Causes of diarrhea in children: The Global Enteric Multicenter Study (GEMS)

Worldwide, diarrheal diseases are the second leading cause of death in children younger than 5 years of age, killing approximately half a million children every year. The causes of diarrhea are multifold, and public health efforts to address this challenge require reliable, consistent estimates of pathogen burden. The Global Enteric Multicenter Study (GEMS) was a prospective, multi-center, case-control study of acute diarrhea in children 0-59 months of age from seven high-burden sites across Asia and Africa. Funded by the Bill and Melinda Gates Foundation, coordinated by the University of Maryland School of Medicine’s Center for Vaccine Development, and conducted by investigators representing an international consortium of institutions and organizations involved in vaccine development and diarrheal disease research, the study enrolled 9,439 children with diarrhea and 13,129 children without diarrhea between 2007 and 2011. GEMS was the largest-ever and most comprehensive study of the etiology, incidence, morbidity and mortality associated with childhood diarrheal diseases in developing countries.

The first report of the principal study analysis was published in 2013 by Kotloff and colleagues in the journal Lancet.1 The analysis found that four pathogens were primarily responsible for moderate-to-severe diarrhea in the study populations—Rotavirus, Cryptosporidium, specific strains of enterotoxigenic Escherichia coli (ST-ETEC), and Shigella. Notably, ST-ETEC was associated with increased risk of death in infants aged 0–11 months, suggesting that this pathogen would be an important target for life-saving intervention strategies.

Since 2012, the GEMS consortium has resulted in the publication of more than 40 peer-reviewed scientific journal articles that discuss epidemiological methods, techniques, challenges, and additional sub-analyses of the original work.

Of particular interest is a recent study by Liu and colleagues, also published in Lancet in 2016.2 This research group sought to address a number of technical limitations in the original GEMS analysis that could potentially have resulted in inaccurate estimates of pathogen burden; namely, lack of universal methods for pathogen detection, and the inability to estimate the impact of asymptomatic carriage.

In their re-analysis, Liu and colleagues employed quantitative molecular diagnostics (quantitative real-time PCR) with a panel of 32 enteric pathogens, in order to thoroughly examine the etiology and burden of diarrheal disease from the GEMS sample, both at a population level and at the level of individual children. Their findings gave better insight into the order or prioritization for study and intervention, showing that the most significant pathogens—accounting for 78% of all attributable cases of diarrhea—were Shigella spp, rotavirus, adenovirus 40/41, heat-stable ETEC, Cryptosporidium spp, and Campylobacter spp.

Despite the availability of oral rehydration solutions (ORS) and other interventions, diarrheal diseases cause too many deaths every year. Ventria Bioscience is actively engaged in research, also sponsored by the Bill and Melinda Gates Foundation, to improve the efficacy of ORS in alleviating the symptoms of diarrhea that contribute to morbidity and mortality. We’ll have more information about that program in a future blog post, or you can read here about our lead candidate, VEN BETA for Enterotoxigenic E. Coli gastroenteritis.


  1. Liu J, Platts-Mills JA, Juma J et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016;388(10051):1291-1301.
  2. Kotloff KL, Nataro JP, Blackwelder WC et al. 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. Lancet 2013;382:209-222.