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

doi:10.1016/s2214-109x(18)30349-8

Abstract

SummaryBackgroundOptimum 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.MethodsWe 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.FindingsWe 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]).InterpretationQuantitative 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.FundingBill & Melinda Gates Foundation.

Highlights

Diarrhoea mortality has declined substantially since 1990, diarrhoeal incidence and morbidity remain a substantial problem.[1,2,3] Studies of diarrhoea aetiology estimates of the aetiology and burden of diarrhoea at the community level could help ameliorate this morbidity by informing treatment guidelines and public health interventions.(S S Khan MSc, M O Islam MSc, Prof T Ahmed MBBS, R Haque PhD); Christian Medical College, Vellore, India (I Praharaj MD, R Rajendiran MSc, B Benny MSc, Prof G Kang MD); have focused on children presenting to care, but this only The application of molecular diagnostics for entero-University of Venda, represents a minority of diarrhoea episodes.[4]
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), Department of Public Health Sciences (E T Rogawski, T L McMurry PhD, J H Roberts), University of Virginia, Charlottesville, VA, USA; 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
We have previously reported diarrhoea aetiology estimates in the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite birth cohort study,[13] using qualitative diagnostics to assess a subset of specimens.[14]

Summary

Introduction

Diarrhoea mortality has declined substantially since 1990, diarrhoeal incidence and morbidity remain a substantial problem.[1,2,3] Studies of diarrhoea aetiology estimates of the aetiology and burden of diarrhoea at the community level could help ameliorate this morbidity by informing treatment guidelines and public health interventions.(S S Khan MSc, M O Islam MSc, Prof T Ahmed MBBS, R Haque PhD); Christian Medical College, Vellore, India (I Praharaj MD, R Rajendiran MSc, B Benny MSc, Prof G Kang MD); have focused on children presenting to care, but this only The application of molecular diagnostics for entero-University of Venda, represents a minority of diarrhoea episodes.[4]. E R Mduma MPH); Kilimanjaro Clinical Research Institute, Moshi, Tanzania (B Mujaga BSc, I Kiwelu PhD); Federal. J P Leite PhD); Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA (P P Yori MPH, M McGrath ScD, M N Kosek); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA B J J McCormick DPhil, J C Seidman PhD); Foundation for the National Institutes of Health, Bethesda, MD, USA (D Lang PhD, M Gottlieb PhD); National Institute for Communicable Diseases, Johannesburg, South Africa (N Page PhD); Walter Reed/AFRIMS Research Unit, Nepal, Kathmandu, Nepal (S Shrestha MD); and University of Bergen, Bergen, Norway (S Shrestha). Correspondence to: James A Platts-Mills, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA

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