Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Potential role for immune cell signatures as predictors of acute and chronic pain in adolescents post major musculoskeletal surgery.

Abstract

BACKGROUND: Chronic postsurgical pain (CPSP) poses significant challenges to surgical recovery. Although surgical trauma initiates immune responses, there are critical gaps in understanding immune signatures underlying postsurgical pain and recovery. STUDY OBJECTIVE/DESIGN: This prospective, observational and longitudinal study aimed to understand perioperative immune cell changes and signatures associated with acute and chronic postsurgical pain in youth. PATIENTS: Subjects (>=8 years old) with pectus excavatum undergoing Nuss procedure (n = 140, age 15.8 years (IQR 14.4-17.5), 28 % female). METHODS: Demographics, surgical, psychosocial measures, pain scores and analgesics over postoperative day (POD)0-2 were collected. Subjects were followed for 10-12 months for CPSP outcomes. Peripheral blood mononuclear cells (PBMCs) were collected preoperatively (n = 104) and postoperatively (day 2 [n = 44], week 2 [n = 16]), and high-dimensional flow cytometry was used to characterize immune populations. Outcomes studied were acute (pain area under the curve (AUC) over POD0-2) and chronic (CPSP (pain score > 3/10 beyond 2 months post-surgery) post-surgical pain. Associations between baseline (preoperative) counts of immune cell populations and pain outcomes were analyzed using univariable and multivariable regression analyses with adjustment for covariates (patient, surgical and analgesia factors). Mixed effects models were used to associate longitudinal immune cell counts with pain outcomes. RESULTS: The incidence of CPSP was 37.3 % (37/99). We characterized 29 distinct immune clusters longitudinally. Postsurgical decreases were observed in NK, NKT and T cells and non-classical monocytes, while increases were noted in classical and intermediate monocyte subsets. Regression analyses identified patient (sex, age, pediatric pain screening tool score) and analgesic (use of epidural) characteristics associated with immune cell composition perioperatively. In unadjusted analyses, reduced T cells (beta = -0.284 (SE 0.122), p = 0.02) and B cells (beta = -0.028 (SE 0.01), p = 0.006) predicted greater acute pain. Adjusted analyses revealed AUC was negatively associated with monocyte-T doublet cells (beta = -0.191 [SE 0.10], p = 0.049). While baseline associations with CPSP were not identified, higher female sex representation in CPSP (49 % vs. 18 %, p < 0.001) prompted exploratory sex-stratified analysis. This showed baseline intermediate monocytes were inversely correlated with risk of CPSP in females only (beta = -241.2, p = 0.01). Unadjusted longitudinal analyses revealed AUC was associated with higher activated helper T cells (Central Memory) (beta = 0.185 [SE 0.09], p = 0.045) and lower B cell counts (beta = -0.239 [SE 0.092], p = 0.012). CPSP was associated with higher levels of cytotoxic effector T cells (beta = 0.185 [SE 0.092], p = 0.049). In mixed models, main effects were not significant for either outcome. An interaction between the mature classical monocyte cluster and time demonstrated higher classical monocyte counts in the non-CPSP (beta = 0.14, p = 0.04) and higher AUC (beta = 0.13, p = 0.04) groups, leading us to hypothesize that monocyte-associated acute inflammation may be necessary for pain resolution. CONCLUSIONS: Our findings suggest that immune cell signatures are potentially useful as biomarkers, prognostic indicators, and guides for personalized surgical recovery in youth.