Endothelial activation and repair during hantavirus infection: association with disease outcome

Abstract

Background: Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated.

Methods: The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1).

Results: Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity.

Conclusions: Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.

Keywords: Puumala virus; endothelial activation; endothelial surface layer; endothelium; glycocalyx; hantavirus; hemorrhagic fever with renal syndrome; vasculogenesis/angiogenesis.

Figure 1.

Time line kinetics of syndecan-1 (A), endothelial selectin (sE-selectin) (B), soluble intercellular adhesion molecules (sICAM-1) (C), soluble vascular cell adhesion molecule (sVCAM-1) (D), vascular endothelial growth factor (VEGF) (E), angiopoietin (Ang-2) (F), erythropoietin (EPO) (G), and stromal cell-derived factor 1 (SDF-1) (H) in patients with hemorrhagic fever with renal syndrome. The markers are depicted as mean values ± standard error of the mean. Samples were obtained from 19 patients (syndecan-1, sICAM-1, sVCAM-1: 93 samples; sE-selectin and VEGF: 92 samples; EPO: 91 samples) and 17 patients (SDF-1: 44 samples). Asterisks indicate where there is a significant difference between the time points vs the follow-up (>18 days after disease onset) using generalized estimating equations GEEs (***P < .001; **P < .01; *P < .05). The number of patients included in each time point is displayed below the graph point in the respective figures.