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.

重症 COVID-19 患者存在高炎症免疫反应，提示巨噬细胞激活。布鲁顿酪氨酸激酶 (BTK) 调节巨噬细胞信号传导和激活。 Acalabrutinib 是一种选择性 BTK 抑制剂，对 19 名因重症 COVID-19 住院的患者（11 名接受补充供氧；8 名接受机械通气）进行超说明书给药，其中 18 名患者在基线时氧气需求增加。在 10-14 天的治疗过程中，acalabrutinib 通常在 1-3 天内改善了大多数患者的氧合，并且没有明显的毒性。大多数患者的炎症指标（C 反应蛋白和 IL-6）很快恢复正常，淋巴细胞减少症也是如此，这与氧合改善相关。在 acalabrutinib 治疗结束时，吸氧组中 8/11 (72.7%) 的患者已出院，呼吸室内空气，机械通气组中 4/8 (50%) 的患者已成功拔管，其中 2/8 (25%) 排放到室内空气中。离体分析显示，与健康志愿者的血液单核细胞相比，自磷酸化证明了 BTK 活性显着升高，并且重症 COVID-19 患者的血液单核细胞中 IL-6 的产生增加。这些结果表明，用 BTK 抑制剂针对过度的宿主炎症是严重 COVID-19 的一种治疗策略，并已引发一项验证性国际前瞻性随机对照临床试验。