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

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Abstract
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 (≥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. Author Summary: In this study, we explored why recovery after knee replacement surgery varies so widely among older adults. While many people regain mobility and experience pain relief, others continue to struggle with discomfort and limited function. We asked whether differences in the immune system before surgery might help explain these outcomes. To do this, we measured a wide range of immune signals in blood samples collected before surgery and then followed participants over several months, tracking their pain, daily activities, and physical movement. We found that patterns in these immune signals were linked to how well people recovered. Importantly, some of the signals that predicted pain recovery were different from those linked to improvements in physical function, suggesting that these aspects of recovery are driven by distinct biological processes. Our findings place the immune system at the center of recovery from major surgery and highlight its potential as a tool for identifying who may need more support. In the future, this knowledge could help guide more personalized approaches to care and improve recovery for older adults undergoing surgery. Graphical Overview of the PRIME-KNEE Study Workflow and Immune Signatures Predicting Postoperative Resilience.: Pre-operative blood was collected from older adults undergoing elective total knee arthroplasty. Whole blood was incubated under three conditions—unstimulated (NULL), lipopolysaccharide (LPS), or influenza antigen (FLU)—using the TruCulture® system to assess dynamic immune responsiveness. Forty-five pro- and anti-inflammatory biomarkers were quantified in plasma and stimulated culture supernatants. Postoperative pain, pain interference, lower-extremity physical activities of daily living (LE-PADLs), and step counts were used to derive two resilience metrics: Expected Recovery Differential (ERD) and Resilience Trajectory (RT). Stability-selection LASSO models identified pre-operative immune predictors of postoperative resilience. Panels A and B illustrate distinct immune signatures associated with pain versus functional outcomes. Panel A: Pain-related predictors (IFN-α2a, IL-15, IL-1Ra, LBP, LIF, SAA) cluster around local inflammatory and neuroimmune pathways implicated in nociceptor sensitization. Panel B: Function-related predictors (CRP, eotaxin, gp130, IL-6) reflect systemic inflammatory load and broad cytokine signaling associated with reduced functional capacity. Together, these findings highlight biologically distinct immune pathways underlying pain and functional recovery after knee arthroplasty. Graphic created in BioRender.

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