Targeting enteric pathogens to improve childhood survival and growth
Authors: Judd L Walson, Patricia B Pavlinac
Journal: The Lancet Global Health (2018)

Although substantial progress has been made in reducing diarrhoeal deaths among children in low-income and middle-income countries, from approximately 1·6 million in 1990 to 450 000 in 2016,1Global Burden of Disease Collaborative NetworkGlobal Burden of Disease Study 2016 (GBD 2016) Results. Institute for Health Metrics and Evaluation, Seattle2017http://ghdx.healthdata.org/gbd-results-toolDate accessed: September 18, 2018Google Scholar sustaining these improvements will require additional strategies and approaches. These global estimates largely reflect deaths due to acute dehydration and electrolyte imbalance, which are temporally linked to episodes of diarrhoea and therefore are easiest to classify as diarrhoea-associated. However, most deaths and disability associated with diarrhoea occur after the acute episode of diarrhoea has resolved. The Global Enteric Multicenter Study (GEMS) reported that two-thirds of deaths among children with moderate-to-severe diarrhoea occurred more than 7 days after stabilisation.2Kotloff 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 Additionally, 2016 estimates,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 which include longer-term morbidities associated with diarrhoea (such as undernutrition and associated risk of infectious disease) have increased diarrhoea disability-adjusted life-years (DALYs) by 40%, ranking diarrhoea as the third leading contributor to DALYs in children under 5 years globally Current diarrhoea treatment guidelines focus primarily on the management of dehydration and the provision of zinc.4WHOPocket book of hospital care for children: guidelines for the management of common illnesses with limited resources. World Health Organization, Geneva2005Google Scholar Although uptake of these interventions remains poor in many settings and can be improved, these interventions alone might not be sufficient to reduce the residual mortality and morbidity burden associated with diarrhoea. Improved methods of detection can provide a more accurate understanding of the aetiology and health impact of enteric diseases and offer the opportunity for targeted interventions to improve short-term and long-term outcomes. The use of molecular methods has increased our ability to detect pathogens with increased sensitivity. Additionally, quantitative methods allow for causal attribution of specific pathogens by differentiating pathogen load between diarrhoea cases and asymptomatic controls. Re-analyses of faecal samples from large diarrhoea aetiology studies using these methods has substantially increased the attribution of diarrheal episodes to infectious pathogens. In the Lancet Global Health, James A Platts-Mills and colleagues5Platts-Mills JA Liu J Rogawski ET et al.Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study.Lancet Glob Health. 2018; (published online Oct 1.)http://dx.doi.org/10.1016/S2214-109X(18)30349-8Summary Full Text Full Text PDF Scopus (156) Google Scholar attribute 65% of diarrhoeal episodes in the MAL-ED prospective cohort to an infectious aetiology, a substantial increase from 33% using the original MAL-ED study microbiology methods.6Platts-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: e564-e575Summary Full Text Full Text PDF PubMed Scopus (553) Google Scholar Similarly, re-analysis of samples from GEMS increased attribution of enteric pathogens to cases of moderate-to-severe diarrhoea from 52% to 89%.2Kotloff 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, 7Liu 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 Results from these studies have also shifted the relative importance of certain pathogens associated with diarrhoea, particularly those for whom traditional microbiological methods are insensitive. For example, Platts-Mills and colleagues report Shigella as the leading cause of diarrhoea in children under age 2 years.5Platts-Mills JA Liu J Rogawski ET et al.Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study.Lancet Glob Health. 2018; (published online Oct 1.)http://dx.doi.org/10.1016/S2214-109X(18)30349-8Summary Full Text Full Text PDF Scopus (156) Google Scholar Most cases of Shigella-attributed diarrhoea were non-dysenteric and therefore would not be targeted for antimicrobial therapy according to current guidelines. Additionally, the use of molecular detection methods has also resulted in improved estimates of the long-term health impact of cause-specific diarrhoeal episodes. In Lancet Global Health, Elizabeth T Rogawski and colleagues8Rogawski 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; (published online Oct 1.)http://dx.doi.org/10.1016/S2214-109X(18)30351-6Summary Full Text Full Text PDF Scopus (164) Google Scholar report that among children followed in the MAL-ED cohort, diarrhoea caused by bacterial and parasitic pathogens was responsible for modest declines in linear growth in the immediate period following the episode and at age 2 years. These findings support results from other studies suggesting differential short-term and long-term risks associated with specific enteric pathogens. A re-evaluation of diarrhoeal management guidelines on the basis of these updated estimates can inform strategies to maximise reductions in diarrhoea-associated mortality and morbidity. The relatively poor sensitivity of traditional microbiological methods has also limited the comprehensive understanding of risks associated with enteric pathogens in the absence of diarrhoea. Rogawski and colleagues8Rogawski 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; (published online Oct 1.)http://dx.doi.org/10.1016/S2214-109X(18)30351-6Summary Full Text Full Text PDF Scopus (164) Google Scholar report that asymptomatic infection with Shigella, Campylobacter, enteroaggregative Escherichia coli, and Giardia were each associated with substantial declines in linear growth. These findings are supported by other studies suggesting that repeated exposure to enteric pathogens, even in the absence of overt diarrhoeal disease, can result in substantial disruption of the mucosal barrier, impaired absorptive capacity, and translocation of bacterial products, a syndrome termed environmental enteric dysfunction.9Kosek MN MAL-ED Network InvestigatorsCausal pathways from enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study.EBioMedicine. 2017; 18: 109-117Summary Full Text Full Text PDF PubMed Scopus (132) Google Scholar Environmental enteric dysfunction seems to be an important driver of malnutrition and impaired responsiveness to oral vaccines in children in low-resource settings.10Keusch GT Denno DM Black RE et al.Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences.Clin Infect Dis. 2014; 59: S207-S212Crossref PubMed Scopus (181) Google Scholar At present, no international guidelines exist for the management of these subclinical enteric pathogens and interventions aimed at reducing non-specific enteric pathogen exposure, such as improvements in water and sanitation, have demonstrated inconsistent benefits on linear growth. Diarrhoea is a non-specific syndrome that does not fully capture the spectrum of clinically important disease resulting from enteric pathogen exposure in the gut. Emerging data, such as those presented by Platts-Mills and colleagues and Rogawski and colleagues, offer the opportunity to re-examine the burden and relative importance of enteric pathogens associated with diarrhoea and other morbidities, including linear growth faltering. These updated estimates should inform the development of targeted prevention and management approaches to achieve optimum reductions in morbidity and mortality associated with these enteric pathogens. We declare no competing interests. Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort studyQuantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Full-Text PDF Open AccessUse 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 studySubclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Full-Text PDF Open Access