Synovial Fluid Biomarkers for the Diagnosis of Periprosthetic Joint Infection-A Systematic Review and Meta-Analysis of Their Diagnostic Accuracy According to Different Definitions.

BACKGROUND: Different synovial fluid biomarkers have emerged to improve periprosthetic joint infection (PJI) diagnosis. The goals of this paper were (i) to assess their diagnostic accuracy and (ii) to evaluate their performance according to different PJI definitions. METHODS: A systematic review and meta-analysis was performed using studies that reported diagnostic accuracy of synovial fluid biomarkers using validated PJI definitions published from 2010 to March 2022. A database search was performed through PubMed, Ovid MEDLINE, Central, and Embase. The search identified 43 different biomarkers with four being the more commonly studied, with 75 papers overall: alpha-defensin; leukocyte esterase; synovial fluid C-reactive protein; and calprotectin. RESULTS: Overall accuracy was higher for calprotectin, followed by alpha-defensin, leukocyte esterase, and synovial fluid C-reactive protein with sensitivities of 78 to 92% and specificities of 90 to 95%. Their diagnostic performance was different according to which definition was adopted as the reference. Specificity was consistently high across definitions for all four biomarkers. Sensitivity varied the most with lower values for the more sensitive European Bone and Joint Infection Society or Infectious Diseases Society of America definitions with higher values for the Musculoskeletal Infection Society definition. The International Consensus Meeting 2018 definition showed intermediate values. CONCLUSION: All evaluated biomarkers had good specificity and sensitivity, making their use acceptable in the diagnosis of PJI. Biomarkers perform differently according to the selected PJI definitions.

The optimal diagnostic cut-off of WBC and PMN counts for joint aspiration in periprosthetic joint infection is 2479/µL and 67%, respectively: ICM criteria thresholds are too high.

BACKGROUND: Various organizations have published definitions for periprosthetic joint infection (PJI) with significant differences in the cut-offs of white blood cell (WBC) count and polymorphonuclear (PMN) leukocyte cells. Herein, we aim to analyze optimal cut-offs in patients which are planned to undergo a prosthesis revision and compare them with the actual published thresholds of the International Consensus Meeting (ICM) and European Bone and Joint Infection Society (EBJIS). METHODS: A test kit was compiled in a monocentric prospective study, according to the ICM criteria (2018) and 2021 EBJIS criteria. The kit was implemented using: blood samples (including leukocyte count and C-reactive protein); samples for examining the synovial fluid (WBC count, PMN cell differentiation, microbiological culture for incubation over 14 days, alpha-defensin ELISA laboratory test, and leukocyte-esterase test). The cut-offs for WBC and PMN counts were investigated using ROC analyses and Youden index. The ICM 2018 criteria were applied, using alpha-defensin in all cases. Patients which have to undergo a prosthesis revision were included, a pre-operative joint aspiration had been performed, and the patients had been followed up prospectively. RESULTS: 405 patients were examined with the compiled test kit; 100% had a complete dataset with respect to alpha-defensin; 383 patients, according to WBC count; and 256, according to PMN cell differentiation The cut-off of 2478.89 cells/µl in the WBC count (sensitivity: 87.70%; specificity: 88.10%) and the cut-off of 66.99% in PMN differentiation showed the best accuracy (sensitivity: 86.00%; specificity: 88.80%). Other published cut-offs for WBC were tested in this cohort and showed the following accuracy: 3000/µl (EBJIS/ICM; sensitivity: 82.10%; specificity: 91.00%), 2000/µl (sensitivity: 89.60%; specificity: 83.40%), and 1500/µl (sensitivity: 91.50%; specificity: 75.00%). The published cut-offs for PMN had the following accuracy in this cohort: 80% (ICM; sensitivity: 66.3%; specificity: 96.50%), 70% (sensitivity: 82.6%; specificity: 90%), and 65% (EBJIS, sensitivity: 86%; specificity: 88.8%). CONCLUSIONS: This study aims to improve current cut-offs for PMN- and WB-Count, even though PJI diagnosis is based on the combination of all defined tests. The optimal diagnostic cut-off of WBC and PMN counts was found to be 2479/µL and 67%, respectively, whereas ICM cut-offs in this cohort seem too high, as they provide high specificity but very low sensitivity. On the other hand, a cut-off for WBC count of 1500/µl alone would be very low, leading to low specificity and very high suspicion of PJI. The current consensus guidelines could be actualized considering these results to significantly improve the diagnostic quality. LEVEL OF EVIDENCE: II.

Which Minor Criteria is the Most Accurate Predictor for the Diagnosis of Hip and Knee Periprosthetic Joint Infection in the Asian Population?

BACKGROUND: The aim of this study was to evaluate the diagnostic performance of minor criteria from the 2018 International Consensus Meeting (ICM) for the diagnosis of chronic periprosthetic joint infection (PJI) in an Asian population. METHODS: We retrospectively reviewed 76 patients who underwent a revision knee or hip arthroplasty at an academic institution between September 2018 and December 2019. All major and minor 2018 ICM criteria were available for all patients included. Cases with at least 1 major criterion or score ≥6 in minor criteria were considered as infected. The diagnostic performance was evaluated by a receiver operative characteristic curve analysis and area under the curve (AUC) for each minor criterion. An AUC value of more than 0.9 was considered outstanding and 0.8-0.9 as excellent. RESULTS: When using 2018 ICM threshold, the diagnostic performance ranked based on AUC was the following: alpha defensin (0.92), positive histology (0.83), leukocyte esterase (0.82), synovial white blood cell (0.81), serum erythrocyte sedimentation rate (0.78), synovial polymorphonuclear neutrophils (0.77), serum C-reactive protein (0.74), D-dimer (0.59), single positive culture (0.53), and positive intraoperative purulence (0.51). Alpha defensin was considered as an outstanding test among the 2018 ICM minor criteria. Positive histology, leukocyte esterase, and synovial white blood cell were considered as excellent tests. CONCLUSION: Based on our findings, alpha-defensin has the best diagnostic performance in Asian population among the minor criteria of 2018 ICM.

GMI, an Immunomodulatory Peptide from Ganoderma microsporum, Restrains Periprosthetic Joint Infections via Modulating the Functions of Myeloid-Derived Suppressor Cells and Effector T Cells.

Periprosthetic joint infections (PJIs) caused by Staphylococcus aureus infection are difficult to treat due to antibiotic resistance. It is known that the biofilms from methicillin-resistant S. aureus (MRSA) promote expansion of myeloid-derived suppressor cells (MDSCs) to suppress T-cell proliferation and benefit bacterial infections. This study finds that GMI, a fungal immunomodulatory peptide isolated from Ganoderma microsporum, suppresses MDSC expansion to promote the proliferation of cytotoxic T cells. The enhancement is likely attributed to increased expression of IL-6 and TNF-α and reduction in ROS expression. Similar beneficial effects of GMI on the suppression of MDSC expansion and IL-6 expression are also observed in the whole blood and reduces the accumulation of MDSCs in the infected bone region in a mouse PJI infection model. This study shows that GMI is potentially useful for treating S. aureus-induced PJIs.

Synovial Fluid Aspirates Diluted with Saline or Blood Reduce the Sensitivity of Traditional and Contemporary Synovial Fluid Biomarkers.

BACKGROUND: Recent criteria-based diagnostic tools to diagnose periprosthetic infection (PJI), such as the International Consensus Meeting (ICM) definition of PJI, are heavily reliant on synovial fluid laboratory results. Despite the importance of synovial fluid in PJI diagnosis, the effect of the quality of synovial fluid aspirate on testing results has not been studied. Our laboratory has established quality control parameters to identify synovial fluid aspirates that are highly diluted by saline or blood, which appear to degrade the diagnostic performance of synovial fluid laboratory tests. QUESTIONS/PURPOSES: (1) What proportion of synovial fluid aspirates analyzed at one laboratory are of poor quality (defined as having a red blood count > 1M cells/uL or an optical density at 280 nm < 0.324 or > 1.19)? (2) Does a poor-quality aspirate decrease the sensitivities of International Consensus Meeting-based scores and other synovial fluid biomarker tests in terms of their ability to anticipate a positive culture? METHODS: From January 2016 to July 2019, a total of 123,549 synovial fluid samples were submitted to one laboratory for the purpose of diagnostic testing. Of these, 14% (16,773 of 123,549) samples were excluded because they were from a site other than a hip, knee, or shoulder arthroplasty, and an additional 33% (35,660 of 106,776) were excluded due to insufficient requested tests, resulting in 58% (71,116 of 123,549) samples included in this study. Specimens diluted with extreme levels of saline or blood were identified (defined as having a red blood count >1 M cells/uL or an optical density at 280 nm < 0.324 or > 1.19) as poor-quality aspirates. The sensitivities of synovial fluid C-reactive protein, alpha defensin, neutrophil elastase, white blood cell count, polymorphonuclear cell percentage, and the 2018 ICM-based tool were assessed in good-quality versus poor-quality synovial fluid samples. To avoid bias from using these evaluated tests within the reference definition of PJI in this study, a positive culture resulting from the synovial fluid served as the reference diagnosis defining a control cohort of PJI-positive samples. Although the low false-positive rate of synovial fluid culture allows for the valid estimation of synovial fluid test sensitivity, the high false-negative rate of synovial fluid culture prevents the valid estimation of test specificity, which was not evaluated in this study. RESULTS: Of the samples analyzed, 8% (6025 of 71,116) were found to have poor quality, in that they were substantially compromised by saline and/or blood. The sensitivity of all tests to detect culture-positive synovial fluid was lower in poor-quality than in good-quality samples: 2018 International Consensus Meeting-based tool (83% [95% CI 80 to 86] versus 97% [95% CI 96 to 97]), synovial fluid C-reactive protein (65% [95% CI 61 to 69] versus 88% [95% CI 87 to 89]), alpha defensin (70% [95% CI 66 to 73] versus 93% [95% CI 93 to 94]), neutrophil elastase (80% [95% CI 77 to 83] versus 96% [95% CI 96 to 97]), synovial fluid white blood cell count (69% [95% CI 65 to 73] versus 93% [95% CI 93 to 94]), and the polymorphonuclear cell percentage (88% [95% CI 85 to 91] versus 95% [95% CI 94 to 95]), with all p < 0.001. CONCLUSIONS: When synovial fluid is substantially diluted with saline or blood, the biomarkers and cells being measured are also diluted, decreasing the sensitivity of laboratory testing. We recommend that future diagnostic studies exclude these samples because an artificial reduction in test sensitivity will be observed. CLINICAL RELEVANCE: Clinicians should avoid relying on negative synovial fluid testing to rule out PJI when the fluid submitted is substantially constituted of saline or blood. Further studies are necessary to understand the diagnostic utility, if any, of these diluted aspirate samples.

Synovial Fluid Interleukin-16 Contributes to Osteoclast Activation and Bone Loss through the JNK/NFATc1 Signaling Cascade in Patients with Periprosthetic Joint Infection.

Because of lipopolysaccharide (LPS)-mediated effects on osteoclast differentiation and bone loss, periprosthetic joint infection (PJI) caused by Gram-negative bacteria increases the risk of aseptic loosening after reimplantation. Synovial fluid interleukin-16 (IL-16) expression was higher in patients with PJI than in patients without joint infection. Thus, we explored the effects of IL-16 on bone. We investigated whether IL-16 modulates osteoclast or osteoblast differentiation in vitro. An LPS-induced bone loss mice model was used to explore the possible advantages of IL-16 inhibition for the prevention of bone loss. IL-16 directly activated p38 and c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signaling and increased osteoclast activation markers, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, and nuclear factor of activated T cells 1 (NFATc1). IL-16 directly caused monocytes to differentiate into TRAP-positive osteoclast-like cells through NFATc1 activation dependent on JNK/MAPK signaling. Moreover, IL-16 did not alter alkaline phosphatase activity or calcium deposition during osteoblastic differentiation. Finally, IL-16 inhibition prevented LPS-induced trabecular bone loss and osteoclast activation in vivo. IL-16 directly increased osteoclast activation through the JNK/NFATc1 pathway. IL-16 inhibition could represent a new strategy for treating infection-associated bone loss.

Analysis of synovial biomarkers with a multiplex protein microarray in patients with PJI undergoing revision arthroplasty of the hip or knee joint.

INTRODUCTION: Diagnosing a (low-grade) periprosthetic joint infection (PJI) after hip or knee arthroplasty remains a diagnostic challenge. The aim of this study was to evaluate the utility of using a novel multiplex protein microarray system for synovial biomarkers in determining PJI in patients undergoing revision knee or hip arthroplasty. MATERIALS AND METHODS: The individual synovial fluid levels of 12 cytokines (IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, GM-CSF, TNF-α, and INF-γ) were analysed with a novel multiplex protein microarray system in 32 patients undergoing revision hip (n = 22) or knee (n = 10) arthroplasty. Cases were classified into septic and aseptic groups on basis of pre- and interoperative findings: [PJI (n = 14) vs. non-PJI (n = 18)]. Receiver operator characteristic (ROC) curves were calculated to assess the discriminatory strength of the individual parameters. A multiple regression model was used to determine the utility of using a combination of the tested cytokines to determine the infection status. RESULTS: The levels of all of the evaluated cytokines were significantly elevated in the PJI-group. Best sensitivity and specificity were found for IL-6, followed by IL-1b, IL-10, and IL-17. The multiple regression models revealed a combination of IL-2, IL-4, IL-5, IL6, lL-12, and GM-CSF to be associated with the best sensitivity (100%) and specificity (88.9%) for a cut-off value of 0.41, with a likelihood ratio of 9.0. CONCLUSION: Analysis of individual synovial fluid cytokine levels showed both high sensitivity and high specificity in diagnosing PJI. A combined model using several cytokines showed even higher sensitivity and specificity in diagnosing PJI and could thus be a useful predictive tool to determine the probability of PJI in patients with a painful prosthesis. LEVEL OF EVIDENCE: Diagnostic IV.

Diagnostic criteria of periprosthetic joint infection: a prospective study protocol to validate the feasibility of the 2018 new definition for Chinese patients.

BACKGROUND: Periprosthetic joint infection (PJI) is a challenging complication following total joint arthroplasty (TJA), and the diagnostic criteria remains controversial. The 2018 new definition proposed in May 2018 consists of new diagnostic criteria for PJI. We conducted a retrospective study and demonstrated that the new definition could improve the diagnostic efficiency in Chinese patients. However, missing data led to bias in the previous retrospective study. Therefore, this prospective study is designed to further validate the feasibility of 2018 new definition (and its modified version) for Chinese patients. METHODS/DESIGN: This is a single-centre, prospective diagnostic study with 1 year of follow-up. The patients enrolled in the trial will be divided into a PJI group and an Aseptic group based on the eligibility criteria. We will recruit at least 70 patients for each group from October 2019 to October 2020. Blood samples, synovial fluid samples and intraoperative variables of all the included patients will be collected to assess various indicators. We will integrate the results of the various tests and examine the diagnostic efficiency (sensitivity and specificity) of five diagnostic criteria. DISCUSSION: We design the prospective study in the hope of reducing the bias caused by missing data. Therefore, the prospective study will further support the conclusion of our preceding retrospective study. The results of this study will be submitted to a peer-reviewed journal for publication. CONCLUSION: Through this prospective study, we will validate the feasibility of the 2018 new PJI definition (and its modified version) for Chinese patients and determine the optimal method of PJI diagnosis. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025395. Registered on 25 August 2019.

Proceedings from the 2018 International Consensus Meeting on Orthopedic Infections: evaluation of periprosthetic shoulder infection.

The Second International Consensus Meeting on Orthopedic Infections was held in Philadelphia, Pennsylvania, in July 2018. More than 800 experts from all 9 subspecialties of orthopedic surgery and allied fields of infectious disease, microbiology, and epidemiology were assembled to form the International Consensus Group. The shoulder workgroup reached consensus on 27 questions related to culture techniques, inflammatory markers, and diagnostic criteria used to evaluate patients for periprosthetic shoulder infection. This document contains the group's recommendations and rationale for each question related to evaluating periprosthetic shoulder infection.

The Impact of α-Defensin Test in Diagnosing Periprosthetic Infection After Total Ankle Arthroplasty.

Periprosthetic joint infection (PJI) after total ankle arthroplasty (TAA) is a serious complication, and a reliable diagnostic test to identify PJI is needed. The purpose of this study was to investigate the use of synovial α-defensin levels in identifying PJI of the ankle. Data from 33 patients were retrospectively collected between September 2015 and May 2018. Patients who had pain or suspected loosening after TAA and who had undergone joint aspiration were included in the study. Aspiration was performed in a semisterile theatre. Synovial fluid was processed in descending order for microbiological cultures, α-defensin, leukocyte esterase strip test, and cell count. A periprosthetic infection was defined by Musculoskeletal Infection Society criteria. The sensitivity, specificity, and overall accuracy were calculated, and based on a receiver operating characteristic curve, the quality of the α-defensin test was determined. The calculated area under the curve was 0.97 ± 0.32. Two of 33 patients fulfilled the 2014 Musculoskeletal Infection Society criteria and were scheduled for septic revision arthroplasty. Sensitivity, specificity, and overall accuracy of the α-defensin test were 100% (95% confidence interval [CI], 15.8% to 100%), 93.5% (95% CI, 78.6% to 99.2%), and 93.9% (95% CI, 79.8% to 99.3%), respectively. The positive predictive value was 50% (95% CI, 20.7% to 79.3%), and the negative predictive value was 100%. The α-defensin test seems to be the best available synovial test to detect a late-onset PJI after total ankle arthroplasty. Further prospective studies with a larger number of patients are required.

Does the Alpha-defensin Immunoassay or the Lateral Flow Test Have Better Diagnostic Value for Periprosthetic Joint Infection? A Meta-analysis.

BACKGROUND: Measuring alpha-defensin concentrations in synovial fluid may help to diagnose periprosthetic joint infection (PJI). There are two commercially available methods for measuring alpha-defensin in synovial fluid: the enzyme-linked immunosorbent assay-based Synovasure® alpha-defensin immunoassay, which gives a numeric readout within 24 hours, and the Synovasure lateral flow test, which gives a binary readout within 20 minutes. There is no compilation of the existing literature to support the use of one of these two tests over the other. QUESTIONS/PURPOSES: Does the immunoassay or the lateral flow test have better diagnostic value (sensitivity and specificity) in diagnosing PJI? METHODS: We followed PRISMA guidelines and identified all studies on alpha-defensin concentration in synovial fluid as a PJI diagnostic marker, indexed to April 14, 2017, in PubMed, JSTOR, Google Scholar, and OVID databases. The search retrieved 1578 records. All prospective and retrospective studies on alpha-defensin as a PJI marker (PJI classified according to the criteria of the Musculoskeletal Infection Society) after THA or TKA were included in the analysis. All studies used only one of the two commercially available test methods, but none of them was comparative. After excluding studies with overlapping patient populations, four studies investigating the alpha-defensin immunoassay and three investigating the lateral flow test remained. Alpha-defensin immunoassay studies included 482 joints and lateral flow test studies included 119. The quality of the trials was assessed according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The heterogeneity among studies was evaluated by the I index, indicating that the heterogeneity of the included studies was low. Pooled sensitivity, specificity, positive and negative likelihood ratios, and receiver operating curves were calculated for each method and compared with each other. RESULTS: The alpha-defensin immunoassay had superior overall diagnostic value compared with the lateral flow test (area under the curve, 0.98 versus 0.75) with higher sensitivity (96% [90%-98%] versus 71% [55%-83%], p < 0.001), but no difference in specificity with the numbers available (96% [93%-97%] versus 90% [81%-95%], p = 0.060). CONCLUSIONS: Measurement of alpha-defensin in synovial fluid is a valuable complement to existing diagnostic criteria, and the immunoassay test detects PJI more accurately than the lateral flow test. The lateral flow test has lower sensitivity, making it difficult to rule out infection, but its relatively high specificity combined with the advantage of a quick response time can make it useful to rule in infection perioperatively. LEVEL OF EVIDENCE: Level III, diagnostic study.

The terminal complement pathway is activated in septic but not in aseptic shoulder revision arthroplasties.

BACKGROUND: The early diagnosis of suspected periprosthetic low-grade infections in shoulder arthroplasties is important for the outcome of the revision surgical procedures. The aim of this study was to investigate new biomarkers of infection in revision shoulder arthroplasties, taking into account the implant design, patient age, and comorbidities. METHODS: The study included 33 patients with shoulder arthroplasties undergoing revision surgical procedures. Microbiological diagnostic testing was performed in all cases. C-reactive protein serum levels and white blood cell counts were evaluated, and the periprosthetic tissue was stained immunohistologically for the terminal complement pathway components (C3, C5, and C9) and for CD68 and α-defensin. RESULTS: Microbiological diagnostic testing detected a periprosthetic infection in 10 reverse shoulder arthroplasties and in 4 anatomic shoulder arthroplasties, while the remaining 19 shoulder arthroplasties were classified as aseptic. We observed more Staphylococcus epidermidis infections in reverse shoulder arthroplasties and more Staphylococcus aureus infections in anatomic shoulder arthroplasties. The revision rate correlated with pre-existing comorbidities and number of previous surgical procedures. The C-reactive protein values and the incidence of specific periprosthetic radiolucent lines were significantly increased in septic revision cases. We found increased staining for all tested complement factors (C3, C5, and C9) but not for α-defensin and CD68 in septic tissue. The most interesting finding was that C9 separated septic from aseptic tissue with a predictive specificity of 100% and a sensitivity of 88.89%. CONCLUSION: We observed a strong correlation between C9 expressions in septic revision tissue. We propose that the terminal complement pathway, especially C9 deposition, may be a potential biomarker to identify septic complications using tissue biopsy specimens.

An Evidence-Based Clinical Prediction Algorithm for the Musculoskeletal Infection Society Minor Criteria.

BACKGROUND: The diagnosis of a periprosthetic joint infection (PJI) remains a clinical challenge, as there is no uniformly accepted gold standard. In 2011, the Musculoskeletal Infection Society (MSIS) convened a work group to create a standardized definition for a PJI that could be universally adopted. Based on the MSIS criteria, the diagnosis of a PJI can be made with 1 of the 2 major criteria, or 3 of the 5 minor criteria. The purpose of this study was to determine the likelihood of having a PJI based on the number of positive minor criteria and thereby develop a prediction algorithm for differentiating between a chronic PJI and a non-PJI based on the number of positive MSIS minor criteria. METHODS: We retrospectively reviewed 297 patients who presented to a tertiary care center between 2004 and 2014 with a failed total joint arthroplasty and subsequently underwent a PJI workup to exclude chronic PJI. Patients were divided into 2 groups: (1) PJI group and (2) non-PJI group. Patients who had a positive PJI workup and subsequently underwent a 2-stage revision for infection were included in the PJI group. Patients who had a negative clinical and diagnostic workup were included in the non-PJI group. One hundred eighty-two patients met the criteria for inclusion in the study, 91 in each group. Univariate and multiple logistic regression analyses were used to evaluate 21 independent variables in each of the 2 groups. A prediction algorithm for differentiating between a chronic PJI and a non-PJI based on independent multivariate variables was created. RESULTS: Patients who had a PJI differed significantly (P < .05) from those who did not have a PJI with regard to 10 independent variables, which included all the MSIS minor criteria we evaluated. Five independent multivariate variables were identified to differentiate between the 2 groups: positive cultures, elevated synovial white blood cell count, elevated synovial polymorphonuclear neutrophil percentage, elevated erythrocyte sedimentation rate, and elevated C-reactive protein. The predictive probability of a PJI for all 32 combinations of these 5 variables was: 3.6% for 1 positive variable, 19.3% for 2, 58.7% for 3, 83.8% for 4, and 97.8% for 5. The chi-squared test for trend and the area under the receiver-operating characteristic curve (0.977) suggest that the model is highly predictive, with an excellent diagnostic performance in identifying a PJI. CONCLUSIONS: Diagnosing a PJI remains a clinical challenge as there is no gold standard for diagnosis. The development of the MSIS criteria, which is based on a consensus of over 400 of the world's experts in musculoskeletal infection, was a major step forward in defining the diagnosis of a PJI. However, to our knowledge, the likelihood of having a PJI based on the number of positive minor criteria has yet to be validated or quantified. Of the 20 independent variables that were evaluated, 10 were found to be significantly associated with a PJI, including all the MSIS minor criteria evaluated. In addition, a diagnostic prediction algorithm was constructed to determine the likelihood of a PJI based on 5 binary independent multivariate variables. The relationship was also examined with a receiver-operating characteristic curve analysis. The area under the curve was 0.98, indicating excellent diagnostic performance for the MSIS minor criteria in identifying a PJI. LEVEL OF EVIDENCE: III.

Textural features of 18F-fluorodeoxyglucose positron emission tomography scanning in diagnosing aortic prosthetic graft infection.

BACKGROUND: The clinical problem in suspected aortoiliac graft infection (AGI) is to obtain proof of infection. Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography scanning (PET) has been suggested to play a pivotal role, an evidence-based interpretation is lacking. The objective of this retrospective study was to examine the feasibility and utility of 18F-FDG uptake heterogeneity characterized by textural features to diagnose AGI. METHODS: Thirty patients with a history of aortic graft reconstruction who underwent 18F-FDG PET/CT scanning were included. Sixteen patients were suspected to have an AGI (group I). AGI was considered proven only in the case of a positive bacterial culture. Positive cultures were found in 10 of the 16 patients (group Ia), and in the other six patients, cultures remained negative (group Ib). A control group was formed of 14 patients undergoing 18F-FDG PET for other reasons (group II). PET images were assessed using conventional maximal standardized uptake value (SUVmax), tissue-to-background ratio (TBR), and visual grading scale (VGS). Additionally, 64 different 18F-FDG PET based textural features were applied to characterize 18F-FDG uptake heterogeneity. To select candidate predictors, univariable logistic regression analysis was performed (α = 0.16). The accuracy was satisfactory in case of an AUC > 0.8. RESULTS: The feature selection process yielded the textural features named variance (AUC = 0.88), high grey level zone emphasis (AUC = 0.87), small zone low grey level emphasis (AUC = 0.80), and small zone high grey level emphasis (AUC = 0.81) most optimal for distinguishing between groups I and II. SUVmax, TBR, and VGS were also able to distinguish between these groups with AUCs of 0.87, 0.78, and 0.90, respectively. The textural feature named short run high grey level emphasis was able to distinguish group Ia from Ib (AUC = 0.83), while for the same task the TBR and VGS were not found to be predictive. SUVmax was found predictive in distinguishing these groups, but showed an unsatisfactory accuracy (AUC = 0.75). CONCLUSION: Textural analysis to characterize 18F-FDG uptake heterogeneity is feasible and shows promising results in diagnosing AGI, but requires additional external validation and refinement before it can be implemented in the clinical decision-making process.

Microbiological Diagnosis of Implant-Related Infections: Scientific Evidence and Cost/Benefit Analysis of Routine Antibiofilm Processing.

Prosthetic joint infection is one of the most severe complication following joint arthroplasty, producing a significant worsening of patient's quality of life. Management of PJIs requires extended courses of antimicrobial therapy, multiple surgical interventions and prolonged hospital stay, with a consequent economic burden, which is thought to markedly increase in the next years due to the expected burden in total joint arthroplasties. The present review summarizes the present knowledge on microbiological diagnosis of prosthetic joint infections, focusing on aethiological agents and discussing pros and cons of the available strategies for their diagnosis.Intra-operative clinical diagnosis and pathogen identification is considered the diagnostic benchmark, however the presence of bacterial biofilm makes pathogen detection with traditional microbiological techniques highly ineffective. Diagnosis of PJIs is a rather complex challenge for orthopedics and requires a strict collaboration between different specialists: orthopaedics, infectivologists, microbiologists, pathologists and radiologists. Diagnostic criteria have been described by national and international association and scientific societies. Clinicians should be trained on how to use it, but more importantly they should know potential and limitation of the available tests in order to use them appropriately.

The Role of Biomarkers for the Diagnosis of Implant-Related Infections in Orthopaedics and Trauma.

Diagnosis of implant-related (periprosthetic joint) infections poses a major challenge to infection disease physicians and orthopaedic surgeons. Conventional diagnostic tests continue to suffer from issues of accuracy and feasibility. Biomarkers are used throughout medicine for diagnostic and prognostic purposes, as they are able to objectively determine the presence of a disease or a biological state. There is increasing evidence to support the measurement of specific biomarkers in serum and/or synovial fluid of patients with suspected periprosthetic joint infections. Promising serum biomarkers include interleukin (IL)-4, IL-6, tumour necrosis factor (TNF)-α, procalcitonin, soluble intercellular adhesion molecule 1 (sICAM-1), and D-dimer. In addition to c-reactive protein and leucocyte esterase, promising biomarkers that can be measured in synovial fluid include antimicrobial proteins such as human ß-defensin (HBD)-2 and human ß-defensin (HBD)-3, and cathelicidin LL-37, as well as several interleukins such as IL-1ß, IL-6, IL-8, IL-17, TNF- α, interferon-δ, and vascular endothelial growth factor.

Neer Award 2015: Analysis of cytokine profiles in the diagnosis of periprosthetic joint infections of the shoulder.

BACKGROUND: Periprosthetic joint infection (PJI) after shoulder arthroplasty can present a diagnostic and therapeutic challenge. This study evaluated the diagnostic utility of broader synovial fluid cytokine analysis for identifying PJI in patients undergoing revision shoulder arthroplasty. METHODS: Synovial fluid levels of 9 cytokines (interleukin [IL] 6, granulocyte-macrophage colony-stimulating factor, IL-1ß, IL-12, IL-2, IL-8, interferon-γ, IL-10, and tumor necrosis factor-α) were measured in 75 cases of revision shoulder arthroplasty with a multiplex immunoassay. Cases were classified into infection categories and groups based on objective perioperative findings. Differences in cytokine levels among infection groups were evaluated. Receiver operating characteristic curves were used to assess the diagnostic utility of the individual synovial fluid cytokines and combinations of cytokines in determining infection status. RESULTS: Synovial IL-6, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-1ß, IL-2, IL-8, and IL-10 were significantly elevated in cases of revision shoulder arthroplasty classified as infected. Individually, IL-6, IL-1ß, IL-8, and IL-10 showed the best combination of sensitivity and specificity for predicting infection, and a combined cytokine model consisting of IL-6, tumor necrosis factor-α, and IL-2 showed better diagnostic test characteristics than any cytokine alone, with sensitivity of 0.80, specificity of 0.93,, positive and negative predictive values of 0.87 and 0.89, and positive and negative likelihood ratios of 12.0 and 0.21. CONCLUSIONS: Individual and combined synovial fluid cytokine analysis were both more effective than routine perioperative testing, such as serum erythrocyte sedimentation rate and C-reactive protein, in the diagnosis of PJI of the shoulder. Once validated, combined synovial fluid cytokine analysis could be used as a predictive tool to determine the probability of PJI in patients undergoing revision shoulder arthroplasty and better guide treatment.

Transcriptome-Wide High-Density Microarray Analysis Reveals Differential Gene Transcription in Periprosthetic Tissue From Hips With Chronic Periprosthetic Joint Infection vs Aseptic Loosening.

BACKGROUND: Differentiating between periprosthetic hip infection and aseptic hip prosthesis loosening can be challenging, especially in patients with chronic infections. This study used whole-genome microarray analysis to investigate the transcriptomes of periprosthetic hip tissues to identify genes that are differentially transcripted between chronic periprosthetic hip infection and aseptic hip prosthesis loosening. METHODS: In this pilot study, a total of 24 patients with either chronic periprosthetic hip infection (n = 12) or aseptic hip prosthesis loosening (n = 12) were analyzed. Periprosthetic hip infection was diagnosed based on modified criteria of the Musculoskeletal Infection Society. To evaluate differences in gene transcription, whole-genome microarray analysis was performed on the mRNA of periprosthetic tissue. RESULTS: Microarray analysis revealed differential gene transcription in periprosthetic hip tissue affected by chronic hip infection vs aseptic hip prosthesis loosening. A total of 39 genes had area under the curve values greater than 0.9 for diagnosing chronic periprosthetic hip infection; 5 genes had annotations relevant to infection and metabolism. The 39 genes also included 7 genes that were differentially transcribed but that have no apparent connection to immune response processes plus 27 genes with unknown function. CONCLUSION: Differences in gene transcription profiles might represent novel diagnostic targets that can be used to differentiate between chronic periprosthetic hip infections and aseptic hip prosthesis loosening. Secondary metabolites of differentially transcripted genes might serve as easily accessible markers for detecting chronic periprosthetic joint infection in future.

Increased and normalized uptake of 18F-FDG in a case of bone periprosthetic infection treated by antibiotics.

We report the case of a 69 years old man with left hip prosthesis, who presented clinical, biochemical and imaging signs of periprosthetic infection treated with linezolid, an antibacterial agent of the oxazolidinone class. Two weeks after this treatment, a fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan showed increased uptake in the skeleton and also increased uptake in several focal areas in the spine and near the prosthesis and the surgical wound on the left gluteus medius. Bone marrow biopsy was negative; meanwhile the antibiotic therapy, after four weeks of treatment was stopped due to red blood cells and platelets toxicity. Six weeks later, the patient developed high fever again and in order to revaluate the periprosthetic inflammation, he was resubmitted to 18F-FDG PET/CT which showed normal 18F-FDG uptake in the whole skeleton, including the prosthesis and the subcutaneous wound. Some focal areas of increased uptake in the lumbar spine were still detected. In the next 4 weeks the patient was under a "watch and wait" follow-up in a steady state. IN CONCLUSION: In the case we report, since we found no otnt focal areas in the lumbar spine where due to age-related bone deformities including some Schmorl's nodes. The inflammation in the bone prosthesis and the subcutaneous wound responded almost totally to the antibiotic treatment we applied.

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection.

Staphylococcus aureus is a leading cause of prosthetic joint infections (PJIs) that are typified by biofilm formation. Given the diversity of S. aureus strains and their propensity to cause community- or hospital-acquired infections, we investigated whether the immune response and biofilm growth during PJI were conserved among distinct S. aureus clinical isolates. Three S. aureus strains representing USA200 (UAMS-1), USA300 (LAC), and USA400 (MW2) lineages were equally effective at biofilm formation in a mouse model of PJI and elicited similar leukocyte infiltrates and cytokine/chemokine profiles. Another factor that may influence the course of PJI is infectious dose. In particular, higher bacterial inocula could accelerate biofilm formation and alter the immune response, making it difficult to discern underlying pathophysiological mechanisms. To address this issue, we compared the effects of two bacterial doses (10(3) or 10(5) CFU) on inflammatory responses in interleukin-12p40 (IL-12p40) knockout mice that were previously shown to have reduced myeloid-derived suppressor cell recruitment concomitant with bacterial clearance after low-dose challenge (10(3) CFU). Increasing the infectious dose of LAC to 10(5) CFU negated these differences in IL-12p40 knockout animals, demonstrating the importance of bacterial inoculum on infection outcome. Collectively, these observations highlight the importance of considering infectious dose when assessing immune responsiveness, whereas biofilm formation during PJI is conserved among clinical isolates commonly used in mouse S. aureus infection models.