Endothelial glycocalyx degradation in multisystem inflammatory syndrome in children related to COVID-19

Abstract

Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection affecting children that can lead to myocardial injury and shock. Vascular endothelial dysfunction has been suggested to be a common complicating factor in patients with coronavirus disease 2019 (COVID-19). This study aims to characterize endothelial glycocalyx degradation in children admitted with MIS-C. We collected blood and urine samples and measured proinflammatory cytokines, myocardial injury markers, and endothelial glycocalyx markers in 17 children admitted with MIS-C, ten of which presented with inflammatory shock requiring intensive care admission and hemodynamic support with vasopressors. All MIS-C patients presented signs of glycocalyx deterioration with elevated levels of syndecan-1 in blood and both heparan sulfate and chondroitin sulfate in the urine. The degree of glycocalyx shedding correlated with tumor necrosis factor-α concentration. Five healthy age-matched children served as controls. Patients with MIS-C presented severe alteration of the endothelial glycocalyx that was associated with disease severity. Future studies should clarify if glycocalyx biomarkers could effectively be predictive indicators for the development of complications in adult patients with severe COVID-19 and children with MIS-C. KEY MESSAGES : Children admitted with MIS-C presented signs of endothelial glycocalyx injury with elevated syndecan-1 and heparan sulfate level. Syndecan-1 levels were associated with MIS-C severity and correlated TNF-α concentration. Syndecan-1 and heparan sulfate may represent potential biomarkers for patients with severe COVID-19 or MIS-C.

Keywords: COVID-19; Endothelium; Glycocalyx; Heparan sulfate; Inflammation; MIS-C.

Fig. 1

Syndecan-1 concentration increases in children with MIS-C. a Admission level of syndecan-1 (ng/ml) in healthy, MIS-C without shock, and MIS-C with shock patients. Data represent median with interquartile range of plasma and serum samples. **P < 0.01, Mann–Whitney test (non-shock MIS-C vs shock-MIS-C), and (healthy controls vs total MIS-C patients). Black open circle = serum sample and red full circle = plasma sample. b Time course of syndecan-1 plasma concentration in children admitted with MIS-C since hospital admission. The limit of detection of the ELISA is represented by a dotted line. Control data are the average of three control samples. c Correlation of plasma syndecan-1 with NT-proBNP, IL-6, and TNF-α. Spearman correlation test. IL-6, interleukin-6; MIS-C, multisystem inflammatory syndrome in children; NT-proBNP, N-terminal probrain natriuretic peptide; TNF-α, tumor necrosis factor α

Fig. 2

Time course of syndecan-1 concentration according to NT-proBNP, CRP, IL-6, and TNF-α plasma concentration in three MIS-C patients with shock. Control data are the mean of three control samples. CRP, c-reactive protein; IL-6, interleukin-6; MIS-C, multisystem inflammatory syndrome in children; NT-proBNP, N-terminal probrain natriuretic peptide; TNF-α, tumor necrosis factor α

Fig. 3

Sulfation pattern of urinary heparan sulfate and chondroitin sulfate from children with MIS-C. The percentage of variously substituted disaccharides is reported for HS in a and for CS in c. The overall sulfation degree (sulfates/disaccharide) is shown for HS in b and for CS in d. Data represent median with interquartile range. *P < 0.05, **P < 0.01, ***P < 0.001, two-way analysis of variance (ANOVA) with Tukey post hoc t-test (a and c); *P < 0.05, Kruskal–Wallis test with FDR correction (b and d). ΔUA, unsaturated uronic acid ± 2-O-sulfation (2S); GlcNAc, N-acetylglucosamine; NS, N-sulfation; 6S, 6-O-sulfation; 4S, 4-O-sulfation; GalNAc, N-acetylgalactosamine; HS, heparan sulfate; CS, chondroitin sulfate; MIS-C, multisystem inflammatory syndrome in children; UA, uronic acid