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

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%

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

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

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. 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

Aims. The diagnosis of periprosthetic joint infection (PJI) can be challenging as the symptoms are similar to other conditions, and the markers used for diagnosis have limited sensitivity and specificity. Recent research has suggested using blood cell ratios, such as platelet-to-volume ratio (PVR) and platelet-to-lymphocyte ratio (PLR), to improve diagnostic accuracy. The aim of the study was to further validate the effectiveness of PVR and PLR in diagnosing PJI. Methods. A retrospective review was conducted to assess the accuracy of different marker combinations for diagnosing chronic PJI. A total of 573 patients were included in the study, of which 124 knees and 122 hips had a diagnosis of chronic PJI. Complete blood count and synovial fluid analysis were collected. Recently published blood cell ratio cut-off points were applied to receiver operating characteristic curves for all markers and combinations. The area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values were calculated. Results. The results of the analysis showed that the combination of ESR, CRP, synovial white blood cell count (Syn. WBC), and polymorphonuclear neutrophil percentage (PMN%) with PVR had the highest AUC of 0.99 for knees, with sensitivity of 97.73% and specificity of 100%. Similarly, for hips, this combination had an AUC of 0.98, sensitivity of 96.15%, and specificity of 100.00%. Conclusion. This study supports the use of PVR calculated from readily available complete blood counts, combined with established markers, to improve the accuracy in diagnosing chronic PJI in both total hip and knee arthroplasties. Cite this article: Bone Jt Open 2023;4(11):881–888

Aims. This study aimed to explore the diagnostic value of synovial fluid neutrophil extracellular traps (SF-NETs) in periprosthetic joint infection (PJI) diagnosis, and compare it with that of microbial culture, serum ESR and CRP, synovial white blood cell (WBC) count, and polymorphonuclear neutrophil percentage (PMN%). Methods. In a single health centre, patients with suspected PJI were enrolled from January 2013 to December 2021. The inclusion criteria were: 1) patients who were suspected to have PJI; 2) patients with complete medical records; and 3) patients from whom sufficient synovial fluid was obtained for microbial culture and NET test. Patients who received revision surgeries due to aseptic failure (AF) were selected as controls. Synovial fluid was collected for microbial culture and SF-WBC, SF-PNM%, and SF-NET detection. The receiver operating characteristic curve (ROC) of synovial NET, WBC, PMN%, and area under the curve (AUC) were obtained; the diagnostic efficacies of these diagnostic indexes were calculated and compared. Results. The levels of SF-NETs in the PJI group were significantly higher than those of the AF group. The AUC of SF-NET was 0.971 (95% confidence interval (CI) 0.903 to 0.996), the sensitivity was 93.48% (95% CI 82.10% to 98.63%), the specificity was 96.43% (95% CI 81.65% to 99.91%), the accuracy was 94.60% (95% CI 86.73% to 98.50%), the positive predictive value was 97.73%, and the negative predictive value was 90%. Further analysis showed that SF-NET could improve the diagnosis of culture-negative PJI, patients with PJI who received antibiotic treatment preoperatively, and fungal PJI. Conclusion. SF-NET is a novel and ideal synovial fluid biomarker for PJI diagnosis, which could improve PJI diagnosis greatly. Cite this article: Bone Joint Res 2023;12(2):113–120

Aims. Gram-negative infections are associated with comorbid patients, but outcomes are less well understood. This study reviewed diagnosis, management, and treatment for a cohort treated in a tertiary spinal centre. Methods. A retrospective review was performed of all gram-negative spinal infections (n = 32; median age 71 years; interquartile range 60 to 78), excluding surgical site infections, at a single centre between 2015 to 2020 with two- to six-year follow-up. Information regarding organism identification, antibiotic regime, and treatment outcomes (including clinical, radiological, and biochemical) were collected from clinical notes. Results. All patients had comorbidities and/or non-spinal procedures within the previous year. Most infections affected lumbar segments (20/32), with Escherichia coli the commonest organism (17/32). Causative organisms were identified by blood culture (23/32), biopsy/aspiration (7/32), or intraoperative samples (2/32). There were 56 different antibiotic regimes, with oral (PO) ciprofloxacin being the most prevalent (13/56; 17.6%). Multilevel, contiguous infections were common (8/32; 25%), usually resulting in bone destruction and collapse. Epidural collections were seen in 13/32 (40.6%). In total, five patients required surgery, three for neurological deterioration. Overall, 24 patients improved or recovered with a mean halving of CRP at 8.5 days (SD 6). At the time of review (two to six years post-diagnosis), 16 patients (50%) were deceased. Conclusion. This is the largest published cohort of gram-negative spinal infections. In older patients with comorbidities and/or previous interventions in the last year, a high level of suspicion must be given to gram-negative infection with blood cultures and biopsy essential. Early organism identification permits targeted treatment and good initial clinical outcomes; however, mortality is 50% in this cohort at a mean of 4.2 years (2 to 6) after diagnosis. Cite this article: Bone Jt Open 2024;5(5):435–443

Background: Several studies have shown that uncomplicated hip or knee arthroplasties induce an abrupt rise in serum C-reactive protein (CRP) concentration for a few days, falling thereafter to preoperative level within a couple of weeks, if no infection is present. Aim: To evaluate the computer-aided CRP levels analysis in a primary hospital care setting. Material and Methods: 300 patients undergoing total knee and hip replacements were screened before and for 5 days after arthroplasty. The data were recorded in a database and mathematical algorithm to obtain integral and progressive field surface of the CRP curve. Results: An elevated C-reactive protein level on the fifth postoperative day correlated positively with the development of acute periprosthetic infection in the first three months postoperatively. Conclusions: The patient’s individual pattern not following one of the four normal patterns can be argued to necessitate introduction of any infection treatment (whether debridement with retention or antimicrobial therapy alone) within the first three months after the operation

Aims. Implant-related postoperative spondylodiscitis (IPOS) is a severe complication in spine surgery and is associated with high morbidity and mortality. With growing knowledge in the field of periprosthetic joint infection (PJI), equivalent investigations towards the management of implant-related infections of the spine are indispensable. To our knowledge, this study provides the largest description of cases of IPOS to date. Methods. Patients treated for IPOS from January 2006 to December 2020 were included. Patient demographics, parameters upon admission and discharge, radiological imaging, and microbiological results were retrieved from medical records. CT and MRI were analyzed for epidural, paravertebral, and intervertebral abscess formation, vertebral destruction, and endplate involvement. Pathogens were identified by CT-guided or intraoperative biopsy, intraoperative tissue sampling, or implant sonication. Results. A total of 32 cases of IPOS with a mean patient age of 68.7 years (37.6 to 84.1) were included. Diabetes, age > 60 years, and history of infection were identified as risk factors. Patient presentation upon admission included a mean body temperature of 36.7°C (36.1 to 38.0), back pain at rest (mean visual analogue scale (VAS) mean 5/10) and when mobile (mean VAS 6/10), as well as elevated levels of CRP (mean 76.8 mg/l (0.4 to 202.9)) and white blood cell count (mean 9.2 units/nl (2.6 to 32.8)). Pathogens were identified by CT-guided or conventional biopsy, intraoperative tissue sampling, or sonication, and Gram-positive cocci presented as the most common among them. Antibiotic therapy was established in all cases with pathogen-specific treatment in 23 (71.9%) subjects. Overall 27 (84.4%) patients received treatment by debridement, decompression, and fusion of the affected segment. Conclusion. Cases of IPOS are rare and share similarities with spontaneous spondylodiscitis. While procedures such as CT-guided biopsy and sonication are valuable tools in the diagnosis of IPOS, MRI and intraoperative tissue sampling remain the gold standard. Research on known principles of PJI such as implant retention versus implant exchange need to be expanded to the field of spine surgery. Cite this article: Bone Jt Open 2023;4(11):832–838