CORR Insights®: Positive Alpha-defensin at Reimplantation of a Two-stage Revision Arthroplasty Is Not Associated with Infection at 1 Year

Where Are We Now?

Periprosthetic joint infection (PJI) is a devastating complication following total joint arthroplasty that is associated with morbidity, great economic burden for the patient, and sometimes even death. Given the seriousness of PJI and the difficulty in detecting and diagnosing it, the Musculoskeletal Infection Society (MSIS) developed an evidence-based criterion that orthopaedic surgeons use to diagnose PJI [10]. Recent studies have shown that biomarkers can be found in the synovial fluid of an infected prosthetic joint to detect PJI [3, 4], specifically alpha-defensin and leukocyte esterase. Indeed, the synovial alpha-defensin-1 (AD-1) assay test correlated with the MSIS criteria for diagnosing PJI [2]. Once detected, North American orthopaedic surgeons generally choose two-stage revision arthroplasty to manage the infected THA or TKA, though single-stage direct exchange is in more-common use in some other parts of the world [13].

But, as Samuel and colleagues note in the current study [11], some surgeons are using the AD-1 test beyond its intended purpose, specifically to determine whether infection is cleared after the first stage of treatment, which potentially could improve the results of reimplantation. Currently, measuring synovial cytokines and biomarkers, and applying the MSIS criteria have not proven useful in determining resolution of infection in the presence of antibiotic spacers [5]. In fact, there are no reliable indicators that can guide orthopaedic surgeons as to determining when it is safe to reimplant after the first stage of implant removal, which may contribute to the two-stage approach’s relatively high risk of persistent infection (9% to 28%) [9]. Risk factors for persistent infection have been identified that can help surgeons stratify which patients may be at highest risk for reinfection [7], such as those with whom no positive cultures were obtained or those with resistant organisms [8, 9]. High synovial white blood cell counts, positive cultures of aspirated synovial fluid, and a positive leukocyte esterase strip test are clear signs that the first stage did not eradicate the infection [1].

In the current study, Samuel and colleagues wanted to know whether the AD-1 test can determine whether infection has been controlled before reimplantation in two-stage revision. The authors essentially confirm that the AD-1 test is not useful in determining eradication of infection in the presence of a cement spacer and should not be relied upon for this purpose [11].

Where Do We Need To Go?

Based on the results of the current study, several questions remain: How do we improve this situation? How can we better determine when it is safe to perform the definitive reimplantation after a resection arthroplasty? There is some evidence that a negative test may have reliable negative predictive value. However, this test appears not to be accurate if performed on synovial fluid contaminated with blood [6].

Another promising biomarker, D-Dimer, is produced by the breakdown of fibrin. Inflamed synovium produces fibrin that with turnover raises the serum D-Dimer level. Early results suggest that it, too, may be a reliable biomarker to assess clearance of infection after the first stage of a two-stage process for treating PJI [12], but I emphasize that these results really are preliminary. Regardless, it seems clear enough that we can count on a disappointing result if persistent signs of infection are present; our greatest need now is in the area of risk stratification when those signs are absent. Since no single indicator is sufficiently reliable, perhaps composite risk scores may better discern when reimplantation is likely to be successful. The prognostic calculator proposed by Kheir and colleagues [7] is a good start and should also be studied on a larger scale. High-risk patients may need additional surgical steps prior to definitive reimplantation. Some patients may need a spacer exchange to obtain tissue samples for culture and histology and to allow sonication and culture [1] of the removed materials to ensure the infection has been eliminated. Risk stratification should define different pathways for patients of differing risk.

How Do We Get There?

The promising early results of the leukocyte esterase strip test and the predictive value of serum D-Dimer should prompt large prospective studies. Owing to the relatively low number of infections at any given center, studies to assess this approach will need to be multicenter and collaborative in order to provide meaningful results. The MSIS can and should sponsor the organization of these studies. The senior author of the current study [11] is very experienced in organizing multicenter trials, and I suspect he has plans for these studies in the future (if they are not already underway). These studies should be a priority. Given the cost and morbidity of PJI there is no time to waste.