Aims. CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration. Methods. We investigated the effects of mCRP and the signalling pathways that are involved in cultured human primary annulus fibrosus (AF) cells and in the human nucleus pulposus (NP) immortalized cell line HNPSV-1. We determined messenger RNA (mRNA) and protein levels of relevant factors involved in inflammatory responses, by quantitative real-time polymerase chain reaction (RT-qPCR) and western blot. We also studied the presence of mCRP in human AF and NP tissues by immunohistochemistry. Results. We demonstrated that mCRP increases nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and Lipocalin 2 (LCN2) expression in human AF and NP cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signalling of mCRP. Finally, we demonstrated the presence of mCRP in human AF and NP tissues. Conclusion. Our results indicate, for the first time, that mCRP can be localized in IVD tissues, where it triggers a proinflammatory and catabolic state in degenerative and healthy IVD cells, and that NF-κβ signalling may be implicated in the mediation of this mCRP-induced state. Cite this article: Bone Joint Res 2023;12(3):189–198

Aims. Serum inflammatory parameters are widely used to aid in diagnosing a periprosthetic joint infection (PJI). Due to their limited performances in the literature, novel and more accurate biomarkers are needed. Serum albumin-to-globulin ratio (AGR) and serum CRP-to-albumin ratio (CAR) have previously been proposed as potential new parameters, but results were mixed. The aim of this study was to assess the diagnostic accuracy of AGR and CAR in diagnosing PJI and to compare them to the established and widely used marker CRP. Methods. From 2015 to 2022, a consecutive series of 275 cases of revision total hip (n = 129) and knee arthroplasty (n = 146) were included in this retrospective cohort study. Based on the 2021 European Bone and Joint Infection Society (EBJIS) definition, 144 arthroplasties were classified as septic. Using receiver operating characteristic curve (ROC) analysis, the ideal thresholds and diagnostic performances were calculated. The areas under the curve (AUCs) were compared using the z-test. Results. AGR, CAR, and CRP were associated with PJI (p < 0.001). Sensitivities were 62.5% (95% CI 54.3 to 70.0), 73.6% (95% CI 65.8 to 80.1), and 71.5% (95% CI 63.6 to 78.3), respectively. Specificities were calculated with 84.7% (95% CI 77.5 to 89.9), 86.3% (95% CI 79.2 to 91.2), and 87.8% (95% CI 80.9 to 92.4), respectively. The AUC of CRP (0.797 (95% CI 0.750 to 0.843)) was significantly higher than the AUC of AGR (0.736 (95% CI 0.686 to 0.786), p < 0.001), and similar to AUC of CAR (0.799 (95% CI 0.753 to 0.846), p = 0.832). Decreased sensitivities were observed in PJIs caused by low-virulence organisms (AGR: 60%, CAR: 78%) compared to high-virulence pathogens (AGR: 80%, p = 0.042; CAR: 88%, p = 0.158). Higher sensitivities were seen in acute haematogenous (AGR: 83%, CAR: 96%) compared to chronic PJIs (AGR: 54%, p = 0.001; CAR: 65%, p < 0.001). Conclusion. Serum AGR and CAR showed limited diagnostic accuracy (especially in low-grade and chronic infections) and did not outperform the established marker CRP in our study. Hence, neither parameter can be recommended as an additional tool for diagnosing PJI. Cite this article: Bone Joint Res 2024;13(8):372–382

Aims. Monocyte-lymphocyte ratio (MLR) or neutrophil-lymphocyte ratio (NLR) are useful for diagnosing periprosthetic joint infection (PJI), but their diagnostic values are unclear for screening fixation-related infection (FRI) in patients for whom conversion total hip arthroplasty (THA) is planned after failed internal fixation for femoral neck fracture. Methods. We retrospectively included 340 patients who underwent conversion THA after internal fixation for femoral neck fracture from January 2008 to September 2020. Those patients constituted two groups: noninfected patients and patients diagnosed with FRI according to the 2013 International Consensus Meeting Criteria. Receiver operating characteristic (ROC) curves were used to determine maximum sensitivity and specificity of these two preoperative ratios. The diagnostic performance of the two ratios combined with preoperative CRP or ESR was also evaluated. Results. The numbers of patients with and without FRI were 19 (5.6%) and 321 (94.4%), respectively. Areas under the ROC curve for diagnosing FRI were 0.763 for MLR, 0.686 for NLR, 0.905 for CRP, and 0.769 for ESR. Based on the Youden index, the optimal predictive cutoffs were 0.25 for MLR and 2.38 for NLR. Sensitivity and specificity were 78.9% and 71.0% for MLR, and 78.9% and 56.4% for NLR, respectively. The combination of CRP with MLR showed a sensitivity of 84.2% and specificity of 94.6%, while the corresponding values for the combination of CRP with NLR were 89.5% and 91.5%, respectively. Conclusion. The presence of preoperative FRI among patients undergoing conversion THA after internal fixation for femoral neck fracture should be determined. The combination of preoperative CRP with NLR is sensitive tool for screening FRI in those patients. Cite this article: Bone Joint J 2021;103-B(9):1534–1540

Acute Haematogenous Osteomyelitis (AHO) remains a cause of severe illness among children. Contemporary research aims to identify predictors of acute and chronic complications. Trends in C-reactive protein (CRP) following treatment initiation may predict disease course. We have sought to identify factors associated with acute and chronic complications in the New Zealand population. A retrospective review of all patients <16 years with presumed AHO presenting to a tertiary referral centre between 2008–2018 was performed. Multivariate was analysis used to identify factors associated with an acute or chronic complication. An “acute” complication was defined as need for two or more surgical procedures, hospital stay longer than 14-days, or recurrence despite IV antibiotics. A “chronic” complication was defined as growth or limb length discrepancy, avascular necrosis, chronic osteomyelitis, pathological fracture, frozen joint or dislocation. 151 cases met inclusion criteria. The median age was 8 years (69.5% male). Within this cohort, 53 (34%) experienced an acute complication and 18 (12%) a chronic complication. Regression analysis showed that contiguous disease, delayed presentation, and failure to reduce CRP by 50% at day 4/5 predicted an acutely complicated disease course. Chronic complication was predicted by need for surgical management and failed CRP reduction by 50% at day 4/5. We conclude that CRP trends over 96 hours following commencement of treatment differentiate patients with AHO likely to experience severe disease

Aims. The diagnosis of periprosthetic joint infection (PJI) has always been challenging. Recently, D-dimer has become a promising biomarker in diagnosing PJI. However, there is controversy regarding its diagnostic value. We aim to investigate the diagnostic value of D-dimer in comparison to ESR and CRP. Methods. PubMed, Embase, and the Cochrane Library were searched in February 2020 to identify articles reporting on the diagnostic value of D-dimer on PJI. Pooled analysis was conducted to investigate the diagnostic value of D-dimer, CRP, and ESR. Results. Six studies with 1,255 cases were included (374 PJI cases and 881 non-PJI cases). Overall D-dimer showed sensitivity of 0.80 (95% confidence interval (CI) 0.69 to 0.87) and specificity of 0.76 (95% CI 0.63 to 0.86). Sub-group analysis by excluding patients with thrombosis and hyper-coagulation disorders showed sensitivity of 0.82 (95% CI 0.70 to 0.90) and specificity of 0.80 (95% CI 0.70 to 0.88). Serum D-dimer showed sensitivity of 0.85 (95% CI 0.76 to 0.92), specificity of 0.83 (95% CI 0.74 to 0.90). Plasma D-dimer showed sensitivity of 0.67 (95% CI 0.60 to 0.73), specificity of 0.58 (95% CI 0.45 to 0.72). CRP showed sensitivity of 0.78 (95% CI 0.72 to 0.83), specificity of 0.81 (95% CI 0.72 to 0.87). ESR showed sensitivity of 0.68 (95% CI 0.63 to 0.73), specificity of 0.83 (95% CI 0.78 to 0.87). Conclusion. In patients without thrombosis or a hyper-coagulation disorder, D-dimer has a higher diagnostic value compared to CRP and ESR. In patients with the aforementioned conditions, D-dimer has higher sensitivity but lower specificity compared to ESR and CRP. We do not recommend the use of serum D-dimer in patients with thrombosis and hyper-coagulation disorders for diagnosing PJI. Serum D-dimer may perform better than plasma D-dimer. Further studies are needed to compare serum D-dimer and plasma D-dimer in arthroplasty patients. Cite this article: Bone Joint Res 2020;9(10):701–708

Introduction. Diagnosing acute postoperative periprosthetic joint infections (PJIs) after primary total knee arthroplasties (TKAs) remains difficult. Published diagnostic thresholds for ESR, CRP, and synovial fluid analysis have not been replicated. We aimed to validate the optimal cutoffs for detecting acute postoperative PJIs in a large series of primary TKAs. Methods. We retrospectively identified 27,066 primary TKAs performed between 2000–2019. Within 12 weeks, 171 knees (170 patients) had a synovial fluid aspiration. Patients were divided into two groups: evaluation <6 weeks or 6–12 weeks. The 2011 MSIS criteria for PJI diagnosed infection in 22 knees. Mann-Whitney U tests compared medians; ROC analyses determined optimal thresholds. Mean follow-up was 5 years. Results. Within 6 weeks, CRP (101 mg/L vs. 35 mg/L; p=0.01), synovial WBCs (58,295 cells/μL vs. 2121 cells/μL; p=<0.001), and synovial neutrophils (91% vs. 71%; p<0.001) were significantly higher in infected TKAs. ESR did not differ between groups at <6 weeks. Between 6–12 weeks, CRP (85 mg/L vs. 6 mg/L; p<0.001), ESR (33 mm/h vs. 15 mm/h; p=0.02), synovial WBCs (62,247 cells/μL vs. 596 cells/μL; p<0.001), and synovial neutrophils (93% v. 54%; p<0.001) were significantly higher in infected TKAs. Optimal thresholds at <6 weeks were: CRP ≥81 mg/L (sensitivity 80%, specificity 77%), synovial WBCs ≥8515 cells/μL (sensitivity 92%, specificity 90%), and synovial neutrophils≥86% (sensitivity 92%, specificity 72%). Between 6–12 weeks, thresholds were: CRP ≥32 mg/L (sensitivity 100%, specificity 93%), synovial WBCs ≥7450 cells/μL (sensitivity 80%, specificity 98%), and synovial neutrophils ≥84% (sensitivity 80%, specificity 89%). Conclusion. Acute PJI after TKA should be suspected within 6 weeks if CRP is ≥81 mg/L, synovial WBCs are ≥8500 cells/μL, and/or synovial neutrophils≥86%. Between 6–12 weeks, concerning thresholds include a CRP ≥ 32 mg/L, synovial WBC ≥7450, and synovial neutrophils ≥ 84%

Aims. It can be extremely challenging to determine whether to perform reimplantation in patients who have contradictory serum inflammatory markers and frozen section results. We investigated whether patients with a positive frozen section at reimplantation were at a higher risk of reinfection despite normal ESR and CRP. Methods. We retrospectively reviewed 163 consecutive patients with periprosthetic joint infections (PJIs) who had normal ESR and CRP results pre-reimplantation in our hospital from 2014 to 2018. Of these patients, 26 had positive frozen sections at reimplantation. The minimum follow-up time was two years unless reinfection occurred within this period. Univariable and multivariable logistic regression analyses were performed to identify the association between positive frozen sections and treatment failure. Results. Treatment failure occurred in eight (30.77%) of the 26 PJI patients with positive frozen sections at reimplantation, compared with 13 (9.49%) of 137 patients with negative results. In the multivariate analysis, positive frozen section increased the risk of failure (odds ratio 4.70; 95% confidence interval (CI) 1.64 to 13.45). The mean number of months to reinfection was lower in the positive frozen section group than in the control group (p = 0.041). While there were nine (34.62%) patients with positive frozen section and 25 (18.25%) patients with negative frozen section who had prolonged antibiotic use (p = 0.042), the mean duration of antibiotic use was comparable in two groups. Synovial white blood cell count (p = 0.137) and polymorphonuclear leucocyte percentage (p = 0.454) were not associated with treatment failure in logistic regression model. Conclusion. Positive frozen section at reimplantation was independently associated with subsequent failure and earlier reinfection, despite normal ESR and CRP levels pre-reimplantation. Surgeons should be aware of the risk of treatment failure in patients with positive frozen sections and carefully consider benefits of reimplantation. Cite this article: Bone Joint J 2021;103-B(5):916–922

Detection of infection in total joint replacements (TJR) is notoriously difficult. Ideally the diagnosis should be known before revision arthroplasty is undertaken. The level of C-reactive protein (CRP) is one readily available test. Sanzen et al. reported sensitivity of 78% and specificity of 100% for CRP in distinguishing infection in 23 infected TJRs and 33 non-infected TJRs undergoing revision, using a cut off of 2mg/dl. 1. However, they used only intra-operative cultures as the standard to compare the CRP against. We have analysed the reliability of CRP to diagnose infection pre-operatively in a group of patients undergoing revision arthroplasty, using the following criteria as the reference standard for infection: 2 or more intra-operative cultures positive for the same organism; presence of acute inflammatory response on histology; presence of pus in the joint at revision (1/3 positive indicates true infection), as described by Hanssen et al. 2. The results of CRP and the operative investigations of 26 patients undergoing revision arthroplasty (15 hips and 11 knees) were studied prospectively. In our unit CRP is assayed in mg/dl serum by an automated machine. During revision arthroplasty, multiple specimens were taken from around the joint for microbiological and histological examination. Microbiological cultures were carried out on solid media and broth in aerobic and anaerobic conditions. Histological analysis assessed the level of neutrophils present in the tissue. The presence or absence of pus was noted. The results were analysed graphically and a cut off level of CRP was then chosen for analysis of reliability. Thirteen patients were infected and 13 were not. Eleven of the 13 infected patients had a CRP greater than 2 mg/dl, and 10 of the 13 non-infected patients had a CRP less than 2 mg/dl. Using 2 mg/dl as a cut off, CRP had a sensitivity of 85% and a specificity of 77%. If 4mg/dl is taken as the threshold for infection, then CRP is 100% specific but only 61% sensitive. CRP is a useful investigation in the diagnosis of infection in joint replacements. However we have shown that a cut off of 2mg/dl is not 100% specific for non-infected patients. Increasing the threshold improves the specificity, but reduces the sensitivity. Unfortunately there is no single investigation that is 100% accurate in this setting. CRP results must be interpreted in the light of the clinical picture and other investigations. These patients are part of an ongoing study to identify the most reliable criteria for diagnosing the presence of infection in total joint replacement

Clinical prediction algorithms are used to differentiate transient synovitis from septic arthritis. These algorithms typically include the erythrocyte sedimentation rate (ESR), although in clinical practice measurement of the C-reactive protein (CRP) has largely replaced the ESR. We evaluated the use of CRP in a predictive algorithm. The records of 311 children with an effusion of the hip, which was confirmed on ultrasound, were reviewed (mean age 5.3 years (0.2 to 15.1)). Of these, 269 resolved without intervention and without long-term sequelae and were considered to have had transient synovitis. The remaining 42 underwent arthrotomy because of suspicion of septic arthritis. Infection was confirmed in 29 (18 had micro-organisms isolated and 11 had a high synovial fluid white cell count). In the remaining 13 no evidence of infection was found and they were also considered to have had transient synovitis. In total 29 hips were categorised as septic arthritis and 282 as transient synovitis. The temperature, weight-bearing status, peripheral white blood cell count and CRP was reviewed in each patient. A CRP > 20 mg/l was the strongest independent risk factor for septic arthritis (odds ratio 81.9, p < 0.001). A multivariable prediction model revealed that only two determinants (weight-bearing status and CRP > 20 mg/l) were independent in differentiating septic arthritis from transient synovitis. Individuals with neither predictor had a < 1% probability of septic arthritis, but those with both had a 74% probability of septic arthritis. A two-variable algorithm can therefore quantify the risk of septic arthritis, and is an excellent negative predictor.

Serological tests including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently used in the preoperative workup to screen for periprosthetic infection (PPI) in total hip arthroplasty (THA). The cut-off points reported in the literature are arbitrarily chosen by investigators. Similarly, the values used in laboratories to distinguish elevated results vary from one institute to another. Therefore, we intended to define the appropriate cut-off points of ESR and CRP that can be used to differentiate infection from aseptic failure of THA. A review of our joint registry database revealed that 515 THA revisions (131 infected cases) were performed during 2000–2005. Intraoperative samples for culture were taken in all cases. The criteria used for diagnosis of infection were a positive intraoperative culture on solid media, presence of an abscess or sinus tract that communicated with the joint, positive preoperative aspiration culture, and/or elevated fluid cell count and neutrophil differential of the aspirated fluid. Non-infected patients with confounding factors that can elevate ESR and CRP including collagen vascular disease, inflammatory arthropathy, malignancy, and urinary tract infection were excluded. Receiver operator curves were used to determine the ideal cut-off point for both ESR and CRP. The mean value of ESR in the infected group (77mm/ hr) was significantly higher compared to that of the non-infected cohort (29mm/hr) (p=0.0001). Similarly, infected patients presented with a greater mean CRP (9.8 mg/dl) than their non-infected cohort (1.48 mg/ dl) (p=0.0001). The infection threshold for ESR was 45mm/hr with a sensitivity of 85% and specificity of 79%, while the optimal cut-off value for CRP was defined as 1.6 mg/dl which yielded a sensitivity of 86% and specificity of 83%. The optimal threshold values we determined are higher than the arbitrarily chosen values cited in the literature for ESR (30mm/hr) and CRP (1mg/dl). Although it has been previously reported that the sensitivity and specificity of CRP are far greater than that of ESR, we found that the two tests have comparable diagnostic value

The aim of this study was determine if the detection of pathology in children with a limp can be optimised by screening with blood tests for raised inflammatory markers. The entry criteria for the study were children (0–15 years) presenting to our hospital Emergency Department from 2012–2015 with a non-traumatic limp or pseudoparalysis of a limb, and no sign of fracture or malignancy on plain radiographs. ESR and CRP blood tests were performed along with other standard investigations. Children with ESR or CRP over 10 underwent MRI scan of their area of pain or tendernesss, with those under 7 years old having general anaesthetic. MRI provided the diagnosis in cases of osteomyelitis, pyomyositis, fasciitis, cellulitis, discitis, as well as non-infective conditions such as malignancy and fracture not visible on plain radiographs. Where a joint effusion was present, the diagnosis of septic arthritis was made from organisms cultured following surgical drainage, or high white cell count in joint fluid if no organisms were cultured. The study was completed once data from 100 consecutive children was available. 64% of children had an infective cause for their symptoms (osteomyelitis, septic arthritis, pyomyositis, fasciitis, cellulitis or discitis). A further 11% had positive findings on MRI from non-infective causes (juvenile idiopathic arthritis, cancer, or occult fracture). The remaining 25% had either a normal scan, or transient synovitis. ESR was a more sensitive marker than CRP, since ESR was raised in 97% of those with abnormal scans, but CRP in only 70%. There were no complications from any of the GA MRI scans. Conclusion: This shows that MRI imaging of all children with a limp and either raised ESR or CRP is a sensitive method to minimise the chance of missing important pathology in this group, and is not wasteful of MRI resources

Background The exclusion of infection at the site of a painful or failed prosthetic joint replacement is important for pre-operative planning and counselling. A variety of investigations can be used to assist in the diagnosis or exclusion of infection. An ESR and CRP are widely used as the initial screening investigation to differentiate between aseptic and septic loosening of prosthetic joint replacements. 1. Propionobacteria are organisms of low virulence, although they do cause deep peri-prosthetic infections. 2. We believe that Propionobacteria do not always cause a significant rise in ESR and CRP. Methods Between May 2001 and May 2004, we identified 78 patients with prosthetic joint replacements colonised with Propionobacteria. There were 48 hip joint replacements, 27 knee joint replacements, 2 endoprosthetic replacements of the femur and 1 shoulder joint replacement. There were 48 males and 30 females. The preoperative values of ESR and CRP were recorded. For the purposes of this study, an ESR rate of 30mm/hr or higher and a CRP level of 10mg/lt or higher were considered to be suggestive of infection and were deemed a positive result. Results All of the 78 patients had both ESR and CRP measured preoperatively. In only 17 patients (22%) both ESR and CRP were higher than 30mm/hr and 10mg/l respectively. In 33 patients (42%) with prosthetic joint replacements colonised with Propionobacteria, the preoperative values of both ESR and CRP were normal. Conclusion In our study we have shown that 33 out of 78 patients (42%) with prosthetic joint replacements colonised with Propionobacteria had normal preoperative of both ESR and CRP values. This is to suggest that normal preoperative values of ESR and CRP in suspected failed prosthetic joint replacements might not exclude infection, if the causative organism is of low virulence such as Propionobacteria

Aims. This study aims to assess the relationship between history of pseudotumour formation secondary to metal-on-metal (MoM) implants and periprosthetic joint infection (PJI) rate, as well as establish ESR and CRP thresholds that are suggestive of infection in these patients. We hypothesized that patients with a pseudotumour were at increased risk of infection. Methods. A total of 1,171 total hip arthroplasty (THA) patients with MoM articulations from August 2000 to March 2014 were retrospectively identified. Of those, 328 patients underwent metal artefact reduction sequence MRI and had minimum two years’ clinical follow-up, and met our inclusion criteria. Data collected included demographic details, surgical indication, laterality, implants used, history of pseudotumour, and their corresponding preoperative ESR (mm/hr) and CRP (mg/dl) levels. Multivariate logistic regression modelling was used to evaluate PJI and history of pseudotumour, and receiver operating characteristic curves were created to assess the diagnostic capabilities of ESR and CRP to determine the presence of infection in patients undergoing revision surgery. Results. The rate of PJI for all identified MoM THAs was 3.5% (41/1,171), with a mean follow-up of 10.9 years (2.0 to 20.4). Of the patients included in the final cohort, 8.2% (27/328) had PJI, with a mean follow-up of 12.2 years (2.3 to 20.4). Among this cohort, 31.1% (102/328) had a history of pseudotumour. The rate of PJI in these patients was 14.7% (15/102), which was greater than those without pseudotumour, 5.3% (12/226) (p = 0.008). Additionally, logistic regression analysis showed an association between history of pseudotumour and PJI (odds ratio 4.36 (95% confidence interval 1.77 to 11.3); p = 0.002). Optimal diagnostic cutoffs for PJI in patients with history of pseudotumour versus those without were 33.1 mm/hr and 24.5 mm/hr for ESR and 7.37 mg/dl and 1.88 mg/dl for CRP, respectively. Conclusion. Patients with history of pseudotumour secondary to MoM THA had a higher likelihood of infection than those without. While suspicion of infection should be high for these patients, ESR and CRP cutoffs published by the European Bone and Joint Infection Society may not be appropriate for patients with a history of pseudotumour, as ESR and CRP levels suggestive of PJI are likely to be higher than for those without a pseudotumour. Additional investigation, such as aspiration, is highly recommended for these patients unless clinical suspicion and laboratory markers are low. Cite this article: Bone Joint J 2024;106-B(6):555–564

Background. Establishing the diagnosis in a child presenting with an atraumatic limp can be difficult. Clinical prediction algorithms have been devised to distinguish septic arthritis (SA) from transient synovitis (TS). Within Europe measurement of the Erythrocyte Sedimentation Rate (ESR) has largely been replaced with assessment of C-Reactive Protein (CRP) as an acute phase protein. We produce a prediction algorithm to determine the significance of CRP in distinguishing between TS and SA. Method. All children with a presentation of ‘atraumatic limp’ and a proven effusion on hip ultrasound between 2004 and 2009 were included. Patient demographics, details of the clinical presentation and laboratory investigations were documented to identify a response to each of the four variables (Weight bearing status, WCC >12,000 cells/m3, CRP >20mg/L and Temperature >38.5°C). SA was defined based upon culture and microscopy of the operative findings. Results. 311 hips were included within the study. Of these 282 were considered to have transient synovitis. 29 patients met criteria to be classified as SA based upon laboratory assessment of the synovial fluid. The introduction of CRP eliminated the need for a four variable model as the use of two variables (CRP and weight bearing status) had similar efficacy. Treating individuals who were non-weight-bearing and a CRP >20mg/L as SA correctly classified 94.8% individuals, with a sensitivity of 75.9%, specificity of 96.8%, positive predictive value of 71.0%, and negative predictive value of 97.5%. CRP was a significant independent predictor of septic arthritis. Conclusions. CRP was a strong independent risk factor of septic arthritis, and its inclusion within a regression model simplifies the diagnostic algorithm. Nevertheless, this and other models are generally more reliable in excluding SA, than confirming SA, and therefore a clinician's acumen remains important in identifying SA in those individuals with a single abnormal variable

Background:. Until recently, there has been no consensus of the best approach to dIfferentiating aseptic from septic loosening in joint replacement patients. The recent AAOS Clinical Practice Guideline Summary that was published in 2010, tasks orthopedic surgeons with the strong recommendation of obtaining ESR and CRP for all patients needing hip and knee arthroplasty revision surgery and aspirating the joint based upon these results. The purpose of this study is to determine from our patients whether this guideline has been helpful and cost effective in determining periprosthetic joint infections. Methods:. We retrospectively reviewed charts of 50 consecutive patients who underwent revision total hip or knee arthroplasty. Each patient received an ESR and CRP level prior to operation and patients with known periprosthetic joint infections were excluded from the study. As guidelines recommend, aspiration with cultures and cell count were obtained on all knees with either elevated ESR or CRP and all hips with both ESR and CRP elevated. We then determined how many patients needing revision arthroplasty of the hip or knee benefited from ESR, CRP, and aspiration by finding subclinical periprosthetic infection and changing the intraoperative treatment. Hospital charge data was used to report cost of this protocol. Results. Sixty-four percent (32/50) patients had elevated ESR and/or CRP. Eighteen patients (12 hips; 7 knees) required joint aspirations per the guidelines. None of the aspirations were positive for bacterial growth. The total hospital charges for aspiration and cultures in this patient population were $81, 712.44. No sub clinical infection was identified. Conclusion:. Although guidelines may more readily diagnose every case of subclinical joint infection, we must continue to evaluate the cost of this type protocol in a busy revision practice

Diaphyseal femoral fracture (DFF) and fixation elicit a bistep inflammatory response (two-hit model). The timing of fixation potentially affects lung function and blood biochemistry. In 24 patients with DFF we measured CRP, albumin, albumin/globulin ratio (A/G) total protein, triglycerides, low (LDC) and high (HDC) density cholesterol at (1) admission, (2) day of operation, and (3) 48 hours postoperatively. We considered group A: (early fixation, day 1–4, 2.6±0.9, n=12) and B: (late fixation, day 5–12, 8.7±2.6, n=12). Statistical analysis was performed by ANOVA and multivariable tests. CRP increases from injury to operation and further to 48 hours postoperatively (p< 0.001) in both groups. Early fixation results in vigorous CRP increase, compared to late fixation, yet the pattern is parallel. Biphasic decrease of albumin (p< 0.001), A/G (p< 0.001) and total protein (p< 0.001), attributable to the inflammatory response, and that of HDC (p< 0.001) and LDC (p< 0.05) are identical in both groups. It is known that CRP peaks at 48 hours posttrauma. In early operation there is an additive effect of the two inflammatory hits, whereas, in delayed fixation the first hit fades, thus lowering the starting point of the second hit. Protein and HDC biphasic drop is not affected by the timing of fixation. We have no explanation for HDC drop. The timing of femoral shaft fracture fixation affects significantly CRP release and its impact on convalescence is worth investigating

Aims. It remains difficult to diagnose early postoperative periprosthetic joint infection (PJI) following total knee arthroplasty (TKA). We aimed to validate the optimal cutoff values of ESR, CRP, and synovial fluid analysis for detecting early postoperative PJI in a large series of primary TKAs. Methods. We retrospectively identified 27,066 primary TKAs performed between 2000 and 2019. Within 12 weeks, 169 patients (170 TKAs) had an aspiration. The patients were divided into two groups: those evaluated ≤ six weeks, or between six and 12 weeks postoperatively. The 2011 Musculoskeletal Infection Society (MSIS) criteria for PJI diagnosis in 22 TKAs. The mean follow-up was five years (two months to 17 years). The results were compared using medians and Mann-Whitney U tests and thresholds were analyzed using receiver operator characteristic curves. Results. Within six weeks, the median CRP (101 mg/l vs 35 mg/l; p = 0.011), synovial WBCs (58,295 cells/μl vs 2,121 cells/μl; p ≤ 0.001), percentage of synovial neutrophils (91% vs 71% (p < 0.001), and absolute synovial neutrophil count (ANC) (50,748 cells/μl vs 1,386 cells/μl (p < 0.001) were significantly higher in infected TKAs. Between six and 12 weeks, the median CRP (85 mg/l vs 5 mg/l (p < 0.001)), ESR (33 mm/hr vs 14 mm/hr (p = 0.015)), synovial WBCs (62,247 cells/μl vs 620 cells/μl (p < 0.001)), percentage of synovial neutrophils (93% vs 54% (p < 0.001)), and ANC (55,911 cells/μl vs 326 cells/μl (p < 0.001)) were also significantly higher in infected TKAs. Optimal thresholds at ≤ six weeks were: CRP ≥ 82 mg/l (sensitivity 70%, specificity 77%), synovial WBCs ≥ 8,676 cells/μl (83%, 90%), percentage of synovial neutrophils ≥ 88% (67%, 78%), and ANC ≥ 8,346 cells/μl (83%, 91%). Between six and 12 weeks, thresholds were: CRP ≥ 34 mg/l (90%, 93%), synovial WBCs ≥ 1,983 cells/μl (80%, 85%), percentage of synovial neutrophils ≥ 76% (80%, 81%), and ANC ≥ 1,684 cells/μl (80%, 87%). Conclusion. Early PJI after TKA should be suspected within six weeks if the CRP is ≥ 82 mg/l, synovial WBCs are ≥ 8,676 cells/μl, the percentage of synovial neutrophils is ≥ 88%, and/or the ANC is ≥ 8,346 cells/μl. Between six and 12 weeks, thresholds include a CRP of ≥ 34 mg/l, synovial WBC of ≥ 1,983 cells/μl, a percentage of synovial neutrophils of ≥ 76%, and/or an ANC of ≥ 1,684 cells/μl. Cite this article: Bone Joint J 2021;103-B(6 Supple A):177–184

Aims. To investigate the optimal thresholds and diagnostic efficacy of commonly used serological and synovial fluid detection indexes for diagnosing periprosthetic joint infection (PJI) in patients who have rheumatoid arthritis (RA). Methods. The data from 348 patients who had RA or osteoarthritis (OA) and had previously undergone a total knee (TKA) and/or a total hip arthroplasty (THA) (including RA-PJI: 60 cases, RA-non-PJI: 80 cases; OA-PJI: 104 cases, OA-non-PJI: 104 cases) were retrospectively analyzed. A receiver operating characteristic curve was used to determine the optimal thresholds of the CRP, ESR, synovial fluid white blood cell count (WBC), and polymorphonuclear neutrophil percentage (PMN%) for diagnosing RA-PJI and OA-PJI. The diagnostic efficacy was evaluated by comparing the area under the curve (AUC) of each index and applying the results of the combined index diagnostic test. Results. For PJI prediction, the results of serological and synovial fluid indexes were different between the RA-PJI and OA-PJI groups. The optimal cutoff value of CRP for diagnosing RA-PJI was 12.5 mg/l, ESR was 39 mm/hour, synovial fluid WBC was 3,654/μl, and PMN% was 65.9%; and those of OA-PJI were 8.2 mg/l, 31 mm/hour, 2,673/μl, and 62.0%, respectively. In the RA-PJI group, the specificity (94.4%), positive predictive value (97.1%), and AUC (0.916) of synovial fluid WBC were higher than those of the other indexes. The optimal cutoff values of synovial fluid WBC and PMN% for diagnosing RA-PJI after THA were significantly higher than those of TKA. The specificity and positive predictive value of the combined index were 100%. Conclusion. Serum inflammatory and synovial fluid indexes can be used for diagnosing RA-PJI, for which synovial fluid WBC is the best detection index. Combining multiple detection indexes can provide a reference basis for the early and accurate diagnosis of RA-PJI. Cite this article: Bone Joint Res 2023;12(9):559–570

Aims. To investigate the correlations among cytokines and regulatory T cells (T-regs) in ankylosing spondylitis (AS) patients, and their changes after anti-tumour necrosis factor-α (TNF-α) treatment. Methods. We included 72 AS patients with detailed medical records, disease activity score (Bath Ankylosing Spondylitis Disease Activity Index), functional index (Bath Ankylosing Spondylitis Functional Index), and laboratory data (interleukin (IL)-2, IL-4, IL-10, TNF-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, ESR, and CRP). Their peripheral blood mononuclear cells (PBMCs) were marked with anti-CD4, anti-CD25, and anti-FoxP3 antibodies, and triple positive T cells were gated by flow cytometry as T-regs. Their correlations were calculated and the changes after anti-TNF-α therapy were compared. Results. The frequency of T-regs in PBMCs was positively correlated to ESR and CRP in AS (r = 0.35 and 0.43; p = 0.032 and 0.027, respectively), and there was also a significant correlation between serum level of TNF-α and CRP (p = 0.041). The frequency of T-regs in PBMCs positively correlated to serum levels of TNF-α, IL-10, and TGF-β, while IL-2, IL-4, and IFN-γ showed opposite results. After anti-TNF-α treatment, there were significantly lower serum levels of TNF-α, IL-10, TGF-β, and frequency of T-regs in PBMCs among these AS patients (p = 0.026, 0.032, 0.029, and 0.037, respectively). Conclusion. In AS patients, proinflammatory cytokine may give positive feedback to induce more T-reg production and anti-inflammatory cytokine secretion to suppress this inflammatory status, and they can be reversed by anti-TNF-α therapy. However, the detailed interactions among T-regs and complex cytokine networks in autoinflammatory diseases still need more studies and further functional assay. Cite this article: Bone Joint Res 2023;12(2):133–137

Background. Osteomyelitis can be difficult to diagnose. Unlike septic arthritis no defined diagnostic criteria exist as a guide. Inflammatory markers are frequently utilized at initial presentation, (in addition to white cell count). Methods. All radiologically confirmed cases of long bone osteomyelitis without septic arthritis, joint effusion or abscess, in paediatric patients, presenting to one hospital over an eighteen-month period were included. These patients were compared with all culture positive septic arthrides presenting to the same hospital within the same time period. Inflammatory markers taken on the day of admission were studied. Results. Thirty-seven patients with long bone osteomyelitis and thirteen with culture positive septic arthritis were identified. The two groups were comparable with regards to age and gender. At presentation 65% of the osteomyelitis patients had an ESR less than 40mm/hour, 48% below 20mm/hour and 19% within the normal range. 23% of the septic arthritis patients had an ESR below 40mm/hour, and none had an ESR below 20mm/hour or in the normal range. The CRP was in the normal range in 46% of the osteomyelitis patients and none of the septic arthritis patients. The average ESR and CRP in the osteomyelitis patients were 47mm/hour and 35mg/L respectively, while in the septic arthritis group these were 72mm/hour, (P< 0.021), and 107mg/L, (P< 0.028). Conclusions. The initial rise in inflammatory markers due to long bone osteomyelitis is significantly less than that in septic arthritis. A proportion of patients presenting with osteomyelitis have normal inflammatory markers at presentation. A high index of suspicion is required in diagnosing osteomyelitis, and inflammatory markers, while a useful adjunct to monitoring treatment, may offer false reassurance regarding the initial diagnosis