Orthopedics

Review Article 

Serum and Synovial Biomarkers for the Diagnosis of Implant-Associated Infection After Orthopedic Surgery

Xiaonan Liu, MD; Nan Jiang, MD, PhD; Tiantian Wang, PhD; Bin Yu, MD, PhD

Abstract

Implant-associated infection is one of the most devastating complications following orthopedic surgery. Early identification is crucial for treatment. Currently, however, a reliable diagnostic tool is lacking, partly due to disparate bacteria colonies (virulent vs non-virulent), difficulty in distinguishing infection from inflammatory disease, and highly diverse diagnostic thresholds and testing methods. Given the importance of biomarkers in the initial screening for the infection, an extensive effort has been made to develop serum and synovial biomarkers. In this review, the authors summarize the results from the most relevant studies to provide comprehensive information on biomarkers for the diagnosis of implant-associated infection. [Orthopedics. 2021;44(x):xx–xx.]

Abstract

Implant-associated infection is one of the most devastating complications following orthopedic surgery. Early identification is crucial for treatment. Currently, however, a reliable diagnostic tool is lacking, partly due to disparate bacteria colonies (virulent vs non-virulent), difficulty in distinguishing infection from inflammatory disease, and highly diverse diagnostic thresholds and testing methods. Given the importance of biomarkers in the initial screening for the infection, an extensive effort has been made to develop serum and synovial biomarkers. In this review, the authors summarize the results from the most relevant studies to provide comprehensive information on biomarkers for the diagnosis of implant-associated infection. [Orthopedics. 2021;44(x):xx–xx.]

With the aging of the population and the growing incidence of injuries, the number of individuals receiving joint prosthesis replacement and internal fixation is increasing sharply. Currently, approximately 800,000 prostheses are implanted and 2,000,000 fracture fixations are performed annually in the United States, with infection rates of approximately 2% and 5%, respectively.1–3 It is estimated that periprosthetic joint infection (PJI) costs the US health care system $1.6 billion annually, resulting in an economic burden and leading to higher rates of disability and mortality.2,4 Effective treatment of implant-associated infections relies on their early identification. However, this is sometimes difficult owing to multiple factors, including low virulence of bacteria, non-typical clinical signs and symptoms, and confounding postoperative status.2,5 To facilitate the diagnosis of implant-associated infections, the Musculoskeletal Infection Society and the International Consensus Meeting have devised an integrated criterion including serology, microbiology, histology, and physical examination.6

However, the Musculoskeletal Infection Society criterion has limited sensitivity and specificity in distinguishing PJI from aseptic inflammation.7 In contrast, novel serum biomarkers such as interleukin-6 (IL-6), leukocyte esterase (LE), and defensins produced in the host response against infection have been shown to have promising diagnostic accuracy. Additionally, synovial fluid biomarkers have also been useful in the diagnosis of local infection related to implants. Despite the discovery of new biomarkers and testing methods, their true diagnostic values remain inconsistent and under debate. Therefore, it would be beneficial to review and summarize the current understanding and related clinical studies for clinicians.

In this article, the authors discuss different kinds of serum and synovial biomarkers for the diagnosis of implant-associated infections (Figure 1). Their biological origin, clinical use, and strengths and weaknesses are reviewed.

Involvement of different biomarkers in implant-associated infection. Abbreviations: BPI, bactericidal/permeability-increasing protein; ELA-2, neutrophil elastase; G-CSF, granulocyte colony-stimulating factor; I-CAM, intercellular adhesion molecules; IL, interleukin; LE, leukocyte esterase; NGAL, neutrophil gelatinase-associated lipocalin (also lipocalin-2); TLRs, Toll-like receptors; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Figure 1:

Involvement of different biomarkers in implant-associated infection. Abbreviations: BPI, bactericidal/permeability-increasing protein; ELA-2, neutrophil elastase; G-CSF, granulocyte colony-stimulating factor; I-CAM, intercellular adhesion molecules; IL, interleukin; LE, leukocyte esterase; NGAL, neutrophil gelatinase-associated lipocalin (also lipocalin-2); TLRs, Toll-like receptors; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Materials and Methods

The authors reviewed PubMed and Embase to construct a comprehensive overview of serum and synovial biomarkers for the diagnosis of implant-associated infection after orthopedic surgery. They searched these databases using the following keywords: “osteomyelitis”, “bone infection”, “arthroplasty”, “prosthesis”, “infection”, “synovial marker”, “serum marker”, “molecular marker”, “PCR”, and “sequencing”. English-language articles regardless of year of publication readily available through the Southern Medical University, Guangzhou, China, library were included. Unpublished data, letters to the editor, case reports, instructional courses, and animal-only studies were excluded. The authors identified comparative and noncomparative studies of the diagnosis of implant-associated infection, as well as reviews related to the topic.

Results

C-Reactive Protein

As a plasma protein produced by hepatocytes and regulated by IL-6,8 C-reactive protein (CRP) is essential in activating the complement system of innate immunity. In clinical practice, CRP is considered one of the most critical indicators of inflammation. Thus, CRP has been widely used to monitor the body's acute-phase responses, such as trauma, infection, and connective tissue disorders.9 Serum CRP has a high sensitivity (more than 90%) in the diagnosis of bone infection. However, its specificity ranges from 20% to 80%.10 Currently, both the American Academy of Orthopaedic Surgeons and the Musculo-skeletal Infection Society recommend that CRP and erythrocyte sedimentation rate (ESR) be used as screening tools in the diagnosis of PJI.6,11 However, screening for infection with CRP has several disadvantages. First, the specificity of CRP is weak because it also responds to auto-immune disorders and trauma (including surgery) apart from infection. Second, in diagnosing low virulent infections, the sensitivity of CRP is also disappointing. It was reported that the false-negative rate of CRP combined with ESR exceeded 10%, with a sensitivity of lower than 50%, in the diagnosis of Propionibacterium acnes infection of shoulder prostheses.12,13 Finally, patient demographics (age, sex, antibiotics, and disease status) along with testing methods will also affect CRP levels.13,14

As intra-articular CRP level is related to local complement activation and phagocytosis, the diagnostic value of synovial fluid CRP is also being investigated.15,16 It was postulated that intra-articular CRP originated from serum CRP, which diffused into the joint when there was a change in synovial permeability under inflammation.15,16 In 2012, Parvizi et al16,17 first reported that synovial CRP had better accuracy than serum CRP and could achieve a sensitivity of 85% and a specificity of 95% in the diagnosis of periprosthetic knee infection when using a cutoff value of 9.5 mg/L. In a meta-analysis containing 6 studies, synovial fluid CRP was shown to provide higher accuracy than serum CRP, with pooled sensitivity and specificity of 92% and 90%, respectively.18 Nonetheless, there were also studies indicating that the differences in diagnostic values between synovial fluid CRP and blood serum CRP were not statistically significant.15,19 Moreover, extracted synovial fluid could also become too viscous or hemolytic for analysis. These studies were limited by size and immunoassay methods.15,19,20

In general, serum CRP remains one of the simplest and most effective methods to screen for PJIs. The usefulness of synovial fluid CRP is unclear; however, it may have limitations similar to serum CRP because of the nature of CRP as a marker of inflammation rather than local infection.

Procalcitonin

Produced by C cells in the thyroid gland, procalcitonin (PCT) is a precursor of the hormone calcitonin and is stimulated by pro-inflammatory stimuli, especially bacteria.21 Generally, PCT is upregulated within 2 to 4 hours after infection, peaks in 6 to 24 hours, and lasts for 7 days.22 Because of its high level in systemic bacteremia, PCT has been recommended for use as an indicator in monitoring sepsis.23,24 In orthopedics, PCT is used to identify infection under inflammatory, rheumatic, or post-surgery conditions, and the level of PCT is unaffected by immunosuppressants.21,25–28 Despite the promising traits of PCT, its diagnostic accuracy is undesirable.29 At a cutoff value of 0.3 ng/mL, Bottner et al30 showed that serum PCT had a low sensitivity of 33% and a high specificity of 98% in the diagnosis of periprosthetic knee or hip infection. More recently, at a cutoff value of 0.025 ng/mL, Ettinger et al5 demonstrated a high sensitivity of 80% and a low specificity of 37%. In a meta-analysis consisting of 6 studies, the pooled sensitivity and specificity regarding serum PCT were 53% and 92%, respectively.31 Most researchers have concluded that the diagnostic value of serum PCT is inferior to that of CRP or alpha-defensin and that it should not be used as a single test in the diagnosis of PJI.32–35 Regarding synovial fluid PCT, the number of studies is limited. At a cutoff value of 0.5 ng/mL, Saeed et al36 concluded that the sensitivity and specificity of synovial PCT in the diagnosis of septic arthritis were 88% and 57%, respectively. At the same cutoff value, Wang et al37 demonstrated that synovial PCT had both high sensitivity and specificity of 87% and 94%, respectively, in the diagnosis of septic arthritis (including prosthetic joints), outperforming serum PCT.33 However, Wang et al37 excluded patients who underwent joint surgery, which may have led to variability in these results.

In summary, it remains unclear whether the diagnostic value of synovial fluid PCT is better than that of serum PCT.31 Based on current evidence, it is unlikely that serum or synovial PCT will become an ideal biomarker for the diagnosis of PJI. However, PCT might be useful for diagnosing infection in patients with rheumatoid, inflammatory, or surgery conditions, for which CRP is less reliable, and for screening suspected cases at initial evaluation because of its high sensitivity.25,28,38,39

Leukocyte Esterase

Leukocyte esterase is a special enzyme secreted by neutrophils recruited locally in response to bacterial infection and has been investigated for detecting infections of the urinary tract, peritoneum, and various bodily fluids.40 In orthopedics, the role of synovial fluid LE in distinguishing septic arthritis or periprosthetic infection from aseptic conditions has been explored.41,42 To measure this intracellular enzyme, a colorimetric strip test was developed, which included using a detergent for lysis of synovial polymorphonuclear cells, leaking of LE, and combining LE with dye to yield a purple color.40,43 The intensity of color change (read as negative, trace, +, or ++) directly reflects the number of neutrophils. In 2011, Parvizi et al40 reported that LE had a sensitivity and a specificity of 80.6% and 100%, respectively, at a ++ reading for the diagnosis of knee arthroplasty infection. Later studies showed that the sensitivity and specificity of LE for the diagnosis of PJI ranged from 66% to 100% and from 86.6% to 100%, respectively.40,44–47 In 2015, a meta-analysis revealed that the pooled sensitivity and specificity of LE were 81% and 97%, respectively.48 Because of its relatively high specificity and negative predictive value, some have concluded that LE would be a good marker for ruling out aseptic conditions in patients suspected of having infection, especially under trace or negative conditions.44,45,47 Other advantages of LE include its relatively low cost (US $0.17 per test) and its rapid detection (<2 minutes).47,48 The disadvantages of LE mainly relate to the colorimetric testing method. First, viscous aspirate or too much cell debris can render an LE test result un-readable, and this can affect up to one-third of all samples.44,46 Second, because neutrophils exist in many inflammatory conditions, false-positive results can be observed with conditions such as aseptic loosening or inflammatory diseases.45,49–51 Finally, LE has poor accuracy in detecting periprosthetic infection of the shoulder.52

In summary, LE is a quick, efficient, and cost-effective test with good accuracy that is worth further exploration.

Interleukin-6

Interleukin-6 is a cytokine produced by almost all stromal cells and immunocytes.53 It plays an essential role in promoting plasma cell differentiation and eliciting hepatic acute-phase responses, which will cause high fever, anemia, and release of CRP.54–56 The normal serum IL-6 level is approximately 1 to 5 pg/mL, elevating to 30 to 430 pg/mL during menstruation, with cancer, and after surgery.53,57 Following arthroplasty implantation without infection, serum IL-6 reaches its peak in 6 to 12 hours and drops below 50 pg/mL in 48 hours. Because it responds and declines more quickly than CRP or ESR, IL-6 is considered a better indicator of postoperative inflammation.58,59 However, IL-6 does not perform better than traditional bio-markers in the diagnosis of PJI. In 2005, Di Cesare et al57 first reported that, using a cutoff value of 10 pg/mL, serum IL-6 had a sensitivity and a specificity of 100% and 95%, respectively, for diagnosing PJI, outperforming ESR and CRP. In studies concerning the diagnosis of periprosthetic hip or knee infection, the sensitivity and specificity of serum IL-6 vary greatly, ranging from 36% to 100% and from 68% to 95%, respectively.5,30,32,34,57,60,61 The difference in these results, as some have stated, is partly because of the lack of a “gold standard” to diagnose PJI, the rather small number of included patients, and changes in cutoff value and testing method.60,61 In a meta-analysis containing 3 early studies, Berbari et al62 showed that serum IL-6 was more accurate than CRP, ESR, and peripheral white blood cell count. However, later clinical studies showed that IL-6 could not outperform CRP in sensitivity or specificity.5,32,34,60,61 Xie et al63 concluded in a meta-analysis that the pooled sensitivities of serum and synovial fluid IL-6 were 72% and 91%, respectively, and that the pooled specificities of serum and synovial fluid IL-6 were 89% and 90%, respectively. The combination of serum CRP and IL-6 demonstrated a sensitivity of 57% to 100% and a specificity of 68% to 100%.30,32,60,61 Serum IL-6 also had a low sensitivity of 12.5% to 14% in the diagnosis of indolent shoulder infection caused by P acnes.12,59 Further, the level of serum IL-6 could be affected by inflammatory conditions such as sepsis, trauma, and arthritis.57,60

Synovial fluid had a higher concentration of IL-6 than serum and thus acquired better accuracy in the diagnosis of PJI.64,65 In 2007, Nilsdotter-Augustinsson64 demonstrated that synovial IL-6 had a sensitivity and a specificity of 69% and 93%, respectively, at a threshold of 10,000 pg/ mL in the diagnosis of periprosthetic hip infection. Deirmengian et al,66,67 Gollwitzer et al,68 and Jacovides et al69 separately examined and identified synovial fluid biomarkers but reached the same conclusion—synovial IL-6 has great potential in diagnosing prosthetic infection after total knee arthroplasty (TKA) or total hip arthroplasty (THA). In a meta-analysis containing 7 studies, Frangiamore et al7 showed that the overall sensitivity and specificity of synovial IL-6 were 87% and 89%, respectively, sharing the same accuracy as CRP (95%). Interestingly, in another study, Frangiamore et al70 demonstrated that synovial fluid IL-6 had high sensitivity and specificity (87% and 90%, respectively) in diagnosing periprosthetic shoulder infection, which has always been an obstacle for CRP, PCT, and serum IL-6. The disadvantage of synovial IL-6 is the same as that of CRP: being an inflammatory cytokine rather than a specific infection marker. Synovial IL-6 is upregulated in osteoarthritis, rheumatoid arthritis, and cartilage defects, leading to a diagnostic challenge in these cases.71,72

In conclusion, because of its relatively high accuracy and fast response, IL-6 is showing potential as a valuable predictor of PJI.

Defensins

Produced by primitive innate immunity, defensins are small, ubiquitous, and multifunctional polypeptides, acting as effectors in inflammation modulation, chemotaxis, and bactericidal activities.73,74 Defensins play a critical part in the pathogenesis of osteomyelitis and arthritis.75–77 There are three subtypes of defensins: alpha, beta, and theta. Only six alpha-defensins (HD5 and HD6; HNP-1, -2, -3, and -4) and seven beta-defensins (HBD-1, -2, -3, -4, -26, -27, and -28) are identified in the human body.78,79 Alpha-defensins are present mainly in the granules of neutrophils, while beta-defensins are secreted by mucosal cells, which may explain the preference for alpha-defensin in studying synovial fluid defensins.78,80 Recent studies have found that the level of synovial fluid alpha-defensin is unaffected by the type of organism or the preoperative use of antibiotics, making it a promising bio-marker for the diagnosis of implant-associated infection.81,82 In 2013, Gollwitzer et al68 first demonstrated a marked elevation of cathelicidin LL-37 and human beta-defensin-3 (HBD-3) in joint aspirates of 35 PJI patients, with areas under the curve of 0.745 and 0.875, respectively. In a study involving 95 revision THA or TKA patients, some of whom had systemic inflammatory disease, Deirmengian et al67 reported that alpha-defensin had an excellent performance of 100% sensitivity and 100% specificity in the diagnosis of infection. Later studies all reached the same conclusion—alpha-defensin has a sensitivity and a specificity of more than 95% in the diagnosis of PJI, outperforming the LE test.46,82–85 A meta-analysis containing 6 studies calculated that the pooled sensitivity and specificity of alpha-defensin were 100% and 96%, respectively.48 In a more recent study, Yuan et al86 showed that the pooled diagnostic sensitivity of alpha-defensin for PJI was 96% and the specificity was 95%. However, the sensitivity and the specificity of synovial alpha-defensin decrease to 63% and 95%, respectively, for the diagnosis of peri-prosthetic shoulder infection related to P acnes.87 A similar decrease in accuracy has also been reported for the diagnosis of infection in second-stage revision THA or revision TKA (sensitivity, 67%; specificity, 97%).85 Changing the testing method from immunoassay to lateral flow test also deceases the sensitivity to 67% for the diagnosis of PJI.88

Generally, based on its high accuracy, synovial alpha-defensin is now the most promising biomarker for the diagnosis of implant infection and has the potential to be “the orthopedic mirror of the human chorionic gonadotropin test.”89 However, testing for alpha-defensin is expensive (approximately US $760). A standard testing method and the diagnostic value against less virulent bacteria should be determined for alpha-defensin to become a practical biomarker.48,89 The meta-analysis results and the characteristics of current major biomarkers in diagnosing implant-associated infection are summarized in Table 1.

Meta-Analysis and Characteristics of Different Biomarkers for the Diagnosis of Implant-Associated Infection

Table 1:

Meta-Analysis and Characteristics of Different Biomarkers for the Diagnosis of Implant-Associated Infection

Bacterial Genetic Markers

Diagnostic biomarkers based on innate immune response are convenient and ready to use. However, in some circumstances, it is difficult for these biomarkers to distinguish between aseptic inflammation and low virulence infections. Also, testing protein-based biomarkers requires tissue, making early detection difficult.90 As a result of advances in molecular technologies, new methods testing bacterial genetic markers are also being investigated. Typically, with these methods, fluid or tissue samples are collected adjacent to the implant for DNA extraction. Sonication of implants has been shown to improve the specificity of the polymerase chain reaction (PCR) results of the samples.91 Currently, molecular diagnosis of implant-associated infection mainly involves conventional broad-range PCR, specific PCR assays, and sequencing technology. The broad-range PCR tests bacteria-specific genes, including the 16S rDNA gene, the 23S rDNA gene, the rpoB gene, and the 16S–23S intergenic spacer located specifically in bacterial genomes.92 However, only 16S rDNA amplification, when yielding a positive result, allows precise identification of the organisms.93 Specific PCR assays are designed to test pathogen-specific genes and have been shown to be more sensitive than 16S rDNA PCR in testing for Staphylococcus aureus and Mycobacterium tuberculosis infection in bone.93,94 The sensitivity and the specificity of PCR for diagnosing implant-associated infection vary greatly, ranging from 16% to 96% and from 45% to 100%, respectively.90 In a meta-analysis consisting of 9 studies, Liu et al95 concluded that the sensitivity and the specificity of PCR of sonicated fluid for periprosthetic infection were 75% and 96%, respectively, equivalent to or better than those of intra-operative tissue culture. The potential of high-throughput sequencing for diagnosing infection is also being explored. The use of high-throughput sequencing allows for the establishment of a complete library of DNA within the aspirated fluid or tissue, thus providing better resolution than broad-range PCR for identifying possible bacteria. In a recent study, the sensitivity and the specificity of next-generation sequencing were 89.3% and 73.0%, respectively, while the sensitivity and specificity of tissue culture were 60.7% and 97.3%, respectively.96 Although sequencing cannot outperform tissue culture regarding diagnostic value, use of this macrogenomic method provides more thorough information on the whole picture of the organisms within the implant and offers a promising way to identify rare bacterial infections.96,97 Despite the benefits of early detection and organism identification, molecular methods have varied sensitivity and the potential for contamination, posing challenges to their use.92 Although the true value of diagnosis based on bacterial genetic markers remains unclear, they are a promising way to supplement tissue culture and may provide information to target therapy.98

Other Biomarkers

Many other inflammatory cytokines and bactericidal mediators have also been explored in pursuit of an optimal bio-marker for implant-associated infections. Gollwitzer et al68 showed that serum IL-4 and IL-6 had a specificity of 90.0% and 95.0% and a sensitivity of 60.0% and 46.7%, respectively, outperforming synovial IL-4 and IL-6. Gollwitzer et al68 also demonstrated that serum HBD-2 had a sensitivity of 80.0% and a specificity of 70%. Serum tumor necrosis factor-alpha and lipopolysaccharide-binding protein are small molecules induced by cytokines. Studies have found that tumor necrosis factor-alpha has a low sensitivity of 43% and that lipopolysaccharide-binding protein has both low sensitivity and specificity.30,99 In a recent study, Shahi et al100 demonstrated that serum D-dimer had a high sensitivity and specificity of 89% and 93%, respectively, in diagnosing PJI. This is encouraging because D-dimer is frequently tested, convenient, and inexpensive. Regarding synovial fluid biomarkers, Deirmengian et al66,67 identified that IL-1a, IL-1b, IL-6, IL-8, IL-10, IL-17, granulocyte colony-stimulating factor, elastase 2, bactericidal permeability-increasing protein, neutrophil gelatinase-associated lipocalin, lactoferrin, resistin, and thrombospondin all exhibit an area under the curve of more than 0.9, outperforming serum CRP. In addition to these markers, researchers also found that skin-derived antileukoproteinase and vascular endothelial growth factor were markedly elevated after infection and acquired good diagnostic accuracy.66,69 There were also studies focusing on the infected tissue as a whole. Toll-like receptors (TLRs) are a family of transmembrane receptors that take part in the reorganization of microbial components or pathogen-associated molecular patterns. In 2014, Cipriano et al101 investigated the expression of TLR messenger RNA in periprosthetic tissue using real-time PCR and concluded that TLR1 (sensitivity, 95.2%; specificity, 100%) and TLR6 (sensitivity, 85.7%; specificity, 82.8%) could be used to detect PJI.

Conclusion

The difference between implant-associated infection and aseptic inflammation (failure) is essential, both for making the diagnosis and monitoring the response to therapy. In recent years, serum and synovial biomarkers have been shown to predict periprosthetic infection more accurately. However, high-quality, large-scale studies regarding these biomarkers are lacking. Therefore, the identification of implant-associated bacterial infection remains a complicated process relying on a combination of clinical manifestation, examination, and even physician experience. However, as molecular medicine advances, convenient and cost-effective biomarkers will play an important role in the management of implant-associated infections.29,102

References

  1. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645–1654. doi:10.1056/NEJMra040181 [CrossRef] PMID:15483283
  2. Kapadia BH, Berg RA, Daley JA, Fritz J, Bhave A, Mont MA. Periprosthetic joint infection. Lancet. 2016;387(10016):386–394. doi:10.1016/S0140-6736(14)61798-0 [CrossRef] PMID:26135702
  3. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med. 2004;350(14):1422–1429. doi:10.1056/NEJMra035415 [CrossRef] PMID:15070792
  4. 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):61–5.e1. doi:10.1016/j.arth.2012.02.022 [CrossRef] PMID:22554729
  5. 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. doi:10.1093/cid/civ286 [CrossRef] PMID:25870326
  6. Parvizi J, Zmistowski B, Berbari EF, et al. New definition for periprosthetic joint infection: from the workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res. 2011;469(11):2992–2994. doi:10.1007/s11999-011-2102-9 [CrossRef] PMID:21938532
  7. 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 peri-prosthetic joint infection explantation. Clin Orthop Relat Res. 2016;474(7):1630–1639. doi:10.1007/s11999-016-4710-x [CrossRef] PMID:26821163
  8. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279(47):48487–48490. doi:10.1074/jbc.R400025200 [CrossRef] PMID:15337754
  9. Ansar W, Ghosh S. C-reactive protein and the biology of disease. Immunol Res. 2013;56(1):131–142. doi:10.1007/s12026-013-8384-0 [CrossRef] PMID:23371836
  10. 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-B(2):173–176. doi:10.1302/0301-620X.97B2.34550 [CrossRef] PMID:25628278
  11. Della Valle C, Parvizi J, Bauer TW, et al. American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline on: the diagnosis of periprosthetic joint infections of the hip and knee. J Bone Joint Surg Am. 2011;93(14):1355–1357. doi:10.2106/JBJS.9314EBO [CrossRef] PMID:21792503
  12. Grosso MJ, Frangiamore SJ, Saleh A, et al. Poor utility of serum interleukin-6 levels to predict indolent periprosthetic shoulder infections. J Shoulder Elbow Surg. 2014;23(9):1277–1281. doi:10.1016/j.jse.2013.12.023 [CrossRef] PMID:24725902
  13. Enayatollahi MA, Parvizi J. Diagnosis of infected total hip arthroplasty. Hip Int. 2015;25(4):294–300. doi:10.5301/hipint.5000266 [CrossRef] PMID:26044538
  14. Parvizi J, Fassihi SC, Enayatollahi MA. Diagnosis of periprosthetic joint infection following hip and knee arthroplasty. Orthop Clin North Am. 2016;47(3):505–515. doi:10.1016/j.ocl.2016.03.001 [CrossRef] PMID:27241375
  15. Tetreault MW, Wetters NG, Moric M, Gross CE, Della Valle CJ. Is syno-vial C-reactive protein a useful marker for periprosthetic joint infection?Clin Orthop Relat Res. 2014;472(12):3997–4003. doi:10.1007/s11999-014-3828-y [CrossRef] PMID:25070920
  16. Parvizi J, McKenzie JC, Cashman JP. Diagnosis of periprosthetic joint infection using synovial C-reactive protein. J Arthroplasty. 2012;27(8)(suppl):12–16. doi:10.1016/j.arth.2012.03.018 [CrossRef] PMID:22560655
  17. 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. doi:10.1007/s11999-011-1991-y [CrossRef] PMID:21786056
  18. Wang C, Wang Q, Li R, Duan JY, Wang CB. Synovial fluid C-reactive protein as a diagnostic marker for periprosthetic joint infection: a systematic review and meta-analysis. Chin Med J (Engl).2016;129(16):1987–1993. doi:10.4103/0366-6999.187857 [CrossRef] PMID:27503025
  19. Vanderstappen C, Verhoeven N, Stuyck J, Bellemans J. Intra-articular versus serum C-reactive protein analysis in suspected peri-prosthetic knee joint infection. Acta Orthop Belg. 2013;79(3):326–330. PMID:23926737
  20. Ronde-Oustau C, Diesinger Y, Jenny JY, et al. Diagnostic accuracy of intra-articular C-reactive protein assay in periprosthetic knee joint infection: a preliminary study. Orthop Traumatol Surg Res. 2014;100(2):217–220. doi:10.1016/j.otsr.2013.10.017 [CrossRef] PMID:24582652
  21. Ali S, Christie A, Chapel A. The pattern of procalcitonin in primary total hip and knee arthroplasty and its implication in periprosthetic infection. J Clin Med Res. 2009;1(2):90–94. doi:10.4021/jocmr2009.04.1236 [CrossRef] PMID:22505973
  22. Davies J. Procalcitonin. J Clin Pathol. 2015;68(9):675–679. doi:10.1136/jclinpath-2014-202807 [CrossRef] PMID:26124314
  23. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552. doi:10.1097/CCM.0000000000002255 [CrossRef] PMID:28098591
  24. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–810. doi:10.1001/jama.2016.0287 [CrossRef] PMID:26903338
  25. Shaikh MM, Hermans LE, van Laar JM. Is serum procalcitonin measurement a useful addition to a rheumatologist's repertoire? A review of its diagnostic role in systemic inflammatory diseases and joint infections. Rheumatology (Oxford). 2015;54(2): 231–240. doi:10.1093/rheumatology/keu416 [CrossRef] PMID:25349443
  26. Hügle T, Schuetz P, Mueller B, et al. Serum procalcitonin for discrimination between septic and non-septic arthritis. Clin Exp Rheumatol. 2008;26(3):453–456. PMID:18578968
  27. Talebi-Taher M, Shirani F, Nikanjam N, Shekarabi M. Septic versus inflammatory arthritis: discriminating the ability of serum inflammatory markers. Rheumatol Int. 2013;33(2):319–324. doi:10.1007/s00296-012-2363-y [CrossRef] PMID:22447329
  28. Wu JY, Lee SH, Shen CJ, et al. Use of serum procalcitonin to detect bacterial infection in patients with autoimmune diseases: a systematic review and meta-analysis. Arthritis Rheum. 2012;64(9):3034–3042. doi:10.1002/art.34512 [CrossRef] PMID:22605405
  29. Alvand A, Rezapoor M, Parvizi J. The role of biomarkers for the diagnosis of implant-related infections in orthopaedics and trauma. Adv Exp Med Biol. 2017;971:69–79. doi:10.1007/5584_2017_11 [CrossRef] PMID:28243953
  30. 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. doi:10.1302/0301-620X.89B1.17485 [CrossRef] PMID:17259424
  31. Xie K, Qu X, Yan M. Procalcitonin and alpha-defensin for diagnosis of periprosthetic joint infections. J Arthroplasty. 2017;32(4):1387–1394. doi:10.1016/j.arth.2016.10.001 [CrossRef] PMID:27817992
  32. Glehr M, Friesenbichler J, Hofmann G, et al. Novel biomarkers to detect infection in revision hip and knee arthroplasties. Clin Orthop Relat Res. 2013;471(8):2621–2628. doi:10.1007/s11999-013-2998-3 [CrossRef] PMID:23609811
  33. Yuan K, Li WD, Qiang Y, Cui ZM. Comparison of procalcitonin and C-reactive protein for the diagnosis of periprosthetic joint infection before revision total hip arthroplasty. Surg Infect (Larchmt). 2015;16(2):146–150. doi:10.1089/sur.2014.034 [CrossRef] PMID:25658716
  34. Randau TM, Friedrich MJ, Wimmer MD, et al. Interleukin-6 in serum and in synovial fluid enhances the differentiation between peri-prosthetic joint infection and aseptic loosening. PLoS One. 2014;9(2):e89045. doi:10.1371/journal.pone.0089045 [CrossRef] PMID:24586496
  35. Drago L, Vassena C, Dozio E, et al. Procalcitonin, C-reactive protein, interleukin-6, and soluble intercellular adhesion molecule-1 as markers of postoperative orthopaedic joint prosthesis infections. Int J Immunopathol Pharmacol. 2011;24(2):433–440. doi:10.1177/039463201102400216 [CrossRef] PMID:21658317
  36. 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(4):845–849. doi:10.1007/s15010-013-0467-2 [CrossRef] PMID:23645456
  37. Wang C, Zhong D, Liao Q, Kong L, Liu A, Xiao H. Procalcitonin levels in fresh serum and fresh synovial fluid for the differential diagnosis of knee septic arthritis from rheumatoid arthritis, osteoarthritis and gouty arthritis. Exp Ther Med. 2014;8(4):1075–1080. doi:10.3892/etm.2014.1870 [CrossRef] PMID:25187799
  38. Battistelli S, Fortina M, Carta S, Guerranti R, Nobile F, Ferrata P. Serum C-reactive protein and procalcitonin kinetics in patients undergoing elective total hip arthroplasty. BioMed Res Int. 2014;2014:565080. doi:10.1155/2014/565080 [CrossRef] PMID:24877114
  39. Shen CJ, Wu MS, Lin KH, et al. The use of procalcitonin in the diagnosis of bone and joint infection: a systemic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32(6):807–814. doi:10.1007/s10096-012-1812-6 [CrossRef] PMID:23334663
  40. 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. doi:10.2106/JBJS.J.01413 [CrossRef] PMID:22258769
  41. Kheir MM, Ackerman CT, Tan TL, Benazzo A, Tischler EH, Parvizi J. Leukocyte esterase strip test can predict subsequent failure following reimplantation in patients with periprosthetic joint infection. J Arthroplasty. 2017;32(6):1976–1979. doi:10.1016/j.arth.2017.01.031 [CrossRef] PMID:28215967
  42. Gautam VK, Saini R, Sharma S. Effectiveness of leucocyte esterase as a diagnostic test for acute septic arthritis. J Orthop Surg (Hong Kong). 2017;25(1). doi:10.1177/2309499016685019 [CrossRef] PMID:28134047
  43. Aggarwal VK, Tischler E, Ghanem E, Parvizi J. Leukocyte esterase from synovial fluid aspirate: a technical note. J Arthroplasty. 2013;28(1):193–195. doi:10.1016/j.arth.2012.06.023 [CrossRef] PMID:22868070
  44. Wetters NG, Berend KR, Lombardi AV, Morris MJ, Tucker TL, Della Valle CJ. Leukocyte esterase reagent strips for the rapid diagnosis of periprosthetic joint infection. J Arthroplasty. 2012;27(8)(suppl):8–11. doi:10.1016/j.arth.2012.03.037 [CrossRef] PMID:22608686
  45. 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. doi:10.2106/JBJS.M.01591 [CrossRef] PMID:25410511
  46. Deirmengian C, Kardos K, Kilmartin P, et al. The alpha-defensin test for peri-prosthetic joint infection outperforms the leukocyte esterase test strip. Clin Orthop Relat Res. 2015;473(1):198–203. doi:10.1007/s11999-014-3722-7 [CrossRef] PMID:24942960
  47. Colvin OC, Kransdorf MJ, Roberts CC, et al. Leukocyte esterase analysis in the diagnosis of joint infection: can we make a diagnosis using a simple urine dipstick?Skeletal Radiol.2015;44(5):673–677. doi:10.1007/s00256-015-2097-5 [CrossRef] PMID:25626524
  48. Wyatt MC, Beswick AD, Kunutsor SK, Wilson MJ, Whitehouse MR, Blom AW. The alpha-defensin immunoassay and leukocyte esterase colorimetric strip test for the diagnosis of periprosthetic infection: a systematic review and meta-analysis. J Bone Joint Surg Am. 2016;98(12):992–1000. doi:10.2106/JBJS.15.01142 [CrossRef] PMID:27307359
  49. 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. doi:10.2106/JBJS.N.00173 [CrossRef] PMID:25520336
  50. McNabb DC, Dennis DA, Kim RH, Miner TM, Yang CC, Jennings JM. Determining false positive rates of leukocyte esterase reagent strip when used as a detection tool for joint infection. J Arthroplasty. 2017;32(1):220–222. doi:10.1016/j.arth.2016.05.065 [CrossRef] PMID:27369297
  51. Tischler EH, Plummer DR, Chen AF, Della Valle CJ, Parvizi J. Leukocyte esterase: metal-on-metal failure and periprosthetic joint infection. J Arthroplasty. 2016;31(10):2260–2263. doi:10.1016/j.arth.2016.03.012 [CrossRef] PMID:27094243
  52. Nelson GN, Paxton ES, Narzikul A, Williams G, Lazarus MD, Abboud JA. Leukocyte esterase in the diagnosis of shoulder periprosthetic joint infection. J Shoulder Elbow Surg. 2015;24(9):1421–1426. doi:10.1016/j.jse.2015.05.034 [CrossRef] PMID:26279499
  53. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–457. doi:10.1038/ni.3153 [CrossRef] PMID:25898198
  54. Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2(4):288–294. doi:10.1158/2326-6066.CIR-14-0022 [CrossRef] PMID:24764575
  55. Kishimoto T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol. 2005;23(1): 1–21. doi:10.1146/annurev.immunol.23.021704.115806 [CrossRef] PMID:15771564
  56. Hack CE, De Groot ER, Felt-Bersma RJ, et al. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989;74(5):1704–1710. doi:10.1182/blood.V74.5.1704.1704 [CrossRef] PMID:2790194
  57. Di Cesare PE, Chang E, Preston CF, Liu CJ. 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. doi:10.2106/00004623-200509000-00003 [CrossRef] PMID:16140805
  58. Wirtz DC, Heller KD, Miltner O, Zilkens KW, Wolff JM. Interleukin-6: a potential inflammatory marker after total joint replacement. Int Orthop. 2000;24(4):194–196. doi:10.1007/s002640000136 [CrossRef] PMID:11081839
  59. Villacis D, Merriman JA, Yalamanchili R, Omid R, Itamura J, Rick Hatch GF III, . Serum interleukin-6 as a marker of periprosthetic shoulder infection. J Bone Joint Surg Am. 2014;96(1):41–45. doi:10.2106/JBJS.L.01634 [CrossRef] PMID:24382723
  60. Buttaro MA, Tanoira I, Comba F, Piccaluga F. Combining C-reactive protein and interleukin-6 may be useful to detect periprosthetic hip infection. Clin Orthop Relat Res. 2010;468(12):3263–3267. doi:10.1007/s11999-010-1451-0 [CrossRef] PMID:20623261
  61. Elgeidi A, Elganainy AE, Abou Elkhier N, Rakha S. Interleukin-6 and other inflammatory markers in diagnosis of periprosthetic joint infection. Int Orthop. 2014;38(12):2591–2595. doi:10.1007/s00264-014-2475-y [CrossRef] PMID:25117573
  62. Berbari E, Mabry T, Tsaras G, et al. Inflammatory blood laboratory levels as markers of prosthetic joint infection: a systematic review and meta-analysis. J Bone Joint Surg Am. 2010;92(11):2102–2109. doi:10.2106/JBJS.I.01199 [CrossRef] PMID:20810860
  63. Xie K, Dai K, Qu X, Yan M.Serum and synovial fluid interleukin-6 for the diagnosis of periprosthetic joint infection. Sci Rep. 2017;7:1496.
  64. Nilsdotter-Augustinsson A, Briheim G, Herder A, Ljunghusen O, Wahlström O, Ohman L. Inflammatory response in 85 patients with loosened hip prostheses: a prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening. Acta Orthop. 2007;78(5):629–639. doi:10.1080/17453670710014329 [CrossRef] PMID:17966022
  65. Lenski M, Scherer MA. Synovial IL-6 as inflammatory marker in periprosthetic joint infections. J Arthroplasty. 2014;29(6):1105–1109. doi:10.1016/j.arth.2014.01.014 [CrossRef] PMID:24559521
  66. Deirmengian C, Hallab N, Tarabishy A, et al. Synovial fluid biomarkers for periprosthetic infection. Clin Orthop Relat Res.2010;468(8):2017–2023. doi:10.1007/s11999-010-1298-4 [CrossRef] PMID:20300901
  67. 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. doi:10.1007/s11999-014-3543-8 [CrossRef] PMID:24590839
  68. 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. doi:10.2106/JBJS.L.00205 [CrossRef] PMID:23553300
  69. 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. doi:10.1016/j.arth.2011.03.025 [CrossRef] PMID:21570803
  70. Frangiamore SJ, Saleh A, Kovac MF, et al. Synovial fluid interleukin-6 as a predictor of periprosthetic shoulder infection. J Bone Joint Surg Am. 2015;97(1):63–70. doi:10.2106/JBJS.N.00104 [CrossRef] PMID:25568396
  71. Tsuchida AI, Beekhuizen M, Rutgers M, et al. Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model. Arthritis Res Ther. 2012;14(6):R262. doi:10.1186/ar4107 [CrossRef] PMID:23206933
  72. Kokebie R, Aggarwal R, Lidder S, et al. The role of synovial fluid markers of catabolism and anabolism in osteoarthritis, rheumatoid arthritis and asymptomatic organ donors. Arthritis Res Ther. 2011;13(2):R50. doi:10.1186/ar3293 [CrossRef] PMID:21435227
  73. Glynn AA, Milne CM. Lysozyme and immune bacteriolysis. Nature. 1965;207(5003):1309–1310. doi:10.1038/2071309a0 [CrossRef] PMID:5328060
  74. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003;3(9):710–720. doi:10.1038/nri1180 [CrossRef] PMID:12949495
  75. Varoga D, Wruck CJ, Tohidnezhad M, et al. Osteoblasts participate in the innate immunity of the bone by producing human beta defensin-3. Histochem Cell Biol. 2009;131(2): 207–218. doi:10.1007/s00418-008-0522-8 [CrossRef] PMID:18925411
  76. Varoga D, Tohidnezhad M, Paulsen F, et al. The role of human beta-defensin-2 in bone. J Anat. 2008;213(6):749–757. doi:10.1111/j.1469-7580.2008.00992.x [CrossRef] PMID:19094191
  77. Paulsen F, Pufe T, Conradi L, et al. Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J Pathol. 2002;198(3):369–377. doi:10.1002/path.1224 [CrossRef] PMID:12375270
  78. Hazlett L, Wu M. Defensins in innate immunity. Cell Tissue Res. 2011;343(1):175–188. doi:10.1007/s00441-010-1022-4 [CrossRef] PMID:20730446
  79. Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016;44(D1):D1087–D1093. doi:10.1093/nar/gkv1278 [CrossRef] PMID:26602694
  80. Lehrer RI, Lu W. Alpha-defensins in human innate immunity. Immunol Rev. 2012;245(1):84–112. doi:10.1111/j.1600-065X.2011.01082.x [CrossRef] PMID:22168415
  81. Deirmengian C, Kardos K, Kilmartin P, Gulati S, Citrano P, Booth RE Jr, . The alpha-defensin test for periprosthetic joint infection responds to a wide spectrum of organisms. Clin Orthop Relat Res. 2015;473(7):2229–2235. doi:10.1007/s11999-015-4152-x [CrossRef] PMID:25631170
  82. Shahi A, Parvizi J, Kazarian GS, et al. The alpha-defensin test for periprosthetic joint infections is not affected by prior antibiotic administration. Clin Orthop Relat Res. 2016;474(7):1610–1615. doi:10.1007/s11999-016-4726-2 [CrossRef] PMID:26864855
  83. 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. doi:10.1007/s11999-014-3900-7 [CrossRef] PMID:25256621
  84. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Combined measurement of synovial fluid alpha-defensin and C-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection. J Bone Joint Surg Am. 2014;96(17):1439–1445. doi:10.2106/JBJS.M.01316 [CrossRef] PMID:25187582
  85. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. Alpha-defensin accuracy to diagnose periprosthetic joint infection: best available test?J Arthroplasty. 2016;31(2):456–460. doi:10.1016/j.arth.2015.09.035 [CrossRef] PMID:26545577
  86. Yuan J, Yan Y, Zhang J, Wang B, Feng J. Diagnostic accuracy of alpha-defensin in periprosthetic joint infection: a systematic review and meta-analysis. Int Orthop. 2017;41:2447–2455.
  87. Frangiamore SJ, Saleh A, Grosso MJ, et al. Alpha-defensin as a predictor of periprosthetic shoulder infection. J Shoulder Elbow Surg. 2015;24(7):1021–1027. doi:10.1016/j.jse.2014.12.021 [CrossRef] PMID:25672257
  88. Arco AD, Bertrand ML. The diagnosis of periprosthetic infection. Open Orthop J. 2013;7:178–183. doi:10.2174/1874325001307010178 [CrossRef] PMID:23898349
  89. Sheehan E. CORR Insights®: the alpha-defensin test for periprosthetic joint infection outperforms the leukocyte esterase test strip. Clin Orthop Relat Res. 2015;473(1): 204–205. doi:10.1007/s11999-014-3794-4 [CrossRef] PMID:25028108
  90. Omar M, Suero EM, Liodakis E, et al. Diagnostic performance of swab PCR as an alternative to tissue culture methods for diagnosing infections associated with fracture fixation devices. Injury. 2016;47(7):1421–1426. doi:10.1016/j.injury.2016.04.038 [CrossRef] PMID:27181839
  91. Renz N, Cabric S, Morgenstern C, Schuetz MA, Trampuz A. Value of PCR in sonication fluid for the diagnosis of orthopedic hardware-associated infections: has the molecular era arrived?Injury. 2018;49(4):806–811. doi:10.1016/j.injury.2018.02.018 [CrossRef] PMID:29486892
  92. Lévy PY, Fenollar F. The role of molecular diagnostics in implant-associated bone and joint infection. Clin Microbiol Infect. 2012;18(12):1168–1175. doi:10.1111/1469-0691.12020 [CrossRef] PMID:23148447
  93. Fenollar F, Roux V, Stein A, Drancourt M, Raoult D. Analysis of 525 samples to determine the usefulness of PCR amplification and sequencing of the 16S rRNA gene for diagnosis of bone and joint infections. J Clin Microbiol. 2006;44(3):1018–1028. doi:10.1128/JCM.44.3.1018-1028.2006 [CrossRef] PMID:16517890
  94. Lecouvet F, Irenge L, Vandercam B, Nzeusseu A, Hamels S, Gala JL. The etiologic diagnosis of infectious discitis is improved by amplification-based DNA analysis. Arthritis Rheum. 2004;50(9):2985–2994. doi:10.1002/art.20462 [CrossRef] PMID:15457468
  95. Liu K, Fu J, Yu B, Sun W, Chen J, Hao L. Meta-analysis of sonication prosthetic fluid PCR for diagnosing periprosthetic joint infection. PLoS One. 2018;13(4):e0196418. doi:10.1371/journal.pone.0196418 [CrossRef] PMID:29702663
  96. Tarabichi M, Shohat N, Goswami K, et al. Diagnosis of periprosthetic joint infection: the potential of next-generation sequencing. J Bone Joint Surg Am. 2018;100(2):147–154. doi:10.2106/JBJS.17.00434 [CrossRef] PMID:29342065
  97. Street TL, Sanderson ND, Atkins BL, et al. Molecular diagnosis of orthopedic-device-related infection directly from sonication fluid by metagenomic sequencing. J Clin Microbiol. 2017;55(8):2334–2347. doi:10.1128/JCM.00462-17 [CrossRef] PMID:28490492
  98. Suda AJ, Tinelli M, Beisemann ND, Weil Y, Khoury A, Bischel OE. Diagnosis of peri-prosthetic joint infection using alpha-defensin test or multiplex-PCR: ideal diagnostic test still not found. Int Orthop. 2017;41(7): 1307–1313. doi:10.1007/s00264-017-3412-7 [CrossRef] PMID:28160020
  99. Friedrich MJ, Randau TM, Wimmer MD, et al. Lipopolysaccharide-binding protein: a valuable biomarker in the differentiation between periprosthetic joint infection and aseptic loosening?Int Orthop.2014;38(10):2201–2207. doi:10.1007/s00264-014-2351-9 [CrossRef] PMID:24827968
  100. Shahi A, Kheir MM, Tarabichi M, Hosseinzadeh HRS, Tan TL, Parvizi J. Serum D-dimer test is promising for the diagnosis of periprosthetic joint infection and timing of reimplantation. J Bone Joint Surg Am. 2017;99(17):1419–1427. doi:10.2106/JBJS.16.01395 [CrossRef] PMID:28872523
  101. Cipriano C, Maiti A, Hale G, Jiranek W. The host response: toll-like receptor expression in periprosthetic tissues as a bio-marker for deep joint infection. J Bone Joint Surg Am. 2014;96(20):1692–1698. doi:10.2106/JBJS.M.01295 [CrossRef] PMID:25320195
  102. Shahi A, Parvizi J. The role of biomarkers in the diagnosis of periprosthetic joint infection. EFORT Open Rev. 2017;1(7):275–278. doi:10.1302/2058-5241.1.160019 [CrossRef] PMID:28461959

Meta-Analysis and Characteristics of Different Biomarkers for the Diagnosis of Implant-Associated Infection

BiomarkerMain originSampleStudyNo. of studies includedSensitivitySpecificityInfluenced by inflammation or trauma?
CRPLiverSerumYuan et al,33 2014250.820.77Yes
Synovial fluidWang et al,18 201660.920.90
ESRNASerumBerbari et al,62 2010300.750.70Yes
PCTParathyroidSerumXie et al,31 201660.530.92No
LENeutrophilsSynovial fluidWyatt et al,48 201650.810.97Yes
IL-6Stromal cells, immunocytesSerumXie et al,63 2017110.720.89Yes
Synovial fluidXie et al,63 201780.910.90
Alpha-defensinNeutrophilsSynovial fluidYuan et al,86 2017110.960.95No
Authors

The authors are from the Department of Traumatology and Orthopaedic Surgery (XL, NJ, BY), Nanfang Hospital, Southern Medical University, Guangzhou, and the Department of Rehabilitation Medicine (TW), West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Drs Liu and Jiang contributed equally to this work and should be considered as equal first authors.

This work was supported by the National Natural Science Foundation of China (grants 81802182, 81830079) and Guangdong Provincial Science and Technology Plan Projects (grant 2016B090913004).

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Bin Yu, MD, PhD, Department of Traumatology and Orthopaedic Surgery, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Ave North, Baiyun District, Guangzhou, 510515, China ( yubin@smu.edu.cn).

Received: May 15, 2019
Accepted: October 09, 2019
Posted Online: January 07, 2021

10.3928/01477447-20210104-07

Sign up to receive

Journal E-contents