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[JAMA Intern Med读者来信]:皮质类固醇在治疗COVID-19中的不确定作用
2020年08月26日 研究点评, 进展交流 暂无评论

翻译:陈燕

Comment & Response August 3, 2020

The Uncertain Role of Corticosteroids in the Treatment of COVID-19

Theodore G. Liou, Frederick R. Adler, Nathan D. Hatton

JAMA Intern Med. Published online August 3, 2020. doi:10.1001/jamainternmed.2020.2438

To the Editor Infection with coronavirus disease 2019 (COVID-19) causes exuberant lung inflammation leading to respiratory failure, acute respiratory distress syndrome (ARDS), and death. Wu et al1 present early experience and retrospective analysis highlighting potential mortality reduction of COVID-19–associated ARDS using corticosteroids to reduce inflammation. However, despite a novel cause, the clinical syndrome resembles that of older diseases, and the analysis faces statistical challenges that have been encountered previously.

感染冠状病毒病(COVID-19)可致强烈的肺部炎症,导致出现呼吸衰竭、急性呼吸窘迫综合征(ARDS)和死亡。Wu等分享了早期经验及回顾性分析,强调使用皮质类固醇可减少炎症,从而降低COVID-19相关ARDS的潜在死亡率。然而,虽然这是一种新的病因,但其临床综合征与既往疾病类似,其统计分析也面临着既往曾遇到过的挑战。

Prior studies in ARDS reveal variable steroid effects potentially related to different causes and resulting pathophysiologies invisible at the bedside.2 Different studies have found corticosteroid effects ranging from harmful to beneficial. Within 3 cohort studies of influenza A (H1N1) during the 2009 pandemic, as cited,2 steroid use appeared either ineffective or harmful. Other cohort studies and randomized clinical trials for treatment of ARDS wrestled with artifacts due to indication and survivor bias. The former bias is a familiar issue3 created when unblinded clinicians treat individuals with more serious illness more aggressively, in this case using steroids to prevent or mitigate ARDS. The latter bias arises in 2 ways, either by missing patients unable to survive long enough to receive steroids or failing to follow up with patients long enough to record late deaths due to secondary infections or other steroid-associated complications.

ARDS的先前研究显示,不同的类固醇疗效可能与不同的病因和由此产生的床边看不见的病理生理过程有关。不同的研究发现皮质类固醇的疗效从有害到有益不等。在2009年甲型H1N1流感大流行期间进行的3项队列研究中,类固醇的使用不是无效就是有害的。其他关于ARDS治疗的队列研究和随机临床试验都存在因指示偏倚和幸存者偏倚而造成的假象。当非盲临床医生治疗患有更严重疾病的个体时可能会更激进,并在这种情况下使用类固醇来预防或减轻ARDS,此时前一种偏倚更为我们所熟知。后一种偏倚见于2种方式,一种是遗漏了无法生存足够长的时间以接受类固醇的患者,一种是没有对患者进行足够长的随访,以记录由于继发感染或其他类固醇相关并发症导致的远期死亡。

Wu et al1 found that steroid therapy had a low hazard ratio for death for patients receiving steroids for ARDS. However, the result is at odds with results suggesting harm caused by steroids used to prevent ARDS1 and is at odds with another recent report4 using a potentially overlapping patient cohort that found no steroid association with mortality. Wu et al1 suggest that because indication bias usually erroneously suggests harm from a therapy, a beneficial hazard ratio for steroid treatment of ARDS should be believed. However, this assumes that other biases are inconsequential, such as survivor bias due to rapid disease progression compounded by health care resource exhaustion. We note that the Kaplan-Meier curves presented in the original article1 show that substantial numbers of patients were censored, follow-up was substantially shorter than needed to observe steroid adverse reactions, the last observed Kaplan-Meier survival data points of the 2 groups were not statistically different, and, finally, use of steroids was not statistically different between survivors and nonsurvivors of ARDS (Table 3).1

Wu等人发现,类固醇治疗对接受类固醇治疗ARDS的患者的死亡风险比很低。然而,该结果与提示用于预防ARDS的类固醇造成危害的结果不一致,也与最近另一个使用潜在重叠患者队列的研究报告不一致,该报告发现类固醇与死亡率没有关联。Wu等人提出,由于指示偏倚通常错误地提示了一种疗法的危害,所以应该相信类固醇治疗ARDS的有益风险比。然而,这假定了其他偏倚是不重要的,如由于疾病快速进展加上医疗资源枯竭所造成的幸存者偏倚。我们注意到,原文中给出的Kaplan-Meier曲线显示,大量患者被剔除,随访时间大大短于观察类固醇不良反应所需时间,2组最后观察到的Kaplan-Meier生存数据点无统计学差异,且最后,类固醇的使用在ARDS的生存者和非生存者之间无统计学差异。

Thus, we urge caution before using steroids for ARDS due to COVID-19. Meticulous observation as performed by Wu et al1 should continue; however, a rigorous blinded randomized clinical trial is needed to discover the benefit or harm of this therapy with confidence.

因此,我们主张在使用类固醇治疗COVID-19引起的ARDS之前要谨慎。Wu等人进行的细致观察应继续进行;但是,我们需要进行严格的盲法随机临床试验,才能有把握地发现这种治疗的益处或害处。

Comment & Response August 3, 2020

The Uncertain Role of Corticosteroids in the Treatment of COVID-19

Grant B. Ellsworth, Marshall J. Glesby, Roy M. Gulick

JAMA Intern Med. Published online August 3, 2020. doi:10.1001/jamainternmed.2020.2444

To the Editor We question the conclusion of Wu et al1 about the benefit of corticosteroid use in the treatment of coronavirus disease 2019 (COVID-19). The World Health Organization and the US Centers for Disease Control and Prevention have issued clinical guidance against the use of corticosteroids in the treatment of COVID-19 unless another indication is present, such as a chronic obstructive pulmonary disease exacerbation, or as adjunct treatment of septic shock. This guidance was made on the basis of systematic reviews of observational studies of corticosteroids that demonstrated an association with increased mortality and secondary infections in influenza2 and no benefit with possible harms in severe acute respiratory syndrome.3 A retrospective cohort study of Middle East respiratory syndrome showed that corticosteroids were associated with no difference in mortality and prolonged respiratory viral shedding.4

我们质疑吴等人使用皮质类激素治疗COVID-19的结论。世界卫生组织和美国疾控预防中心发布的临床指南中反对使用皮质类激素治疗COVID-19,除非病人出现其他并发症,如AECOPD,或作为脓毒症休克的辅助治疗。该指南是根据皮质类激素观察性研究的系统回顾分析而制定的,证实了皮质类激素与流感的继发性感染和患者死亡率的增加有关,并且对于严重急性呼吸综合征没有益处,并可能有害处。一项关于中东呼吸综合征的回顾性队列研究显示,皮质类固醇与患者死亡率和延长呼吸道病毒脱落期无相关性。

It is unclear that the proportional hazards analysis in the study modeled methylprednisolone administration as a time-dependent covariate, which is necessary to mitigate what has been termed survivor treatment selection bias.5 Stated simply, patients who died rapidly may have been less likely to receive methylprednisolone, leading to an observed difference in mortality that was incorrectly associated with this intervention. Mortality was 23 of 50 (46%) among those with acute respiratory distress syndrome who received methylprednisolone vs 21 of 34 (62%) among those who did not. Even if there were no bias present and methylprednisolone provided some short-term survival benefit, the end point difference of 16% less mortality in those who received corticosteroids is not significant (95% CI, −40% to 8%; P = .23). From the Kaplan-Meier curves, the ultimate mortality rate was roughly similar in both groups—around 60%.

目前尚不清楚该研究模型中甲强龙作为时间相关变量的风险比例分析,因此有必要减少生存者治疗选择偏差。简单地说,快速死亡的患者很少应用甲强龙治疗,导致观察到的死亡率差异与这项干预错误相关。ARDS患者中应用甲强龙治疗的死亡率为23/50 (46%),未应用甲强龙治疗的死亡率为21/34 (62%)。即使没有偏倚存在,甲强龙提供了一定的短期生存获益,但接受皮质类固醇的患者死亡率降低16%的终点差异并不显著(95%CI, -40%to8%; P=0.23)。从K-M曲线来看,两组的最终死亡率大致相似,约60%左右。

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