Inhibition of Bruton tyrosine kinase in patients with severe COVID-19
Inhibition of Bruton tyrosine kinase in patients with severe COVID-19
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DOI：
10.1126/sciimmunol.abd0110
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发表时间：
2020-06-01
影响因子：
24.8
通讯作者：
Wilson, Wyndham H.
中科院分区：
文献类型：
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作者：
Roschewski, Mark;Lionakis, Michail S.;Wilson, Wyndham H.
患有严重COVID-19的患者具有提示巨噬细胞活化的炎症性免疫反应。布鲁顿酪氨酸激酶（BTK）调节巨噬细胞信号传导和活化。Acalabrutinib是一种选择性BTK抑制剂，对19名因严重COVID-19住院的患者（11名接受辅助供氧，8名接受机械通气）进行了标签外给药，其中18名患者在基线时的氧气需求增加。在10至14天的疗程中，大多数患者开始接受acalabrutinib治疗后氧合改善，通常在1至3天内，并且没有明显的毒性。大多数患者的炎症-C反应蛋白和白细胞介素-6（IL-6）指标迅速恢复正常，淋巴细胞减少也是如此，与氧合改善相关。在acalabrutinib治疗结束时，辅助供氧队列中的8/11例（72.7%）患者出院后可呼吸室内空气，机械通气队列中的4/8例（50%）患者成功拔管，2/8例（25%）患者出院后可呼吸室内空气。离体分析显示，与来自健康志愿者的血液单核细胞相比，来自严重COVID-19患者的血液单核细胞中的BTK活性显著升高（如自磷酸化所证明的）和IL-6产生增加。这些结果表明，用BTK抑制剂靶向过度的宿主炎症是严重COVID-19的治疗策略，并导致了一项验证性的国际前瞻性随机对照临床试验。
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 and 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10- to 14-day treatment course, initiation of acalabrutinib treatment was associated with improved oxygenation in a majority of patients, often within 1 to 3 days, and had no discernable toxicity. Measures of inflammation-C-reactive protein and interleukin-6 (IL-6)-normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8 of 11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4 of 8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2 of 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.