Serum IL-6 in combination with synovial IL-6/CRP shows excellent diagnostic power to detect hip and knee prosthetic joint infection

RESEARCH ARTICLE Serum IL-6 in combination with synovial IL-6/ CRP shows excellent diagnostic power to detect hip and knee prosthetic joint infection Jiri Gallo1*, Michal Svoboda1, Jana Zapletalova2, Jitka Proskova3, Jarmila Juranova4 1 Department of Orthopaedics, Teaching Hospital Olomouc, Faculty of Medicine, Palacky University Olomouc, Olomouc, Czech Republic, 2 Department of Medical Biophysics, Faculty of Medicine, Palacky University Olomouc, Olomouc, Czech Republic, 3 Department of Clinical Biochemistry, Teaching Hospital Olomouc, Olomouc, Czech Republic, 4 Department of Hemato-Oncology, Teaching Hospital Olomouc, Faculty of Medicine, Palacky University Olomouc, Olomouc, Czech Republic a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 * Abstract Background OPEN ACCESS Citation: Gallo J, Svoboda M, Zapletalova J, Proskova J, Juranova J (2018) Serum IL-6 in combination with synovial IL-6/CRP shows excellent diagnostic power to detect hip and knee prosthetic joint infection. PLoS ONE 13(6): e0199226. https://doi.org/10.1371/journal. pone.0199226 Editor: Hiroyuki Tsuchiya, Kanazawa University, JAPAN The diagnosis of prosthetic joint infection (PJI) is still a challenge in some patients after total joint replacement. Interleukin-6 (IL-6) strongly participates in the arrangement of the hostbacteria response. Therefore, increased levels of IL-6 should accompany every PJI. Purpose The aim of the study was to show diagnostic characteristics of serum IL-6 for the diagnosis of prosthetic joint infection (PJI). We also compared the diagnostic values of serum IL-6 with synovial IL-6 (sIL-6) and synovial C-reactive protein (sCRP). Received: February 4, 2018 Accepted: June 4, 2018 Published: June 21, 2018 Copyright: © 2018 Gallo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The corresponding author received grant support from the Agency of Health Research, Ministry of Health Czech Republic project No. VES 17-29680A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Study design We performed a prospective study of 240 patients in whom serum IL-6 was determined before total hip (n = 124) or knee (n = 116) reoperations. The PJI diagnosis was based on the MSIS (Musculoskeletal Infection Society) criteria (2011). Receiver operating characteristic plots were constructed for IL-6, sIL-6, and sCRP. Results PJI was diagnosed in 93 patients, and aseptic revision was diagnosed in 147 patients. The AUC (area under curve) for IL-6 was 0.938 (95% CI; 0.904–0.971). The optimal IL-6 cut-off value for PJI was 12.55 ng/L. Positive and negative likelihood ratios for IL-6 were 8.24 (95% CI; 4.79–14.17) and 0.15 (95% CI; 0.09–0.26), respectively. The optimal sIL-6 and sCRP cut-off values were 20,988 ng/L and 8.80 mg/L, respectively. Positive and negative likelihood ratios for sIL-6 were 40.000 (95% CI; 5.7–280.5) and 0.170 (95% CI; 0.07–0.417), respectively. Negative likelihood ratio for sCRP was 0.083 (95% CI; 0.022–0.314). PLOS ONE | https://doi.org/10.1371/journal.pone.0199226 June 21, 2018 1 / 16 Serum IL-6 and synovial IL-6 and CRP are valuable for diagnosis of hip and knee prosthetic joint infection Competing interests: The authors have declared that no competing interests exist. Conclusions The present study identified the cut-off values for serum/synovial IL-6 and synovial CRP for diagnostics of PJI at the site of THA and TKA and separately for each site. The diagnostic odds ratio for serum/synovial IL-6 and synovial CRP is very good. Simultaneous positivity of serum IL-6 either with synovial IL-6 or synovial CRP almost excludes false negative detection of PJI at the site of interest. Introduction Prosthetic joint infection (PJI) is a feared complication of total joint arthroplasty (TJA). PJI accounts for almost 50% of failed total knee arthroplasties (TKA), [1], and around 17% of reoperated total hip arthroplasties (THA), [2]. The presence or absence of PJI has a crucial impact on the orthopaedic surgeon’s decision about the further treatment strategy. However, discrimination between infected and aseptic failed total joint arthroplasties can be difficult in some cases, as the physical examination does not reveal pathology except pain, and laboratory results may be equivocal. On the other side of the clinical presentation spectrum are patients with increased suspicion of PJI with painful joints and cloudy dense yellow/white viscous joint fluid who may be negative for PJI [3]. Interleukin-6 (IL-6) is a soluble mediator expressed as part of host defense against a wide range of environmental stresses including microorganism invasion [4]. This is why it is one of the key cytokines, which is strongly up-regulated during septic inflammation. IL-6, among others, contributes to the expression and release of CRP (C-reactive protein). It is also known that the serum/local expressions of IL-6 in patients with PJI differ detectably from those with aseptic failure [5]. Importantly, the postoperative decrease of serum IL-6 is rapid for applying the test early postoperatively [6, 7]. A number of studies have examined the diagnostic behavior of pre-operative detection of serum/synovial IL-6 in patients with PJI [8–13]. Diagnostic accuracy of the serum IL-6 test for PJI has been examined also in the meta-analysis/systematic reviews of these studies [14, 15]. The most recent one of them concludes that serum IL-6 is less sensitive than the synovial fluid IL-6 test but still could have a value for patients with prosthetic failure due to its high specificity. The purpose of the current diagnostic study is to show the diagnostic characteristics of serum interleukin-6 for the pre-operative diagnosis of PJI either as a single test or in combination of synovial IL-6 (sIL-6) and CRP (sCRP), to assess the optimal threshold value, and to compare these results with the currently available diagnostic standards. Materials and methods The Ethical Committee of the Faculty of Medicine and Dentistry, Palacky University Olomouc and the Teaching Hospital Olomouc approved this study as part of the Internal Grant Agency, Ministry of Health Czech Republic project No. NT11049-5 Patients and controls We prospectively collected blood/synovial fluid samples from 240 patients who underwent revisions of total hip or knee replacements at our Department (Table 1). Every patient who underwent a revision knee or hip arthroplasty at our institution between October 2010 and June 2016 was potentially eligible for the current study (Fig 1). We enrolled PLOS ONE | https://doi.org/10.1371/journal.pone.0199226 June 21, 2018 2 / 16 S (...truncated)