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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的严重烧伤会迅速激活全身炎症反应和心血管功能障碍，导致与内皮通透性增加和器官损伤相关的分布性休克。脓毒症是一个主要的严重烧伤患者的死亡原因，占烧伤患者死亡率的近75%。及早预防或识别脓毒症是防止烧伤患者预后不良的关键。然而，它是难以 (1) 在重症监护病房就诊时发现脓毒症风险较高的烧伤患者，以及 (2) 区分脓毒症和严重烧伤的非感染性炎症反应。迄今为止，大多数用于检测非烧伤患者感染和败血症的数据并不一定能为烧伤患者的诊断提供依据鉴于烧伤的特殊性，患者群体。尽管一些研究已经发现了潜力生物标志物作为烧伤患者的候选化脓性标志物，这些标志物源自极少数患者或未合并，显示出有限的预测价值。因此，由于独特的严重烧伤的病理生理学，识别早期生物标志物特征的临床需求尚未得到满足烧伤患者群体中有败血症和败血性休克风险的患者。我们的中心假设是，宿主对烧伤的最初反应可能导致继发性败血症。也就是说，严重烧伤成年患者的心血管损伤和炎症状况失调烧伤患者患败血症的风险更高。在这个提案中，我们将纵向分析大量严重烧伤的烧伤患者 (n=400) 的血浆样本和临床结果。免疫失调和心血管损伤的生物标志物分析将用于定义亚表型患者并与主要终点（脓毒症）和次要结果（死亡率、ICU 住院时间、器官衰竭）。这项大型前瞻性队列研究的原理证明结果将用于指导和为未来的前瞻性试验和治疗干预模拟试验提供信息，以确定 (1) 人群脓毒症风险较高，以及（2）可以针对预防继发性脓毒症的治疗途径高危人群。最后，我们将比较没有脓毒症的烧伤患者之间的蛋白质组特征（即，非脓毒症全身炎症反应）和烧伤脓毒症患者和对照非烧伤危重症患者脓毒症或脓毒性休克患者。这些研究的结果将为鉴定提供重要见解脓毒症特有的生物标志物和蛋白质组学特征，并提高我们识别脓毒症的能力。