Objective To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis, propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Results Sepsis remains one of the most debilitating and expensive illnesses, and its incidence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness (CCI), rarely fully recover and often experience an indolent death. Patients with CCI often exhibit ‘a persistent inflammatory-immunosuppressive and catabolic syndrome’ or PICS, and it is proposed here that PICS contributes to many of these adverse clinical outcomes. The underlying cause of PICS is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusion Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with CCI and PICS may require a more complementary approach.

BACKGROUND Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Based on our chronic sepsis animal models, we hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. METHODS Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, as well as in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. RESULTS After SS/SS, CD33+CD11b+HLA-DR−/low MDSCs were dramatically increased out to 28 days (p<0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (p<0.05). Additionally, septic MDSCs had suppressed HLA gene expression and upregulated ARG1 expression (p<0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged ICU stays, and poor functional status at discharge (p<0.05). CONCLUSION After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

Prognostic, level II.

There is increasing adjunctive use of AE in patients managed both operatively and nonoperatively. Intra-abdominal complications are common in these salvaged patients with severe liver injuries. Those patients that underwent early-AE received significantly fewer blood transfusions and more commonly had sterile hepatic collections. Only 26% of patients required liver-related surgery after AE. Therefore, the integration of AE as an adjunctive modality for patients with high-grade liver injuries is a safe and effective therapeutic option.

Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.

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.

Sepsis and trauma are both leading causes of death in the United States and represent major public health challenges. Murine models have largely been used in sepsis and trauma research to better understand the pathophysiological changes that occur after an insult and to develop potential life-saving therapeutic agents. Mice are favorable subjects for this type of research given the variety of readily available strains including inbred, outbred, and transgenic strains. In addition, they are relatively easy to maintain and have a high fecundity. However, pharmacological therapies demonstrating promise in preclinical mouse models of sepsis and trauma often fail to demonstrate similar efficacy in human clinical trials, prompting considerable criticism surrounding the capacity of murine models to recapitulate complex human diseases like sepsis and traumatic injury. Fundamental differences between the two species include, but are not limited to, the divergence of the transcriptomic response, the mismatch of temporal response patterns, differences in both innate and adaptive immunity, and heterogeneity within the human population in comparison to the homogeneity of highly inbred mouse strains. Given the ongoing controversy, this narrative review aims to not only highlight the historical importance of the mouse as an animal research model but also highlight the current benefits and limitations of the model as it pertains to sepsis and trauma. Lastly, this review will propose future directions that may promote further use of the model.

Recent comparisons of the murine and human transcriptome in health and disease have called into question the appropriateness of the use of murine models for human sepsis and trauma research. More specifically, researchers have debated the suitability of mouse models of severe inflammation that is intended for eventual translation to human patients. This mini-review outlines this recent research, as well as specifically defines the arguments for and against murine models of sepsis and trauma research based on these transcriptional studies. In addition, we review newer advancements in murine models of infection and injury and define what we envision as an evolving but viable future for murine studies of sepsis and trauma. J. Leukoc. Biol. 98: 945-952;