title: Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.
abstract: OBJECTIVE
  To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences.
  
  
  BACKGROUND
  Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival.
  
  
  METHODS
  Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo.
  
  
  RESULTS
  Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves).
  
  
  CONCLUSIONS
  These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.
authors.affiliation: *Blizard Institute, Queen Mary University of London, London, United Kingdom †Barts Health HPB Centre, Royal London Hospital, London, United Kingdom ‡William Harvey Research Institute, Queen Mary University of London, London, United Kingdom §University College London, London, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Lahiri
authors.forename: Yannick
authors.initials: Y
authors.lastname: Derwa
authors.forename: Zora
authors.initials: Z
authors.lastname: Bashir
authors.forename: Edward
authors.initials: E
authors.lastname: Giles
authors.forename: Hew D T
authors.initials: HD
authors.lastname: Torrance
authors.forename: Helen C
authors.initials: HC
authors.lastname: Owen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Dwyer
authors.forename: Alastair
authors.initials: A
authors.lastname: O'Brien
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stagg
authors.forename: Satyajit
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.forename: William
authors.initials: W
authors.lastname: Alazawi
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D011446:Prospective Studies; D012307:Risk Factors; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5