title: Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery.
abstract: BACKGROUND
  Recovery after surgery is highly variable. Risk-stratifying patients based on their predicted recovery profile will afford individualized perioperative management strategies. Recently, application of mass cytometry in patients undergoing hip arthroplasty revealed strong immune correlates of surgical recovery in blood samples collected shortly after surgery. However, the ability to interrogate a patient's immune state before surgery and predict recovery is highly desirable in perioperative medicine.
  
  
  METHODS
  To evaluate a patient's presurgical immune state, cell-type-specific intracellular signaling responses to ex vivo ligands (lipopolysaccharide, interleukin [IL]-6, IL-10, and IL-2/granulocyte macrophage colony-stimulating factor) were quantified by mass cytometry in presurgical blood samples. Selected ligands modulate signaling processes perturbed by surgery. Twenty-three cell surface and 11 intracellular markers were used for the phenotypic and functional characterization of major immune cell subsets. Evoked immune responses were regressed against patient-centered outcomes, contributing to protracted recovery including functional impairment, postoperative pain, and fatigue.
  
  
  RESULTS
  Evoked signaling responses varied significantly and defined patient-specific presurgical immune states. Eighteen signaling responses correlated significantly with surgical recovery parameters (|R| = 0.37 to 0.70; false discovery rate < 0.01). Signaling responses downstream of the toll-like receptor 4 in cluster of differentiation (CD) 14 monocytes were particularly strong correlates, accounting for 50% of observed variance. Immune correlates identified in presurgical blood samples mirrored correlates identified in postsurgical blood samples.
  
  
  CONCLUSIONS
  Convergent findings in pre- and postsurgical analyses provide validation of reported immune correlates and suggest a critical role of the toll-like receptor 4 signaling pathway in monocytes for the clinical recovery process. The comprehensive assessment of patients' preoperative immune state is promising for predicting important recovery parameters and may lead to clinical tests using standard flow cytometry.
authors.affiliation: From the Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, California (G.K.F., B.G., N.A., G.P.N.); Department of Microbiology and Immunology, Stanford University, Stanford, California (G.K.F., G.P.N.); and Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, California (B.G., E.A.G., M.T., M.S.A.).
authors.forename: Gabriela K
authors.initials: GK
authors.lastname: Fragiadakis
authors.forename: Brice
authors.initials: B
authors.lastname: Gaudillière
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ganio
authors.forename: Nima
authors.initials: N
authors.lastname: Aghaeepour
authors.forename: Martha
authors.initials: M
authors.lastname: Tingle
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.forename: Martin S
authors.initials: MS
authors.lastname: Angst
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000276:immunology* / Q000503:physiopathology*; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D007376:Interleukin-2 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D011183:Postoperative Complications / Q000097:blood / Q000276:immunology*; D011300:Preoperative Care / Q000379:methods* / Q000706:statistics & numerical data*; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D007376:Interleukin-2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor