Administrative Supplement: Stratifying Patient Immune Endotypes in Sepsis (SPIES Study)

摘要 脓毒症仍然是当今医院死亡的主要原因。尽管它的发病率由于老龄化而不断增加 在合并症较多的人群中，住院死亡率在过去十年中显著下降。这 这在很大程度上是由于在早期脓毒症治疗中更早地认识到并更好地遵守了最佳做法。 尽管住院死亡率有所改善，但很大比例(在一些研究中高达50%)败血症幸存者从未 完全康复和发展慢性危重病(CCI)，其特征是持续的免疫抑制， 反复感染、脓毒症复发和远期预后差。然而，有三个关键挑战， 阻碍这些败血症幸存者的免疫治疗的发展：i)如何内在型患者 谁是免疫抑制的败血症；ii)如何量化免疫抑制的程度；iii)如何识别 有希望在个体免疫抑制患者中使用免疫兴奋剂？我们认为，目前的努力 免疫抑制的内型败血症幸存者并未完全成功，因为他们未能 直接评估免疫功能，而不是使用基因组或蛋白质组的免疫状态衡量标准。这里 我们建议：1)评估是否刺激T细胞产生干扰素-γ和刺激单核细胞产生 ELISpot定量的肿瘤坏死因子α能更好地预测脓毒症幸存者的感染和长期结局 而不是基于蛋白质水平、表达和核酸浓度的常规静态测量；以及 2)用ELISpot法检测T细胞产生干扰素-γ和单核细胞产生肿瘤坏死因子α。 脓毒症幸存者将在体外检查不同免疫刺激剂逆转脓毒症的比较效果- 诱导免疫抑制。在最初的奖励下，我们提出了一项270人的前瞻性观察性试验 有脓毒症的患者(使用脓毒症-3标准)与90名无脓毒症的危重病患者(总计 390人，30名健康受试者进行质量控制和验证)，在3个学术机构。在这里，在这里 补充申请第一年，我们建议增加30名创伤患者和15名烧伤患者，尽管 在父母资助的整个生命周期中，我们希望招募60名创伤患者和45名烧伤患者。在1、4和 脓毒症、创伤或危重疾病确诊后7天(烧伤后7天和14天)，血液样本将 获得的T细胞和单核细胞产生的干扰素-γ和肿瘤坏死因子α将分别通过以下方法测定 埃利斯波特。继发感染将是临床预后的主要指标，次要指标包括 再次住院和180天的死亡率。此外，我们将在这个ELISpot平台上评估EX T细胞产生干扰素-γ和单核细胞产生肿瘤坏死因子α的体内反应 不同浓度的免疫刺激剂目前正在考虑作为潜在的治疗药物。 适用于脓毒症患者。这项申请提出了一种新的功能生物测定的有效性，以识别 将从免疫疗法中受益的患者，并确定将受益的不同免疫疗法 个别病人。

ABSTRACT Sepsis remains the leading cause of hospital mortality today. Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality has significantly declined over the past decade. This is due in large part to earlier recognition and better compliance with best practices in early sepsis management. Despite improved in-hospital mortality, a large proportion (up to 50% in some studies) of sepsis survivors never fully recover and develop chronic critical illness (CCI), characterized by persistent immune suppression, recurrent infections, sepsis recidivism and poor long-term outcomes. There are three key challenges, however, hindering the development of immunological therapies in these sepsis survivors: i) how to endotype patients with sepsis who are immunosuppressed; ii) how to quantify the degree of immune suppression; and iii) how to identify promising immune stimulants in individual immunosuppressed patients? We believe that current efforts to endotype sepsis survivors as being immunosuppressed have not been fully successful because they fail to directly assess immune function, instead using either genomic or proteomic measures of immune status. Here we propose to: 1) assess whether stimulated T cell production of IFN-γ and stimulated monocyte production of TNFα, as quantitated by ELISpot, better predicts infectious and long-term outcomes in sepsis survivors than common static measurements based on protein levels, expression and nucleic acid concentrations; and 2) to employ ELISpot assessment of IFN-γ production by T-cells and TNFα production by monocytes from sepsis survivors to examine ex vivo the comparative efficacy of different immune stimulants to reverse sepsis- induced immunosuppression. Under the original award, we proposed a prospective, observational trial of 270 patients with sepsis (using Sepsis-3 criteria) compared to 90 patients with critical illness without sepsis (total of 390 with 30 healthy subjects for quality control and validation) at 3 academic institutions. Here in this supplement application for the first year, we propose to add 30 trauma and 15 burn patients, although over the life of the parent grant, we hope to enroll 60 trauma patients and 45 burn patients. At 1, 4 and 7 days post sepsis, trauma or critical illness diagnosis (7 and 14 days in burns), blood samples will be obtained and blood T-cell and monocyte production of IFN-γ and TNFα, respectively, will be determined by ELISpot. Secondary infections will be the primary clinical index of outcome, with secondary indices including hospital readmission, and 180-day mortality. In addition, we will evaluate in this ELISpot platform the ex vivo response of IFN-γ production by T-cells and TNFα production by monocytes stimulated with varying concentrations of immune stimulants are currently under consideration as potential therapeutics for sepsis patients. This application proposes the validation of a novel functional bioassay to identify patients who would benefit from immunotherapy, and to identify different immune therapies that would benefit the individual patient.