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.