Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.

After the introduction of the rotavirus vaccine, the number of rotavirus-associated deaths and the predicted annual rotavirus detection rate had slightly declined worldwide. Taking in account that in Colombia, Rotarix vaccine was introduced in 2009, the purpose of this study was to evaluate the pres...

Full description

Autores:
Ruiz Sáenz, Julián
Martínez Gutiérrez, Marlen
Arcila Quiceno, Víctor Hernán
Trejos Suárez, Juanita
Tipo de recurso:
Article of journal
Fecha de publicación:
2019
Institución:
Universidad Cooperativa de Colombia
Repositorio:
Repositorio UCC
Idioma:
OAI Identifier:
oai:repository.ucc.edu.co:20.500.12494/15181
Acceso en línea:
https://hdl.handle.net/20.500.12494/15181
Palabra clave:
Acute diarrhoea
Colombia
Molecular characterization
Post-vaccination
Rotavirus
Rights
openAccess
License
Atribución
id COOPER2_83c270b5f735262c0330eaa7e89e2312
oai_identifier_str oai:repository.ucc.edu.co:20.500.12494/15181
network_acronym_str COOPER2
network_name_str Repositorio UCC
repository_id_str
dc.title.spa.fl_str_mv Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
title Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
spellingShingle Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
Acute diarrhoea
Colombia
Molecular characterization
Post-vaccination
Rotavirus
title_short Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
title_full Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
title_fullStr Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
title_full_unstemmed Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
title_sort Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.
dc.creator.fl_str_mv Ruiz Sáenz, Julián
Martínez Gutiérrez, Marlen
Arcila Quiceno, Víctor Hernán
Trejos Suárez, Juanita
dc.contributor.author.none.fl_str_mv Ruiz Sáenz, Julián
Martínez Gutiérrez, Marlen
Arcila Quiceno, Víctor Hernán
Trejos Suárez, Juanita
dc.subject.spa.fl_str_mv Acute diarrhoea
Colombia
Molecular characterization
Post-vaccination
Rotavirus
topic Acute diarrhoea
Colombia
Molecular characterization
Post-vaccination
Rotavirus
description After the introduction of the rotavirus vaccine, the number of rotavirus-associated deaths and the predicted annual rotavirus detection rate had slightly declined worldwide. Taking in account that in Colombia, Rotarix vaccine was introduced in 2009, the purpose of this study was to evaluate the presence of rotavirus A in children under five years who were treated for acute diarrhoea in Bucaramanga, Colombia and, moreover, to determine the genotypes of rotavirus present in those children. We performed an analytical cross-sectional study of rotavirus A in faecal samples from children up to five years of age. Stool samples were screened for rotavirus A using a lateral-flow immunochromatographic assay and confirmed using a VP6 sandwich ELISA. Genotyping of rotavirus A-positive samples was performed by PCR and sequencing of VP7 and VP4 genes. The overall prevalence of rotavirus was 30.53% (95% confidence interval [CI] 21.2 - 39.7). Most of the children with rotavirus (86.2%) had received two doses of the rotavirus vaccine. G3 strains accounted for the vast majority of cases (82.8%), followed by G12 strains (13.8%) and G3/G9 coinfections (3.4%). Among the P genotypes, P[8] was the most prevalent (69%), followed by P[9] (31%). The most common G[P] genotype combination was G3P[8], followed by G3P[9]. The main finding in this study was that rotavirus, in a Colombian region, is still an important pathogen in children under five years old, previously vaccinated. The results showed that different factors, such as kindergarten attendance, could explain the epidemiology and transmission of rotavirus in Bucaramanga.
publishDate 2019
dc.date.accessioned.none.fl_str_mv 2019-11-22T13:23:27Z
dc.date.available.none.fl_str_mv 2019-11-22T13:23:27Z
dc.date.issued.none.fl_str_mv 2019-07-01
dc.type.none.fl_str_mv Artículo
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.coar.none.fl_str_mv http://purl.org/coar/resource_type/c_6501
dc.type.coarversion.none.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.driver.none.fl_str_mv info:eu-repo/semantics/article
dc.type.version.none.fl_str_mv info:eu-repo/semantics/publishedVersion
format http://purl.org/coar/resource_type/c_6501
status_str publishedVersion
dc.identifier.issn.spa.fl_str_mv 1678-9946
dc.identifier.uri.spa.fl_str_mv doi: 10.1590/S1678-9946201961034.
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/20.500.12494/15181
dc.identifier.bibliographicCitation.spa.fl_str_mv Martinez-Gutierrez M, Arcila-Quiceno V, Trejos-Suarez J, Ruiz-Saenz J. (2019) Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia. Rev Inst Med Trop Sao Paulo. 2019 Jul 1;61:e34. doi: 10.1590/S1678-9946201961034.
identifier_str_mv 1678-9946
doi: 10.1590/S1678-9946201961034.
Martinez-Gutierrez M, Arcila-Quiceno V, Trejos-Suarez J, Ruiz-Saenz J. (2019) Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia. Rev Inst Med Trop Sao Paulo. 2019 Jul 1;61:e34. doi: 10.1590/S1678-9946201961034.
url https://hdl.handle.net/20.500.12494/15181
dc.relation.isversionof.spa.fl_str_mv https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31269110/
dc.relation.ispartofjournal.spa.fl_str_mv Rev Inst Med Trop Sao Paulo
dc.relation.references.spa.fl_str_mv 1. Nguyen TV, Le Van P, Le Huy C, Weintraub A. Diarrhea caused by rotavirus in children less than 5 years of age in Hanoi, Vietnam. J Clin Microbiol. 2004;42:5745-50.
2. Mokomane M, Kasvosve I, Melo E, Pernica JM, Goldfarb DM. The global problem of childhood diarrhoeal diseases: emerging strategies in prevention and management. Ther Adv Infect Dis. 2018;5:29-43.
3. GBD Diarrhoeal Diseases Collaborators. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17:909-48.
4. Crawford SE, Ramani S, Tate JE, Parashar UD, Svensson L, Hagbom M, et al. Rotavirus infection. Nat Rev Dis Primers. 2017;3:17083.
5. Parashar UD, Gibson CJ, Bresse J, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis. 2006;12:304-6.
6. World Health Organization. Meeting of the immunization Strategic Advisory Group of Experts, April 2009: conclusions and recommendations. Wkly Epidemiol Rec. 2009;84:220-36.
7. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization-Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000-2013. Clin Infect Dis. 2016;62 Suppl 2:S96-105.
8. Troeger C, Khalil IA, Rao PC, Cao S, Blacker BF, Ahmed T, et al. Rotavirus vaccination and the global burden of rotavirus diarrhea among children younger than 5 years. JAMA Pediatr. 2018;172:958-65.
9. Bucardo F, Nordgren J. Impact of vaccination on the molecular epidemiology and evolution of group A rotaviruses in Latin America and factors affecting vaccine efficacy. Infect Genet Evol. 2015;34:106-13.
10. Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Dis. 2016;62 Suppl 2:S91-5.
11. Cáceres DC, Peláez D, Sierra N, Estrada E, Sánchez L. La carga de la enfermedad por rotavirus en niños menores de cinco años, Colombia, 2004. Rev Panam Salud Publica. 2006;20:9-21.
12. Uribe Yepes MA, Rodríguez Villamizar LA, Gómez González YA, Olaya Gamboa LE, Rodríguez Santamaría SM. Aislamientos de patógenos comunes asociados con enfermedad diarreica aguda en menores de cinco años, Bucaramanga, Colombia. MedUNAB. 2009;12:72-9.
13. World Health Organization. Manual of rotavirus detection and characterization methods. Geneva: WHO; 2009.
14. Gouvea V, Glass RI, Woods P, Taniguchi K, Clark HF, Forrester B, et al. Polymerase chain reaction amplification and typing of rotavirus nucleic acid from stool specimens. J Clin Microbiol. 1990;28:276-82.
dc.rights.license.none.fl_str_mv Atribución
dc.rights.accessrights.none.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.coar.none.fl_str_mv http://purl.org/coar/access_right/c_abf2
rights_invalid_str_mv Atribución
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.coverage.temporal.spa.fl_str_mv 61
dc.publisher.spa.fl_str_mv Universidad Cooperativa de Colombia, Facultad de Ciencias de la Salud, Medicina Veterinaría y Zootecnia, Bucaramanga
dc.publisher.program.spa.fl_str_mv Medicina veterinaria y zootecnia
dc.publisher.place.spa.fl_str_mv Bucaramanga
institution Universidad Cooperativa de Colombia
bitstream.url.fl_str_mv https://repository.ucc.edu.co/bitstreams/2756e005-5747-4b7a-a8b7-b269ffbe1444/download
https://repository.ucc.edu.co/bitstreams/3e5cbcfb-e968-4847-8652-33cf9eb810d0/download
https://repository.ucc.edu.co/bitstreams/e4d7bb0b-b563-4b05-9392-61e7996987e2/download
https://repository.ucc.edu.co/bitstreams/25477a12-f65c-4cc7-b9e0-f04bd4566bf4/download
https://repository.ucc.edu.co/bitstreams/63b84747-4f31-48e3-a007-f0f945a73d79/download
https://repository.ucc.edu.co/bitstreams/be2c3ad3-4221-4235-b841-7f374c556c0c/download
https://repository.ucc.edu.co/bitstreams/cb98abf0-a6a9-46a9-8177-f4cba10e3cd0/download
bitstream.checksum.fl_str_mv 3bce4f7ab09dfc588f126e1e36e98a45
eecc6b2b98bb8481374d8545d36b6812
c27e057573518047c618f780c5ba12c0
89367e313359b3fd3cc5b7b3446e4264
a558be4521d3f2a5ce4126428facc589
705970d8b30337cf5440d8f65ff0aa3e
9cefe903971384917fdf0deb4249fa08
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Cooperativa de Colombia
repository.mail.fl_str_mv bdigital@metabiblioteca.com
_version_ 1808789312252149760
spelling Ruiz Sáenz, JuliánMartínez Gutiérrez, MarlenArcila Quiceno, Víctor HernánTrejos Suárez, Juanita612019-11-22T13:23:27Z2019-11-22T13:23:27Z2019-07-011678-9946doi: 10.1590/S1678-9946201961034.https://hdl.handle.net/20.500.12494/15181Martinez-Gutierrez M, Arcila-Quiceno V, Trejos-Suarez J, Ruiz-Saenz J. (2019) Prevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia. Rev Inst Med Trop Sao Paulo. 2019 Jul 1;61:e34. doi: 10.1590/S1678-9946201961034.After the introduction of the rotavirus vaccine, the number of rotavirus-associated deaths and the predicted annual rotavirus detection rate had slightly declined worldwide. Taking in account that in Colombia, Rotarix vaccine was introduced in 2009, the purpose of this study was to evaluate the presence of rotavirus A in children under five years who were treated for acute diarrhoea in Bucaramanga, Colombia and, moreover, to determine the genotypes of rotavirus present in those children. We performed an analytical cross-sectional study of rotavirus A in faecal samples from children up to five years of age. Stool samples were screened for rotavirus A using a lateral-flow immunochromatographic assay and confirmed using a VP6 sandwich ELISA. Genotyping of rotavirus A-positive samples was performed by PCR and sequencing of VP7 and VP4 genes. The overall prevalence of rotavirus was 30.53% (95% confidence interval [CI] 21.2 - 39.7). Most of the children with rotavirus (86.2%) had received two doses of the rotavirus vaccine. G3 strains accounted for the vast majority of cases (82.8%), followed by G12 strains (13.8%) and G3/G9 coinfections (3.4%). Among the P genotypes, P[8] was the most prevalent (69%), followed by P[9] (31%). The most common G[P] genotype combination was G3P[8], followed by G3P[9]. The main finding in this study was that rotavirus, in a Colombian region, is still an important pathogen in children under five years old, previously vaccinated. The results showed that different factors, such as kindergarten attendance, could explain the epidemiology and transmission of rotavirus in Bucaramanga.http://scienti.colciencias.gov.co:8081/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000153095https://scienti.colciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000213748https://orcid.org/0000-0002-1447-1458https://orcid.org/0000-0002-9429-0058julian.ruizs@campusucc.edu.coMarlen.martinezg@campucucc.edu.covictor.arcila@ucc.edu.cohttps://scholar.google.com/citations?user=o3Y7mZwAAAAJ&hl=eshttps://scholar.google.es/citations?user=flSrsSIAAAAJ&hl=esUniversidad Cooperativa de Colombia, Facultad de Ciencias de la Salud, Medicina Veterinaría y Zootecnia, BucaramangaMedicina veterinaria y zootecniaBucaramangahttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31269110/Rev Inst Med Trop Sao Paulo1. Nguyen TV, Le Van P, Le Huy C, Weintraub A. Diarrhea caused by rotavirus in children less than 5 years of age in Hanoi, Vietnam. J Clin Microbiol. 2004;42:5745-50.2. Mokomane M, Kasvosve I, Melo E, Pernica JM, Goldfarb DM. The global problem of childhood diarrhoeal diseases: emerging strategies in prevention and management. Ther Adv Infect Dis. 2018;5:29-43.3. GBD Diarrhoeal Diseases Collaborators. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17:909-48.4. Crawford SE, Ramani S, Tate JE, Parashar UD, Svensson L, Hagbom M, et al. Rotavirus infection. Nat Rev Dis Primers. 2017;3:17083.5. Parashar UD, Gibson CJ, Bresse J, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis. 2006;12:304-6.6. World Health Organization. Meeting of the immunization Strategic Advisory Group of Experts, April 2009: conclusions and recommendations. Wkly Epidemiol Rec. 2009;84:220-36.7. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization-Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000-2013. Clin Infect Dis. 2016;62 Suppl 2:S96-105.8. Troeger C, Khalil IA, Rao PC, Cao S, Blacker BF, Ahmed T, et al. Rotavirus vaccination and the global burden of rotavirus diarrhea among children younger than 5 years. JAMA Pediatr. 2018;172:958-65.9. Bucardo F, Nordgren J. Impact of vaccination on the molecular epidemiology and evolution of group A rotaviruses in Latin America and factors affecting vaccine efficacy. Infect Genet Evol. 2015;34:106-13.10. Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Dis. 2016;62 Suppl 2:S91-5.11. Cáceres DC, Peláez D, Sierra N, Estrada E, Sánchez L. La carga de la enfermedad por rotavirus en niños menores de cinco años, Colombia, 2004. Rev Panam Salud Publica. 2006;20:9-21.12. Uribe Yepes MA, Rodríguez Villamizar LA, Gómez González YA, Olaya Gamboa LE, Rodríguez Santamaría SM. Aislamientos de patógenos comunes asociados con enfermedad diarreica aguda en menores de cinco años, Bucaramanga, Colombia. MedUNAB. 2009;12:72-9.13. World Health Organization. Manual of rotavirus detection and characterization methods. Geneva: WHO; 2009.14. Gouvea V, Glass RI, Woods P, Taniguchi K, Clark HF, Forrester B, et al. Polymerase chain reaction amplification and typing of rotavirus nucleic acid from stool specimens. J Clin Microbiol. 1990;28:276-82.Acute diarrhoeaColombiaMolecular characterizationPost-vaccinationRotavirusPrevalence and molecular typing of rotavirus in children with acute diarrhoea in Northeastern Colombia.Artículohttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionAtribucióninfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2PublicationLICENSElicense.txtlicense.txttext/plain; charset=utf-84334https://repository.ucc.edu.co/bitstreams/2756e005-5747-4b7a-a8b7-b269ffbe1444/download3bce4f7ab09dfc588f126e1e36e98a45MD54ORIGINALMartinez-Gutierrez Rotavirus 2019.pdfMartinez-Gutierrez Rotavirus 2019.pdfTrabajo de gradoapplication/pdf607156https://repository.ucc.edu.co/bitstreams/3e5cbcfb-e968-4847-8652-33cf9eb810d0/downloadeecc6b2b98bb8481374d8545d36b6812MD51Licencia_de_uso_Rotavirus.pdfLicencia_de_uso_Rotavirus.pdfFormato de autorizaciónapplication/pdf169103https://repository.ucc.edu.co/bitstreams/e4d7bb0b-b563-4b05-9392-61e7996987e2/downloadc27e057573518047c618f780c5ba12c0MD53THUMBNAILMartinez-Gutierrez Rotavirus 2019.pdf.jpgMartinez-Gutierrez Rotavirus 2019.pdf.jpgGenerated Thumbnailimage/jpeg5490https://repository.ucc.edu.co/bitstreams/25477a12-f65c-4cc7-b9e0-f04bd4566bf4/download89367e313359b3fd3cc5b7b3446e4264MD55Licencia_de_uso_Rotavirus.pdf.jpgLicencia_de_uso_Rotavirus.pdf.jpgGenerated Thumbnailimage/jpeg5437https://repository.ucc.edu.co/bitstreams/63b84747-4f31-48e3-a007-f0f945a73d79/downloada558be4521d3f2a5ce4126428facc589MD56TEXTMartinez-Gutierrez Rotavirus 2019.pdf.txtMartinez-Gutierrez Rotavirus 2019.pdf.txtExtracted texttext/plain43663https://repository.ucc.edu.co/bitstreams/be2c3ad3-4221-4235-b841-7f374c556c0c/download705970d8b30337cf5440d8f65ff0aa3eMD57Licencia_de_uso_Rotavirus.pdf.txtLicencia_de_uso_Rotavirus.pdf.txtExtracted texttext/plain5568https://repository.ucc.edu.co/bitstreams/cb98abf0-a6a9-46a9-8177-f4cba10e3cd0/download9cefe903971384917fdf0deb4249fa08MD5820.500.12494/15181oai:repository.ucc.edu.co:20.500.12494/151812024-08-09 12:02:20.747open.accesshttps://repository.ucc.edu.coRepositorio Institucional Universidad Cooperativa de Colombiabdigital@metabiblioteca.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