雾化用弹性蛋白酶治疗重症 COVID-19 肺炎的抗炎治疗：一项随机、非盲试验。
Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.
机构信息
UCL Respiratory, University College London, London, United Kingdom.
University College London Hospitals NHS Trust, London, United Kingdom.
出版信息
Elife. 2024 Jul 16;12:RP87030. doi: 10.7554/eLife.87030.
BACKGROUND
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
METHODS
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
RESULTS
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
CONCLUSIONS
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
FUNDING
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
CLINICAL TRIAL NUMBER
NCT04359654.
背景
中性粒细胞细胞外陷阱（NETs）和其他细胞来源的促炎细胞外染色质存在于 COVID-19 患者中，可能促进发病机制。我们确定了肺部给予内切酶脱氧核糖核酸酶是否通过清除细胞外染色质来减轻全身炎症。
方法
合格的患者被随机分为最佳现有治疗（包括地塞米松）组（R-BAC）或最佳现有治疗加每日两次雾化脱氧核糖核酸酶组（R-BAC+DA），治疗时间为 7 天或直至出院。两倍于匹配的同期对照组（CC-BAC）为额外的对照。主要终点是使用重复测量混合模型分析的 CRP 随时间的改善，该模型根据基线因素进行了调整。
结果
我们招募了 39 名可评估的参与者：30 名随机接受脱氧核糖核酸酶（R-BAC+DA），9 名随机接受 BAC（R-BAC），并纳入了 60 名 CC-BAC 参与者。脱氧核糖核酸酶的耐受性良好，与 T-BAC 组相比，CRP 降低了 33%。R-BAC+DA 组的地塞米松后 LS 平均 CRP 从 101.9mg/L 降至 23.23mg/L，而 T-BAC 组从 99.5mg/L 降至 34.82mg/L，第 7 天差异有统计学意义（p=0.01）。仅对随机参与者进行亚组和敏感性分析进一步证实了脱氧核糖核酸酶的抗炎作用，减轻了使用 CC-BAC 参与者相关的潜在偏倚。脱氧核糖核酸酶使活出院率增加了 63%（HR 1.63，95%CI 1.01-2.61，p=0.03），增加了淋巴细胞计数（LS 均值：1.08 对 0.87，p=0.02），并降低了循环 cf-DNA 和凝血标志物 D-二聚体（LS 均值：570.78 对 1656.96μg/mL，p=0.004）。
结论
脱氧核糖核酸酶降低 COVID-19 肺炎的致病性炎症，证明了针对细胞外染色质的具有成本效益的治疗方法的益处。
资助
LifeArc、Breathing Matters、弗朗西斯·克里克研究所（CRUK、医学研究委员会、惠康信托基金会）。
临床试验注册号
NCT04359654。
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