Immunological Endotyping of Chronic Critical Illness after Severe Trauma or Sepsis

摘要 严重创伤性损伤和脓毒症是急性促炎性损伤，可引发“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）。然而，许多患者 先前死于早期难治性MOF，复苏和器官支持的进展 导致越来越多的患者存活进入慢性危重病（CCI）状态，定义为 一名长期入住重症监护室（ICU）且器官功能障碍未消退的患者。目前，作为 ICU中多达25%的创伤和40%的脓毒症患者发生CCI。除了长期住院外 当然，这些ICU“幸存者”有复发性感染，无法身体康复， 出院到高资源护理设施，长期结果令人沮丧。两种临床表现占主导地位 CCI表型的过程：1）反复的医院内和出院后感染，表明CCI的状态。 慢性免疫抑制，和2）急性肌肉萎缩，虚弱和身体虚弱，表明 持续性炎症有越来越多的证据表明，持续性脑缺血的潜在综合征 炎症、免疫抑制和炎症反应（PICS）是CCI的关键机制驱动因素。我们假设 PICS是其自身独立于索引事件的独特的免疫学内型，并且是共享的免疫学内型。 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。 损伤，以及来自原发性/继发性感染的微生物产物（PAMP）。这一失败的回归 免疫稳态也驱动CCI中所见的持续器官功能障碍。肌肉，临床上 相关的和未充分研究的，作为一个新的研究领域，从炎症介导的结束， 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 然后释放我们实验室未来五年的研究计划目标包括： 通过识别不同的免疫反应， 基于随时间推移的免疫轨迹的内型，以及这些内型是否被性别、年龄和 2）确定PICS内型是否是创伤或脓毒症后的常见机制途径， CCI的临床发展;和3）确定肌肉炎症是否既是慢性炎症的组成部分， 终末器官损伤，以及通过内源性的全身释放的全身炎症介质 危言耸听。拟议的工作是新颖的，创新的和重要的。目前没有治疗干预措施 除了对创伤或脓毒症后越来越常见的CCI状况的支持疗法之外。我们认为 只有全面了解CCI的免疫学内型， 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得到充分开发。

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.