The Lancet Global Health (Dec 2018)
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, MD,
- Jie Liu, PhD,
- Elizabeth T Rogawski, PhD,
- Furqan Kabir, MSc,
- Paphavee Lertsethtakarn, PhD,
- Mery Siguas, BSc,
- Shaila S Khan, MSc,
- Ira Praharaj, MD,
- Arinao Murei, BSc,
- Rosemary Nshama, BSc,
- Buliga Mujaga, BSc,
- Alexandre Havt, PhD,
- Irene A Maciel, PhD,
- Timothy L McMurry, PhD,
- Darwin J Operario, PhD,
- Mami Taniuchi, PhD,
- Jean Gratz, MS,
- Suzanne E Stroup, MS,
- James H Roberts,
- Adil Kalam, MSc,
- Fatima Aziz, MSc,
- Shahida Qureshi, MSc,
- M Ohedul Islam, MSc,
- Pimmada Sakpaisal, MSc,
- Sasikorn Silapong, B BSc,
- Pablo P Yori, MPH,
- Revathi Rajendiran, MSc,
- Blossom Benny, MSc,
- Monica McGrath, ScD,
- Benjamin J J McCormick, DPhil,
- Jessica C Seidman, PhD,
- Dennis Lang, PhD,
- Michael Gottlieb, PhD,
- Richard L Guerrant, MD,
- Aldo A M Lima, ProfPhD,
- Jose Paulo Leite, PhD,
- Amidou Samie, PhD,
- Pascal O Bessong, ProfPhD,
- Nicola Page, PhD,
- Ladaporn Bodhidatta, MD,
- Carl Mason, MD,
- Sanjaya Shrestha, MD,
- Ireen Kiwelu, PhD,
- Estomih R Mduma, MPH,
- Najeeha T Iqbal, PhD,
- Zulfiqar A Bhutta, ProfPhD,
- Tahmeed Ahmed, ProfMBBS,
- Rashidul Haque, PhD,
- Gagandeep Kang, ProfMD,
- Margaret N Kosek, MD,
- Eric R Houpt, ProfMD,
- 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
Affiliations
- James A Platts-Mills, MD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA; Correspondence to: James A Platts-Mills, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA
- Jie Liu, PhD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- Elizabeth T Rogawski, PhD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
- Furqan Kabir, MSc
- Aga Khan University, Karachi, Pakistan
- Paphavee Lertsethtakarn, PhD
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
- Mery Siguas, BSc
- Asociación Benéfica PRISMA, Iquitos, Peru
- Shaila S Khan, MSc
- International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
- Ira Praharaj, MD
- Christian Medical College, Vellore, India
- Arinao Murei, BSc
- University of Venda, Thohoyandou, South Africa
- Rosemary Nshama, BSc
- Haydom Global Health Institute, Haydom, Tanzania
- Buliga Mujaga, BSc
- Kilimanjaro Clinical Research Institute, Moshi, Tanzania
- Alexandre Havt, PhD
- Federal University of Ceara, Fortaleza, Brazil
- Irene A Maciel, PhD
- Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Timothy L McMurry, PhD
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
- Darwin J Operario, PhD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- Mami Taniuchi, PhD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- Jean Gratz, MS
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- Suzanne E Stroup, MS
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- James H Roberts
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
- Adil Kalam, MSc
- Aga Khan University, Karachi, Pakistan
- Fatima Aziz, MSc
- Aga Khan University, Karachi, Pakistan
- Shahida Qureshi, MSc
- Aga Khan University, Karachi, Pakistan
- M Ohedul Islam, MSc
- International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
- Pimmada Sakpaisal, MSc
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
- Sasikorn Silapong, B BSc
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
- Pablo P Yori, MPH
- Asociación Benéfica PRISMA, Iquitos, Peru; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Revathi Rajendiran, MSc
- Christian Medical College, Vellore, India
- Blossom Benny, MSc
- Christian Medical College, Vellore, India
- Monica McGrath, ScD
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Fogarty International Center, National Institutes of Health, Bethesda, MD, USA
- Benjamin J J McCormick, DPhil
- Fogarty International Center, National Institutes of Health, Bethesda, MD, USA
- Jessica C Seidman, PhD
- Fogarty International Center, National Institutes of Health, Bethesda, MD, USA
- Dennis Lang, PhD
- Foundation for the National Institutes of Health, Bethesda, MD, USA
- Michael Gottlieb, PhD
- Foundation for the National Institutes of Health, Bethesda, MD, USA
- Richard L Guerrant, MD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- Aldo A M Lima, ProfPhD
- Federal University of Ceara, Fortaleza, Brazil
- Jose Paulo Leite, PhD
- Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Amidou Samie, PhD
- University of Venda, Thohoyandou, South Africa
- Pascal O Bessong, ProfPhD
- University of Venda, Thohoyandou, South Africa
- Nicola Page, PhD
- National Institute for Communicable Diseases, Johannesburg, South Africa
- Ladaporn Bodhidatta, MD
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
- Carl Mason, MD
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
- Sanjaya Shrestha, MD
- Walter Reed/AFRIMS Research Unit, Nepal, Kathmandu, Nepal; University of Bergen, Bergen, Norway
- Ireen Kiwelu, PhD
- Kilimanjaro Clinical Research Institute, Moshi, Tanzania
- Estomih R Mduma, MPH
- Haydom Global Health Institute, Haydom, Tanzania
- Najeeha T Iqbal, PhD
- Aga Khan University, Karachi, Pakistan
- Zulfiqar A Bhutta, ProfPhD
- Aga Khan University, Karachi, Pakistan
- Tahmeed Ahmed, ProfMBBS
- International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
- Rashidul Haque, PhD
- International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
- Gagandeep Kang, ProfMD
- Christian Medical College, Vellore, India
- Margaret N Kosek, MD
- Asociación Benéfica PRISMA, Iquitos, Peru; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Eric R Houpt, ProfMD
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
- 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
- Journal volume & issue
-
Vol. 6,
no. 12
pp. e1309 – e1318
Abstract
Summary: 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.
