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An uncommon disease that usually begins as a localized granulomatous inflammation of upper and/or lower respiratory tract mucosa and may progress into generalized necrotizing granulomatous vasculitis and glomerulonephritis.
Etiology and Incidence
The etiology is unknown. Though the disease resembles an infectious process, no causative agent has been isolated. Because of the characteristic histologic changes, hypersensitivity has been postulated as the basis for the disease. The male:female ratio is 2:1. The disease can occur at any age.
Pathology
Biopsy of inflamed granular material in the nose and nasopharynx discloses granulomatous tissue containing epithelioid cells, Langhans' cells, and foreign-body giant cells together with much vascular disruption, sheets of released RBCs, and numerous leukocytes in varying degrees of cytoclasis. Pulmonary and skin biopsies show inflammatory perivascular exudate and fibrin deposition in small arteries, capillaries, and venules. Renal biopsy shows a focal and segmental glomerulonephritis of varying severity, occasionally with necrotizing vasculitis. Immunohistochemical studies of the kidney biopsy show extensive deposits of fibrin in blood vessels and glomeruli, the latter suggesting a partial activation of a clotting factor (Hageman). Immune complexes precipitated by C1q have been found and shown to disappear on therapy with cyclophosphamide and prednisone. Dense subepithelial deposits suggestive of an immune complex reaction are detectable by electron microscopy on the epithelial side of the basement membrane. Immunofluorescence techniques may show scattered deposits of complement and IgG.
Symptoms, Signs, and Laboratory Findings
Onset may be insidious or acute, and the full spectrum of the disease may take years to evolve. Presenting complaints usually are referable to the upper respiratory tract and include severe hemorrhagic rhinorrhea, paranasal sinusitis, nasal mucosal ulcerations (with consequent secondary bacterial infection), serous or purulent otitis media with hearing loss, cough, hemoptysis, and pleuritis. Patients usually present with a granulomatous process of the nose often mistaken for chronic sinusitis. The nasal mucous membrane has a red, raised granular appearance and is friable and bleeds easily. Nasal perforation may be seen. Other initial symptoms include fever, malaise, anorexia, weight loss, migratory polyarthritis, granulomatous skin lesions, and ocular manifestations with nasolacrimal duct obstruction, proptosis, and episcleritis. Chondritis of the ear, myocardial infarction from vasculitis, and aseptic meningitis and nonhealing granulomas of the CNS may occur.
Eventually, a disseminated vascular phase may develop and is associated with necrotizing inflammatory skin lesions, pulmonary lesions with cavitation, diffuse leukocytoclastic vasculitis, and focal glomerulitis that may progress to generalized crescentic glomerulonephritis with hypertension and uremia. Renal involvement is the hallmark of generalized disease. Urinalysis shows proteinuria, hematuria, and RBC casts. Functional renal impairment is inevitable without immediate appropriate therapy. Occasionally, the disease is limited to pulmonary involvement. Anemia may be profound.
Serum complement levels are normal or elevated. The ESR is elevated. Leukocytosis is present. Antinuclear antibodies and LE cells are not present. High titers of antibodies to neutrophilic cytoplasmic proteins are invariably present and may provide a relatively specific and sensitive marker for following the disease course.
Diagnosis
Early diagnosis and treatment are crucial, since a high remission rate is now possible (see below), including the avoidance or lessening of the critical renal complications. Diagnosis is established by the characteristic clinical and pathologic findings. Renal biopsy determines the extent of renal involvement and is vital in early detection of renal dissemination. Sometimes, open pulmonary biopsy of a solid or cavitating lesion leads to diagnosis. Clusters of densely packed atypical cells may be found in the sputum of patients with pulmonary involvement. Differential diagnosis includes polyarteritis, the vascular renal phase of SBE, rapidly or slowly progressive glomerulonephritis, SLE, and lethal midline granuloma, ie, lymphoma. Polyarteritis is ruled out by biopsy of the skin lesions and by pathologic localization of the vascular lesions. Eosinophilia, not a feature of Wegener's granulomatosis, is often present in polyarteritis; nasal and pulmonary granulomatous inflammation is absent. Characteristic blood cultures and changing cardiac murmurs are present in SBE. In SLE, antinuclear antibodies and LE cells are present in the serum, and the serum complement level is depressed. Vasculitic granulomatous inflammation is absent in lethal midline granuloma (lymphoma). Antibody titers to neutrophil lysosomes and their contents are elevated only in patients with necrotizing vasculitis of any kind.
Course, Prognosis, and Treatment
The complete syndrome usually progresses rapidly to renal failure once the diffuse vascular phase begins. Patients with the limited form of the disease may have nasal and pulmonary lesions, with little or no systemic involvement. Pulmonary manifestations may improve or may worsen spontaneously.
Prognosis, once fatal, has been dramatically improved by treatment with immunosuppressive cytotoxic agents. Cyclophosphamide (1 to 2 mg/kg/day orally, or by rapid IV infusion as a single dose q 2 to 3 wk) is the drug of choice. Corticosteroids, which reduce the vasculitic edema, are given concurrently (prednisone 1 mg/kg/day orally). After 2 to 3 mo, prednisone is gradually decreased until the patient is maintained solely on cyclophosphamide. This drug is given at least a full year after a clinical remission of the disease. Oral dosage then is tapered by a 25-mg decrease q 2 to 3 mo (IV dosage is reduced equivalently). Azathioprine is less effective but may be used as an alternative or adjunct to cyclophosphamide for those who cannot tolerate cyclophosphamide. Long-term prophylactic oral trimethoprim/sulfamethoxazole (160/800 mg to 480/2400 mg daily) seems to be highly effective for the upper respiratory tract lesions and may suffice as the sole long-term treatment once all systemic features have been ablated by cyclophosphamide and corticosteroids. Occasionally, the associated anemia may be so profound that blood transfusion is required.
Side effects of cyclophosphamide include leukopenia, leading to risk of infections; hemorrhagic cystitis; gonadal dysfunction; and some hair loss, reversible on discontinuing the drug. Long-term complete remission can be achieved with therapy, even with advanced disease. Kidney transplantation has been successful in renal failure. A report of one patient who received a cadaver kidney implant is interesting in that typical renal lesions of Wegener's granulomatosis developed. An increased incidence of solid tumors after many years may reflect high-dose cyclophosphamide usage.
MIXED CONNECTIVE TISSUE DISEASE
Fluid & Electrolyte
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