Identification of sub-phenotypes of severely ill burn patients and risk for secondary sepsis: SEPSISBURN

识别严重烧伤患者的亚表型和继发性败血症的风险：SEPSISBURN

• 批准号: 10720049
• 负责人: Matthieu Legrand
• 金额: $ 48.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720049
• 关键词: Accounting; Adult; Anti-Inflammatory Agents; Antibiotic Prophylaxis; Antibiotics; Biological Assay; Biological Markers; Body Surface Area; Burn Units; Burn injury; Cardiovascular system; Cause of Death; Clinical; Clinical Data; Critical Illness; Data; Diagnosis; Early identification; Endothelium; Enrollment; Functional disorder; Future; Goals; Immune; Immune response; Infection; Inflammatory; Inflammatory Response; Intensive Care Units; Intervention; Knowledge; Length of Stay; Link; Measures; Metabolism; Molecular; Multiple Organ Failure; Organ failure; Outcome; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Population; Predictive Value; Prevention strategy; Production; Prospective, cohort study; Proteomics; Risk; Sampling; Secondary to; Sepsis; Septic Shock; Shock; Signs and Symptoms; Specificity; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; biomarker identification; biomarker signature; cardiovascular injury; cohort; cytokine; high risk; high risk population; immunoregulation; improved; improved outcome; insight; longitudinal analysis; mortality; mortality risk; organ injury; patient population; potential biomarker; prevent; preventive intervention; primary endpoint; prophylactic; prospective; proteomic signature; response; secondary infection; secondary outcome; septic; septic patients; severe burns; specific biomarkers; systemic inflammatory response; tool; Accounting; Adult; Anti-Inflammatory Agents; Antibiotic Prophylaxis; Antibiotics; Biological Assay; Biological Markers; Body Surface Area; Burn Units; Burn injury; Cardiovascular system; Cause of Death; Clinical; Clinical Data; Critical Illness; Data; Diagnosis; Early identification; Endothelium; Enrollment; Functional disorder; Future; Goals; Immune; Immune response; Infection; Inflammatory; Inflammatory Response; Intensive Care Units; Intervention; Knowledge; Length of Stay; Link; Measures; Metabolism; Molecular; Multiple Organ Failure; Organ failure; Outcome; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Population; Predictive Value; Prevention strategy; Production; Prospective, cohort study; Proteomics; Risk; Sampling; Secondary to; Sepsis; Septic Shock; Shock; Signs and Symptoms; Specificity; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; biomarker identification; biomarker signature; cardiovascular injury; cohort; cytokine; high risk; high risk population; immunoregulation; improved; improved outcome; insight; longitudinal analysis; mortality; mortality risk; organ injury; patient population; potential biomarker; prevent; preventive intervention; primary endpoint; prophylactic; prospective; proteomic signature; response; secondary infection; secondary outcome; septic; septic patients; severe burns; specific biomarkers; systemic inflammatory response; tool

Abstract Severe burn injury rapidly activates a systemic inflammatory response and cardiovascular dysfunction, causing distributive shock associated with increased endothelial permeability and organ injury. Sepsis is a leading cause of death in patients with severe burn injury, accounting for nearly 75% of mortality among burn patients. Preventing or recognizing sepsis early is key to preventing poor outcomes in burn patients. However, it is difficult to (1) detect burn patients at higher risk of sepsis at the time of intensive care unit presentation and (2) distinguish between sepsis and the non-infective inflammatory response to severe burn injury. To date, most data for detecting infection and sepsis in non-burn patients do not necessarily inform diagnosis in the burn patient population given the specificities of burn injury. Though some studies have identified potential biomarkers as candidate septic markers in burn patients, these markers are derived from a very small number of patients or were not combined and showed limited predictive value. Thus, due to the unique pathophysiology of severe burns, there is an unmet clinical need to identify early biomarker signatures of patients at risk of sepsis and septic shock in the burn patient population. Our central hypothesis is that the initial host response to burn injury could predispose to secondary sepsis. That is, a dysregulated cardiovascular injury and inflammatory profile in adult patients with severe burn injury exposes burn patients to a higher risk of developing sepsis. In this proposal, we will longitudinally analyze plasma samples and clinical outcomes in a large cohort of burn patients (n=400) with severe burn injury. Biomarker analysis of immune dysregulation and cardiovascular injury will be used to define sub-phenotypes of patients and linked to the primary endpoint (sepsis) and secondary outcomes (mortality, ICU length of stay, organ failure). Proof of principle results from this large prospective cohort study will then be used to guide and inform future prospective trials and emulated trials of therapeutic interventions to identify (1) populations at higher risk of sepsis and (2) therapeutic pathways that could be targeted to prevent secondary sepsis in this high-risk population. Finally, we will compare proteomic signatures between burn patients without sepsis (i.e., non-septic systemic inflammatory response) and burn patients with sepsis and control non-burn critically ill patients with sepsis or septic shock. The results of these studies will provide key insights into the identification of biomarkers and proteomic signatures specific to sepsis and improve our ability to recognize sepsis.

抽象的 严重的烧伤损伤迅速激活全身性炎症反应和心血管功能障碍，导致 与内皮渗透性增加和器官损伤相关的分布冲击。败血症是领先 严重烧伤患者的死亡原因，占烧伤患者死亡率的近75％。 尽早预防或识别败血症是预防烧伤患者预后不良的关键。但是，是 很难（1）在重症监护病房表现时检测出脓毒症风险较高的烧伤患者，以及（2） 区分败血症和对严重烧伤损伤的非感染炎症反应。迄今为止，大多数 检测非燃烧患者感染和败血症的数据不一定告知烧伤的诊断 鉴于烧伤的特异性，患者人数。尽管一些研究已经确定了潜力 生物标志物作为燃烧患者的候选化粪池标记，这些标记源自很少 患者或没有合并的预测值有限。因此，由于独特 严重烧伤的病理生理学，未满足的临床需要识别早期生物标志物特征 烧伤患者人群有脓毒症和败血性休克的风险。 我们的中心假设是，最初的宿主对烧伤损伤的反应可能会倾向于继发性败血症。 也就是说，成人严重烧伤患者的心血管损伤失调和炎症性表现 暴露于烧伤患者患败血症的风险更高。在此提案中，我们将纵向分析 在大量烧伤患者（n = 400）中，血浆样品和临床结果具有严重的烧伤。 免疫失调和心血管损伤的生物标志物分析将用于定义 患者并与主要终点（败血症）和次要结果有关（死亡率，ICU的住院时间， 器官故障）。这项大型前瞻性队列研究的原则结果证明将用于指导和 告知未来的前瞻性试验并模拟治疗干预措施的试验，以确定（1）人口 败血症的较高风险和（2）可以针对预防继发性败血症的治疗途径 高风险人口。最后，我们将比较没有败血症的烧伤患者之间的蛋白质组学特征（即 非性能全身性炎症反应）并燃烧患有败血症的患者和对照非燃烧的患者 败血症或败血性休克患者。这些研究的结果将为身份证明提供关键的见解 生物标志物和蛋白质组学特异性特定的蛋白质组学特征，并提高了我们识别败血症的能力。