Objective

Severely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients.

Methods

Retrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 μg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome.

Results

Subcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104–335) and 331 (140–476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment.

Conclusion

Overall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.

中文翻译：

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高剂量皮下注射阿那白滞素治疗重症 COVID-19 患者继发于细胞因子风暴综合征的急性呼吸窘迫综合征。

客观的

重症 COVID-19 患者可能会导致急性呼吸窘迫综合征 (ARDS) 和多器官衰竭。其中一些人会因炎症因子的大量释放而出现全身性高炎症状态，称为细胞因子风暴综合征（CSS）。阿那白滞素 (ANK) 抑制 IL-1 是治疗严重 CSS 病例的潜在救生疗法。我们提出了使用皮下 ANK 的理由，并回顾了我们在一小群重症 COVID-19 CSS 患者中的初步经验。

方法

对发生 ARDS（PaO2/FiO2 <300）并表现出过度炎症迹象（铁蛋白 >1000 ng/mL 和/或 d-二聚体 > 1.5 μg/mL，加上 IL-6 < 40 mg/mL 的 COVID-19 患者的回顾性队列研究）收到ANK。为了进行比较，使用了与接受 IL-6 抑制剂托珠单抗 (TCZ) 治疗的患者历史队列相匹配的倾向评分。患者之前接受过阿奇霉素、羟氯喹和甲基泼尼松龙的联合治疗。监测实验室检查结果、呼吸功能和不良反应。ARDS 在治疗的前 7 天内得到缓解被认为是一个有利的结果。

结果

9 名 COVID-19 ARDS CSS 患者（77.8% 为男性）皮下注射 ANK（每 6 小时 100 毫克）。中位年龄为 62 岁（范围：42 至 87 岁）。通过倾向评分匹配选择了 18 名患者组成的 TCZ 队列，对于体重 > 75 Kg 的患者，采用静脉单剂量 600 mg 进行治疗，如果体重 < 75 Kg，则采用 400 mg 静脉单剂量治疗。治疗前，ANK 组和 TCZ 组的中位 PaO2/FiO2 比值分别为 193 和 249 (p = 0.131)。治疗 7 天后，两组 PaO2/FiO2 比值分别改善至 279 (104-335) 和 331 (140-476，p = 0.099)。第 7 天，ANK 组中的铁蛋白 (p = 0.046)、CRP (p = 0.043) 和 IL-6 (p = 0.043) 水平显着降低，但 TCZ 组中仅 CRP (p = 0.001) 水平显着降低。ANK 和 TCZ 队列中分别有 55.6% 和 88.9% 取得了良好的结果 (p = 0.281)。两名对 TCZ 无效的患者在 ANK 治疗后病情有所改善。TCZ 组的转氨酶水平在第 1 天和第 7 天之间显着增加 (p = 0.004)。两组的死亡率相同（11%）。各组中没有任何机会性感染，也没有因治疗引起的其他不良反应。

结论

总体而言，接受 ANK 治疗的 COVID-19 ARDS CSS 患者中有 55.6% 表现出良好的结果，不逊色于 TCZ 治疗的匹配队列。对于转氨酶升高的患者，ANK 可能是 TCZ 的潜在替代品，并且可能对 TCZ 无反应者有用。