Synovial based tests outperform serum markers to rule out infection in total knee arthroplasty and total hip arthroplasty: A systematic review and meta-analysis.

Published:December 21, 2021DOI:



      Total knee arthroplasty provides successful results in most patients. Periprosthetic joint infection accounts for up to 25% of failed TKAs needing revision. In clinical practice, consensus in diagnostic strategy for excluding or diagnosing PJI is still lacking. In this systematic review and meta-analysis we aim to provide a simplified data driven diagnostic strategy for aseptic knee and hip revision surgeons to rule out PJI in the outpatient clinic phase.


      A literature search in EMBASE, Medline, Pubmed and Cochrane was conducted. Studies involving the diagnosis of PJI in patients with failed TKA’s and THA’s needing revision were identified. Only studies using the MSIS criteria were included. Quality was assessed using MINORS criteria. Meta-analysis was performed for each diagnostic test identified in the included studies. Pooled estimates of diagnostic accuracy measures were calculated using a bivariate model and plotted in summary receiver operator characteristic curves. Positive and negative predictive values were calculated in a hypothetical sample of patients with a given disease prevalence.


      24 studies met the inclusion criteria, describing a total of 2,974 patients. Quality scores ranged from 13-19. Meta-analysis could be performed on 7 unique diagnostic tests. Highest pooled sensitivity and specificity was demonstrated for α-defensin with values of 86% and 96.6% respectively. α-defensin and white blood cell count in synovial fluid demonstrate highest NPV values.


      We recommend, in a clinical setting with low-intermediate prevalence of PJI, performing arthrocentesis and joint fluid analysis using α-defensin and/or white blood cell count prior to revision TKA and revision THA surgery to rule out PJI.


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        • Schiffner E.
        • Latz D.
        • Karbowski A.
        • et al.
        Loosening of total knee arthroplasty – always aseptic?.
        J Clin Orthop Trauma. 2020; 11: S234-S238
      1. the Dutch Arthroplasty Register (LROI).

        • Scholten R.
        • Visser J.
        • Van Susante J.L.C.
        • Van Loon C.J.M.
        Low sensitivity of a-defensin (Synovasure) test for intra-operative exclusion of prosthetic joint infection.
        Acta Orthop. 2018; 89: 357-359
        • Parvizi J.
        • Zmistowski B.
        • Berbari E.F.
        • et al.
        New definition for periprosthetic joint infection: From the workgroup of the musculoskeletal infection society.
        Clin Orthop Relat Res. 2011; 469: 2992-2994
        • Carli A.V.
        • Abdelbary H.
        • Ahmadzai N.
        • et al.
        Diagnostic Accuracy of Serum, Synovial, and Tissue Testing for Chronic Periprosthetic Joint Infection after Hip and Knee Replacements: A Systematic Review.
        J Bone Jt Surg - Am. 2019; 101: 635-649
        • Lee Y.S.
        • Koo K.
        • Kim H.J.
        • Tian S.
        Synovial Fluid Biomarkers for the Diagnosis of Periprosthetic Joint Infection.
        J Bone Jt Surg. 2017; (Published online): 2077-2084
        • McInnes M.D.F.
        • Moher D.
        • Thombs B.D.
        • et al.
        Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies The PRISMA-DTA Statement.
        JAMA - J Am Med Assoc. 2018; 319: 388-396
        • Parvizi J.
        • Gehrke T.
        • Chen A.F.
        Proceedings of the International Consensus on Periprosthetic Joint Infection.
        Bone Joint J. 2013; (Published online): 1450-1452
        • Slim Karem
        • Nini E.
        • Forestier D.
        • Kwiatkowski F.
        • Panis Y.
        • Chiponi J.
        ANZ J Surg. 2003; : 712-716
        • Reitsma J.B.
        • Glas A.S.
        • Rutjes A.W.
        Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews.
        J Clin Epidemiol. 2005; 58: 982-990
      2. Cochrane Methods. Cochrane handbook for DTA reviews. Published online 2013.

      3. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Published online 2021.

        • Deeks J.J.
        • Macaskill P.
        • Irwig L.
        The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed.
        J Clin Epidemiol. 2006; 58: 882-893
      4. The Cochrane Collaboration. Review Manager (RevMan) [Computer program]. Published online 2020.

      5. Victoria Nyawira Nyaga. “METADTA: Stata module to perform fixed- and random-effects meta-analysis and meta-regression of diagnostic accuracy studies” Statistical Software Components S458794, Boston College Department of Economics, revised 01 May 2021. Published online 2020.

      6. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Published online 2020.

        • Xiong L.
        • Li S.
        • Dai M.
        Comparison of D-dimer with CRP and ESR for diagnosis of periprosthetic joint infection.
        J Orthop Surg Res. 2019; 14: 240
        • Ansar W.
        • Ghosh S.
        C-reactive protein and the biology of disease.
        Immunol Res. 2013; 56: 131-142
        • Schulak D.J.
        • Convery R.
        The Erythrocyte Sedimentation Rate in Orthopaedic Patients.
        Clin Orthop Relat Res. 1982; (Published online): 197-202
        • Saleh A.
        • George J.
        • Faour M.
        • Klika A.K.
        • Higuera C.A.
        Serum biomarkers in periprosthetic joint infections.
        Bone Jt Res. 2020; 7: 85-93
        • Leeflang M.M.G.
        • Bossuyt P.M.M.
        • Irwig L.
        Diagnostic test accuracy may vary with prevalence : implications for evidence-based diagnosis.
        J Clin Epidemiol. 2009; 62: 5-12
        • Qin L.
        • Li F.
        • Gong X.
        • Wang J.
        • Huang W.
        • Hu N.
        Combined Measurement of D-Dimer and C-Reactive Protein Levels: Highly Accurate for Diagnosing Chronic Periprosthetic Joint Infection.
        J Arthroplasty. 2020; 35: 229-234
        • Sousa R.
        • Serrano P.
        • Gomes Dias J.
        • Oliveira J.C.
        • Oliveira A.
        Improving the accuracy of synovial fluid analysis in the diagnosis of prosthetic joint infection with simple and inexpensive biomarkers: C-reactive protein and adenosine deaminase.
        Bone Joint J. 2017; 99-B: 351-357
        • Elgeidi A.
        • Elganainy A.E.
        • Abou Elkhier N.
        • Rakha S.
        Interleukin-6 and other inflammatory markers in diagnosis of periprosthetic joint infection.
        Int Orthop. 2014; 38: 2591-2595
        • Randau T.M.
        • Friedrich M.J.
        • Wimmer M.D.
        • et al.
        Interleukin-6 in serum and in synovial fluid enhances the differentiation between periprosthetic joint infection and aseptic loosening.
        PLoS One. 2014; 9
        • Ettinger M.
        • Calliess T.
        • Kielstein J.T.
        • et al.
        Circulating biomarkers for discrimination between aseptic joint failure, low-grade infection, and high-grade septic failure.
        Clin Infect Dis. 2015; 61: 332-341
      7. Bonanzinga T, Zahar A, Dütsch M, Lausmann C, Kendoff D, Gehrke T. How Reliable Is the Alpha-defensin Immunoassay Test for Diagnosing Periprosthetic Joint Infection ? A Prospective Study. Published online 2016. doi:10.1007/s11999-016-4906-0

        • Kasparek M.F.
        • Kasparek M.
        • Boettner F.
        • Faschingbauer M.
        • Hahne J.
        • Dominkus M.
        Intraoperative Diagnosis of Periprosthetic Joint Infection Using a Novel Alpha-Defensin Lateral Flow Assay.
        J Arthroplasty. 2016; 31: 2871-2874
        • Frangiamore S.J.
        • Gajewski N.D.
        • Saleh A.
        • Farias-Kovac M.
        • Barsoum W.K.
        • Higuera C.A.
        α-Defensin Accuracy to Diagnose Periprosthetic Joint Infection-Best Available Test?.
        J Arthroplasty. 2016; 31: 456-460
        • Sousa R.
        • Serrano P.
        • Gomes Dias J.
        • Oliveira J.C.
        • Oliveira A.
        Improving the accuracy of synovial fluid analysis in the diagnosis of prosthetic joint infection with simple and inexpensive biomarkers.
        Bone Jt J. 2017; 99B: 351-357
        • Sigmund I.K.
        • Holinka J.
        • Gamper J.
        • et al.
        Qualitative α-defensin test (Synovasure) for the diagnosis of periprosthetic infection in revision total joint arthroplasty.
        Bone Joint J. 2017; 99-B: 66-72
        • Renz N.
        • Yermak K.
        • Perka C.
        • Trampuz A.
        Alpha defensin lateral flow test for diagnosis of periprosthetic joint infection: Not a screening but a confirmatory test.
        J Bone Jt Surg - Am. 2018; 100: 742-750
        • Balato G.
        • Franceschini V.
        • Ascione T.
        • et al.
        High performance of α-defensin lateral flow assay (Synovasure) in the diagnosis of chronic knee prosthetic infections.
        Knee Surg Sports Traumatol Arthrosc. 2018; 26: 1717-1722
        • Balato G.
        • Franceschini V.
        • Ascione T.
        • Lamberti A.
        • Balboni F.
        • Baldini A.
        Diagnostic accuracy of synovial fluid, blood markers, and microbiological testing in chronic knee prosthetic infections.
        Arch Orthop Trauma Surg. 2018; 138: 165-171
        • Kanwar S.
        • Al-Mansoori A.A.
        • Chand M.R.
        • Villa J.M.
        • Suarez J.C.
        • Patel P.D.
        What Is the Optimal Criteria to Use for Detecting Periprosthetic Joint Infections Before Total Joint Arthroplasty?.
        J Arthroplasty. 2018; 33: S201-S204
        • Kleiss S.
        • Jandl N.M.
        • Novo de Oliveira A.
        • Rüther W.
        • Niemeier A.
        Diagnostic accuracy of alpha-defensin enzyme-linked immunosorbent assay in the clinical evaluation of painful hip and knee arthroplasty with possible prosthetic joint infection: A prospective study of 202 cases.
        Bone Jt J. 2019; 101 B: 970-977
        • Xu H.
        • Xie J.
        • Huang Q.
        • Lei Y.
        • Zhang S.
        • Pei F.
        Plasma Fibrin Degradation Product and D-Dimer Are of Limited Value for Diagnosing Periprosthetic Joint Infection.
        J Arthroplasty. 2019; 34: 2454-2460
        • Fu J.
        • Ni M.
        • Chai W.
        • Li X.
        • Hao L.
        • Chen J.
        Synovial Fluid Viscosity Test is Promising for the Diagnosis of Periprosthetic Joint Infection.
        J Arthroplasty. 2019; 34: 1197-1200
      8. Deirmengian CA, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Combined measurement of synovial fluid α-Defensin and C-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection. Published online 2014:1439-1445. doi:10.2106/JBJS.M.01316

        • Klim S.M.
        • Amerstorfer F.
        • Gruber G.
        • et al.
        Fibrinogen – A Practical and Cost Efficient Biomarker for Detecting Periprosthetic Joint Infection.
        Sci Rep. 2018. November 2017; : 1-6
        • Gehrke T.
        • Lausmann C.
        • Citak M.
        • Bonanzinga T.
        • Frommelt L.
        • Zahar A.
        The Accuracy of the Alpha Defensin Lateral Flow Device for Diagnosis of Periprosthetic Joint Infection: Comparison with a Gold Standard.
        J Bone Joint Surg Am. 2018; 100: 42-48
        • Li R.
        • Shao H.Y.
        • Hao L.B.
        • et al.
        Plasma Fibrinogen Exhibits Better Performance Than Plasma D-Dimer in the Diagnosis of Periprosthetic Joint Infection: A Multicenter Retrospective Study.
        J Bone Jt Surg - Am. 2019; 101: 613-619
        • Qin L.
        • Li F.
        • Gong X.
        • Wang J.
        • Huang W.
        • Hu N.
        Combined Measurement of D-Dimer and C-Reactive Protein Levels: Highly Accurate for Diagnosing Chronic Periprosthetic Joint Infection.
        J Arthroplasty. 2020; 35: 229-234
        • Qin L.
        • Hu N.
        • Li X.
        Evaluation of synovial fluid neutrophil CD64 index as a screening biomarker of prosthetic joint infection.
        Bone Jt J. 2020; 102 B: 463-469