Abstract
Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.
Highlights
Coronavirus 2019 (COVID-19) is a new pandemic disease caused by a single-stranded RNA zoonotic virus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]
Patient Characteristics This prospective off-label clinical study includes 19 hospitalized patients with severe COVID-19 who received off-label acalabrutinib between March 20, 2020 through April 10, 2020 with formal data collection completed on April 23, 2020 (Table S1)
Our clinical and correlative laboratory studies have revealed that Bruton tyrosine kinase (BTK) is a likely instigator of the pathological inflammatory response in severe COVID-19
Summary
Coronavirus 2019 (COVID-19) is a new pandemic disease caused by a single-stranded RNA zoonotic virus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The spectrum of COVID-19 ranges from a mild respiratory illness to a severe disease requiring hospitalization in up to a third of patients, with frequent progression to acute respiratory distress syndrome (ARDS) and a high mortality [2]. A virus-induced hyperinflammatory response or “cytokine storm” [5] has been hypothesized to be a major pathogenic mechanism of ARDS in these patients through modulation of pulmonary macrophages, dendritic cells and/or neutrophils [6,7,8,9,10]. The hyperinflammatory response in COVID-19 shares biological characteristics with macrophage activation syndrome, suggesting that targeting the innate immune system may be an effective strategy [13]
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