Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy

Hiroyuki Horiguchi, Tyler J. Loftus, Russell B. Hawkins, Steven L. Raymond, Julie A. Stortz, McKenzie K. Hollen, Brett P. Weiss, Elizabeth S. Miller, Azra Bihorac, Shawn D. Larson, Alicia M. Mohr, Scott C. Brakenridge, Hironori Tsujimoto, Hideki Ueno, Frederick A. Moore, Lyle L. Moldawer, Philip A. Efron, The Sepsis and Critical Illness Research Center Investigators

Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI), defined as ≥14 days requiring intensive care unit (ICU) resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients.