Type-specific risk factors and outcome in an outbreak with 2 different Clostridium difficile types simultaneously in 1 hospital.

BACKGROUND: Clostridium difficile infection (CDI) due to polymerase chain reaction (PCR) ribotype 027 (type 027) has been described worldwide. In some countries, an increase was reported of toxin A-negative PCR ribotype 017 (type 017). We encountered an outbreak due to these 2 types occurring simultaneously in a 980-bed teaching hospital in the Netherlands. METHODS: In a case-control study from May 2005 through January 2007, we investigated general and type-specific risk factors as well as outcome parameters for CDI due to type 027 or 017. Clonal dissemination was investigated by multilocus variable number of tandem repeat analysis (MLVA). RESULTS: We identified 168 CDI patients: 57 (34%) with type 017, 46 (27%) with type 027, and 65 (39%) with 1 of 36 different other types. As controls, we included 77 non-CDI diarrheal patients and 162 patients without diarrhea. Risk factors for CDI were nasogastric intubation, recent hospitalization, and use of cephalosporins and clindamycin. Type-specific risk factors were older age for both types 017 and 027, use of clindamycin and immunosuppressive agents for type 017, and use of fluoroquinolones for type 027. At day 30 of follow-up, the overall mortality among patients with types 017, 027, other types, non-CDI diarrheal patients, and nondiarrheal patients was 23%, 26%, 3%, 2%, and 6%, respectively. MLVA showed persistent clonal dissemination of types 017 and 027, despite appropriate infection control measures. CONCLUSIONS: Patients with CDI have type-specific risk factors and mortality rates, with prolonged clonal spread of type 027 or 017.

Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity.

AIMS: To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet. MATERIALS AND METHODS: In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated. RESULTS: Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml). CONCLUSIONS: Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.

A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis.

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

Subjective sleep efficiency of hemodialysis patients.

BACKGROUND: Sleep disturbances have a major influence on quality of life. A commonly used measure of sleep disturbances is sleep efficiency. The purpose of this study was to investigate the prevalence of decreased subjective sleep efficiency in hemodialysis patients. An additional goal was to identify clinical, dialysis or laboratory parameters that are independently associated with decreased sleep efficiency. METHODS: Adult stable hemodialysis patients (n = 112) filled out a sleep questionnaire during a three day investigation period. In addition, healthy control subjects (n = 44) filled out the same questionnaire. From this questionnaire sleep efficiency (ratio of total sleep time to time spent in bed) was derived as a measure for sleep disturbances in this population. Laboratory, demographic and dialysis data were collected during the investigation period. For statistical analysis linear regression models were used. RESULTS: Median subjective sleep efficiency in hemodialysis patients was 80%, which was significantly less compared to the median subjective sleep efficiency of control subjects of 88% (p pound 0.05). Approximately 40% of the patients used sleep medication. However, less than 20% of them indicated improved sleep behavior when using these drugs. Elevated levels of phosphate and urea correlated independently with impaired sleep efficiency. Hemoglobin levels between 10 and 12 g/dl were associated with better sleep efficiency. CONCLUSION: In conclusion, decreased sleep efficiency was frequently reported in hemodialysis patients and can be associated with biochemical parameters. Hemoglobin, phosphate and urea levels can affect subjective sleep efficiency.

Community-onset Clostridium difficile-associated diarrhoea not associated with antibiotic usage--two case reports with review of the changing epidemiology of Clostridium difficile-associated diarrhoea.

The emergence of hypervirulent strains of Clostridium difficile causing outbreaks in hospitals and nursing homes may result in a greater than before spread of the bacterium in the community. By consequence, the incidence of community-onset cases of Clostridium difficile-associated diarrhoea (CDAD) may increase outside known risk groups that are currently characterised by prior hospitalisation, prior antibiotic usage, older age and significant comorbidity. Here, we describe two case histories of community-onset CDAD. The first concerns a previously healthy young female with community-acquired CDAD without recent hospitalisation or antibiotic usage. The second patient developed diarrhoea in the community after discharge from a hospital where--in retrospect--an outbreak of CDAD occurred. The cases illustrate that CDAD should be included in the differential diagnosis of patients seeking care for community-onset diarrhoea, even in those without characteristic risk factors for CDAD.

Henoch-Schönlein purpura presenting as terminal ileitis and complicated by thrombotic microangiopathy.

We report here on a 40-year-old woman with abdominal pain, low-grade fever, and diarrhea in whom the cutaneous features of Henoch-Schönlein purpura (HSP) appeared only a few days after acute abdominal symptoms. Endoscopy showed terminal ileitis, and histopathological examination of a biopsy of the ileum showed a picture of IgA vasculitis. The clinical course was further complicated by the development of microangiopathic hemolytic anemia, thrombocytopenia, and severe renal failure.

The value of indirect immunofluorescence and solid phase techniques for ANCA detection. A report on the first phase of an international cooperative study on the standardization of ANCA assays. EEC/BCR Group for ANCA Assay Standardization.

This study describes the results of phase I of an international effort to develop and standardize assays for the detection of anti-neutrophil cytoplasmic antibodies (ANCA). 12 sera, four of which were selected for their potential to cause problems in the detection of various ANCA specificities, were analyzed in the standard indirect immunofluorescence (IIF) test and in ELISAs for ANCA routinely performed in the seven participating laboratories. The IIF methodology differed with respect to the dilution of the serum being screened and the concentration of the conjugate used. Results from sera with high ANCA titers were similar, although the quantitative values could not be compared. In sera containing rheumatoid factor and anti-nuclear antibodies (ANA), ANCA-unrelated staining patterns were observed. Six antigen preparations were used in ELISA for the detection of cANCA. In ELISA with purified proteinase-3 all three cANCA sera were positive, but not anti-myeloperoxidase (MPO) or anti-lactoferrin (LF) positive sera. The other assays were less sensitive or gave inconsistent results. Various preparations of purified MPO and LF used in ELISA were readily recognized by anti-MPO and anti-LF positive sera. From this study it can be concluded that the IIF test, although performed with different methods, shows comparable results using strongly positive sera. In general solid phase assays for cANCA detection are not well standardized and need improvement although the purified proteinase-3 ELISA is possibly an exception. MPO and LF can be used in ELISA procedures for the detection of pANCA-related antibodies.

Isolation of a protein complex from purulent sputum consisting of proteinase-3 and alpha 1-antitrypsin reactive with anti neutrophil cytoplasmic antibodies.

The detection of ANCA (anti-neutrophil cytoplasmic antibodies) is of importance in the diagnosis of Wegener's granulomatosis (WG) and solid-phase assays for the detection of c-ANCA have been set up by various groups, using purified proteinase-3 (PR-3) in an ELISA or RIA. For the isolation of PR-3 large numbers of PMNs are needed. We therefore examined the possibility of isolating PR-3 from the purulent sputum of patients with chronic bronchitis or cystic fibrosis, since large numbers of PMNs and their degranulation products are present in such material. By a three-step chromatographic procedure (4-phenylbutylamine affinity chromatography, Biorex 70 cation exchange chromatography and monoclonal antibody anti-PR-3 affinity chromatography) we isolated a 53 kDa protein that was recognized on immunoblot by MoAbs directed against PR-3 and alpha 1-antitrypsin (alpha 1AT). We show that the 53 kDa protein is a complex of PR-3 and alpha 1AT. This complex is reactive with a selected set of c-ANCA positive sera from patients with Wegener's granulomatosis.

Development and standardization of solid phase assays for the detection of anti-neutrophil cytoplasmic antibodies (ANCA). A report on the second phase of an international cooperative study on the standardization of ANCA assays.

Anti-neutrophil cytoplasmic antibodies (ANCA) are diagnostic markers for systemic vasculitis. They are classically detected by an indirect immunofluorescence test using normal donor neutrophils as substrate. This assay lacks antigenic specificity and is not quantitative. The 'EC/BCR Project for ANCA Assay Standardization' is an international collaboration study with the aim to develop and standardize solid phase assays for ANCA detection. In this part of the study the isolation and characterization of proteinase-3 and myeloperoxidase, the two main target molecules for ANCA, and the development and standardization of ELISAs with these antigens are described. Six laboratories successfully isolated purified proteinase-3 preparations that could be used. Three of these preparations, together with one myeloperoxidase preparation, were subsequently used for ANCA testing by ELISA. The ELISA technique was standardized in two rounds of testing in the 14 participating laboratories. The coefficient of variation of these new assays decreased from values of approx. 50% in the first round to approx. 20% in the second round. We conclude that purified proteinase-3 and myeloperoxidase can be used in standardized ELISAs for ANCA detection. Whether such procedures offer advantages over the IIF test will be determined in a prospective clinical study.

Distribution of renal lesions in idiopathic systemic vasculitis: A three-dimensional analysis of 87 glomeruli.

Extracapillary proliferation and fibrinoid necrosis are the main diagnostic glomerular lesions in renal biopsy specimens of patients with idiopathic systemic vasculitis. Neither the incidence nor the correlation between extracapillary proliferation and fibrinoid necrosis in renal biopsy specimens from patients with systemic vasculitis has been systematically evaluated. By means of a three-dimensional analysis, we made a topographic reconstruction of the distribution of extracapillary proliferation and fibrinoid necrosis in affected glomeruli and tested different biopsy-processing protocols to optimize histopathologic analysis in clinical practice. Paraffin blocks of renal biopsy specimens from six patients diagnosed with systemic vasculitis were completely and serially sectioned in 2-microm thick sections and stained with the Gomori trichrome method. Glomeruli were scored per section for the presence of fibrinoid necrosis and extracapillary proliferation. Subsequently, a three-dimensional reconstruction was obtained for 87 glomeruli. In only one glomerulus did fibrinoid necrosis occur without extracapillary proliferation; in 51%, a combination of the two lesions was found; in 22%, extracapillary proliferation occurred in the absence of fibrinoid necrosis; and 26% did not show either lesion. Using the standard protocol from our department (ie, evaluation of 20 consecutive sections in various stainings), the chance of finding extracapillary proliferation was 100% and that of finding fibrinoid necrosis was 73%. If 5 sections stained with the Gomori trichrome were added, the latter percentage increased to 86%. Using skip-serial sections, even better results (87% to 92%) were obtained, with four skips as the best option (92%). In conclusion, our finding that fibrinoid necrosis rarely occurs in the absence of extracapillary proliferation may imply that both lesions are etiologically related. In addition, our observations indicate that the incidence of fibrinoid necrosis may be underestimated in clinical practice, depending on the number of sections evaluated.

Fundamental and clinical aspects of anti neutrophil cytoplasmic antibodies (ANCA).

Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with different forms of both primary and secondary vasculitis and glomerulonephritis. These antibodies are directed against different enzymes located in granulocyte granules. In this review ANCA-related antigens and solid phase assays for ANCA detection will be discussed. Furthermore, we will address the clinical relevance of ANCA and will deliberate on their possible pathogenic implications.

International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.

Exocrine pancreatic insufficiency and pancreatic fibrosis due to duodenal somatostatinoma in a patient with neurofibromatosis.

A case of duodenal somatostatinoma is described in a patient with Von Recklinghausen neurofibromatosis. The patient presented with exocrine pancreatic insufficiency, probably due to distal obstruction of the pancreatic duct by the tumor. Preoperative evaluation with calcium-pentagastrin and tolbutamide stimulation tests were nondiagnostic. At laparotomy, local excision of the tumor was performed. Pathological findings were compatible with duodenal somatostatinoma, causing pancreatic fibrosis. Somatostatin extracted from the tumor coeluted with the somatostatin-14 standard on high performance liquid chromatography (HPLC).

Autoantibodies to neutrophil cytoplasmic enzymes in Felty's syndrome.

In this study we determined the occurrence of anti-neutrophil cytoplasmic antibodies (ANCA) and the specificity of these antibodies (Ab) in the serum of patients with Felty's syndrome (FS) and in serum of patients with uncomplicated rheumatoid arthritis (RA). ANCA, detected by indirect immunofluorescence on ethanol-fixed neutrophils, was found in 77% of 30 patients with FS and in 36% of 50 RA patients. Ab against lactoferrin (LF) occurred more frequently in FS patients (50%) than in RA patients (4%), whereas reactivity against the other cytoplasmic antigens tested (proteinase-3, myeloperoxidase and elastase) did not differ significantly between these patient groups. The specific reactivity of FS sera with LF was established by demonstrating that the Ab reactivity resided in IgG, was located in the F(ab')2 fragments and could be inhibited from binding to the ELISA plate-bound LF by purified LF in the fluid phase. These results demonstrate that anti-LF Ab occur in FS and suggest that the detection of anti-LF Ab in patients with FS may be useful in the diagnosis of FS.

Compassionate treatment of Wegener's granulomatosis with rabbit anti-thymocyte globulin.

UNLABELLED: The purpose of this study was to evaluate the effect of treatment with anti-thymocyte globulin in patients with Wegener's granulomatosis, untreatable with cyclophosphamide and steroids. MATERIALS AND METHODS: Five patients with active Wegener's granulomatosis, either not responsive to standard therapy, or who could not tolerate alkylating agents received a single course of rabbit anti-thymocyte globulin (ATG). RESULTS: Four patients showed a favourable response to treatment with partial or complete remission of disease activity, during a follow-up period of five to twelve months. One patient had progressive retroorbital granuloma, which resulted in enucleation of the eye. Side effects of the ATG treatment were mild with chills and fever during the first infusion, and development of serum sickness in two patients. Two other patients had labial herpes simplex shortly after the start of treatment, no other infectious complications were seen. CONCLUSIONS: We conclude that ATG treatment seems to be an effective treatment for patients with severe Wegener's granulomatosis.

Renal granulomas in systemic vasculitis. EC/BCR Project for ANCA-Assay Standardization.

Renal granulomas are a relatively infrequent finding in the kidney biopsy. They have been described in a number of syndromes such as Wegener's granulomatosis, anti-GBM glomerulonephritis, and sarcoidosis, and are commonly believed to be indicative of a fulminant clinical course. In leading textbooks, diverse definitions of renal granulomas are presented, which has led to controversies in identifying them. This, in combination with their rare occurrence, makes it difficult for the general pathologist to identify them. We present the clinical data of 16 patients with renal granulomas, from a total group of 157 patients with systemic vasculitis. Their renal functioning was not significantly different from the other 141 patients in whose renal biopsies renal granulomas were present. Furthermore, we present two practical definitions for the recognition of renal granulomas in the kidney biopsy, and we show a number of examples of their various histopathological shapes.

Cerebral involvement in two patients with Wegener's granulomatosis.

Two cases of cerebral involvement in Wegener's granulomatosis (WG) are described. The course of the disease in both patients was characterized by sudden onset and fatal outcome, despite maximum immunosuppressive therapy. Cerebral involvement is a rare complication of WG. Over the past two decades, only a small number of case-reports appeared of patients with WG who showed this complication. Since the era of cyclophosphamide therapy, it is commonly assumed that cerebral involvement in WG has no influence on patient survival. However, the two patients described here both died shortly after the occurrence of central neurological symptoms.

Therapy of proliferative lupus glomerulonephritis: a prospective trial in The Netherlands.

Proliferative glomerulonephritis is a severe clinical manifestation of systemic lupus erythematosus, and it remains a major determinant of morbidity and mortality in this disease, despite the progress that has been made by treating patients with a combination of corticosteroids and cytotoxic drugs. Earlier controlled clinical trials have demonstrated the superior efficacy of a combination of pulse cyclophosphamide with steroids over treatment with steroids alone. However, cyclophosphamide carries a substantial risk of short-term and long-term toxicity in this predominantly young population, and previous trials have not convincingly shown any benefit over the milder treatment with a combination of azathioprine and steroids. We propose to conduct a Dutch multicentre trial to test whether similar renal survival can be achieved with an azathioprine-based regimen, compared to the widely used cyclophosphamide treatment, with a possibly lower risk of adverse effects.

Anti-lactoferrin antibodies in patients with rheumatoid arthritis with vasculitis.

Anti-lactoferrin antibodies (anti-LF Ab) are more frequently found in patients with rheumatoid arthritis (RA) complicated by vasculitis when compared to patients with uncomplicated RA. Therefore the detection of anti-LF Ab in serum of patients with RA may be useful in the diagnosis of vasculitis in RA patients.