Does the Alpha Defensin ELISA Test Perform Better Than the Alpha Defensin Lateral Flow Test for PJI Diagnosis? A Systematic Review and Meta-analysis of Prospective Studies

Abstract

Background Periprosthetic joint infection (PJI) following total joint arthroplasty is a serious complication that causes severe morbidity and adds a major financial burden to the healthcare system. Although there is plenty of research on the alpha-defensin (AD) test, a meta-analysis consisting of only prospective studies investigating AD's diagnostic efficacy has not been performed. Additionally, some important subgroups such as THA and TKA have not been separately analyzed, particularly regarding two commonly used versions of the AD test, the laboratory-based (ELISA) and lateral-flow (LF). Questions/purposes (1) Does the AD ELISA test perform better in the detection of PJI than the AD LF test, in terms of pooled sensitivity and specificity, when including prospective studies only? (2) Are there differences in sensitivity or specificity when using AD ELISA and AD LF tests for PJI diagnosis of THA or TKA PJI separately? Methods Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, we included prospective studies describing the use of either AD test in the workup of pain after total joint arthroplasty (primary or revision, but not after resection arthroplasty). Fifteen studies (AD ELISA: 4; AD LF: 11) were included, with 1592 procedures. Subgroup data on THA and TKA could be retrieved for 1163 procedures (ELISA THA: 123; LF THA: 257; ELISA TKA: 228; LF TKA: 555). Studies not describing THA or TKA, those not using Musculoskeletal Infection Society (MSIS) criteria as the standard for determining the presence or absence of PJI, those not clearly reporting data for the AD test for the total cohort, and those describing data published in another study were excluded. Studies were not excluded based on follow-up duration; the MSIS criteria could be used within a few weeks, when test results were available. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Study quality was generally good. The most frequent sources of bias were related to patient selection (such as unclear inclusion and exclusion criteria) and flow and timing (uncertainty in place and time of aspiration, for example). Heterogeneity was moderate to high; a bivariate random-effects model therefore was used. To answer both research questions, sensitivity and specificity were calculated for AD ELISA and LF test groups and THA and TKA subgroups, and were compared using z-test statistics and meta-regression analysis. Results No differences were found between the AD ELISA and the AD LF for PJI diagnosis in the pooled cohorts (THA and TKA combined), in terms of sensitivity (90% versus 86%; p = 0.43) and specificity (97% versus 96%; p = 0.39). Differences in sensitivity for PJI diagnosis were found between the THA and TKA groups for the AD ELISA test (70% versus 94%; p = 0.008); pooled AD LF test sensitivity did not differ between THA and TKA (80% versus 87%; p = 0.20). No differences in specificity were found in either subgroup. Conclusions Both the AD ELISA and AD LF test can be used in clinical practice because both have high sensitivity and very high specificity for PJI diagnosis. The lower sensitivity found for diagnosis of PJI in THA for the AD ELISA test must be carefully interpreted because the pooled data were heterogenous and only two studies for this group were included. Future research should analyze TKAs and THAs separately to confirm or disprove this finding. Level of Evidence Level II diagnostic study.

Are Accuracy Studies for Periprosthetic Joint Infection Diagnosis Inherently Flawed? And What to Do with Schrödinger’s Hips? A Prospective Analysis of the Alpha Defensin Lateral-Flow Test in Chronic Painful Hip Arthroplasties

“…This prospective study that included patients with chronic painful THA was conducted in order to evaluate the results of the AD-LF test; according to our findings, sensitivity and specificity were comparable to those reported in other studies on the AD-LF test 7) . To the best of our knowledge, this is the first prospective study investigating the AD-LF test exclusively for hip arthroplasty, which is important, because PJI of the hip and PJI of the knee are probably not exactly the same 7) . For example, in this study, exclusion of one quarter of all aspirated patients was required because of an insufficient amount of fluid; in our experience, such “dry taps” are more common in hip aspirations, compared to knee aspirations.…”

“…The modified 2018 International Consensus Meeting (ICM) ( Supplementary Table 2 ) and European Bone and Joint Infection Society (EBJIS) 2021 criteria ( Supplementary Fig. 1 ), which were recently published, include alpha-defensin (AD), an antimicrobial peptide released by neutrophils in response to pathogens 7) . Two different AD tests are available: the ELISA test, which requires performance of analysis in a laboratory, and the lateral-flow (LF) test, which has the practical advantages of providing a result within 10 minutes and that the analysis can be performed virtually anywhere 7) .…”

“…1 ), which were recently published, include alpha-defensin (AD), an antimicrobial peptide released by neutrophils in response to pathogens 7) . Two different AD tests are available: the ELISA test, which requires performance of analysis in a laboratory, and the lateral-flow (LF) test, which has the practical advantages of providing a result within 10 minutes and that the analysis can be performed virtually anywhere 7) . Differences in diagnostic accuracies between various joints have been reported 7 8) ; a recent meta-analysis reported sensitivity and specificity for THA separate from TKA: pooled sensitivity for THA PJI diagnosis using the LF test was 80%, and specificity was 92%, slightly lower than its accuracy for TKA (87% and 96%, respectively) 7) .…”

Performance of alpha-defensin lateral flow test after synovial fluid centrifugation for diagnosis of periprosthetic knee infection

“…It is noteworthy to mention that, although some recent systematic reviews and meta-analyses present higher pooled values for the lateral flow, the moderate-to-high heterogeneity among the included studies compels careful interpretation. Even so, the 83% sensitivity and 94% specificity found in these studies are still slightly lower than the achieved here[ 14 , 27 ]. In our series, the centrifuged lateral flow performed similarly to ELISA, which also demonstrated excellent results in concordance to the literature[ 16 , 27 ].…”

“…Even so, the 83% sensitivity and 94% specificity found in these studies are still slightly lower than the achieved here[ 14 , 27 ]. In our series, the centrifuged lateral flow performed similarly to ELISA, which also demonstrated excellent results in concordance to the literature[ 16 , 27 ].…”