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      Global disability-adjusted life-year estimates of long-term health burden and undernutrition attributable to diarrhoeal diseases in children younger than 5 years

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          Summary

          Background

          Diarrhoea is a leading cause of death and illness globally among children younger than 5 years. Mortality and short-term morbidity cause substantial burden of disease but probably underestimate the true effect of diarrhoea on population health. This underestimation is because diarrhoeal diseases can negatively affect early childhood growth, probably through enteric dysfunction and impaired uptake of macronutrients and micronutrients. We attempt to quantify the long-term sequelae associated with childhood growth impairment due to diarrhoea.

          Methods

          We used the Global Burden of Diseases, Injuries, and Risk Factors Study framework and leveraged existing estimates of diarrhoea incidence, childhood undernutrition, and infectious disease burden to estimate the effect of diarrhoeal diseases on physical growth, including weight and height, and subsequent disease among children younger than 5 years. The burden of diarrhoea was measured in disability-adjusted life-years (DALYs), a composite metric of mortality and morbidity. We hypothesised that diarrhoea is negatively associated with three common markers of growth: weight-for-age, weight-for-height, and height-for-age Z-scores. On the basis of these undernutrition exposures, we applied a counterfactual approach to quantify the relative risk of infectious disease (subsequent diarrhoea, lower respiratory infection, and measles) and protein energy malnutrition morbidity and mortality per day of diarrhoea and quantified the burden of diarrhoeal disease due to these outcomes caused by undernutrition.

          Findings

          Diarrhoea episodes are significantly associated with childhood growth faltering. We found that each day of diarrhoea was associated with height-for-age Z-score (–0·0033 [95% CI −0·0024 to −0·0041]; p=4·43 × 10 −14), weight-for-age Z-score (–0·0077 [–0·0058 to −0·0097]; p=3·19 × 10 −15), and weight-for-height Z-score (–0·0096 [–0·0067 to −0·0125]; p=7·78 × 10 −11). After addition of the DALYs due to the long-term sequelae as a consequence of undernutrition, the burden of diarrhoeal diseases increased by 39·0% (95% uncertainty interval [UI] 33·0–46·6) and was responsible for 55 778 000 DALYs (95% UI 49 125 400–62 396 200) among children younger than 5 years in 2016. Among the 15 652 300 DALYs (95% UI 12 951 300–18 806 100) associated with undernutrition due to diarrhoeal episodes, more than 84·7% are due to increased risk of infectious disease, whereas the remaining 15·3% of long-term DALYs are due to increased prevalence of protein energy malnutrition. The burden of diarrhoea has decreased substantially since 1990, but progress has been greater in long-term (78·7% reduction [95% UI 69·3–85·5]) than in acute (70·4% reduction [95% UI 61·7–76·5]) DALYs.

          Interpretation

          Diarrhoea represents an even larger burden of disease than was estimated in the Global Burden of Disease Study. In order to adequately address the burden of its long-term sequelae, a renewed emphasis on controlling the risk of diarrhoea incidence may be required. This renewed effort can help further prevent the potential lifelong cost on child health, growth, and overall potential.

          Funding

          Bill & Melinda Gates Foundation.

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          Most cited references20

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          The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease.

          More than one-fifth of the world's population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7-9 years old. A child's height at their second birthday is therefore the best predictor of cognitive development or 'human capital'. To this 'double burden' of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a 'triple burden' of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty.
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            Malnutrition as an enteric infectious disease with long-term effects on child development.

            Malnutrition is a major contributor to mortality and is increasingly recognized as a cause of potentially lifelong functional disability. Yet, a rate-limiting step in achieving normal nutrition may be impaired absorptive function due to multiple repeated enteric infections. This is especially problematic in children whose diets are marginal. In malnourished individuals, the infections are even more devastating. This review documents the evidence that intestinal infections lead to malnutrition and that malnutrition worsens intestinal infections. The clinical data presented here derive largely from long-term cohort studies that are supported by controlled animal studies. Also reviewed are the mechanisms by which enteric infections lead to undernutrition and by which malnutrition worsens enteric infections, with implications for potential novel interventions. Further intervention studies are needed to document the relevance of these mechanisms and, most importantly, to interrupt the vicious diarrhea-malnutrition cycle so children may develop their full potential.
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              Mechanisms of nutrient modulation of the immune response.

              Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.
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                Author and article information

                Contributors
                Journal
                Lancet Glob Health
                Lancet Glob Health
                The Lancet. Global Health
                Elsevier Ltd
                2214-109X
                09 February 2018
                March 2018
                09 February 2018
                : 6
                : 3
                : e255-e269
                Affiliations
                [a ]Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA
                [b ]Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
                [c ]Global Enterics, LLC, Seattle, WA, USA
                [d ]Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
                [e ]Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
                [f ]Departments of Pediatrics and Medicine, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA
                [g ]Bureau of HIV/AIDS Prevention and Control, New York City Department of Health and Mental Hygiene, New York, NY, USA
                [h ]Uniformed Services University of the Health Sciences, Bethesda, MD, USA
                Author notes
                [* ]Correspondence to: Prof Ali H Mokdad, University of Washington, Institute for Health Metrics and Evaluation, Seattle, WA 98121, USACorrespondence to: Prof Ali H Mokdad, University of WashingtonInstitute for Health Metrics and EvaluationSeattleWA98121USA mokdaa@ 123456uw.edu
                Article
                S2214-109X(18)30045-7
                10.1016/S2214-109X(18)30045-7
                5861379
                29433665
                809ff4ac-5b71-4b6b-9f32-bd54fcd3ec85
                © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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