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

行政补充：脓毒症患者免疫内型分层（SPIES 研究）

• 批准号: 10683437
• 负责人: LYLE L MOLDAWER
• 金额: $ 42.47万
• 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/10683437
• 关键词: Administrative Supplement; Age; Animal Model; Antibiotics; Award; Biological Assay; Biological Markers; Blood; Blood specimen; Blunt Trauma; Burn injury; 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; 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; Mononuclear; Natural Immunity; Nosocomial Infections; Nucleic Acids; Oncology; Organ; Outcome; Pathogenicity; Patients; Phenotype; Plasma; Production; Proteins; Proteomics; Quality Control; Race; Randomized Clinical Trials; Recurrence; Sampling; Savings; Sepsis; Severities; Surrogate Markers; Survivors; T-Lymphocyte; TNF gene; TNFSF4 gene; Testing; Therapeutic; Time; Trauma; Trauma patient; Validation; adaptive immunity; aging population; anti-PD-1; base; clinical development; comorbidity; comparative efficacy; efficacy evaluation; hospital readmission; immune function; immune stimulant; immunological status; immunosuppressed; improved; in vivo; indexing; individual patient; monocyte; mortality; novel; parent grant; pathogen; patient stratification; predictive modeling; prospective; recidivism; recurrent infection; resiquimod; response; secondary infection; secondary outcome; septic patients; sex; tertiary care; transcriptomics; treatment response; tumor

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.

摘要 脓毒症仍然是当今医院死亡的主要原因。尽管随着年龄的增长， 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 在很大程度上是由于早期认识和更好地遵守早期脓毒症管理的最佳实践。 尽管住院死亡率有所改善，但很大一部分（在一些研究中高达50%）脓毒症幸存者从未接受过治疗。 完全恢复并发展为慢性危重病（CCI），其特征是持续的免疫抑制， 复发性感染、败血症复发和不良长期结局。然而，有三个关键挑战， 阻碍了在这些脓毒症幸存者中免疫疗法的发展：i）如何对患有 免疫抑制的脓毒症患者; ii）如何量化免疫抑制的程度;以及iii）如何识别 有前途的免疫刺激剂在个体免疫抑制患者？我们认为，目前为 免疫抑制的内源性脓毒症幸存者还没有完全成功，因为他们不能 直接评估免疫功能，而不是使用免疫状态的基因组学或蛋白质组学测量。这里 我们建议：1）评估刺激的T细胞产生IFN-γ和刺激的单核细胞产生 通过ELISpot定量的TNFα，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、表达和核酸浓度的普通静态测量;以及 2)采用ELISpot评估T细胞产生IFN-γ和单核细胞产生TNFα的能力， 脓毒症幸存者，以检查不同免疫刺激剂逆转脓毒症的体外比较功效， 诱导免疫抑制。根据最初的裁决，我们提出了一个前瞻性的，观察性的试验，270 脓毒症患者（使用脓毒症-3标准）与90例无脓毒症的危重病患者（总计 390例，30例健康受试者进行质量控制和验证）。在这个 在第一年的补充申请中，我们建议增加30名创伤和15名烧伤患者，尽管 在父母补助金的有效期内，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、创伤或危重病诊断后7天（烧伤为7天和14天），将采集血样， 将通过以下方法分别测定获得的IFN-γ和TNFα的血T细胞和单核细胞产量： ELISpot。继发性感染将是结局的主要临床指标，次要指标包括 再入院和180天死亡率。此外，我们将在这个ELISpot平台上评估前 刺激的T细胞产生IFN-γ和单核细胞产生TNFα的体内应答 目前正在考虑将不同浓度的免疫刺激剂作为潜在的治疗剂 对于败血症患者。本申请提出了一种新的功能性生物测定法的验证，以鉴定 患者将受益于免疫疗法，并确定不同的免疫疗法， 个别病人。

项目成果

Adverse Long-Term Outcomes and an Immune Suppressed Endotype in Sepsis Patients with Reduced Interferon-γELISpot: A Multicenter, Prospective Observational Study.

干扰素减少的脓毒症患者的长期不良结果和免疫抑制内型 - γELISpot：一项多中心、前瞻性观察研究。

• DOI: 10.1101/2023.09.13.23295360
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Barrios,EvanA;Mazer,MontyB;McGonagill,Patrick;Bergmann,ChristianB;Goodman,MichaelD;Gould,Robert;Rao,Mahil;Polcz,Valerie;Davis,Ruth;DelToro,Drew;Dirain,Marvin;Dram,Alexandra;Hale,Lucas;Heidarian,Mohammad;Kucaba,TamaraA;L
• 通讯作者: L