Changes in innate immune function predict post-operative systemic inflammatory response syndrome (SIRS) following major Hepatico-pancreatico-biliary (HPB) surgery.

Abstract

Introduction Patients undergoing major surgery are at risk of life-threatening complications including systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of patients at risk of SIRS would allow tailored post-operative care and improve survival. Elevated serum IL-6 levels have been shown patients with poor post-operative outcomes, but the mechanisms underlying this response are unknown. We studied these mechanisms in patients undergoing major surgery to identify early biomarkers of altered inflammatory responses and poor clinical outcomes. Methods Serial blood samples were taken from consenting, adult patients undergoing major hepatic or pancreatic surgery pre-operatively and on days one and two post-operatively. Patients with inflammatory co-morbidities, pre-operative sepsis and those taking anti-inflammatory medications were excluded. Peripheral blood mononuclear cells (PBMCs) were isolated, stimulated for 24 hours with lipopolysaccharide (LPS) or flagellin and cytokine production was quantified by ELISA. PBMC surface expression of CD14, CD16, TLR4 and TLR5 was assessed by flow cytometry. Transcription factor phosphorylation was evaluated using Phosflow. SIRS was defined by internationally agreed consensus criteria. Results Serum concentrations of IL-6 on postoperative Day 2 were significantly increased in 12 patients who developed SIRS (median postoperative day 6) compared with 27 patients who did not. PBMCs from SIRS patients following surgery (before clinical signs of SIRS) displayed significantly greater TLR4 and TLR5 expression and produced significantly more IL-6 in response to LPS and flagellin. Consistent with these data, TLR-driven phosphorylation of NF- 5 κB was increased post-operatively, and interferon alpha-mediated STAT1 phosphorylation was higher pre-operatively in SIRS patients. Differences in TLR4 and TLR5 expression were greatest in the CD14++CD16+ ‘intermediate’ monocyte population. Intermediate monocyte TLR4 and TLR5 expression post-operatively predicted SIRS development with an accuracy of 0.89 - 1.0 (calculated areas under the receiver operator curves). Conclusion Markers of innate immune dysfunction can be used 5 days before the onset of clinical signs to identify patients at risk of SIRS.