Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.
Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.
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DOI：
10.1016/s2665-9913(21)00012-6
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发表时间：
2021-04
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通讯作者：
Dagna L
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作者：
Cavalli G;Larcher A;Tomelleri A;Campochiaro C;Della-Torre E;De Luca G;Farina N;Boffini N;Ruggeri A;Poli A;Scarpellini P;Rovere-Querini P;Tresoldi M;Salonia A;Montorsi F;Landoni G;Castagna A;Ciceri F;Zangrillo A;Dagna L
患有严重COVID-19的患者会对病毒产生危及生命的过度炎症反应。白细胞介素（IL）-1或IL-6抑制剂已被用于治疗这一患者群体，但这些不同的策略的比较有效性仍然是不确定的。我们旨在比较因COVID-19、呼吸功能不全和炎症过度而入院的患者的IL-1和IL-6抑制。这项队列研究纳入了在San Raffaele医院（意大利米兰）住院的COVID-19、呼吸功能不全（定义为氧分压与吸入氧分数的比值≤ 300 mm Hg）和炎症过度（定义为血清C反应蛋白浓度≥ 100 mg/L或铁蛋白浓度≥ 900 ng/mL）患者。主要终点是生存率，次要终点是死亡或机械通气（不良临床结局）的复合终点。在考虑基线差异后，使用多变量考克斯回归分析比较接受IL-1抑制剂（阿那白滞素）或IL-6抑制剂（托珠单抗或sar）的患者与未接受白介素抑制剂的患者的临床结局。所有患者均接受标准治疗。根据C-反应蛋白或乳酸脱氢酶浓度，使用相互作用试验评估生存概率。在2020年2月25日至5月20日期间纳入的392例患者中，275例未接受白细胞介素抑制剂，62例接受IL-1抑制剂阿那白滞素，55例接受IL-6抑制剂（29例接受托珠单抗，26例接受sar）。在多变量分析中，与未接受白细胞介素抑制剂治疗的患者相比，接受IL-1抑制剂治疗的患者死亡风险显著降低（风险比[HR] 0.450，95% CI 0.204 - 0.990，p= 0.047），但接受IL-6抑制剂治疗的患者死亡风险没有降低（0.900，0.412 - 1.966; p= 0.79）。在多变量分析中，与未接受白细胞介素抑制剂治疗的患者相比，接受IL-1抑制剂治疗（HR 0·866，95% CI 0·482-1·553; p=0·63）或IL-6抑制剂治疗（HR 0·882，0·452-1·722; p=0·71）的患者不良临床结局风险无差异。对于C反应蛋白浓度升高，与未接受白细胞介素抑制剂治疗的患者相比，接受白细胞介素6抑制剂治疗的患者死亡率（HR 0.990，95% CI 0.981 - 0.999; p= 0.031）和不良临床结局（0.987，0.979 - 0.995; p= 0.0021）风险显著降低。对于降低血清乳酸脱氢酶浓度，用IL-1抑制剂治疗的患者和用IL-6抑制剂治疗的患者具有降低的死亡风险;在接受白细胞介素抑制剂的患者中，乳酸脱氢酶浓度的增加与死亡风险的增加相关（IL-1抑制剂HR 1.009，95% CI 1.003 - 1.014，p= 0.0011; IL-6抑制剂HR 1.006，95% CI 1.001 - 1.011，p= 0.028）和不良临床结局与未接受白细胞介素抑制剂治疗的患者相比（IL-1抑制剂组为1·006，1·002-1·010，p=0·0031; IL-6抑制剂组为1·005，1·001-1·010，p=0·016）。IL-1抑制而非IL-6抑制与因COVID-19、呼吸功能不全和炎症过度而入院的患者的死亡率显著降低相关。IL-6抑制在C-反应蛋白浓度明显高的患者亚组中有效，而IL-1和IL-6抑制在乳酸脱氢酶浓度低的患者中有效。没有。
Patients with severe COVID-19 develop a life-threatening hyperinflammatory response to the virus. Interleukin (IL)-1 or IL-6 inhibitors have been used to treat this patient population, but the comparative effectiveness of these different strategies remains undetermined. We aimed to compare IL-1 and IL-6 inhibition in patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation. This cohort study included patients admitted to San Raffaele Hospital (Milan, Italy) with COVID-19, respiratory insufficiency, defined as a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of 300 mm Hg or less, and hyperinflammation, defined as serum C-reactive protein concentration of 100 mg/L or more or ferritin concentration of 900 ng/mL or more. The primary endpoint was survival, and the secondary endpoint was a composite of death or mechanical ventilation (adverse clinical outcome). Multivariable Cox regression analysis was used to compare clinical outcomes of patients receiving IL-1 inhibition (anakinra) or IL-6 inhibition (tocilizumab or sarilumab) with those of patients who did not receive interleukin inhibitors, after accounting for baseline differences. All patients received standard care. Interaction tests were used to assess the probability of survival according to C-reactive protein or lactate dehydrogenase concentrations. Of 392 patients included between Feb 25 and May 20, 2020, 275 did not receive interleukin inhibitors, 62 received the IL-1 inhibitor anakinra, and 55 received an IL-6 inhibitor (29 received tocilizumab and 26 received sarilumab). In the multivariable analysis, compared with patients who did not receive interleukin inhibitors, patients treated with IL-1 inhibition had a significantly reduced mortality risk (hazard ratio [HR] 0·450, 95% CI 0·204–0·990, p=0·047), but those treated with IL-6 inhibition did not (0·900, 0·412–1·966; p=0·79). In the multivariable analysis, there was no difference in adverse clinical outcome risk in patients treated with IL-1 inhibition (HR 0·866, 95% CI 0·482–1·553; p=0·63) or IL-6 inhibition (0·882, 0·452–1·722; p=0·71) relative to patients who did not receive interleukin inhibitors. For increasing C-reactive protein concentrations, patients treated with IL-6 inhibition had a significantly reduced risk of mortality (HR 0·990, 95% CI 0·981–0·999; p=0·031) and adverse clinical outcome (0·987, 0·979–0·995; p=0·0021) compared with patients who did not receive interleukin inhibitors. For decreasing concentrations of serum lactate dehydrogenase, patients treated with an IL-1 inhibitor and patients treated with IL-6 inhibitors had a reduced risk of mortality; increasing concentrations of lactate dehydrogenase in patients receiving either interleukin inhibitor were associated with an increased risk of mortality (HR 1·009, 95% CI 1·003–1·014, p=0·0011 for IL-1 inhibitors and 1·006, 1·001–1·011, p=0·028 for IL-6 inhibitors) and adverse clinical outcome (1·006, 1·002–1·010, p=0·0031 for IL-1 inhibitors and 1·005, 1·001–1·010, p=0·016 for IL-6 inhibitors) compared with patients who did not receive interleukin inhibitors. IL-1 inhibition, but not IL-6 inhibition, was associated with a significant reduction of mortality in patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation. IL-6 inhibition was effective in a subgroup of patients with markedly high C-reactive protein concentrations, whereas both IL-1 and IL-6 inhibition were effective in patients with low lactate dehydrogenase concentrations. None.