Elizabeth Hofheinz, M.P.H., M.Ed.
A new study in The Journal of Bone and Joint Surgery has undertaken an effort to evaluate the lateral flow test for synovial fluid alpha defensin with a formal diagnostic study and see how this test stacks up against traditional lab-based alpha defensin tests for periprosthetic joint infection (PJI).
The research, “Validation of the Alpha Defensin Lateral Flow Test for Periprosthetic Joint Infection,” appears in the January. 20, 2021 edition of The Journal of Bone and Joint Surgery.
Asked why there were no existing prospective diagnostic clinical trials for any PJI test, co-author Carl Deirmengian, M.D., an orthopedic surgeon at The Rothman Orthopaedic Institute in Philadelphia, told OSN: “There are really two reasons. First, it is only recently that gold standard diagnostic tools, like those of the MSIS [Musculoskeletal Infection Society] and ICM [International Consensus Meeting] definitions, were available for use in a formal study. Therefore, the ability to conduct a study at the level necessary for FDA review was only recently possible. Second, the alpha-defensin test was the first test with performance that is optimized specifically for use in synovial fluid, facilitating the intended use of diagnosing PJI.”
Standout study design
“There are several reasons that I believe that this is the most robust diagnostic study in the field thus far,” says Dr. Deirmengian. “First, its design was a collaboration between surgeons, commercial diagnostics veterans, and the FDA, which balances many important points of view and minimizes bias in design. Second, selection bias was minimized by including three different arthroplasty institutions. Third, several blinding strategies were used in the study, preventing the potential impact of investigator biases. For example, the surgeon panel assigning an MSIS diagnosis to each study patient was blinded to alpha-defensin results and overall study results. And finally, a contract research organization was engaged to run the study, which periodically audited the study processes and compiled the data for final analysis, which keeps the investigators at an arm’s length from study activity. These critical features provide this study with a level of rigor that has not been previously demonstrated in orthopaedic diagnostics.”
The study was comprised of 57 patients with PJI and 248 patients without PJI. “The sensitivity and specificity of the alpha defensin lateral flow test were 89.5% and 94.8%, respectively,” wrote the authors. “The sensitivity increased to 94.3% after exclusion of 17 patients with grossly bloody aspirates. Among the supplemental control cohort of fresh synovial fluid samples, including 65 samples from patients with PJI and 397 from patients without PJI, the sensitivity and specificity of the alpha defensin lateral flow test were 98.5% and 98.2%, respectively. A comparison of the sensitivity and specificity of the alpha defensin lateral flow test with those of the alpha defensin enzyme-linked immunosorbent assay (ELISA) in the combined cohort did not demonstrate a significant difference in sensitivity (94.3% compared with 93.0%) or specificity (96.9% compared with 97.8%).”
Dr. Deirmengian: “There are two important results in this study. First, the accuracy of the alpha-defensin test was maintained in a formal large multicenter prospective study designed for FDA evaluation. This means that the alpha-defensin test is not only accurate but can be expected to provide reliability across many institutions. Second, despite previous small studies suggesting that the alpha-defensin lateral flow test is not as accurate as the laboratory test, this study demonstrated no substantial differences in performance of the alpha-defensin lateral flow versus laboratory test.”
Alpha-defensin: keeping it simple
“It is now well-established that the diagnostic performance of the alpha-defensin test is very good, arguably as good or better than any other existing test for PJI. But what alpha-defensin really brings to the table is standardization and reliability of interpretation. At a big picture level, what is the likelihood that all surgeons are correctly using the MSIS or ICM criteria accurately? These tools and their tests are complex, requiring unit conversions, threshold applications, and scoring calculations. Although they work well in retrospective research, they may be error prone when prospectively applied by a population of surgeons.”
“Alpha-defensin provides for PJI what troponins provide for acute myocardial infarction: a reliable and accurate test which can supplement a more complex multiple-criteria tool, with the biggest impact where the multiple-criteria tools are not being optimally applied.”
Work performed at the Mayo Clinic, Rochester, Minnesota, the Cleveland Clinic, Cleveland, Ohio, and the Rubin Institute for Advanced Orthopedics, Baltimore, Maryland.
Disclosure: Carl Deirmengian is a consultant for Zimmer Biomet which manufactures the Synovasure literal flow test for alpha-defensin.