Estimating the true burden of an enteric pathogen: enterotoxigenic Escherichia coli and Shigella spp

Global estimates of the importance of specific microbes as causes of childhood diarrhoea deaths and illnesses have been done to guide disease control programmes and investments in new technologies, especially vaccines.1GBD Diarrhoeal Diseases CollaboratorsEstimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Infect Dis. 2017; 17: 909-948Summary Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 2Lanata CF Fischer-Walker CL Olascoaga AC et al.Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.PLoS One. 2013; 8: e72788Crossref PubMed Scopus (445) Google Scholar In their Article published in The Lancet Infectious Diseases, Ibrahim Khalil and colleagues3Khalil I Troger C Blacker B et al.Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990–2016.Lancet Infect Dis. 2018; (published online Sept 25.)http://dx.doi.org/10.1016/S1473-3099(18)30475-4Summary Full Text Full Text PDF Scopus (260) Google Scholar use modelling at the global, regional, and country level to estimate diarrhoeal mortality and incidence in 2016, by age and sex, for enterotoxigenic Escherichia coli (ETEC) and Shigella spp. They find that the disease burden of shigellosis is higher than that of previous estimates, especially in the elderly, whereas the burden of ETEC is lower. As with all model estimates, caution is needed when interpreting the results, given the uncertainties around many assumptions made by the authors. Their previous application of this spatiotemporal model resulted in highly unlikely claims that cholera was the leading cause of childhood diarrhoea deaths in Canada, western Europe, and Latin America in 2015.1GBD Diarrhoeal Diseases CollaboratorsEstimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Infect Dis. 2017; 17: 909-948Summary Full Text Full Text PDF PubMed Scopus (663) Google Scholar Since little information is available on the aetiology of diarrhoea resulting in death, the general assumption is that the aetiology in cases considered severe (ie, those requiring admission to hospital) could be a proxy for those with a fatal outcome in the absence of care.2Lanata CF Fischer-Walker CL Olascoaga AC et al.Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.PLoS One. 2013; 8: e72788Crossref PubMed Scopus (445) Google Scholar The use of molecular methods has increased the sensitivity of detection for most pathogens and, in the case of shigella, doubled its detection during diarrhoea.4Liu 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: 1291-1301Summary Full Text Full Text PDF PubMed Scopus (467) Google Scholar The traditional assumption is that if an agent is found in a stool sample, it is the cause of the diarrhoeal episode; however, asymptomatic infection is common and multiple pathogens are often detected in diarrhoeal stools in low-income and middle-income countries.2Lanata CF Fischer-Walker CL Olascoaga AC et al.Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.PLoS One. 2013; 8: e72788Crossref PubMed Scopus (445) Google Scholar, 4Liu 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: 1291-1301Summary Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 5Kotloff 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: 209-222Summary Full Text Full Text PDF PubMed Scopus (2261) Google Scholar Asymptomatic carriage has been attributed to several factors, including maternal immunity, breastfeeding, immunity gained from previous clinical or subclinical infections, and the intestinal microbiome (which affects the likelihood that an enteric pathogen induces disease).6Vogt SL Finlay BB Gut microbiota-mediated protection against diarrheal infections.J Travel Med. 2017; 24: S39-S43Crossref PubMed Scopus (42) Google Scholar Khalil and colleagues used the population attributable fraction approach, which compares the detection of a pathogen in cases to that in controls, to attribute episodes of diarrhoea to a certain pathogen. They then extrapolated these findings to deaths from diarrhoea using the results of the Global Enteric Multicenter Study (GEMS), which was done in seven sites in Africa and Asia.4Liu 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: 1291-1301Summary Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 5Kotloff 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: 209-222Summary Full Text Full Text PDF PubMed Scopus (2261) Google Scholar Cases had moderate-to-severe diarrhoea (most were moderate) identified in health facilities and were matched to community controls without diarrhoea in the previous 7 days. The assumption that these cases of moderate severity can be a proxy for deaths is questionable, and the authors' definition of controls includes children with prolonged pathogen excretion after illness, perhaps incorrectly dismissing or diminishing their importance. The GEMS study found that, despite matching, cases were different from controls in terms of malnutrition and other factors, suggesting that confounding might be possible.7Donnenberg MS Hazen TH Farag TH et al.Bacterial factors associated with lethal outcome of enteropathogenic Escherichia coli infection: genomic case-control studies.PLoS Negl Trop Dis. 2015; 9: e0003791Crossref PubMed Scopus (18) Google Scholar Notably, the application of the population attributable fractions for diarrhoea pathogens in children aged 1–4 years in GEMS to older children and adults who will have acquired immunity in these highly endemic settings probably results in an overestimation of the deaths, especially for shigella, in these age groups. A prospective, community-based study of mild-to-moderate diarrhoea in eight sites in Latin America, Africa, and southeast Asia (the MAL-ED study)8Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: 564-575Summary Full Text Full Text PDF PubMed Scopus (553) Google Scholar reported population attributable fractions for enteric pathogens that were different from those of GEMS, including a higher fraction of diarrhoea due to norovirus and a lower fraction due to Crysptosporidium spp. A more fundamental question is how to evaluate the true burden of an enteric pathogen? Although the evaluation of cases of severe diarrhoea might continue to be used as a proxy for death from diarrhoea, new information will be gained from minimally invasive autopsies of children and adults, as these techniques become more widely used.9Bassat Q Castillo P Martinez MJ et al.Validity of a minimally invasive autopsy tool for cause of death determination in pediatric deaths in Mozambique: an observational study.PLoS Med. 2017; 14: e1002317Crossref PubMed Scopus (67) Google Scholar For other outcomes, the MAL-ED study has shown that diarrhoea was less important than the presence of enteric pathogens in the gut and their role in causing inflammation, which was linked to poor growth, reduced psychomotor development, and poor vaccine immune response.10Mal-Ed Network InvestigatorsThe MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments.Clin Infect Dis. 2014; 59: S193-S206Crossref PubMed Scopus (248) Google Scholar, 11Scharf RJ Rogawski ET Murray-Kolb LE et al.Early childhood growth and cognitive outcomes: findings from the MAL-ED study.Matern Child Nutr. 2018; 14: e12584Crossref PubMed Scopus (29) Google Scholar More data are needed for all age groups on enteric pathogens associated with severe diarrhoea and deaths, with proper controls, in more low-income and middle-income countries. A new approach is also needed to fully understand the public health importance of an enteric pathogen, through the whole life cycle of an individual. This approach will be important as WHO and partners develop a new conceptual model, called Total Systems Effectiveness,12Giersing B Total systems effectiveness. Evaluating all trade-off to inform choice. Product Development for Vaccines Advisory Committee Meeting. World Health Organization, June, 2018http://www.who.int/immunization/research/meetings_workshops/pdvac_june18/en/Date accessed: August 7, 2018Google Scholar to identify the complete public health value of different vaccine products for each country and to guide priorities for new and existing products. We declare no competing interests. Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990–2016The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden. Full-Text PDF Open Access

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