Background Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. Methods Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. Results Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. Conclusions Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS. Data are available upon reasonable request.

中文翻译：

---

IL-18 介导的铁蛋白升高与急性呼吸窘迫综合征 (ARDS) 的全身炎症和死亡率相关

背景 急性呼吸窘迫综合征 (ARDS) 中已鉴定出炎症亚表型。脓毒症中的高铁蛋白血症与过度炎症、较差的临床结果相关，并且可以预测免疫调节的益处。我们的目的是确定升高的铁蛋白是否可以识别 ARDS 患者的亚表型。方法 通过辛伐他汀（辛伐他汀在急性肺损伤中抑制羟甲基戊二酰辅酶 A 还原酶以减少肺功能障碍 2 (HARP-2)；探索队列，英国）和神经肌肉阻滞的两项随机对照试验，测量 ARDS 患者的基线血浆铁蛋白浓度（ROSE；验证队列，美国）。使用具有限制三次样条的逻辑回归模型对结果进行分析，以确定与 28 天死亡率相关的铁蛋白阈值。结果 HARP-2 的 511 名患者（登记的患者的 95%）和 ROSE 的 847 名患者（登记的患者的 84%）测量了铁蛋白。在两项研究中，铁蛋白始终与 28 天死亡率相关，并且根据荟萃分析，铁蛋白的对数倍增加与 28 天死亡率的 OR 1.71（95% CI 1.01 至 2.90）相关。在两项研究中，铁蛋白 >1380 ng/mL（HARP-2 28%，ROSE 24%）的患者 28 天死亡率显着较高，且无需呼吸机的天数也较少。包括混杂因素（急性生理学和慢性健康评估-II 评分以及 ARDS 病因学）在内的中介分析表明，白细胞介素 (IL)-18 作为铁蛋白和死亡率之间的中间途径具有统计学上的显着贡献。结论 铁蛋白是 ARDS 中临床上有用的生物标志物，并且与较差的患者预后相关。这些结果为针对 ARDS 患者高铁蛋白血症亚组中针对 IL-18 的免疫调节剂的前瞻性介入试验提供了支持。数据可根据合理要求提供。