J. Guardado1, O. Abdul-Malak1, Y. Vodovotz1, T. R. Billiar1, R. A. Namas1 1University Of Pittsburg,Surgery,Pittsburgh, PA, USA
Introduction: Traumatic injury elicits broad systemic inflammatory and pathophysiological responses that if go awry, result in immune dysregulation. Clinically, this manifests as remote multiple organ dysfunction (MODS) and increased risk to nosocomial infection (NI), culminating in to a state of persistent critical illness (PCI). Prior studies demonstrated the central role of multiple inflammatory mediators in regulating the post-traumatic inflammatory response, yet, the role of Innate Lymphoid Cells (ILC) and their downstream mediators has not been fully elucidated. Accordingly, we carried out an extensive time course analysis of circulating ILC biomarkers in a cohort of blunt trauma patients to gain insights into the trauma-induced inflammatory response associated with PCI.
Methods: In a cohort of 472 blunt trauma survivors, we performed a retrospective case–control study where 44 trauma patients with a complicated course i.e. with NI were identified and compared to 44 patients with an uncomplicated course i.e. no-NI, selected by matching for demographics, injury severity, and mechanism of injury. Plasma was sampled 3 times within the first 24 h and then from D1 to D7 post-injury, and assayed for IL-22, IL-23, IL-25, and IL-33 biomarkers. MODScore was calculated from the inpatient electronic record. Two-way analysis of variance (ANOVA) and Area under the Curve (AUC) were used to determine statistical significance (p<0.05) and fold change respectively between the two groups. Spearman Correlation Coefficient (CC) was performed to determine the association between MODS and ILC mediators.
Results: Patients with complicated clinical course had a significantly longer ICU length of stay (LOS), hospital LOS, and days on mechanical ventilation when compared to patients with uncomplicated clinical course. Indeed, patients with complicated clinical course exhibited a higher degree of organ dysfunction suggested by a higher Marshall MODScore persistently elevated across D1 through D7. Circulating levels of IL-22, IL-23, IL-25, and IL-33 were significantly elevated upon admission and remained elevated in patients with complicated clinical course. In parallel to these results, AUC analysis revealed a two-fold increase in the aforementioned mediators in patients with complicated clinical course. In addition, MODS correlated positively with levels of IL-22, IL-23, IL-25, and IL-33 in patients with complicated clinical course as compared to patients with uncomplicated clinical course.
Conclusion: These data provide some of the first evidence in humans that cytokines derived from stressed epithelial cells are elevated early and over time in critically ill trauma patients. We have previously shown that Th2-derived cytokines (IL-4, IL-5, and IL-13) are also elevated in these patients. Since IL-5 and IL-33 are known to drive Th2 immunity, these processes may be linked and contribute to organ injury in this patient population.