Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma

Abstract

Background: We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level.

Methods: We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14.

Results: Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings.

Conclusion: Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS.

Level of evidence: Epidemiologic study, level III.

Figure 1

We propose a new model of the human response after traumatic injury. Trauma causes pro- and anti-inflammation that result in simultaneous SIRS and CARS. Modern ICUs have become much better at recognizing and treating shock early and providing effective evidence based guideline-driven standard operating procedure treatment. This limits the progression into refractory shock and allows fewer patients to express the early multiple organ failure/fulminant death trajectory. Some surviving patients rapidly return to immunologic homeostasis, and experience rapid recover and are discharged from the ICU after a few days. Unfortunately, most have persistent derangement in both innate and adaptive immunity for weeks and progress into a syndrome of chronic critical illness, which in a high percentage of patients (>40%) progresses to PICS. We are presented with the challenge of managing simultaneous chronic dysfunctional inflammation and adaptive immunosuppression, protecting against secondary nosocomial infection, and preventing severe protein catabolism with resultant cachexia, which leads to an indolent death.

Figure 2

Heat maps of gene ontology pathways from isolated leukocyte subpopulations were evaluated to determine which pathways appeared to be differently expressed between complicated, uncomplicated and control patients on day 7 after traumatic injury. Difference from reference (DFR) was calculated to determine significance of expression between the cohorts in pathways which were identified to be different. A. Scatter plots of the selected canonical pathways involved in increased inflammation on day 7 in neutrophils (PMN), monocyte and T-cell’s. The natural log for the DFR scores were calculated for each patient in the complicated, uncomplicated, and control cohorts for IL-1 receptor signaling pathway in PMNs, and the chronic inflammatory response pathway in monocytes and T-cells. Statistical analysis showed the complicated patients had significant up regulation of these pathways compared to uncomplicated patients and controls (p<0.05). B. Scatter plots of selected gene ontology pathways involved in suppression of adaptive immunity on day 7 in PMN and monocyte’s. The natural log of the DFR scores were calculated for each patient in the complicated, uncomplicated, and control cohorts for the antigen processing and presentation pathway in PMNs and the antigen processing and presentation via MHC class II pathway in monocytes. Statistical analysis showed the complicated patients had significant down regulation of these pathways compared to uncomplicated patients and controls (p<0.05).