Two-sided effects of neutrophil extracellular traps and changes in the myeloid compartment in acute COVID-19: A histopathological study on autopsy cases from the first and second COVID-19 waves in Switzerland.

Severe COVID-19 is characterized by complex immunopathology that involves inflammation, endothelial dysfunction, and immunothrombosis. Neutrophil extracellular traps (NETs) have been recognized as key factors in the severity of the disease, with their emergence correlating to viral load, immmunothrombosis, and organ damage. In this study, we investigated the role of NETosis and macrophage activation in the course of severe COVID-19. We analyzed 23 autopsy samples from patients who died from COVID-19 and performed immunohistochemical staining and stereological point counting to quantify leukocyte infiltration and NET formation among other histopathological parameters. Our results showcase 2 evident immunophenotypes: lowNET and highNET. The lowNET group displayed lower NET formation, higher viral loads, and an increased incidence of secondary infections, as well as shorter survival times. In contrast, the highNET group exhibited increased neutrophil activation, pronounced endothelial damage and thrombotic complications, as well as prolonged survival times. Our data suggest a dual role of NETosis in COVID-19: initially protective, limiting viral replication, but later likely detrimental through immunothrombosis and tissue damage. These findings underline the need for tailored therapeutic actions, with early antiviral and immune-modulating interventions for lowNET patients and strategies aiming to limit excessive NETosis and coagulopathy in highNET patients. Further research is needed to define the timing of interventions based on the dynamics of NETosis.