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

Justin de Brabander*, Erik Duijvelaar, the CounterCOVID Study Group, Job R. Schippers, Patrick J. Smeele, Hessel Peters-Sengers, Jan Willem Duitman, Jurjan Aman, Harm J. Bogaard, Tom van der Poll, Lieuwe D.J. Bos

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number2200780
JournalEuropean Respiratory Journal
Volume60
Issue number6
DOIs
Publication statusPublished - 1 Dec 2022

Bibliographical note

Support statement: This project was funded by an unrestricted grand from the Amsterdam Medical Center Foundation and a bottom-up grant from Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW (10430 01 201 0007). In addition, this project received funding from the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 101005142). The funders of this study had no role in study design, data collection, data analysis, data interpretation or writing of the report. Funding information for this article has been deposited with the Crossref Funder Registry.

Publisher Copyright: Copyright © The authors 2022.

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