Inflammatory phenotypes after total knee arthroplasty: a testable framework for biomarker-stratified enhanced...

Recovery after total knee arthroplasty (TKA) remains heterogeneous despite mature surgical techniques and standardized enhanced recovery after surgery (ERAS) pathways. Perioperative inflammation offers an unusually actionable basis for stratification because it can be measured before surgery, tracked during recovery, linked to pain, swelling, and quadriceps dysfunction, and modified by available interventions. We advance a three-axis inflammatory phenotype comprising preoperative inflammatory tone, acute response magnitude, and resolution kinetics. Preoperative systemic immune-inflammation index (SII), conventionally calculated from a CBC obtained at a prespecified time point, can contribute to Axis 1, and serial SII may be evaluated as a candidate trajectory; the modified frailty index (mFI) summarizes preoperative deficit burden. The framework tests whether their information is complemented by the joint temporal response to surgical perturbation and the coordination of systemic, local, and functional recovery. The three axes are primarily continuous dimensions; any latent classes are exploratory and require reproducibility across sites. Serial interleukin-6, C-reactive protein, fibrinogen, cytokine-panel, swelling, and temperature studies support these complementary dimensions. Prognostic cohorts connect inflammatory profiles with pain, function, complications, and recovery trajectories, while randomized trials demonstrate that the acute response can be pharmacologically shifted. The framework integrates accessible C-reactive protein and complete blood count-derived ratios with targeted cytokines and local swelling or temperature. Each signal is paired with mechanism-aligned outcomes such as voluntary activation, quadriceps strength, Timed Up and Go performance, and Knee injury and Osteoarthritis Outcome Score domains. The model organizes prospective, safety-gated tests of phenotype-adapted ERAS and rehabilitation, including protocol- or trial-based anti-inflammatory strategies, compression, neuromuscular electrical stimulation, nutritional support, progressive resistance training, and extended supervised rehabilitation. Five prospective predictions link each phenotype axis to a distinct recovery mechanism and intervention response. Multicenter trajectory cohorts can derive and validate the phenotype, followed by biomarker-stratified factorial trials powered for treatment-by-phenotype interaction. This framework converts perioperative inflammation from an isolated laboratory signal into a dynamic recovery phenotype and proposes a testable blueprint for prospective evaluation of adaptive ERAS and precision rehabilitation after TKA. Incremental utility relative to existing indices remains a prospective hypothesis.