Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI (preprint)

Introduction: Microvascular abnormalities and impaired 129Xe gas transfer have been observed in patients with COVID 19. The progression of pathophysiological pulmonary changes during the post acute period in these patients remains unclear. Methods: Patients who were hospitalised due to COVID 19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 50 weeks after hospital admission. The imaging protocol included: ultra short echo time, dynamic contrast enhanced lung perfusion, 129Xe lung ventilation, 129Xe diffusion weighted and 129Xe 3D spectroscopic imaging of gas exchange. Results: 9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 50 (n=3) weeks after hospital admission. At 6 weeks after hospital admission, patients demonstrated impaired 129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6 to 25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 and 25 week follow up, significant improvements in 129Xe gas transfer were observed compared to 6 week examinations, however 129Xe gas transfer remained abnormally low. Conclusions: This study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID 19. Persistent impairment of xenon transfer may represent a physiological mechanism underlying ongoing symptoms in some patients and may indicate damage to the pulmonary microcirculation.

Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin. (preprint)

Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in COVID-19 and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to LPS compared to cells from healthy control subjects. A subset of patients were captured at follow-up clinics (3-4 month post-infection) and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and PMA-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.