Introduction Immunological dysfunction is common in critically ill patients but its clinical significance and the optimal method to measure it are unknown. The level of tumor necrosis factor alpha (TNF-α) after ex-vivo whole blood stimulation with lipopolysaccharide (LPS) has been proposed as a possible method to quantify immunological function. We hypothesized that in a cohort of critically ill patients, those with a lower post-stimulation TNF-α level would have increased rates of nosocomial infections (NIs) and worse clinical outcomes. Methods A secondary analysis of a phase 2 randomized, multi-centre, double-blinded placebo-controlled trial. As there was no difference between treatment and control arms in outcomes and NI rate, all the patients were analyzed as one cohort. On enrolment, day 4, 7, and weekly until day 28, whole blood was incubated with LPS ex-vivo and subsequent TNF-α level was measured. Patients were grouped in tertiles according to delta and peak TNF-α level. The primary outcome was the association between NIs and tertiles of TNF-α level post LPS stimulation; secondary outcomes included ICU and 90-day mortality, and ICU and hospital length of stay. Results Data was available for 201 patients. Neither the post LPS stimulation delta TNF-α group nor the peak TNF-α post-stimulation group were associated with the development of NIs or clinical outcomes. Patients in the highest tertile for post LPS stimulation delta TNF-α compared to the lowest tertile were younger [61.1 years ± 15.7 vs. 68.6 years ± 12.8 standard deviations (SD) in the lowest tertile], had lower acuity of illness (APACHE II 25.0 ± 9.7 vs. 26.7 ± 6.1) and had lower baseline TNF-α (9.9 pg/mL ± 19.0 vs. 31.0 pg/mL ± 68.5). When grouped according to peak post-stimulation TNF-α levels, patients in the highest tertile had higher serum TNF-α at baseline (21.3 pg/mL ± 66.7 compared to 6.5 pg/mL ± 9.0 in the lowest tertile). Conclusion In this prospective multicenter study, ex-vivo stimulated TNF-α level was not associated with the occurrence of NIs or clinical outcomes. Further study is required to better ascertain whether TNF levels and ex-vivo stimulation can be used to characterize immune function in critical illness and if other assays might be better suited to this task.

中文翻译：

---

通过刺激的离体肿瘤坏死因子 α 水平测量的免疫状态与危重机械通气患者获得医院感染之间的关系

介绍 免疫功能障碍在危重患者中很常见，但其临床意义和测量它的最佳方法尚不清楚。已提出用脂多糖 (LPS) 离体全血刺激后肿瘤坏死因子 α (TNF-α) 的水平作为量化免疫功能的可能方法。我们假设，在一组危重患者中，那些刺激后 TNF-α 水平较低的患者会增加医院感染 (NI) 的发生率和更差的临床结果。方法 对 2 期随机、多中心、双盲安慰剂对照试验的二次分析。由于治疗组和对照组在结果和 NI 率方面没有差异，所有患者都作为一个队列进行分析。在注册时，第 4、7 天和每周直到第 28 天，全血与 LPS 离体孵育，随后测量 TNF-α 水平。根据 delta 和峰值 TNF-α 水平将患者分组为三分位数。主要结果是 NI 与 LPS 刺激后 TNF-α 水平的三分位数之间的关联；次要结果包括 ICU 和 90 天死亡率，以及 ICU 和住院时间。结果 可获得 201 名患者的数据。LPS 刺激后 delta TNF-α 组和 TNF-α 刺激后峰值组均与 NI 的发生或临床结果无关。与最低三分位数相比，LPS 刺激后 delta TNF-α 最高三分位数的患者更年轻 [61.1 岁 ± 15.7 岁与最低三分位数的 68.6 岁 ± 12.8 标准差 (SD)]，具有较低的疾病敏锐度 (APACHE II 25.0 ± 9.7 与 26.7 ± 6.1) 并且具有较低的基线 TNF-α (9. 9 pg/mL ± 19.0 与 31.0 pg/mL ± 68.5）。当根据刺激后 TNF-α 峰值水平分组时，最高三分位数的患者在基线时具有较高的血清 TNF-α（21.3 pg/mL ± 66.7 与最低三分位数的 6.5 pg/mL ± 9.0）。结论 在这项前瞻性多中心研究中，离体刺激的 TNF-α 水平与 NI 的发生或临床结果无关。需要进一步研究以更好地确定 TNF 水平和离体刺激是否可用于表征危重疾病的免疫功能，以及其他检测方法是否更适合这项任务。结论 在这项前瞻性多中心研究中，离体刺激的 TNF-α 水平与 NI 的发生或临床结果无关。需要进一步研究以更好地确定 TNF 水平和离体刺激是否可用于表征危重疾病的免疫功能，以及其他检测方法是否更适合这项任务。结论 在这项前瞻性多中心研究中，离体刺激的 TNF-α 水平与 NI 的发生或临床结果无关。需要进一步研究以更好地确定 TNF 水平和离体刺激是否可用于表征危重疾病的免疫功能，以及其他检测方法是否更适合这项任务。