Plasma D-dimer Does Not Anticipate the Fate of Reimplantation in Two-stage Exchange Arthroplasty for Periprosthetic Joint Infection: A Preliminary Investigation
Authors: Pannu Tejbir S. , Villa Jesus M. , Engh Charles , Patel Arpan , Levine Brett R. , Piuzzi Nicolas S. , Higuera Carlos A. , Riesgo Aldo M. 
Published: April 2021

Abstract

Background
Inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels have always been a part of the diagnostic criteria for periprosthetic joint infection (PJI), but they perform poorly anticipating the outcome of reimplantation. D-dimer has been reported in a small series as a potential marker to measure infection control after single-stage revisions to treat PJI. Nonetheless, its use to confirm infection control and decide the proper timing of reimplantation remains uncertain.

Questions/purposes
(1) What is the best diagnostic threshold and accuracy values for plasma D-dimer levels compared with other inflammatory markers (ESR and CRP) or what varying combinations of these tests are associated with persistent infection after reimplantation? (2) Do D-dimer values above this threshold, ESR, CRP, and varying test combinations at the time of reimplantation indicate an increased risk of subsequent persistent infection after reimplantation?

Methods
We retrospectively studied the electronic medical records of all 53 patients who had two-stage revisions for PJI and who underwent plasma D-dimer testing before reimplantation at one of two academic institutions from November 22, 2017 to December 5, 2020. During that period, all patients undergoing two-stage revisions also had a D-dimer test drawn. The minimum follow-up duration was 1 year. We are reporting at this early interval (rather than the more typical 2-year time point) because of the poorer-than-expected performance of this diagnostic test. Of these 53 patients, 17% (9) were lost to follow-up before 1 year and could not be analyzed; the remaining 44 patients (17 hips and 27 knees) were studied here. The mean follow-up was 503 ± 135 days. Absence or persistence of infection after reimplantation were defined according to the Delphi criteria. The conditions included in these criteria were: (1) control of infection, as characterized by a healed wound without fistula, drainage, or pain; (2) no subsequent surgical intervention owing to infection after reimplantation; and (3) no occurrence of PJI-related mortality. The absence of any of the aforementioned conditions until the final follow-up examination was deemed a persistent infection after reimplantation. Baseline patient characteristics were not different between patients with persistent infection (n = 10) and those with absence of it after reimplantation (n = 34) as per the Delphi criteria. Baseline patient characteristics evaluated were age, gender, self-reported race (white/Black/other) or ethnicity (nonHispanic/Hispanic), BMI, American Society of Anesthesiologists (ASA) status, smoking status(smoker/nonsmoker), and joint type (hip/knee). The optimal D-dimer threshold to differentiate between persistence of infection or not after reimplantation was calculated using the Youden index. A receiver operating characteristic curve analysis was performed to test the accuracy of D-dimer, ESR, CRP, and their combinations to establish associations, if any, with persistent infection after reimplantation. A Kaplan-Meier survival analysis (free of infection after reimplantation) with a log-rank test was performed to investigate if D-dimer, ESR, and CRP were associated with absence of infection after reimplantation. Survival or being free of infection after reimplantation was determined as per Delphi criteria. Alpha was set at p < 0.05.

Results
In the receiver operating characteristic curve analysis, with an area under the curve of 0.62, D-dimer showed low accuracy and did not anticipate persistent infection after reimplantation. The optimal D-dimer threshold differentiating between persistence of infection or not after reimplantation was 3070 ng/mL. When using this threshold, D-dimer demonstrated a sensitivity of 90% (95% CI 55.5% to 99.7%) and negative predictive value of 94% (95% CI 70.7% to 99.1%), but low specificity (47% [95% CI 29.8% to 64.9%]) and positive predictive value (33% [95% CI 25.5% to 42.2%]). Although D-dimer showed the highest sensitivity, the combination of D-dimer with ESR and CRP showed the highest specificity (91% [95% CI 75.6% to 98%]) defining the persistence of infection after reimplantation. Based on plasma D-dimer levels, with the numbers available, there was no difference in survival free from infection after reimplantation (Kaplan-Meier survivorship free from infection at minimum 1 year in patients with D-dimer below 3070 ng/mL versus survivorship free from infection with D-dimer above 3070 ng/mL: 749 days [95% CI 665 to 833 days] versus 615 days [95% CI 471 to 759 days]; p = 0.052). Likewise, there were no associations between high ESR and CRP levels and persistent infection after reimplantation, but the number of events was very small, and insufficient power is a concern with this analysis.

Conclusion
In this preliminary series, with the numbers available, D-dimer alone had poor accuracy and was not associated with survival free from infection after reimplantation in patients who underwent two-stage exchange arthroplasty. D-dimer alone might be used to establish that PJI is unlikely, and the combination of D-dimer, ESR, and CRP should be considered to confirm PJI diagnosis in the setting of reimplantation.

Level of Evidence Level IV, diagnostic study.