The janus-kinase inhibitor ruxolitinib in SARS-CoV-2 induced acute respiratory distress syndrome (ARDS)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.

Conflict of interest statement

AB receives research support for a pan-European research consortium on chronic myelogenous leukemia (EUTOS) and obtained a lecture honorarium from Novartis. CFV gave presentations at symposia and/or served on scientific advisory boards sponsored by AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira and MedUpdate. CS received research funding and served as a consultant for Hycor Biomedical and Thermo Fisher Scientific, from Mead Johnson Nutrition (MJN) she received research funding and served as a consultant for Bencard Allergie. AN, CSB, and JJ had received institutional funding from Novartis for this study. EM received a lecture honorarium and served on an advisory board for Roche. The remaining authors declare no competing financial interests.

© 2021. The Author(s).

Figures

Fig. 1. Kaplan–Meier estimated 28-day overall survival in the intention-to-treat population (N = 16).

Gray denotes 95% pointwise confidence intervals (as based on the log hazard).

Fig. 2. Condition of all patients during ICU treatment.

Individual patient outcomes and times on ICU with the duration of invasive mechanical ventilation in the intention-to-treat population are shown (N = 16).

Fig. 3. Biomarkers during ruxolitinib treatment.

C-reactive protein (panel A), interleukin-6 (panel B), and ferritin (panel C) levels over 28 days treatment period in the intention-to-treat population (N = 16) with corresponding numbers of patients observed at each assessment. Note that the y axes are log-scale. Asterisks show significance level of p value obtained in two-sided Wilcoxon-Mann–Whitney test for a given assessment when compared to baseline distribution (*P < 0.05; **P < 0.01; ***P < 0.001). Please note, that these values have not been corrected for multiple testing.

Fig. 4. Lymphocyte to neutrophile ratio at baseline (log-scale) in day-28 survivors (N = 11) and non-survivors (N = 3).

Note that the y axis is log-scale. Only 14 patients were evaluable as one leukemic patient had to be excluded, and in another patient no data were available. P < 0.01 (Exact Wilcoxon-Mann–Whitney test).