February 17, 2016

Evaluation of Synovial Fluid Biomarkers in the Diagnosis of Periprosthetic Joint Infections of the Shoulder

Promising results may lead to better clinical testing

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By Eric Ricchetti, MD

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Periprosthetic joint infection (PJI) following shoulder arthroplasty can present both a diagnostic and therapeutic challenge. But a team of Cleveland Clinic researchers found that synovial fluid biomarkers offer improved diagnosis of infection.

The clinical problem

Established algorithms for diagnosis of PJI following hip and knee arthroplasty are based on serum tests, joint fluid aspirate analysis and cultures, and evaluation of intraoperative tissue specimens. However, identifying PJI with these tools following shoulder arthroplasty can be difficult due to the indolent nature of the common infecting organisms, including Proprionobacterium acnes (P. acnes) and coagulase-negative Staphylococcus species (CNSS).

Many of these diagnostic tests are found to be negative when these organisms are present. This can result in the common occurrence of unexpected positive culture results following one-stage revision shoulder arthroplasty, in which standard preoperative and intraoperative diagnostic tests are negative despite the growth of positive intraoperative cultures following surgery.

The significance of such cultures and their appropriate management remain unclear. There is debate on the type of treatment and whether all positive cultures require treatment, as these indolent bacteria are a part of the normal skin flora and may at times represent a culture contaminant. Therefore, improved diagnostic tools are needed for determining the likelihood of infection prior to or at the time of revision surgery. This will help guide decision-making regarding treatment, including the decision to proceed with one-stage versus two-stage revision and the need for postoperative antibiotics.

A new potential diagnostic tool

Synovial fluid biomarkers, including pro-inflammatory cytokines and antimicrobial peptides, are part of the innate response to pathogens, and early studies show the ability to improve diagnosis of infection with use of these markers.

Recent work from our research group shows promise in utilizing these markers as diagnostic tools for PJI of the shoulder. Synovial fluid interleukin-6 (IL-6), a pro-inflammatory cytokine, was first prospectively evaluated in a study of 35 cases of revision shoulder arthroplasty surgery. Using receiver operating characteristic curve analysis, a cutoff value of 359.3 pg/mL led to sensitivity, specificity, positive and negative likelihood ratios of 87 percent, 90 percent, 8.45 and 0.15, respectively, for diagnosis of shoulder PJI – test characteristics that outperform current diagnostic tests.

Seven patients with negative preoperative workup were later diagnosed with infection based on multiple positive intraoperative cultures, and the synovial IL-6 level was elevated in five of them, with a mean level of 1400 pg/mL. Levels were also significantly elevated in patients with P. acnes infections.

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In a follow-up study, synovial fluid α-defensin, an anti-microbial peptide, was evaluated in 33 cases of revision shoulder arthroplasty surgery. Sensitivity, specificity, positive and negative likelihood ratios were 63 percent, 95 percent, 12.1, and 0.38, respectively, for diagnosis of shoulder PJI. α-defensin was also significantly elevated in the presence of cultures positive for P. acnes and moderately correlated with the number of positive intraoperative cultures.

This single biomarker analysis subsequently led us to look at the efficacy of broader synovial fluid cytokine analysis in the diagnosis of PJI of the shoulder.

In a study of 74 patients undergoing revision shoulder arthroplasty, nine different pro-inflammatory cytokines were evaluated in the synovial fluid, with all nine markers showing significant correlation with regards to likelihood of infection. Nearly all culture-positive cases in this study, similar to the first two studies, were P. acnes, coagulase-negative staphylococcus, or another indolent organism.

Four cytokines – IL-6, IL-1β, IL-8, IL-10, in particular – showed the best diagnostic performance and were combined to create a model for predicting probability of infection in a given patient based on the patient’s combined cytokine profile.

The future

These promising results with synovial fluid cytokine analysis show the potential for one or more of these biomarkers to be developed into a clinical test that can be used preoperatively and/or intraoperatively for patients undergoing revision shoulder arthroplasty. Improved diagnostic accuracy can improve the algorithms for diagnosis and management of those patients with positive intraoperative culture results. Ultimately, such improvements will lead to better clinical outcomes and reduce treatment costs.

Dr. Ricchetti is Fellowship Director for Shoulder and Elbow Surgery and specializes in all aspects of shoulder surgery.

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Figure 1. (A) Anteroposterior radiograph of a painful right total shoulder arthroplasty that underwent revision for humeral implant malpositioning. Preoperative workup for infection was negative, but intraoperative frozen section tissue specimens demonstrated acute inflammation concerning for infection, and (B) an antibiotic-impregnated cement spacer was placed. Intraoperative cultures subsequently produced P. acnes, and following antibiotic treatment, the patient ultimately underwent (C) reimplantation with a reverse total shoulder arthroplasty due to glenoid bone loss and rotator cuff deficiency.

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Figure 2. Diagnostic parameters of synovial fluid IL-6.

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Figure 3. Diagnostic parameters of synovial fluid α-defensin.

Suggested Reading

Frangiamore SJ, Saleh A, Kovac MF, Grosso MJ, Zhang X, Bauer TW, Daly TM, Ricchetti ET, Iannotti JP. Synovial fluid interleukin-6 as a predictor of periprosthetic shoulder infection. Journal of Bone and Joint Surgery – American. 97:63-70, 2015.

Frangiamore SJ, Saleh A, Grosso MJ, Kovac MF, Higuera CA, Iannotti JP, Ricchetti ET. α-defensin as a predictor of periprosthetic shoulder infection. Journal of Shoulder and Elbow Surgery. 24: 1021-1027, 2015.

Frangiamore, SJ, Saleh, A, Grosso, MJ, Farias-Kovac, M, Zhang, XS, Daly, TM, Bauer, TW, Iannotti, JP, Ricchetti, ET. Analysis of cytokine profiles in the diagnosis of periprosthetic joint infections of the shoulder (American Academy of Orthopaedic Surgeons 82nd Annual Meeting, March 24-28, 2015).

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