Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study
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DOI：
10.1016/s2665-9913(20)30127-2
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发表时间：
2020-06-01
影响因子：
25.4
通讯作者：
Dagna, Lorenzo
中科院分区：
文献类型：
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作者：
Cavalli, Giulio;De Luca, Giacomo;Dagna, Lorenzo
背景冠状病毒病2019(新冠肺炎)、急性呼吸窘迫综合征和全身炎症患者的死亡率很高。在大流行暴发地区，患者人数可能超过重症监护病房(ICU)的最大容量，因此，这些人经常在ICU外接受无创呼吸机。迫切需要对这一人群进行有效的治疗。Anakinra是一种重组白介素1受体拮抗剂，可能对该患者群体有益。方法我们在意大利米兰的San Raffaele医院进行了一项回顾性队列研究。我们纳入了连续的患者(年龄8岁)，患有新冠肺炎、中到重度急性呼吸窘迫综合征和炎症(定义为血清C反应蛋白=100 mg/L，铁蛋白=900 ng/mL，或两者兼而有之)，他们在ICU外接受无创机械通气管理，接受标准治疗，每日两次口服羟氯喹200 mg，以及每日两次口服洛匹那韦400 mg和利托那韦100 mg。我们比较了接受Anakinra额外治疗(每天两次静脉注射5毫克/公斤[大剂量]或皮下注射100 mg/kg[低剂量])和未接受Anakinra治疗的一组患者(称为标准治疗组)的存活率、非机械通气存活率、C反应蛋白、呼吸功能和临床状态的变化。所有结果在第21天进行评估。这项研究是新冠肺炎生物库研究的一部分，该研究已在ClinicalTrials.gov注册，NCT04318366。研究发现，在2020年3月17日至3月27日期间，29名患者接受了大剂量静脉无创呼吸机、无创呼吸机和标准治疗。在2020年3月10日至3月17日期间，16名患者仅接受了无创机械通气和标准治疗，并构成了本研究的对照组。另有7名患者除接受无创机械通气和标准治疗外，还接受了小剂量的阿纳金拉治疗；然而，阿纳金拉治疗在7天后中断，因为对血清C-反应蛋白和临床状态的影响很小。在治疗21天后，29名患者中有21名(72%)接受大剂量阿纳金纳治疗后血清C-反应蛋白降低，呼吸功能逐渐改善；5名(17%)患者接受机械通气治疗，3名(10%)死亡。在标准治疗组中，16名患者中有8名(50%)在21天后呼吸改善；1名(6%)患者接受机械通气，7名(44%)死亡。第21天，大剂量阿纳金纳组存活率为90%，标准治疗组存活率为56%(p=0.009)。Anakinra组的无机械通气存活率为72%，标准治疗组为50%(p=0.15)。接受大剂量Anakinra治疗的29名患者中有4名(14%)出现菌血症，接受标准治疗的16名患者中有2名(13%)出现菌血症。在这项对新冠肺炎和急性呼吸窘迫综合征患者进行的回顾性队列研究中，使用大剂量的阿纳金纳治疗是安全的，并且与临床改善相关。疗效的确认将需要对照试验。版权所有(C)2020爱思唯尔有限公司。保留所有权利。
Background Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population.Methods We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged >= 8 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein >= 100 mg/L, ferritin >= 900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov , NCT04318366.Findings Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0.009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0.15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses.Interpretation In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials. Copyright (C) 2020 Elsevier Ltd. All rights reserved.