rev Infect Dis 1983;5(6):1019–1032. DOI: 10.1093/clinids/5.6.1019.
Eichenwald HF, Shinefield HR. Viral infections of the fetus and of the premature and newborn infant. Adv Pediatr 1962;12:249–305. PMID: 13889553.
Pedrosa C, Lage MJ, Virella D. Congenital echovirus 21 infection causing fulminant hepatitis in a neonate. BMJ Case Rep 2013;2013 DOI: 10.1136/bcr-2012-008394.
Ventura KC, Hawkins H, Smith MB, Walker DH. Fatal neonatal echovirus 6 infection: Autopsy case report and review of the literature. Mod Pathol 2001;14(2):85–90. DOI: 10.1038/modpathol.3880260.
Leggiadro RJ, Darras BT. Viral and bacterial pathogens of suspected sepsis in young infants. Pediatr Infect Dis 1983;2(4):287–289. DOI: 10.1097/00006454-198307000-00006.
Krober MS, Bass JW, Powell JM, et al. Bacterial and viral pathogens cause fever in infants less than 3 months old. Am J Dis Child 1985;139(9):889–892. DOI: 10.1001/archpedi.1985.02140110043025.
Rorabaugh ML, Berlin LE, Heldrich F, et al. Aseptic meningitis in infants younger than 2 years of age: Acute illness and neurologic complications. Pediatrics 1993;92(2):206–211.
Modlin JF, Rotbart HA. Group B coxsackie disease in children. Curr Top Microbiol Immunol 1997;223:53–80. DOI: 10.1007/978-3-642- 60687-8_4.
Fowlkes AL, Honarmand S, Glaser C, et al. Enterovirus-associated encephalitis in the California encephalitis project, 1998–2005. J Infect Dis 2008;198(11):1685–1691. DOI: 10.1086/592988.
Chonmaitree T, Menegus MA, Powell KR. The clinical relevance of ‘CSF viral culture’. A two-year experience with aseptic meningitis in Rochester, NY. JAMA 1982;247(13):1843–1847.
Zhang L, Zhao N, Huang X, et al. Molecular epidemiology of acute hemorrhagic conjunctivitis caused by coxsackie A type 24 variant in China, 2004–2014. Sci Rep 2017;7:45202. DOI: 10.1038/srep 45202.
Hughes JR, Wilfert CM, Moore M, et al. Echovirus 14 infection associated with fatal neonatal hepatic necrosis. Am J Dis Child 1972;123(1):61–67. DOI: 10.1001/archpedi.1972.02110070111017.
Kleinman H, Prince JT, Mathey WE, et al. ECHO 9 virus infection and congenital abnormalities: A negative report. Pediatrics 1962;29: 261–269. PMID: 14456823.
Landsman JB, Grist NR, Ross CA. ECHO 9 virus infection and congenital malformations. Br J Prev Soc Med 1964;18:152–156. DOI: 10.1136/jech.18.3.152.
Mirand A, Henquell C, Archimbaud C, et al. Prospective identification of enteroviruses involved in meningitis in 2006 through direct genotyping in cerebrospinal fluid. J Clin Microbiol 2008;46(1):87–96. DOI: 10.1128/JCM.01020-07.
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):2698–2704. DOI: 10.1128/JCM.00542-06.
Oberste MS, Maher K, Kilpatrick DR, et al. Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol 1999;37(5):1288–1293. DOI: 10.1128/JCM.37.5.1288-1293.1999.
Dagan R, Menegus MA. A combination of four cell types for rapid detection of enteroviruses in clinical specimens. J Med Virol 1986;19(3):219–228. DOI: 10.1002/jmv.1890190304.
Trabelsi A, Grattard F, Nejmeddine M, et al. Evaluation of an enterovirus group-specific anti-VP1 monoclonal antibody, 5-D8/1, in comparison with neutralization and PCR for rapid identification of enteroviruses in cell culture. J Clin Microbiol 1995;33(9):2454–2457. DOI: 10.1128/jcm.33.9.2454-2457.1995.
Bell EJ, McCartney RA, Basquill D, et al. Mu-antibody capture ELISA for the rapid diagnosis of enterovirus infections in patients with aseptic meningitis. J Med Virol 1986;19(3):213–217. DOI: 10.1002/jmv.1890190303.
Pozzetto B, Gaudin OG, Aouni M, et al. Comparative evaluation of immunoglobulin M neutralizing antibody response in acute-phase sera and virus isolation for the routine diagnosis of enterovirus infection. J Clin Microbiol 1989;27(4):705–708. DOI: 10.1128/jcm.27.4. 705-708.1989.
Torres–Torres S, Myers AL, Klatte JM, et al. First use of investigational antiviral drug pocapavir (v-073) for treating neonatal enteroviral sepsis. Pediatr Infect Dis J 2015;34(1):52–54. DOI: 10.1097/INF.0000 000000000497.
Pevear DC, Tull TM, Seipel ME, et al. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 1999;43(9):2109–2115. DOI: 10.1128/AAC.43.9.2109.
Yen MH, Huang YC, Chen MC, et al. Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. J Clin Virol 2015;64:92–96. DOI: 10.1016/j.jcv.2015.01.013.
Abzug MJ, Keyserling HL, Lee ML, et al. Neonatal enterovirus infection: Virology, serology, and effects of intravenous immune globulin. Clin Infect Dis 1995;20(5):1201–1206. DOI: 10.1093/clinids/20.5.1201.
Johnston JM, Overall JC Jr. Intravenous immunoglobulin in disseminated neonatal echovirus 11 infection. Pediatr Infect Dis J 1989;8(4):254–256. PMID: 2717278.
Jantausch BA, Luban NL, Duffy L, et al. Maternal plasma transfusion in the treatment of disseminated neonatal echovirus 11 infection. Pediatr Infect Dis J 1995;14(2):154–155. PMID: 7746702.
Ruan F, Yang T, Ma H, et al. Risk factors for hand, foot, and mouth disease and herpangina and the preventive effect of hand-washing. Pediatrics 2011;127(4):e898–e904. DOI: 10.1542/peds.2010-1497.
Chang SC, Li WC, Huang KY, et al. Efficacy of alcohols and alcohol-based hand disinfectants against human enterovirus 71. J Hosp Infect 2013;83(4):288–293. DOI:10.1016/j.jhin.2012.12.010.
Siegel JD, Rhinehart E, Jackson M, et al. 2007 Guideline for isolation precautions: Preventing transmission of infectious agents in healthcare settings. Am J Infect Control 2007;35(10 Suppl. 2):S65–164. DOI: 10.1016/j.ajic.2007.10.007.
Li Y, Zhou Y, Cheng Y, et al. Effectiveness of EV-A71 vaccination in prevention of paediatric hand, foot, and mouth disease associated with EV-A71 virus infection requiring hospitalisation in Henan, China, 2017–18: A test-negative case–control study. Lancet Child Adolesc Health 2019;3(10):697–704. DOI: 10.1016/S2352-4642(19)30185-3.
Wei M, Meng F, Wang S, et al. 2-Year efficacy, immunogenicity, and safety of Vigoo enterovirus 71 vaccine in healthy Chinese children: A randomized open-label study. J Infect Dis 2017;215(1):56–63. DOI: 10.1093/infdis/jiw502.
Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014;370(9):829–837. DOI: 10.1056/NEJMoa1303224.
Nguyen TT, Chiu CH, Lin CY, et al. Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 2022;399(10336):1708–1717. DOI: 10.1016/S0140-6736(22)00313-0.
Lu JY, Brewer G, Li ML, et al. Secretory carrier membrane protein 3 interacts with 3A viral protein of enterovirus and participates in viral replication. Microbiol Spectr 2021;9(1):e0047521. DOI: 10.1128/Spectrum.00475-21.
Shakeel S, Seitsonen JJ, Kajander T, et al. Structural and functional analysis of coxsackievirus A9 integrin alphavbeta6 binding and uncoating. J Virol 2013;87(7):3943–3951. DOI: 10.1128/JVI. 02989-12.
Laufman O, Perrino J, Andino R. Viral generated inter-organelle contacts redirect lipid flux for genome replication. Cell 2019;178(2): 275–289.e16. DOI: 10.1016/j.cell.2019.05.030.
Louten J. Virus replication. Essential Human Virol 2016:49–70. DOI: 10.1016/B978-0-12-800947-5.00004-1.
Maciejewski S, Nguyen JH, Gomez–Herreros F, et al. Divergent requirement for a DNA repair enzyme during enterovirus infections. mBio 2015;7(1):e01931–15. DOI: 10.1128/mBio.01931-15.
Merkle I, van Ooij MJ, van Kuppeveld FJ, et al. Biological significance of a human enterovirus B-specific RNA element in the 3’ nontranslated region. J Virol 2002;76(19):9900–9909. DOI: 10.1128/jvi.76.19.9900-9909.2002.
Yuan J, Shen L, Wu J, et al. Enterovirus A71 proteins: Structure and function. Front Microbiol 2018;9:286. DOI: 10.3389/fmicb.2018. 00286.
Lee KM, Wu CC, Wu SE, et al. The RNA-dependent RNA polymerase of enterovirus A71 associates with ribosomal proteins and positively regulates protein translation. RNA Biol 2020;17(4):608–622. DOI: 10.1080/15476286.2020.1722448.
