Elsevier

The Lancet

Volume 382, Issue 9888, 20–26 July 2013, Pages 209-222
The Lancet

Articles
Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study

https://doi.org/10.1016/S0140-6736(13)60844-2Get rights and content

Summary

Background

Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia.

Methods

The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0–59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth.

Findings

We enrolled 9439 children with moderate-to-severe diarrhoea and 13 129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8–12·5, p<0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99–3·5) and typical enteropathogenic E coli (HR 2·6; 1·6–4·1) in infants aged 0–11 months, and Cryptosporidium (HR 2·3; 1·3–4·3) in toddlers aged 12–23 months.

Interpretation

Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes.

Funding

The Bill & Melinda Gates Foundation.

Introduction

Globally, one in ten child deaths result from diarrhoeal disease during the first 5 years of life, resulting in about 800 000 fatalities worldwide annually, most occurring in sub-Saharan Africa and south Asia.1 Although diarrhoeal mortality remains unacceptably high, it is decreasing by about 4% per year,1 whereas disease incidence is declining more modestly.2 Interventions that target the main causes and focus on the most susceptible children should further accelerate these declines. To guide these efforts, robust data characterising the burden, risk factors, microbiological aetiology, sequelae, and case fatality of most life-threatening and disabling episodes are essential; heretofore, such data have been scarce in regions with the highest child mortality. To address these knowledge gaps, we created the Global Enteric Multicenter Study (GEMS),3 the capstone component of which is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0–59 months residing in censused populations and seeking care at medical facilities serving seven sites in sub-Saharan Africa and South Asia.4 We used a common research protocol with standardised epidemiological and microbiological methods to facilitate inter-site comparisons and allow aggregate estimates of aetiology and incidence.4, 5, 6

Section snippets

Study design and participants

The primary objective of GEMS was to measure the population-based burden, microbiological aetiology, and adverse clinical effects (eg, growth faltering and death) of moderate-to-severe diarrhoea in developing countries, overall and by age, pathogen, and site.4 The rationale and underlying epidemiological assumptions,3, 7 and the clinical or epidemiological,4 microbiological,5 data management,8 and analytical6 methods have been detailed. Salient points are summarised below.

Seven field sites were

Results

During the 36-month case-control study at seven DSS sites, children aged 0–59 months cumulatively contributed about 487 386 child-years of observation. They made 626 519 visits to an SHC, of which 66 009 (11%) were by children with diarrhoea (12·2% of the visits for infants, 14·7% of the visits for toddlers, and 6·3% of the visits for children); 14 753 children met enrolment criteria for moderate-to-severe diarrhoea (22% of diarrhoea cases), of whom 9980 were invited to participate (68% of

Discussion

Using a comprehensive panel of microbiological assays, GEMS was performed to better define the incidence, aetiology, and clinical outcome of moderate-to-severe paediatric diarrhoea in seven sites, located in regions where more than 80% of deaths in children younger than 5 years occur,17 and representing a range of health indicators (eg, malaria, HIV prevalence), health-care accessibility, economic development, and environmental conditions. By including matched control children without

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