Synovial Fluid C-reactive Protein Clinical Decision Limit and Diagnostic Accuracy for Periprosthetic Joint Infection

Abstract

Introduction C-reactive protein (CRP) has long served as a prototypical biomarker for periprosthetic joint infection (PJI). Recently, synovial fluid (SF)-CRP has garnered interest as a diagnostic tool, with several studies demonstrating its diagnostic superiority over serum CRP for the diagnosis of PJI. Although previous studies have identified diagnostic thresholds for SF-CRP, they have been limited in scope and employed various CRP assays without formal validation for PJI diagnosis. This study aimed to conduct a formal single clinical laboratory validation to determine the optimal clinical decision limit of SF-CRP for the diagnosis of PJI. Methods A retrospective analysis of prospectively collected data was performed using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. Synovial fluid samples from hip and knee arthroplasties, received from over 2,600 institutions, underwent clinical testing for PJI at a single clinical laboratory (CD Laboratories, Zimmer Biomet, Towson, MD) between 2017 and 2022. Samples were assayed for SF-CRP, alpha-defensin, white blood cell count, neutrophil percentage, and microbiological culture. After applying selection criteria, the samples were classified with the 2018 ICM PJI scoring system as "infected," "not infected," or "inconclusive." Data were divided into training and validation sets. The Youden Index was employed to optimize the clinical decision limit. Results A total of 96,061 samples formed the training (n = 67,242) and validation (n = 28,819) datasets. Analysis of the biomarker median values, culture positivity, anatomic distribution, and days from aspiration to testing revealed nearly identical specimen characteristics in both the training set and validation set. SF-CRP demonstrated an AUC of 0.929 (95% confidence interval (CI): 0.926-0.932) in the training set, with an optimal SF-CRP clinical decision limit for PJI diagnosis of 4.45 mg/L. Applying this cutoff to the validation dataset yielded a sensitivity of 86.1% (95% CI: 85.0-87.1%) and specificity of 87.1% (95% CI: 86.7-87.5%). No statistically significant difference in diagnostic performance was observed between the validation and training sets. Conclusion This study represents the largest single clinical laboratory evaluation of an SF-CRP assay for PJI diagnosis. The optimal CRP cutoff (4.45 mg/L) for PJI, which yielded a sensitivity of 86.1% and a specificity of 87.1%, is specific to the assay methodology and laboratory performing the assay. We propose that an SF-CRP test with a laboratory-validated optimal clinical decision limit for PJI may be preferable, in a clinical diagnostic setting, to serum CRP tests that do not have laboratory-validated clinical decision limits for PJI.

The False-Positive Rate of Synovial Fluid Culture at a Single Clinical Laboratory Using Culture Bottles

“…First, to allow for categorical classification as "not infected" using a gold standard, a modified 2018 ICM score [11] was calculated based on the minor preoperative criteria from SF (Table 1). The score used in this study was considered a modified score because the serum CRP (threshold = 10 mg/L) was replaced by SF-CRP (threshold = 4.45 mg/L) for scoring [12]. This decision is supported by robust evidence in the literature demonstrating not only a correlation between the serum and SF-CRP but also a consistent demonstration that the SF-CRP is either diagnostically equivalent or superior to the serum CRP [13,14].…”