Skip to main content
Top
Published in: BMC Infectious Diseases 1/2018

Open Access 01-12-2018 | Research article

Molecular characterization of an outbreak of enterovirus-associated meningitis in Mossel Bay, South Africa, December 2015–January 2016

Authors: Heidi Smuts, Sarah Cronje, Juno Thomas, Delene Brink, Stephen Korsman, Diana Hardie

Published in: BMC Infectious Diseases | Issue 1/2018

Login to get access

Abstract

Background

Human enteroviruses (HEVs) are common causal agents of aseptic meningitis in young children. Laboratory and syndromic surveillance during December 2015 and January 2016 noted an unusually high number of paediatric aseptic meningitis cases at a hospital in Mossel Bay, Western Cape Province, South Africa. HEV was detected in clinical samples, prompting an outbreak investigation.

Methods

Epidemiological investigations were conducted to ascertain possible linkage between cases. Amplification, sequencing and phylogenetic analysis of the 5’UTR and VP1 regions was undertaken to determine the HEV serotype associated with the outbreak as well as other cases of aseptic meningitis in the area in the preceding 6 weeks.

Results

Over the 2-month period, 63 CSF samples were available for testing. A total of 43 outbreak cases (68.3%) were observed, and the 26 (60.5%) that could be typed were coxsackie virus A9 (CVA9). Children attending three crèche facilities were epidemiologically linked, accounting for 60.5% (26/43) of the CVA9 cases. The majority of patients were under 10 years of age (55/63, 87.3%) and there was a male predominance (66%). Nucleotide sequence analysis of the 5’UTR and VP1 regions identified 2 lineages of CVA9 co-circulating during the outbreak, although the VP1 capsid protein sequence was identical as all nucleotide differences were synonymous. There was a unique isoleucine at position 64 and all outbreak viruses had a valine to threonine change in the hypervariable BC loop of VP1. Other HEV types circulating in the preceding period were echovirus 30 (n = 4), echovirus 5 (n = 3) and 1 each of echovirus 6, echovirus 9 and echovirus 15.

Conclusion

CVA9 was identified as the pathogen responsible for the large outbreak of aseptic meningitis, with 2 distinct co-circulating lineages.
Appendix
Available only for authorised users
Literature
1.
go back to reference Pallansch MA, Oberste MS, Whitton JL. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In Knipe DM, Howley P, editors. Fields virology 2. 6th ed. Lippincott Williams & Wilkins; 2013. Pallansch MA, Oberste MS, Whitton JL. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In Knipe DM, Howley P, editors. Fields virology 2. 6th ed. Lippincott Williams & Wilkins; 2013.
2.
go back to reference Pons-Salort M, Parker EP, Grassly NC. The epidemiology of non-polio enteroviruses: recent advances and outstanding questions. Curr Opin Infect Dis. 2015;28:479–87.CrossRef Pons-Salort M, Parker EP, Grassly NC. The epidemiology of non-polio enteroviruses: recent advances and outstanding questions. Curr Opin Infect Dis. 2015;28:479–87.CrossRef
3.
go back to reference Julbert B and Lipton HL. Enterovirus/Picornavirus infections. Chapter 18 in Handb Clin Neurol, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors 2013. Julbert B and Lipton HL. Enterovirus/Picornavirus infections. Chapter 18 in Handb Clin Neurol, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors 2013.
5.
go back to reference Bailly J-L, Be’Guet A, Chambon M, Henquell C, Lafeuille HP. Nosocomial transmission of echovirus 30: molecular evidence by phylogenetic analysis of the VP1 encoding sequence. J Clin Microbiol. 2000;38:2889–92.PubMedPubMedCentral Bailly J-L, Be’Guet A, Chambon M, Henquell C, Lafeuille HP. Nosocomial transmission of echovirus 30: molecular evidence by phylogenetic analysis of the VP1 encoding sequence. J Clin Microbiol. 2000;38:2889–92.PubMedPubMedCentral
6.
go back to reference Romero JR. Reverse-transcription polymerase chain reaction detection of the enteroviruses. Arch Pathol Lab Med. 1999;123:1161–9.PubMed Romero JR. Reverse-transcription polymerase chain reaction detection of the enteroviruses. Arch Pathol Lab Med. 1999;123:1161–9.PubMed
7.
go back to reference Knowles NJ, Hovi T, Hyypiä T, King AMQ, Lindberg AM, Pallansch MA, Palmenberg AC, Simmonds P, Skern T, Stanway G, Yamashita T, Zell R. Picornaviridae. In: King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ, editors. (ed), virus taxonomy: classification and nomenclature of viruses: ninth report of the international committee on taxonomy of viruses. San Diego, CA: Elsevier; 2012. p. 855–80. Knowles NJ, Hovi T, Hyypiä T, King AMQ, Lindberg AM, Pallansch MA, Palmenberg AC, Simmonds P, Skern T, Stanway G, Yamashita T, Zell R. Picornaviridae. In: King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ, editors. (ed), virus taxonomy: classification and nomenclature of viruses: ninth report of the international committee on taxonomy of viruses. San Diego, CA: Elsevier; 2012. p. 855–80.
8.
go back to reference 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;73:1941–8.PubMedPubMedCentral 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;73:1941–8.PubMedPubMedCentral
10.
go back to reference Caro V, Guillot S, Delpeyroux F, Crainic R. 2001. Molecular strategy for “serotyping” of human enteroviruses. J Gen Virol. 2001;82:79–91.CrossRef Caro V, Guillot S, Delpeyroux F, Crainic R. 2001. Molecular strategy for “serotyping” of human enteroviruses. J Gen Virol. 2001;82:79–91.CrossRef
11.
go back to reference Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA. 2000;283:2680–5.CrossRef Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA. 2000;283:2680–5.CrossRef
12.
go back to reference Norder H, Bjerregaard L, Magnius L, Lina B, Aymard M, Chomel J-J. Sequencing of “untypeable” enteroviruses reveals two new type, EV-77 and EV-78, within human enteroviruses type B and substitutions in the BC loop of the VP1 protein for known types. J Gen Virol. 2003;84:827–36.CrossRef Norder H, Bjerregaard L, Magnius L, Lina B, Aymard M, Chomel J-J. Sequencing of “untypeable” enteroviruses reveals two new type, EV-77 and EV-78, within human enteroviruses type B and substitutions in the BC loop of the VP1 protein for known types. J Gen Virol. 2003;84:827–36.CrossRef
13.
go back to reference Lee BE, Davies HD. Aseptic meningitis. Curr Opin Infect Dis. 2007;20:272–7.CrossRef Lee BE, Davies HD. Aseptic meningitis. Curr Opin Infect Dis. 2007;20:272–7.CrossRef
14.
go back to reference McIntyre JP, Keen GA. Laboratory surveillance of viral meningitis by examination of cerebrospinal fluid in Cape Town, 1981-9. Epidemiol Infect. 1993;111(2):357–71.CrossRef McIntyre JP, Keen GA. Laboratory surveillance of viral meningitis by examination of cerebrospinal fluid in Cape Town, 1981-9. Epidemiol Infect. 1993;111(2):357–71.CrossRef
15.
go back to reference Yeats J, Smuts H, Serfontein CJ, Kannemeyer J. Investigation into a school enterovirus outbreak using PCR detection and serotype identification based on the 5′ non-coding region. Epidemiol Infect. 2005;133(6):1123–30.CrossRef Yeats J, Smuts H, Serfontein CJ, Kannemeyer J. Investigation into a school enterovirus outbreak using PCR detection and serotype identification based on the 5′ non-coding region. Epidemiol Infect. 2005;133(6):1123–30.CrossRef
16.
go back to reference Smuts H, Hardie D. Phylogenetic identification of human enteroviruses associated with clusters of meningitis in 2009 and 2010. Commun Dis Surv Bull. 2010;8:55–7. Smuts H, Hardie D. Phylogenetic identification of human enteroviruses associated with clusters of meningitis in 2009 and 2010. Commun Dis Surv Bull. 2010;8:55–7.
17.
go back to reference Wolfaardt M, Buchner A, Myburgh M, Avenant T, du Plessis NM, Taylor MB. Molecular characterization of enteroviruses and clinical findings from a cluster of paediatric viral meningitis cases in Tshwane, South Africa 2010-2011. J Clin Virol. 2014;61:400–5.CrossRef Wolfaardt M, Buchner A, Myburgh M, Avenant T, du Plessis NM, Taylor MB. Molecular characterization of enteroviruses and clinical findings from a cluster of paediatric viral meningitis cases in Tshwane, South Africa 2010-2011. J Clin Virol. 2014;61:400–5.CrossRef
18.
go back to reference McWilliam Leitch EC, Harvala H, Robertson I, Ubillos I, Templeton K, Simmonds P. Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol. 2009;44:119–24.CrossRef McWilliam Leitch EC, Harvala H, Robertson I, Ubillos I, Templeton K, Simmonds P. Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol. 2009;44:119–24.CrossRef
19.
go back to reference McLeish NJ, Witteveldt J, Clasper L, McIntyre C, McWilliam Leitch EC, Hardie A, et al. Development and assay of RNA transcripts of enterovirus species a to D, rhinovirus species a to C, and human parechovirus: assessment of assay sensitivity and specificity of real-time screening and typing methods. J Clin Microbiol. 2012;50(9):2910–7.CrossRef McLeish NJ, Witteveldt J, Clasper L, McIntyre C, McWilliam Leitch EC, Hardie A, et al. Development and assay of RNA transcripts of enterovirus species a to D, rhinovirus species a to C, and human parechovirus: assessment of assay sensitivity and specificity of real-time screening and typing methods. J Clin Microbiol. 2012;50(9):2910–7.CrossRef
22.
go back to reference Pickett BE, Sadat EL, Zhang Y, Noronha JM, Squires RB, Hunt V, et al. ViPR: an open bioinformatics database and analysis resource for virology research. Nucleic Acids Res. 2012;40(Database issue):D593–8.CrossRef Pickett BE, Sadat EL, Zhang Y, Noronha JM, Squires RB, Hunt V, et al. ViPR: an open bioinformatics database and analysis resource for virology research. Nucleic Acids Res. 2012;40(Database issue):D593–8.CrossRef
23.
go back to reference Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for windows 95/98/NT. Nucl acids Symp. Ser. 1999;41:95–8. Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for windows 95/98/NT. Nucl acids Symp. Ser. 1999;41:95–8.
24.
go back to reference Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0 Mol Biol Evol 2013; 30(12):2725–2729. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0 Mol Biol Evol 2013; 30(12):2725–2729.
26.
go back to reference Chan JH, Law CK, Hamblion E, Fung H, Rudge J. Best practices to prevent transmission and control outbreaks of hand, foot, and mouth disease in childcare facilities: a systematic review Hong Kong Med J. 2017;23(2):177–90.PubMed Chan JH, Law CK, Hamblion E, Fung H, Rudge J. Best practices to prevent transmission and control outbreaks of hand, foot, and mouth disease in childcare facilities: a systematic review Hong Kong Med J. 2017;23(2):177–90.PubMed
27.
go back to reference Mohle-Boetani JC, Matkin C, Pallansch M, Helfand R, Fenstersheib M, Blanding JA, Solomon SL. Viral meningitis in child care Centre staff and parents: an outbreak of echovirus 30 infections. Public Health Rep. 1999;114(3):249–56.CrossRef Mohle-Boetani JC, Matkin C, Pallansch M, Helfand R, Fenstersheib M, Blanding JA, Solomon SL. Viral meningitis in child care Centre staff and parents: an outbreak of echovirus 30 infections. Public Health Rep. 1999;114(3):249–56.CrossRef
28.
go back to reference Helfand RF, Khan AS, Pallansch MA, Alexander JP, Meyers HB, DeSantis RA, Schonberger LB, Anderson LJ. Echovirus 30 infection and aseptic meningitis in parents of children attending a child care Centre. J Infect Dis. 1994;169(5):1133–7.CrossRef Helfand RF, Khan AS, Pallansch MA, Alexander JP, Meyers HB, DeSantis RA, Schonberger LB, Anderson LJ. Echovirus 30 infection and aseptic meningitis in parents of children attending a child care Centre. J Infect Dis. 1994;169(5):1133–7.CrossRef
29.
go back to reference Faustini A, Fano V, Muscillo M, Zaniratti S, La Rosa G, Tribuzi L, Carlo A. Perucci CA. 2006. 297 An outbreak of aseptic meningitis due to echovirus 30 associated with attending school and swimming in pools. Intern J of Infect Dis 2006; 10: 291–297. Faustini A, Fano V, Muscillo M, Zaniratti S, La Rosa G, Tribuzi L, Carlo A. Perucci CA. 2006. 297 An outbreak of aseptic meningitis due to echovirus 30 associated with attending school and swimming in pools. Intern J of Infect Dis 2006; 10: 291–297.
30.
go back to reference Dente FA, Blanchollun E, Delicnierex A, Flamen P. 1974. Coxsackievirus A16 infection from lake water. JAMA. 1974;228:1370–1. Dente FA, Blanchollun E, Delicnierex A, Flamen P. 1974. Coxsackievirus A16 infection from lake water. JAMA. 1974;228:1370–1.
31.
go back to reference Kee F, McElroy G, Steward D, Coyle P, Watson J. 1994. A community outbreak of echovirus infection associated with an outdoor swimming pool. J Public Health Med. 1994;16:145–8.CrossRef Kee F, McElroy G, Steward D, Coyle P, Watson J. 1994. A community outbreak of echovirus infection associated with an outdoor swimming pool. J Public Health Med. 1994;16:145–8.CrossRef
32.
go back to reference Nakao T, Nitta T, Miura R, Ogata K, Kume T, Nobuta K, Hinuma Y. Clinical and epidemiological studies on an outbreak of aseptic meningitis caused by Coxsackie B5 and A9 viruses in Aomori in 1961. Tohoku J Exp Med. 1964;83:94–102.CrossRef Nakao T, Nitta T, Miura R, Ogata K, Kume T, Nobuta K, Hinuma Y. Clinical and epidemiological studies on an outbreak of aseptic meningitis caused by Coxsackie B5 and A9 viruses in Aomori in 1961. Tohoku J Exp Med. 1964;83:94–102.CrossRef
33.
go back to reference Connolly JH, O'Neill HJ. Coxsackie A9 virus outbreak in Northern Ireland during 1970. Ulster Med J. 1971;40(2):146–50.PubMedPubMedCentral Connolly JH, O'Neill HJ. Coxsackie A9 virus outbreak in Northern Ireland during 1970. Ulster Med J. 1971;40(2):146–50.PubMedPubMedCentral
34.
go back to reference Kocielska W, Gruszecka A. An epidemic of meningitis caused by Coxsackie A9 virus in the City of Wrocław in 1974. Przegl Epidemiol. 1975;29(4):431–2.PubMed Kocielska W, Gruszecka A. An epidemic of meningitis caused by Coxsackie A9 virus in the City of Wrocław in 1974. Przegl Epidemiol. 1975;29(4):431–2.PubMed
35.
go back to reference Holówka A, Gawron H, Janowicz M, Wysoczyńska H, Zabicka J. An epidemic of meningitis in the Kwidzyń County caused by Coxsackie A9 virus. Przegl Epidemiol. 1975;29(4):433–7.PubMed Holówka A, Gawron H, Janowicz M, Wysoczyńska H, Zabicka J. An epidemic of meningitis in the Kwidzyń County caused by Coxsackie A9 virus. Przegl Epidemiol. 1975;29(4):433–7.PubMed
36.
go back to reference Bello M, Más Lago P, Palomera R, Castillo A, Amín N, Acosta B, et al. Enterovirus meningoencephalitis in the last 5 years. Rev Cubana Med Trop. 1996;48(2):118–22.PubMed Bello M, Más Lago P, Palomera R, Castillo A, Amín N, Acosta B, et al. Enterovirus meningoencephalitis in the last 5 years. Rev Cubana Med Trop. 1996;48(2):118–22.PubMed
37.
go back to reference Farías A, Cabrerizo M, Ré V, Glatstein N, Pisano B, Spinsanti L, et al. Molecular identification of human enteroviruses in children with neurological infections from the central region of Argentina. Arch Virol. 2011;156(1):129–33.CrossRef Farías A, Cabrerizo M, Ré V, Glatstein N, Pisano B, Spinsanti L, et al. Molecular identification of human enteroviruses in children with neurological infections from the central region of Argentina. Arch Virol. 2011;156(1):129–33.CrossRef
38.
go back to reference Butsch R, Tapparel C, Keller P, Herzog K, Krause M, Wunderli W, et al. Family outbreak of an infection with a recombinant Coxsackie a virus in eastern Switzerland. Infection. 2013;41:231–5.CrossRef Butsch R, Tapparel C, Keller P, Herzog K, Krause M, Wunderli W, et al. Family outbreak of an infection with a recombinant Coxsackie a virus in eastern Switzerland. Infection. 2013;41:231–5.CrossRef
39.
go back to reference Pabbaraju K, Wong S, Chan EN, Tellier R. Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010. Virol J. 2013;10:93–101.CrossRef Pabbaraju K, Wong S, Chan EN, Tellier R. Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010. Virol J. 2013;10:93–101.CrossRef
40.
go back to reference Peci A, Winter A-L, Eshaghi A, Marchand-Austin A, Olsha R, Lombardi N, et al. Coxsackie viruses in Ontario, January 2005 to December 2011. International J Infect Dis. 2014;25:136–41.CrossRef Peci A, Winter A-L, Eshaghi A, Marchand-Austin A, Olsha R, Lombardi N, et al. Coxsackie viruses in Ontario, January 2005 to December 2011. International J Infect Dis. 2014;25:136–41.CrossRef
41.
go back to reference 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;7:72–80.CrossRef 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;7:72–80.CrossRef
42.
go back to reference Santti J, Hyypiä T, Kinnunen L, Salminen M. Evidence of recombination among enteroviruses. J Virol. 1999;73(10):8741–9.PubMedPubMedCentral Santti J, Hyypiä T, Kinnunen L, Salminen M. Evidence of recombination among enteroviruses. J Virol. 1999;73(10):8741–9.PubMedPubMedCentral
43.
go back to reference Oberste MS, Peñaranda S, Pallansch MA. RNA recombination plays a major role in genomic change during circulation of coxsackie B viruses. J Virol. 2004;78(6):2948–55.CrossRef Oberste MS, Peñaranda S, Pallansch MA. RNA recombination plays a major role in genomic change during circulation of coxsackie B viruses. J Virol. 2004;78(6):2948–55.CrossRef
44.
go back to reference Hellferscee O, Tempia S, Walaza S, Variava E, Dawood H, Wolter N, et al. Enterovirus genotypes among patients with severe acute respiratory illness, influenza-like illness, and asymptomatic individuals in South Africa, 2012-2014. J Med Virol. 2017;89(10):1759–67.CrossRef Hellferscee O, Tempia S, Walaza S, Variava E, Dawood H, Wolter N, et al. Enterovirus genotypes among patients with severe acute respiratory illness, influenza-like illness, and asymptomatic individuals in South Africa, 2012-2014. J Med Virol. 2017;89(10):1759–67.CrossRef
45.
go back to reference Norder H, Bjerregaard L, Magnius LO. Homotypic echoviruses share amino terminal VP1 sequence homology applicable for typing. J Med Virol. 2001;63(1):35–44.CrossRef Norder H, Bjerregaard L, Magnius LO. Homotypic echoviruses share amino terminal VP1 sequence homology applicable for typing. J Med Virol. 2001;63(1):35–44.CrossRef
46.
go back to reference Reimann BY, Zell R, Kandolf R. Mapping of a neutralizing antigenic site of Coxsackievirus B4 by construction of an antigen chimera. J Virol. 1991;65(7):3475–80.PubMedPubMedCentral Reimann BY, Zell R, Kandolf R. Mapping of a neutralizing antigenic site of Coxsackievirus B4 by construction of an antigen chimera. J Virol. 1991;65(7):3475–80.PubMedPubMedCentral
Metadata
Title
Molecular characterization of an outbreak of enterovirus-associated meningitis in Mossel Bay, South Africa, December 2015–January 2016
Authors
Heidi Smuts
Sarah Cronje
Juno Thomas
Delene Brink
Stephen Korsman
Diana Hardie
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2018
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-018-3641-4

Other articles of this Issue 1/2018

BMC Infectious Diseases 1/2018 Go to the issue