Identifying a hyperinflammatory subphenotype of ARDS associated with worse outcomes: may ferritin help?
Identifying a hyperinflammatory subphenotype of ARDS associated with worse outcomes: may ferritin help?
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确定与较差结果相关的 ARDS 的高炎症亚表型：铁蛋白有帮助吗？
DOI：
10.1136/thorax-2023-221131
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发表时间：
2024
期刊：
影响因子：
10
通讯作者：
Siempos,IliasI
中科院分区：
文献类型：
--
作者：
Torres,LisaK;Siempos,IliasI
急性呼吸窘迫综合征（ARDS）的归因死亡率相当高。然而，在治疗ARDS的药物策略的随机对照试验（RCT）中没有显示生存益处。这被认为是符合ARDS标准的患者中临床和生物学过程异质性的结果。3为了解决异质性问题，最近的努力已经阐明了呼吸道微生物组的作用4，并在有ARDS风险的患者中确定了5和ARDS患者中可重复的亚表型，如“低炎症”和“高炎症”亚表型;后者与更差的结局相关。这些亚表型是通过对入组RCT或观察性研究的患者的临床和血浆生物标志物数据进行事后分析确定的。由于缺乏前瞻性验证以及需要对患者分层所需的多种生物标志物进行快速、实时测量，亚表型在临床实践中的实施迄今为止受到限制。此外，这些生物标志物的测量只能在研究实验室环境中进行。因此，如果临床环境中常规可用的单一标志物而不是多种生物标志物可用于对患者进行分层，并且具体地，鉴定具有更差结果风险的ARDS患者，则将是期望的。在本期杂志中，Mehta等评估了铁蛋白（一种常规可用的标记物）是否可以识别有死亡风险的ARDS患者。7作者利用了来自先前入组HARP-2研究（衍生队列;辛伐他汀与安慰剂的RCT）或ROSE研究（验证队列;连续48小时深度镇静与常规护理（无神经肌肉阻滞和轻度镇静）的RCT）的受试者的个体患者水平数据。8 9尽管入选标准相似，但HARP-2（< 300 mm Hg）的动脉氧分压与吸入氧分数的比率高于ROSE（< 150 mm Hg）。8 9两项随机对照试验均在ARDS发作后48小时内和随机化前采集血浆。使用市售ELISA试剂盒测量每个RCT中的铁蛋白水平。8 9使用限制性三次样条逻辑回归模型，作者发现铁蛋白的对数倍增加与28天死亡率的OR为1.71相关。他们还确定铁蛋白阈值> 1380 ng/mL（存在于28%的HARP-2患者和24%的ROSE患者中）与较高的死亡率相关。最后，作者进行了一项中介分析，证明铁蛋白和死亡率之间的关联是由白细胞介素（IL）18介导的，在调整混杂因素（如ARDS病因学和APACHE II评分）后，影响较小但具有统计学显著性。关注IL-18背后的基本原理是基于先前的证据，表明铁蛋白促进炎性小体活化，IL-18是炎性小体活性的替代标志物，并且IL-18水平在患有炎症性疾病的患者中升高。
Attributable mortality of acute respiratory distress syndrome (ARDS) is considerable. 1 2 Yet, no survival benefit has been shown in randomised controlled trials (RCTs) of pharmacological strategies to treat ARDS. This is assumed to be a consequence of the heterogeneity of clinical and biological processes among patients meeting criteria for ARDS. 3 In an attempt to address heterogeneity, recent efforts have led to elucidation of the role of respiratory microbiome 4 and to identification both in patients at risk of ARDS 5 and in patients with ARDS 6 of reproducible subphenotypes, such as the ‘hypoinflammatory’and ‘hyperinflammatory’subphenotypes; the latter being associated with worse outcomes. Those subphenotypes were identified through post hoc analyses of clinical and plasma biomarker data of patients enrolled in RCTs or in observational studies. 5 6 Implementation of subphenotypes in clinical practice has so far been limited due to lack of prospective validation as well as the need for rapid, real-time measurement of multiple biomarkers needed to stratify patients. Moreover, measurement of those biomarkers can only be undertaken in the research laboratory setting. Therefore, it would be desirable if, instead of multiple biomarkers, a single marker that is routinely available in the clinical setting could be used to stratify patients and, specifically, identify patients with ARDS at risk for worse outcomes. In this issue of the journal, Mehta et al evaluated whether ferritin, a routinely available marker, could identify patients with ARDS at risk for mortality. 7 The authors took advantage of individual patient-level data from subjects previously enrolled in either the HARP-2 study (the derivation cohort; an RCT of simvastatin vs placebo) or the ROSE study (the validation cohort; an RCT of continuous cisatracurium with deep sedation for 48 hours vs usual care without neuromuscular blockade and with lighter sedation). 8 9 Although inclusion criteria were similar, the partial pressure of arterial oxygen to fraction of inspired oxygen ratio for enrolment was higher in HARP-2 (< 300 mm Hg) than ROSE (< 150 mm Hg). 8 9 Both RCTs had plasma collected in the first 48 hours after ARDS onset and prior to randomisation. Ferritin levels were measured in each RCT using commercially available ELISA kits. 8 9 Using a logistic regression model with restricted cubic splines, the authors found that a log-fold increase in ferritin was associated with an OR of 1.71 for 28-day mortality. 7 They also determined that a threshold of ferritin> 1380 ng/mL (present in 28% of HARP-2 patients and 24% of ROSE patients) was associated with higher mortality. Finally, the authors performed a mediation analysis demonstrating that the association between ferritin and mortality was mediated by interleukin (IL) 18 to a small but statistically significant effect, after adjustment for confounders, such as aetiology of ARDS and APACHE II Score. The rationale behind the focus on IL-18 was based on previous evidence indicating that ferritin promotes inflammasome activation, that IL-18 is a surrogate marker for inflammasome activity and that IL-18 levels are elevated in patients with