依库珠单抗作为重症监护病房中成年重症 COVID-19 患者的紧急治疗：一项概念验证研究。
Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.
作者信息
Annane Djillali, Heming Nicholas, Grimaldi-Bensouda Lamiae, Frémeaux-Bacchi Véronique, Vigan Marie, Roux Anne-Laure, Marchal Armance, Michelon Hugues, Rottman Martin, Moine Pierre
机构信息
FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), RHU RECORDS (Rapid rEcognition of CORticosteroiD resistant or sensitive Sepsis), Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation - U1173, School of Medicine Simone Veil, University Versailles Saint Quentin - University Paris Saclay, INSERM, 104 Boulevard Raymond Poincaré, Garches 92380, France.
Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation - U1173, School of Medicine Simone Veil, University Versailles Saint Quentin - University Paris Saclay, INSERM, Garches, France.
出版信息
EClinicalMedicine. 2020 Nov;28:100590. doi: 10.1016/j.eclinm.2020.100590. Epub 2020 Nov 5.
BACKGROUND
Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19.
METHODS
All patients ( = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed.
FINDINGS
At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%).
INTERPRETATION
Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed.
FUNDING
Programme d'Investissements d'Avenir: ANR-18-RHUS60004.
背景
补体途径抑制可能对由病毒感染（如2019冠状病毒病）引起的严重急性呼吸道疾病有益。我们展示了一项关于补体C5抑制剂依库珠单抗治疗重症2019冠状病毒病的非随机概念验证研究的结果。
方法
纳入2020年3月10日至5月5日期间入住我们重症监护病房的所有确诊严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染且患有重症2019冠状病毒病的患者（n = 80）。45例患者接受标准治疗，35例患者通过扩大准入紧急治疗接受标准治疗加依库珠单抗。预先设定的主要结局为第15天的生存率。还评估了临床实验室值和生物标志物、补体水平以及治疗中出现的严重不良事件（TESAEs）。
结果
在第15天，接受依库珠单抗治疗的患者估计生存率为82.9%（95%置信区间：70.4%‒95.3%），未接受依库珠单抗治疗的患者为62.2%（48.1%‒76.4%）（对数秩检验，P = 0.04）。与未接受依库珠单抗治疗的患者相比，接受依库珠单抗治疗的患者乳酸、血尿素氮、总胆红素和结合胆红素水平下降明显更快，血小板计数、凝血酶原时间以及动脉血氧分压与吸入氧分数之比升高明显更快。依库珠单抗引起的补体水平、实验室值和生物标志物变化与末端补体抑制、缺氧减轻和炎症减轻一致。在接受/未接受依库珠单抗治疗的患者中，发生率超过5%的特别关注的TESAEs为呼吸机相关性肺炎（51%/24%）、菌血症（11%/2%）、胃十二指肠出血（14%/16%）和溶血（3%/18%）。
解读
这项概念验证研究的结果表明，依库珠单抗可能改善重症2019冠状病毒病患者的生存率并减轻缺氧。需要进行评估这种治疗方法疗效和安全性的随机研究。
资助
未来投资计划：ANR-18-RHUS60004。
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