Who, what, and when-effective therapy for severe COVID-19.
Who, what, and when-effective therapy for severe COVID-19.
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DOI：
10.1016/s2665-9913(21)00353-2
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Cron RQ
中科院分区：
文献类型：
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作者：
Kelmenson DA;Cron RQ
新冠肺炎大流行仍在继续，而SARS-CoV-2的三角洲变异已导致疾病死灰复燃。在感染SARS-CoV-2的人中，多达20%的人患有高炎症的新冠肺炎，导致患者因新冠肺炎肺炎入院治疗。1虽然老年和合并疾病(如糖尿病、肥胖和高血压)是严重新冠肺炎的危险因素，但Delta变异已经影响到年轻的、通常以前健康的人，其中一些人必须进入重症监护病房。尽管糖皮质激素的广泛免疫抑制已经挽救了生命，2定义那些可能受益于靶向方法抑制促炎细胞因子的新冠肺炎高炎性患者一直是具有挑战性的。3在大流行早期，严重新冠肺炎患者的血清白介素6浓度升高，多项临床试验探索了针对白介素6或白介素6受体的治疗性单抗。尽管个别试验得出了相互矛盾的结果，但荟萃分析表明，阻断IL-6信号可能会提高重症新冠肺炎患者的存活率。4在《柳叶刀》风湿病学杂志上，Xavier Mariette及其同事代表CORIMUNO-19合作小组，5采用多中心、开放标签、贝叶斯随机、适应性试验方法，探索IL-6受体单抗Sarilumab用于治疗中重度新冠肺炎肺炎。Mariette和他的同事招募了148名因新冠肺炎而住院的成年人，他们的氧气浓度超过3L/分钟，但不需要高流量氧气或机械通气(世卫组织临床进展量表评分为5)。这些患者被随机分配到沙利鲁单抗或常规治疗中，144名患者中有29名(20%)还接受了糖皮质激素(试验发生在RECOVERY2发表之前)。主要结果是第4天WHOCPS评分高于5分，第14天在没有高流量氧气或机械通气的情况下存活。两组结果均无差异。在68例患者中，有18例(26%)在第4天WHO-CPS评分>5，而在常规护理组76例中，有20例(26%)在第4天时WHO-CPS评分>5(中位后验绝对风险差0.2%；90%可信区间-11.7~12.2)，第14天时，沙律单抗组有25例(37%)患者需要呼吸机治疗或死亡(一般护理组26例(34%))(后风险比中位数为1.10；可信区间为0.69-1.74)。沙利单抗组的不良事件总数高于常规护理组，但严重不良事件的数目没有显著差异。这项研究的局限性包括样本量小，无掩蔽设计，没有标准化的日常护理。尽管各种临床试验的结果喜忧参半，关于抑制IL-6治疗重症新冠肺炎的益处，但可能有一些人将从这种疗法中受益。也许，与那些使用糖皮质激素改善的患者类似，那些呼吸支持定义的疾病最严重的患者将获得最大的好处。2另一种选择是，血清IL-6或IL-6反应C反应蛋白浓度高的患者接受IL-6阻断的帮助最大。尽管如此，荟萃分析已经报道，抑制IL-6的生存优势在于那些需要补充氧气的患者，而不是那些需要有创机械通气的患者。4此外，IL-6途径中断所带来的益处仅见于同期使用糖皮质激素治疗的患者。4因此，糖皮质激素的联合应用和时机(需要氧气，但在侵袭性机械治疗之前)…
The COVID-19 pandemic is ongoing, and the SARS-CoV-2 delta variant has resulted in disease resurgence. As many as 20% of people infected with SARS-CoV-2 suffer from hyperinflammatory COVID-19, resulting in hospitalisation with COVID-19 pneumonia. 1 Although old age and comorbidities (eg, diabetes, obesity, and hypertension) are risk factors for severe COVID-19, the delta variant has affected young, often previously healthy, individuals, some of whom have to be admitted to intensive care units. Although broad immunosuppression with glucocorticoids has been life-saving, 2 defining those with hyperinflammatory COVID-19 who might benefit from targeted approaches to dampening proinflammatory cytokines has been challenging. 3 Early during the pandemic, concentrations of serum interleukin (IL)-6 were noted to be elevated in patients with severe COVID-19, and multiple clinical trials have explored therapeutic monoclonal antibodies to IL-6 or the IL-6 receptor. Although individual trials have yielded conflicting results, meta-analyses suggest that blockade of IL-6 signalling might enhance survival for patients with severe COVID-19. 4 In The Lancet Rheumatology, Xavier Mariette and colleagues, on behalf of the CORIMUNO-19 Collaborative group, 5 explore the IL-6 receptor monoclonal antibody sarilumab for treatment of moderate-to-severe COVID-19 pneumonia using a multi-centric, open-label, Bayesian randomised, adaptive trial approach. Mariette and colleagues enrolled 148 adults hospitalised for COVID-19 on more than 3L/min oxygen but not requiring high-flow oxygen or mechanical ventilation (WHO Clinical Progression Scale [CPS] score of 5). The patients were randomly assigned to sarilumab or usual care, and 29 (20%) of 144 patients also received glucocorticoids (the trial occurred before the publication of RECOVERY2). The primary outcomes were a WHOCPS score higher than 5 on day 4 and survival without high-flow oxygen or mechanical ventilation on day 14. There was no difference in either outcome between the two groups. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0· 2%; 90% credible interval–11· 7 to 12· 2), and at day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died (median posterior hazard ratio 1· 10; 90% credible interval 0· 69–1· 74). There was a higher total number of adverse events in the sarilumab group than in the usual care group, but no significant difference in the number of serious adverse events. Limitations of the study include its small sample size, unmasked design, and no standardisation of usual care.Although the results of various clinical trials are mixed as to the benefit of IL-6 inhibition in treating severe COVID-19, there are likely subsets of individuals who will benefit from this therapy. Perhaps, similar to those who improve with glucocorticoids, those with the most severe disease, as defined by respiratory support, will best benefit. 2 Alternatively, those with high concentrations of serum IL-6 or IL-6-responsive C-reactive protein might receive the most aid from IL-6 blockade. Nonetheless, meta-analyses have reported that the survival advantage seen for IL-6 inhibition was in those with supplemental oxygen requirement but not those requiring invasive mechanical ventilation. 4 Moreover, the benefit afforded by IL-6 pathway disruption was only noted in those on concomitant glucocorticoid therapy. 4 Thus, co-administration of glucocorticoids and timing (requiring oxygen but before invasive mechanical …