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      Diagnosing Periprosthetic Joint Infection: Has the Era of the Biomarker Arrived?

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          Abstract

          Background

          The diagnosis of periprosthetic joint infection (PJI) remains a serious clinical challenge. There is a pressing need for improved diagnostic testing methods; biomarkers offer one potentially promising approach.

          Questions/purposes

          We evaluated the diagnostic characteristics of 16 promising synovial fluid biomarkers for the diagnosis of PJI.

          Methods

          Synovial fluid was collected from 95 patients meeting the inclusion criteria of this prospective diagnostic study. All patients were being evaluated for a revision hip or knee arthroplasty, including patients with systemic inflammatory disease and those already receiving antibiotic treatment. The Musculoskeletal Infection Society (MSIS) definition was used to classify 29 PJIs and 66 aseptic joints. Synovial fluid samples were tested by immunoassay for 16 biomarkers optimized for use in synovial fluid. Sensitivity, specificity, and receiver operating characteristic curve analysis were performed to assess for diagnostic performance.

          Results

          Five biomarkers, including human α-defensin 1-3, neutrophil elastase 2, bactericidal/permeability-increasing protein, neutrophil gelatinase-associated lipocalin, and lactoferrin, correctly predicted the MSIS classification of all patients in this study, with 100% sensitivity and specificity for the diagnosis of PJI. An additional eight biomarkers demonstrated excellent diagnostic strength, with an area under the curve of greater than 0.9.

          Conclusions

          Synovial fluid biomarkers exhibit a high accuracy in diagnosing PJI, even when including patients with systemic inflammatory disease and those receiving antibiotic treatment. Considering that these biomarkers match the results of the more complex MSIS definition of PJI, we believe that synovial fluid biomarkers can be a valuable addition to the methods utilized for the diagnosis of infection.

          Level of Evidence

          Level II, diagnostic study. See Instructions for Authors for a complete description of levels of evidence.

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          Most cited references33

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          Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.

          Abderrazzaq Belaaouaj, Ronald McCarthy, Mary Baumann … (1998)
          Neutrophil elastase (NE) is a potent serine proteinase whose expression is limited to a narrow window during myeloid development. In neutrophils, NE is stored in azurophil granules along with other serine proteinases (cathepsin G, proteinase 3 and azurocidin) at concentrations exceeding 5 mM. As a result of its capacity to efficiently degrade extracellular matrix, NE has been implicated in a variety of destructive diseases. Indeed, while much interest has focused on the pathologic effects of this enzyme, little is known regarding its normal physiologic function(s). Because previous in vitro data have shown that NE exhibits antibacterial activity, we investigated the role of NE in host defense against bacteria. Generating strains of mice deficient in NE (NE-/-) by targeted mutagenesis, we show that NE-/- mice are more susceptible than their normal littermates to sepsis and death following intraperitoneal infection with Gram negative (Klebsiella pneumoniae and Escherichia coli) but not Gram positive (Staphylococcus aureus) bacteria. Our data indicate that neutrophils migrate normally to sites of infection in the absence of NE, but that NE is required for maximal intracellular killing of Gram negative bacteria by neutrophils.
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            Inflammatory blood laboratory levels as markers of prosthetic joint infection: a systematic review and meta-analysis.

            Mark J Spangehl, Daniel P Erwin, James M. Steckelberg … (2010)
            The preoperative diagnosis of prosthetic joint infection in patients with a total hip or knee arthroplasty may rely in part on the use of systemic inflammation markers. These markers have unclear accuracy. The objective of this review was to summarize the evidence on the accuracy of the peripheral white blood-cell count, the erythrocyte sedimentation rate, serum C-reactive protein levels, and serum interleukin-6 levels for the diagnosis of prosthetic joint infection. We searched electronic databases (MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus) from 1950 through 2009. Eligible studies evaluated the accuracy of white blood-cell count, erythrocyte sedimentation rate, serum C-reactive protein level, and serum interleukin-6 level for the intraoperative diagnosis of prosthetic joint infection at the time of revision arthroplasty. Two reviewers working independently extracted study characteristics and data to estimate the diagnostic odds ratio and 95% confidence interval for each result. We included thirty eligible studies that included 3909 revision total hip or knee arthroplasties. The prevalence of prosthetic joint infection was 32.5% (1270 of 3909). The accuracy of assessed inflammation markers, represented with a diagnostic odds ratio, was 314.7 (95% confidence interval, 113.0 to 876.8) for interleukin-6 (three studies), 13.1 (95% confidence interval, 7.9 to 21.7) for C-reactive protein level (twenty-three studies), 7.2 (95% confidence interval, 4.7 to 10.9) for erythrocyte sedimentation rate (twenty-five studies), and 4.4 (95% confidence interval, 2.9 to 6.6) for white blood-cell count (fifteen studies). The diagnostic accuracy for prosthetic joint infection was best for interleukin-6, followed by C-reactive protein level, erythrocyte sedimentation rate, and white blood-cell count. Given the limited numbers of studies assessing interleukin-6 levels, further investigations assessing the accuracy of interleukin-6 for the diagnosis of prosthetic joint infection are warranted.
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              Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty.

              S Sporer, Wayne Paprosky, Mark Schinsky … (2008)
              While multiple tests are used to determine the presence of infection at the site of a total hip arthroplasty, few studies have applied a consistent algorithm to determine the utility of the various tests that are available. The purpose of the present study was to evaluate the utility of commonly available tests for determining the presence of periprosthetic infection in patients undergoing revision total hip arthroplasty. Two hundred and thirty-five consecutive total hip arthroplasties in 220 patients were evaluated by one of two surgeons using a consistent algorithm to identify infection and were treated with reoperation. Receiver-operating-characteristic curve analysis was used to determine the optimal cut-point values for the white blood-cell count and the percentage of polymorphonuclear cells of intraoperatively aspirated hip synovial fluid. Sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were determined. Patients were considered to have an infection if two of three criteria were met; the three criteria were a positive intraoperative culture, gross purulence at the time of reoperation, and positive histopathological findings. Thirty-four arthroplasties were excluded because of the presence of a draining sinus, incomplete data, or a preoperative diagnosis of inflammatory arthritis, leaving 201 total hip arthroplasties available for evaluation. Fifty-five hips were judged to be infected. No hip in a patient with a preoperative erythrocyte sedimentation rate of 4200 white blood cells/mL for the white blood-cell count and >80% polymorphonuclear cells for the differential count. However, when combined with an elevated erythrocyte sedimentation rate and C-reactive protein level, the optimal cut-point for the synovial fluid cell count was >3000 white blood cells/mL, which yielded the highest combined sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the tests studied. A synovial fluid cell count of >3000 white blood cells/mL was the most predictive perioperative testing modality in our study for determining the presence of periprosthetic infection when combined with an elevated preoperative erythrocyte sedimentation rate and C-reactive protein level in patients undergoing revision total hip arthroplasty.
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                Author and article information

                Contributors
                Carl Deirmengian: carl.deirmengian@rothmaninstitute.com
                Journal
                Journal ID (nlm-ta): Clin Orthop Relat Res
                Journal ID (iso-abbrev): Clin. Orthop. Relat. Res
                Title: Clinical Orthopaedics and Related Research
                Publisher: Springer US (Boston )
                ISSN (Print): 0009-921X
                ISSN (Electronic): 1528-1132
                Publication date (Electronic): 4 March 2014
                Publication date PMC-release: 4 March 2014
                Publication date (Print): November 2014
                Volume: 472
                Issue: 11
                Pages: 3254-3262
                Affiliations
                [ ]CD Diagnostics Inc, Lankenau Institute for Medical Research, 100 Lancaster Avenue, MOB 456, Wynnewood, PA 19096 USA
                [ ]The Rothman Institute, Thomas Jefferson University, Philadelphia, PA USA
                Article
                Publisher ID: 3543
                DOI: 10.1007/s11999-014-3543-8
                PMC ID: 4182392
                PubMed ID: 24590839
                SO-VID: 0a418c48-ed67-4895-b900-1c9a8556ea99
                Copyright © © The Author(s) 2014
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Categories
                Subject: Symposium: 2013 Musculoskeletal Infection Society
                Custom metadata
                issue-copyright-statement © The Association of Bone and Joint Surgeons® 2014

                ScienceOpen disciplines: Orthopedics
                Data availability:
                ScienceOpen disciplines: Orthopedics

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