Published 1/1/2014
Terry Stanton

Using Biomarkers to Diagnose Periprosthetic Joint Infection

Study finds testing synovial fluid may be a promising approach

The diagnosis of periprosthetic joint infection (PJI) remains a clinical challenge. It currently requires an algorithmic approach using a varied assortment of clinical and laboratory considerations. Considering the substantial harm that PJI causes—in accounting for 25 percent of failed knee arthroplasties and 15 percent of failed hip arthroplasties—an improvement in diagnostic capability would provide an appreciable benefit to patient health as well as serve to blunt the economic impact of this complication.

One avenue with promising potential for diagnostic utility is the testing of synovial fluid for biomarkers for infection. In a presentation during the 2013 annual meeting of the American Association of Hip and Knee Surgeons, Carl A. Deirmengian, MD, of the Rothman Institute, related the results of an 8-year program culminating in the evaluation of the diagnostic profile of 16 promising biomarkers.

The research included a study of a series of 95 patients who were being evaluated for infection in the setting of revision hip or knee arthroplasty. In two thirds (66) of the patients, aseptic failure was the reason for revision; the remaining patients (29) had PJI. Five biomarkers were identified that appear to be diagnostic for PJI.

The current diagnostic method, as prescribed by the Musculoskeletal Infection Society (MSIS) in its consensus definition of PJI, involves a combination of clinical data and use of six tests, including local and systemic measures of inflammation in blood and fluid, radiologic tests, and bacterial isolation techniques. The complexity of the approach is due to the failure of single tools to reliably diagnose infection.

More accuracy, lower cost
Dr. Deirmengian said that he and his colleagues “believe that synovial fluid biomarkers can improve the accuracy and speed of diagnosing infection while simultaneously reducing the cost for the health system.” He explained that their research was based on “substantial evidence that there exists a primitive, but specific, innate immune response to pathogens.” When this innate immune system recognizes pathogens, it triggers a cascade of protective pathways in the host.

“Microarray techniques have demonstrated a unique gene expression signature exhibited by the synovial fluid white blood cells from infected joints, characteristic of the innate host immune response to infection,” he explained. This unique response has also been confirmed at the level of the proteome—the collection of proteins found in a particular cell type under a particular set of conditions—revealing several biomarkers that diagnostically outperformed the currently available tests for PJI.

In their study, the investigators conducted assays for 16 biomarkers (Table 1). Of the 29 patients with infection, 23 were culture-positive and 6 were culture-negative, but met the other MSIS criteria for PJI. Eight patients with a septic diagnosis also had a diagnosis of systemic inflammatory disease, such as rheumatoid arthritis or hepatitis C. At the time of the diagnostic aspiration, two patients were taking a medication that modulates the immune system and six patients diagnosed with a PJI were being treated with antibiotics.

Five biomarkers (α-defensin, ELA2, BPI, NGAL, and LF) correctly predicted the diagnosis as defined by the MSIS criteria for every patient in the study. These biomarkers had 100 percent sensitivity and specificity.

First to report
Dr. Deirmengian noted that the diagnostic potential of synovial fluid biomarkers of PJI had been previously reported. “Similar to these previous studies,” he continued, “we found that cytokines and proteins with antimicrobial function provide the greatest utility for diagnosing PJI. To our knowledge, this study is the first to describe the performance of these five synovial fluid biomarkers—α-defensin, ELA2, BPI, NGAL, and LF—for the diagnosis of PJI.

“These proteins are known to be involved in the innate immune response to infection. When pathogens are present, these biomarkers become more concentrated in the synovial fluid to provide host protection. Therefore, it is no surprise that these proteins are found to be diagnostically important for PJI.”

Because the study excluded patients in the immediate postoperative period and those with suspected hip metallosis, “it may not be valid to extend the results of this study to those patient groups,” noted Dr. Deirmengian. In addition, the assumption that the patient population and prevalence of disease is similar to the more general population of such patients is a limiting factor, although the prevalence of PJI in the patients in this study is similar to that calculated in a recent diagnostic meta-analysis.

Among salient strengths of the study, Dr. Deirmengian said, is the fact that, “to our knowledge, this is the largest diagnostic study to date that utilizes the rigorous MSIS definition for PJI.” Also, patients usually excluded from similar diagnostic studies, such as those on antibiotics and those with systemic inflammatory diseases, were included in the study to emulate standard clinical practice. Finally, he said, “although some diagnostic biomarker studies limit their samples of PJI to a single organism, our study included all infected patients diagnosed by the MSIS criteria, demonstrating the utility of the biomarkers for most representative pathogens.”

If the biomarkers simply mirrored the state of inflammation, researchers would have expected strong correlations between them and the synovial fluid leukocyte count. “However,” he said, “we did not identify many strong correlations between biomarkers and the synovial fluid white blood cell count among infected patients. Nor did we identify many strong correlations between differing biomarkers. Therefore, it appears that these biomarkers are not merely redundant proxies for the local level of inflammation, but instead are being modulated by other underlying causes.

“Measuring biomarkers in the synovial fluid makes sense as a diagnostic strategy,” he continued, “because the synovial compartment is a relatively closed system where biomarkers can concentrate, avoid the influence of systemic changes, and provide an accurate snapshot of the state of the joint.” This makes them a valuable tool for diagnosing PJI and may provide unprecedented diagnostic accuracy in a currently challenging diagnostic setting.

Coauthors with Dr. Deirmengian are Keith Kardos, PhD, Patrick Kilmartin, MS, Alexander Cameron, Kevin Schiller, and Javad Parvizi, MD, FRCS. The paper “Diagnosing Periprosthetic Joint Infection: The Era of the Biomarker Has Arrived” has been submitted to Clinical Orthopaedics and Related Research.

Disclosure information: Dr. Deirmengian—Synthes, Zimmer, Biomet, Biostar Venture Fund partner, CD Diagnostics, Trice, Domain, Journal of Bone and Joint Surgery; Dr. Kardos—CD Diagnostics; Mr. Kilmartin—CD Diagnostics; Mr. Cameron—CD Diagnostics; Mr. Schiller—CD Diagnostics; Dr. Parvizi—3M, Cadence, Ceramtec, Pfizer, Smith & Nephew, TissueGene, Zimmer, Baxter, DePuy, National Institutes of Health, Stryker.

Terry Stanton is a senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom Line

  • Periprosthetic joint infections are a significant cause of morbidity in knee and hip arthroplasties.
  • The current diagnostic method relies on an assortment of clinical data, tests, and imaging modalities.
  • This study investigated the diagnostic utility of 16 synovial fluid biomarkers in patients undergoing arthroplasty.
  • Five biomarkers (α-defensin, ELA2, BPI, NGAL, and LF) were found to correctly predict the diagnosis as defined by the MSIS criteria for every patient with infection.