Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi

Chisomo L. Msefula, Franziska Olgemoeller, Ndaru Jambo, Dalitso Segula, Trinh Van Tan, Tonney S. Nyirenda, Wilfred Nedi, Neil Kennedy, Matthew Graham, Marc Y.R. Henrion, Stephen Baker, Nicholas Feasey, Melita Gordon, Robert S. Heyderman

Research output: Contribution to journalArticle

Abstract

Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0-4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62-94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.

LanguageEnglish
Article numbere0007539
Number of pages16
JournalPLoS Neglected Tropical Diseases
Volume13
Issue number7
DOIs
Publication statusPublished - 17 Jul 2019

Fingerprint

Malawi
Hospitalized Child
Salmonella
Fever
Polymerase Chain Reaction
Typhoid Fever
Typhoid-Paratyphoid Vaccines
Immunoglobulin M
Real-Time Polymerase Chain Reaction
Immunoglobulin G
Antigens
Hemolysin Proteins
Africa South of the Sahara
Blood Volume
Tertiary Care Centers
Bile
Cohort Studies
Vaccines
Enzyme-Linked Immunosorbent Assay
Blood Culture

Cite this

Msefula, C. L., Olgemoeller, F., Jambo, N., Segula, D., Van Tan, T., Nyirenda, T. S., ... Heyderman, R. S. (2019). Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi. PLoS Neglected Tropical Diseases, 13(7), [e0007539]. https://doi.org/10.1371/journal.pntd.0007539
Msefula, Chisomo L. ; Olgemoeller, Franziska ; Jambo, Ndaru ; Segula, Dalitso ; Van Tan, Trinh ; Nyirenda, Tonney S. ; Nedi, Wilfred ; Kennedy, Neil ; Graham, Matthew ; Henrion, Marc Y.R. ; Baker, Stephen ; Feasey, Nicholas ; Gordon, Melita ; Heyderman, Robert S. / Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi. In: PLoS Neglected Tropical Diseases. 2019 ; Vol. 13, No. 7.
@article{40f6a191b90941e0b9b31268afaa0355,
title = "Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi",
abstract = "Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0-4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8{\%}) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62-94{\%}. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.",
author = "Msefula, {Chisomo L.} and Franziska Olgemoeller and Ndaru Jambo and Dalitso Segula and {Van Tan}, Trinh and Nyirenda, {Tonney S.} and Wilfred Nedi and Neil Kennedy and Matthew Graham and Henrion, {Marc Y.R.} and Stephen Baker and Nicholas Feasey and Melita Gordon and Heyderman, {Robert S.}",
year = "2019",
month = "7",
day = "17",
doi = "10.1371/journal.pntd.0007539",
language = "English",
volume = "13",
journal = "PLoS Neglected Tropical Diseases",
issn = "1935-2727",
publisher = "Public Library of Science",
number = "7",

}

Msefula, CL, Olgemoeller, F, Jambo, N, Segula, D, Van Tan, T, Nyirenda, TS, Nedi, W, Kennedy, N, Graham, M, Henrion, MYR, Baker, S, Feasey, N, Gordon, M & Heyderman, RS 2019, 'Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi', PLoS Neglected Tropical Diseases, vol. 13, no. 7, e0007539. https://doi.org/10.1371/journal.pntd.0007539

Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi. / Msefula, Chisomo L.; Olgemoeller, Franziska; Jambo, Ndaru; Segula, Dalitso; Van Tan, Trinh; Nyirenda, Tonney S.; Nedi, Wilfred; Kennedy, Neil; Graham, Matthew; Henrion, Marc Y.R.; Baker, Stephen; Feasey, Nicholas; Gordon, Melita; Heyderman, Robert S.

In: PLoS Neglected Tropical Diseases, Vol. 13, No. 7, e0007539, 17.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi

AU - Msefula, Chisomo L.

AU - Olgemoeller, Franziska

AU - Jambo, Ndaru

AU - Segula, Dalitso

AU - Van Tan, Trinh

AU - Nyirenda, Tonney S.

AU - Nedi, Wilfred

AU - Kennedy, Neil

AU - Graham, Matthew

AU - Henrion, Marc Y.R.

AU - Baker, Stephen

AU - Feasey, Nicholas

AU - Gordon, Melita

AU - Heyderman, Robert S.

PY - 2019/7/17

Y1 - 2019/7/17

N2 - Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0-4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62-94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.

AB - Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0-4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62-94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.

UR - http://www.scopus.com/inward/record.url?scp=85070788775&partnerID=8YFLogxK

U2 - 10.1371/journal.pntd.0007539

DO - 10.1371/journal.pntd.0007539

M3 - Article

VL - 13

JO - PLoS Neglected Tropical Diseases

T2 - PLoS Neglected Tropical Diseases

JF - PLoS Neglected Tropical Diseases

SN - 1935-2727

IS - 7

M1 - e0007539

ER -