Immune Biomarker Signatures as Predictors of Functional and Pain Recovery After Total Knee Arthroplasty in Older Adults

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles, measured in plasma and through ex vivo whole blood stimulation, predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (greater or equal to 60 years) in the PRIME KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower extremity physical activities of daily living (LE PADLs), and step counts. An exploratory stability selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers, including LBP, leptin, TNFR1, CD30, and LIF, was consistently selected across models. Immune predictors explained ~12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain related predictors mapped to local inflammatory and neuroimmune pathways, whereas function related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain related and function related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune based perioperative risk assessment.