Immunological Endotyping of Chronic Critical Illness after Severe Trauma or Sepsis

严重创伤或脓毒症后慢性危重疾病的免疫内分型

• 批准号: 10272487
• 负责人: Scott Charles Brakenridge
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272487
• 关键词: Acute; Area; Catabolism; Chronic; Clinical; Critical Illness; Ethnic Origin; Event; Failure; Functional disorder; Genomics; Goals; Health care facility; Heterogeneity; Homeostasis; Hospitals; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Infection; Inflammation; Inflammatory; Innate Immune Response; Intensive Care Units; Laboratory Research; Mediating; Mediator of activation protein; Multiple Organ Failure; Muscle; Muscular Atrophy; Organ; Outcome; Pathway interactions; Patients; Phenotype; Production; Race; Recurrence; Refractory; Research; Resources; Resuscitation; Role; Sepsis; Source; Supportive care; Survivors; Syndrome; Therapeutic Intervention; Time; Trauma; Trauma patient; Traumatic injury; Work; base; clinical development; clinical phenotype; clinically relevant; cytokine release syndrome; design; indexing; innovation; microbial; mortality; novel; organ injury; programs; recurrent infection; secondary infection; septic patients; severe injury; sex; systemic inflammatory response; therapeutically effective

ABSTRACT Severe traumatic injury and sepsis are acute pro-inflammatory insults that trigger a “genomic and cytokine storm” by the host innate immune response that can result in multiple organ failure (MOF). Whereas many patients previously succumbed to early refractory MOF, progressive advancements in resuscitation and organ support have led to an increasing number of patients surviving to enter a state of chronic critical illness (CCI), defined as a patient with an extended intensive care unit (ICU) stay and non-resolving organ dysfunction. Currently, as many as 25% of trauma and 40% of septic patients in the ICU develop CCI. In addition to a prolonged hospital course, these ICU “survivors” have recurrent infections, are unable to physically rehabilitate, and are frequently discharged to high-resource care facilities with dismal long-term outcomes. Two clinical manifestations dominate the course of the CCI phenotype: 1) recurrent nosocomial and post-discharge infections indicative of a state of chronic immunosuppression, and 2) acute muscle wasting, weakness and physical debilitation indicative of persistent inflammation. There is an expanding body of evidence that an underlying syndrome of persistent inflammation, immunosuppression and catabolism (PICS) is a key mechanistic driver of CCI. We hypothesize that PICS is its own unique immunological endotype independent of the index event, and is the shared mechanistic pathway leading from either trauma or sepsis to the clinical phenotype of CCI. This maladaptive host response is sustained by the ongoing release of endogenous alarmins (DAMPs) associated with end-organ injury, as well as microbial products from primary/secondary infections (PAMPs). This failure to return to immunologic homeostasis also drives the persistent organ dysfunction seen in CCI. Muscle, being both clinically relevant and understudied, serves as a novel area of study from the standpoint of inflammation-mediated end- organ injury both as a driver of acute muscle wasting, as well as a potential source of ongoing alarmin production and release. The goals for our laboratory’s research program over the next five years include the following: 1) characterize the heterogeneity of the host response after severe trauma and sepsis by identifying distinct endotypes based on immune trajectory over time, and whether these endotypes are modified by sex, age and ethnicity/race; 2) determine if the PICS endotype is the common mechanistic pathway after trauma or sepsis to the clinical development of CCI; and 3) determine whether muscle inflammation is both a component of chronic end-organ injury, as well as a mediator of systemic inflammation through the systemic release of endogenous alarmins. The proposed work is novel, innovative and vital. There are currently no therapeutic interventions other than supportive therapies for the increasingly common condition of CCI after trauma or sepsis. We believe that only through a complete understanding of the immunological endotype of CCI can effective therapeutic interventions be designed. Focusing on interactions between host immunity and muscle inflammation is a novel, under-explored area of research for the long-term management of severe trauma and sepsis.

抽象的 严重创伤性损伤和败血症是急性促炎性损伤，会引发“基因组和细胞因子风暴” 由宿主先天免疫反应引起，可导致多器官衰竭（MOF）。而很多患者 先前死于早期难治性 MOF，复苏和器官支持方面的进步 导致越来越多的患者幸存并进入慢性危重疾病（CC​​I）状态，定义为 重症监护病房 (ICU) 住院时间延长且器官功能障碍未解决的患者。目前，作为 ICU 中多达 25% 的创伤患者和 40% 的脓毒症患者会发生 CCI。除了长期住院 当然，这些ICU“幸存者”反复感染，身体无法康复，经常被 出院到资源丰富的护理机构，长期结果不佳。主要有两种临床表现 CCI 表型的病程：1) 反复出现的院内感染和出院后感染，表明处于一种状态 慢性免疫抑制，以及 2) 急性肌肉萎缩、虚弱和身体虚弱 持续性炎症。越来越多的证据表明，持续性的潜在综合症 炎症、免疫抑制和分解代谢（PICS）是 CCI 的关键机制驱动因素。我们假设 PICS 是其自身独特的免疫学内型，独立于索引事件，并且是共享的 从创伤或脓毒症到 CCI 临床表型的机制途径。这种适应不良 宿主反应是通过与终末器官相关的内源性警报素 (DAMP) 的持续释放来维持的 损伤以及原发/继发感染 (PAMP) 产生的微生物产物。这次失败返回 免疫稳态也导致 CCI 中出现的持续性器官功能障碍。肌肉，在临床上都是 相关且尚未得到充分研究，从炎症介导的终末期的角度来看，它是一个新的研究领域 器官损伤既是急性肌肉萎缩的驱动因素，也是持续产生警报素的潜在来源 并释放。我们实验室未来五年研究计划的目标包括：1) 通过识别不同的特征来表征严重创伤和脓毒症后宿主反应的异质性 基于随时间推移的免疫轨迹的内型，以及这些内型是否会因性别、年龄和 民族/种族； 2) 确定PICS内型是否是创伤或脓毒症后常见的机制途径 CCI 的临床发展； 3）确定肌肉炎症是否是慢性疾病的一个组成部分 终末器官损伤，以及通过系统性释放内源性炎症的介质 警报。拟议的工作新颖、创新且充满活力。目前没有治疗干预措施 除了针对创伤或脓毒症后日益常见的 CCI 病症的支持疗法之外。我们相信 只有充分了解CCI的免疫学内型才能有效治疗 设计干预措施。关注宿主免疫和肌肉炎症之间的相互作用是一种新颖的、 严重创伤和脓毒症长期管理的研究领域尚未充分探索。