Immunological Endotyping of Chronic Critical Illness after Severe Trauma or Sepsis

摘要 严重创伤和脓毒症是一种急性促炎侮辱，会引发“基因组和细胞因子风暴”。 通过宿主的先天免疫反应可导致多器官衰竭(MOF)。鉴于许多患者 之前死于早期难治性多器官衰竭，在复苏和器官支持方面取得进展 导致越来越多的患者存活下来进入慢性危重疾病(CCI)状态，定义为 一名长期住在重症监护病房(ICU)的患者出现器官功能障碍。目前，AS ICU中多达25%的创伤和40%的败血症患者会发生CCI。除了延长住院时间外 当然，这些重症监护室的幸存者有反复感染，身体无法康复，而且经常 出院到资源丰富的护理机构，长期结果令人沮丧。主要有两种临床表现 CCI表型的病程：1)反复发生的医院和出院后感染表明 慢性免疫抑制，以及2)急性肌肉萎缩、虚弱和身体虚弱表明 持续性炎症。越来越多的证据表明，一种持续存在的潜在综合症 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是独立于索引事件的其自身唯一的免疫内型，并且是共享的 从创伤或脓毒症到CCI临床表型的机制途径。这是不适应的 宿主的反应是由与末端器官相关的内源性警报(DAMP)的持续释放来维持的 伤害，以及原发/继发感染的微生物产物(PAMP)。这一未能回到 免疫动态平衡也推动了CCI中出现的持续性器官功能障碍。肌肉，在临床上既是 相关的和未被研究的，作为一个新的研究领域，从炎症介导性末端的观点出发。 器官损伤既是急性肌肉萎缩的驱动因素，也是持续产生警报的潜在来源 然后释放。我们实验室未来五年的研究计划目标包括：1) 鉴定严重创伤和脓毒症后宿主反应的异质性 基于免疫轨迹的内型，以及这些内型是否会因性别、年龄和 种族/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)确定肌肉炎症是否既是慢性炎症的一个组成部分 终末器官损伤，以及通过全身释放内源性激素而引起全身炎症的介质 警报员。建议的工作是新颖、创新和重要的。目前还没有治疗干预措施 除了针对创伤或脓毒症后日益常见的CCI的支持性治疗之外。我们相信 只有全面了解CCI的免疫内型才能有效治疗 应设计干预措施。关注宿主免疫和肌肉炎症之间的相互作用是一项新的研究， 严重创伤和脓毒症的长期治疗研究不足的领域。

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.