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Akcaalan, S.;  Ozaslan, H.I.;  Caglar, C.;  Şimşek, M.E.;  Citak, M.;  Akkaya, M. Biomarkers in Synovial Fluid. Encyclopedia. Available online: https://encyclopedia.pub/entry/38364 (accessed on 12 April 2024).
Akcaalan S,  Ozaslan HI,  Caglar C,  Şimşek ME,  Citak M,  Akkaya M. Biomarkers in Synovial Fluid. Encyclopedia. Available at: https://encyclopedia.pub/entry/38364. Accessed April 12, 2024.
Akcaalan, Serhat, Halil Ibrahim Ozaslan, Ceyhun Caglar, Mehmet Emin Şimşek, Mustafa Citak, Mustafa Akkaya. "Biomarkers in Synovial Fluid" Encyclopedia, https://encyclopedia.pub/entry/38364 (accessed April 12, 2024).
Akcaalan, S.,  Ozaslan, H.I.,  Caglar, C.,  Şimşek, M.E.,  Citak, M., & Akkaya, M. (2022, December 08). Biomarkers in Synovial Fluid. In Encyclopedia. https://encyclopedia.pub/entry/38364
Akcaalan, Serhat, et al. "Biomarkers in Synovial Fluid." Encyclopedia. Web. 08 December, 2022.
Biomarkers in Synovial Fluid
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The levels of some biomarkers in serum are not increased in low-grade virulence infections, even though they are included in the ICM diagnostic criteria for the diagnosis of PJI (Periprosthetic joint infection). 

periprosthetic joint infection biomarker blood

1. Synovial Fluid WBC Count and Neutrophil Percentage

The total leukocyte count and neutrophil percentage in synovial fluid are two different parameters frequently used in the diagnosis of PJI [1]. The MSIS criteria for the diagnosis of PJI also include the synovial fluid WBC count. Studies have shown that both the synovial fluid WBC count and neutrophil percentage can be successful diagnostic tools for the diagnosis of PJI [2][3]. In different studies, a range of 1000–5000 cells/μL was determined for the synovial fluid WBC count and the cut-off value was determined as 60–89% for the synovial fluid neutrophil percentage [1]. When 1700 cells/μL was taken as the cut-off value, the sensitivity of the WBC count in synovial fluid was 94% and its specificity was 88%, and when the cut-off value was accepted as 65%, the sensitivity of the neutrophil percentage in synovial fluid was 97% and its specificity was 98% [4]. The existing literature contains various sensitivity and specificity values for various cut-off settings. Although they have advantages in diagnosing PJI, like all synovial fluid examinations, there are some limitations in using the WBC count and neutrophil percentage in synovial fluid [5]. The need for a high-quality synovial fluid sample in order to conduct an effective evaluation is one of the most significant limitations in this respect. Therefore, joint fluid aspiration should be performed under appropriate conditions and by experienced people [4], since blood admixture in the joint fluid makes both quantitative and qualitative examination difficult [4]. An appropriately shaped and high-quality synovial fluid sample can play a key role in diagnosing PJI.

2. Synovial CRP Level

CRP is an inflammatory marker that is synthesized and secreted by many different cells, such as hepatocyte cells, smooth muscle cells, and endothelial cells, and is frequently used in the diagnosis of infectious diseases [6]. Although this inflammatory marker is frequently used, it is non-specific and has been shown to accumulate intensively in tissue damage/inflammation regions [7]. This characteristic led to the hypothesis that the CRP level in synovial fluid could be utilized to diagnose PJI, and studies have confirmed this hypothesis [8]. The relationship between the serum CRP level and synovial CRP level was demonstrated in different studies and a positive correlation was found between the two. The reason for this finding was stated to be increased vascular and synovial permeability due to the infectious condition [8][9]. In a study published in 2022, which analyzed 621 patients, the sensitivity of the synovial CRP level was determined as 74.2% and its specificity as 98% [10]. The same study also revealed that the synovial CRP level alone was superior to the serum CRP level in diagnosing PJI and showed near perfect accuracy [10]. Even though the synovial CRP level has not been thoroughly investigated and is not currently among the diagnostic criteria for PJI, the synovial CRP level appears to be a promising biomarker for diagnosing the condition. However, further research investigating this biomarker is required.

3. Synovial IL-6 Level

Since there is an increase in the WBC and PMN% in the synovial fluid due to inflammation, there is bound to be an increase in levels of proinflammatory cytokines, such as interleukins [11]. This led researchers to hypothesize that the synovial IL-6 level could be used in the diagnosis of PJI. The fact that local expression of IL-6 was found to be higher in patients with PJI compared to those with aseptic failure also supported the usefulness of the synovial IL-6 in the diagnosis of PJI [12]. In this context, the synovial IL-6 level has started to be used in the diagnosis of PJI and studies have shown that its sensitivity is 85–100% and its specificity is 62–100% [13]. Despite these successful results, it has been stated that the IL-6 level in synovial fluid is not superior to the WBC count and PMN percentage in synovial tissue in the diagnosis of PJI. Additionally, the synovial IL-6 level does not provide any additional benefit in the diagnosis of PJI [13]. Again, in a meta-analysis published in 2022 supporting these findings, it was stated that the synovial fluid IL-6 level may be more useful as a confirmatory biomarker rather than as a diagnostic biomarker [14].

4. Synovial Alpha-Defensin Level

Alpha-defensin is an antimicrobial peptide released by activated neutrophils that targets the cell membrane of infective organisms [15]. The sensitivity and specificity of the alpha-defensin level were reported to be 87% and 97%, respectively, in a meta-analysis of research on the subject [16]. Although the alpha-defensin immunoassay has good sensitivity and specificity, comparative studies with routinely used markers are available in the literature because the alpha-defensin immunoassay cannot be routinely performed in most centers and is expensive [17][18]. In patients with total joint arthroplasty requiring two-stage revision, the alpha-defensin immunoassay has been used before re-implantation. It was shown in a different study that testing the synovial alpha-defensin level did not provide any additional benefit [19]. On the contrary, in a large-scale meta-analysis, it was emphasized that the alpha-defensin level was one of the best biomarkers in diagnosing PJI [20]. Despite conflicting views in the literature, incorporating the synovial alpha-defensin test into routine examinations for the diagnosis of PJI appears to be difficult owing to its high cost and challenging accessibility, barring additional studies.

5. Synovial Procalcitonin Level

Procalcitonin, a precursor of calcitonin, is a protein molecule produced by different cell groups of the thyroid gland and is found at very low levels in serum [21]. Like other markers mentioned, the procalcitonin level increases after bacterial infection [22]. However, a meta-analysis reported that the sensitivity and specificity of the serum PCT level failed to diagnose PJI [23]. For this reason, there have been a limited number of studies examining the PCT levels in synovial fluid to provide a more sensitive and specific diagnostic marker for PJI [24][25]. These studies have shown that the diagnostic accuracy of the synovial PCT level is better than that of the serum PCT level, but both PCT levels do not have sufficient potency to diagnose PJI [25][26].

6. Synovial Calprotectin Level

Although calprotectin is known as a cystic fibrosis antigen, it is a protein complex that is part of the inflammatory response [27]. This protein complex is secreted by neutrophils and involved in leukocyte migration and stimulation [27]. Even though there are few studies on the use of the synovial calprotectin level in the diagnosis of PJI, a meta-analysis found that this biomarker had a specificity of 84–99% and sensitivity of 84–98% in the diagnosis of PJI [27].In light of these data, it has been stated that the synovial calprotectin level can be used as a reliable biomarker in the diagnosis of PJI and it has been argued that it may be preferred owing to its low cost [28]. These promising developments have been supported by the findings of another recent meta-analysis and study [29][30]. It is obvious that the synovial calprotectin level, a promising agent in the diagnosis of PJI, will increasingly occupy a place in daily practice in the future.

References

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  11. Deirmengian, C.; Lonner, J.H.; Booth, R.E. The Mark Coventry Award: White blood cell gene expression: A new approach toward the study and diagnosis of infection. Clin. Orthop. Relat. Res. 2005, 440, 38–44.
  12. Worthington, T.; Dunlop, D.; Casey, A.; Lambert, P.; Luscombe, J.; Elliott, T. Serum procalcitonin, interleukin-6, soluble intercellular adhesin molecule-1 and IgG to short-chain exocellular lipoteichoic acid as predictors of infection in total joint prosthesis revision. Br. J. Biomed. Sci. 2010, 67, 71–76.
  13. Mihalič, R.; Zdovc, J.; Brumat, P.; Trebše, R. Synovial fluid interleukin-6 is not superior to cell count and differential in the detection of periprosthetic joint infection. Bone Jt. Open 2020, 1, 737–742.
  14. Cheok, T.; Smith, T.; Siddiquee, S.; Jennings, M.P.; Jayasekera, N.; Jaarsma, R.L. Synovial fluid calprotectin performs better than synovial fluid polymerase chain reaction and interleukin-6 in the diagnosis of periprosthetic joint infection: A systematic review and meta-analysis. Bone Jt. J. 2022, 104, 311–320.
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  16. Chen, Y.; Kang, X.; Tao, J.; Zhang, Y.; Ying, C.; Lin, W. Reliability of synovial fluid alpha-defensin and leukocyte esterase in diagnosing periprosthetic joint infection (PJI): A systematic review and meta-analysis. J. Orthop. Surg. Res. 2019, 14, 453.
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  18. Shahi, A.; Parvizi, J.; Kazarian, G.S.; Higuera, C.; Frangiamore, S.; Bingham, J.; Beauchamp, C.; Della Valle, C.; Deirmengian, C. The Alpha-defensin Test for Periprosthetic Joint Infections Is Not Affected by Prior Antibiotic Administration. Clin. Orthop. Relat. Res. 2016, 474, 1610–1615.
  19. Owens, J.M.; Dennis, D.A.; Abila, P.M.; Johnson, R.M.; Jennings, J.M. Alpha-Defensin Offers Limited Utility in Work-Up Prior to Reimplantation in Chronic Periprosthetic Joint Infection in Total Joint Arthroplasty Patients. J. Arthroplast. 2022, 37, 2431–2436.
  20. Tang, H.; Xu, J.; Yuan, W.; Wang, Y.; Yue, B.; Qu, X. Reliable Diagnostic Tests and Thresholds for Preoperative Diagnosis of Non-Inflammatory Arthritis Periprosthetic Joint Infection: A Meta-analysis and Systematic Review. Orthop. Surg. 2022, 14, 2822–2836.
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  24. Saeed, K.; Dryden, M.; Sitjar, A.; White, G. Measuring synovial fluid procalcitonin levels in distinguishing cases of septic arthritis, including prosthetic joints, from other causes of arthritis and aseptic loosening. Infection 2013, 41, 845–849.
  25. Sa-Ngasoongsong, P.; Wongsak, S.; Jarungvittayakon, C.; Limsamutpetch, K.; Channoom, T.; Kawinwonggowit, V. Comparison of Synovial Fluid and Serum Procalcitonin for Diagnosis of Periprosthetic Joint Infection: A Pilot Study in 32 Patients. BioMed Res. Int. 2018, 2018, 8351308.
  26. Busch, A.; Jäger, M.; Engler, H.; Haversath, M.; Bielefeld, C.; Landgraeber, S.; Wegner, A. Is Procalcitonin (PCT) a reliable biomarker for preoperative diagnosing of low grade periprosthetic joint infection? A prospective study. BMC Musculoskelet. Disord. 2020, 21, 257.
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  30. Grassi, M.; Salari, P.; Farinelli, L.; D’Anzeo, M.; Onori, N.; Gigante, A. Synovial Biomarkers to Detect Chronic Periprosthetic Joint Infection: A Pilot Study to Compare Calprotectin Rapid Test, Calprotectin ELISA Immunoassay and Leukocyte Esterase Test. J. Arthroplast. 2022, 37, 781–786.
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