Estimating health-loss due to enteric pathogens: importance and challenges
Authors: Christopher Troeger, Ibrahim A Khalil, Robert C Reiner
Journal: The Lancet Global Health (2019)

There is growing recognition among researchers and public health experts that diarrhoea causes loss of health beyond death. Many global health burden estimates use disability-adjusted life-years (DALYs), which is the sum of years of life lost and years lived with disability. When deaths occur in children, as for diarrhoea, the burden is largely captured in the years of life lost. Diarrhoea tends to be a short-term, acute infection, with most cases resolving quickly. Yet, diarrhoea can cause long-term outcomes beyond acute infection.1Khalil IA Troeger C Rao PC et al.Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study.Lancet Glob Health. 2018; 6: e758-e768Summary Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 2Rogawski ET Liu J Platts-Mills JA et al.Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.Lancet Glob Health. 2018; 6: e1319-e1328Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 3Troeger C Colombara DV Rao PC et al.Global disability-adjusted life-year estimates of long-term health burden and undernutrition attributable to diarrhoeal diseases in children younger than 5 years.Lancet Glob Health. 2018; 6: e255-e269Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar There have been efforts to quantify proposed long-term outcomes associated with enteric infections, such as linear growth faltering, vaccine failure, and cognitive deficits; these estimates suggest a large burden in years lived with disability. Research in this area suggests that the effect of enteric pathogens is not the same, with possible variation by bacterial, viral, and protozoan pathogens. In The Lancet Global Health, John D Anderson IV and colleagues4Anderson JD Bagamian KH Muhib F et al.Burden of enterotoxigenic Escherichia coli and shigella non-fatal diarrhoeal infections in 79 low-income and lower middle-income countries: a modelling analysis.Lancet Glob Health. 2019; 7: e321-e330Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar present estimates of the mortality and long-term loss of health associated with enterotoxigenic Escherichia coli (ETEC) and shigella among 79 low-income and lower-middle income countries. Their results show the importance of these two bacterial pathogens in childhood diarrhoea among the most at-risk children.5Khalil IA Troeger C Blacker BF 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; 18: 1229-1240Summary Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 6Kotloff KL Riddle MS Platts-Mills JA Pavlinac P Zaidi AKM Shigellosis.Lancet. 2018; 391: 801-812Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar Accounting for infectious disease mortality attributable to linear growth faltering due to ETEC-related and shigella-related diarrhoea increased the deaths caused by these pathogens by 24% and 28%, respectively. Burden estimates are restricted by sparse data that require modeling and methodological assumptions. Results from the Global Enteric Multicenter Study (GEMS)7Kotloff 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 have become a gold standard in the enterics field and are leveraged heavily by Anderson and colleagues and others for burden estimation. Adjustment of pathogen diagnostics for misclassification has a substantial effect on estimates, as shown by a sensitivity analysis performed by Anderson and colleagues. They also identified the aetiological fraction, the proportion of diarrhoea episodes or deaths that have ETEC or shigella—different from the population attributable fraction used in some other burden estimates—and the fraction of all episodes that are moderate-to-severe diarrhoea as having the largest effect on burden estimates. Results from GEMS were used to estimate an adjustment scalar for diagnostic misclassification and for the proportion of moderate-to-severe diarrhoea in their study.8Liu 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 scope of the GEMS results is broad, covering a range of exposures and outcomes associated with moderate-to-severe diarrhoea, including aetiologies, growth, and risk factors (such as safe water, sanitation, and risk of mortality). However, GEMS is a case-control study done in seven sites in South Asia and sub-Saharan Africa. The authors dependence on GEMS for the estimation of enteric infection burden is a limitation of their study, particularly when attempting to capture longitudinal changes, such as growth, or for defining parameters that will be used globally. Anderson and colleagues suggest, in the final paragraph of their manuscript, other potential long-term outcomes of ETEC and shigella diarrhoea, such as reduced cognitive function, educational attainment, earnings, and chronic diseases. These outcomes remain hypothetical when they are based on biological plausibility, animal models, and a restricted number of observational studies.9Guerrant RL DeBoer MD Moore SR Scharf RJ Lima AAM The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease.Nat Rev Gastroenterol Hepatol. 2013; 10: 220-229Crossref PubMed Scopus (362) Google Scholar Such longitudinal outcomes are unlikely to be quantifiable using the GEMS results and are an example of the need for cohort studies. One major cohort study of childhood diarrhoea and linear growth, the MAL-ED study,10MAL-ED Network InvestigatorsRelationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: findings from the MAL-ED birth cohort study.BMJ Glob Health. 2017; 2: e000370PubMed Google Scholar was not used for inputs in the Article by Anderson and colleagues and provides additional evidence for some of the parameters that were used in their estimates. In the MAL-ED study, researchers validated some of the findings relating to shigella, showing that, even in the absence of diarrhoea, shigella can have significant effects on linear growth among children.2Rogawski ET Liu J Platts-Mills JA et al.Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.Lancet Glob Health. 2018; 6: e1319-e1328Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar The MAL-ED study shows that diarrhoea might just be the tip of the burden iceberg with much of the hidden burden due to enteric infections resulting in the long-term outcomes suggested by Anderson and colleagues.2Rogawski ET Liu J Platts-Mills JA et al.Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study.Lancet Glob Health. 2018; 6: e1319-e1328Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 10MAL-ED Network InvestigatorsRelationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: findings from the MAL-ED birth cohort study.BMJ Glob Health. 2017; 2: e000370PubMed Google Scholar This observation could be an extremely important consideration in evaluating interventions, including vaccine efficacy. Rotavirus vaccine efficacy appears to be higher in preventing moderate-to-severe diarrhoea than in non-severe diarrhoea;11Lamberti LM Ashraf S Walker CLF Black RE A systematic review of the effect of rotavirus vaccination on diarrhoea outcomes among children younger than 5 years.Pediatr Infect Dis J. 2016; 35: 992-998Crossref PubMed Scopus (74) Google Scholar however, a vaccine against shigella or ETEC should be evaluated on how well it prevents not just moderate-to-severe diarrhoea but also infection because preventing infection could substantially affect subsequent linear growth faltering. The work by Anderson and colleagues is helping to shape and more clearly define our understanding of the disease burden of enteric pathogens and illustrates how many data gaps exist in this field. Studies on the scale of GEMS or MAL-ED are unlikely to be funded in the future, therefore clearly identifying these data gaps and finding ways to obtain data through existing surveillance systems, birth cohorts, or aetiological studies should be a priority. Further expanding such evidence generation to upper-middle and high-income countries might help to quantify differences in exposure and linear growth compared with lower-income countries. While openly describing their limitations, Anderson and colleagues have made an important contribution to the body of evidence that childhood infectious diseases have a long-lasting negative effect on global health. We declare no competing interests. Burden of enterotoxigenic Escherichia coli and shigella non-fatal diarrhoeal infections in 79 low-income and lower middle-income countries: a modelling analysisThe expanded effects of non-fatal ETEC and shigella-related diarrhoeal episodes can have lasting consequences. Prevention of these infections could reduce the risk of direct death and stunting and deaths due to other infectious diseases. Understanding the countries and populations with the highest disease risk helps to target interventions for the most vulnerable populations. Full-Text PDF Open Access