Immunothrombosis and Complement Activation Contribute to Disease Severity and Adverse Outcome in COVID-19.

Severe COVID-19 is characterized by systemic inflammation and multiple organ dysfunction syndrome (MODS). Arterial and venous thrombosis are involved in the pathogenesis of MODS and fatality in COVID-19. There is evidence that complement and neutrophil activation in the form of neutrophil extracellular traps are main drivers for development of microvascular complications in COVID-19. Plasma and serum samples were collected from 83 patients infected by SARS-CoV-2 during the two first waves of COVID-19, before the availability of SARS-CoV-2 vaccination. Samples were collected at enrollment, day 11, and day 28; and patients had differing severity of disease. In this comprehensive study, we measured cell-free DNA, neutrophil activation, deoxyribonuclease I activity, complement activation, and D-dimers in longitudinal samples of COVID-19 patients. We show that all the above markers, except deoxyribonuclease I activity, increased with disease severity. Moreover, we provide evidence that in severe disease there is continued neutrophil and complement activation, as well as D-dimer formation and nucleosome release, whereas in mild and moderate disease all these markers decrease over time. These findings suggest that neutrophil and complement activation are important drivers of microvascular complications and that they reflect immunothrombosis in these patients. Neutrophil activation, complement activation, cell-free DNA, and D-dimer levels have the potential to serve as reliable biomarkers for disease severity and fatality in COVID-19. They might also serve as suitable markers with which to monitor the efficacy of therapeutic interventions in COVID-19.

Immunotherapy With Antiprogrammed Cell Death 1 Antibody Improves Outcome in a Mouse Model of Spinal Cord Injury Followed by Staphylococcus aureus Pneumonia.

OBJECTIVES: In patients with spinal cord injury, spinal cord injury-immune depression syndrome induces pneumonia. We aimed to develop a new spinal cord injury-immune depression syndrome mouse model and to test antiprogrammed cell death 1 therapy. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: RjOrl: SWISS and BALB/cJ mice. INTERVENTIONS: Mouse model of spinal cord injury-immune depression syndrome followed by a methicillin-susceptible Staphylococcus aureus pneumonia. Lung injuries were assessed by histologic analysis. Membrane markers and intracytoplasmic cytokines were assessed by flow cytometry. Cytokine production was assessed by quantitative polymerase chain reaction (messenger RNA) and enzyme-linked immunosorbent assay (protein). Animals were treated with blocking antiprogrammed cell death 1 antibodies (intraperitoneal injection). MEASUREMENTS AND MAIN RESULTS: Spinal cord injury mice were more susceptible to methicillin-susceptible S. aureus pneumonia (increased mortality rate). An early inflammatory response was observed in spinal cord injury mice characterized in lungs by a decreased percentage of aerated tissue, an increased production of proinflammatory cytokines (tumor necrosis factor-α). In spleen, an increased expression of major histocompatibility complex class II molecules on dendritic cells, and an increased production of proinflammatory cytokines (interleukin-12, interferon-γ) was observed. Following this pulmonary and systemic inflammation, spinal cord injury-immune depression syndrome was observed in spleens as acknowledged by a decrease of spleen's weight, a lymphopenia, a decrease of major histocompatibility complex class II expression on dendritic cells. An increase of interleukin-10 production and the increase of a cell exhaustion marker expression, programmed cell death 1 receptor on T-cell were also observed. Blockade of programmed cell death 1 molecules, improved survival of spinal cord injury infected mice and enhanced interferon-γ production by natural killer T cells as well as number of viable CD4 T cells. CONCLUSIONS: This model of spinal cord injury in mice mimics a clinical scenario rendering animals prone to a secondary pneumonia. We show for the first time an acute T-cell exhaustion-like phenomenon following an initial inflammatory response. Finally, inhibition of exhaustion pathway should be considered as a new therapeutic option to overcome spinal cord injury-immune depression syndrome and to decrease the rate of nosocomial pneumonia.