Early ultrastructural lesions of diphenylamine-induced renal papillary necrosis in Syrian hamsters

Wegener's granulomatosis (WG) is characterized by necrotizing granulomas and vasculitis that may affect any organ. The upper and lower respiratory tract and kidney usually are affected. WG is diagnosed by determination of anti-neutrophil cytoplasm antibody (ANCA), a highly sensitive and specific test that is particularly important in the early stages to achieve the best prognosis. We describe a case in a 28-year-old man that exemplifies some of the diagnostic features of WG.     

The place of Mitrofanoff neourethra in the repair of exstrophy-epispadias complex

BACKGROUND: Wegener's granulomatosis is an immunepathogenic disease of unknown origin. The histopathological picture shows granulomatous inflammation with epitheloid cells, granulomas, and general vasculitis. The diagnosis of Wegener's granulomatosis is made on the basis of the clinical picture, serum cANCA, and histologic examination of biopsies. PATIENT: We present the case of a 57-year-old white male patient who was admitted to our ENT Hospital with a six weeks' history of otalgia and incomplete ipsilateral facial palsy since the day before admission. The patient had clinical features of acute otitis media without signs of mastoiditis. Despite a ten days' course of intravenous antibiotic treatment, the intensity of facial palsy progressed and the general condition of the patient worsened. A mastoidectomy and decompression of the facial nerve were performed, demonstrating sclerosis of the mastoid cells. Three weeks after release from the hospital, the patient was admitted again with recurrent fever, cephalea, loss of weight, and arthritic pain. There were no signs of recurrent otitis media or mastoiditis, and sigmoid sinus thrombosis was ruled out. Even under aggressive, intravenous antibiotic treatment the general physical condition continued to worsen; septic temperatures and signs of beginning renal failure occurred. The patient was transferred to the ICU with the diagnosis of sepsis of unknown origin. There bloodtests were positive for cANCA, which is highly specific for Wegener's granulomatosis. Under therapy with cyclophosphamide and i.v. corticosteroid, the patient recovered with 14 days. CONCLUSION: The lack of symptoms in the upper respiratory tract in our patient was unusual, indicating that in patients with recurrent otitis media, facial palsy, mastoiditis, or external otitis Wegener's granulomatosis should be ruled out as differential diagnosis.     

Necrotizing crescentic glomerulonephritis without significant immune deposits: a clinical and serological study

To determine the spectrum of systemic diseases associated with pauci-immune necrotizing crescentic glomerulonephritis, we have analysed extra-renal manifestations, occurrence of extra-glomerular vasculitis and incidence and specificity of antinuclear cytoplasmic antibodies (ANCA) in 40 patients selected only on renal histological criteria. Extra-renal symptoms were unexpectedly observed in all patients but one, and were suggestive of vasculitis in 24. Extra-glomerular vasculitis was seen in 18 kidney biopsies and four biopsies from other organs. Among the 33 patients with suspected or established vasculitis, 13 had presumed or biopsy-proven Wegener's granulomatosis, three had a macroscopic form of polyarteritis nodosa and 17 could not be adequately classified. An additional patient had clinical signs of Wegener's granulomatosis without clinical and histological evidence of vasculitis. ANCAs were detected in 28 of 33 and 25 of 34 sera tested by immunofluorescence and enzyme-linked immunoassay, respectively: 19 contained anti-myeloperoxidase antibodies and six had anti-proteinase 3 activity. Anti-myeloperoxidase and anti-proteinase 3 antibodies were present in all clinical subgroups but with various frequencies: anti-myeloperoxidase antibodies were more common (six of 12) than anti-proteinase 3 (four of 12) in patients with suspected or histologically proven Wegener's granulomatosis. Anti-proteinase 3 antibodies were 3- to 4-fold more common in patients with Wegener's granulomatosis than in those with systemic vasculitis of other causes (one of 12) or necrotizing crescentic glomerulonephritis without evidence of extra-renal vasculitis (one of 10). These results strongly suggest that pauci-immune necrotizing crescentic glomerulonephritis belongs to the broad spectrum of necrotizing vasculitides affecting glomerular capillaries. This study shows substantial improvement in renal prognosis and life expectancy with aggressive immunosuppressive therapy despite the older age of the patients, dissemination of the vasculitic process and often delayed diagnosis.     

Inflammatory myopathy: unusual presentation of a case of Wegener disease

The case is presented of a 66-year-old man who developed an inflammatory myopathy picture predominantly consisting in leg weakness. Wegener's granulomatosis was diagnosed on the basis of suggestive thoracic imaging, microhematuria and necrotizing arteritis with granulomas in muscular biopsy. An increasing titer of anti-neutrophilic cytoplasm auto-antibodies (ANCA) confirmed the diagnosis. Rapid resolution was obtained by classic immunosuppressor treatment (cyclophosphamide and corticoids), without worsening of renal function. In discussion we emphasize the importance of ANCA measurement for diagnosis and follow-up.     

Systemic necrotizing vasculitis

The revival of interest in systemic necrotizing vasculitis was initiated by the discovery of its association with anti-neutrophil cytoplasmic antibodies (ANCA). The close association of certain ANCA subspecificities, for example, proteinase 3 (Pr3) and myeloperxoidase ANCA, with Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome has led to their designation as 'ANCA-associated vasculitides'. This article describes the common and divergent clinical and immunological features of the members of this 'new' family of systemic necrotizing vasculitis, which continues to grow with the widespread use of ANCA testing. In addition, the 'standard' treatment for systemic necrotizing vasculitis (daily 'low dose' cyclophosphamide plus glucocorticosteroids or 'Fauci's scheme') is compared with new stage and activity adapted therapeutic regimens.     

Wegener's granulomatosis presenting with a renal mass

Wegener's granulomatosis (WG) is a systemic disease characterized by necrotizing granulomatous vasculitis that involves primarily the upper and lower respiratory tracts and, in most cases, the kidneys. Kidney involvement in WG presenting as a mass is recognized, but is very rare. We describe a case of WG presenting with upper and lower respiratory symptoms and a renal mass due to both WG and renal cell carcinoma.     

Pulmonary vasculitis

Pulmonary vascular inflammation may be seen in a variety of primary lung diseases and in the setting of numerous systemic illnesses. This article reviews those entities in which pulmonary vasculitis represents a central feature of the pathologic process (Wegener's granulomatosis, Churg-Strauss syndrome, and pulmonary capillaritis). In addition, features of pulmonary involvement in other systemic vasculitides (Giant Cell Arteritis, Takayasu's Arteritis, and Beh?et's disease) are described. Finally, general principles for the treatment of vasculitis are reviewed.     

Meditation for prevention of disease

Antineutrophil cytoplasmatic antibodies (ANCA)-associated vasculitides (Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome) show quite variable courses. Clinical features of the full blown generalized systemic vasculitis are usually found in the respiratory tract and the kidney. Pulmonary involvement of Wegener's granulomatosis shows commonly nodules and cavitations but also diffuse alveolar hemorrhage. We report the case of a 57 year-old man suffering from dyspnea, thoracal pain, arthralgia, purpura, scleritis and tinitus. Specimen of the kidney showed segmental glomerulosclerosis and tubulointerstitial nephritis. Because of the presence of cANCA Wegener's disease was assumed. Pulmonary infiltrates developed under immunosuppressive treatment with cyclophosphamid. As differential diagnosis of the pulmonary infiltrates, we considered invasive pulmonary aspergillosis as well as infiltrates due to Wegener's granulomatosis. In spite of maximal therapeutic management of patient died of respiratory and cardiovascular failure. The findings at autopsy showed distinct invasive pulmonary aspergillosis and perifocal hemorrhage.     

The case for a heroin substitution treatment trial in Canada

A patient with malaise, uveitis and a nodular infiltrate in the left lower lobe of the lung is described. An open lung biopsy established the diagnosis of necrotizing sarcoid granulomatosis. The differential diagnosis of necrotizing sarcoid granulomatosis with sarcoidosis and angiocentric granulomatosis (Wegener's disease) is extensively discussed. Our case illustrates that NSG and sarcoidosis could be pathogenetically related.     

Muscle architecture and function in humans

We describe a 58-year-old woman who developed Wegener's granulomatosis (WG) complicated by a perforation of the transverse colon caused by necrotizing granulomatous vasculitis. In addition, her colon lesion continued in spite of high dose corticosteroid and cyclophosphamide therapy. She was admitted to our hospital because of her severe tonsillitis in Dec., 1994. She was diagnosed as having WG because she had oral ulcer, antibiotics-resistant lung infiltration, renal dysfunction and positive C-ANCA. Just after we started high dose steroid therapy, the transverse colon was perforated because of vasculitis, and she underwent emergency operation. Many vasculitic lesions were found in the small intestine, colon, and mesenterium. The disease was improved by corticosteroid and cyclophosphamide therapy except for a sustained ulcer with necrotizing vasculitis in the sigmoid colon region even 1 year after the operation. Although WG rarely complicates digestive tract lesions as initial manifestations, they reach 12% of the causes of death of WG in Japan. Therefore, we should take care of digestive tract lesions when we follow-up patients with WG.     

Pathogenesis of Wegener's granulomatosis

Although a single disease entity, Wegener's granulomatosis (WG) displays a set of clinical manifestations, each with a different immunopathogenesis. Granuloma formation, "pauci-immune" vasculitis and glomerulonephritis (= renal vasculitis) are the histologic hallmarks of WG which can occur together (WG triad) in full-blown disease, or separately in "initial phase" disease or the formes frustes. The different clinical manifestations are characterised by multiple immune abnormalities that culminate in the over-production of autoantibodies directed mainly against proteinase 3 (PR3-ANCA). A number of in vitro observations point to the potential mechanisms by which ANCA could induce neutrophil-mediated vascular injury, i.e. vasculitis. The most commonly postulated scenario for ANCA-mediated vasculitis involves the interaction of polymorphonuclear neutrophils (PMN) and endothelial cells (EC) via cell adhesion molecule interactions. The initiating event is ANCA-induced leukocyte activation, in which PMN-derived mediators (i.e. cytokines, lipid metabolites, etc.) are intimately involved. The result is necrotizing inflammation of blood vessel walls. However, the clinical and pathological hallmark of WG is the coexistence of vasculitis and granuloma. The causative agent(s) leading to granuloma formation, predominantly in the respiratory tract, is still unknown, but the presence of T cells in the granulomatous inflammation indicates T-cell hyperactivity. Immunohistochemical studies have shown that the cellular infiltrations in renal and pulmonary lesions of WG primarily contain CD4+ T-cells and macrophages. Recent investigations have demonstrated that CD4+ T-cells from granulomatous lesions in the nose and from bronchoalveolar lavage (BAL) mainly express the Th1 cytokine profile, which stimulates predominantly cell-mediated immune responses. This result supports the hypothesis that due to the two-phase course of WG there occurs a polarisation of the T-cell sub-population (Th1 versus Th2 type) which may explain the transition from the initial (granulomatous) phase of WG (so-called localized or locoregional restricted WG) to the generalized (vasculitic) phase. In conclusion, although the initiating events in the development of WG are still unknown, remarkable advances have been made in characterizing the infiltrating inflammatory cells and their products, which is of major importance in understanding the pathogenesis of this disease. In this regard, the use of specific mediators (i.e. cytokines, adhesions molecule antagonists, anti-Id ANCA, etc.) to modulate the inflammatory response may prove beneficial in the therapy of WG.     

Wegener's granulomatosis with meningeal involvement: clinic-radiological correlations

INTRODUCTION: Wegener's granulomatosis is a systemic vasculitis which, in its classical form, is characterized by involvement of the superior and inferior respiratory tract and the kidneys. The vasculitis may be multisystemic. Ophthalmic and neurological involvement are common (22% and 54% of those affected respectively). When considering involvement of the nervous system, the commonest finding is peripheral neuropathy, particularly in the form of multiple mononeuritis. Meningeal involvement is exceptional. CLINICAL CASE AND CONCLUSIONS: We present a case of Wegener's granulomatosis with meningeal involvement, studied using CT and MR. The findings using imaging techniques are described, and conditions which should be considered in the differential diagnosis are discussed.     

Suppurative lesions without prominent epithelioid cell response in abscess-forming granulomatous lymphadenitis

To clarify the clinicopathological significance of the suppurative lesions without an epithelioid granulomatous response (SLs without Ep) in lymph nodes and their relationship to abscess-forming granulomatous lymphadenitis (AGL) and cat scratch disease (CSD), 10 cases were assessed clinicopathologically and immunohistologically. SLs without Ep were located in the subcapsular sinus, paracortical area and medullary cords, but not in the germinal centers. The microabscesses were surrounded by collections of monocytoid B-lymphocytes (MBLs), histiocytes without epithelioid features, neutrophils, small lymphocytes and small numbers of plasma cells. The majority of the MBLs seen in the SLs without Ep were of the large cell type. The histological triad of toxoplasmic lymphadenitis, i.e., reactive follicular hyperplasia, small clusters of epithelioid cells and aggregates of MBLs, were also seen in all cases. Some of the clinical and pathological findings in our 10 cases were characteristic of CSD, i.e., (1) cat exposure before the lymphadenopathy was in four of the 10 cases, (2) occurrence in autumn and winter months in all cases, (3) typical suppurative granulomas surrounded by palisaded epithelioid cells were in four of the 10 cases, and (4) Warthin-Starry silver stain-positive bacteria were detected in seven of the 10 cases. The results of our study suggest that SLs without Ep are an early stage of CSD.     

Nasal cocaine abuse presenting as a central facial destructive granuloma

We describe a 36-year-old patient with an aggressive, midline intranasal and naso- and oropharyngeal destructive process. For months the patient denied heavy abuse of nasal cocaine, but finally admitted it. Necrosis and atrophy of the inferior and middle nasal turbinates bilaterally, prominent naso and oropharyngeal ulcers, nasal septal as well as hard palate perforation were observed clinically. Repeated biopsies revealed focal areas of chronic inflammation and necrosis, but there was no evidence of vasculitis or granuloma formation. Since serum was slightly positive for antineutrophil cytoplasmic antibody, the initial diagnosis was Wegener's granulomatosis. In the United States there have been a few reports on a new cocaine-associated syndrome presenting as an aggressive, midline, intranasal and intrapharyngeal destructive process mimicking limited Wegener's granulomatosis and midline reticulosis. We report the first such case in Europe and offer guidelines for the diagnostic work-up of such cases.     

Fine-needle aspiration of histiocytic necrotizing lymphadenitis (Kikuchi's disease)

Fine-needle aspiration (FNA) of the lymph node was done in five patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease). In four patients, the aspirates were found to have many small and large atypical lymphocytes, some reactive, phagocytic histiocytes, and intense extracellular debris. Neutrophils, plasma cells, or multinucleated giant cells were not seen. These cytologic findings were considered diagnostic for Kikuchi's disease. In one patient, the aspirate did not show significant histiocytosis or tissue necrosis and was considered nondiagnostic. In patients with both typical clinical features and characteristic cytologic findings in the lymph node aspirates, FNA of the lymph node alone will suffice for diagnosis. In those patients with typical clinical features but nondiagnostic findings in the FNA aspirates, the diagnosis of Kikuchi's disease may have to be established either on repeated nodal FNA or on lymph node biopsy.     

Survival and vasculitis activity in patients with end-stage renal disease due to Wegener's granulomatosis

BACKGROUND: In patients with end-stage renal disease (ESRD) due to Wegener's granulomatosis, a decrease in vasculitis activity after the development of ESRD, as described in other autoimmune diseases, has been postulated. However, up to now no data in a larger group of patients with Wegener's granulomatosis on chronic dialysis have been available. METHODS: We retrospectively analysed the clinical course of 35 patients with Wegener's granulomatosis and ESRD during chronic dialysis treatment. Diagnosis was based on clinical manifestation, antineutrophil cytoplasmic antibodies and/or histology. RESULTS: During a mean follow-up of 43 months (5-113 months), six patients died, three related to treatment toxicity. The patient survival rates (according to Kaplan-Meier calculation) were 93% after 2 years and 79% after 5 years. Twenty-nine relapses of Wegener's granulomatosis occurred in 17 patients (relapse rate 0.24/patient/year); 2/3 of the relapses were seen during treatment with steroids, 1/6 during cyclophosphamide therapy. The relapses were not related to the dialysis membrane used. Remission or partial remission could be achieved in 93% of the relapses. CONCLUSIONS: The survival of patients on chronic dialysis treatment due to Wegener's granulomatosis was comparable to that of other patient groups with ESRD. The relapse rate was not different from that of non-dialysed patients with Wegener's granulomatosis, and this finding underlines the need for a therapeutic strategy to maintain long-term remission in dialysis-dependent patients, too.     

Unexpected death due to gestational choriocarcinoma: a report of two cases

The clinical and pathological manifestations of severe intestinal involvement in Wegener's granulomatosis were studied by a review of the literature and reports of two patients. Altogether, six cases, two females and four males, were studied. One patient developed two episodes of bowel manifestations necessitating immediate surgical interventions. The average age at onset of intestinal symptoms was 43.3 yr (26-55 yr) and, in all cases, the first signs of such manifestations developed within the first 2 yr of disease. Prior to the onset of intestinal symptoms, immunosuppressive therapy was administered in six of seven instances. Acute abdominal pain with signs of peritonitis or distention only constituted the main clinical picture in six of the seven events. The last episode was manifested clinically with profuse diarrhoea with blood and mucus. Of the seven instances of severe intestinal manifestations, the small bowel was involved in two, the large bowel in three, and both the small and large bowel were affected in two episodes. Histological evidence of vasculitis in the bowel was demonstrated in three of the seven biopsy specimens, while in four, ischaemia, inflammation and ulceration were the pathological findings. Intestinal perforation was seen four times and surgery was performed in six of seven episodes. Severe intestinal involvement is rare in Wegener's granulomatosis. The initial bowel manifestations occur within the first 2 yr of disease, and affect both the large and small bowel. Histologically, vasculitis, ischaemia, inflammation and ulceration are the prevailing findings. Death due to intestinal catastrophy occurred in one of the six patients reported. Most likely, the manifestations are associated with the disease process rather than related to the use of immunosuppressive agents.     

Comparison of the Nebraska collar, a new prototype cervical immobilization collar, with three standard models

This is a retrospective reassessment of the most important cytopathologic features of 23 FNA smears with a cytologic diagnosis of panniculitis (PN). Patients were sent by clinicians. Clinical diagnoses were as follows: 16 suspicious of PN; three cutaneous metastases of an extracutaneous primary neoplasm; four with no clinical diagnosis. Thirteen cases were subsequently submitted to histopathologic study. The following cytoarchitectural patterns were found to be very useful for the cytologic diagnosis of PN: adipocytes intermingled with foamy histiocytes, donut-like granulomas, aggregates of adipocytes intermingled with plump histiocytes, a granular basophilic background forming a lattice-like pattern, and well-formed granulomas with or without multinucleated giant cells. Inflammatory cells could be seen combined with any of these cytoarchitectural patterns. FNA does not pretend to replace excisional biopsy as the diagnostic procedure for these entities but it is a very useful diagnostic tool in certain cases: for confirming the recurrence of PN previously diagnosed by histology, for evaluating the onset of subcutaneous nodules in patients with a non-cutaneous malignant primary neoplasm, for evaluating cutaneous nodules with no clinical suspicion, and for confirming a clinical diagnosis of PN and differentiating it from other entities that mimic PN clinically.     

"Idiopathic" extracapillary glomerulonephritides without immune deposits are vascularitides: clinical and serologic analysis

To determine the spectrum of systemic diseases potentially associated with pauci-immune rapidly progressive glomerulonephritis (GN), most of which being considered as idiopathic, we have analyzed extra-renal manifestations, occurrence of extra-glomerular vasculitis and incidence and specificity of ANCAs in 40 patients selected only on histological criteria. Extra-renal symptoms were unexpectedly observed in all patients but one, and were suggestive of vasculitis in 24 of them. Extra-glomerular vasculitis was evidenced in 18 kidney biopsies and four biopsies from other organs. Among the 33 patients with suspected or established vasculitis, 13 had presumed or biopsy-proven Wegener's granulomatosis (WG), three had a macroscopic form of polyarteritis nodosa and 17 had a clinical presentation compatible with the so-called microscopic polyarteritis previously described in the british literature. An additional patient had clinical signs of WG without clinical and histological evidence of vasculitis. ANCAs were detected in 28/33 and 25/34 sera tested by IF and ELISA, respectively: 19 contained anti-myeloperoxidase (MPO) antibodies and 6 had anti-proteinase 3 (Pr3) activity. Anti-MPO and anti-Pr3 antibodies were present in all clinical subgroups but with various incidences: anti-MPO antibodies were surprisingly more often detected (6/12) than anti-Pr3 (4/12) in patients with suspected or histologically proven WG but anti-Pr3 antibodies were nonetheless 3- to 4-fold more frequent in WG than in non-WG systemic vasculitis (1/12) and necrotizing CGN without evidence of extra-renal vasculitis (1/10). These results strongly suggest that pauci-immune necrotizing CGNs belong to the broad spectrum of necrotizing vasculitides affecting glomerular capillaries. This hypothesis is also supported by the good response of patients to immunosuppressive treatments known for their efficacy in vasculitides, whereas these treatments are usually less successful in severe forms of extra-capillary GN with immune deposits.