Stratifying Patient Immune Endotypes in Sepsis (SPIES Study)

脓毒症患者免疫内型分层（SPIES 研究）

基本信息

批准号：
10651650
负责人：
LYLE L MOLDAWER
金额：
$ 73.48万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10651650
关键词：
Age Animal Model Antibiotics Biological Assay Biological Markers Blood Blood specimen CD14 gene Cell physiology Cells Chronic Clinical Clinical Trials Communicable Diseases 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 Hour IL7 gene Immune Immune response Immunity Immunocompetence Immunocompromised Host Immunologic Adjuvants Immunology procedure Immunophenotyping 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 Recurrence Sampling Sepsis Severities Surrogate Markers Survivors T-Lymphocyte TNFSF4 gene Testing Therapeutic Time Validation Whole Blood adaptive immunity aging population anti-PD-1 clinical development comorbidity comparative efficacy design efficacy evaluation hospital care hospital readmission immune function immune stimulant immunological status immunosuppressed improved in vivo indexing individual patient monocyte mortality novel pathogen patient stratification predictive modeling prospective randomized, clinical trials recidivism recurrent infection response secondary infection secondary outcome septic patients sex tertiary care transcriptomics treatment response tumor

项目摘要

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.

抽象的脓毒症仍然是当今医院死亡的主要原因。1 尽管脓毒症的发病率由于老龄化而不断增加由于患有更多合并症的人群，过去十年来院内死亡率显着下降。2 这在很大程度上是由于早期脓毒症管理中的早期认识和更好地遵守最佳实践。尽管院内死亡率有所改善，但很大一部分（某些研究中高达 50%）3-5 脓毒症幸存者从未完全康复并发展为慢性危重疾病（CCI），其特征是持续的免疫抑制，然而，反复感染、脓毒症累犯和长期结果不佳存在三个关键挑战：阻碍这些脓毒症幸存者免疫疗法的发展：i）如何对患有脓毒症的患者进行内型分析免疫抑制的败血症；ii) 如何量化免疫抑制的程度；以及 iii) 如何识别；我们认为，目前的努力是对个体免疫抑制患者有希望的免疫刺激剂吗？内型败血症幸存者作为免疫抑制者尚未完全成功，因为他们未能直接评估免疫功能，而不是使用免疫状态的基因组或蛋白质组测量。我们建议：1) 评估是否刺激 T 细胞产生 IFN-γ 和刺激单核细胞产生 IFN-γ 与 ELISpot 相比，TNFα 可以更好地预测脓毒症幸存者的感染性和长期结果基于蛋白质水平、表达和核酸浓度的常见静态测量；2) 采用 ELISpot 评估脓毒症 T 细胞产生的 IFN-α 和单核细胞产生的 TNFα 幸存者离体检查不同免疫刺激剂逆转败血症引起的比较功效为了实现这些目标，我们建议对 270 名患有免疫抑制的患者进行一项前瞻性观察性试验。脓毒症（使用 Sepsis-3 标准）与 90 名没有脓毒症的危重患者（总共 390 名，其中 30 名）进行比较脓毒症后 1、4 和 7 天在 3 个学术机构进行的健康受试者的质量控制和验证。诊断后，将获取血样并检测血液 T 细胞和单核细胞产生 IFN-α 和 TNFα，分别由 ELISpot 测定。此外，还将获取其他生物标志物的样本，包括血浆蛋白（IL-6 和 sPD-L1）、HLA-DR 的 CD14+ 细胞表达、淋巴细胞总数和全血继发感染将是结果的主要临床指标6，次要指标包括此外，我们将在此 ELISpot 平台上评估离体情况。 T 细胞产生 IFN-α 和单核细胞产生 TNFα 的反应使用随机区组设计测定 IL-7、抗 PD-1 mAb、GITRL、OX40L 或 4-1BB 的浓度。目前正在考虑将免疫刺激剂作为脓毒症患者的潜在治疗方法。该申请提出了一种新型生物功能测定的验证，以确定哪些患者将从中受益免疫疗法，并确定对个体患者有益的不同免疫疗法。