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Letter to the Editor on “The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria”

      To the Editor:
      We read with interest the article entitled “The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria” by Parvizi et al [
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • Higuera C.
      • Della Valle C.
      • Chen A.F.
      • et al.
      The 2018 definition of periprosthetic Hip and knee infection: an evidence-based and validated criteria.
      ]. Our group includes pathologists with subspecialty expertise in hemostasis and thrombosis testing and orthopedic surgeons; we are especially interested in the proposed use of D-dimer in modified scoring criteria for diagnosis of periprosthetic joint infection.
      We believe that there are several issues with including D-dimer in the proposed modified scoring criteria. First, the article refers to serum D-dimer; however, the commonly used clinical laboratory assays we are aware of measure D-dimer in patient plasma [
      • Longstaff C.
      • Adcock D.
      • Olson J.D.
      • Jennings I.
      • Kitchen S.
      • Mutch N.
      • et al.
      Harmonisation of D-dimer - a call for action.
      ]. Next, the criteria were developed from data contributed by 3 different academic medical centers [
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • Higuera C.
      • Della Valle C.
      • Chen A.F.
      • et al.
      The 2018 definition of periprosthetic Hip and knee infection: an evidence-based and validated criteria.
      ]. Given the variety of D-dimer assay kits that are currently commercially available, it is likely that different centers are using different assays, but the type and laboratory performance characteristics of the assay used in each center are not clearly stated in the article [
      • Lippi G.
      • Tripodi A.
      • Simundic A.M.
      • Favaloro E.J.
      International survey on D-dimer test reporting: a call for standardization.
      ,
      • Olson J.D.
      • Cunningham M.T.
      • Higgins R.A.
      • Eby C.S.
      • Brandt J.T.
      D-dimer: simple test, tough problems.
      ]. D-dimer assays are not well standardized and the variability among kits may impact whether any individual kit may be used in the proposed criteria. We have seen an example of assay variability making certain D-dimer assays inappropriate for use in the HERDOO2 clinical decision rule, which is designed to identify women with first unprovoked VTE who are at low risk of VTE recurrence and could discontinue anticoagulant therapy [
      • Rodger M.A.
      • Le Gal G.
      • Langlois N.J.
      • Gin B.
      • Mallick R.
      • Giulivi A.
      • et al.
      "HERDOO2" clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. Can I use any d-Dimer?.
      ]. If a laboratory does not know which D-dimer kit was used to create the proposed periprosthetic joint infection criteria, it will not be able to determine whether its D-dimer result can be used in the criteria for clinical decision-making. A clarification of the D-dimer assays used by the participating institution will be helpful to the readers. It is also likely that if a laboratory or practice would like to adopt these criteria, some validation or verification of the local D-dimer assay for this specific indication may be needed. Second, D-dimer may be reported in several different unit magnitudes (eg, ng/mL, μg/L, and others) and there are 2 different unit types (fibrinogen equivalent units [FEU] and D-dimer units [D-DU]) [
      • Lippi G.
      • Tripodi A.
      • Simundic A.M.
      • Favaloro E.J.
      International survey on D-dimer test reporting: a call for standardization.
      ,
      • Olson J.D.
      • Cunningham M.T.
      • Higgins R.A.
      • Eby C.S.
      • Brandt J.T.
      D-dimer: simple test, tough problems.
      ]. The unit magnitude and type must be included with numeric D-dimer results to allow laboratories to properly interpret and compare the result; however, the D-dimer values included in the article only describe the unit magnitude (ng/mL) [
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • Higuera C.
      • Della Valle C.
      • Chen A.F.
      • et al.
      The 2018 definition of periprosthetic Hip and knee infection: an evidence-based and validated criteria.
      ]. For example, if the proposed threshold for D-dimer as presented by Parvizi et al is 860 ng/mL D-DU, applying this 860 ng/mL D-DU cutoff to a D-dimer result measured in FEU will give false-positive results. The mathematical relationship between the unit types indicates that approximately 2 ng/mL FEU is equal to 1 ng/mL DDU; therefore, a cutoff of 860 ng/mL D-DU would be equivalent to a threshold of 1720 ng/mL FEU. If the proposed threshold represents ng/mL FEU, then applying an 860 ng/mL FEU threshold to results measured in D-DU will give false-negative results (given that the equivalent threshold in D-DU is 430 ng/mL D-DU). Inadequate communication of the specific D-dimer assays appropriate for use in these criteria and of the D-dimer unit type will prevent laboratories from being able to provide appropriate D-dimer testing needed for adoption of these criteria in clinical practice. Furthermore, the observed contribution of D-dimer to the proposed criteria may not hold when one accounts for the effects of D-dimer assay variability.
      In conclusion, the issues we identify in the use of D-dimer in proposed scoring criteria for periprosthetic joint infection presented by Parvizi et al result from a well-described root cause, namely the lack of standardization of D-dimer assays. D-dimer assays lack standardization in unit reporting and lack a common calibrator to standardize the varied assays in common clinical use; furthermore, D-dimer assays use over 20 different monoclonal antibodies of differing specificity, further contributing to differences in assay performance [
      • Longstaff C.
      • Adcock D.
      • Olson J.D.
      • Jennings I.
      • Kitchen S.
      • Mutch N.
      • et al.
      Harmonisation of D-dimer - a call for action.
      ,
      • Lippi G.
      • Tripodi A.
      • Simundic A.M.
      • Favaloro E.J.
      International survey on D-dimer test reporting: a call for standardization.
      ]. Until standardization of D-dimer assays improves, we will continue to see confusion in clinical use and reporting of D-dimer results. Due to lack of standardization, D-dimer assays are currently not interchangeable, and patient results obtained in different laboratories using different D-dimer assays cannot be compared or evaluated for trends. We reiterate that collaboration among regulatory bodies, professional organizations, and reagent manufacturers is necessary to improve standardization and use of D-dimer results and thus enhance the validity of research and subsequently improve patient outcomes [
      • Goodwin A.J.
      • Higgins R.A.
      • Moser K.A.
      • Smock K.J.
      • Chandler W.L.
      • Kottke-Marchant K.
      • et al.
      Issues surrounding age-adjusted d-dimer cutoffs that practicing physicians need to know when evaluating patients with suspected pulmonary embolism.
      ]. In light of the issues we have highlighted with D-dimer measurement, we find it concerning that the use of D-dimer for diagnosis of periprosthetic joint infection as proposed by Parvizi et al is mentioned in additional more recent publications, which show a similar lack of detail about the D-dimer assays used in the patients studied [
      • Shohat N.
      • Tan T.L.
      • Della Valle C.J.
      • Calkins T.E.
      • George J.
      • Higuera C.
      • et al.
      Development and validation of an evidence-based algorithm for diagnosing periprosthetic joint infection.
      ,
      • Qin L.
      • Li F.
      • Gong X.
      • Wang J.
      • Huang W.
      • Hu N.
      Combined measurement of D-dimer and C-reactive protein levels: highly accurate for diagnosing chronic periprosthetic joint infection.
      ]. There is a risk to patients for clinical and surgical mismanagement if D-dimer assays are used in the proposed periprosthetic joint infection criteria given the limitations we outline above.

      Appendix A. Supplementary Data

      References

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        • Tan T.L.
        • Goswami K.
        • Higuera C.
        • Della Valle C.
        • Chen A.F.
        • et al.
        The 2018 definition of periprosthetic Hip and knee infection: an evidence-based and validated criteria.
        J Arthroplasty. 2018; 33: 1309-1314.e2
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        • Adcock D.
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        • Kitchen S.
        • Mutch N.
        • et al.
        Harmonisation of D-dimer - a call for action.
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        International survey on D-dimer test reporting: a call for standardization.
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        • Cunningham M.T.
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        D-dimer: simple test, tough problems.
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        • Le Gal G.
        • Langlois N.J.
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        • Mallick R.
        • Giulivi A.
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        "HERDOO2" clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. Can I use any d-Dimer?.
        Thromb Res. 2018; 169: 82-86
        • Goodwin A.J.
        • Higgins R.A.
        • Moser K.A.
        • Smock K.J.
        • Chandler W.L.
        • Kottke-Marchant K.
        • et al.
        Issues surrounding age-adjusted d-dimer cutoffs that practicing physicians need to know when evaluating patients with suspected pulmonary embolism.
        Ann Intern Med. 2017; 166: 361-363
        • Shohat N.
        • Tan T.L.
        • Della Valle C.J.
        • Calkins T.E.
        • George J.
        • Higuera C.
        • et al.
        Development and validation of an evidence-based algorithm for diagnosing periprosthetic joint infection.
        J Arthroplasty. 2019; 34: 2730-2736.e1
        • Qin L.
        • Li F.
        • Gong X.
        • Wang J.
        • Huang W.
        • Hu N.
        Combined measurement of D-dimer and C-reactive protein levels: highly accurate for diagnosing chronic periprosthetic joint infection.
        J Arthroplasty. 2020; 35: 229-234

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