Neutrophil Extracellular Traps Are Induced by Coronavirus 2019 Disease-Positive Patient Plasma and Persist Longitudinally: A Possible Link to Endothelial Dysfunction as Measured by Syndecan-1

Background: Neutrophil extracellular trap (NET) formation is a mechanism that neutrophils possess to respond to host infection or inflammation. However, dysregulation of NETosis has been implicated in many disease processes. Although the exact mechanisms of their involvement remain largely unknown, this study aimed to elucidate NET formation over the time course of coronavirus disease 2019 (COVID-19) infection and their possible role in endothelial injury. Patients and Methods: Plasma samples from COVID-19–positive patients were obtained at six timepoints during hospitalization. Neutrophils were extracted from healthy donors and treated with COVID-19–positive patient plasma. Myeloperoxidase (MPO) assay was used to assess for NETosis. Syndecan-1 (SDC-1) enzyme-linked immunosorbent assay (ELISA) was run using the same samples. Immunocytochemistry allowed for further quantification of NETosis byproducts MPO and citrullinated histone 3 (CitH3). The receiver operating characteristic (ROC) curve discriminated between admission levels of SDC-1 and MPO in predicting 30-day mortality and need for ventilator support. Results: Sixty-three patients with COVID-19 were analyzed. Myeloperoxidase was upregulated at day 3, 7, and 14 (p = 0.0087, p = 0.0144, p = 0.0421). Syndecan-1 levels were elevated at day 7 and 14 (p = 0.0188, p = 0.0026). Neutrophils treated with day 3, 7, and 14 plasma expressed increased levels of MPO (p < 0.001). Immunocytochemistry showed neutrophils treated with day 3, 7, and 14 plasma expressed higher levels of MPO (p < 0.001) and higher levels of CitH3 when treated with day 7 and 14 plasma (p < 0.01 and p < 0.05). Admission SDC-1 and MPO levels were found to be independent predictors of 30-day mortality and need for ventilator support. Conclusions: Neutrophil dysregulation can be detrimental to the host. Our study shows that COVID-19 plasma induces substantial amounts of NET formation that persists over the course of the disease. Patients also exhibit increased SDC-1 levels that implicate endothelial injury in the pathogenesis of COVID-19 infection. Furthermore, MPO and SDC-1 plasma levels are predictive of poor outcomes.