JBJI Journal of Bone and Joint Infection JBJI J. Bone Joint Infect. 2206-3552 Ivyspring Göttingen, Germany 10.7150/jbji.26492 Limited Predictive Value of Serum Inflammatory Markers for Diagnosing Fracture-Related Infections: results of a large retrospective multicenter cohort study Bosch Paul 1 den Janna van 2 Plate Joost D.J. 2 IJpma Frank F.A. 1 Houwert R. Marijn 2 Huisman Albert 3 Hietbrink Falco 2 Leenen Luke P.H. 2 Govaert Geertje A.M. 2 Department of General Surgery, Subdivision of Trauma Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Trauma Surgery, University of Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands Department of Clinical Chemistry and Haematology, University Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands 06 07 2018 3 3 130 137 Copyright: © 2018 Paul Bosch et al. 2018 This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/ This article is available from https://jbji.copernicus.org/articles/3/130/2018/jbji-3-130-2018.html The full text article is available as a PDF file from https://jbji.copernicus.org/articles/3/130/2018/jbji-3-130-2018.pdf

<p class="p p-first" id="__p3"><strong><em>Introduction</em>:</strong> Diagnosing Fracture-Related Infections (FRI) based on clinical symptoms alone can be challenging and additional diagnostic tools such as serum inflammatory markers are often utilized. The aims of this study were 1) to determine the individual diagnostic performance of three commonly used serum inflammatory markers: C-Reactive Protein (CRP), Leukocyte Count (LC) and Erythrocyte Sedimentation Rate (ESR), and 2) to determine the diagnostic performance of a combination of these markers, and the additional value of including clinical parameters predictive of FRI.</p><p id="__p4"><strong><em>Methods</em>:</strong> This cohort study included patients who presented with a suspected FRI at two participating level I academic trauma centers between February 1<sup>st</sup> 2009 and December 31<sup>st</sup> 2017. The parameters CRP, LC and ESR, determined at diagnostic work-up of the suspected FRI, were retrieved from hospital records. The gold standard for diagnosing or ruling out FRI was defined as: positive microbiology results of surgically obtained tissue samples, or absence of FRI at a clinical follow-up of at least six months. The diagnostic accuracy of the individual serum inflammatory markers was assessed. Analyses were done with both dichotomized values using hospital thresholds as well as with continuous values. Multivariable logistic regression analyses were performed to obtain the discriminative performance (Area Under the Receiver Operating Characteristic, AUROC) of (1) the combined inflammatory markers, and (2) the added value of these markers to clinical parameters.</p><p id="__p5"><strong><em>Results</em>:</strong> A total of 168 patients met the inclusion criteria and were included for analysis. CRP had a 38% sensitivity, 34% specificity, 42% positive predictive value (PPV) and 78% negative predictive value (NPV). For LC this was 39%, 74%, 46% and 67% and for ESR 62%, 64%, 45% and 76% respectively. The diagnostic accuracy was 52%, 61% and 80% respectively. The AUROC was 0.64 for CRP, 0.60 for LC and 0.58 for ESR. The AUROC of the combined inflammatory markers was 0.63. Serum inflammatory markers combined with clinical parameters resulted in AUROC of 0.66 as opposed to 0.62 for clinical parameters alone.</p><p class="p p-last" id="__p6"><strong><em>Conclusion:</em></strong> The added value of CRP, LC and ESR for diagnosing FRI is limited. Clinicians should be cautious when interpreting the results of these tests in patients with suspected FRI.</p>

 References Metsemakers WJ, Onsea J, Neutjens E, Steffens E, Schuermans A, McNally M. et al. Prevention of fracture-related infection: a multidisciplinary care package. International orthopaedics. 2017;41(12):2457–69. Metsemakers WJ, Morgenstern M, McNally MA, Moriarty TF, McFadyen I, Scarborough M. et al. Fracture-related infection: A consensus on definition from an international expert group. Injury. 2017;49(3):505–510. Bose D, Kugan R, Stubbs D, McNally M. Management of infected nonunion of the long bones by a multidisciplinary team. The bone & joint journal. 2015;97B(6):814–7. Metsemakers WJ, Kuehl R, Moriarty TF, Richards RG, Verhofstad MH, Borens O. et al. Infection after fracture fixation: Current surgical and microbiological concepts. Injury. 2016;49(3):511–522. Metsemakers WJ, Smeets B, Nijs S, Hoekstra H. Infection after fracture fixation of the tibia: Analysis of healthcare utilization and related costs. Injury. 2017;48(6):1204–10. McNally M, Nagarajah K. (iv) Osteomyelitis. Orthopaedics and Trauma. 2010;24(6):416–29. [Google Scholar] Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury. 2006;37(Suppl 2):S59–66. Huerfano E, Bautista M, Huerfano M, Bonilla G, Llinas A. Screening for Infection Before Revision Hip Arthroplasty: A Meta-analysis of Likelihood Ratios of Erythrocyte Sedimentation Rate and Serum C-reactive Protein Levels. The Journal of the American Academy of Orthopaedic Surgeons. 2017;25(12):809–17. Berbari E, Mabry T, Tsaras G, Spangehl M, Erwin PJ, Murad MH. et al. Inflammatory blood laboratory levels as markers of prosthetic joint infection: a systematic review and meta-analysis. The Journal of bone and joint surgery American volume. 2010;92(11):2102–9. Renz N, Muller M, Perka C, Trampuz A. [Implant-associated infections - Diagnostics] Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen. 2016;87(10):813–21. Stucken C, Olszewski DC, Creevy WR, Murakami AM, Tornetta P. Preoperative diagnosis of infection in patients with nonunions. The Journal of bone and joint surgery American volume. 2013;95(15):1409–12. Yang F, Yang Z, Feng J, Zhang L, Ma D, Yang J. Three phase bone scintigraphy with (99m)Tc-MDP and serological indices in detecting infection after internal fixation in malunion or nonunion traumatic fractures. Hellenic journal of nuclear medicine. 2016;19(2):130–4. Wang S, Yin P, Quan C, Khan K, Wang G, Wang L. et al. Evaluating the Use of Serum Inflammatory Markers for Preoperative Diagnosis of Infection in Patients with Nonunions. BioMed research international. 2017;2017:9146317. [PMC free article] Govaert GA, Glaudemans AW, Ploegmakers JJ, Viddeleer AR, Wendt KW, Reininga IH. Diagnostic strategies for posttraumatic osteomyelitis: a survey amongst Dutch medical specialists demonstrates the need for a consensus protocol. European journal of trauma and emergency surgery: official publication of the European Trauma Society; 2017. [PMC free article] Fischer CL, Gill C, Forrester MG, Nakamura R. Quantitation of "acute-phase proteins" postoperatively. Value in detection and monitoring of complications. American journal of clinical pathology. 1976;66(5):840–6. Scherer MA, Neumaier M, von Gumppenberg S. C-reactive protein in patients who had operative fracture treatment. Clinical orthopaedics and related research. 2001;393:287–93. Ettinger M, Calliess T, Kielstein JT, Sibai J, Bruckner T, Lichtinghagen R. et al. Circulating biomarkers for discrimination between aseptic joint failure, low-grade infection, and high-grade septic failure. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2015;61(3):332–41. Chmielewski PP, Strzelec B. Elevated leukocyte count as a harbinger of systemic inflammation, disease progression, and poor prognosis: a review. Folia morphologica; 2017. Kunakornsawat S, Tungsiripat R, Putthiwara D, Piyakulkaew C, Pluemvitayaporn T, Pruttikul P. et al. Postoperative Kinetics of C-Reactive Protein and Erythrocyte Sediment Rate in One-, Two-, and Multilevel Posterior Spinal Decompressions and Instrumentations. Global Spine J. 2017;7(5):448–51. [PMC free article] Ellitsgaard N, Andersson AP, Jensen KV, Jorgensen M. Changes in C-reactive protein and erythrocyte sedimentation rate after hip fractures. International orthopaedics. 1991;15(4):311–4. Neumaier M, Metak G, Scherer MA. C-reactive protein as a parameter of surgical trauma: CRP response after different types of surgery in 349 hip fractures. Acta orthopaedica. 2006;77(5):788–90. Yoon SI, Lim SS, Rha JD, Kim YH, Kang JS, Baek GH. et al. The C-reactive protein (CRP) in patients with long bone fractures and after arthroplasty. International orthopaedics. 1993;17(3):198–201. Kang KT, Son DW, Lee SH, Song GS, Sung SK, Lee SW. Variation of C-Reactive Protein and White Blood Cell Counts in Spinal Operation: Primary Fusion Surgery Versus Revision Fusion Surgery. Korean J Spine. 2017;14(3):66–70. [PMC free article] Neumaier M, Scherer MA. C-reactive protein levels for early detection of postoperative infection after fracture surgery in 787 patients. Acta orthopaedica. 2008;79(3):428–32. Neumaier M, Scherer MA, Busch R, Von Gumppenberg S. C-reactive protein as a routine parameter for complications in trauma surgery. Unfallchirurgie. 1999;25(6):247–53. [Google Scholar] Kraft CN, Kruger T, Westhoff J, Luring C, Weber O, Wirtz DC. et al. CRP and leukocyte-count after lumbar spine surgery: fusion vs. nucleotomy. Acta orthopaedica. 2011;82(4):489–93. [PMC free article] Lam SW, Leenen LP, van Solinge WW, Hietbrink F, Huisman A. Evaluation of hematological parameters on admission for the prediction of 7-day in-hospital mortality in a large trauma cohort. Clinical chemistry and laboratory medicine. 2011;49(3):493–9. Groeneveld KM, Heeres M, Leenen LP, Huisman A, Koenderman L. Immunophenotyping of posttraumatic neutrophils on a routine haematology analyser. Mediators of inflammation. 2012;2012:509513. [PMC free article] Jou JM, Lewis SM, Briggs C, Lee SH, De La Salle B, McFadden S. ICSH review of the measurement of the erythocyte sedimentation rate. Int J Lab Hematol. 2011 Apr;33(2):125–32. Kortram K, Bezstarosti H, Metsemakers WJ, Raschke MJ, Van Lieshout EMM, Verhofstad MHJ. Risk factors for infectious complications after open fractures; a systematic review and meta-analysis. International orthopaedics. 2017;41(10):1965–82. Müller AO Classification of Fracutres-Long bones. Avalaible from: https:// www.aofoundation.org/Documents/mueller_ao_class.pdf. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. The Journal of bone and joint surgery American volume. 1976;58(4):453–8. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): the TRIPOD Statement. The British journal of surgery. 2015;102(3):148–58. Schinsky MF, Della Valle CJ, Sporer SM, Paprosky WG. Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty. The Journal of bone and joint surgery American volume. 2008;90(9):1869–75. Pfitzner T, Krocker D, Perka C, Matziolis G. [C-reactive protein. An independent risk factor for the development of infection after primary arthroplasty] Der Orthopade. 2008;37(11):1116–20. Muller M, Morawietz L, Hasart O, Strube P, Perka C, Tohtz S. Diagnosis of periprosthetic infection following total hip arthroplasty-evaluation of the diagnostic values of pre- and intraoperative parameters and the associated strategy to preoperatively select patients with a high probability of joint infection. Journal of orthopaedic surgery and research. 2008;3:31. [PMC free article] Fink B, Makowiak C, Fuerst M, Berger I, Schafer P, Frommelt L. The value of synovial biopsy, joint aspiration and C-reactive protein in the diagnosis of late peri-prosthetic infection of total knee replacements. The Journal of bone and joint surgery British volume. 2008;90(7):874–8. Neumaier M, Braun KF, Sandmann G, Siebenlist S. C-Reactive Protein in Orthopaedic Surgery. Acta chirurgiae orthopaedicae et traumatologiae Cechoslovaca. 2015;82(5):327–31. Michail M, Jude E, Liaskos C, Karamagiolis S, Makrilakis K, Dimitroulis D. et al. The performance of serum inflammatory markers for the diagnosis and follow-up of patients with osteomyelitis. The international journal of lower extremity wounds. 2013;12(2):94–9. Chevillotte CJ, Ali MH, Trousdale RT, Larson DR, Gullerud RE, Berry DJ. Inflammatory laboratory markers in periprosthetic hip fractures. The Journal of arthroplasty. 2009;24(5):722–7. Horst K, Hildebrand F, Pfeifer R, Koppen K, Lichte P, Pape HC. et al. Plate osteosynthesis versus hemiarthroplasty in proximal humerus fractures-does routine screening of systemic inflammatory biomarkers makes sense? European journal of medical research. 2015;20:5. [PMC free article] Jiang N, Qin CH, Hou YL, Yao ZL, Yu B. Serum TNF-alpha, erythrocyte sedimentation rate and IL-6 are more valuable biomarkers for assisted diagnosis of extremity chronic osteomyelitis. Biomarkers in medicine; 2017. Omar M, Suero EM, Liodakis E, Reichling M, Guenther D, Decker S. et al. Diagnostic performance of swab PCR as an alternative to tissue culture methods for diagnosing infections associated with fracture fixation devices. Injury. 2016;47(7):1421–6. Buhl T, Stentzer K, Hede A, Kjær A, Hesse B. Bone infection in patients suspected of complicating osteomyelitis: The diagnostic value of dual isotope bone-granulocyte scintigraphy. Clinical physiology and functional imaging. 2005;25(1):20–6. Gittings DJ, Courtney PM, Ashley BS, Hesketh PJ, Donegan DJ, Sheth NP. Diagnosing Infection in Patients Undergoing Conversion of Prior Internal Fixation to Total Hip Arthroplasty. The Journal of arthroplasty. 2017;32(1):241–5. Pavlou M, Ambler G, Seaman SR, Guttmann O, Elliott P, King M. et al. How to develop a more accurate risk prediction model when there are few events. BMJ. 2015;351:h3868. [PMC free article]