Halstead E Scott, McKeone Daniel J, Samuelsen Abigail M, Zhou Shouhao, Bonavia Anthony S
Division of Critical Care Medicine, Department of Pediatrics, Penn State University College of Medicine, Hershey, PA, United States.
Department of Molecular and Precision Medicine, Penn State University College of Medicine, Hershey, PA, United States.
Front Immunol. 2025 May 9;16:1520848. doi: 10.3389/fimmu.2025.1520848. eCollection 2025.
Recent studies of adult sepsis patients demonstrate the existence of two subphenotypes that differ in risk of mortality: a hyper-inflammatory subphenotype with a high risk of mortality, and a hypo-inflammatory or "not hyper-inflamed" subphenotype with a relatively lower risk of mortality. We recently investigated the association of organ dysfunction with immune profiling in sixty (60) critically ill adult patients with sepsis. In this secondary analysis we measured cytokine biomarkers with an automated, microfluidic immunoassay device (Ella™) and sought to investigate the functional immune profiles of patients in the hyper/hypo-inflammatory subphenotype groups.
Subjects were consecutively identified adults, older than 18 years, and enrolled within 48 hours of sepsis onset. Whole blood cytokine analysis was performed in all patients. Additionally, cytokine production was measured following 4h of stimulation. Cytokine concentrations were measured using the Ella™ automated immunoassay system.
Subjects were divided into hypo-inflammatory (42 patients) and hyper-inflammatory (18 patients) subtypes using a previously validated parsimonious model based on concentrations of IL-6, TNFR1 and bicarbonate. The hyper- and hypo-inflammatory clusters demonstrated a near four-fold difference in 30-day mortality (44.4% vs 11.9%, p=0.0046). Following 4h of stimulation with LPS, TNF production was lower in the hyper-inflammatory group as compared with the hypo-inflammatory group (p=0.0159). phorbol 12-myristate 13-acetate (PMA)-stimulated IFN-γ production (4h) by whole blood did not differ between groups.
These data further validate the use of IL-6, TNFR1 and bicarbonate to discern inflammatory sub-groups of patients with critical illness. They also confirm the observation that the presence of the hyper-inflammatory subphenotype is often accompanied by a compensatory anti-inflammatory response syndrome. Future investigations should focus on prospective validation of this panel for prognostic enrichment of clinical research studies.
近期对成年脓毒症患者的研究表明，存在两种死亡率风险不同的亚表型：一种是高死亡率风险的高炎症亚表型，另一种是死亡率风险相对较低的低炎症或“非高炎症”亚表型。我们最近调查了60例成年重症脓毒症患者器官功能障碍与免疫谱的关联。在这项二次分析中，我们使用自动化微流控免疫分析设备（Ella™）测量细胞因子生物标志物，并试图研究高/低炎症亚表型组患者的功能性免疫谱。
连续纳入年龄大于18岁且在脓毒症发作后48小时内入院的成年患者。对所有患者进行全血细胞因子分析。此外，在刺激4小时后测量细胞因子产生情况。使用Ella™自动化免疫分析系统测量细胞因子浓度。
根据白细胞介素-6（IL-6）、肿瘤坏死因子受体1（TNFR1）和碳酸氢盐浓度，采用先前验证的简约模型将受试者分为低炎症（42例患者）和高炎症（18例患者）亚型。高炎症和低炎症组在30天死亡率上显示出近4倍的差异（44.4%对11.9%，p = 0.0046）。用脂多糖（LPS）刺激4小时后，高炎症组的肿瘤坏死因子（TNF）产生低于低炎症组（p = 0.0159）。两组间全血经佛波酯12 - 肉豆蔻酸酯13 - 乙酸酯（PMA）刺激4小时后的γ干扰素（IFN-γ）产生无差异。
这些数据进一步验证了使用IL-6、TNFR1和碳酸氢盐来区分重症患者的炎症亚组。它们还证实了高炎症亚表型的存在常伴有代偿性抗炎反应综合征这一观察结果。未来的研究应集中于对该指标进行前瞻性验证，以用于临床研究的预后富集。
