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Use of Erythrocyte Sedimentation Rate and C-Reactive Protein Level to Diagnose Infection Before Revision Total Knee ArthroplastyA Prospective Evaluation
Nelson V. Greidanus, MD, MPH, FRCSC1; Bassam A. Masri, MD, FRCSC1; Donald S. Garbuz, MD, MHSc, FRCSC1; S. Darrin Wilson, MBBCh, MD, FRCS1; M. Gavan McAlinden, MBBCh, MPH, MD, FRCS1; Min Xu, MSc1; Clive P. Duncan, MD, MSc, FRCSC1
1 Department of Orthopaedics, University of British Columbia, Laurel Pavilion, 910 West 10th Avenue, Vancouver, BC V5Z 4E3, Canada. E-mail address for N.V. Greidanus: nelson.greidanus@vch.ca
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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. A commercial entity (Zimmer, Warsaw, Indiana) paid or directed in any one year, or agreed to pay or direct, benefits in excess of $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which one or more of the authors, or a member of his or her immediate family, is affiliated or associated.
A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).
Investigation performed at the Division of Lower Limb Reconstruction and Oncology, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Jul 01;89(7):1409-1416. doi: 10.2106/JBJS.D.02602
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Abstract

Background: Despite the widespread use of several diagnostic tests, there is still no perfect test for the diagnosis of infection at the site of a total knee arthroplasty. The purpose of this study was to evaluate the diagnostic test characteristics of the erythrocyte sedimentation rate and C-reactive protein level for the assessment of infection in patients presenting for revision total knee arthroplasty.

Methods: One hundred and fifty-one knees in 145 patients presenting for revision total knee arthroplasty were evaluated prospectively for the presence of infection with measurement of the erythrocyte sedimentation rate and the C-reactive protein level. The characteristics of these tests were assessed with use of two different techniques: first, receiver-operating-characteristic curve analysis was performed to determine the optimal positivity criterion for the diagnostic test, and, second, previously accepted criteria for establishing positivity of the tests were used.

Results: A diagnosis of infection was established for forty-five of the 151 knees that underwent revision total knee arthroplasty. The receiver-operating-characteristic curves indicated that the optimal positivity criterion was 22.5 mm/hr for the erythrocyte sedimentation rate and 13.5 mg/L for the C-reactive protein level. Both the erythrocyte sedimentation rate (sensitivity, 0.93; specificity, 0.83; positive likelihood ratio, 5.81; accuracy, 0.86) and the C-reactive protein level (sensitivity, 0.91; specificity, 0.86; positive likelihood ratio, 6.89; accuracy, 0.88) have excellent diagnostic test performance.

Conclusions: The erythrocyte sedimentation rate and the C-reactive protein level provide excellent diagnostic test information for establishing the presence or absence of infection prior to surgical intervention in patients with pain at the site of a knee arthroplasty.

Level of Evidence: Diagnostic Level I. See Instructions to Authors for a complete description of levels of evidence.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Nelson V. Greidanus
    Posted on October 18, 2007
    Optimal Operating Points Determination for ESR and CRP
    University of British Columbia

    The stated purpose of our published manuscript was “to prospectively evaluate the diagnostic test characteristics of the erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) level for the diagnosis of infection prior to revision total knee arthroplasty” (1). We collected data prospectively and evaluated the diagnostic performance of the ESR and CRP against the so-called ‘gold standard’ diagnosis of infection---positive growth of bacteria on culture of intra-articular fluid or tissue specimen. Microsoft Excel(Redmond, Washington) and SPSS(version 10.0; SPSS) software were employed to tabulate, graphically illustrate, and analyze the data including the development of receiver-operator-characteristic (ROC) curves for the respective ESR and CRP tests. Our goals were to plot the ROC curves, identify optimal cutpoints for the ESR and CRP, and to objectively illustrate the performance of these tests using standardized nomenclature with 95% confidence intervals. We selected to illustrate the ‘ideal cutpoints’ alongside the so-called ‘traditional cutpoints’ for ESR and CRP so that the readership may understand the differences in test performance should they choose to use cutpoints from the historical literature or those recommended from the hip arthroplasty literature(2).

    Dr. Lin et al. identify a number of methods for ROC curve evaluation and ‘cut-point’ determination. While numerous methods are available for determining the optimal cut-point there is no evidence that one method is superior or is the so-called ‘gold standard’(3). One method that is commonly utilized is to use the apex of the ROC curve (upper left corner of the curve) as the optimal cut-point as this represents the point at which sensitivity and specificity are optimized. This is the method that we used, which corresponds with the Youden index(4). While we recommend the selection of cutpoints of 22.5 mm/hr for ESR and 13.5mg/L for CRP on the basis of this method we do not claim statistical superiority (p <_.05 of="of" this="this" cutpoint="cutpoint" over="over" the="the" traditional="traditional" cutpoints="cutpoints" _30mm="_30mm" hr="hr" and="and" _10mg="_10mg" l="l" for="for" esr="esr" crp="crp" respectively.="respectively." is="is" evident="evident" from="from" overlapping="overlapping" _95="_95" confidence="confidence" intervals="intervals" in="in" table="table" _3.="_3." variance="variance" seen="seen" point="point" estimates="estimates" our="our" modest="modest" sample="sample" size="size" do="do" not="not" permit="permit" us="us" to="to" demonstrate="demonstrate" statistical="statistical" superiority="superiority" proposed="proposed" reported="reported" crp.="crp." however="however" knowledge="knowledge" report="report" first="first" an="an" evidence-based="evidence-based" determination="determination" optimal="optimal" diagnose="diagnose" infection="infection" prior="prior" revision="revision" knee="knee" arthroplasty.="arthroplasty." data="data" analytic="analytic" methods="methods" suggest="suggest" that="that" these="these" are="are" _22.5mm="_22.5mm" _13.5mg="_13.5mg" p="p" /> When performing ‘area under curve’(AUC) analyses we calculated the AUC (with 95% confidence intervals) for ESR ROC as 0.925 (0.884-0.967) and for CRP ROC as 0.908 (0.857-0.960). This AUC data does not prove statistical superiority of one test over the other but rather demonstrates that both the ESR and CRP are ‘highly accurate’ diagnostic tests as defined by criteria of(5). Our calculations and subsequent recommendations for using ESR and CRP together in ‘combination testing’ (for improved sensitivity and specificity) are based on Bayesion methods as recommended by Black et al.(6). We did not develop ROC curves and AUC analyses for the 'combination testing' of ESR and CRP and therefore are unable to comment on AUC differences which might occur in such scenarios.

    In summary, we have demonstrated objective ‘evidence-based’ cutpoints for ESR and CRP in the population of patients assessed for revision total knee arthroplasty. Furthermore, we have developed and demonstrated ROC curves which prove that the ESR and CRP tests are highly accurate when evaluating for possible infection. Finally, we have suggested ‘combination testing’ of the ESR and CRP as a method to increase the diagnostic information from these tests whether screening patients for the possibility of infection or seeking confirmation of a presumptive diagnosis of infection.

    References:

    1. Greidanus NV, Masri BA, Garbuz DS, Wilson SD, McAlinden MG., Xu M, Duncan CP. Use of erythrocyte sedimentation rate and C-reactive protein level to diagnose infection before revision total knee arthroplasty. A prospective evaluation. J Bone Joint Surg Am 2007;89:1409-1416.

    2. Spangehl MJU, Masri BA, O'Connell JX, Duncan CP. Prospective analysis of preoperative and intraoperative investigations for the diagnosis of injection at the sites of two hundred and two evision total hip arthroplasties. J bone Joint Surg Am. 1999;81:672-83.

    3. Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev Vet Med 2000;45:23-41.

    4. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32-35.

    5. Swetts JA. Measuring the accuracy of diagnostic systems. Science 1988; 240: 1285-1293.

    6. Black ER, Panzer RJ, Mayewski RJ, Griner PF. Characteristics of diagnostic tests and principles for their use in quantitative decision making. In: Black ER, Bordley DR, Tape TG, Panzer RJ. Diagnostic strategies of common medical problems. Philadelphia: American College of Physicians; 1999. p 8-10

    Zong-I Lin, M.D.
    Posted on August 22, 2007
    Optimal Operating Points Determination
    Chung Shan Medical University Hospital, TAIWAN

    To The Editor:

    In their recent article, "Use of Erythrocyte Sedimentation Rate and C-Reactive Protein Level to Diagnose Infection Before Revision Total Knee Arthroplasty. A Prospective Evaluation" Greidanus et al.(1) did not publish the data of the area under the curve (AUC) of the respective receiver-operating characteristic (ROC) curve of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, ESR or CRP positive, and ESR and CRP level positive. They also did not compare the AUC between ESR or CRP positive and ESR and CRP level positive by statistical tests.

    We found, with or without receiving antibiotics, there were no statistically significant difference between the overall accuracy of 22.5 mm/hr for ESR and of 30 mm/hr for ESR, of 13.5 mg/L for CRP and of 10 mg/L for CRP, of 22.5 mm/hr for ESR or 13.5 mg/L for CRP and of 30 mm/hr for ESR or 10 mg/L for CRP, and of 22.5 mm/hr for ESR and 13.5 mg/L for CRP and of 30 mm/hr for ESR and 10 mg/L for CRP. The combination of ESR and CRP tests provides better diagnostic information statistically when selecting 22.5 mm/hr for ESR and 13.5 mg/L for CRP, not 30 mm/hr for ESR and 10 mg/L for CRP.

    In addition, Greidanus et al.(1) also did not mention clearly which method they used to determine the optimal operating point of ESR and CRP, probably by choosing cut-points at the apex of the ROC. We rechecked the cut-off points of ESR and CRP by the Youden index (J), maximum {Sensitivity + Specificity -1}(2), and we reached the same conclusion. We could not, however, perform the t test to compare the difference because of lacking of the complete data set, and we wonder about the statistical significance. The criteria for the optimal cut-off determination include a plot of sensitivity and specificity as a function of the cut-off value, Youden index, odds ratio, likelihood ratio, efficiency, kappa, misclassification-cost term, optimized likelihood ratio for a given prevalence, slope approach, and many more(3). We wish the authors will provide details about their method for determining the optimal cut-off points and the statistical significance.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References:

    1. Greidanus NV, Masri BA, Garbuz DS, Wilson SD, McAlinden MG., Xu M, Duncan CP. Use of erythrocyte sedimentation rate and C-reactive protein level to diagnose infection before revision total knee arthroplasty. A prospective evaluation. J Bone Joint Surg Am 2007;89:1409-1416.

    2. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32-35.

    3. Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev Vet Med 2000;45:23-41.

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