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Differentiating mortality risk of individual infants and children to improve survival: opportunity for impact

Children are not born equal in their likelihood of survival. The risk of mortality is highest during and shortly after
birth. In the immediate postnatal period and beyond, perinatal events, nutrition, infections, family and environmental
exposures, and health services largely determine the risk of death. We argue that current public health programmes
do not fully acknowledge this spectrum of risk or respond accordingly. As a result, opportunities to improve the care,
survival, and development of children in resource-poor settings are overlooked. Children at high risk of mortality are
underidentified and commonly treated using guidelines that do not differentiate care according to the magnitude or
drivers of those risks. Children at low risk of mortality are often provided with more intensive care than needed,
disproportionately using limited health-care resources with minimal or no benefits. Declines in newborn, infant, and
child mortality rates globally are slowing, and further reductions are likely to be incrementally more difficult to
achieve once simple, high impact interventions have been universally implemented. Currently, 63 countries have
rates of neonatal mortality that are off track to meet the Sustainable Development Goal 2030 target
of 12 deaths per 1000 livebirths or less, and 54 countries have rates of mortality in children younger than 5 years that
are off track to meet the target of 25 deaths per 1000 livebirths or less. If these targets are to be met, a change of
approach is needed to address infant and child mortality and for health-care systems to more efficiently address
residual mortality.

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Intestinal disturbances associated with mortality of children with complicated severe malnutrition

Abstract
Background Children admitted to hospital with complicated severe malnutrition (CSM) have high mortality despite compliance with standard WHO management guidelines. Limited data suggests a relationship between intestinal dysfunction and poor prognosis in CSM, but this has not been explicitly studied. This study aimed to evaluate the role of intestinal disturbances in CSM mortality.

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Rebalancing of mitochondrial homeostasis through an NAD+ – SIRT1 pathway preserves intestinal barrier function in severe malnutrition

Abstract
Background

The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact
processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and
organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health.

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Inhibition of mTOR improves malnutrition induced hepatic metabolic dysfunction

Abstract

Severe malnutrition accounts for half-a-million deaths annually in children under the age of five. Despite improved WHO guidelines, inpatient mortality remains high and is associated with metabolic dysfunction. Previous studies suggest a correlation between hepatic metabolic dysfunction and impaired autophagy. We aimed to determine the role of mTORC1 inhibition in a murine model of malnutrition-induced hepatic dysfunction. Wild type weanling C57/B6 mice were fed a 18 or 1% protein diet for two weeks. A third low-protein group received daily rapamycin injections, an mTORC1 inhibitor. Hepatic metabolic function was assessed by histology, immunofluorescence, gene expression, metabolomics and protein levels. Low protein-fed mice manifested characteristics of severe malnutrition, including weight loss, hypoalbuminemia, hypoglycemia, hepatic steatosis and cholestasis. Low protein-fed mice had fewer mitochondria and showed signs of impaired mitochondrial function. Rapamycin prevented hepatic steatosis, restored ATP levels and fasted plasma glucose levels compared to untreated mice. This correlated with increased content of LC3-II, and decreased content mitochondrial damage marker, PINK1. We demonstrate that hepatic steatosis and disturbed mitochondrial function in a murine model of severe malnutrition can be partially prevented through inhibition of mTORC1. These findings suggest that stimulation of autophagy could be a novel approach to improve metabolic function in severely malnourished children.

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Organoids as a model to study intestinal and liver dysfunction in severe malnutrition

ABSTRACT
Hospitalized children with severe malnutrition face high mortality rates and often suffer from hepatic and intestinal dysfunction, with negative impacts on their survival. New treatments cannot be developed without
understanding the underlying pathophysiology. We have established and characterized translational organoid
models of severe malnutrition of the liver and the intestine. In these models, amino acid starvation recapitulates
the expected organ-specific functional changes (e.g., hepatic steatosis, barrier dysfunction) accompanied by
reduced mitochondrial and peroxisomal proteins, and altered intestinal tight junction proteins. Resupplementation of amino acids or pharmacological interventions with rapamycin or fenofibrate lead to partial recovery. Restoration of protein levels aligned with signs of improved peroxisomal function in both organoids, and increased mitochondrial proteins and tight junction protein claudin-3 in intestinal organoids. We
present two organoid models as novel tools to gain mechanistic insights and to act as a testing platform for
potential treatments for intestinal and hepatic dysfunction in severe malnutrition.

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The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction

Abstract

Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.

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Characterising paediatric mortality during and after acute illness in Sub-Saharan Africa and South Asia: a secondary analysis of the CHAIN cohort using a machine learning approach

Background

A better understanding of which children are likely to die during acute illness will help clinicians and policy makers target resources at the most vulnerable children. We used machine learning to characterise mortality in the 30-days following admission and the 180-days after discharge from nine hospitals in low and middle-income countries (LMIC).

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Treatment-seeking and recovery among young undernourished children post-hospital discharge in Bangladesh

Abstract

Introduction

Post-hospital discharge mortality is high among undernourished children in many low and middle-income countries. Although a number of quantitative studies have highlighted a range of potential socio-cultural, economic and health system factors influencing paediatric post-discharge treatment-seeking and recovery, few studies have explored family and provider perspectives of the post-discharge period in-depth.

Methods

This work was part of a large, multi-country prospective cohort study, the Childhood Acute Illness and Nutrition (CHAIN) Network. We conducted a qualitative sub-study to understand the post-discharge treatment-seeking and recovery experiences of families of undernourished children aged 2–23 months admitted in a rural and urban icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) hospital. Methods included repeat in-depth interviews (73 interviews in total) with 29 family members of 17 purposively selected children. These data were supplemented by interviews with 33 health workers, and by observations in hospitals and homes.

Results

Important drivers of treatment-seeking perceived to support recovery included advice provided to family members while in hospital, media campaigns on hygiene practice, availability of free treatment, and social and financial support from family members, relatives and neighbours. Key perceived challenges included low household incomes, mothers having to juggle multiple responsibilities in addition to caring for the sick child, lack of support (sometimes violence) from the child’s father, and family members’ preference for relatively accessible drug shops, physicians or healers over hospital admission.

Conclusion

Development of interventions that address the challenges that families face is essential to support post-discharge adherence to medical advice and recovery. Potential interventions include strengthening information giving during hospitalization on what post-discharge care is needed and why, reducing direct and indirect costs associated with hospital visits, engaging fathers and other ‘significant others’ in post-discharge advice, and building mobile phone-based support for follow-up care.

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