Stratifying Patient Immune Endotypes in Sepsis (SPIES Study)

脓毒症患者免疫内型分层（SPIES 研究）

• 批准号: 10254395
• 负责人: LYLE L MOLDAWER
• 金额: $ 76.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10254395
• 关键词: Age; Animal Model; Antibiotics; Biological Assay; Biological Markers; Blood; Blood specimen; CD14 gene; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Critical Illness; Data; Defect; Development; Diagnosis; Early Diagnosis; Effectiveness; Enrollment; Ethnic Origin; Exclusion Criteria; Failure; Functional disorder; Future; Genomics; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-DR Antigens; Hospital Mortality; Hospitalization; Hospitals; Hour; IL7 gene; Immune; Immune response; Immunity; Immunocompetence; Immunocompromised Host; Immunologic Adjuvants; Immunology procedure; Immunosuppression; Immunotherapy; Impairment; Incidence; Incubated; Individual; Infection; Inpatients; Institution; Interferon Type II; Interferons; Interleukin-6; Invaded; Knowledge; Laboratories; Length of Stay; Life; Lymphocyte Count; Measurement; Measures; Monoclonal Antibodies; Mononuclear; Natural Immunity; Nosocomial Infections; Nucleic Acids; Oncology; Organ; Outcome; Pathogenicity; Patients; Phenotype; Plasma; Plasma Proteins; Production; Proteins; Proteomics; Quality Control; Race; Randomized; Randomized Clinical Trials; Recurrence; Sampling; Savings; Sepsis; Severities; Surrogate Markers; Survivors; T-Lymphocyte; TNF gene; TNFSF4 gene; Testing; Therapeutic; Time; Validation; Whole Blood; adaptive immunity; aging population; anti-PD-1; base; clinical development; comorbidity; comparative efficacy; design; efficacy evaluation; hospital readmission; immune function; immunological status; immunosuppressed; improved; in vivo; indexing; individual patient; monocyte; mortality; novel; pathogen; patient stratification; predictive modeling; prospective; recidivism; recurrent infection; response; secondary infection; secondary outcome; septic patients; sex; tertiary care; transcriptomics; tumor

ABSTRACT Sepsis remains the leading cause of hospital mortality today.1 Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality has significantly declined over the past decade.2 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)3-5 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 TNF 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- production by T-cells and TNF production by monocytes from sepsis survivors to examine ex vivo the comparative efficacy of different immune stimulants to reverse sepsis-induced immunosuppression. To achieve these goals, we propose 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. At 1, 4 and 7 days post sepsis diagnosis, blood samples will be obtained and blood T-cell and monocyte production of IFN- and TNF, respectively, will be determined by ELISpot. In addition, samples will be obtained for other biomarkers, including plasma proteins (IL-6 and sPD-L1), CD14+ cell expression of HLA-DR, total lymphocyte count and whole blood genomics. Secondary infections will be the primary clinical index of outcome6, 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- production by T-cells and TNF production by monocytes stimulated with varying concentrations of IL-7, anti-PD-1 mAb, GITRL, OX40L or 4-1BB, using a randomized block design. These 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.

摘要 脓毒症仍然是当今医院死亡的主要原因1，尽管由于老龄化，其发病率不断上升 合并症较多的人群，住院死亡率在过去十年中显著下降。 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提高，但很大一部分(在一些研究中高达50%)脓毒症幸存者从未 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 用ELISpot定量的肿瘤坏死因子更好地预测脓毒症幸存者的感染和长期结局 基于蛋白质水平、表达和核酸浓度的常见静态测量；以及2) 用ELISPOT法检测脓毒症患者T细胞产生干扰素-和单核细胞产生肿瘤坏死因子 幸存者将在体外检查不同免疫兴奋剂逆转脓毒症的疗效比较 免疫抑制。为了实现这些目标，我们提出了一项针对270名患者的前瞻性观察性试验 脓毒症(使用脓毒症-3标准)与90名无脓毒症的危重病患者(总共390人，30人)进行比较 质量控制和验证的健康对象)在3个学术机构。脓毒症后1、4和7天 诊断后，采集血样，血T细胞和单核细胞产生干扰素-和肿瘤坏死因子， 将由ELISpot决定。此外，还将获取其他生物标志物的样本，包括 血浆蛋白(IL-6、SPD-L1)、CD14+细胞、人类白细胞抗原DR的表达、淋巴细胞总数和全血 基因组学。继发感染将是结果的主要临床指标6，次要指标包括 再次入院，180天死亡率。此外，我们将在这个ELISpot平台上评估体外 不同剂量刺激T细胞产生干扰素-和单核细胞产生肿瘤坏死因子的反应 IL-7、抗PD-1单抗、GITRL、OX40L或4-1BB浓度，采用随机区组设计。这些 免疫兴奋剂目前正在被考虑作为脓毒症患者的潜在治疗药物。这 应用程序建议验证一种新的功能生物测定，以确定哪些患者将受益于 免疫疗法，并确定不同的免疫疗法，将使个别患者受益。