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      The Alpha-defensin Test for Periprosthetic Joint Infection Outperforms the Leukocyte Esterase Test Strip

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          Abstract

          Background

          Synovial fluid biomarkers have demonstrated diagnostic accuracy surpassing the currently used diagnostic tests for periprosthetic joint infection (PJI).

          Questions/purposes

          The purpose of this study is to directly compare the sensitivity and specificity of the synovial fluid α-defensin immunoassay to the leukocyte esterase (LE) colorimetric test strip.

          Methods

          Synovial fluid was collected from 46 patients meeting the inclusion criteria of this prospective diagnostic study. Synovial fluid samples were tested with both a novel synovial-fluid-optimized immunoassay for α-defensin and the LE colorimetric test strip. The Musculoskeletal Infection Society (MSIS) definition was used to classify 23 periprosthetic infections and 23 aseptic failures; this classification was used as the standard against which the two diagnostic tests were compared.

          Results

          The synovial fluid α-defensin immunoassay correctly predicted the MSIS classification of all patients in the study, demonstrating a sensitivity and specificity of 100% for the diagnosis of PJI. The α-defensin assay could be read for all samples, including those with blood in the synovial fluid. The leukocyte esterase test strip could not be interpreted in eight of 46 samples (17%) as a result of blood interference. Analysis of the LE strips that could be interpreted yielded a sensitivity of 69% and a specificity of 100%.

          Conclusions

          The synovial fluid α-defensin immunoassay outperformed the LE colorimetric test strip in this study and provided reliable results even when the LE test strip failed as a result of blood interference. The simple analytic results provided by the α-defensin immunoassay, compared with the more complex and interpretive nature of both the MSIS criteria and LE colorimetric test strip, make it a highly attractive diagnostic tool.

          Level of Evidence

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

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          Most cited references10

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          Defensins. Natural peptide antibiotics of human neutrophils.

          T Ganz, M E Selsted, D Szklarek … (1985)
          We extracted a granule-rich sediment from normal human neutrophils and subjected it to chromatographic, electrophoretic, and functional analysis. The extract contained three small (molecular weight less than 3,500) antibiotic peptides that were named human neutrophil peptide (HNP)-1, HNP-2, and HNP-3, and which will be referred to as "defensins." HNP 1-3, a mixture of the three defensins, killed Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli effectively in vitro when tested in 10 mM phosphate buffer containing certain nutrients, but it had little or no bactericidal activity in nutrient-free buffer. In contrast, the nutrient-free buffer supported a high degree of activity by HNP 1-3 against Cryptococcus neoformans. In addition to its antibacterial and antifungal properties, HNP 1-3 directly inactivated herpes simplex virus, Type 1. Two of the individual purified defensins, HNP-1 and HNP-2, were as microbicidal as the mixture HNP 1-3. HNP-3 was less active than the other defensins against most but not all of the microbes tested. Immunoperoxidase stains revealed HNP 1-3 to have a granular localization in the neutrophil's cytoplasm by light microscopy. Frozen thin section immunogold transmission electron microscopy showed HNP 1-3 to be localized in azurophil granules. These studies define a broad-spectrum antimicrobial system in human neutrophils. The defensin system may operate in conjunction with or independently from oxygen-dependent microbicidal processes to enable human neutrophils to inactivate and destroy potential pathogens.
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            Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme.

            Javad Parvizi, Elie Ghanem, Valentin Antoci … (2011)
            The white blood-cell count and neutrophil differential of the synovial fluid have been reported to have high sensitivity and specificity in the diagnosis of periprosthetic infection following total knee arthroplasty. We hypothesized that neutrophils recruited into an infected joint secrete enzymes that may be used as markers for infection. In this prospective study, we determined the sensitivity and specificity of one of these enzymes, leukocyte esterase, in diagnosing periprosthetic joint infection. Between May 2007 and April 2010, synovial fluid was obtained preoperatively from the knees of patients with a possible joint infection and intraoperatively from the knees of patients undergoing revision knee arthroplasty. The aspirate was tested for the presence of leukocyte esterase with use of a simple colorimetric strip test. The color change (graded as negative, trace, +, or ++), which corresponded to the level of the enzyme, was noted after one or two minutes. On the basis of clinical, serological, and operative criteria, thirty of the 108 knees undergoing revision arthroplasty were infected and seventy-eight were uninfected. When only a ++ reading was considered positive, the leukocyte esterase test was 80.6% sensitive (95% confidence interval [CI], 61.9% to 91.9%) and 100% specific (95% CI, 94.5% to 100.0%), with a positive predictive value of 100% (95% CI, 83.4% to 100.0%) and a negative predictive value of 93.3% (95% CI, 85.4% to 97.2%). The leukocyte esterase level correlated strongly with the percentage of polymorphonuclear leukocytes (r = 0.7769) and total white blood-cell count (r = 0.5024) in the aspirate as well as with the erythrocyte sedimentation rate (r = 0.6188) and C-reactive protein level (r = 0.4719) in the serum. The simple colorimetric strip test that detects the presence of leukocyte esterase in synovial fluid appears to be an extremely valuable addition to the physician's armamentarium for the diagnosis of periprosthetic joint infection. The leukocyte esterase reagent strip has the advantages of providing real-time results, being simple and inexpensive, and having the ability to both rule out and confirm periprosthetic joint infection. However, additional multicenter studies are required to substantiate the results of our preliminary investigation before the reagent strip can be used confidently in the clinic or intraoperative setting.
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              Antimicrobial peptides and proinflammatory cytokines in periprosthetic joint infection.

              Yvonne Dombrowski, M Perić, Rüdiger von Kries … (2013)
              Differentiation between septic and aseptic loosening of joint replacements is essential for successful revision surgery, but reliable markers for the diagnosis of low-grade infection are lacking. The present study was performed to assess intra-articular and systemic levels of antimicrobial peptides and proinflammatory cytokines as diagnostic markers for periprosthetic joint infection. Fifteen consecutive patients with staphylococcal periprosthetic joint infections and twenty control patients with aseptic loosening of total hip and knee replacements were included in this prospective, single-center, controlled clinical trial. Expression of the antimicrobial peptides human β-defensin-2 (HBD-2), human β-defensin-3 (HBD-3), and cathelicidin LL-37 (LL-37) was determined by ELISA (enzyme-linked immunosorbent assay) in serum and joint aspirates. Proinflammatory cytokines were assessed in serum and joint aspirates with use of cytometric bead arrays. C-reactive protein in serum, microbiology, and histopathology of periprosthetic tissue served as the "gold standard" for the diagnosis of infection. The antimicrobial peptides HBD-3 and LL-37 were significantly elevated in joint aspirates from patients with periprosthetic joint infection compared with patients with aseptic loosening, and the area under the curve (AUC) in a receiver operating characteristic curve analysis was equal to 0.745 and 0.875, respectively. Additionally, significant local increases in the proinflammatory cytokines interleukin (IL)-1β, IL-4, IL-6, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were observed to be associated with infection. Logistic regression analysis indicated that the combination of an antimicrobial peptide with another synovial fluid biomarker improved diagnostic accuracy; the AUC value was 0.916 for LL-37 and IL-4, 0.895 for LL-37 and IL-6, 0.972 for HBD-3 and IL-4, and 0.849 for HBD-3 and IL-6. In contrast, the only antimicrobial peptides and cytokines in serum that showed a significant systemic increase in association with infection were HBD-2, IL-4, and IL-6 (all of which had an AUC value of <0.75). The present study showed promising results for the use of antimicrobial peptides and other biomarkers in synovial fluid for the diagnosis of periprosthetic joint infection, and analysis of the levels in synovial fluid was more accurate than analysis of serum.
              Article 0 comments Cited 48 times – based on 0 reviews     Review now
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                Author and article information

                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): 19 June 2014
                Publication date PMC-release: 19 June 2014
                Publication date (Print): January 2015
                Volume: 473
                Issue: 1
                Pages: 198-203
                Affiliations
                [ ]CD Diagnostics Inc, Lankenau Institute for Medical Research, The Rothman Institute, 100 Lancaster Avenue, MOB 456, Wynnewood, PA 19096 USA
                [ ]The Rothman Institute, Thomas Jefferson University, Philadelphia, PA USA
                [ ]Aria 3B Orthopaedic Specialists, Philadelphia, PA USA
                Article
                Publisher ID: 3722
                DOI: 10.1007/s11999-014-3722-7
                PMC ID: 4390923
                PubMed ID: 24942960
                SO-VID: a96c5fa7-cf10-48ad-aed0-0ba340c1774e
                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: 2014 Knee Society Proceedings
                Custom metadata
                issue-copyright-statement © The Association of Bone and Joint Surgeons® 2015

                ScienceOpen disciplines: Orthopedics
                Data availability:
                ScienceOpen disciplines: Orthopedics

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