Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group.

Twenty-six symptomatic subjects with clinical evidence plus either high-resolution computed tomography (HRCT, n = 25) or open-lung biopsy (OLB, n = 1) patterns typical for idiopathic usual interstitial pneumonia (idiopathic UIP) were entered into a randomized prospective treatment trial using high-dose prednisone (n = 12) versus colchicine (n = 14). The minimum dose of prednisone used was 60 mg/d for 1 mo, tapered to 40 mg/d over the second month, tapered to 40 mg every other day during the third month, with subsequent doses adjusted as clinically indicated. The dose of colchicine was 0.6-1.2 mg/d, as tolerated. The presence of a rim of subpleural honeycomb change was present in all of the 25 subjects who had HRCT. Subjects treated with high-dose prednisone alone experienced a higher incidence of serious side effects and also exhibited a trend (not statistically significant, p = 0.391) to more rapid decline of pulmonary function and shortened survival than did those treated with colchicine alone. In most subjects with typical clinical and HRCT features of idiopathic UIP, neither prednisone nor colchicine resulted in objective improvement, and the disease continued to progress in the majority. Colchicine appears to be a safer alternative to a trial of high-dose prednisone but may be no different than no therapy.

Colchicine versus prednisone as treatment of usual interstitial pneumonia.

OBJECTIVE: To assess the results with colchicine and prednisone as initial single-drug therapy in patients with usual interstitial pneumonia (UIP). MATERIAL AND METHODS: We reviewed the serial pulmonary function test results in 22 patients with typical clinical and high-resolution computed tomographic features of UIP who were treated with colchicine as initial single-agent therapy and compared them with a group of 22 historical patients with UIP of similar severity diagnosed by open-lung biopsy who were given prednisone as initial single-drug therapy. RESULTS: No significant difference was detected in the rate of decline of pulmonary function or in the time to "failure" between the two study groups. A trend was suggested for more rapid decline of pulmonary function in the prednisone-treated than in the colchicine-treated group. The design of this study does not allow distinction between a possible beneficial effect of colchicine and a possible adverse effect related to weaning from high-dose prednisone. Colchicine was well tolerated; few side effects other than mild diarrhea were noted in those patients able to take the drug long enough to return for pulmonary function testing at 3 months. In comparison, the side effects of prednisone were more serious and were not always reversible with cessation of therapy. CONCLUSION: This study lends further support to the assumption that colchicine may be a satisfactory and less hazardous substitute for prednisone in the treatment of patients with UIP.

Carcinoid tumors and sarcoidosis--does a link exist?

OBJECTIVE: To attempt to determine whether a relationship exists between carcinoid tumors and sarcoidosis. MATERIAL AND METHODS: We present a series of seven case reports and discuss hypotheses about possible disease associations. RESULTS: Certain malignant lesions have tended to occur in patients with sarcoidosis. Seven patients who were encountered at Mayo Clinic Rochester between 1950 and 1994 had both sarcoidosis and carcinoid tumors. These patients ranged in age from 31 to 66 years, and three of the patients had a history of benign thyroid disorders. Malignant tumors have been thought to be related to sarcoidosis in one of two ways: (1) immunologic abnormalities in sarcoidosis may promote the development of neoplasms or (2) malignant disease may promote the onset of sarcoidosis either by causing local sarcoid reactions that progress or by directly initiating the manifestations of systemic sarcoidosis. Because the chronology of events differed in our seven cases, various mechanisms of action may have a role in the manifestations of these two disease entities. Our cases emphasize the importance of avoiding the diagnosis of disseminated malignant disease in patients with cancer and associated hilar and mediastinal lymphadenopathy without biopsy confirmation of metastatic disease. CONCLUSION: Application of the knowledge gained about the mechanisms of disease in sarcoidosis will perhaps facilitate identification of the pathogenesis of carcinoid tumors and other neuroendocrine tumors.

Lung toxicity associated with cyclophosphamide use. Two distinct patterns.

Cyclophosphamide-induced lung toxicity may be difficult to recognize because of the presence of confounding variables such as concomitant use of other cytotoxic drugs, opportunistic infections, diffuse pulmonary malignancy, radiation pneumonitis, and oxygen toxicity. The purpose of this retrospective analysis was to identify the clinical spectrum of pulmonary toxicity of cyclophosphamide. In our review of case records, we sought to identify patients in whom cyclophosphamide was the only identifiable etiologic factor for lung toxicity. In a 20-yr period six patients were identified with cyclophosphamide-induced lung disease, including five men and one woman ranging in age from 42 to 78 yr. Clinical features of toxicity include dyspnea, fever, cough, new parenchymal infiltrates, gas exchange abnormalities on pulmonary function tests, and pleural thickening on chest roentgenogram. Two patterns of cyclophosphamide-induced lung toxicity were identified. A single patient presented with early-onset pneumonitis and responded to discontinuation of the drug. Five patients with late-onset pneumonitis developed progressive pulmonary fibrosis associated with bilateral pleural thickening. Patients with late-onset pneumonitis showed no response to cessation of cyclophosphamide and institution of corticosteroid therapy. Three of these patients died of respiratory failure. Careful review of the individual cases reported in the literature as cyclophosphamide lung toxicity revealed only 12 cases in whom none of the additional confounding factors could be identified. These could easily be divided in the same two categories. Early-onset pneumonitis is reversible and may respond to corticosteroid therapy. Late-onset pneumonitis, frequently associated with pleural thickening, is clinically distinct from idiopathic pulmonary fibrosis but has a chronically progressive course. It appears unresponsive to corticosteroid therapy.

Nasal and nasopharyngeal angiocentric T-cell lymphomas.

Thirty patients (24 mean and 6 women) with a median age of 44.5 years who had angiocentric T-cell lymphoma were studied. The neoplastic cells in each had a T-cell phenotype. Epstein-Barr virus RNA was detected in the neoplastic cells in 29 of 30 patients. The most common presenting symptom was nasal obstruction followed by purulent rhinorrhea. Patients with early presentation had only a friable nasal or nasopharyngeal mucosa; late clinical signs included septal perforation in 40%. Twenty-one of 30 patients received radiation therapy as initial treatment; 22 of 30 patients achieved a complete remission. Fifteen patients relapsed: 10 with local recurrence and 5 with systemic disease. In long-term follow-up, 10 patients were alive and disease free, 6 patients died of unrelated causes, and 12 patients died of disease.

The spectrum of pulmonary vasculitis.

Wegener's granulomatosis and Churg-Strauss syndrome are the predominant pulmonary vasculitides. Next in frequency are the various diffuse alveolar haemorrhage syndromes, which may be related to the antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases, such as Wegener's granulomatosis and Churg-Strauss syndrome, or may be a part of a collagen vascular disease, such as lupus erythematosus, or associated with antiglomerular basement membrane antibody (AGBM) and fall within the definition of Goodpasture's syndrome. Whereas Behçlet's disease and Takayasu's arteritis have major pulmonary manifestations, they are rare diseases. Entities previously confused with pulmonary vasculitis include lymphomatoid granulomatosis or polymorphic reticulosis, and benign lymphocytic angiitis and granulomatosis, which are probably in the spectrum of T-cell lymphomas. Necrotizing sarcoid and sarcoidosis can involve blood vessels, but do not follow a typical course associated with the traditional concept of vasculitis.

Wegener's granulomatosis.

Since its first description by Wegener in 1936, Wegener's granulomatosis has undergone significant changes in terms of clinical scope, diagnosis, and treatment. It is no longer tenable to insist on the fulfillment of the Wegener's triad to make the diagnosis. The wide range of clinical presentations is encompassed by the ELK (ear, nose, and throat; lung; kidney) classification in which any combination or singular involvement of the major sites can be considered within the Wegener's spectrum if supported by the appropriate pathologic findings or the presence of a cytoplasmic antineutrophil cytoplasmic antibody pattern. Treatment is based on the extent of involvement and clinical tempo. Trimethoprim-sulfamethoxazole may be used for patients with localized disease. Systemic disease, including involvement of the kidney, mononeuritis multiplex, and skin vasculitis, is treated with systemic glucocorticoids and cyclophosphamide. Research into the antineutrophil cytoplasmic antibody phenomenon is yielding new insights into possible pathogenic mechanisms.

Neurologic manifestations of Churg-Strauss syndrome.

OBJECTIVE: To determine the frequency and the types of neurologic involvement in a series of patients with Churg-Strauss syndrome (CSS). DESIGN: We reviewed the medical records of 47 consecutive patients with CSS who were examined at the Mayo Clinic between January 1974 and June 1992. MATERIAL AND METHODS: The study patients were classified into two groups: (1) those with a histopathologically confirmed diagnosis of CSS who had evidence of either vasculitis or Churg-Strauss granuloma, the presence of asthma, and peripheral eosinophilia (more than 10% eosinophils) on at least one differential leukocyte count (N = 33) and (2) those with a clinical diagnosis of CSS who had evidence of vasculitis based on either multiple mononeuropathy or necrotizing cutaneous lesions, the presence of asthma, and peripheral eosinophilia (more than 10% eosinophils) on at least one differential leukocyte count (N = 14). RESULTS: Of the 47 patients, 29 (62%) had neurologic involvement. Peripheral neuropathy was detected in 25 patients: 17 had multiple mononeuropathy, 7 had distal symmetric polyneuropathy, and 1 had an asymmetric polyneuropathy. Three patients had cerebral infarctions. Less commonly identified problems included radiculopathies, ischemic optic neuropathy, and bilateral trigeminal neuropathy. Asthma preceded the onset of neurologic involvement in all cases (mean duration, 6.7 years. Follow-up data, when available, showed that corticosteroid therapy usually yielded improvement or stabilization. CONCLUSION: Neurologic involvement is common in CSS, usually manifesting as peripheral neuropathy. In this series of patients, asthma preceded the neurologic manifestations.

Tracheobronchial involvement in Wegener's granulomatosis.

This study was designed to characterize the clinical spectrum and course of tracheobronchial involvement in Wegener's granulomatosis (WG). Of the 51 patients with biopsy-proven WG who underwent bronchoscopy at least once at our institution between January 1982 and November 1993, 30 (59%) had endobronchial abnormalities due to WG. Initial findings included subglottic stenosis in five (17%), ulcerating tracheobronchitis with or without inflammatory pseudotumors in 18 (60%), tracheal or bronchial stenosis without inflammation in four (13%), and hemorrhage without identifiable source in two (4%) patients. Nine patients with ulcerating tracheobronchitis on initial study had subsequent bronchoscopies for continued symptoms, which in seven cases documented the progression from ulcerating tracheobronchitis to stenosis without inflammation. Bronchoscopic interventions included dilation by rigid bronchoscope in three, YAG-laser treatment in one, and placement of silastic airway stents in three patients. Only the stents provided persistent airway patency. Endobronchial biopsies were performed on 21 occasions in 17 patients. Half of the specimens were helpful in establishing the diagnosis and in all but three in assessing disease activity. While antineutrophil cytoplasmic antibody titers reflect overall disease activity, no correlation with endobronchial inflammatory activity was apparent.

Sarcoidosis.

Sarcoidosis is a systemic granulomatous process of unknown cause. Pathologically, it is characterized by noncaseous granuloma, and in more than 90% of patients, the lung or intrathoracic lymph nodes are affected. A roentgenographic staging system (stages I, II, and III), based on the appearance of the plain chest roentgenogram, conveys important information about prognosis, degree of symptoms, and pulmonary function abnormalities. The diagnosis should be confirmed by histopathologic examination and exclusion of known causes for the noncaseous granulomatous reaction. When indicated, treatment with alternate-day regimens of prednisone is highly effective. Serial chest roentgenography, pulmonary function studies, and the serum angiotensin-converting enzyme level are useful for monitoring the course of the disease.

Cutaneous Wegener's granulomatosis: clinical, histopathologic, and immunopathologic features of thirty patients.

BACKGROUND: Wegener's granulomatosis (WG) is a systemic disease characterized by necrotizing granulomatous inflammation and vasculitis. Its cutaneous manifestations vary. OBJECTIVE: We reviewed and characterized the clinical, pathologic, and immunopathologic features of the specific cutaneous manifestations of WG and investigated the sensitivity and the specificity of anti-neutrophilic cytoplasmic antibody (c-ANCA) in the cutaneous manifestations of this disease. METHODS: A retrospective analysis was conducted of 244 cases of WG observed between 1988 and 1992. RESULTS: Skin involvement occurred in 14% of the patients and was more frequent in generalized WG. Skin lesions may be an early premonitory sign of renal disease. Necrotizing ulcerations resembling pyoderma gangrenosum were not uncommon. Leukocytoclastic vasculitis was the most common cutaneous pathologic pattern. Findings of c-ANCA were positive in 81% of patients with cutaneous WG. CONCLUSION: Skin involvement usually occurred at presentation with generalized disease. c-ANCA is a valuable adjunct to diagnosis and follow-up of WG.

Lesions of the respiratory tract associated with the finding of anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern.

OBJECTIVE: To characterize the clinicopathologic spectrum of respiratory tract involvement in patients with positive results of immunofluorescence microscopy for anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern (p-ANCA) and to assess the clinical value of p-ANCA testing. DESIGN: We retrospectively reviewed the medical records of all patients at Mayo Clinic Rochester in whom p-ANCA were detected by indirect immunofluorescence microscopy during 1992. MATERIAL AND METHODS: Additional target antigen identification was performed with use of enzyme-linked immunosorbent assays for antibodies against myeloperoxidase (MPO) and proteinase 3. We summarized the clinical findings in MPO-positive and MPO-negative patients. RESULTS: Sera were positive for p-ANCA in 42 of 2,381 patients (1.8%). In 13 of these 42 patients (31%), the respiratory tract was involved. Twelve patients had chest roentgenographic abnormalities, including a diffuse alveolar filling pattern (N = 8), a diffuse interstitial pattern (N = 2), and a combined interstitial and alveolar pattern (N = 2); three others had nasal inflammation. Ten of 16 sera tested were positive for MPO, and proteinase 3 antibodies were detected in 1 specimen. All patients with alveolar hemorrhage were positive for MPO antibodies. CONCLUSION: Testing for p-ANCA by immunofluorescence microscopy discloses a wide range of clinical disorders distinct from the main cytoplasmic-staining ANCA-associated disease--namely, Wegener's granulomatosis. In particular, the respiratory tract is affected much less frequently. Further evaluation of positive p-ANCA immunofluorescence test results by enzyme-linked immunosorbent assay to determine whether MPO is the target antigen is necessary to obtain clinically useful information from this test.

Severe asthma complicated by bilateral diaphragmatic paralysis attributed to Parsonage-Turner syndrome.

Progressive dyspnea that developed in a 52-year-old woman with a lifelong history of asthma did not respond to high-dose orally administered glucocorticoids. Initially, a diagnosis of allergic bronchopulmonary aspergillosis or hypersensitivity pneumonia was suggested as the cause of the worsening dyspnea. Pulmonary function tests demonstrated severe airway obstruction; substantial improvement was noted after bronchodilator therapy. Maximal inspiratory pressure was decreased, and the diffusing capacity of the lungs was abnormal. Computed tomography of the chest showed no parenchymal or mediastinal abnormalities. During a sniff test, fluoroscopy of her diaphragm disclosed paradoxical motion of both hemidiaphragms during inspiration, consistent with bilateral hemidiaphragmatic paralysis. Parsonage-Turner syndrome was diagnosed. The dose of glucocorticoids was tapered. Follow-up of the patient by telephone contact in March 1994 (9 months after her initial examination at our clinic) revealed that the dyspnea was still severe.