SERUM HUMANIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE-ORGAN DYSFUNCTION SYNDROME

Abstract

Background: Multiple-organ dysfunction syndrome disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and multiple-organ dysfunction syndrome in a prospectively enrolled cohort of pediatric septic shock. Methods: Human MT-RNR2 ELISA was used to determine sHN concentrations on days 1 and 3. The primary outcome was thrombocytopenia-associated multiorgan failure (TAMOF). Secondary outcomes included individual organ dysfunctions on day 7. Associations across pediatric sepsis biomarker (PERSEVERE)-based mortality risk strata and correlation with platelet and markers of endothelial activation were tested. Results: One hundred forty subjects were included in this cohort, of whom 39 had TAMOF. The concentration of sHN was higher on day 1 relative to day 3 and among those with TAMOF phenotype in comparison to those without. However, the association between sHN and TAMOF phenotype was not significant after adjusting for age and illness severity in multivariate models. In secondary analyses, sHN was associated with presence of day 7 sepsis-associated acute kidney injury ( P = 0.049). Furthermore, sHN was higher among those with high PERSEVERE-mortality risk strata and correlated with platelet counts and several markers of endothelial activation. Conclusion: Future investigation is necessary to validate the association between sHN and sepsis-associated acute kidney injury among children with septic shock. Furthermore, mechanistic studies that elucidate the role of HN may lead to therapies that promote organ recovery through restoration of mitochondrial homeostasis among those critically ill.

Figure 1

a. Box and whisker plots comparing serum humanin (sHN) concentrations in day 1 and 3 serum samples. 1b. Correlation between day 1 sHN concentrations and day 1 platelet counts. 1c and 1d. Comparison of day 1 and 3 sHN concentrations among patients with and without thrombocytopenia associated multiorgan failure clinical phenotype (TAMOF) in the cohort.

Figure 2.

Box and whisker plots comparing sHN concentrations across pediatric sepsis biomarker based (PERSEVERE) low, intermediate, and high- mortality risk strata. P-values are shown for non-parametric Kruskal Wallis test with adjustment for multiple comparisons testing. There were no statistically significant differences in sHN concentrations between low vs. intermediate nor intermediate vs. high strata. However, the difference in sHN concentration when comparing low vs. high-risk strata was significant (p=0.02), with the highest concentrations noted among the latter group.

Figure 3.

Correlation between sHN concentrations and markers of endothelial activation in the cohort. Serum humanin was negatively correlated with Angiopoietin-1 (Angpt-1) and TEK tyrosine kinase (Tie-2), positively correlated with Angiopoietin-2 (Angpt-2), Angpt-2/Angpt-1 ratio, Angpt-2/Tie-2 ratio, Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1). There was no statistically significant association between sHN and concentrations of soluble thrombomodulin (sTM) and platelet endothelial cell adhesion molecule (PECAM-1).