Synovial Neutrophils Research Articles

Septic Arthritis in Immunosuppressed Patients: Do Laboratory Values Help?

Introduction:Previous studies have recommended synovial fluid cell count thresholds of 50,000 cells/mm−3 to diagnose septic arthritis; however, data to support this are limited. It is also unknown if this value is valid in immunosuppressed patients.Methods:We retrospectively reviewed 33 immunosuppressed patients treated at our institution from 2008 to 2018. We compared culture-positive patients with culture-negative patients.Results:We found no statistically significant differences in synovial fluid cell count, percent synovial fluid neutrophils, erythrocyte sedimentation rate, or C-reactive protein between the groups (all P = 0.081). The median synovial fluid cell count in the culture-positive cohort was 29,000 cells/mm−3, with only 31.2% having >50,000 cells/mm−3.Conclusion:Traditional synovial fluid cell thresholds are not a reliable method of diagnosing septic arthritis in immunosuppressed patients.

NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS.

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18-dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets.

Rheumatoid Arthritis Morning Stiffness Is Associated With Synovial Fibrin and Neutrophils.

Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. This study was undertaken to determine whether any histologic features of synovium are associated with this symptom. Data on patient-reported morning stiffness duration and severity, and Disease Activity Score in 28 joints (DAS28) were collected from 176 patients with RA undergoing arthroplasty. Synovium was scored for 10 histopathologic features: synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells, detritus, neutrophils, and mucin. Fibrinolysis of clots seeded with various cell types was measured in turbidimetric lysis assays. Stiffness severity and morning stiffness duration were both significantly associated with DAS28 (P = 0.0001 and P = 0.001, respectively). None of the synovial features examined were associated with patient-reported stiffness severity. The presence of neutrophils and fibrin in RA synovial tissue were significantly associated (P < 0.0001) with patient-reported morning stiffness of ≥1 hour, such that 73% of patients with both synovial fibrin and neutrophils reported morning stiffness of ≥1 hour. Further, neutrophils and fibrin deposits colocalized along the synovial lining. In in vitro analyses, fibrin clots seeded with necrotic neutrophils were more resistant to fibrinolysis than those seeded with living neutrophils or no cells (P = 0.008). DNase I treatment of necrotic neutrophils abrogated the delay in fibrinolysis. In RA, prolonged morning stiffness may be related to impaired fibrinolysis of neutrophil-enmeshed fibrin deposits along the synovial membrane. Our findings also suggest that morning stiffness severity and duration may reflect distinct pathophysiologic phenomena.

A Case Report and Literature Review to Aid in the Management of Trunnion Failure in Hip Arthroplasty Patients: Can Trunnionosis and Prosthetic Joint Infection Co-Exist?

Trunnionosis is a type of corrosion and wear at the head-neck taper junction of the femoral implant, and it can be a slow and silent catastrophe. Simultaneous prosthetic joint infection (PJI) is occasionally possible based on the fulfillment of a few of the minor criteria from the Musculoskeletal Infection Society (MSIS), but the existing literature lacks adequate evidence to support that the infection actually exists. We are presenting a case of an 82-year-old man with right total hip arthroplasty performed over a decade prior to presenting to the emergency room with a sudden-onset pop followed by groin pain and difficulty in walking. Radiographs showed a dissociated femoral implant at the level of trunnion with malalignment and heterotopic ossification. Metal Artifact Reduction Sequence MRI of the right hip showed mixed type-two and type-three pseudotumors, and atrophy of surrounding abductor muscles. The erythrocyte sedimentation rate was within normal limits, C-reactive protein was borderline raised, and serum cobalt-chromium levels were elevated without any signs of systemic metal toxicity. Hip joint aspirate revealed blood-stained fluid flooded with red blood cells, leukocytes and neutrophils, and a positive alpha-defensin assay. These findings were interpreted as positive for prosthetic joint infection. Intraoperatively, there was severe wear of the inferomedial aspect of the femoral head-neck junction and extensive metallosis throughout the right hip. Tissue and fluid specimens were sent for cultures, sensitivities, and histopathology for pseudotumor and infection evaluation. An articulating antibiotic spacer was then placed with the intent to perform a staged reconstruction of the femur and right acetabulum. Final synovial, bone, and soft tissue cultures, as well as histopathological photomicrograph of the tissue slides, were negative for infection. This case demonstrates the striking features of metallosis associated with trunnion failure of a metal-on-polyethylene total hip joint prosthesis that was simultaneously showing signs of prosthetic infection by satisfying the minor criteria according to the latest guidelines by the MSIS with a strikingly high cell count of red blood cells in the synovial fluid exam, indicating inflamed hyper-vascular pseudotumors vs. hemarthrosis vs. bloody tap. Diagnostic dilemma led by positive synovial fluid alpha defensin, high synovial neutrophil and white cell count results with negative final cultures or infection on histological slides raises concern that infection was not present and two-stage revision arthroplasty with six weeks of antibiotics was not necessary along with increased risk of morbidity, mortality as well as cost of care.

Serum interleukin 6 could be a valuable initial diagnostic tool in prosthetic knee joint infections.

Accurate preoperative diagnosis of prosthetic joint infection (PJI) in the absence of obvious clinical signs or laboratory findings is challenging. Interleukin 6 (IL-6) has been proposed as an infection marker but supportive data are limited. We studied the diagnostic utility of serum IL-6 in infected total knee arthroplasty (TKA). A prospective cohort study was done in 52 patients (59 knees) with a painful TKA. The abnormal limits for serum IL-6, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), synovial fluid white cell counts (WBC) and synovial fluid neutrophils (PMN) were determined from receiver operating characteristic curves. An infection was defined as the presence of sinus tract or positive culture > two separate tissue or fluid samples. We utilized Mann-Whitney test, Spearman's correlation and Fischer's exact test to determine the sensitivity, specificity, positive predictive value, negative predictive value (NPV) and accuracy of serum IL-6. The optimal threshold concentration of serum IL-6 was 9.14pg/ml. Independently, this yielded a sensitivity, specificity and NPV of 81%, 63% and 85%, respectively, and when combined with synovial fluid WBC, values were 100%, 90%, 100%, respectively. The sensitivity and specificity of ESR (70%, 63.6%), CRP (66.7%, 66.7%), synovial WBC (66.7%, 81%) and synovial PMN (82.4%, 73.7%) were also calculated. Serum IL-6 levels strongly correlate with all markers in PJI. Serum IL-6 improves the diagnosis of PJI over existing methods, especially when combined with synovial fluid WBC. Its optimal usage is as an excellent screening test to rule out infected total knee arthroplasty. Diagnostic Level II.

Pro-inflammatory mediators and neutrophils are increased in synovial fluid from heifers with acute ruminal acidosis

BackgroundAcute ruminal acidosis (ARA) is a metabolic disease of cattle characterized by an aseptic synovitis. ARA is the result of an increased intake of highly fermentable carbohydrates that frequently occurs in dairy cattle subjected to high production requirements. In human joint diseases such as rheumatoid arthritis and gout, several pro-inflammatory molecules are increased in the synovial fluid, including cytokines, prostaglandin E2 (PGE2), metalloproteinases, and neutrophil extracellular traps (NETs). The aim of this study was to identify the presence of proinflammatory mediators and neutrophils in the synovial fluid of heifers with ARA, induced by an oligofructose overload.Five heifers were challenged with an oligofructose overload (13 g/kg BW) dissolved in water. As a control, a similar vehicle volume was used in four heifers. Synovial fluid samples were collected from the tarso-crural joint and PGE2, IL-6, IL-1β, ATP, lactate dehydrogenase (LDH), albumin, glucose, matrix metalloproteinase-9 (MMP-9), cellular free DNA, NETs, and serpin B1 were analyzed at 0, 9, and 24 h post treatment.ResultsAt 9 h post oligofructose overload, an increase of IL-1β, IL-6, PGE2, serpin B1 and LDH was detected in the joints when compared to the control group. At 24 h, the synovial fluid was yellowish, viscous, turbid, and contained abundant neutrophils. An increase of DNA-backbone-like traps, histone 3 (H3cit), aggregated neutrophil extracellular traps (aggNETs), and serpin B1 were observed 24 h post treatment. Furthermore, albumins, LDH, ATP, MMP-9, IL-6, and IL-1β were increased after 24 h.ConclusionsThe overall results indicate that IL-1β, IL-6 and PGE2, were the earliest proinflammatory parameters that increased in the synovial fluid of animals with ARA. Furthermore, the most sever inflammatory response in the joint was observed after 24 h and could be associated with a massive presence of neutrophils and release of aggNETs.

IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis

ObjectiveAnimal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They...

Recurrent pseudogout after therapy with immune checkpoint inhibitors: a case report with immunoprofiling of synovial fluid at each flare

BackgroundDespite ground-breaking clinical success in the treatment of different cancers, immune checkpoint inhibitors can cause profound inflammatory and immune-related adverse events. Autoimmune inflammatory arthritis following immune checkpoint inhibitor treatment has been reported; however, to date, no cases of crystal arthritis following immune checkpoint inhibitors have been identified.Case presentationWe report the first case of recurrent pseudogout, an inflammatory crystal arthritis, in a patient treated with nivolumab, a PD-1 inhibitor, for renal cell carcinoma. The patient had recurrent pseudogout flares about week to 10 days after each nivolumab infusion. After treatment with prophylactic colchicine, the patient well tolerated additional nivolumab infusions without adverse events. In parallel, we characterized immune cells of synovial fluid at each flare. Immunoprofiling of synovial fluid showed that the proportion of inflammatory IL-17-producing CD4+ T cells and amount of IL-17 were notably increased in synovial fluid with every recurrent flair, and correlated with the increase in number of synovial neutrophils, suggesting a potential role of T helper 17 (Th17) cells in neutrophil-driven inflammation during pseudogout arthritis.ConclusionsThis case suggests a potential influence of Th17 cells on the neutrophil recruitment and neutrophil-driven inflammatory events leading to pseudogout induced by immune checkpoint inhibitor therapy.

Extractable synovial fluid in inflammatory and non-inflammatory arthritis of the knee.

We hypothesized that mechanical compression of the knee in rheumatoid arthritis (RA) would mobilize occult extractable fluid and improve arthrocentesis success. Sixty-seven consecutive knees with RA and 186 knees with OA and were included. Conventional arthrocentesis was performed and success and volume (milliliters) determined; the needle was left intraarticularly, and mechanical compression was applied with an elastomeric knee brace. Arthrocentesis was then resumed until fluid return ceased. Fluid was characterized as to volume and cell counts. In the RA, knee mechanical compression decreased failed diagnostic arthrocentesis from 56.7% (38/67) to 26.9% (18/67) (- 47.4%, p = 0.003) and increased absolute arthrocentesis yield from 4.7 ± 10.3ml to 9.8 ± 9.8ml (108% increase, 95% CI - 8.5 < - 5.1 < - 1.7 p = 0.0038). Total extractable fluid yield was 96% greater in RA (9.8 ± 9.8ml) than OA (5.0 ± 9.4ml, p = 0.0008), and occult extractable fluid was 77% greater in RA than OA (RA 5.3 ± 8.7ml, OA 3.0 ± 5.5ml, p = 0.046). Large effusions versus small effusions in RA demonstrated increased neutrophils in synovial fluid (p = 0.04) but no difference in radiologic arthritis grade (p = 0.87). In contrast, large effusions versus small effusions in OA demonstrated no difference in neutrophils in synovial fluid (p = 0.87) but significant different radiologic arthritis grade (p = 0.04). Mechanical compression improves the success of diagnostic and therapeutic knee arthrocentesis in both RA and OA. Large effusions in RA are associated with increased neutrophil counts but not arthritis grade; in contrast, large effusions in OA are associated with more severe arthritis grades but not increased neutrophil counts. Key points• Mechanical compression of the painful knee improves arthrocentesis success and fluid yield in both rheumatoid arthritis and osteoarthritis.• The painful rheumatoid knee contains approximately 100% more fluid than the osteoarthritic knee.• Large effusions in the osteoarthritic knee are characterized by higher grades of mechanical destruction but not increased neutrophil counts.• In contrast, large effusions in the rheumatoid knee are characterized by higher synovial fluid neutrophil counts but not the grade of mechanical destruction, indicating different mechanisms of effusion formation in rheumatoid arthritis versus osteoarthritis.

Calprotectin discriminates septic arthritis from pseudogout and rheumatoid arthritis.

We aimed to determine whether calprotectin and α-defensins could discriminate septic from other inflammatory arthritides. Synovial fluids with a predominance of neutrophils from patients with septic arthritis, pseudogout and RA were prospectively collected. Neutrophil-related proteins calprotectin and human neutrophil α-defensins levels were assessed in synovial fluids. Demographic parameters and biomarkers with P-value ⩽0.05 for differentiating septic from non-septic arthritis were included in a multivariable model. Multivariable logistic regression with stepwise selection was performed to build the final combined model. A total of 74 patients were included: septic arthritis (n = 26), pseudogout (n = 28) and RA (n = 20). Patients with septic arthritis were more likely to be male and young, and to display higher synovial neutrophil count. Calprotectin was significantly increased in patients with septic arthritis. The multivariable model included calprotectin, synovial fluid neutrophil count and gender. Calprotectin was the only biomarker that discriminated septic arthritis from non-septic inflammatory arthritides, with 76% sensitivity, 94% specificity and a positive likelihood ratio = 12.2 at the threshold for calprotectin of 150 mg/l. Synovial fluid calprotectin is a relevant biomarker to discriminate septic arthritis from other inflammatory arthritides. This biomarker should be tested in an independent cohort.

Traditional Laboratory Markers Hold Low Diagnostic Utility for Immunosuppressed Patients With Periprosthetic Joint Infections

BackgroundAlthough predictive laboratory markers and cutoffs for immunocompetent patients are well-studied, similar reference ranges and decision thresholds for immunosuppressed patients are less understood. We investigated the utility of typical laboratory markers in immunosuppressed patients undergoing aspiration of a prosthetic hip or knee joint. MethodsA retrospective review of adult patients with an immunosuppressed state that underwent primary and revision total joint arthroplasty with a subsequent infection at our tertiary, academic institution was conducted. Infection was defined by Musculoskeletal Infection Society criteria. A multivariable analysis was used to identify independent factors associated with acute (<90 days) and chronic (>90 days) infection. Area under the receiver-operator curve (AUC) was used to determine the best supported laboratory cut points for identifying infection. ResultsWe identified 90 patients with immunosuppression states totaling 172 aspirations. Mean follow-up from aspiration was 33 months. In a multivariate analysis, only synovial fluid cell count and synovial percent neutrophils were found to be independently correlated with both acute and chronic infection. A synovial fluid cell count cutoff value of 5679 nucleated cells/mm3 maximized the AUC (0.839) for predicting acute infection, while a synovial fluid cell count cutoff value of 1293 nucleated cells/mm3 maximized the AUC (0.931) for predicting chronic infection. ConclusionPhysicians should be aware of lower levels of synovial nucleated cell count and percentage of neutrophils in prosthetic joint infections of the hip or knee in patients with immunosuppression. Further investigation is necessary to identify the best means of diagnosing periprosthetic joint infection in this patient population.

Does inflammatory joint diseases affect the accuracy of infection biomarkers in patients with periprosthetic joint infections? A prospective comparative reliability study

BackgroundThe diagnosis of periprosthetic joint infections (PJI) in patients with inflammatory joint diseases (IJD) could be challenging. Several tests used for diagnosing PJI may be inaccurate due to baseline inflammatory characteristics of such diseases. We aimed to evaluate the accuracy of several infection biomarkers, in a specific subgroup of patients with PJI and IJD. MethodsFrom January 2014 to August 2017, patients with resisting pain at the relevant site, following total knee arthroplasty were evaluated prospectively. A total of 38 patients were undergone revision arthroplasty. Patients were categorized in terms of MSIS criteria: Patients with PJI (Group 1, n = 17) and patients without PJI (Group 2, n = 21). Serum ESR, CRP, Procalcitonin, synovial cell count, percentage of neutrophils in synovial fluid, synovial CRP, Lactoferrin, ELA-2, Thiol – Disulphide levels, BPI and the Alpha defensin test results were obtained. The results of two groups were compared and the diagnostic accuracy of each variable was evaluated. ResultsThere were 22 women, 16 men with a mean age of 67.8 ± 6.9 years. The differences were significant in all evaluated biomarkers in terms of PJI (p values of all biomarker were <0.001). Alpha defensin, Lactoferrin, ELA-2, BPI, Procalcitonin and synovial CRP were the most accurate tests with area under curve >0.90. ConclusionsOur results demonstrated that IJD may not affect the accuracy of infection biomarkers in patients with PJI. Alpha defensin test, Lactoferrin, ELA-2, BPI, Procalcitonin and synovial CRP can be used in the diagnosis of PJI in patients with IJD.

Association between levels of synovial anti‐citrullinated peptide antibodies and neutrophil response in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated peptide antibodies (ACPAs) and neutrophils infiltrating the synovial fluid (SF) of the affected joints. The aim of this work was to analyze whether the presence of ACPAs in SF is associated with neutrophil infiltration and with their phenotype in the inflamed joints of RA patients. We found that in the presence of ACPAs, the number of synovial neutrophils correlated with severe disease activity. The SF were divided according to synovial ACPA levels in negative- (<25 U/mL), low- (25-200 U/mL) and high level (˃200 U/mL; ACPAhigh ). We observed that IL-6, IL-17, and IL-8 were significantly elevated in ACPAhigh SF and that IL-8 levels correlated positively with neutrophil counts and with worse clinical manifestations. Additionally, in vitro incubation of neutrophils with ACPAhigh SF resulted in an increased ROS production and extracellular DNA release compared to neutrophils incubated with ACPA-negative SF. These exacerbated effector functions were associated with a fraction of ICAM-1-positive neutrophils, which were induced by ACPAhigh SF. Likewise, in in vivo, we could also detect this subset among neutrophils present in ACPAhigh SF. In conclusion, the data presented here shed light on the role of SF-ACPAs as inductors of a proinflammatory profile in neutrophils.

Laboratory Tests for Diagnosis of Chronic Periprosthetic Joint Infection Can Help Predict Outcomes of Two-Stage Exchange.

Although 2-stage exchange arthroplasty is the most effective treatment among available strategies for managing chronic periprosthetic joint infection (PJI), rates of its success vary greatly. The purpose of our study was to examine whether objective measurements collected at the time of the diagnosis of PJI could be used to identify patients at risk of failure of 2-stage exchange. We identified 205 patients across 4 institutions who underwent 2-stage exchange arthroplasty for the treatment of PJI following total hip or total knee arthroplasty. Demographic, surgical, and laboratory data were obtained for each patient from their medical chart. Laboratory values included serum erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, synovial fluid white blood-cell (WBC) count and neutrophil percentage, synovial fluid and/or tissue culture, and Gram stain. Patients who underwent revision surgery for recurrent infection were considered to have failed the 2-stage procedure. Demographic, surgical, and laboratory variables were compared between the 2 groups. Receiver operating characteristic (ROC) curves were constructed to determine threshold cutoffs for significant laboratory values. Risk ratios and 95% confidence intervals were calculated. Overall, 2-stage exchange was unsuccessful for 27.3% of the patients. Preoperative serum ESR (p = 0.035) and synovial fluid WBC count (p = 0.008) and neutrophil percentage (p = 0.041) were greater in patients with recurrent infection. ROC curve analysis revealed a threshold of >60,000 cells/μL for synovial fluid WBC count, >92% for synovial fluid WBC neutrophil percentage, and >99 mm/hr for serum ESR. Failure of 2-stage exchange was 2.5 times more likely for patients with an elevated preoperative synovial fluid WBC count, 2.0 times more likely for those with an elevated preoperative synovial fluid WBC neutrophil percentage, and 1.8 times more likely for those with an elevated preoperative serum ESR. Our results demonstrated that a greater number of patients in whom 2-stage exchange arthroplasty ultimately failed had a preoperative synovial fluid WBC count of >60,000 cells/μL, a synovial fluid WBC neutrophil percentage of >92%, or a serum ESR of >99 mm/hr. Patients with elevated laboratory values had 1.8 to 2.5 times the risk of treatment failure. These data can serve as a clinical guideline to identify patients most at risk for failure of 2-stage exchange. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

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

BackgroundThe 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. MethodsWe 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. ResultsPatients 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. ConclusionsDiagnosing 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 EvidenceIII.

Distinguishing Pediatric Lyme Arthritis of the Hip from Transient Synovitis and Acute Bacterial Septic Arthritis: A Systematic Review and Meta-analysis.

ObjectiveLyme arthritis is an increasingly recognized clinical entity that often prompts orthopaedic evaluation in pediatric patients. While Lyme arthritis is most common in the knee, the clinical presentation of Lyme arthritis of the hip can be similar to both acute bacterial septic arthritis and transient synovitis. Accurately distinguishing these clinical entities is important since the definitive treatment of each is distinct. Because there is limited literature on monoarticular Lyme arthritis of the hip, the purpose of this study was to perform a systematic review and meta-analysis of clinical and laboratory parameters associated with Lyme arthritis (LA) of the hip and compare them to septic arthritis (SA) and transient synovitis (TS). Study designA systematic review of the literature was performed using the following search terms, including the variants and plural counterparts “hip” and “Lyme arthritis.” A final database of individual patients was assembled from the published literature and direct author correspondence, when available. A previously published cohort of patients with hip transient synovitis or septic arthritis was used for comparative analysis. A comparative statistical analysis was performed to the assembled database to assess differences in laboratory and clinical variables between the three diagnoses. ResultsData on 88 patients diagnosed with Lyme arthritis of the hip was collected and consolidated from the 12 articles meeting inclusion criteria. The average age of patients presenting with Lyme arthritis was 7.5 years (± 3.5 years), the mean erythrocyte sedimentation rate (ESR), and the C-reactive protein (CRP) was 41 mm/hr and 3.9 mg/L, respectively. Peripheral white blood cell (WBC) count averaged 10.6 x 109cells/L with the synovial WBC count averaging 55,888 cells/mm3. Compared to a previous cohort of patients with confirmed transient synovitis or septic arthritis, the 95% confidence interval for ESR was 21 - 33 mm/hr in those diagnosed with toxic synovitis (TS), 37 - 46 mm/hr for Lyme arthritis (LA), and 44 - 64 mm/hr for septic arthritis (SA). Synovial WBC counts (cells/mm3) 95% confidence intervals (CI) were 5,644 - 15,388 cells/mm3 for TS, 47,533 - 64,242 cells/mm3 for LA, and 105,432 - 260,214 cells/mm3 for SA. There was a statistically significant difference in the incidence of fever > 38.5oC (P < 0.001) and refusal to bear weight (P < 0.01) between SA, LA, and TS.ConclusionsMonoarticular Lyme arthritis can be a cause of hip pain in certain geographic areas and has clinical and diagnostic overlap with transient synovitis and acute bacterial septic arthritis. This study consolidates the available literature and represents the largest series of patients diagnosed with Lyme arthritis of the hip to date. We propose a diagnostic algorithm that serially incorporates ESR, followed by a synovial neutrophil count, when evaluating pediatric patients with an irritable hip in Lyme endemic areas.

Diagnostic accuracy of synovial fluid, blood markers, and microbiological testing in chronic knee prosthetic infections.

This retrospective study was undertaken to define cut-off values for synovial fluid (SF) leukocyte count and neutrophil percentage for differentiating aseptic failure and periprosthetic joint infection (PJI) and to evaluate the diagnostic accuracy of blood inflammatory markers, and microbiological testing according to the criteria proposed by the International Consensus Meeting (ICM) of Philadelphia. All patients who underwent revision total knee arthroplasty from January 2010 to July 2015 were included: we identified and classified 31 PJIs and 136 aseptic joints. The diagnostic performance of single test was assessed by receiver operating characteristic curve analyses. The sensitivity and specificity were calculated for each of the cut-off values and the area under the curve (AUC) was calculated. The median SF leukocyte count as well as the neutrophil percentage and inflammatory markers were significantly higher in patients with PJI than in those with aseptic failure (p<0.001). A leukocyte count of>2.8×103/μL had a sensitivity of 83.8% and a specificity of 89.7% whereas a neutrophil percentage of>72% yielded a marginally higher sensitivity of 84% and a specificity of 91%. Applying the ICM criteria we found a significant correlation between all these diagnostic measures and PJI (p<0.001) except for a single positive culture. The most accurate criterion of the ICM was the synovial neutrophil differential (AUC=0.89; 95% CI 0.81-0.97), followed by SF leukocyte count (AUC=0.86; 95% CI 0.78-0.94), increased inflammatory markers (AUC=0.85; 95% CI 0.76-0.93), and two positive periprosthetic cultures (AUC=0.84; 95% CI 0.73-0.94). The presence of sinus tract communicating with the joint and a single positive culture showed unfavourable diagnostic accuracy (AUC=0.60, 95% CI 0.47-0.72; AUC=0.49, 95% CI 0.38-0.61, respectively) CONCLUSIONS: The present study highlights the adequate ability of fluid cell count and neutrophil differential to distinguish between PJI and aseptic loosening. The clinical utility of fluid analysis in diagnosing infection can be improved by evaluation of other diagnostic criteria. Level I Diagnostic Study.

Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein-Associated Serine Protease 2.

Complement plays an important role in the pathogenesis of rheumatoid arthritis. Although the alternative pathway (AP) is known to play a key pathogenic role in models of rheumatoid arthritis, the importance of the lectin pathway (LP) pattern recognition molecules such as ficolin (FCN) A, FCN B, and collectin (CL)-11, as well as the activating enzyme mannose-binding lectin-associated serine protease-2 (MASP-2), are less well understood. We show in this article that FCN A-/- and CL-11-/- mice are fully susceptible to collagen Ab-induced arthritis (CAIA). In contrast, FCN B-/- and MASP-2-/-/sMAp-/- mice are substantially protected, with clinical disease activity decreased significantly (p < 0.05) by 47 and 70%, respectively. Histopathology scores, C3, factor D, FCN B deposition, and infiltration of synovial macrophages and neutrophils were similarly decreased in FCN B-/- and MASP-2-/-/sMAp-/- mice. Our data support that FCN B plays an important role in the development of CAIA, likely through ligand recognition in the joint and MASP activation, and that MASP-2 also contributes to the development of CAIA, likely in a C4-independent manner. Decreased AP activity in the sera from FCN B-/- and MASP-2-/-/sMAp-/- mice with arthritis on adherent anti-collagen Abs also support the hypothesis that pathogenic Abs, as well as additional inflammation-related ligands, are recognized by the LP and operate in vivo to activate complement. Finally, we also speculate that the residual disease seen in our studies is driven by the AP and/or the C2/C4 bypass pathway via the direct cleavage of C3 through an LP-dependent mechanism.

Papers of note in Science Immunology 2 (10)

This month’s articles show that cholesterol-based ligands position splenic dendritic cells near T cells; how synovial fibroblasts and neutrophils promote inflammation in arthritis; that type I interferon activates liver T cells in obese mice; and how the alternative complement pathway plays a role in antibacterial immunity.

Utility of Synovial White Blood Cell Count and Differential Before Reimplantation Surgery

BackgroundDetermining optimal timing of reimplantation during 2-stage exchange for periprosthetic joint infection (PJI) remains elusive. Joint aspiration for synovial white blood cell (WBC) count and neutrophil percentage (PMN%) before reimplantation is widely performed; yet, the implications are rarely understood. Therefore, this study investigates (1) the diagnostic yield of synovial WBC count and differential analysis and (2) the calculated thresholds for persistent infection. MethodsInstitutional PJI databases identified 129 patients undergoing 2-stage exchange arthroplasty who had joint aspiration before reimplantation between February 2005 and May 2014. Persistent infection was defined as a positive aspirate culture, positive intraoperative cultures, or persistent symptoms of PJI—including subsequent PJI-related surgery. Receiver-operating characteristic curve was used to calculate thresholds maximizing sensitivity and specificity. ResultsThirty-three cases (33 of 129; 25.6%) were classified with persistent PJI. Compared with infection-free patients, these patients had significantly elevated PMN% (62.2% vs 48.9%; P = .03) and WBC count (1804 vs 954 cells/μL; P = .04). The receiver-operating characteristic curve provided thresholds of 62% and 640 cells/μL for synovial PMN% and WBC count, respectively. These thresholds provided sensitivity of 63% and 54.5% and specificity of 62% and 60.0%, respectively. The risk of persistent PJI for patients with PMN% >90% was 46.7% (7 of 15). ConclusionSynovial fluid analysis before reimplantation has unclear utility. Although statistically significant elevations in synovial WBC count and PMN% are observed for patients with persistent PJI, this did not translate into useful thresholds with clinical importance. However, with little other guidance regarding the timing of reimplantation, severely elevated WBC count and differential analysis may be of use.