Diagnosis: Wegener's granulomatosis

Follow-up: The day after the biopsies, a report of an elevated serum ANCA to proteinase 3 was received. The patient was begun on prednisone and cyclophosphamide and improved rapidly over the next week. At discharge on 6/7 (3 weeks after admission), he had minimal dyspnea while breathing air, the creatinine was 2.6 mg/dl, and the chest radiograph had cleared markedly. All cultures from the bronchoscopy, blood, lung, and kidney were negative for bacteria, fungus, and mycobacteria. Respiratory cultures were negative for mycoplasma and legionella. Medications at discharge included prednisone, cyclophosphamide, and Bactrim, the last for prophylaxis against pneumocystis. At no time were upper respiratory tract symptoms or signs noted. At follow-up, the serum creatinine was noted to have declined to 1 mg/dl.


Wegener's Granulomatosis

Introduction: Wegener's granulomatosis (WG) is a relapsing, multisystem, inflammatory disease that usually involves the upper and lower respiratory tracts and kidneys, but may involve any other organ. Occurring in adults of any age, it is a rare disease with a peak incidence in the 6th decade [1]. Men and women are affected equally. It is characterized histologically by granulomatosis, necrosis, and a destructive angiitis of medium- and small-sized vessels--veins, arteries, venules, arterioles, and capillaries. The presence of anti-neutrophil cytoplasmic antibodies in the serum of many patients with WG serves to link it to other ANCA-positive diseases--Churg-Strauss syndrome, microscopic polyangiitis, and renal-limited, pauci-immune, necrotizing, crescentic glomerulonephritis--all of which are treated in a similar fashion. Diagnostic criteria are still being debated, especially the weight to be given to the anti-neutrophil cytoplasmic antibodies [2].

Pulmonary manifestations: Most patients present with upper and/or lower airway symptoms, the latter including cough, dyspnea, hemoptysis, or pleuritis. Pulmonary opacities or nodules are found initially in 45% of patients, and lung disease eventually develops in 85%. About 1/3 of patients with pulmonary abnormalities at onset, however, have no respiratory symptoms [3]. Bronchoscopy may show mucosal ulceration or inflammation, which is sometimes nodular; bronchial stenosis; or hemorrhage [4,5]. Analysis of BAL fluid in 13 patients with untreated, active disease showed a mean of 42% PMNs and 4% eosinophils, both of which were greater than those found in usual interstitial pneumonia, another neutrophilic alveolitis [6]. Other manifestations are described by organ system below. Non-specific, systemic symptoms of fever and weight loss also occur.


Other Manifestations of WG

Ear, Nose, & Throat: Sinusitis, otitis, nasal ulcers, septal perforation or deformity, hearing loss, or subglottic stenosis may occur. Of patients with WG, 15-30% have ear ache, discharge, or deafness. Hearing loss is usually conductive, but sensorineural loss also occurs. Fluid or inflammation in and around the Eustachian tube and middle ear produces conduction abnormalities. Vasculitis of the VIIIth nerve causes nerve deafness, sometimes reversible [7]. Upper airways are involved at onset in 73% of cases, increasing to 92% during the course of the disease [3].

Kidney: Hematuria, red cell casts, proteinuria, and renal failure are characteristic. Presentation with renal disease is unusual (18% of patients), but renal disease eventually occurs in 77% [3]. This discrepancy in percentages explains the finding of disease "limited" initially to the upper or lower airways, but renal disease should always be expected [1].

Eye disease: Proptosis, conjunctivitis, eye pain [3]

Joint symptoms: Arthralgias, arthritis, myalgias [3]

Skin disease: Palpable purpura, ulcers, vesicles, papules, subcutaneous nodules [3], pyoderma gangrenosum-like lesions [8]

Nervous system: Mononeuritis multiplex, stroke, cranial nerve palsies [3]

Cardiovascular system: Pericarditis, myocarditis, coronary arteritis, endocarditis [3]


Laboratory tests: Leukocytosis, anemia, thrombocytosis, and elevated ESR are common [3,4]. Antineutrophil cytoplasmic antibodies (cytoplasmic or c-ANCA to proteinase 3 (PR3) or perinuclear or p-ANCA to myeloperoxidase (MPO)) are useful in diagnosis and follow-up of disease. These antibodies can be detected in two ways--by indirect immunofluorescence of formalin-fixed PMNs and by enzyme-linked immunosorbent assays (ELISA). One problem with the ANCA results is the lack of standardized test performance and reporting. However, in a multi-center study of standardized assays for ANCAs, it was found that for WG the sensitivity of a positive test for indirect immunofluorescence and a positive ELISA (c-ANCA/anti-PR3-positive or p-ANCA/anti-MPO-positive) was 72.5% and the specificity (related to disease controls) was 98.4%, both of which percentages were higher than those for immunofluorescence or ELISA alone. ANCA test results, however, may be negative in the disease, and false positive results occur [9]. Further, the diagnosis of WG in this study was based on the definitions proposed by the Chapel Hill Consensus Conference [2], but not all of the patients had histologic evidence of vasculitis or granulomatosis, and some had received treatment [9].

It has recently been found that expression of MHC class II antigens on PMNs correlates with disease activity but not with ANCA activity, making it a potential marker for patients who are ANCA negative [10]. This unusual reactivity was not found in control patients with infection or rheumatoid arthritis, and the authors suggest that it may be a better test for relapse than ANCAs [10]. In another report, alpha1-antitrypsin deficiency was associated with ANCA-positive vasculitides [11].

Radiographic changes: Radiographs or CTs typically show nodules or irregular opacities that spare the apices. In one study, nodules varied from 0.5 to 10 cm, with the larger ones often being cavitated. The number was usually less than 10, and they tended to increase in size and number as the disease progressed. Nodules occurred in 69% of 77 patients. They were unilateral in 26% and cavitated in 49%. Irregular opacities were present in 53% of the 77 cases and were unilateral in 37% of them. These opacities were 1) diffuse, bilateral, and of low density, usually signifying alveolar hemorrhage, 2) patchy and low density, clearing or progressing over time, or 3) dense and localized consolidations. Cavities were less frequent (17%) in the irregular opacities than in the nodules. Hilar and mediastinal adenopathy was rare [4]. In another study of 98 HRCT examinations in 73 patients, only one of 25 patients with active disease had consolidation as in our patient. Its extent was not given. This study also indicated that there was considerable overlap between the findings in active and chronic, treated disease; that is, resolution did not always occur. However, nodules/masses and parenchymal opacifications tended to be absent when disease became inactive, but parenchymal bands persisted [12].

Histologic features of Wegener's granulomatosis: The histologic features are summarized below (Table 1) with links to detailed descriptions. Because several features must be identified, transbronchial biopsies are seldom diagnostic [3]. Further, granulomatosis with palisading histiocytes and destructive angiitis may occur with infectious diseases, which must be excluded before a diagnosis of WG can be made. Opportunistic infections must be considered in the treated patient with WG.

Table 1: Summary of Histologic Findings in Lungs of Patients with WG [13]

Histologic Variants: Sometimes, the diagnosis may be obscured by the prominence of unusual histologic features. For example, eosinophils may predominate in the lesions in the absence of peripheral blood eosinophilia and asthma that would suggest Churg-Strauss syndrome [14]. Cases with extensive COP (BOOP)-like areas have also been described [15]. A bronchocentric granulomatosis pattern may simulate infection, aspiration bronchitis, or changes seen in allergic bronchopulmonary aspergillosis [16]. Airway disease also includes acute and chronic inflammation and follicular bronchiolitis. Cartilage destruction and airway stenosis may be a consequence of disease in large airways [17]. Finally, xanthogranulomatous lesions (endogenous lipoid pneumonia) with interstitial and alveolar foamy histiocytes have also been reported [17]. In all cases, however, typical angiitis and granulomatosis were also present, and the diagnosis of WG could be made.

Histologic findings in treated disease (recurrence or autopsy): Lesions of WG were described in 20 patients with pulmonary disease 6 da to 13 y after treatment was begun. The differential diagnosis included opportunistic infection, malignancy, drug reaction, ARDS, and embolic disease. Vascular lesions were found in 75%, and granulomatosis, in 60%. Other findings, many of which indicate scarring rather than resolution of lesions, are listed below [18].

Diagnosis of WG: Criteria for defining WG are still being debated. In 1990, the American College of Rheumatology described criteria to separate patients with angiitis (not necessarily biopsy-proven) into diagnostic categories. They found that in patients with angiitis, the presence of 2 of 4 features listed below classified patients as WG (sensitivity 88%, specificity 92%) [19,20].

Criteria for WG of the American College of Rheumatology [20]

These criteria were meant for classification of patients with various vasculitides, but have been used for diagnosis in patients without evidence of angiitis. A study to determine their positive predictive value (PPV) in a group of patients suspected of having vasculitis found that the PPV for WG was 25% for the entire group and only 40% for patients with definite vasculitis. The authors concluded that the criteria should not be used for diagnosis [21]. More recently, names and definitions of different vasculitides were proposed at the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis, but diagnostic criteria have not been determined [2].

Histologic diagnostic criteria: Based on a study of head and neck biopsies, histologic criteria for diagnosis, which can probably be generalized to other biopsy sites, have been proposed. Three diagnostic features were identified: granulomatosis, necrosis, and angiitis [22,23]. It should be noted that all three features were present in only 16% of head/neck biopsies, and 2 features were present in 21-23% [23]. The authors proposed the following.

ANCAs in diagnosis: The use of ANCAs in the diagnosis of pauci-immune, crescentic glomerulonephritis was studied in a group of 4,185 patients who underwent renal biopsy. The positive and negative predictive values for ANCAs varied depending on age and the pretest probability of disease based on clinical signs and symptoms. For example, in a patient with hematuria, proteinuria, and creatinine >3 mg/dl, a positive ANCA has a PPV of 92%, but in a patient with hematuria, proteinuria, and a creatinine <1.5 mg/dl, a positive ANCA has a PPV of 47%, indicating that many of the positive results for ANCA are false positives in these patients. However, even if the pretest suspicion is low, a positive ANCA may increase the PPV enough to warrant a biopsy. On the other hand, a negative ANCA result in a patient with low clinical suspicion of disease helps to exclude the possibility of an ANCA-related disease [24]. Serial ANCA tests performed in another study indicated that a persistently positive immunofluorescence or ELISA test for PR3 or MPO indicated active disease or predicted relapse. In contrast, patients with negative or decreasing titers tended to have fewer relapses [25].

Pathogenesis: Proteinase 3, a serine protease, which can degrade matrix proteins, is located in azurophilic granules of PMNs and small granules in monocytes [26]. Myeloperoxidase is located in the same granules, but moves to the perinuclear membrane when PMNs are fixed in ethanol for indirect immunofluorescence, thereby allowing the cytoplasmic and perinuclear patterns to be distinguished [27]. ANCAs with a perinuclear (p-ANCA) pattern are directed against a number of different proteins--myeloperoxidase, elastase, lactoferrin, cathepsin G, or bactericidal/permeability-increasing protein [9]. P-ANCAs with activity against proteins other than MPO usually occur in patients with other autoimmune diseases [28]. The ELISA test indicates whether the antibody is against myeloperoxidase or other proteins. Rarely, both types of antibodies are found in the same person [29,30]. ANCAs are not believed to cause disease, but evidence based on in vitro experiments suggests that they are involved in the inflammatory response to agents (possibly bacterial or viral) that activate cells (Table 2) [31-33].

Table 2: Evidence for ANCAs As Inflammatory Mediators

Differential diagnosis of WG:

Therapy and Outcome: In one study, complete clinical remission was achieved in 75% of 133 patients treated with prednisone and cyclophosphamide at a median time of 1 year, but in 50% of patients one or more relapses occurred, some after 5 or more years [3]. In a series of 77 patients with lung disease who were treated with prednisone and cyclophosphamide, 21% died [4]. In another study, 77 treated patients, who were observed for a mean of 7.1 y, showed a 5-year survival of 75% of expected. The standardized mortality ratio was 4.6 (6.8 for women and 4 for men) [35]. In a controlled, 2-year study of the effectiveness of co-trimoxazole to prevent relapse in WG in mid-course, it was found that, when tolerated, the drug significantly reduced the relapse rate: 82% of the treated patients maintained remission at 24 months compared to 60% in the placebo group. However, only upper airway relapse was reduced, not lung or renal relapse [36]. The immunosuppressive therapy for WG predisposes to pneumocystis pneumonia (6% of patients in one study), and the authors advocate giving prophylactic treatment for pneumocystis while patients are receiving daily glucocorticoid therapy [37].

Morbidity can be classified as in Table 3. Mortality related to disease in this study was 13%, and its cause was about equally distributed among renal disease, pulmonary disease, infections, and malignancy [3].

Table 3: Morbidity in Wegener's Granulomatosis [3]

Morbidity from disease

Morbidity from disease + therapy

Morbidity from therapy

Renal insufficiency 42% (8 renal transplants with recurrence of WG in 1)

Chronic sinus dysfunction 47% (± S. aureus infection)

Cystitis 43% (bladder cancer 2.8%)

Hearing loss 35%

Pulmonary insufficiency 17% (restrictive scar from disease/cytoxan or obstruction from endobronchial disease)

Cataracts 21%

Nasal deformities 28%

Hair loss 17%

Tracheal stenosis 13%

Fractures 11%

Visual loss 8%

Infections 46%

Diabetes mellitus

Infertility

Lymphoma

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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 8/29/99

Copyright 1999 by Martha L. Warnock. All rights reserved.