ABSTRACT
PURPOSE OF REVIEW: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular. RECENT FINDINGS: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Microbiota , Antibodies, Antineutrophil Cytoplasmic , Humans , PhenotypeABSTRACT
BACKGROUND: Urinary tract infections (UTIs) are frequently encountered at the Emergency Department (ED). Given the anatomical differences between men and women, we aimed to clarify differences in the diagnostic performance of urinary parameters at the ED. METHODS: A cohort study of adults presenting at the ED with fever and/or clinical suspected UTI. Performance of urine dipstick (UD) and automated urinalysis (UF-1000i) were analysed for the total study population and men and women separately. We focused on 1) UTI diagnosis and 2) positive urine culture (UC, ≥105 CFU/ml) as outcome. RESULTS: In 360 of 917 cases (39.3%) UTI was established (men/women 35.1%/43.6%). Diagnostic accuracy of UD was around 10% lower in women compared to men. Median automated leucocyte and bacterial count were higher in women compared to men. Diagnostic performance by receiver operating analysis was 0.851 for leucocytes (men/women 0.879/0.817) and 0.850 for bacteria (men/women 0.898/0.791). At 90% sensitivity, cut-off values of leucocyte count (men 60/µL, women 43/µL), and bacterial count (men 75/µL, women 139/µL) showed performance differences in favour of men. In both men and women, diagnostic performance using specified cut-off values was not different between normal and non-normal bladder evacuation. UC was positive in 327 cases (men/women 149/178), as with UTI diagnosis, diagnostic values in men outperformed women. CONCLUSIONS: Overall diagnostic accuracy of urinary parameters for diagnosing UTI is higher in men. The described differences in cut-off values for leukocyte and bacterial counts for diagnosing UTI necessitates gender-specific cut-off values, probably reflecting the influence of anatomical and urogenital differences.
Subject(s)
Urinalysis , Urinary Tract Infections , Adult , Cohort Studies , Emergency Service, Hospital , Female , Fever , Humans , Male , Sensitivity and Specificity , Urinary Tract Infections/diagnosisABSTRACT
BACKGROUND: Urinary tract infections (UTIs) are frequently encountered. Diagnostics of UTI (urine dipstick, Gram stain, urine culture) lack proven accuracy and precision in the emergency department. Utility of automated urinalysis shows promise for UTI diagnosis but has not been validated. METHODS: A total of 381 cases presenting with fever and/or clinically suspected UTI were analyzed. Diagnosis was based on clinical presentation, urine culture and/ or blood culture, and successful treatment. Performance of standard diagnostics and automated urinalysis (Sysmex UF-1000i) was analyzed at various cutoff values, and diagnostic algorithms were tested. RESULTS: One hundred forty-three (37.5%) cases were diagnosed with UTI. Sensitivity of urine dipstick nitrite was 32.9% and specificity was 93.7%. Sensitivity of urine dipstick leukocyte esterase (3+) was 80.4% and specificity was 82.8%. Receiver operating characteristic curves of automated bacterial and leukocyte count showed area under the curve of 0.851 and 0.872, respectively. Cutoff values of 133 bacteria/µL and 48 leukocytes/µL resulted in >90% sensitivity. Diagnostic values for complicated cases (antibiotics, catheters) were inferior to uncomplicated cases. Algorithms combining dipstick and automated counts did not improve accuracy with the exception of a 5.2% increase in uncomplicated cases (n=247). CONCLUSIONS: Automated leukocyte and bacterial count can be used in the emergency department setting with comparable accuracy compared with standard dipstick analysis with minor improvement when combined.
Subject(s)
Diagnostic Tests, Routine/methods , Emergency Service, Hospital , Urinary Tract Infections/urine , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , ROC Curve , Urinalysis/methods , Urinary Tract Infections/diagnosisABSTRACT
Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Biological Products/pharmacology , Animals , HumansABSTRACT
BACKGROUND: The urine dipstick that detects nitrite and leukocyte esterase, and urine sediment is commonly used to diagnose or exclude urinary tract infections (UTIs) as the source of infection in febrile patients admitted to the emergency department of Dutch hospitals. However, the diagnostic accuracy of the urine dipstick and urine sediment has never been studied in this specific situation. METHODS: Urinary samples of 104 febrile consecutive patients were examined. Urine culture with ≥ 10(5) colonies/ml of one or two known uropathogen was used as the gold standard. The diagnostic value of the urine dipstick, urine sediment and Gram stain at various cut-off points was determined and used to develop a new diagnostic algorithm. This algorithm was validated in a new group of sepsis patients based on systemic inflammatory response syndrome (SIRS) criteria. RESULTS: A positive nitrite on the urine dipstick (specificity 99%) rules in UTI. This is the first step of our diagnostic algorithm. The second step is to exclude UTI by absence of bacteria in the urine sediment (sensitivity 94%). The third and last step is the number of leucocytes/high-power field (hpf) in the urine sediment. Less than 10 leucocytes/hpf makes UTI unlikely whereas ≥ 10 leucocytes/hpf indicates UTI. In contrast to urine dipstick and/or urine sediment results alone, our algorithm showed both a high sensitivity (92%) and specificity (92%) and was validated in a new sepsis population. CONCLUSION: Our accurate and fast diagnostic algorithm, which combines the selective results of urine dipstick and urine sediment, can be easily used to diagnose UTI in febrile patients at the emergency department of Dutch hospitals.
Subject(s)
Algorithms , Fever/etiology , Urinary Tract Infections/diagnosis , Urinary Tract Infections/urine , Aged , Colony Count, Microbial , Female , Humans , Leukocyte Count , Male , Middle Aged , Nitrites/urine , Sensitivity and Specificity , Urinary Tract Infections/microbiology , Urine/cytology , Urine/microbiologyABSTRACT
BACKGROUND AND OBJECTIVES: The objective of this study was to characterize CD4(+) and CD8(+) T-cell populations in blood and urine of renal transplant patients with BK virus (BKV) infection or allograft rejection. MATERIALS AND METHODS: Percentages and absolute numbers of CD4(+) and CD8(+) effector memory T-cell subtype (TEM ) and terminal differentiated T cells (TTD ) in renal transplant patients with BKV infection (n = 14), with an episode of allograft rejection (n = 9), and in uncomplicated renal transplant patients with a stable kidney function (n = 12) were measured and compared using 4-color fluorescence-activated cell sorting. Results were correlated with the number of CD4(+) and CD8(+) T cells in renal biopsies. RESULTS: In patients with allograft rejection, the number of urinary CD4(+) TEM and CD8(+) TEM cells was significantly increased compared to patients with BKV infection or patients without complications. Positive correlation was found between the number of CD4(+) and CD8(+) cells in the renal biopsies and the number of CD4(+) and CD8(+) cells in urine. In patients with rejection, after 2 months of immunosuppressive therapy, a reduction in urinary CD8(+) TEM cells was found. CONCLUSIONS: CD4(+) TEM and CD8(+) TEM cells in urine could be a marker to distinguish allograft rejection from BKV-associated nephropathy and to monitor therapy effectiveness in renal transplant patients with allograft rejection.
Subject(s)
BK Virus , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Graft Rejection/urine , Kidney Transplantation/adverse effects , Kidney/pathology , Polyomavirus Infections/urine , Tumor Virus Infections/urine , Adult , Aged , Allografts/immunology , Biopsy , CD4 Lymphocyte Count , Female , Graft Rejection/blood , Graft Rejection/immunology , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Polyomavirus Infections/blood , Polyomavirus Infections/immunology , T-Lymphocyte Subsets , Tumor Virus Infections/blood , Tumor Virus Infections/immunology , Urine/cytology , Young AdultABSTRACT
OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/prevention & control , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antirheumatic Agents/therapeutic use , Secondary Prevention/methods , Azathioprine/therapeutic use , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Prednisone/therapeutic use , Prospective Studies , Recurrence , Remission Induction/methods , Rituximab , Time Factors , Treatment OutcomeABSTRACT
The objective of this study is to evaluate urinary high mobility group box 1 (HMGB1) levels as markers for active nephritis in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in comparison with urinary CD4(+) effector memory T cells and urinary monocyte chemoattractant protein-1 (MCP-1). Twenty-four AAV patients with active nephritis and 12 healthy controls (HC) were evaluated. In nine patients, samples were also obtained during remission. Urinary levels of HMGB1 were measured by Western blot. CD4(+) T cells and CD4(+) effector memory T cells (CD4(+) CD45RO(+) CCR7(-) ) were determined in urine and whole blood by flow cytometry. Measurement of urinary levels of MCP-1 and serum HMGB1 levels were performed by enzyme-linked immunosorbent assay (ELISA). AAV patients with active nephritis had higher median intensity of HMGB1 in urine than HC [10·3 (7·05-18·50) versus 5·8 (4·48-7·01); P = 0·004]. Both urinary HMGB1 and MCP-1 levels decreased significantly from active nephritis to remission. The urinary MCP-1/creatinine ratio correlated with Birmingham Vasculitis Activity Score (BVAS) (P = 0·042). No correlation was found between the HMGB1/creatinine ratio and 24-h proteinuria, estimated glomerular filtration rate (eGFR), MCP-1/creatinine ratio, BVAS and serum HMGB1. A positive correlation was found between urinary HMGB1/creatinine ratio and CD4(+) T cells/creatinine ratio (P = 0·028) and effector memory T cells/creatinine ratio (P = 0·039) in urine. Urinary HMGB1 levels are increased in AAV patients with active nephritis when compared with HC and patients in remission, and urinary HMGB1 levels are associated with CD4(+) T cells and CD4(+) effector memory T cells in urine. Measurement of urinary HMGB1 may be of additional value in identifying active glomerulonephritis in AAV patients.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications , Glomerulonephritis/etiology , Glomerulonephritis/urine , HMGB1 Protein/urine , Adult , Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Biomarkers , Chemokine CCL2/urine , Female , Glomerulonephritis/blood , HMGB1 Protein/blood , Humans , Immunologic Memory , Male , Middle Aged , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Granulomatosis with Polyangiitis/drug therapy , Immunosuppressive Agents/therapeutic use , Microscopic Polyangiitis/drug therapy , Remission Induction/methods , Adult , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Azathioprine/administration & dosage , Azathioprine/therapeutic use , Cross-Over Studies , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Rituximab , Treatment OutcomeABSTRACT
OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is infrequently seen in women of childbearing age. Only a limited number of pregnancies in women with AAV have been reported, and often they were associated with complications. METHODS: This was a single-center retrospective observational study. All pregnancies in women with granulomatosis with polyangiitis (Wegener's) (n = 13) and microscopic polyangiitis (n = 1) were included. Women of childbearing age were counseled to abstain from pregnancy during or shortly after disease activity or <1 year after cyclophosphamide treatment. RESULTS: We described 22 pregnancies in 14 women with AAV (median age at diagnosis was 25 years [range 19-36 years]) diagnosed between 1982-2008. The ear, nose, and throat region (71%) and kidneys (50%) were predominantly involved. All women were in remission at conception and cyclophosphamide had been administered to 9 women (15 pregnancies). The median gestational age was 39+4 weeks, including 2 preterm deliveries. The median birth weight was 3,400 gm (1,860-3,890 gm). Hypothyroidism occurred in 1 newborn and a cleft palate in 1 newborn of a twin pregnancy. Otherwise, the fetal outcome was excellent. Preeclampsia was diagnosed in 2 pregnancies. A caesarean section was performed in 2 patients. The median followup after the last conception was 98 months (range 11-307 months). Eight women experienced a relapse 21 months (range 7-62 months) after conception, 1 during pregnancy, and 7 after delivery. CONCLUSION: In this study, the pregnancy outcome in patients with AAV in remission was excellent. Pregnancy in women with AAV in remission does not seem to be associated with increased risk of relapse. Counseling, careful management, and close followup are essential in pregnant women with AAV.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Pregnancy Complications, Cardiovascular/diagnosis , Pregnancy Complications, Cardiovascular/therapy , Pregnancy Outcome , Adult , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/therapy , Antirheumatic Agents/therapeutic use , Cyclophosphamide/therapeutic use , Female , Humans , Hypothyroidism/epidemiology , Incidence , Pre-Eclampsia/epidemiology , Pregnancy , Remission Induction , Retrospective Studies , Secondary Prevention , Treatment OutcomeABSTRACT
Few randomized clinical trials (RCTs) have been performed in patients with Churg-Strauss syndrome. Therefore, it is recommended to treat patients with this syndrome in accordance with the current practice guidelines for therapy for patients with ANCA-associated vasculitis. Standard therapy is prednisolone in combination with cyclophosphamide. Cyclophosphamide is stopped 3-6 months after diagnosis and subsequently azathioprine is started. Recently, it was demonstrated in two RCTs that B cell depletion by rituximab can be used as therapy for moderate to severe ANCA-associated vasculitis. Remission rates and adverse events were comparable with those of treatment with cyclophosphamide. It is pivotal to start therapy in patients with Churg-Strauss syndrome as soon as possible after the diagnosis is made.
Subject(s)
Churg-Strauss Syndrome/diagnosis , Churg-Strauss Syndrome/drug therapy , Anti-Inflammatory Agents/therapeutic use , Azathioprine/therapeutic use , Cyclophosphamide/therapeutic use , Drug Therapy, Combination , Evidence-Based Medicine , Humans , Immunosuppressive Agents/therapeutic use , Practice Guidelines as Topic , Prednisolone/therapeutic use , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: Several reports suggest an increased rate of adverse reactions to azathioprine in patients with Crohn's disease. AIM: To compare the incidence of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease (IBD) with that in patients with vasculitis. METHODS: This retrospective analysis was performed using data collected in three databases by two university hospitals (241 patients with IBD and 108 patients with vasculitis) and one general district hospital (72 patients with IBD). RESULTS: The cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease equalled that of ulcerative colitis (UC) (2.6% vs. 3.7%) and this did not differ from vasculitis patients (2.6% vs.1.9%). In addition, the cumulative incidence of thiopurine-induced acute pancreatitis in UC patients was not different from that in vasculitis patients. In the IBD group, 100% of thiopurine-induced acute pancreatitis patients were women, whereas in the vasculitis group the two observed thiopurine-induced acute pancreatitis cases (n = 2 of 2) concerned were men (P = 0.012). CONCLUSIONS: In this study, the alleged higher cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease compared with vasculitis or UC patients was not confirmed. Female gender appears to be a risk factor for developing thiopurine-induced acute pancreatitis in IBD patients.
Subject(s)
Antimetabolites/adverse effects , Azathioprine/adverse effects , Crohn Disease/drug therapy , Mercaptopurine/adverse effects , Pancreatitis/chemically induced , Acute Disease , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies , Statistics as Topic , Young AdultABSTRACT
A disintegrin and metalloproteinase (ADAM)17 sheds growth factors from the cell membrane, including epidermal growth factor receptor (EGFR) ligand transforming growth factor (TGF)-alpha. In mice, angiotensin II infusion induces renal fibrosis via ADAM17-mediated TGF-alpha shedding and subsequent EGFR activation. Pharmacological ADAM17 inhibition reduced renal fibrotic lesions and improved renal function, positioning ADAM17 as a promising target of intervention in renal disease. We studied ADAM17 expression in the human kidney. ADAM17 mRNA was constitutively expressed in normal adult kidneys, with highest expression in distal tubules. In human renal disease, ADAM17 was de novo expressed in proximal tubules, peritubular capillaries, and glomerular mesangium and upregulated in podocytes. Glomerular mesangial and endothelial ADAM17 were associated with mesangial matrix expansion, focal glomerulosclerosis, and glomerular macrophage infiltration (P < 0.01). Peritubular capillary and proximal tubular ADAM17 were associated with interstitial fibrosis and interstitial macrophage infiltration (P < 0.05). Both glomerular and interstitial ADAM17 were associated with decreased renal function (P < 0.05). In renal fibrosis, ADAM17 colocalized with TGF-alpha. Moreover, in cultured human podocytes and proximal tubular cells, pharmacological ADAM17 inhibition reduced constitutive TGF-alpha shedding by 78% (P < 0.005) and 100% (P < 0.05), respectively, and phorbol ester-induced TGF-alpha shedding by 84% (P < 0.005) and 92% (P = 0.005), respectively. Finally, ADAM17 inhibition reduced cellular proliferation. In conclusion, the ADAM17 expression pattern and its role in shedding TGF-alpha from cultured human kidney cells suggest a role in the development of fibrosis. Since EGFR signaling is implicated in renal fibrosis, targeting ADAM17 to reduce availability of EGFR ligand TGF-alpha may represent a promising way of intervention in human renal disease.
Subject(s)
ADAM Proteins/metabolism , Kidney Diseases/enzymology , Kidney/enzymology , Transforming Growth Factor alpha/metabolism , ADAM Proteins/antagonists & inhibitors , ADAM Proteins/genetics , ADAM17 Protein , Adolescent , Adult , Aged , Aged, 80 and over , Capillaries/enzymology , Cell Line , Cell Proliferation , Child , Child, Preschool , Creatinine/blood , Dose-Response Relationship, Drug , Female , Fibrosis , Glomerular Filtration Rate , Humans , Hydroxamic Acids/pharmacology , Kidney/blood supply , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Kidney Tubules, Proximal/enzymology , Kidney Tubules, Proximal/pathology , Male , Middle Aged , Podocytes/enzymology , Protease Inhibitors/pharmacology , RNA, Messenger/metabolism , Up-RegulationABSTRACT
BACKGROUND: Both preoperative left ventricular dysfunction and postoperative renal function deterioration are associated with increased long-term mortality after cardiac surgery. The influence of preoperative left ventricular dysfunction on postoperative renal dysfunction and long-term mortality is not defined. METHODS: We collected data from 641 consecutive patients undergoing coronary bypass surgery with cardiopulmonary bypass in 1991 at our institution. Prospective follow-up was through to July 2004. RESULTS: In-hospital mortality was 2.7% (17 of 641). During follow-up, 248 (40%) patients discharged alive died (5 and 10 yr survival 90% and 70%, respectively). On univariate analysis, preoperative left ventricular dysfunction (ejection fraction <50%) and an increase in serum creatinine > or =25% in the first postoperative week were associated with long-term mortality. The associated mortality risk was additive in predominantly non-overlapping patients groups: the hazard ratio (HR) for renal function deterioration only was 1.41 [95% confidence interval (CI) 0.95-2.32, P=0.083; n=64] and for left ventricular dysfunction only 1.71 (95% CI 1.26-2.95, P=0.0026; n=73). In patients in whom both were present, HR was 3.23 (95% CI 2.52-20.28, P<0.0001; n=20). Although postoperative renal dysfunction was associated with left ventricular dysfunction (P=0.008), both left ventricular dysfunction and postoperative renal function deterioration were independently associated with long-term mortality on multivariate analysis, as were age and the use of venous conduits. CONCLUSIONS: Both postoperative renal function deterioration and preoperative left ventricular dysfunction independently identify largely non-overlapping groups of patients with increased long-term mortality after coronary bypass surgery. In the group of patients with both factors present, the mortality risks appear additive.
Subject(s)
Acute Kidney Injury/etiology , Coronary Artery Bypass/adverse effects , Ventricular Dysfunction, Left/complications , Acute Kidney Injury/therapy , Aged , Biomarkers/blood , Cardiopulmonary Bypass , Coronary Artery Bypass/mortality , Creatinine/blood , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Postoperative Care/methods , Prognosis , Renal Replacement Therapy , Ventricular Dysfunction, Left/mortalityABSTRACT
OBJECTIVE: Wegener's granulomatosis (WG) is strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against proteinase 3 (PR3). Recent studies have shown that membrane-bound PR3 (mPR3) is differentially expressed and colocalizes with CD177/NB1 on circulating neutrophils. We undertook this study to assess the differential expression of CD177 on neutrophils from patients with ANCA-associated systemic vasculitis (ASV) in comparison with patients with systemic lupus erythematosus (SLE), patients with rheumatoid arthritis (RA), and healthy individuals, and to investigate whether colocalization of mPR3 and CD177 affects anti-PR3-mediated neutrophil activation. METHODS: Expression of CD177 and mPR3 was analyzed by flow cytometry on isolated neutrophils from patients with ASV (n=53), those with SLE (n=30), those with RA (n=26), and healthy controls (n=31). Neutrophil activation mediated by anti-PR3 antibodies was assessed by measuring the oxidative burst with a dihydrorhodamine assay. RESULTS: Percentages of CD177-expressing neutrophils were significantly higher in patients with ASV and those with SLE than in healthy controls. In 3 healthy donors, CD177 expression was not detected. After priming with tumor necrosis factor alpha, neutrophils remained negative for CD177 while mPR3 expression was induced. Neutrophils from CD177-negative donors or CD177- neutrophils sorted from donors with bimodal expression were susceptible to anti-PR3-mediated oxidative burst. Variation in the extent of anti-PR3-mediated neutrophil activation among different donors occurred independent of the percentage of CD177-expressing neutrophils. CONCLUSION: Membrane expression of CD177 on circulating neutrophils is increased in patients with ASV and in those with SLE, but not in RA patients. However, primed neutrophils from CD177-negative individuals also express mPR3 and are susceptible to anti-PR3-mediated oxidative burst, suggesting that recruitment of CD177-independent mPR3 is involved in anti-PR3-induced neutrophil activation.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/analysis , Isoantigens/analysis , Membrane Glycoproteins/analysis , Myeloblastin/analysis , Neutrophil Activation/physiology , Neutrophils/chemistry , Neutrophils/immunology , Receptors, Cell Surface/analysis , Vasculitis/immunology , Antibodies, Antineutrophil Cytoplasmic/immunology , Arthritis, Rheumatoid/immunology , Cell Membrane/enzymology , Flow Cytometry , GPI-Linked Proteins , Granulomatosis with Polyangiitis/immunology , Humans , Lupus Erythematosus, Systemic/immunology , Myeloblastin/immunology , Myeloblastin/physiology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.
Subject(s)
Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/psychology , Aged , Female , Humans , Male , Surveys and QuestionnairesABSTRACT
OBJECTIVES: Wegener's granulomatosis (WG) is a systemic vasculitis characterised by relapsing and remitting disease activity. Immunosuppressive drugs are used to control disease, but increase susceptibility to infection. Therefore, influenza vaccination should be considered in WG patients. This study was performed to assess the immunogenicity of influenza vaccination in WG patients. METHODS: A randomised, controlled trial was performed in WG patients with quiescent disease, defined as a Birmingham vasculitis activity score (BVAS) less than 2. Patients were randomly assigned to receive influenza vaccination (n = 49) or to participate as controls (n = 23). In addition, healthy controls (n = 49) were vaccinated. At entry and at 1 and 3-4 months after entry, antibody responses to vaccination were determined. Furthermore, disease activity was measured (BVAS), adverse effects were recorded and antineutrophil cytoplasmic autoantibody (ANCA) titres were determined. RESULTS: WG patients achieved high seroprotection rates to all three influenza strains, comparable with healthy controls. Only the A/H1N1 strain patients had a lower seroconversion rate (p = 0.002) and geometric mean titre (p = 0.037) than controls. After 1 month, one control and one vaccinated WG patient had developed active disease. At 3-4 months, two additional control patients had developed active disease compared with none of the vaccinated patients (p = 0.099). Vaccination did not influence ANCA titres. Adverse effects did not differ between patients and healthy controls. CONCLUSIONS: Influenza vaccination in WG patients with quiescent disease induced a sufficient antibody response. TRIAL REGISTRATION NUMBER: NTR1130.
Subject(s)
Antibodies, Viral/blood , Granulomatosis with Polyangiitis/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/immunology , Orthomyxoviridae/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Antineutrophil Cytoplasmic/blood , Case-Control Studies , Chi-Square Distribution , Female , Granulomatosis with Polyangiitis/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Influenza, Human/prevention & control , Male , Middle Aged , Prospective Studies , Treatment Outcome , Vasculitis/immunologyABSTRACT
BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) with a C-ANCA or P-ANCA pattern are detected in ANCA-associated vasculitis (AAV). While in most patients with AAV a C-ANCA pattern is due to reactivity with proteinase-3 (PR3)-ANCA, some C-ANCA-positive sera do not react with PR3. OBJECTIVE: The development and evaluation of a direct enzyme-linked immunosorbent assay (ELISA) for PR3-ANCA with increased sensitivity. METHODS: A mixture of human native (hn) and human recombinant (hr) PR3 was used as antigen coating. The resulting ELISA (anti-PR3-hn-hr) was compared with ELISAs using directly coated hn-PR3 or hr-PR3, as well as with a hn-PR3 capture ELISA. Assay characteristics were determined in patients with AAV (n = 248), with special attention for those patients with C-ANCA (n = 132), as well as disease controls (n = 585) and healthy controls (n = 429). Additionally, for prediction of relapses serial samples of 46 patients with PR3-AAV were analysed. RESULTS: At a predefined specificity of 99% both ELISAs containing hr-PR3 revealed a substantial increase in sensitivity. For the prediction of relapses by rises in PR3-ANCA titres the capture ELISA was most optimal (odds ratio 12.5). With an odds ratio of 8.9 the novel anti-PR3-hn-hr ELISA was second best. CONCLUSIONS: Owing to the very high sensitivity of the novel anti-PR3-hn-hr ELISA for the detection of PR3-ANCA in C-ANCA-positive samples of patients with AAV this assay has an excellent diagnostic performance. This feature is combined with a good predictability of clinical relapses in patients with PR3-AAV. These characteristics challenge the dogma that, for detection of PR3-ANCA, capture ELISAs are superior for diagnosis and follow-up.