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Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

ABSTRACT: Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died (n = 92) from those who survived (n = 92). Fatalities were characterized by increased energetic substrates (tricarboxylic acid cycle metabolites), microbial metabolites (e.g., propionate and isobutyrate), acute phase proteins (e.g., calprotectin and C-reactive protein), and inflammatory markers (e.g., interleukin-8 and tumor necrosis factor-α). These perturbations indicated disruptions in mitochondria-related bioenergetic pathways and sepsis-like responses. This study identified specific biomolecular disturbances associated with CSM mortality, revealing that systemic inflammation and bioenergetic deficits are targetable pathophysiological processes for improving survival of this vulnerable population.

SUBMITTER: Wen B

PROVIDER: S-EPMC8849276 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

Wen Bijun B Njunge James M JM Bourdon Celine C Gonzales Gerard Bryan GB Gichuki Bonface M BM Lee Dorothy D Wishart David S DS Ngari Moses M Chimwezi Emmanuel E Thitiri Johnstone J Mwalekwa Laura L Voskuijl Wieger W Berkley James A JA Bandsma Robert Hj RH

Science advances 20220216 7

Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died (<i>n</i> = 92) from those who survived (<i>n< ...[more]

PMID: 35171682

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Project description:BackgroundMalnutrition underlies 45% of under-5 deaths globally. Severe acute malnutrition (SAM) is the most serious form of undernutrition, characterized by wasting with or without edema. Mortality remains high (10%-40%) among children requiring hospitalization for complicated SAM.ObjectivesWe aimed to systematically document the factors independently associated with inpatient mortality in children with SAM.MethodsEmbase, Ovid MEDINE, the Cochrane Library, and clinicaltrials.gov were searched for articles published between January 2000 and January 2020, using a prespecified protocol. Eligible studies included children aged ≤59 mo hospitalized with SAM and used multivariable analysis to assess the baseline factors independently associated with inpatient mortality. Random-effects meta-analysis, stratified by the stated measure of effect, was used where >20% of studies included the same factor in analyses.ResultsTwenty-eight of 1432 studies fulfilled inclusion criteria: 19 studies included all children with SAM and 9 included specific subgroups of children with SAM. All 19 main studies were from 8 countries across Africa, with a median of 400 children/study. The mean inpatient mortality was 15.7% (95% CI: 10.4%, 21.0%) and HIV prevalence ranged from 2.1% to 51%. Nine factors were included in the meta-analysis, stratified by HR and OR. HIV infection (HR: 4.32; 95% CI: 2.31, 8.08), weight-for-height z score (WHZ) (OR: 0.44; 95% CI: 0.24, 0.80), diarrhea (HR: 2.84; 95% CI: 1.40, 5.75), pneumonia (HR: 1.89; 95% CI: 1.19, 3.02), presence of shock (HR: 3.67; 95% CI: 2.24, 6.03), and lack of appetite (HR: 2.16; 95% CI: 1.48, 3.16) were associated with increased mortality, whereas child age and sex were not. The association between edema and mortality was difficult to ascertain from the available studies.ConclusionsHIV infection, diarrhea, pneumonia, shock, lack of appetite, and lower WHZ are independent predictors of inpatient mortality in children with SAM. These factors may help to risk-stratify children being hospitalized with complicated SAM.This systematic review/meta-analysis protocol was registered at www.crd.york.ac.uk/prospero as CRD42019152267.

Project description:ObjectivesWe tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis.DesignProspective cohort study.SettingTertiary PICU.PatientsChildren with 100 separate admission episodes of severe sepsis were enrolled.InterventionsBlood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using C-reactive protein and ferritin thresholds was developed.Measurements and main resultsA C-reactive protein of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 24.20 [95% CI, 5.50-106.54]). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 [35%]; p < 0.05).ConclusionsA C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis.

Project description:BackgroundSevere acute malnutrition (SAM) is the most life-threatening form of undernutrition, and children hospitalised with complications have unacceptably high mortality. Complicated SAM is a multisystem disease characterised pathophysiologically by muscle wasting, systemic inflammation, metabolic dysfunction, and malnutrition enteropathy including epithelial barrier dysfunction. There is a clear need for novel interventions to address the underlying pathogenic perturbations of complicated SAM.MethodsIn this analysis of tertiary outcomes from a phase II multi-centre trial in Zambia and Zimbabwe, multiplex biomarkers were measured in 122 children (57% male) with SAM randomised following stabilisation ('baseline') to one of four interventions for 14 days to treat malnutrition enteropathy: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care. Following measurement of 35 biomarkers from day 15 plasma samples using Luminex and ELISA, the dimensionality of biomarker data was reduced using principal component analysis.FindingsBoth budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP), while children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide, suggesting better restoration of epithelial barrier function. N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).InterpretationInterventions aimed at ameliorating malnutrition enteropathy showed plausible effects on biomarkers of inflammation and epithelial regeneration, demonstrating an interdependence of systemic inflammation and enteropathy markers seen in structural analysis. Given the interplay between inflammation and tissue restoration in malnutrition, this mechanism of action supports larger trials to determine the clinical benefits of interventions, either alone or in combination, in children with complicated SAM.FundingThis analysis of tertiary outcomes for the TAME trial was funded by a Wellcome grant to JPS (220566/Z/20/Z). The TAME trial was funded by a grant from the Medical Research Council (UK), number MR/P024033/1. AJP is funded by Wellcome (108065/Z/15/Z). Takeda UK provided teduglutide at a discounted price.

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Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

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Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

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