Serum angiotensin-converting enzyme activity. Its use in the evaluation and management of hypercalcemia associated with sarcoidosis.

Serum angiotensin-converting enzyme (SACE) was measured in 14 patients (eight women and six men) with sarcoidosis and hypercalcemia. Thirteen patients were treated with prednisone, and 12 achieved normal or nearly normal serum calcium values. Two patients had coexistent hyperparathyroidism. Seven of eight patients with serial SACE measurements exhibited parallel falls in SACE and serum calcium levels. Eleven patients were successfully treated with alternate-day prednisone regimens. The data suggest that serial SACE measurements are useful in the evaluation and management of sarcoidosis with hypercalcemia. In patients with sarcoidosis, the reduction of SACE levels during glucocorticoid treatment may be due to a suppression of granuloma formation. Concomitant falls in serum calcium level suggest an important role of the granuloma or its cellular precursors in vitamin D metabolism.

Two-dimensional echocardiographic findings in systemic sarcoidosis.

The records of 88 patients with systemic sarcoidosis who underwent 2-dimensional echocardiography were reviewed to define the typical echocardiographic abnormalities in patients with clinical evidence of cardiac involvement. Twelve patients (14%) had echocardiographic evidence of left ventricular systolic dysfunction attributed to cardiac sarcoidosis (segmental hypokinesis in 8 patients and global hypokinesis in 4 patients). A high incidence of congestive heart failure (9 of 12) and conduction system disease (7 of 12) was characteristic of these patients. The remaining 76 patients had normal echocardiograms or abnormalities attributed to nonsarcoid sources. In 8 (11%) of these 76 patients, there were significant clinically unexplained conduction abnormalities likely related to sarcoidosis.

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.

Non-Hodgkin's lymphoma associated with hypercalcemia and increased activity of serum angiotensin-converting enzyme.

We describe two patients with diffuse non-Hodgkin's lymphoma, hypercalcemia, and increased activity of serum angiotensin-converting enzyme. A mechanism similar to that operative in sarcoidosis is speculated to have caused the hypercalcemia. A lymphokine elaborated by the malignant lymphoma may cause activated macrophages to produce 1,25-dihydroxyvitamin D3.

55 degrees oblique hilar tomography.

Fifty-five-degree oblique hilar tomography is an accurate and simple means of evaluating hilar anatomy and pathology. It is of most value in proving the hilum to be normal in cases in which plain chest roentgenograms suggest a hilar lesion. It is accurate in differentiating hilar adenopathy from hilar masses and in both of these it is helpful in determining the extent and bilaterality of the disease process. Unfortunately, granulomatous infiltrates within the hilum cannot be differentiated from tumor. The procedure is of limited value in the presence of diffuse perihilar pulmonary fibrosis, and at this time caution must be advised in the interpretation of small, unilateral, ill-defined hilar densities as tumors.

Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis.

We reviewed the epidemiologic, laboratory, roentgenographic, pulmonary function, and survival data from 28 patients who had a histologic diagnosis of lymphomatoid granulomatosis (LG) with involvement of the lungs. The mean age at the time of diagnosis was 51 years, and the male-to-female ratio was 3:2. Ten patients had other underlying diseases before LG was diagnosed. The most prominent symptoms were cough, dyspnea, fever, and rash, which were usually present for several months before diagnosis of LG. Multiple nodules were detected on a chest roentgenogram in 68% of the patients. Immunoglobulin concentrations were abnormal in 8 of 12 patients studied. Although bronchoscopy established the diagnosis in approximately a third of the patients who underwent this procedure, open-lung biopsy was uniformly diagnostic. The median survival was 72 months, with follow-up through 12 years. In 11 patients, the original diagnosis of LG was eventually changed to lymphoma. In five of these patients, the change in diagnosis was based on immunohistologic data obtained shortly after LG was discovered. Lymphoma diagnosed in this way was associated with a better prognosis than lymphoma diagnosed on the basis of conventional histopathologic findings. In three patients, solid tumors eventually developed. The diversity of clinical outcomes and frequent revisions of the diagnosis led us to consider the possibility that LG may also represent a histopathologic finding that occurs transiently in several disease processes.

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.

Wegener's granulomatosis: observations on treatment with antimicrobial agents.

Twelve patients with Wegener's granulomatosis were treated with antimicrobial agents, chiefly trimethoprim-sulfamethoxazole. The clinical course improved in 11 of the 12 patients who received this treatment. The success of antimicrobial treatment suggests the possibility of a microbial infection as the inciting cause of Wegener's granulomatosis in some patients. Alternatively, these agents--in particular, trimethoprim-sulfamethoxazole--may possess immunosuppressant activity.

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.

Polymorphic reticulosis, lymphomatoid granulomatosis. Two diseases or one?

Clinical and pathologic data on 40 patients (31 men, 9 women) with polymorphic reticulosis are presented. The disease may involve the upper respiratory tract, notably the nose, paranasal sinuses, nasopharynx, or palate, as well as the lung, skin, gastrointestinal tract, and central nervous system. Polymorphic reticulosis is identical pathologically to lymphomatoid granulomatosis. Localized disease, particularly that in the upper airway, responds well to radiation therapy. Corticosteroids and cytotoxic agents appear to be ineffective with multisite involvement.

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.

Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases.

The clinical and morphologic findings of allergic granulomatosis and angiitis of Churg and Strauss in 21 men and 9 women were reviewed. The classic features are those of systemic vasculitis in a setting of bronchial asthma and eosinophilia. Pathologically there is necrotizing vasculitis of small arteries and veins with extravascular granulomas, and infiltration of vessels and perivascular tissues with eosinophilia. These features differentiate it from poly-arteritis nodosa. The lungs, peripheral nerves, and skin are most frequently involved. Renal failure was encountered in only one patient in this series. Shortness of the interval from onset of asthma to appearance of vasculitis is an unfavorable prognostic sign. Corticosteroids seem to influence long-term survival favorably.

Wegener's granulomatosis associated with vasculitis of the temporal artery: report of five cases.

Between January 1973 and October 1991 at the Mayo Clinic, 5 of 345 patients with Wegener's granulomatosis initially had features suggestive of giant cell arteritis and subsequently were found to have biopsy-proven vasculitis of the temporal artery. All five patients were older than 60 years of age and had jaw claudication, sudden loss of vision, severe headache with or without diplopia, or polymyalgia rheumatica at the time of initial examination. The erythrocyte sedimentation rate was high at the time of onset of symptoms in four patients (and unavailable in one patient). A temporal artery biopsy specimen revealed giant cell arteritis in one patient and non-giant cell arteritis in four patients. All five patients subsequently had pulmonary and renal lesions characteristic of Wegener's granulomatosis, with typical histopathologic features on biopsy or positive cytoplasmic staining antineutrophil cytoplasmic antibodies. Thus, overlapping features of giant cell arteritis and Wegener's granulomatosis do occur in some patients.

The predictive value of serum angiotensin-converting enzyme activity in the differential diagnosis of hypercalcemia.

Serum angiotensin-converting enzyme (SACE) activity is usually elevated in sarcoidosis, and this raises the possibility that SACE may be a useful diagnostic tool in distinguishing sarcoidosis from other hypercalcemic disorders. We therefore measured SACE in a large number of patients with various granulomatous, metabolic, and hypercalcemic disorders to determine its predictive value. We found elevated SACE activity in 4 of 35 surgically proven cases of primary hyperparathyroidism and in 3 of 13 patients with oncogenic hypercalcemia. In six patients with sarcoidosis and hypercalcemia, SACE activity was elevated; corticosteroid therapy lowered both the serum calcium and SACE levels to normal. We conclude that SACE activity is not a specific test for the differential diagnosis of hypercalcemia but that it remains useful as a chemical marker of successful treatment of sarcoidosis.

Respiratory vasculitis.

Respiratory vasculitis is characterized by granulomatous changes pathologically. Both upper and lower respiratory tracts may be involved. It is convenient to separate three entities: (1) Wegener's granulomatosis, (2) allergic granulomatosis and angiitis, or Churg-Strauss syndrome, and (3) polymorphic reticulosis/lymphomatoid granulomatosis complex. Churg-Strauss syndrome responds well to glucocorticoids. Cytotoxic drugs appear necessary for ultimate control of Wegener's granulomatosis. Radiation therapy is effective in controlling polymorphic reticulosis/lymphomatoid granulomatosis when it is localized to one site. Evidence suggests that polymorphic reticulosis/lymphomatoid granulomatosis may be closely related to lymphoproliferative disorders.

Benign lymphocytic angiitis and granulomatosis: experience with three cases.

Of three patients with lung-biopsy-proven benign lymphocytic angiitis and granulomatosis, two experienced complete resolution of their disease from therapy with chlorambucil and one underwent spontaneous remission with no drug therapy after lung biopsy and removal of a benign spindle cell thymoma. Clinically, it is difficult to determine whether benign lymphocytic angiitis is a low-grade (prelymphomatous) lymphoma or a vasculitis. Its position in this spectrum of diseases is uncertain. Nonetheless, benign lymphocytic angiitis and granulomatosis corresponding to a low-grade angiocentric immunoproliferative lesion is a clinicopathologically useful concept.

Role of testing for anticytoplasmic autoantibodies in the differential diagnosis of scleritis and orbital pseudotumor.

Wegener's granulomatosis is a multisystem disease often with protean manifestations. Eye signs and symptoms can be prominent and may be the patient's initial complaint. For a definitive diagnosis of Wegener's granulomatosis, a tissue biopsy specimen must show vasculitis and necrotizing granuloma. The presence of anticytoplasmic autoantibodies in the serum of patients has been found to be highly specific for Wegener's granulomatosis and can considerably facilitate early diagnosis and be used to monitor disease activity. In two illustrative cases, the utility of this laboratory test in the differential diagnosis of scleritis and orbital pseudotumor is demonstrated.

Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener's granulomatosis.

Sixty-five patients with biopsy-proven Wegener's granulomatosis (WG), 54 with systemic vasculitis, 22 with relapsing polychondritis, 20 with sarcoidosis, 20 with malignant pulmonary lesions, and 15 with other conditions underwent determination of anticytoplasmic autoantibodies (ACPA) by the indirect immunofluorescence technique on neutrophil cytospin preparations to assess the specificity of ACPA for WG, their sensitivity in relationship to the extent and activity of the disease, and their value for follow-up of WG. Of these 65 patients with WG, 38 were ACPA positive. Two patients in the vasculitis group, best categorized as having microscopic polyarteritis, were ACPA positive. We obtained 125 serum samples from the 65 patients with WG and assigned them to one of two categories (limited or generalized), based on the extent of disease. Each of these categories was then subdivided into "active" or "in remission." Median ACPA titers were significantly different between active disease and remission in each category, as well as between active limited and active generalized disease. All patients whose disease changed from active to in remission had reductions in ACPA titer levels; those who experienced flares had titer increases. Patients with intercurrent illnesses or complications of treatment, mimicking WG flares, did not have titer increases. We conclude that ACPA determined by the indirect immunofluorescence technique is highly specific for WG. The sensitivity is dependent on the extent and activity of WG, and serial titer determinations are valuable in monitoring disease activity.

Wegener's granulomatosis. Anatomic correlates, a proposed classification.

Based on a 10-year experience with 50 patients who had Wegener's granulomatosis, a new classification is proposed based on anatomic site of involvement: upper airway or ear, nose, and throat (designated E), lung (L), and kidney (K). All combinations of ELK were seen. The system is offered as a unifying concept to embrace the terms midline granuloma, generalized or classic Wegener's granulomatosis, and limited Wegener's granulomatosis. Fourteen patients have died despite the use of corticosteroids and immunosuppressant therapy. Thirteen patients with renal involvement have survived for periods as long as 114 months; all were taking immunosuppressive agents.

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.