Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients.

Autor:	de Brabander J; Amsterdam UMC, location University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Amsterdam, The Netherlands j.debrabander@amsterdamumc.nl., Duijvelaar E; Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands., Schippers JR; Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands., Smeele PJ; Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands., Peters-Sengers H; Amsterdam UMC, location University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Amsterdam, The Netherlands., Duitman JW; Amsterdam UMC, location University of Amsterdam, Department of Pulmonary Medicine, Amsterdam, The Netherlands.; Amsterdam UMC, location University of Amsterdam, Department of Experimental Immunology (EXIM), Amsterdam, The Netherlands., Aman J; Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands., Bogaard HJ; Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands., van der Poll T; Amsterdam UMC, location University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Amsterdam, The Netherlands., Bos LDJ; Amsterdam UMC, location University of Amsterdam, Department of Pulmonary Medicine, Amsterdam, The Netherlands.; Amsterdam UMC, location University of Amsterdam, Department of Intensive Care and Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2022 Dec 15; Vol. 60 (6). Date of Electronic Publication: 2022 Dec 15 (Print Publication: 2022).
DOI:	10.1183/13993003.00780-2022
Abstrakt:	Background: Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. Methods: We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. Results: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). Conclusions: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes. Competing Interests: Conflict of interest: L.D.J. Bos reports grants from the Dutch Lung Foundation, the Dutch Lung Foundation and Health Holland (Public–Private Partnership grant), the Dutch Lung Foundation (Dirkje Postma Award), the IMI COVID-19 initiative, and Amsterdam UMC fellowship; and consulting fees from Scailyte and Sobi; outside the submitted work. J. Aman is inventor on a patent (WO2012150857A1; 2011) covering protection against endothelial barrier dysfunction through inhibition of the tyrosine kinase Abl-related gene (ARG); and reports serving as a non-compensated scientific advisor for Exvastat. All other authors declare no conflicting interests. (Copyright ©The authors 2022.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu