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Cell Count and Differential of Aspirated Fluid in the Diagnosis of Infection at the Site of Total Knee Arthroplasty
Elie Ghanem, MD1; Javad Parvizi, MD, FRCS1; R. Stephen J. Burnett, MD, FRCS2; Peter F. Sharkey, MD1; Nahid Keshavarzi, MSc1; Ajay Aggarwal, MD2; Robert L. Barrack, MD2
1 Rothman Institute of Orthopedics at Jefferson, 925 Chestnut Street, Philadelphia, PA 19107. E-mail address for J. Parvizi: parvj@aol.com
2 The Barnes-Jewish Hospital, One Barnes-Jewish Hospital Plaza, St. Louis, MO, 63110
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Stryker Orthopedics. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Smith and Nephew). 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.
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Investigation performed at the Rothman Institute of Orthopedics, Thomas Jefferson University, Philadelphia, Pennsylvania

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2008 Aug 01;90(8):1637-1643. doi: 10.2106/JBJS.G.00470
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Abstract

Background: Although there is no absolute diagnostic test for periprosthetic infection, the synovial fluid leukocyte count and neutrophil percentage have been reported to have high sensitivity and specificity. However, the cutoff values for these tests are not agreed upon. We sought to identify definite cutoff values for both the fluid leukocyte count and the neutrophil percentage that may help to diagnose infection at the site of a prosthetic joint.

Methods: We analyzed synovial fluid that had been aspirated preoperatively from 429 knees that had undergone revision arthroplasty at three different academic institutions; 161 knees were found to be infected, and 268 knees were not. Using receiver operating characteristic curves, we determined cutoff values for the fluid leukocyte count and neutrophil differential with an optimal balance of sensitivity and specificity for the diagnosis of periprosthetic infection. The sensitivity, specificity, and predictive values were calculated for those cutoff values. The erythrocyte sedimentation rate and C-reactive protein level cutoff values of 30 mm/hr and 10 mg/L, respectively, were combined with the cutoff values for the fluid leukocyte count and neutrophil percentage.

Results: The cutoff values for optimal accuracy in the diagnosis of infection were >1100 cells/10-3cm3 for the fluid leukocyte count and >64% for the neutrophil differential. When both tests yielded results below their cutoff values, the negative predictive value of the combination increased to 98.2% (95% confidence interval, 95.5% to 99.5%), whereas when both tests yielded results greater than their cutoff values, infection was confirmed in 98.6% (95% confidence interval, 94.9% to 99.8%) of the cases in our cohort. Similarly, when both the neutrophil percentage and the C-reactive protein level were less than the cutoff values of 64% and 10 mg/L, respectively, the presence of periprosthetic infection was very unlikely.

Conclusions: The synovial fluid leukocyte count and differential are useful adjuncts to the erythrocyte sedimentation rate and the C-reactive protein level in the preoperative workup of infection at the site of a total knee arthroplasty. The present study identified cutoff values for the leukocyte count (>1100 cells/10-3cm3) and neutrophil percentage (>64%) that can be used to diagnose infection. Combining the peripheral blood tests with the synovial fluid cell count and differential can improve their diagnostic value.

Level of Evidence: Diagnostic Level III. 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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    Elie Ghanem, MD
    Posted on June 01, 2009
    Dr. Ghanem and colleagues respond to Dr. Elsissy and colleagues
    Rothman Institute of Orthopedics, Philadelphia, Pennsylvania

    EDITOR'S NOTE: As the attached Letters to the Editor indicate, in two articles previously published in the Journal of Arthroplasty, a concern was raised that the value of the white blood cell count in the joint aspirate for the diagnosis of an infection utilized an incorrect unit for the number of white blood cells. The editorial staff of the Journal of Arthroplasty has investigated this issue and has published an Erratum in the December 2009 issue of the journal identifying that the units were incorrect (Journal of Arthroplasty, Volume 24, Issue 8, Page 1293).

    We thank Dr Elsissy and colleagues for their comments.

    Indeed, we reported the cell count as the number of cells per 10 -3 cm 3 , which is the equivalent of one µl, as was requested by the Journal in using metric measurements. We also reported the cell counts in both the papers of Kersey et al. (1) and Mason et al. (2) as cells per microliter (µL) rather than cells per milliliter (mL) (as reported by those authors), because we believe there was a typographical error on their part, since reporting cells per milliliter (mL) raises inconsistencies with the literature. This was done in good faith and not intended to cause confusion.

    We also agree with Elsissy et al. who state in the last paragraph of their letter that, if our assumption that all authors who used cells/mL to report values actually intended to use cells/ µL is true, then the data become much more uniform with recommended cut-off values falling between 500 and 2,500 cells per microliter, a much more clinically useful range. We suggest that a clarification of the units used in the papers by Kersey et al. (1) and Mason et al. (2) be made by those authors in hopes of clarifying this issue and avoiding further confusion in interpreting cell counts in total joint arthroplasty.

    References

    1. Kersey R, Benjamin J, Marson B. White blood cell counts and differential in synovial fluid of aseptically failed total knee arthroplasty. J Arthroplasty. 2000;15:301-4.

    2. Mason JB, Fehring TK, Odum SM, Griffin WL, Nussman DS. The value of white blood cell counts before revision total knee arthroplasty. J Arthroplasty. 2003;18:1038-43.

    Peter G. Elsissy, MD
    Posted on May 16, 2009
    Inconsistencies in Units Used to Report Cell Counts From Aspirates of Infected Arthroplasties
    Loma Linda University Medical Center, Loma Linda, CA

    To the Editor:

    In their recent study (1), Ghanem et al. report results of cell counts in terms of cells/10 −3 cm 3 (equivalent to cells/µL). However, in two articles that they cite by Kersey et al.(2), and Mason et al.(3) they state those authors reported cell count values as cells/10 −3 cm 3 . In fact, each of those authors used cells/mL to report their values. Elsewhere in the literature, some authors have reported values in terms of cells per milliliter (mL), while others use cells per microliter (µL). This 1000-fold error in units has introduced confusion to interpreting this important body of literature.

    The frequently quoted guidelines from the American College of Rheumatology (ACR) for cut-off values suggestive of infection in natural joints (joints without implants) use cells per microliter (50,000 leukocytes/µL and 75% neutrophils)(4-8). Therefore, one would assume that studies investigating cut-off values in the setting of an infected prosthetic joint should use these same units.

    Based on our review of the literature (Table 1), we feel that authors who reported cell counts in terms of cells/milliliter may have intended to use cells/microliter (as established by the ACR guidelines). If the data are reviewed exactly as each author has reported it, the recommended cut-off values range from as little as 2, to as high as 1,760, cells per microliter (1-3, 9-13). However, if our assumption that all authors who used cells/mL to report values actually intended to use cells/µL is true, then the data become much more uniform with recommended cut-off values falling between 500 and 2,500 cells per microliter, a much more clinically useful range.

    Table 1: Review of Recommended Cut-off Values and Units.
    Study Design / Number of patients Units Used Units Referenced Recommended Cut-off Values Discussion Points
    Ghanem et al. 1

    JBJS 2008

    Multi-center retrospective review. 429 pts cells/10 −3 cm 3 (Microliter) Incorrectly cites Kersey et al. and Mason et al. data in cells/ microliter (both original authors use cells/ milliliter ) 1100 cells/microliter and 64% PMNs Correctly site ACR guidelines for native knees with cut-off at 50,000 cells per microliter.
    Parvizi et al. 9

    JBJS 2006

    Single center retrospective review. 168 pts (145 TKA/23 THA) Cells/microliter Accurately references Spangehl et al. and Trampuz et al. in cells/microliter 1760 cells/microliter and 73% PMNs  
    Bauer et al. 10

    JBJS 2006

    Current Concepts Review Cells/microliter References Spangehl et al., Kersey et al., Mason et al. and Trampuz et al. in proper units used by original authors 500 cells/microliter Comment on inconsistency in units used by various authors and suggest that units may be erroneous
    Trampuz et al. 11

    American Journal of Medicine 2004

    Prospective study. 133 pts Cells/microliter Incorrectly cites Kersey et al. and Mason et al. data in cells/microliter (both original authors use cells/milliliter) 1700 cells/microliter and 65% PMNs  
    Mason et al. 3

    Journal of Arthroplasty 2003

    Retrospective review. 86 pts Cells/milliliter in body text Cells/mm 3 (microliter ) in Abstract Incorrectly cites multiple authors in cells/milliliter when original data is in microliters 2500 cells/milliliter (2.5 cells/microliter) and 60% PMN 1000-fold error in units
    Kersey et al. 2

    Journal of Arthroplasty 2000

    Prospective study of 79 knees aspirated prior to revision for aseptic failure Cells/milliliter One case had infection leading to discussion of cut-off values <2,000 cells/mL (2 cells/microliter ) and <50% PMN had 98% NPV for absence of infection Frequently misquoted, along with Mason et al. in cells/microliter .
    Spangehl et al. 12

    JBJS 1999

    Prospective study. 183 pts Cells/microliter Analyzed aspirates using correct ACR recommended cut-off for non-implanted knees Used ACR 50,000 cells/microliter and 75% PMN criteria for septic arthritis Poor sensitivity (36%) for infected TKA using ACR criteria for non-implanted knees.

    Despite the disparities in cell count analysis, there is fairly uniform agreement that differentials showing greater than 60 to 75% neutrophils are highly suggestive of infection (1-3, 9-13).

    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. Ghanem E, Parvizi J, Burnett RS, Sharkey PF, Keshavarzi N, Aggarwal A, Barrack RL. Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty. J Bone Joint Surg Am. 2008;90:1637-43.

    2. Kersey R, Benjamin J, Marson B. White blood cell counts and differential in synovial fluid of aseptically failed total knee arthroplasty. J Arthroplasty. 2000;15:301-4.

    3. Mason JB, Fehring TK, Odum SM, Griffin WL, Nussman DS. The value of white blood cell counts before revision total knee arthroplasty. J Arthroplasty. 2003;18:1038-43.

    4. Hasselbacher et al. Arthrocentesis synovial fluid and synovial biopsy. Primer on rheumatologic disease. 11th edition. 1999.

    5. Kortekangas P, Aro HT, Tuominen J, Toivanen A. Synovial fluid leukocytosis in bacterial arthritis vs. reactive arthritis and rheumatoid arthritis in the adult knee. Scand J Rheumatol. 1992;21:283-88.

    6. Krey PR, Bailen DA. Synovial fluid leukocytosis. A study of extremes. Am J Med. 1979;67:436-42.

    7. Kunnamo I, Pelkonen P. Routine analysis of synovial fluid cells is of value in the differential diagnosis of arthritis in children. J Rheumatol. 1986;13:1076-80.

    8. McCarty DJ. Synovial fluid. In: Koopman WJ, editor. Arthritis and allied conditions: a textbook of rheumatology. 13th edition. Baltimore, Williams and Wilkins; 1997. p 81-102.

    9. Parvizi J, Ghanem E, Menashe S, Barrack RL, Bauer TW. Periprosthetic infection: what are the diagnostic challenges? J Bone Joint Surg Am. 2006;88 Suppl 4:138-47.

    10. Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am. 2006;88:869-82.

    11. Trampuz A, Hanssen AD, Osmon DR, Mandrekar J, Steckelberg JM, Patel R. Synovial fluid leukocyte count and differential for the diagnosis of prosthetic knee infection. Am J Med. 2004;117:556-62.

    12. Spangehl MJ, Masri BA, O'Connell JX, Duncan CP. Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties. J Bone Joint Surg Am. 1999;81:672-83.

    13. Leone JM, Hanssen AD. Management of infection at the site of a total knee arthroplasty. Instr Course Lect. 2006;55:449-61.

    Javad Parvizi, MD, FRCS
    Posted on October 14, 2008
    Dr. Parvizi responds to Drs. Chen and Lin
    Rothman Institute of Orthopedics, Philadelphia, PA

    We would like to take this opportunity to respond to an important concern raised by Drs. Chen and Lin in their recent Letter to the Editor They state that the MedCalc software which we used to determine cut-off values for diagnosing periprosthetic infection implies a 50% prevalence of the disease in the population under study by default. The software also gives an option for choosing the prevalence of the disease upon which the statistical analysis is based. T

    The results we presented in our article(1)were established employing the periprosthetic joint infection (PJI) prevalence of 37.5% present in our study population (1). We acknowledge the inherent vulnerability of predictive values to disease fluctuations, which constrains their clinical applicability to the disease prevalence in a particular study. Although the prevalence of periprosthetic infection after total knee arthroplasty (TKA) has been reported to approach 1% (2), the percentage of revision TKA for PJI among the total number of knees being revised is much greater (3) and can reach up to 25% (4). Barrack et al. (5) concluded that preoperative knee aspirations should not be performed routinely on all TKA revisions but only in patients with a high index of suspicion in order to improve the clinical value of the test. Hence, one would expect that aspirates for infected TKA would constitute a large portion of the total aspirates in a given study population as was the case in our population (35%). The percentage of aspirated TKA with PJI should not constitute 2% of all the aspirates in a given study,or else the authors would be aspirating every TKA prior to revision and thereby inherently limiting the diagnostic value of the aspirate as was determined by Barrack et al (5).

    Nonetheless, we acknowledge the fact that likelihood ratios are independent of the prevalence assumptions that plague predictive values and can be compared among different studies with varying prevalence of the disease. Likelihood ratios are a relatively new statistical concept that have not been properly introduced into the orthopedic literature for general assimilation as is the case with ROC,regression analyses,Kaplan Meier risk assessment,and kappa coefficients. It is clear that residents and surgeons attending journal clubs, grand rounds, or conferences require proper instruction on complex statistical methodologies and their interpretation as the orthopedic literature expands and becomes more complex. We would ask the Journal to dedicate an edition of its Current Concept Reviews to the interpretation and utility of these novel statistical tools.

    References

    1. Ghanem E, Parvizi J, Burnett RS, Sharkey PF, Keshavarzi N, Aggarwal A, Barrack RL. Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty. J Bone Joint Surg Am. 2008;90:1637-43.

    2. Phillips JE, Crane TP, Noy M, Elliott TS, Grimer RJ. The incidence of deep prosthetic infections in a specialist orthopaedic hospital: a 15-year prospective survey. J Bone Joint Surg Br. 2006;88:943-8.

    3. Vessely MB, Whaley AL, Harmsen WS, Schleck CD, Berry DJ. The Chitranjan Ranawat Award: Long-term survivorship and failure modes of 1000 cemented condylar total knee arthroplasties. Clin Orthop Relat Res. 2006;452:28-34.

    4. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;7-13.

    5. Barrack RL, Jennings RW, Wolfe MW, Bertot AJ. The Coventry Award. The value of preoperative aspiration before total knee revision. Clin Orthop Relat Res. 1997;8-16.

    Javad Parvizi, MD, FRCS
    Posted on October 14, 2008
    Dr. Parvizi responds to Dr. Luker and Mr. Smith
    Rothman Institute of Orthopedics, Philadelphia, PA

    We are writing this response letter to an apparent error in the text concerning the function of receiver operating curves (ROC) that was brought to our attention by Dr. Luker and colleagues in a recent Letter to the Editor. The ROC axes of the diagrams in our recently published article “Cell Count and Differential of Aspirated Fluid in the Diagnosis of Infection at the Site of Total Knee Arthroplasty” depict the relationship between true-positive results (sensitivity) plotted against false-positive results (1-specificity) (1). Unfortunately, the text on page 1639 stated that the ROC depicts the relationship between true-positive (sensitivity) and false-negative (specificity) results instead of false-positive. We thank the authors of the response letter for pointing out this mistake in the text. However, this error on our part has no impact at all on the ROC graphs, the analysis and results or our final conclusions.

    References

    1. Ghanem E, Parvizi J, Burnett RS, Sharkey PF, Keshavarzi N, Aggarwal A, Barrack RL. Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty. J Bone Joint Surg Am. 2008;90:1637-43.

    Mark Luker, MD
    Posted on September 29, 2008
    Error in description of ROC curve
    Rocky Mountain Orthopaedic Associates

    To the Editor:

    We're writing about an apparent error in the text of the article: Ghanem E, Parvizi J, Burnet RSJ, Sharkey PF, et al. Cell Count and Differential of Aspirated Fluid in the Diagnosis of Infection at the Site of Total Knee Arthroplasty. JBJS.2008;90:1637-1643. We reviewed this important and interesting article in our journal club on September 25, 2008 and found an error in the description of the ROC curve. The text on page 1639 reads as follows:

    Receiver operating characteristic curves, which depict the relationship between true-positive results (sensitivity) and false-negative results (1 - specificity), were constructed for the fluid leukocyte count and the neutrophil percentage (Figs. 1-A and 1-B).

    The ROC curve axes represent true positive (sensitivity) plotted against false positive (1- specificity), not false negative results. We believe this small but important mistake, in a text seeking to illuminate the use of ROC curves in analysis of diagnostic test performance, should be corrected. Thank you.

    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.

    Chih-Hui Chen
    Posted on August 14, 2008
    Beware of the numerical instability of the predictive values
    Department of Orthopaedics, Taichung Veterans General Hospital

    To the Editor:

    We read with interest the article entitled "Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty" by Ghanem et al (1). We have several points to make:

    The authors did not cite which software they used to make a receiver operating characteristic (ROC) curve analysis. It seems that the authors used MedCalc for Windows (MedCalc Software, Mariakerke, Belgium) for ROC analysis. The authors determined the cutoff values for fluid leukocyte count and neutrophil differential that achieved optimal balance between sensitivity and specificity with use of ROC analysis (1). MedCalc for Windows determines the criterion value with the maximum of the Youden index (2,3). This implies the prevalence in the target population is about 50% and that the costs of false-positive and false-negative test results are equivalent (4). Consequently, these cut-off values might not be optimal for other prevalences and cost ratios. Studies provide the cut-off values under certain cost and prevalence assumptions are urgently needed.

    Positive and negative predictive values are highly attractive test properties, but predictive values are highly vulnerable to disease prevalence fluctuations, causing numeric instability, which markedly constraining the clinical usefulness (5). When disease prevalence increases, the positive predictive value increase, and the negative predictive value decreases. As the prevalence decreases, the negative predictive value increases and the positive predictive value decreases. To use the predictive values properly, one must know the prevalence of the target disorder in the parent cohort to which the patient belongs. If we lower the prevalence of infection from 37.5% to, for example, 2%, with fixed sensitivity (90.7%) and specificity (88.1%) for fluid leukocyte count as the authors provided, the negative predictive value increases from 91.5% to 99.8% but the positive predictive value drops from 87.2% to 13.5%. Similarly, with fixed sensitivity (95%) and specificity (94.7%) for neutrophil differential as the authors provided, changing the prevalence of infection from 37.5% to 2% also increases the negative predictive value of neutrophil differential test results from 96.6% to 99.9%, but also decreases the positive predictive value from 91.6% to 26.8%. Predictive values are problematic and potentially misleading, and consequentially less suitable for clinical use than other more robust counterparts, sensitivity and specificity and likelihood ratios (5).

    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. Ghanem E, Parvizi J, Burnett RS, Sharkey PF, Keshavarzi N, Aggarwal A, Barrack RL. Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty. J Bone Joint Surg Am. 2008;90:1637-43.

    2. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32-5.

    3. Schoonjans F.ROC curve analysis in MedCalc. 2008. http://www.medcalc.be/manual/roc_analysis_in_medcalc.php. Accessed August 12, 2008.

    4. 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.

    5. Gallagher EJ. Numeric instability of predictive values. Ann Emerg Med. 2005;46:311-3.

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