Utilizing Immune Phenotypes to Prevent Chronic Critical Illness

项目摘要 虽然危重病人在急性疾病期间的存活率继续提高，但从长远来看， 这些患者的结果是令人沮丧的。当重症监护病房幸存者进展到慢性危重疾病状态时(≥14 在ICU中)，大多数人发展为严重残疾和康复时间延长，充满了多发性 并发症。最终，大约50%的人最终在一年后死于疾病。不幸的是，有一次 患者进展到慢性危重疾病的状态，没有什么比支持性护理更好的了。考虑到 据估计，管理这些患者所需的医疗费用每年超过200亿美元，慢性危重病 疾病正在造成一场新的医疗危机。作为一名ICU医生和基础科学研究人员，我有 独一无二的能力，既能在床边管理这些患者，又能积极探索新的方法来改善他们的 关心。在这些患者身上投入了所有的努力来帮助他们度过急性病，这似乎是一个失败 我们无法长期帮助他们。 进展为慢性危重疾病的最大风险因素是严重的免疫抑制。 这是有可能发生的。在对损伤或感染的正常反应中，先天免疫系统和获得性免疫系统 一旦炎症性侮辱被清除，就停用。然而，如果受到严重的侮辱，比如创伤或败血症， 失活的免疫细胞被来自骨髓的更未成熟的细胞取代，这些细胞已经减少或 打压活动，可能无法有效根除源头。许多人已经能够证明这一点 危重病人的免疫抑制状态，但没有人能够逆转这种反应。这 该提案结合了人类和动物研究，以更好地了解个体如何 对重大伤害或感染作出反应，并尝试逆转可能发生的任何免疫抑制。在……里面 在第一个项目中，使用了四种不同的小鼠损伤或感染模型，并对每种模型的免疫图谱进行了分析 识别出单个鼠标。如果它们在先天免疫或获得性免疫中表现出任何类型的抑制 系统，或两者，特定的逆转剂被注射，以确定我们是否可以提高他们的免疫力 回应。在第二个项目中，住进外科ICU的危重病人的血液样本是 在入院的头两周进行分析，以确定他们的免疫状况。单变量和多变量 然后进行回归分析，以确定哪些免疫表型与病情恶化有关 结果，主要结果是慢性危重疾病。成功完成这些研究将 显著推进免疫表型领域，为个性化发展奠定基础 为各种危重病人提供免疫治疗。

Project Summary While survival rates for critically ill patients during their acute illness continues to improve, the long-term outcomes for these patients are dismal. When ICU survivors progress to a state of chronic critical illness (≥14 days in the ICU), the majority develop significant disability and prolonged recovery times fraught with multiple complications. Ultimately, about 50% eventually succumb to their illness at one year. Unfortunately, once patients progress to a state of chronic critical illness, there is nothing more than supportive care. Given that the healthcare costs required to manage these patients is estimated to be over $20 billion per year, chronic critical illness is creating a new health care crisis. As an ICU physician and basic science researcher, I have the unique ability to both manage these patients at the bedside and actively investigate new ways to improve their care. With all the effort invested in these patients to help them survive their acute illness, it seems like a failure that we are not able to help them long term. The greatest risk factor for the progression to chronic critical illness is the profound immunosuppression that can occur. In the normal response to injury or infection, both the innate and adaptive immune systems deactivate once the inflammatory insult is cleared. However, with a significant insult, such as trauma or sepsis, deactivated immune cells are replaced by more immature cells from the bone marrow that have decreased or suppressive activity and may be unable to effectively eradicate the source. Many have been able to show this immunosuppressed state in critically ill patients, but no one has been able to reverse this response. This proposal synergizes both human and animal studies to better understand the diversities on how individuals respond to a significant injury or infection and attempt to reverse any immunosuppression that may occur. In the first project, four different murine models of injury or infection are utilized and the immune profile of each individual mouse is identified. If they display any type of suppression in their innate or adaptive immune system, or both, specific reversal agents are administered to determine if we can improve their immune response. In the second project, blood samples from critically ill patients admitted to the Surgical ICU are analyzed to determine their immune profiles over the first two weeks of admission. Univariate and multivariate regression analyses will then be performed to determine which immune phenotypes are associated with worse outcomes, with the primary outcome being chronic critical illness. Successful completion of these studies will significantly advance the field of immune phenotypes and set the groundwork for developing individualized immune therapies for a variety of critically ill patients.