CCM：血浆白细胞介素-18升高可识别高风险急性呼吸窘迫综合征患者，而传统的炎症细胞因子的潜在类别分析无法区分:两项随机临床试验的回顾性分析

OBJECTIVES: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct “high-risk” patients not captured by prior LCA classifications.白细胞介素-18 (IL-18)血浆水平和潜在类别分析(LCA)分别被证明可预测急性呼吸窘迫综合征(ARDS)的预后和治疗反应。IL-18是一种炎症小体激活的测量方法，这一途径可能不同于定义之前发表的LCA类别的生物标志物捕捉到的炎症。我们假设升高的IL-18将识别出不同的“高危”患者，而这些患者没有被之前的LCA分类所捕获。

DESIGN: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar’s test and then tested the cor- relation between IL-18 and LCA biomarkers using Pearson’s exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup.他汀类药物治疗脓毒症急性肺损伤(SAILS)和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试验(HARP-2)是两项针对ARDS的大型随机对照试验，其中LCA分配和IL-18水平均可预测死亡率。我们首先使用McNemar检验评估高水平IL-18(≥800 pg/mL)与之前LCA分类之间的重叠，然后使用对log-2转换值的Pearson精确检验检验IL-18和LCA生物标志物之间的相关性。我们的主要分析是IL-18水平与低炎症LCA类别的60天死亡率之间的关联，使用Fisher精确检验和Cox比例风险模型评估，校正年龄、急性生理学和慢性健康评估评分和性别。次要分析包括每个IL-18/LCA亚组中IL-18和LCA与死亡率的相关性。

SETTING: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. 对2项ARDS患者的多中心、随机对照临床试验进行二次分析。

SUBJECTS: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. SAILS组683例，HARP-2组511例。

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17–0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8–6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2–3.8; p = 0.009). 我们发现33%的 SAILS组和在HARP-2组中IL-18水平和LCA分级不一致。我们进一步发现，IL-18水平与LCA分配中使用的细胞因子仅适度相关(0.17-0.47)。大量被LCA分类为低炎症的个体(14%的SAILS和43%的HARP-2)因IL-18升高而被归类为高危。这些个体在两项SAILS试验中均有较高的死亡风险(60 d死亡率为42%，优势比[OR] 3.3;95% CI, 1.8–6.1; p < 0.001)和HARP-2 (60 d死亡率27%，95% CI, 1.2–3.8; p = 0.009)。

CONCLUSIONS: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.血浆IL-18水平为两个大型ARDS队列中主要由传统炎症生物标志物定义的LCA亚表型提供了重要的额外预后信息。