title: Synovial Cytokines and the MSIS Criteria Are Not Useful for Determining Infection Resolution After Periprosthetic Joint Infection Explantation.
abstract: BACKGROUND
  Diagnosing periprosthetic joint infection (PJI) requires a combination of clinical and laboratory parameters, which may be expensive and difficult to interpret. Synovial fluid cytokines have been shown to accurately differentiate septic from aseptic failed total knee (TKA) and hip (THA) arthroplasties. However, after first-stage explantation, there is still no reliable test to rule out PJI before a second-stage reimplantation procedure.
  
  
  OBJECTIVE
  (1) Which synovial fluid cytokines have the highest diagnostic accuracy for PJI? (2) Which cytokine shows the greatest decrease associated with the resolution of infection in the same patient between explantation and subsequent reimplantation of an infected arthroplasty? (3) What is the accuracy of synovial fluid cytokines and the Musculoskeletal Infection Society (MSIS) criteria to rule out PJI after first-stage explantation? (4) What are the most studied synovial fluid cytokines for diagnosing PJI as reported in the literature and what are their cumulative diagnostic accuracy?
  
  
  METHODS
  Between May 2013 and March 2014, 104 patients with painful THA and TKA evaluated for possible PJI were included in our study. Of these, 90 (87%) had cytokine levels measured from synovial fluid samples collected as part of this prospective study (n = 33 hips, n = 57 knees). A second group of 35 patients (n = 36 samples) who presented during the same time period with an antibiotic spacer also had synovial cytokines measured before second-stage reimplantation. For the first group of 90 patients, the MSIS definition classified each joint at the time of surgery as infected (n = 31) or not infected (n = 59) and was used as the standard to test the accuracy in diagnosing PJI. Of the 35 patients with synovial marker data before second-stage surgery, 15 patients had cytokine measurements both at explantation and reimplantation and were used to quantify the change between stages. The reimplantation group had a minimum 1-year followup (with four [11%] patients lost to followup) and was classified into successful or failed treatment based on Delphi-based consensus data and was used to test the accuracy in detecting infection resolution at reimplantation.
  
  
  RESULTS
  Interleukin (IL)-1β and interferon-γ demonstrated the highest diagnostic utility (area under the curve 0.92, 0.91, respectively); IL-1β and IL-6 had the highest sensitivities (0.90 [95% confidence interval {CI}, 0.74-0.98] and 0.81 [0.63-0.93]). As a measure of infection resolution, IL-1β had the greatest decrease (12.4-fold; level at explantation: 232.4 [range, 23.1-1545.7]; level at reimplantation: 18.8 (range 1.2-298.9); mean difference: 325.5 [95% CI, 65.0-596.0]; p = 0.0001), and IL-6 had a nearly similar decrease (11.2-fold; level at explantation: 228.1 [range, 10,158.4-182,725.0]; level at reimplantation: 2518.2 [range, 10.4-41,319.3]; mean difference: 33,176.0 [95% CI, 7543.6-58,808.3]; p < 0.0001). Cytokines and MSIS criteria had low sensitivity to rule out infection in a joint treated for PJI.
  
  
  CONCLUSIONS
  IL-6 and IL-1β demonstrated high sensitivities to diagnose PJI and showed the greatest decrease between first and second stages, which may potentially be used to monitor treatment response to PJI. However, cytokines and MSIS criteria had low sensitivity to rule out infection before reimplantation.
  
  
  METHODS
  Level III, diagnostic study.
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA.
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Frangiamore
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA.
authors.forename: Marcelo B P
authors.initials: MB
authors.lastname: Siqueira
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA.
authors.forename: Anas
authors.initials: A
authors.lastname: Saleh
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daly
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA. higuerc@ccf.org.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Higuera
authors.affiliation: Department of Orthopaedic Surgery, Cleveland Clinic, 9500 Euclid Avenue/A41, Cleveland, OH, 44195, USA.
authors.forename: Wael K
authors.initials: WK
authors.lastname: Barsoum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D019540:Area Under Curve; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects* / Q000295:instrumentation; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects* / Q000295:instrumentation; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003697:Delphi Technique; D020878:Device Removal; D005260:Female; D006622:Hip Prosthesis / Q000009:adverse effects*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007720:Knee Prosthesis / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016459:Prosthesis-Related Infections / Q000175:diagnosis / Q000378:metabolism / Q000382:microbiology / Q000601:surgery*; D012372:ROC Curve; D012086:Reoperation; D012307:Risk Factors; D013582:Synovial Fluid / Q000378:metabolism* / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D016207:Cytokines; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6
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