Background: Chronic periprosthetic joint infection (PJI) is a devastating complication that can occur following total joint replacement. Patients with chronic PJI report a substantially lower quality of life and face a higher risk of short-term mortality. Establishing a diagnosis of chronic PJI is challenging because of conflicting guidelines, numerous tests, and limited evidence. Delays in diagnosing PJI are associated with poorer outcomes and morbid revision surgery. The purpose of this systematic review was to compare the diagnostic accuracy of serum, synovial, and tissue-based tests for chronic PJI. Methods: This review adheres to the Cochrane Collaboration’s diagnostic test accuracy methods for evidence searching and syntheses. A detailed search of MEDLINE, Embase, the Cochrane Library, and the grey literature was performed to identify studies involving the diagnosis of chronic PJI in patients with hip or knee replacement. Eligible studies were assessed for quality and bias using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Meta-analyses were performed on tests with sufficient data points. Summary estimates and hierarchical summary receiver operating characteristic (HSROC) curves were obtained using a bivariate model. Results: A total of 12,616 citations were identified, and 203 studies met the inclusion criteria. Of these 203 studies, 170 had a high risk of bias. Eighty-three unique PJI diagnostic tests were identified, and 17 underwent meta-analyses. Laboratory-based synovial alpha-defensin tests and leukocyte esterase reagent (LER) strips (2+) had the best performance, followed by white blood-cell (WBC) count, measurement of synovial C-reactive protein (CRP) level, measurement of the polymorphonuclear neutrophil percentage (PMN%), and the alpha-defensin lateral flow test kit (Youden index ranging from 0.78 to 0.94). Tissue-based tests and 3 serum tests (measurement of interleukin-6 [IL-6] level, CRP level, and erythrocyte sedimentation rate [ESR]) had a Youden index between 0.61 to 0.75 but exhibited poorer performance compared with the synovial tests mentioned above. Conclusions: The quality of the literature pertaining to chronic PJI diagnostic tests is heterogeneous, and the studies are at a high risk for bias. We believe that greater transparency and more complete reporting in studies of diagnostic test results should be mandated by peer-reviewed journals. The available literature suggests that several synovial fluid-based tests perform well for diagnosing chronic PJI and their use is recommended in the work-up of any suspected case of chronic PJI. Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

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