Endothelial glycocalyx degradation and its association with clinical outcomes and host response aberrations in community-acquired pneumonia across different care settings

Background: Endothelial glycocalyx degradation has been implicated in the pathogenesis of sepsis. Previous studies linked elevated plasma syndecan-1, an established biomarker of glycocalyx disruption, to mortality in sepsis. We aimed to determine the association of plasma syndecan-1 levels with clinical outcomes and host response changes in patients with community-acquired pneumonia (CAP) with various disease severities. Methods: We included CAP patients upon presentation in three care settings: emergency department (ED), general ward, and intensive care unit (ICU). We stratified patients in a Normal-Syndecan-1 and an Elevated-Syndecan-1 group based on syndecan-1 levels measured in outpatient controls without infection, and measured 32 biomarkers reflective of five pathophysiological domains involved in sepsis immunopathology: coagulation activation, endothelial cell activation and dysfunction, cytokines, neutrophil degranulation, systemic inflammation and organ damage. We analyzed blood transcriptomes to obtain insight in changes in host response pathways in circulating leukocytes related with glycocalyx disruption. Results: We included 50 non-infectious control patients and 384 CAP patients, with samples collected from 95 in the ED, 124 after admission to the general ward, and 165 after admission to the ICU. The Elevated-Syndecan-1 group showed significantly reduced 30-day survival compared to the Normal-Syndecan-1 group (log-rank p < 0.05). The relationship between syndecan-1 (continuous variable) and 30-day mortality was non-linear and independent of comorbidities and disease severity. Most biomarkers were already strongly elevated in the Normal-Syndecan-1 group relative to non-infectious controls, spanning all pathophysiological domains. All biomarkers showed further increases in the Elevated-Syndecan-1 group relative to non-infectious controls, which was also reflected in direct comparisons between the Normal-Syndecan-1 and Elevated-Syndecan-1 groups. Gene set enrichment analysis of blood leukocytes indicated a link between elevated syndecan-1 and increased expression of genes involved in extracellular matrix organization and hemostasis. Conclusions: Glycocalyx degradation, as measured by plasma syndecan-1, shows a non-linear association with mortality in patients with CAP. Key systemic host response changes implicated in sepsis pathogenesis occur prior to detectable glycocalyx degradation in this population.