title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  The Bill & Melinda Gates Foundation.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. kkotloff@medicine.umaryland.edu
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authors.lastname: Kotloff
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mesh_terms: D017954:Africa South of the Sahara; D001211:Asia, Western / Q000453:epidemiology; D001424:Bacterial Infections / Q000401:mortality*; D016022:Case-Control Studies; D002675:Child, Preschool; D017281:Cost of Illness; D003906:Developing Countries; D003967:Diarrhea / Q000382:microbiology* / Q000401:mortality*; D003968:Diarrhea, Infantile / Q000382:microbiology / Q000401:mortality; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D012400:Rotavirus Infections / Q000401:mortality*