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Clinical recovery from surgery correlates with single-cell immune signatures.

ABSTRACT: Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-?B (nuclear factor ?B) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.

SUBMITTER: Gaudilliere B

PROVIDER: S-EPMC4334126 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Clinical recovery from surgery correlates with single-cell immune signatures.

Gaudillière Brice B Fragiadakis Gabriela K GK Bruggner Robert V RV Nicolau Monica M Finck Rachel R Tingle Martha M Silva Julian J Ganio Edward A EA Yeh Christine G CG Maloney William J WJ Huddleston James I JI Goodman Stuart B SB Davis Mark M MM Bendall Sean C SC Fantl Wendy J WJ Angst Martin S MS Nolan Garry P GP

Science translational medicine 20140901 255

Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subse ...[more]

PMID: 25253674

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Project description: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.

Project description:To study the implementation of an enhanced recovery after surgery (ERAS) program at a large University Hospital from "pilot study" to "standard of care".The study was designed as a prospective single centre cohort study. A prospective evaluation of compliance to a protocol based on full application of all ERAS principles, through the progressive steps of its implementation, was performed. Results achieved in the initial pilot study conducted by a dedicated team (n = 47) were compared to those achieved in the shared protocol phase (n = 143) three years later. Outcomes were length of postoperative hospital stay, readmission rate, compliance to the protocol and morbidity. Primary endpoint was the description of the results and the identification of critical issues of large scale implementation of an ERAS program in colorectal surgery emerged in the experience of a single center. Secondary endpoint was the identification of interventions that have been proven to be effective for facilitating the transition from traditional care pathways to a multimodal management protocol according to ERAS principles in colorectal surgery at a single center.During the initial pilot study (March 2009 to December 2010; 47 patients) conducted by a dedicated multidisciplinary team, compliance to the items of ERAS protocol was 93%, with a median length of hospital stay (LOS) of 3 d. Early anastomotic fistulas were observed in 2 cases (4.2%), which required reoperation (Clavien-Dindo grade IIIb). None of the patients had been discharged before the onset of the complication, which could therefore receive prompt treatment. There were also four (8.5%) minor complications (Clavien-Dindo grade II). Thirty days readmission rate was 4%. Perioperative mortality was nil. After implementation of the protocol throughout the Hospital in unselected patients (May 2012 to December 2012; 147 patients) compliance was 74%, with a median LOS of 6 d. Early anastomotic fistulas were observed in 11 cases (7.7%), 5 (3.5%) of which required reoperation (Clavien-Dindo grade IIIb). Two early anastomotic fistulas were treated by radiologic/endoscopic manoeuvres and 4 were treated conservatively. There were also 36 (25.2%) minor complications, 21 (14.7%) of which were Clavien-Dindo grade II and 15 (10.5%) of which were Clavien-Dindo grade?I. Only two patients whose course was adversely affected by the development of an anastomotic leak had been discharged before the onset of the complication itself, requiring readmission. Readmission rate within 30 d was 4%. Perioperative mortality was 1%.Our results confirm that introduction of an ERAS protocol for colorectal surgery allows quicker postoperative recovery and shortens the length of stay compared to historical series.

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Clinical recovery from surgery correlates with single-cell immune signatures.

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Clinical recovery from surgery correlates with single-cell immune signatures.

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