Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study

The MAL-ED Network Investigators

Research output: Contribution to journalArticle

Abstract

Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

Original languageEnglish (US)
Pages (from-to)e1309-e1318
JournalThe Lancet Global Health
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2018

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Molecular Pathology
Diarrhea
Cohort Studies
Shigella
Sapovirus
Incidence
Bacillary Dysentery
Norovirus
Enterotoxigenic Escherichia coli
Enteropathogenic Escherichia coli
Polymerase Chain Reaction
Cryptosporidium
Nepal
Campylobacter jejuni
Peru
Bangladesh
Tanzania
Rotavirus
Pakistan
Child Development

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{b4792204fd5e47dabc84b1e759a3b06a,
title = "Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study",
abstract = "Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9{\%} of diarrhoea episodes (95{\%} CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8{\%} (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4{\%} of overall incidence, 95{\%} CI 33·6–39·5) was more common than bacterial (25·0{\%}, 23·4–28·4) and parasitic diarrhoea (3·5{\%}, 3·0–5·2). Ten pathogens accounted for 95·7{\%} of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95{\%} CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2{\%} of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4{\%} [95{\%} CI 46·7–54·1], specificity 84·0{\%} [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5{\%} [95{\%} CI 12·1–17·3], specificity 96·5{\%} [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.",
author = "{The MAL-ED Network Investigators} and Platts-Mills, {James A.} and Jie Liu and Rogawski, {Elizabeth T.} and Furqan Kabir and Paphavee Lertsethtakarn and Mery Siguas and Khan, {Shaila S.} and Ira Praharaj and Arinao Murei and Rosemary Nshama and Buliga Mujaga and Alexandre Havt and Maciel, {Irene A.} and McMurry, {Timothy L.} and Operario, {Darwin J.} and Mami Taniuchi and Jean Gratz and Stroup, {Suzanne E.} and Roberts, {James H.} and Adil Kalam and Fatima Aziz and Shahida Qureshi and Islam, {M. Ohedul} and Pimmada Sakpaisal and Sasikorn Silapong and {Penataro Yori}, Pablo and Revathi Rajendiran and Blossom Benny and Monica McGrath and McCormick, {Benjamin J.J.} and Seidman, {Jessica C.} and Dennis Lang and Michael Gottlieb and Guerrant, {Richard L.} and Lima, {Aldo A.M.} and Leite, {Jose Paulo} and Amidou Samie and Bessong, {Pascal O.} and Nicola Page and Ladaporn Bodhidatta and Carl Mason and Sanjaya Shrestha and Ireen Kiwelu and Mduma, {Estomih R.} and Iqbal, {Najeeha T.} and Kosek, {Margaret N.} and Robert Black and Laura Caulfield and William Checkley and Kerry Schulze",
year = "2018",
month = "12",
day = "1",
doi = "10.1016/S2214-109X(18)30349-8",
language = "English (US)",
volume = "6",
pages = "e1309--e1318",
journal = "The Lancet Global Health",
issn = "2214-109X",
publisher = "Elsevier BV",
number = "12",

}

TY - JOUR

T1 - Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings

T2 - a reanalysis of the MAL-ED cohort study

AU - The MAL-ED Network Investigators

AU - Platts-Mills, James A.

AU - Liu, Jie

AU - Rogawski, Elizabeth T.

AU - Kabir, Furqan

AU - Lertsethtakarn, Paphavee

AU - Siguas, Mery

AU - Khan, Shaila S.

AU - Praharaj, Ira

AU - Murei, Arinao

AU - Nshama, Rosemary

AU - Mujaga, Buliga

AU - Havt, Alexandre

AU - Maciel, Irene A.

AU - McMurry, Timothy L.

AU - Operario, Darwin J.

AU - Taniuchi, Mami

AU - Gratz, Jean

AU - Stroup, Suzanne E.

AU - Roberts, James H.

AU - Kalam, Adil

AU - Aziz, Fatima

AU - Qureshi, Shahida

AU - Islam, M. Ohedul

AU - Sakpaisal, Pimmada

AU - Silapong, Sasikorn

AU - Penataro Yori, Pablo

AU - Rajendiran, Revathi

AU - Benny, Blossom

AU - McGrath, Monica

AU - McCormick, Benjamin J.J.

AU - Seidman, Jessica C.

AU - Lang, Dennis

AU - Gottlieb, Michael

AU - Guerrant, Richard L.

AU - Lima, Aldo A.M.

AU - Leite, Jose Paulo

AU - Samie, Amidou

AU - Bessong, Pascal O.

AU - Page, Nicola

AU - Bodhidatta, Ladaporn

AU - Mason, Carl

AU - Shrestha, Sanjaya

AU - Kiwelu, Ireen

AU - Mduma, Estomih R.

AU - Iqbal, Najeeha T.

AU - Kosek, Margaret N.

AU - Black, Robert

AU - Caulfield, Laura

AU - Checkley, William

AU - Schulze, Kerry

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

AB - Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

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DO - 10.1016/S2214-109X(18)30349-8

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AN - SCOPUS:85056358756

VL - 6

SP - e1309-e1318

JO - The Lancet Global Health

JF - The Lancet Global Health

SN - 2214-109X

IS - 12

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