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

摘要 严重烧伤可迅速激活全身炎症反应和心血管功能障碍， 与内皮通透性增加和器官损伤相关的分布性休克。脓毒症是一种主要的 是严重烧伤患者的主要死亡原因，约占烧伤患者死亡率的75%。 早期预防或识别脓毒症是预防烧伤患者预后不良的关键。但据 难以（1）在重症监护室就诊时检测出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， 在非烧伤患者中检测感染和脓毒症的数据不一定能为烧伤的诊断提供信息 考虑到烧伤的特殊性。尽管一些研究发现 生物标志物作为烧伤患者中的候选脓毒症标志物，这些标志物来源于非常少的 的患者或未合并，并显示有限的预测价值。由于独特的 由于严重烧伤的病理生理学，存在未满足的临床需要，以鉴定严重烧伤的早期生物标志物特征， 烧伤患者人群中存在脓毒症和脓毒性休克风险的患者。 我们的中心假设是，最初的主机响应烧伤可能会导致继发性脓毒症。 也就是说，严重烧伤成人患者的心血管损伤和炎症反应失调 使烧伤患者暴露于更高的发展脓毒症的风险。在这份提案中，我们将纵向分析 血浆样本和严重烧伤患者（n=400）大队列的临床结果。 免疫失调和心血管损伤的生物标志物分析将用于定义 患者并与主要终点（脓毒症）和次要结局（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的模拟试验提供信息，以确定（1） 脓毒症的风险更高，以及（2）在这种情况下，可以有针对性地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）和烧伤患者脓毒症和对照非烧伤危重病 脓毒症或脓毒性休克患者。这些研究的结果将为识别 脓毒症特异性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。

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.