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Lancet. 2016 Sep 24;388(10051):1291-301. doi: 10.1016/S0140-6736(16)31529-X.

Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study.

Author information

1
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.
2
Center for Global Health Research, Kenya Medical Research Institute, Nairobi, Kenya.
3
Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
4
Center for Vaccine Development and Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
5
Medical Research Council Unit, Banjul, The Gambia.
6
International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B), Dhaka, Bangladesh.
7
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique; Barcelona Centre for International Health Research (CRESIB, Hospital Clinic-Universitat de Barcelona), Barcelona, Spain.
8
Global Disease Detection Division, Kenya Office of the US Centers for Disease Control and Prevention, Nairobi, Kenya.
9
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
10
Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
11
Center for Vaccine Development and Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
12
National Institute of Cholera and Enteric Diseases, Kolkata, India.
13
Centre pour le Développement des Vaccins, Bamako, Mali.
14
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA.
15
Center for Vaccine Development and Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
16
Center for Vaccine Development and Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
17
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA. Electronic address: erh6k@virginia.edu.

Abstract

BACKGROUND:

Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS).

METHODS:

GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children.

FINDINGS:

We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2-96·0) at the population level, compared with 51·5% (48·0-55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6-80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections.

INTERPRETATION:

A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised.

FUNDING:

Bill & Melinda Gates Foundation.

PMID:
27673470
PMCID:
PMC5471845
DOI:
10.1016/S0140-6736(16)31529-X
[Indexed for MEDLINE]
Free PMC Article

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