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(University of Virginia Health System), Jie Liu(University of Virginia), Elizabeth T. Rogawski McQuade(University of Virginia Health System), Furqan Kabir(Aga Khan University), Paphavee Lertsethtakarn(Armed Forces Research Institute of Medical Science), Mery Siguas(Prisma), Shaila Khan(International Centre for Diarrhoeal Disease Research), Ira Praharaj(Christian Medical College, Vellore), Arinao Murei(University of Venda), Rosemary Nshama(Haydom Lutheran Hospital), Buliga Mujaga(Kilimanjaro Christian Medical Centre), Alexandre Havt(Universidade Federal do Ceará), Irene A Maciel(Fundação Oswaldo Cruz), Timothy L. McMurry(University of Virginia), Darwin J. Operario(University of Virginia), Mami Taniuchi(University of Virginia), Jean Gratz(University of Virginia), Suzanne Stroup(University of Virginia), James H. Roberts(University of Virginia), Adil Kalam(Aga Khan University), Fátima Aziz(Aga Khan University), Shahida Qureshi(Aga Khan University), Mamunul Islam(International Centre for Diarrhoeal Disease Research), Pimmada Sakpaisal(Armed Forces Research Institute of Medical Science), Sasikorn Silapong(Armed Forces Research Institute of Medical Science), Pablo P Yori(Johns Hopkins University), Revathi Rajendiran(Christian Medical College, Vellore), Blossom Benny(Christian Medical College, Vellore), Monica McGrath(National Institutes of Health), Benjamin McCormick(National Institutes of Health), Jessica C. Seidman(National Institutes of Health), Dennis Lang(Foundation for the National Institutes of Health), Michael Gottlieb(Foundation for the National Institutes of Health), Richard L. Guerrant(University of Virginia), Aldo Â. M. Lima(Universidade Federal do Ceará), José Paulo Gagliardi Leite(Fundação Oswaldo Cruz), Amidou Samie(University of Venda), Pascal Bessong(University of Venda), Nicola Page(National Institute for Communicable Diseases), Ladaporn Bodhidatta(Armed Forces Research Institute of Medical Science), Carl J. Mason(Armed Forces Research Institute of Medical Science), Sanjaya K. Shrestha(University of Bergen), Ireen Kiwelu(Kilimanjaro Christian Medical Centre), Estomih Mduma(Haydom Lutheran Hospital), Najeeha Talat Iqbal(Aga Khan University), Zulfiqar A Bhutta(Aga Khan University), Tahmeed Ahmed(International Centre for Diarrhoeal Disease Research), Rashidul Haque(International Centre for Diarrhoeal Disease Research), Gagandeep Kang(Christian Medical College, Vellore), Margaret Kosek(Johns Hopkins University), Eric R. Houpt(University of Virginia), Angel Mendez Acosta, Rosa Burga, César Banda Chávez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed(International Centre for Diarrhoeal Disease Research), Didar Alam(Aga Khan University), Asad Ali, Muneera A. Rasheed, Sajid Soofi, Ali Turab, Aisha K. Yousafzai, Anita K. M. Zaidi, Binob Shrestha(University of Bergen), Bishnu Bahadur Rayamajhi, Tor A. Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila George, Dinesh Hariraju, Mats 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(Haydom Lutheran Hospital), Reeba Roshan, Srujan Lam 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(University of Virginia), Karen H. Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal(University of Venda), Ladislaus Yarrot, Leah J. Barrett, Rebecca Dillingham, William A. Petri, Rebecca J. Scharf, AM Shamsir Ahmed(International Centre for Diarrhoeal Disease Research), Md Ashraful Alam(Aga Khan University), Umma Haque(International Centre for Diarrhoeal Disease Research), Md Iqbal Hossain, M Munirul Islam(International Centre for Diarrhoeal Disease Research), Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram K. Chandyo, Prakash Shrestha(University of Bergen), Rita Shrestha(University of Bergen), Manjeswori Ulak, Aubrey Bauck, Robert E. Black(University of Virginia), Laura E. Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E. Murray‐Kolb, A. Catharine Ross, Barbara A. Schaefer, Suzanne Simons(University of Virginia), Laura Pendergast, Cláudia Buhamra Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M. Leite(Fundação Oswaldo Cruz), Noélia L. Lima(Universidade Federal do Ceará), Ila F.N. Lima(Universidade Federal do Ceará), Bruna Leal Lima Maciel(Fundação Oswaldo Cruz), Pedro H.Q.S. Medeiros, Milena Lima de Moraes, Francisco Suetônio Bastos Mota, Reinaldo B. Oriá, Josiane da Silva Quetz, Alberto M. Soares, Rosa MS Mota, Crystal L. Patil, Cloupas Mahopo, Angelina Maphula, Emanuel Nyathi
The Lancet Global Health
October 1, 2018
10.1016/s2214-109x(18)30349-8
Cited by 396Open Access
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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.

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