Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI.

Objective: This study sought to examine mortality, health-related quality of life (HRQOL), and physical function among sepsis survivors who developed chronic critical illness (CCI).

Prognostic, level II.

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.

Objective To determine the incidence and risk factors of chronic critical illness (CCI) after severe blunt trauma. Design Prospective observational cohort study (NCT01810328). Setting Two Level-1 trauma centers in the United States. Patients 135 adult blunt trauma patients with hemorrhagic shock who survived beyond 48-hours after injury. Interventions None Measurements and Main Results CCI was defined as an ICU stay lasting ≥14-days with evidence of persistent organ dysfunction. Three subjects (2%) died within the first seven-days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to CCI. Patients who developed CCI were older (55 vs 44-years-old; p=0.01), had more severe shock (base deficit −9.2 vs −5.5, p=0.005), greater organ failure severity (Denver MOF score, 3.5±2.4 vs 0.8±1.1, p<0.0001) and developed more infectious complications (84% vs 35%, p<0.0001). CCI patients were more likely to be discharged to a long-term care setting (56% vs 34%, p=0.008) than to a rehabilitation facility/home. At four-months, CCI patients had higher mortality (16.0% vs 1.9%; p<0.05), with survivors scoring lower in general health measures (p<0.005). Multivariate analysis revealed age ≥55-years, systolic hypotension ≤70-mmHg, transfusion ≥5-units packed red blood cells within 24-hours, and Denver MOF score at 72-hours as independent predictors of CCI (AUC 0.87, 95% CI [0.75, 0.95]). Conclusions While early mortality is low after severe trauma, CCI is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity and persistent organ dysfunction are predictive of CCI. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.

Early host recognition of microbial invasion or damaged host tissues provides an effective warning system by which protective immune and inflammatory processes are initiated. Host tissues responsible for continuous sampling of their local environment employ cell surface and cytosolic pattern recognition receptors (PRRs) that provide redundant and overlapping identification of both microbial and host alarmins. Microbial products containing pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) serve as principle ligands for recognition by these PRRs. It is this interaction which plays both an essential survival role in response to infection and injury, as well as the pathologic role in tissue and organ injury associated with severe sepsis and trauma. Elucidating the interaction between ligands and their respective PRRs can provide both a better understanding of the host response, as well as a rational basis for therapeutic intervention.