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Patients with severe COVID 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 11 on supplemental oxygen; 8 on mechanical ventilation , 18 of whom had increasing oxygen requirements at baseline. Over a day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within days, and had no discernable toxicity.
Measures of inflammation β C-reactive protein and IL-6 β normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. 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 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 and has led to a confirmatory international prospective randomized controlled clinical trial.
The spectrum of COVID 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. It has been reported that COVID patients can have a biphasic clinical course with deterioration following initial improvement, consistent with a delayed and exaggerated immune activation 2 β 4.
