Subject(s)
Azetidines/therapeutic use , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Interferon-alpha/therapeutic use , Interferon-beta/therapeutic use , Interferons/therapeutic use , Pneumonia, Viral/drug therapy , Sulfonamides/therapeutic use , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/immunology , Interferon-alpha/genetics , Interferon-alpha/immunology , Interferon-beta/genetics , Interferon-beta/immunology , Interferons/genetics , Interferons/immunology , Interleukin-1/genetics , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/immunology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Purines , Pyrazoles , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.
Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Severe Acute Respiratory Syndrome/prevention & control , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Drug Dosage Calculations , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Janus Kinase 2/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Nitriles , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacokinetics , Pyrimidines , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction/drug effectsABSTRACT
A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).