Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition

James M Njunge,Robert H J Bandsma,Moses Ngari,Judd L Walson,Emily Nyatichi,James A Berkley,Evelyn N Gitau,Nelson K Kibinge,Gerard Bryan Gonzales,Lydia Nyamako,Johnstone Thitiri,Agnes Gwela

doi:10.1038/s41598-019-42436-y

Abstract

High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2–59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery.

Highlights

Malnutrition is an underlying cause of nearly half of global deaths in children below 5 years mainly in sub-Saharan Africa and Asia[1,2]
We hypothesized that early post-discharge mortality in children with Severe Acute Malnutrition (SAM) is associated with derangements in certain biological processes that could be ascertained by measuring plasma proteins measured before discharge from the hospital
Post-discharge deaths occurred a median of 19 (Interquartile range, interquartile ranges (IQRs) 7–34) days after sampling, mostly (60%) during readmission to the study hospitals, while the rest were in the community (31%) and other hospitals (8%) (Table 2)

Summary

Introduction

Malnutrition is an underlying cause of nearly half of global deaths in children below 5 years mainly in sub-Saharan Africa and Asia[1,2]. A recent systematic review reported paediatric post-discharge mortality rates in resource-poor countries of up to 18% which may exceed in-hospital mortality rates in many settings[18,23] This implies that processes underlying susceptibility to mortality continue beyond the clinically evident acute www.nature.com/scientificreports/. Whilst mechanisms resulting in post-discharge deaths are not well understood, they are likely to involve the interaction between the metabolic consequences of malnutrition, infection, and intestinal dysfunction, whose causes and consequences are “cyclic” and self-reinforcing[7,24]. This sustained risk of death post-discharge following apparent medical stabilization calls for an understanding of processes that could be amenable to intervention. We used both untargeted (plasma protein profiles) and targeted (cytokines, chemokines, and leptin) approaches to determine associations with mortality within the 60 days among children who had been judged medically stabilized according to WHO guidelines

Objectives

Methods

Results

Discussion

Conclusion