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The Role of Synovial Cytokines in the Diagnosis of Periprosthetic Joint Infections: Current Concepts
Take-Home Points
- In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
- Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
- Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable.
- Synovial fluid cytokines have been shown to accurately diagnose PJIs.
- Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.
Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.1 Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.2 Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.2 Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.3 At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.4 Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.
Diagnosis of Periprosthetic Joint Infection
Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).8 The acute and acute-on-chronic presentations are often associated with obvious signs of infection.9 However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.10 As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.11 According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).
Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.12 Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.13 The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.12,14
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
α-Defensin
α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.41 Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.43
Leukocyte Esterase
Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.44,45 In a study conducted by Parvizi and colleagues,7 this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues45 found sensitivity of 92.6% and specificity of 97%.
Other Synovial Markers
Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.6 Deirmengian and colleagues6 screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.32
Serum Markers
In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy46 and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.48 Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.49
Limitations of Synovial Cytokines
The literature suggests that some synovial fluid cytokines have promise.6 However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others32,42,50 (Table 2). 
Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.19
Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.51 These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.13 As reported by Jacovides and colleagues,13 this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.
Conclusion
PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.
1 Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
2. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 suppl):61-65.e1.
3. Sierra RJ, Trousdale RT, Pagnano MW. Above-the-knee amputation after a total knee replacement: prevalence, etiology, and functional outcome. J Bone Joint Surg Am. 2003;85(6):1000-1004.
4. Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am. 2006;88(4):869-882.
5. Deirmengian C, Hallab N, Tarabishy A, et al. Synovial fluid biomarkers for periprosthetic infection. Clin Orthop Relat Res. 2010;468(8):2017-2023.
6. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
7. Parvizi J, Jacovides C, Antoci V, Ghanem E. Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme. J Bone Joint Surg Am. 2011;93(24):2242-2248.
8. Kuiper JW, Willink RT, Moojen DJF, van den Bekerom MP, Colen S. Treatment of acute periprosthetic infections with prosthesis retention: review of current concepts. World J Orthop. 2014;5(5):667-676.
9. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645-1654.
10. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25.
11. Parvizi J, Gehrke T; International Consensus Group on Periprosthetic Joint Infection. Definition of periprosthetic joint infection. J Arthroplasty. 2014;29(7):1331.
12. Saleh A, Guirguis A, Klika AK, Johnson L, Higuera CA, Barsoum WK. Unexpected positive intraoperative cultures in aseptic revision arthroplasty. J Arthroplasty. 2014;29(11):2181-2186.
13. Jacovides CL, Kreft R, Adeli B, Hozack B, Ehrlich GD, Parvizi J. Successful identification of pathogens by polymerase chain reaction (PCR)–based electron spray ionization time-of-flight mass spectrometry (ESI-TOF-MS) in culture-negative periprosthetic joint infection. J Bone Joint Surg Am. 2012;94(24):2247-2254.
14. Barrack RL, Aggarwal A, Burnett RS, et al. The fate of the unexpected positive intraoperative cultures after revision total knee arthroplasty. J Arthroplasty. 2007;22(6 suppl 2):94-99.
15. Macheras GA, Koutsostathis SD, Kateros K, Papadakis S, Anastasopoulos P. A two stage re-implantation protocol for the treatment of deep periprosthetic hip infection. Mid to long-term results. Hip Int. 2012;22(suppl 8):S54-S61.
16. George J, Kwiecien G, Klika AK, et al. Are frozen sections and MSIS criteria reliable at the time of reimplantation of two-stage revision arthroplasty? Clin Orthop Relat Res. 2016;474(7):1619-1626.
17. Kusuma SK, Ward J, Jacofsky M, Sporer SM, Della Valle CJ. What is the role of serological testing between stages of two-stage reconstruction of the infected prosthetic knee? Clin Orthop Relat Res. 2011;469(4):1002-1008.
18. Lonner JH, Siliski JM, Della Valle C, DiCesare P, Lotke PA. Role of knee aspiration after resection of the infected total knee arthroplasty. Am J Orthop. 2001;30(4):305-309.
19. Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am. 2000;82(11):1552-1557.
20. Love C, Marwin SE, Palestro CJ. Nuclear medicine and the infected joint replacement. Semin Nucl Med. 2009;39(1):66-78.
21. Zimmerli W, Moser C. Pathogenesis and treatment concepts of orthopaedic biofilm infections. FEMS Immunol Med Microbiol. 2012;65(2):158-168.
22. Fontana A, Hengartner H, Weber E, Fehr K, Grob PJ, Cohen G. Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int. 1982;2(2):49-53.
23. Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest. 1989;83(2):585-592.
24. Wang G. Human antimicrobial peptides and proteins. Pharmaceuticals (Basel). 2014;7(5):545-594.
25. Stylianou E, Saklatvala J. Interleukin-1. Int J Biochem Cell Biol. 1998;30(10):1075-1079.
26. Gollwitzer H, Dombrowski Y, Prodinger PM, et al. Antimicrobial peptides and proinflammatory cytokines in periprosthetic joint infection. J Bone Joint Surg Am. 2013;95(7):644-651.
27. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Combined measurement of synovial fluid α-defensin and C-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection. J Bone Joint Surg Am. 2014;96(17):1439-1445.
28. Randau TM, Friedrich MJ, Wimmer MD, et al. Interleukin-6 in serum and in synovial fluid enhances the differentiation between periprosthetic joint infection and aseptic loosening. PLoS One. 2014;9(2):e89045.
29. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621-636.
30. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888.
31. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
32. Lenski M, Scherer MA. Synovial IL-6 as inflammatory marker in periprosthetic joint infections. J Arthroplasty. 2014;29(6):1105-1109.
33. Mortensen RF. C-reactive protein, inflammation, and innate immunity. Immunol Res. 2001;24(2):163-176.
34. Parvizi J, McKenzie JC, Cashman JP. Diagnosis of periprosthetic joint infection using synovial C-reactive protein. J Arthroplasty. 2012;27(8 suppl):12-16.
35. Ghanem E, Antoci V, Pulido L, Joshi A, Hozack W, Parvizi J. The use of receiver operating characteristics analysis in determining erythrocyte sedimentation rate and C-reactive protein levels in diagnosing periprosthetic infection prior to revision total hip arthroplasty. Int J Infect Dis. 2009;13(6):e444-e449.
36. Johnson AJ, Zywiel MG, Stroh A, Marker DR, Mont MA. Serological markers can lead to false negative diagnoses of periprosthetic infections following total knee arthroplasty. Int Orthop. 2011;35(11):1621-1626.
37. Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin Orthop Relat Res. 2012;470(1):54-60.
38. Lehrer RI, Lichtenstein AK, Ganz T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol. 1993;11:105-128.
39. Ganz T, Selsted ME, Szklarek D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76(4):1427-1435.
40. Chalifour A, Jeannin P, Gauchat JF, et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood. 2004;104(6):1778-1783.
41. Ulm H, Wilmes M, Shai Y, Sahl HG. Antimicrobial host defensins—specific antibiotic activities and innate defense modulation. Front Immunol. 2012;3:249.
42. Bingham J, Clarke H, Spangehl M, Schwartz A, Beauchamp C, Goldberg B. The alpha defensin-1 biomarker assay can be used to evaluate the potentially infected total joint arthroplasty. Clin Orthop Relat Res. 2014;472(12):4006-4009.
43. Deirmengian C, Kardos K, Kilmartin P, Gulati S, Citrano P, Booth RE. The alpha-defensin test for periprosthetic joint infection responds to a wide spectrum of organisms. Clin Orthop Relat Res. 2015;473(7):2229-2235.
44. Tischler EH, Cavanaugh PK, Parvizi J. Leukocyte esterase strip test: matched for Musculoskeletal Infection Society criteria. J Bone Joint Surg Am. 2014;96(22):1917-1920.
45. De Vecchi E, Villa F, Bortolin M, et al. Leucocyte esterase, glucose and C-reactive protein in the diagnosis of prosthetic joint infections: a prospective study. Clin Microbiol Infect. 2016;22(6):555-560.
46. Di Cesare PE, Chang E, Preston CF, Liu C. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty. J Bone Joint Surg Am. 2005;87(9):1921-1927.
47. Ettinger M, Calliess T, Kielstein JT, et al. Circulating biomarkers for discrimination between aseptic joint failure, low-grade infection, and high-grade septic failure. Clin Infect Dis. 2015;61(3):332-341.
48. Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Götze C. Interleukin-6, procalcitonin and TNF-alpha: markers of peri-prosthetic infection following total joint replacement. J Bone Joint Surg Br. 2007;89(1):94-99.
49. Galliera E, Drago L, Vassena C, et al. Toll-like receptor 2 in serum: a potential diagnostic marker of prosthetic joint infection? J Clin Microbiol. 2014;52(2):620-623.
50. Frangiamore SJ, Siqueira MB, Saleh A, Daly T, Higuera CA, Barsoum WK. Synovial cytokines and the MSIS criteria are not useful for determining infection resolution after periprosthetic joint infection explantation. Clin Orthop Relat Res. 2016;474(7):1630-1639.
51. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
52. Omar M, Ettinger M, Reichling M, et al. Synovial C-reactive protein as a marker for chronic periprosthetic infection in total hip arthroplasty. Bone Joint J. 2015;97(2):173-176.
53. Tetreault MW, Wetters NG, Moric M, Gross CE, Della Valle CJ. Is synovial C-reactive protein a useful marker for periprosthetic joint infection? Clin Orthop Relat Res. 2014;472(12):3997-4003.
54. Omar M, Ettinger M, Reichling M, et al. Preliminary results of a new test for rapid diagnosis of septic arthritis with use of leukocyte esterase and glucose reagent strips. J Bone Joint Surg Am. 2014;96(24):2032-2037.
Take-Home Points
- In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
- Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
- Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable.
- Synovial fluid cytokines have been shown to accurately diagnose PJIs.
- Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.
Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.1 Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.2 Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.2 Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.3 At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.4 Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.
Diagnosis of Periprosthetic Joint Infection
Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).8 The acute and acute-on-chronic presentations are often associated with obvious signs of infection.9 However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.10 As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.11 According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).
Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.12 Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.13 The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.12,14
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
α-Defensin
α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.41 Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.43
Leukocyte Esterase
Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.44,45 In a study conducted by Parvizi and colleagues,7 this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues45 found sensitivity of 92.6% and specificity of 97%.
Other Synovial Markers
Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.6 Deirmengian and colleagues6 screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.32
Serum Markers
In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy46 and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.48 Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.49
Limitations of Synovial Cytokines
The literature suggests that some synovial fluid cytokines have promise.6 However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others32,42,50 (Table 2).
Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.19
Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.51 These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.13 As reported by Jacovides and colleagues,13 this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.
Conclusion
PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.
Take-Home Points
- In cases of failed TJA, it is important to differentiate between septic and aseptic etiologies.
- Chronic and low-grade infections are challenging for orthopedic surgeons, as the symptoms often overlap with aseptic etiologies.
- Verification of infection eradication before beginning the second-stage reimplantation surgery is extremely important, but pre- and intraoperative findings can be unreliable.
- Synovial fluid cytokines have been shown to accurately diagnose PJIs.
- Synovial fluid cytokines may help surgeons differentiate between septic and aseptic cases of failed TJA.
Total joint arthroplasty (TJA) is an effective procedure that has been extensively used to relieve pain and improve quality of life in patients with various forms of joint disease. Although advances in technology and surgical technique have improved the success of TJA, periprosthetic joint infection (PJI) remains a serious complication. In the United States, it is estimated that PJI is the most common reason for total knee arthroplasty failure and the third most common reason for total hip arthroplasty revision.1 Although the incidence of PJI is 1% to 2%, the dramatic increase in TJA volume is expected to be accompanied by a similar rise in the number of infected TJAs; that number is expected to exceed 60,000 in the United States by 2020.2 Moreover, management of PJI is expensive and imposes a heavy burden on the healthcare system, with costs expected to hit $20 billion by 2020 in the US.2 Therefore, treating asepsis cases as infections imposes a heavy burden on the healthcare system and may result in excessive morbidity.3 At the same time, inadequate management of a PJI may result in recurrences that require infection treatment with morbid procedures, such as arthrodesis or amputation. Accurate diagnosis of PJI is of paramount importance in preventing potential implications of a misdiagnosed case. Unfortunately, the PJI diagnosis is extremely challenging, and the available diagnostic tests are often unreliable.4 Thus, research has recently focused on use of several synovial fluid cytokines in the detection of PJI.5-7 In this article, we provide an overview of the synovial biomarkers being used to diagnose PJI.
Diagnosis of Periprosthetic Joint Infection
Differentiating between septic and aseptic failed TJA is important, as the treatment options differ considerably. PJI can be broadly classified as acute or early postoperative (<6 weeks), late chronic (indolent onset), and acute-on-chronic (acute onset in well-functioning prosthesis, secondary to hematogenous spread).8 The acute and acute-on-chronic presentations are often associated with obvious signs of infection.9 However, chronic and low-grade infections pose a challenge to modern orthopedic practice, as the symptoms often overlap with that of aseptic causes of TJA failure.10 As a result, the International Consensus Group on Periprosthetic Joint Infection developed complex criteria using the Musculoskeletal Infection Society definition of PJI and involving a battery of tests for PJI diagnosis.11 According to these criteria, PJI is diagnosed when 1 of the 2 major criteria or 3 of the 5 minor criteria are met (Table 1).
Although these criteria constitute the most agreed on and widely used standard for PJI diagnosis, the definition is complex and often incomplete until surgical intervention. An ideal diagnostic test would aid in managing a PJI and provide results before a treatment decision is made. Many revision surgeries are being performed with insufficient information about the true diagnosis, and the diagnosis might change during or after surgery. About 10% of the revisions presumed to be aseptic may unexpectedly grow cultures during surgery and thereby satisfy the criteria for PJI after surgery.12 Moreover, with the use of novel methods such as polymerase chain reaction, microorganisms were identified in more than three-fourths of the presumed aseptic revisions.13 The optimal management of such cases is controversial, and it is unclear whether positive cultures should be treated as possible contaminants or true infection.12,14
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
α-Defensin
α-Defensin, a natural peptide produced and secreted by neutrophils in response to pathogens, has antimicrobial and cytotoxic properties,38-40 signals for the secretion of various cytokines, and acts as a chemoattractant for various immune cells.41 Deirmengian and colleagues6 found that α-defensin was consistently elevated in patients with PJI. α-Defensin is extremely accurate in diagnosing PJI; it has sensitivity ranging from 97% to 100% and specificity ranging from 96% to 100%.6,27,42 Moreover, α-defensin was effective in diagnosing PJI caused by a wide spectrum of organisms, including various low-virulence bacteria and fungi.43
Leukocyte Esterase
Leukocyte esterase is an enzyme produced and secreted by neutrophils at sites of active infection.7,44 Testing for this enzyme is performed with a colorimetric strip and was originally performed for the diagnosis of urinary tract infections.44,45 In a study conducted by Parvizi and colleagues,7 this strip was used to test for leukocyte esterase in synovial fluid samples; a ++ reading was found to have sensitivity of 80.6% and specificity of 100% in diagnosing knee PJI. Similarly, De Vecchi and colleagues45 found sensitivity of 92.6% and specificity of 97%.
Other Synovial Markers
Research has identified numerous molecular biomarkers that may be associated with the pathogenesis of PJI. Although several (eg, cytokines) have demonstrated higher levels in synovial fluid in patients with PJI than in normal controls, only a few have had clinically relevant diagnostic utility.6 Deirmengian and colleagues6 screened 43 synovial fluid biomarkers that potentially could be used in the diagnosis of PJI. Besides the cytokine α-defensin, 4 other biomarkers—lactoferrin, neutrophil gelatinase-associated lipocalcin, neutrophil elastase 2, and bactericidal/permeability-increasing protein—had accuracy of 100%. In addition, 8 cytokines and biomarkers (IL-8, CRP, resistin, thrombospondin, IL-1β, IL-6, IL-10, IL-1α) had area under the curve values higher than 0.9. Studies have also evaluated the diagnostic utility of metabolic products such as lactate, lactate dehydrogenase, and glucose; their accuracy was comparable to that of serum CRP.32
Serum Markers
In addition to the synovial fluid cytokines, several serum inflammatory cytokines have been studied as potential targets in diagnosing infection. Serum IL-6 has had excellent diagnostic accuracy46 and, when combined with CRP, could increase sensitivity in diagnosing PJI; such a combination (vs either test alone) could be useful in screening patients.47,48 Biomarkers such as tumor necrosis factor α and procalcitonin are considered very specific for PJI and may be useful in confirmatory testing.48 Evidence also suggests that toll-like receptor 2 proteins are elevated in the serum of patients with PJI and therefore are a potential diagnostic tool.49
Limitations of Synovial Cytokines
The literature suggests that some synovial fluid cytokines have promise.6 However, the best biomarker or combination of biomarkers is yet to be determined. Results have been consistent with α-defensin and other cytokines but mixed with IL-6 and still others32,42,50 (Table 2).
Information on the utility of synovial biomarkers in detecting persistent infection is limited. Frangiamore and colleagues50 found that IL-1 and IL-6 levels decreased between the stages of 2-stage revision. Unfortunately, none of the synovial fluid cytokines investigated (IL-1, IL-2, IL-6, IL-8, Il-10, interferon γ, granulocyte macrophage-colony stimulating factor, tumor necrosis factor α, IL-12p70) satisfactorily detected resolution of infection in the setting of prior treatment for PJI. Although cytokines are expected to be elevated in the presence of infection, the internal milieu at the time of stage 2 of the revision makes diagnosis of infection difficult. In addition, presence of spacer particles and recent surgery may activate immune pathways and yield false-positive results. Furthermore, antibiotic cement spacers may suppress the microorganisms to very low levels and yield false-negative results even if these organisms remain virulent.19
Even though the synovial molecular markers can detect the presence of infection, they are unable to identify pathogens. As identifying the pathogen is important in the treatment of PJI, there has been interest in using polymerase chain reaction (PCR) techniques.51 These tests may also provide specific information about the pathogen, such as its antibiotic sensitivity. A recently developed technology, the Ibis T5000 Universal Biosensor (Ibis Biosciences), uses novel pan-domain primers in a series of PCRs. This biosensor is useful in diagnosing infections when cultures are negative and appears to be more accurate than conventional PCR.13 As reported by Jacovides and colleagues,13 this novel PCR technique identified an organism in about 88% of presumed cases of aseptic revision.
Conclusion
PJI poses an extreme challenge to the healthcare system. Given the morbidity associated with improper management of PJI, accurate diagnosis is of paramount importance. Given the limitations of current tests, synovial fluid cytokines hold promise in the diagnosis of PJIs. However, these cytokines are expensive, and their clinical utility in PJI management is not well established. More research is needed before guidelines for synovial fluid cytokines and biomarkers can replace or be incorporated into guidelines for the treatment of PJIs.
1 Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
2. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 suppl):61-65.e1.
3. Sierra RJ, Trousdale RT, Pagnano MW. Above-the-knee amputation after a total knee replacement: prevalence, etiology, and functional outcome. J Bone Joint Surg Am. 2003;85(6):1000-1004.
4. Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am. 2006;88(4):869-882.
5. Deirmengian C, Hallab N, Tarabishy A, et al. Synovial fluid biomarkers for periprosthetic infection. Clin Orthop Relat Res. 2010;468(8):2017-2023.
6. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
7. Parvizi J, Jacovides C, Antoci V, Ghanem E. Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme. J Bone Joint Surg Am. 2011;93(24):2242-2248.
8. Kuiper JW, Willink RT, Moojen DJF, van den Bekerom MP, Colen S. Treatment of acute periprosthetic infections with prosthesis retention: review of current concepts. World J Orthop. 2014;5(5):667-676.
9. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645-1654.
10. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25.
11. Parvizi J, Gehrke T; International Consensus Group on Periprosthetic Joint Infection. Definition of periprosthetic joint infection. J Arthroplasty. 2014;29(7):1331.
12. Saleh A, Guirguis A, Klika AK, Johnson L, Higuera CA, Barsoum WK. Unexpected positive intraoperative cultures in aseptic revision arthroplasty. J Arthroplasty. 2014;29(11):2181-2186.
13. Jacovides CL, Kreft R, Adeli B, Hozack B, Ehrlich GD, Parvizi J. Successful identification of pathogens by polymerase chain reaction (PCR)–based electron spray ionization time-of-flight mass spectrometry (ESI-TOF-MS) in culture-negative periprosthetic joint infection. J Bone Joint Surg Am. 2012;94(24):2247-2254.
14. Barrack RL, Aggarwal A, Burnett RS, et al. The fate of the unexpected positive intraoperative cultures after revision total knee arthroplasty. J Arthroplasty. 2007;22(6 suppl 2):94-99.
15. Macheras GA, Koutsostathis SD, Kateros K, Papadakis S, Anastasopoulos P. A two stage re-implantation protocol for the treatment of deep periprosthetic hip infection. Mid to long-term results. Hip Int. 2012;22(suppl 8):S54-S61.
16. George J, Kwiecien G, Klika AK, et al. Are frozen sections and MSIS criteria reliable at the time of reimplantation of two-stage revision arthroplasty? Clin Orthop Relat Res. 2016;474(7):1619-1626.
17. Kusuma SK, Ward J, Jacofsky M, Sporer SM, Della Valle CJ. What is the role of serological testing between stages of two-stage reconstruction of the infected prosthetic knee? Clin Orthop Relat Res. 2011;469(4):1002-1008.
18. Lonner JH, Siliski JM, Della Valle C, DiCesare P, Lotke PA. Role of knee aspiration after resection of the infected total knee arthroplasty. Am J Orthop. 2001;30(4):305-309.
19. Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am. 2000;82(11):1552-1557.
20. Love C, Marwin SE, Palestro CJ. Nuclear medicine and the infected joint replacement. Semin Nucl Med. 2009;39(1):66-78.
21. Zimmerli W, Moser C. Pathogenesis and treatment concepts of orthopaedic biofilm infections. FEMS Immunol Med Microbiol. 2012;65(2):158-168.
22. Fontana A, Hengartner H, Weber E, Fehr K, Grob PJ, Cohen G. Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int. 1982;2(2):49-53.
23. Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest. 1989;83(2):585-592.
24. Wang G. Human antimicrobial peptides and proteins. Pharmaceuticals (Basel). 2014;7(5):545-594.
25. Stylianou E, Saklatvala J. Interleukin-1. Int J Biochem Cell Biol. 1998;30(10):1075-1079.
26. Gollwitzer H, Dombrowski Y, Prodinger PM, et al. Antimicrobial peptides and proinflammatory cytokines in periprosthetic joint infection. J Bone Joint Surg Am. 2013;95(7):644-651.
27. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Combined measurement of synovial fluid α-defensin and C-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection. J Bone Joint Surg Am. 2014;96(17):1439-1445.
28. Randau TM, Friedrich MJ, Wimmer MD, et al. Interleukin-6 in serum and in synovial fluid enhances the differentiation between periprosthetic joint infection and aseptic loosening. PLoS One. 2014;9(2):e89045.
29. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621-636.
30. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888.
31. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
32. Lenski M, Scherer MA. Synovial IL-6 as inflammatory marker in periprosthetic joint infections. J Arthroplasty. 2014;29(6):1105-1109.
33. Mortensen RF. C-reactive protein, inflammation, and innate immunity. Immunol Res. 2001;24(2):163-176.
34. Parvizi J, McKenzie JC, Cashman JP. Diagnosis of periprosthetic joint infection using synovial C-reactive protein. J Arthroplasty. 2012;27(8 suppl):12-16.
35. Ghanem E, Antoci V, Pulido L, Joshi A, Hozack W, Parvizi J. The use of receiver operating characteristics analysis in determining erythrocyte sedimentation rate and C-reactive protein levels in diagnosing periprosthetic infection prior to revision total hip arthroplasty. Int J Infect Dis. 2009;13(6):e444-e449.
36. Johnson AJ, Zywiel MG, Stroh A, Marker DR, Mont MA. Serological markers can lead to false negative diagnoses of periprosthetic infections following total knee arthroplasty. Int Orthop. 2011;35(11):1621-1626.
37. Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin Orthop Relat Res. 2012;470(1):54-60.
38. Lehrer RI, Lichtenstein AK, Ganz T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol. 1993;11:105-128.
39. Ganz T, Selsted ME, Szklarek D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76(4):1427-1435.
40. Chalifour A, Jeannin P, Gauchat JF, et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood. 2004;104(6):1778-1783.
41. Ulm H, Wilmes M, Shai Y, Sahl HG. Antimicrobial host defensins—specific antibiotic activities and innate defense modulation. Front Immunol. 2012;3:249.
42. Bingham J, Clarke H, Spangehl M, Schwartz A, Beauchamp C, Goldberg B. The alpha defensin-1 biomarker assay can be used to evaluate the potentially infected total joint arthroplasty. Clin Orthop Relat Res. 2014;472(12):4006-4009.
43. Deirmengian C, Kardos K, Kilmartin P, Gulati S, Citrano P, Booth RE. The alpha-defensin test for periprosthetic joint infection responds to a wide spectrum of organisms. Clin Orthop Relat Res. 2015;473(7):2229-2235.
44. Tischler EH, Cavanaugh PK, Parvizi J. Leukocyte esterase strip test: matched for Musculoskeletal Infection Society criteria. J Bone Joint Surg Am. 2014;96(22):1917-1920.
45. De Vecchi E, Villa F, Bortolin M, et al. Leucocyte esterase, glucose and C-reactive protein in the diagnosis of prosthetic joint infections: a prospective study. Clin Microbiol Infect. 2016;22(6):555-560.
46. Di Cesare PE, Chang E, Preston CF, Liu C. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty. J Bone Joint Surg Am. 2005;87(9):1921-1927.
47. Ettinger M, Calliess T, Kielstein JT, et al. Circulating biomarkers for discrimination between aseptic joint failure, low-grade infection, and high-grade septic failure. Clin Infect Dis. 2015;61(3):332-341.
48. Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Götze C. Interleukin-6, procalcitonin and TNF-alpha: markers of peri-prosthetic infection following total joint replacement. J Bone Joint Surg Br. 2007;89(1):94-99.
49. Galliera E, Drago L, Vassena C, et al. Toll-like receptor 2 in serum: a potential diagnostic marker of prosthetic joint infection? J Clin Microbiol. 2014;52(2):620-623.
50. Frangiamore SJ, Siqueira MB, Saleh A, Daly T, Higuera CA, Barsoum WK. Synovial cytokines and the MSIS criteria are not useful for determining infection resolution after periprosthetic joint infection explantation. Clin Orthop Relat Res. 2016;474(7):1630-1639.
51. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
52. Omar M, Ettinger M, Reichling M, et al. Synovial C-reactive protein as a marker for chronic periprosthetic infection in total hip arthroplasty. Bone Joint J. 2015;97(2):173-176.
53. Tetreault MW, Wetters NG, Moric M, Gross CE, Della Valle CJ. Is synovial C-reactive protein a useful marker for periprosthetic joint infection? Clin Orthop Relat Res. 2014;472(12):3997-4003.
54. Omar M, Ettinger M, Reichling M, et al. Preliminary results of a new test for rapid diagnosis of septic arthritis with use of leukocyte esterase and glucose reagent strips. J Bone Joint Surg Am. 2014;96(24):2032-2037.
1 Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
2. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 suppl):61-65.e1.
3. Sierra RJ, Trousdale RT, Pagnano MW. Above-the-knee amputation after a total knee replacement: prevalence, etiology, and functional outcome. J Bone Joint Surg Am. 2003;85(6):1000-1004.
4. Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am. 2006;88(4):869-882.
5. Deirmengian C, Hallab N, Tarabishy A, et al. Synovial fluid biomarkers for periprosthetic infection. Clin Orthop Relat Res. 2010;468(8):2017-2023.
6. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
7. Parvizi J, Jacovides C, Antoci V, Ghanem E. Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme. J Bone Joint Surg Am. 2011;93(24):2242-2248.
8. Kuiper JW, Willink RT, Moojen DJF, van den Bekerom MP, Colen S. Treatment of acute periprosthetic infections with prosthesis retention: review of current concepts. World J Orthop. 2014;5(5):667-676.
9. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645-1654.
10. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25.
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