Wellcome-Wolfson Institute for Experimental Medicine, Centre for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland.
Regional Intensive Care Unit, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland.
Crit Care. 2022 Jun 7;26(1):164. doi: 10.1186/s13054-022-04025-w.
Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18.
In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1β compared.
511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30-2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1β.
In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.
白细胞介素（IL）-18 是炎症小体激活的标志物，基线血浆中高浓度的 IL-18 与脓毒症诱导的急性呼吸窘迫综合征（ARDS）患者的死亡率增加有关。本分析的目的是确定辛伐他汀是否与 ARDS 患者和高血浆 IL-18 患者的获益相关。
在 HARP-2 研究的二次分析中，我们使用 Cox 比例风险分析比较了根据基线血浆 IL-18 水平，辛伐他汀治疗与安慰剂治疗的 28 天死亡率和对辛伐他汀的反应。另外，从健康志愿者的单核细胞来源的巨噬细胞在受到 ATP 和 LPS 刺激之前用辛伐他汀或罗苏伐他汀孵育，比较其对分泌的 IL-18 和 IL-1β 的影响。
HARP-2 中有 511 名患者有可用数据。高基线血浆 IL-18（≥800pg/ml）与 28 天死亡率增加相关（高 IL-18 组为 30.6%，低 IL-18 组为 17.5%；HR 1.89[95%CI 1.30-2.73]；p=0.001）。与安慰剂相比，高基线血浆 IL-18 患者中给予辛伐他汀治疗与较低的 28 天死亡率相关（24.0%比 36.8%；p=0.01）。最后，辛伐他汀而非罗苏伐他汀降低了刺激的巨噬细胞分泌 IL-18 和 IL-1β。
在基线血浆 IL-18 水平较高的患者中，辛伐他汀与生存概率较高相关，这种作用可能是由于炎症小体激活减少所致。这些数据表明，基线血浆 IL-18 可能通过识别可能从辛伐他汀治疗中获益的 ARDS 患者，从而允许进行个性化治疗。
