Clinical Review

The Role of Synovial Cytokines in the Diagnosis of Periprosthetic Joint Infections: Current Concepts

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Verification of Infection Eradication

A 2-stage revision procedure, widely accepted as the standard treatment for PJI, has success rates approaching 94%.15 In this procedure, it is important to verify infection eradication before beginning the second-stage reimplantation. Verification is crucial in avoiding reimplantation of an infected joint.16 After the first stage, patients are usually administered intravenous antibiotics for at least 6 weeks; these antibiotics are then withheld, and systemic inflammatory markers are evaluated for infection eradication. Although reliable criteria have been established for PJI diagnosis, guidelines for detecting eradication of infection are rudimentary. Most surgeons monitor the decrease in serologic markers, such as erythrocyte sedimentation rate and C-reactive protein (CRP) level, to assess the response to treatment. However, noninfectious etiologies may result in continued elevation of these markers.17 Even though aspirations are often performed to diagnose persistent infection before the second-stage procedure, their diagnostic utility may be limited.18 Use of cultures is also limited, as presence of antibiotic-loaded spacers can decrease the sensitivity of culture.19 Inadequate diagnosis often leads to unnecessary continuation of antimicrobial therapy or additional surgical débridement. Nuclear scans often remain positive because of aseptic inflammation related to surgery and are not useful in documenting sepsis arrest.20 Given the limitations of available tests, novel strategies for identifying the presence of infection at the second stage are being tested.

Synovial Fluid Cytokines

PJI pathogenesis begins with colonization of the implant surfaces with microorganisms and subsequent formation of biofilms.21 The human immune system is activated by the microbial products, cell wall components, and various biofilm proteins. Immune cells are recruited to the site, where they secrete a myriad of inflammatory biomarkers, such as cytokines, which promote further recruitment of inflammatory cells and aid in the eradication of pathogens.9 These inflammatory cytokines and cells are involved in aseptic inflammatory joint conditions, such as rheumatoid arthritis22,23; however, some are specifically involved in immune pathways combating pathogens.24 This action is the basis for increasing interest in using various synovial fluid cytokines and other biomarkers in the diagnosis of PJI. Here we describe some of the commonly studied cytokines.

Interleukin 1β

Interleukin 1β (IL-1β) is a major proinflammatory cytokine that is synthesized by multiple cells, including macrophages and monocytes.25 IL-1β is produced in response to microorganisms, other cytokines, antigen-presenting cells, and immune complexes; stimulates production of acute-phase proteins by the liver; and is an important pyrogen.25 Deirmengian and colleagues5 found that synovial IL-1β increased 258-fold in patients with a PJI. Studies have found that synovial IL-1β has sensitivity ranging from 66.7% to 100% and specificity ranging from 87% to 100%, with 1 study reporting an accuracy of 100%.5,6,26,27

Interleukin 6

Also produced by macrophages and monocytes, interleukin 6 (IL-6) is a potent stimulator of acute-phase proteins.28,29 IL-6 has a role as a chemoattractant and helps with cell differentiation when changing from innate to acquired immunity.30 It is also used as an aid in diagnosing PJI; it has sensitivity ranging from 62% to 100% and specificity ranging from 85% to 100%.5,6,26,31,32 Synovial IL-6 measurements were more accurate than serum IL-6 measurements.26 Furthermore, synovial IL-6 can be increased up to 27-fold in PJI cases.5 In one study, synovial IL-6 levels >2100 pg/mL had sensitivity of 62.5% and specificity of 85.7% in PJI diagnosis26; in another study, an IL-6 threshold of 4270 pg/mL had sensitivity of 87.1%, specificity of 100%, and accuracy of 94.6%.31

C-Reactive Protein

CRP is an acute-phase reactant. Blood levels increase in response to aseptic inflammatory processes and systemic infection.33 CRP plays an important role in host defense by activating complement and helping mediate phagocytosis.33,34 Although serum CRP levels have been used in diagnosing PJIs,6 they can yield false-negative results.35,36 Therefore, attention turned to synovial CRP levels, which were found to be increased 13-fold in PJI cases.5 It has been shown that synovial CRP levels are significantly higher in infected vs noninfected prosthetic joints34 and had diagnostic accuracy better than that of serum CRP levels in diagnosing PJI.37 One study found that CRP at a threshold of 3.7 mg/L had sensitivity of 84%, specificity of 97.1%, and accuracy of 91.5%,37 whereas another study found that CRP at a threshold of 3.61 mg/L had sensitivity of 87.1%, specificity of 97.7%, and accuracy of 93.3%.31

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