Background

High levels of serum interleukin-6 (IL-6) correlate with disease severity in COVID-19. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters.

Methods

The TOCICOVID study included a prospective cohort of patients aged 16–80 years with severe (requiring > 6 L/min of oxygen therapy to obtain Sp02 > 94%) rapidly deteriorating (increase by ≥ 3 L/min of oxygen flow within the previous 12 h) COVID-19 pneumonia with ≥ 5 days of symptoms and C-reactive protein levels > 40 mg/L. They entered a compassionate use program of treatment with intravenous tocilizumab (8 mg/kg with a maximum of 800 mg per infusion; and if needed a second infusion 24 to 72 h later). A control group was retrospectively selected with the same inclusion criteria. Outcomes were assessed at D28 using inverse probability of treatment weighted (IPTW) methodology.

Results

Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, baseline disease severity, and concomitant medications were broadly similar between the tocilizumab (n = 49) and the control (n = 47) groups. In the IPTW analysis, treatment with tocilizumab was associated with a reduced need for overall ventilatory support (49 vs. 89%, wHR: 0.39 [0.25–0.56]; p < 0.001). Albeit lacking statistical significance, there was a substantial trend towards a reduction of mechanical ventilation (31% vs. 45%; wHR: 0.58 [0.36–0.94]; p = 0.026). However, tocilizumab did not improve overall survival (wHR = 0.68 [0.31–1.748], p = 0.338). Among the 85 (89%) patients still alive at D28, patients treated with tocilizumab had a higher rate of oxygen withdrawal (82% vs. 73.5%, wHR = 1.66 [1.17–2.37], p = 0.005), with a shorter delay before being weaned of oxygen therapy (mean 11 vs. 16 days; p < 0.001). At D28, the rate of patients discharged from hospital was higher in the tocilizumab group (70% vs. 40%, wHR = 1.82 [1.22–2.75]; p = 0.003). The levels of CRP and fibrinogen post therapy (p < 0.001 for both variables) were significantly lower in the tocilizumab group (interaction test, mixed model). Rates of neutropenia (35% vs. 0%; p < 0.001) were higher in the tocilizumab group, yet rates of infections (22% vs. 38%, p = 0.089) including ventilator-acquired pneumonia (8% vs. 26%, p = 0.022) were higher in the control group.

Conclusion

These data could be helpful for the design of future trials aiming to counter COVID-19-induced inflammation, especially before patients require admission to the intensive care unit.

中文翻译：

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托珠单抗治疗严重恶化的 COVID-19 肺炎：倾向评分分析

背景

高水平的血清白细胞介素 6 (IL-6) 与 COVID-19 的疾病严重程度相关。我们假设托珠单抗（一种重组人源化抗 IL-6 受体）可以改​​善 COVID-19 肺炎严重恶化和高炎症参数的选定患者的预后。

方法

TOCICOVID 研究包括一个年龄在 16-80 岁的患者的前瞻性队列，患者严重（需要 > 6 L/min 的氧气治疗以获得 SpO2 > 94%）迅速恶化（在过去 12 年内氧气流量增加 ≥ 3 L/min h) COVID-19 肺炎，症状 ≥ 5 天且 C 反应蛋白水平 > 40 mg/L。他们进入了静脉注射托珠单抗治疗的同情使用计划（8 mg/kg，每次输注最多 800 mg；如果需要，在 24 至 72 小时后进行第二次输注）。以相同的纳入标准回顾性选择对照组。在第 28 天使用治疗加权的逆概率 (IPTW) 方法评估结果。

结果

在 96 名患者中（81% 为男性，平均 (SD) 年龄：60 (12.5) 岁），托珠单抗 ( n  = 49) 和对照组 ( n  = 47) 组。在 IPTW 分析中，托珠单抗治疗与整体通气支持需求的减少相关（49% vs. 89%，wHR：0.39 [0.25–0.56]；p  < 0.001）。尽管缺乏统计学意义，但机械通气减少的趋势明显（31% vs. 45%；wHR：0.58 [0.36–0.94]；p  = 0.026）。然而，托珠单抗并未提高总体生存率（wHR = 0.68 [0.31–1.748]，p = 0.338）。在第 28 天仍存活的 85 名 (89%) 患者中，接受托珠单抗治疗的患者停氧率更高（82% 对 73.5%，wHR = 1.66 [1.17–2.37]，p  = 0.005），延迟更短在停止氧疗之前（平均 11 天 vs. 16 天；p  < 0.001）。在第 28 天，托珠单抗组的出院率较高（70% 对 40%，wHR = 1.82 [1.22–2.75]；p  = 0.003）。托珠单抗组治疗后的 CRP 和纤维蛋白原水平（两个变量p  < 0.001）显着降低（相互作用测试，混合模型）。托珠单抗组的中性粒细胞减少率（35% 对 0%；p  < 0.001）较高，但感染率（22% 对 38%，p = 0.089）包括呼吸机获得性肺炎（8% 对 26%，p  = 0.022）在对照组中较高。

结论

这些数据可能有助于设计旨在对抗 COVID-19 引起的炎症的未来试验，尤其是在患者需要进入重症监护病房之前。