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

James A Platts-Mills, Jie Liu, Elizabeth T Rogawski, Furqan Kabir, Paphavee Lertsethtakarn, Mery Siguas, Shaila S Khan, Ira Praharaj, Arinao Murei, Rosemary Nshama, Buliga Mujaga, Alexandre Havt, Irene A Maciel, Timothy L McMurry, Darwin J Operario, Mami Taniuchi, Jean Gratz, Suzanne E Stroup, James H Roberts, Adil Kalam, Fatima Aziz, Shahida Qureshi, M Ohedul Islam, Pimmada Sakpaisal, Sasikorn Silapong, Pablo P Yori, Revathi Rajendiran, Blossom Benny, Monica McGrath, Benjamin J J McCormick, Jessica C Seidman, Dennis Lang, Michael Gottlieb, Richard L Guerrant, Aldo A M Lima, Jose Paulo Leite, Amidou Samie, Pascal O Bessong, Nicola Page, Ladaporn Bodhidatta, Carl Mason, Sanjaya Shrestha, Ireen Kiwelu, Estomih R Mduma, Najeeha T Iqbal, Zulfiqar A Bhutta, Tahmeed Ahmed, Rashidul Haque, Gagandeep Kang, Margaret N Kosek, Eric R Houpt, MAL-ED Network Investigators, Angel Mendez Acosta, Rosa Rios de Burga, Cesar Banda Chavez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed, Didar Alam, Asad Ali, Muneera Rasheed, Sajid Soofi, Ali Turab, Aisha Yousafzai, Anita Km Zaidi, Binob Shrestha, Bishnu Bahadur Rayamajhi, Tor Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila T George, Dinesh Hariraju, M Steffi Jennifer, Sushil John, Shiny Kaki, Priyadarshani Karunakaran, Beena Koshy, Robin P Lazarus, Jayaprakash Muliyil, Preethi Ragasudha, Mohan Venkata Raghava, Sophy Raju, Anup Ramachandran, Rakhi Ramadas, Karthikeyan Ramanujam, Anuradha Rose, Reeba Roshan, Srujan L Sharma, Shanmuga Sundaram, Rahul J Thomas, William K Pan, Ramya Ambikapathi, J Daniel Carreon, Viyada Doan, Christel Hoest, Stacey Knobler, Mark A Miller, Stephanie Psaki, Zeba Rasmussen, Stephanie A Richard, Karen H Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal, Ladislaus Yarrot, Leah Barrett, Rebecca Dillingham, William A Petri, Rebecca Scharf, Am Shamsir Ahmed, Md Ashraful Alam, Umma Haque, Md Iqbal Hossain, Munirul Islam, Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram Krishna Chandyo, Prakash Sunder Shrestha, Rita Shrestha, Manjeswori Ulak, Aubrey Bauck, Robert Black, Laura Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E Murray-Kolb, A Catharine Ross, Barbara Schaefer, Suzanne Simons, Laura Pendergast, Cláudia B Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M Leite, Noélia L Lima, Ila F Lima, Bruna Ll Maciel, Pedro Hqs Medeiros, Milena Moraes, Francisco S Mota, Reinaldo B Oriá, Josiane Quetz, Alberto M Soares, Rosa Ms Mota, Crystal L Patil, Cloupas Mahopo, Angelina Maphula, Emanuel Nyathi, James A Platts-Mills, Jie Liu, Elizabeth T Rogawski, Furqan Kabir, Paphavee Lertsethtakarn, Mery Siguas, Shaila S Khan, Ira Praharaj, Arinao Murei, Rosemary Nshama, Buliga Mujaga, Alexandre Havt, Irene A Maciel, Timothy L McMurry, Darwin J Operario, Mami Taniuchi, Jean Gratz, Suzanne E Stroup, James H Roberts, Adil Kalam, Fatima Aziz, Shahida Qureshi, M Ohedul Islam, Pimmada Sakpaisal, Sasikorn Silapong, Pablo P Yori, Revathi Rajendiran, Blossom Benny, Monica McGrath, Benjamin J J McCormick, Jessica C Seidman, Dennis Lang, Michael Gottlieb, Richard L Guerrant, Aldo A M Lima, Jose Paulo Leite, Amidou Samie, Pascal O Bessong, Nicola Page, Ladaporn Bodhidatta, Carl Mason, Sanjaya Shrestha, Ireen Kiwelu, Estomih R Mduma, Najeeha T Iqbal, Zulfiqar A Bhutta, Tahmeed Ahmed, Rashidul Haque, Gagandeep Kang, Margaret N Kosek, Eric R Houpt, MAL-ED Network Investigators, Angel Mendez Acosta, Rosa Rios de Burga, Cesar Banda Chavez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed, Didar Alam, Asad Ali, Muneera Rasheed, Sajid Soofi, Ali Turab, Aisha Yousafzai, Anita Km Zaidi, Binob Shrestha, Bishnu Bahadur Rayamajhi, Tor Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila T George, Dinesh Hariraju, M Steffi Jennifer, Sushil John, Shiny Kaki, Priyadarshani Karunakaran, Beena Koshy, Robin P Lazarus, Jayaprakash Muliyil, Preethi Ragasudha, Mohan Venkata Raghava, Sophy Raju, Anup Ramachandran, Rakhi Ramadas, Karthikeyan Ramanujam, Anuradha Rose, Reeba Roshan, Srujan L Sharma, Shanmuga Sundaram, Rahul J Thomas, William K Pan, Ramya Ambikapathi, J Daniel Carreon, Viyada Doan, Christel Hoest, Stacey Knobler, Mark A Miller, Stephanie Psaki, Zeba Rasmussen, Stephanie A Richard, Karen H Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal, Ladislaus Yarrot, Leah Barrett, Rebecca Dillingham, William A Petri, Rebecca Scharf, Am Shamsir Ahmed, Md Ashraful Alam, Umma Haque, Md Iqbal Hossain, Munirul Islam, Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram Krishna Chandyo, Prakash Sunder Shrestha, Rita Shrestha, Manjeswori Ulak, Aubrey Bauck, Robert Black, Laura Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E Murray-Kolb, A Catharine Ross, Barbara Schaefer, Suzanne Simons, Laura Pendergast, Cláudia B Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M Leite, Noélia L Lima, Ila F Lima, Bruna Ll Maciel, Pedro Hqs Medeiros, Milena Moraes, Francisco S Mota, Reinaldo B Oriá, Josiane Quetz, Alberto M Soares, Rosa Ms Mota, Crystal L Patil, Cloupas Mahopo, Angelina Maphula, Emanuel Nyathi

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.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Attributable incidence of pathogen-specific diarrhoea at ages 0–11 months (A) and 12–24 months (B) in the MAL-ED cohort study by quantitative PCR Error bars show 95% CI. ETEC=enterotoxigenic E coli. tEPEC=typical enteropathogenic E coli. EAEC=enteroaggregative E coli. aEPEC=atypical enteropathogenic E coli. STEC=Shiga toxin-producing E coli.
Figure 2
Figure 2
Attributable incidence of pathogen-specific diarrhoea by site in the MAL-ED cohort study by quantitative PCR The ten pathogens with the highest overall attributable incidence are shown. Error bars show 95% CI. ETEC=enterotoxigenic E coli. tEPEC=typical enteropathogenic E coli. *Sites where rotavirus vaccine has been added to the national immunisation schedule.
Figure 3
Figure 3
Aetiologic detections and co-infections in diarrhoea episodes (A) Number of pathogens detected in diarrhoea episodes. Aetiologic quantity was defined as an AFe of 0·5 or more. (B) Distribution of pathogen detections, stratified by aetiologic attribution. When more than one aetiologic detection was present, the primary aetiology was defined as the pathogen with the highest AFe. Pathogens are ordered according to the proportion of aetiologic detections for which they were the primary aetiology. Cq=quantification cycles. ETEC=enterotoxigenic E coli. tEPEC=typical enteropathogenic E coli. AFe=attributable fraction for that episode.

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Source: PubMed

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