Complement factors C3 and C5 as tissue biomarkers for differentiating periprosthetic joint infection from aseptic implant failure

Background: The diagnosis of periprosthetic joint infection (PJI), and particularly low-grade ((LG) PJI) infections, remains a clinical challenge. Systemic inflammatory markers sometimes yield false-negative results in inapparent cases, complicating the differentiation from aseptic loosening (AL). This exploratory study evaluated tissue-based complement factors C3 and C5 as biomarkers compared to terminal factor C9 and established systemic parameters. Methods: Fifty-five patients undergoing revision arthroplasty were categorized into high-grade PJI (HG) PJI, N = 20), (LG) PJI (N = 14), and AL (N = 21). Serum parameters (C-reactive protein (CRP), white blood cells (WBC)) were analyzed by immunohistochemistry for tissue-based C3, C5, and C9. Diagnostic performance was assessed via ROC analysis. Results: Pathogen spectra differed significantly, with (LG) PJI dominated by Cutibacterium acnes and (HG) PJI by staphylococci. ROC analysis showed that serum CRP accurately identified (HG) -PJI, but failed in (LG) PJI. WBC demonstrated limited accuracy. In contrast, C3 detection in tissues exhibited superior performance, particularly for identifying (LG) PJI versus (HG) PJI. C5 detection remained robust in both PJI types. Terminal factor C9 yielded lower overall discrimination and significant cross-reactivity in AL cases. Conclusions: Central complement factors C3 and C5 serve as robust tissue biomarkers for PJI, outperforming C9 and systemic parameters. Their implementation may improve clinical decision-making, especially in (LG) PJI cases, where standard diagnostic criteria remain inconclusive.