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The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

Background: Urinary tract infection (UTI) is a widespread infectious disease in humans. Urine culture, a huge workload in the microbiology laboratory, is still the standard diagnostic test for UTI, but most of the cultures are negative. A reliable screening method could reduce unnecessary cultures and quicken reporting of negative results.Methods: We evaluated the usefulness of a flow cytometry (FC) screening method in the prediction of positive urine culture to reduce the number of urine cultures. The urine specimens sent to the laboratory for culture were tested with the flow cytometer Accuri C6. FC bacterial counts were compared to standard urine culture results to assess the best cut-off values.Results: Two hundred nine urine samples were included, of which 79 (37.8 %) were culture positive. On comparing the culture and the FC data in the ROC curve, the FC bacterial counts of >= 10(6) bacteria/mL provided a reliable screening for bacteriuria with a sensitivity and specificity of 99 and 58 %, respectively. All negative FC results (= 10(8)/mL showed a positive predictive value of 99 % with a positive likelihood ratio of 60.9.Conclusions: Counting bacteria in human urine samples by the FC is a fast, accurate and cost-effective screening method for bacteriuria. Our results showed that FC is able to rule out UTI, which can lead to a substantial reduction (36 %) of urine cultures. It also demonstrated that this method predicts positive cultures accurately.

In this study we have evaluated a new, fully automated fluorescent-enzyme immuno-assay (FEIA) for detection and quantification of anti-PR3 and anti-MPO ANCA in diagnosis and follow-up of ANCA-associated small vessel vasculitis (AAV). PR3- and MPO-ANCA were determined by FEIA technology in (1) sera of 87 consecutive patients with biopsy-proven, pauci-immune necrotizing crescentic glomerulonephritis (NCGN) and 72 controls; (2) 120 sera (60 patients with Wegener's granulomatosis and 60 controls) that were previously used in a multicentre comparison of direct and capture ELISAs for PR3-ANCA; (3) in samples preceding relapse in 23 PR3-AAV patients with and 23 matched PR3-AAV patients without relapse for prediction of relapses. PR3- and/or MPO-ANCA detection in pauci-immune NCGN by FEIA revealed an overall sensitivity of 82.8%. The FEIA specificity was 96% and 100% for PR3- and MPO-ANCA, respectively. The overall sensitivity of MPO- and PR3-ANCA could be increased to 88.5% by lowering the cut-off values without affecting the specificity (ROC-curve analysis), which is similar to a multistep ANCA procedure that combines indirect immunofluorescence with direct and capture ELISAs. The sensitivity for Wegener's granulomatosis (WG) of the PR3-ANCA FEIA (60%) was more comparable to direct ELISAs (64%) than to capture ELISAs (74%). A rise of 100% in ANCA level as measured by FEIA appeared optimal (ROC-curve) for prediction of relapses and such a rise was observed in 26 patients. In 18 of these 26 patients the rise was followed by a relapse (PPV 69%), whereas in 15 of the 20 patients without a rise no relapse was observed (NPV 75%). In conclusion, detection of PR3- and MPO-ANCA by FEIA has excellent performance in terms of diagnosis of AAV patients. Furthermore, detection of rises in PR3-ANCA by FEIA for prediction of relapses gives results comparable to other techniques.

Objective: To study the cefpirome pharmacokinetics of patients with sepsis and multiple organ failure treated with CVVH. Design: Measurements of serum and ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated micro-organisms. Setting: University hospital-based, single ICU. Patients: Six critically ill CVVH- dependent patients with sepsis and multiple organ dysfunction syndrome in need of antimicrobial therapy. Age range: 60–75 years; APACHE II score for severity of illness on admission: 19–30. One patient survived. Interventions: Cefpirome i. v. was started at 2 g in 30 min, then continued 1 g i. v. b. i. d. Measurements: The UF rate was 27 ± 7 ml/min on day 1 and 34 ± 2 ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated high performance liquid chromatography assay. Volume of distribution: 23 · 5(SD ± 4 · 6) l. Total cefpirome clearance was 32 ± 6 · 3 ml/min; cefpirome CVVH clearance (ClCVVH): 17 ± 4.2 ml/min; mean serum half-life (t1/2): 8.8 ± 2.3 h; mass transfer on day 1: 660 ± 123 mg/12 h (33 ± 6 % of administered dose)and day 2: 642 ± 66 mg/12 h (64 ± 7 %). Estimated sieving coefficient (ClCVVH/UF rate): 64 ± 11 %. In vitro sensitivity of isolated microbes was excellent except for two non-sensitive enterococci and Candida spp. Conclusions: The sieving coefficient (64 %) indicates that a substantial fraction of the drug is not filtered; clearance by pathways other than CVVH mounted to 50 % of the total clearance and increased on day 2, indicating that the dosing schedule used is appropriate for this setting. Cefpirome appeared to be safe in these patients and effective for most of the nosocomial microbial isolates. During more than 90 % of the time, serum levels were maintained above killing concentrations for susceptible micro-organisms.

Objective: Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. Patients, design: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CIT) was calculated from serum concentrations. Results: All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip/taz concentration ratio of 20 : 1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10 : 1 on day 2. The CIT of pip was 2.52 +/- 1.38 l/h (t 1/2 : 5.9 +/- 2.9 h), and CIT of taz 4.44 +/- 2.28 l/h (t 1/2 : 8.1 +/- 3.7 h). The CIT and t 1/2 of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CI, taz has a longer half-life, because of a higher volume of distribution. Conclusion: In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip.

Sepsis-induced multi-organ dysfunction syndrome (MODS) still has a high mortality. Improvements await a better understanding of the pathophysiological mechanisms. The angiopoietin (Ang)1/2 and Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) ligand/receptor system is an important regulator of endothelial cell responses to severe insults. Plasma Ang2 levels are prognostic in sepsis, but data on Ang/Tie responses in organs in humans are lacking.. We hypothesized that, in kidneys of patients who died of sepsis with acute kidney injury (AKI), the Ang/Tie signaling system is changed in such a way that microvessels become destabilized.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic inflammatory disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome and renal limited vasculitis (RLV). Extracellular high-mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a biomarker of disease activity as well as an autoantigen in systemic lupus erythematosus (SLE) and, possibly, in AAV. This study aims to assess antibodies against HMGB1 and HMGB1 levels as biomarkers for AAV disease activity and predictors of relapsing disease.Methods: AAV patients with active disease and healthy controls (HC) were evaluated for anti-HMGB1 antibodies while serum HMGB1 levels were measured longitudinally in AAV patients at presentation, during remission, prior to and at relapses.Results: HMGB1 levels were similar between AAV patients at presentation (n = 52) and HC (n = 35) (2.64 +/- 1.80 ng/ml vs. 2.39 +/- 1.09 ng/ml; P = 0.422) and no difference regarding HMGB1 levels could be found among AAV disease subsets (GPA: 2.66 +/- 1.83 ng/ml vs. MPA: 3.11 +/- 1.91 ng/ml vs. RLV: 1.92 +/- 1.48 ng/ml; P = 0.369). AAV patients with renal involvement had lower HMGB1 levels than patients without renal involvement at presentation (2.35 +/- 1.48 ng/ml vs. 3.52 +/- 2.41 ng/ml; P = 0.042). A negative correlation was observed between HMGB1 levels and 24-hour proteinuria (rho = -0.361, P = 0.028). Forty-nine AAV patients were evaluated for HMGB1 levels during follow-up and no differences were observed between relapsing and nonrelapsing patients (P = 0.350). No significant increase in HMGB1 levels was observed prior to a relapse compared with the remission period and changes in HMGB1 levels were not associated with an increased risk for relapse in AAV. Positivity for anti-HMGB1 antibodies was low in patients with active AAV (three out of 24 patients).Conclusions: Serum HMGB1 levels at presentation are not increased and are lower in patients with renal involvement. Relapses are not preceded or accompanied by significant rises in HMGB1 levels and changes in HMGB1 levels are not related to ensuing relapses. Anti-HMGB1 antibodies are present in only a few patients in AAV. In contrast to SLE, HMGB1 is not a useful biomarker in AAV.

Introduction: Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV.Methods: Male patients with AAV in remission were included in this study. Fatigue and HRQOL were assessed by the multi-dimensional fatigue inventory (MFI)-20 and RAND-36 questionnaires.Results: Seventy male patients with a mean age of 59 years (SD 12) were included. Scores of almost all subscales of both questionnaires were significantly worse in patients compared to controls. Mean total testosterone and free testosterone levels were 13.8 nmol/L (SD 5.6) and 256 pmol/L (SD 102), respectively. Androgen deficiency (defined according to Endocrine Society Clinical Practice Guidelines) was present in 47% of patients. Scores in the subscales of general health perception, physical functioning and reduced activity were significantly worse in patients with androgen deficiency compared to patients with normal androgen levels. Testosterone and age were predictors for the RAND-36 physical component summary in multiple linear regression analysis. Testosterone, age, vasculitis damage index (VDI) and C-reactive protein (CRP) were associated with the MFI-20 subscale of general fatigue.Conclusions: This study showed that androgen deficiency was present in a substantial number of patients with AAV. Testosterone was one of the predictors for physical functioning and fatigue. Testosterone may play a role in fatigue, reduced physical performance and HRQOL in male patients with AAV.

Wegener's granulomatosis (WG) is a form of systemic vasculitis. It is characterized by granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis, and is strongly associated with antineutrophil cytoplasmic antibodies against proteinase 3. Since the etiology of the disease is not clear, treatment, consisting of corticosteroids and immunosuppressives, is nonspecific and associated with severe side effects. Pinpointing the trigger(s) of the disease would highly improve treatment. Clinical evidence shows that an infectious agent, the bacterium Staphylococcus aureus, is a risk factor for disease relapse, suggesting its involvement in the pathogenesis of WG. Here we review both clinical and experimental data that either indicate or support a role for S. aureus in WG.