Interferon-α Treatment of Four Patients with the Churg-Strauss Syndrome

Case Reports

Patient 1

A 48-year-old man presented with the Churg-Strauss syndrome involving the upper and lower respiratory tract, skin, musculoskeletal system, and heart. He had a blood eosinophil count of 5940 cells/mm³ (Table 1 and Table 2). Unstable angina pectoris originated from angiographically verified coronary angiitis. Initial treatment with daily oral cyclophosphamide and prednisolone led to marked clinical improvement and normalization of the eosinophil count. Subsequent tapering of prednisolone therapy to dosages less than 20 to 30 mg/d consistently resulted in worsening of asthma and myocardial symptoms and increases in the eosinophil count. Treatment was complicated by recurrent purulent airway infections. Cyclophosphamide was therefore replaced by interferon-α, and this change resulted in substantial clinical improvement, normalization of the eosinophil count, and successful tapering of the prednisolone dosage to 5 mg/d (Figure 1). After the patient had received 3 million U of interferon-α three times weekly and 5 mg of prednisolone per day for 7 months, his eosinophil count began to gradually increase. Four months later, the patient had a relapse involving the upper and lower respiratory tract and the heart. Ten million U of interferon-α three times weekly restored clinical remission and a normal eosinophil count. The patient continues to receive stable doses of interferon-α and prednisolone, and no more infections have occurred.

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Figure 1. Patient 1. Patient 2. Patient 3. Patient 4. Time 0 represents the beginning of interferon-α therapy for each patient. The disease extent index is a measure of the number of organ systems involved (range, 0 to 21 points ). IFN-α = interferon-α; MU = million units; PRED = prednisolone. Blood eosinophil counts (triangles), disease extent index scores (circles), and dosages of interferon-α and prednisolone in four patients with the Churg-Strauss syndrome. Top.Upper middle.Lower middle.Bottom.[9]

Patient 2

A 41-year-old woman presented with the Churg-Strauss syndrome involving the upper and lower respiratory tract, skin, peripheral nervous system, musculoskeletal system, and heart. Her blood eosinophil count was 4200 cells/mm³. Significant ST-segment depression responded to high-dose corticosteroid therapy. Intravenous pulse cyclophosphamide (1000 mg every 3 weeks) resulted in clinical remission, normalization of the eosinophil count, and reduction of the patient's prednisolone requirement to 7.5 mg/d. After 10 months, cyclophosphamide was replaced by 22.5 mg of intravenous methotrexate per week. After receiving this treatment for 12 months, the patient had relapse with severe asthma, pleural effusion, eosinophilic pneumonitis, and a blood eosinophil count of 2047 cells/mm³. Methotrexate was replaced by interferon-α, 3 million U three times weekly, and a short course of 40 mg of prednisolone per day. The patient improved temporarily, but the blood eosinophil count increased again and was not curbed by an increase in the interferon-α dosage to 5 million U three times weekly. A subsequent clinical relapse with eosinophilic pleurisy was successfully countered by a further increase of the interferon-α dosage to 7.5 million U three times per week, but a second relapse with eosinophilic pneumonitis occurred when the prednisolone dosage was tapered from 4 to 3 mg/d. Because of influenza-like symptoms, the patient could not tolerate interferon-α 2b therapy at a dosage of 9 million U per day but could tolerate the same dosage of interferon-α 2a. This led to lasting remission and normalization of the eosinophil count.

Patient 3

A 25-year-old woman had the Churg-Strauss syndrome involving the upper and lower respiratory tract, skin, musculoskeletal system, peripheral nervous system, and heart. She had a blood eosinophil count of 5633 cells/mm³. Pericardiocentesis showed an effusion rich in eosinophils, and the ventricular arrhythmia responded to immunosuppression. Treatment with daily oral cyclophosphamide resulted in only partial remission, and the prednisolone dosage could not be tapered to less than 15 mg/d. Repeated purulent airway infections led to worsening of asthma. Alternative treatment with intravenous pulse cyclophosphamide alleviated neither the patient's infectious complications nor her corticosteroid dependence. Interferon-α was substituted for cyclophosphamide, a change that almost completely abolished the infections and stabilized the clinical condition. The prednisolone dosage was tapered uneventfully to 5 mg/d, but further reduction led to a surge in the blood eosinophil count to 1058 cells/mm³ and clinical, pulmonary, and cardiac relapse. This prompted an increase of the interferon-α dosage to 3 million U per day, but intolerable nausea and fatigue necessitated subsequent tapering of the dosage to 4 million U three times per week. This was followed by another relapse. Interferon-α 2a was substituted for interferon-α 2b and was tolerated at a dose sufficient to maintain lasting remission.

Patient 4

A 40-year-old man presented with the Churg-Strauss syndrome with involvement of the upper and lower respiratory tract, musculoskeletal system, and peripheral nervous system. His blood eosinophil count was 5180 cells/mm³. Myocardial biopsy showed perivascular infiltrates with mononuclear cells and eosinophils. Ventricular arrhythmias and a pericardial effusion responded to high-dose corticosteroids. Treatment was initiated with daily oral cyclophosphamide and prednisolone; this led to complete clinical remission and normalization of the eosinophil count. After the patient had received this treatment for 12 months, maintenance therapy with interferon-α and 5 mg of prednisolone per day was instituted. This resulted in lasting remission. The patient remained stable when interferon-α therapy was discontinued 14 months later.

Details of Interferon-α Dosing

Interferon-α 2b (Intron A, Essex Pharma, Munich, Germany) was administered subcutaneously at an initial dosage of 3 million U three times weekly, and this dosage was subsequently increased or decreased according to efficacy and tolerability. If this therapy resulted in complete remission over 12 months, the dosage was tapered; in case of lasting remission under tapered dosages, interferon-α therapy was terminated. Because of intolerance to interferon-α 2b at the appropriate dosages, two patients were switched to interferon-α 2a (Roferon, Roche, Grenzach-Wyhlen, Germany). No patient received allergy immunotherapy or antileukotrienes.

Discussion

Initial reports described the Churg-Strauss syndrome as a granulomatous and vasculitic condition that, in contrast to other vasculitides, is usually highly responsive to corticosteroids [10]. This view was later challenged, and current experience shows that a sizable proportion of patients with the Churg-Strauss syndrome require more aggressive treatment [11-13]. Because of the rarity of this syndrome, such treatment options are being applied on an empirical basis. Many centers use treatment protocols devised for Wegener granulomatosis, specifically, daily oral cyclophosphamide or intravenous pulse cyclophosphamide [12, 14]. The value of cyclophosphamide is limited by its serious toxicity, particularly its detrimental effects on host defenses against infections, its myelotoxic effects, and its oncogenic potential [15, 16]. Treatments other than corticosteroids and cyclophosphamide are definitely needed.

Our observations suggest that interferon-α may meet this need. Our patients had particularly severe cases of the Churg-Strauss syndrome, and all four had cardiac involvement, which is associated with a notoriously poor prognosis [2, 3, 17]. Patients 1, 2, and 3 attained only partial remission with cyclophosphamide or methotrexate treatment and required substantial doses of corticosteroids to maintain partial remission. Patients 1 and 3 had repeated respiratory tract infections, which are common in patients with the Churg-Strauss syndrome, especially those receiving immunosuppressive treatment. By contrast, during interferon-α treatment, no infections were seen and the patients' corticosteroid requirements decreased substantially. Patients 1, 2, and 3 benefited from interferon-α at dosages of 30 to 63 million U per week, and their course indicates a dose-dependent effect of interferon-α on both the clinical manifestations of disease and the blood eosinophil count (Figure 1). The clinical course of patient 4, who has remained in remission while receiving interferon-α plus low-dose prednisolone, does not show whether this patient actually benefited from interferon-α. Of note, patients 2 and 3 had poor tolerance for interferon-α 2b but were successfully switched to interferon-α 2a.

Our observations corroborate previous reports by showing that the blood eosinophil count is a sensitive indicator of disease activity in the Churg-Strauss syndrome [1]. Indeed, in our patients, clinical relapse was always preceded by an increase in the eosinophil count and clinical improvement was accompanied by a decrease in this count. The obvious similarities, in this respect, between the Churg-Strauss syndrome and the idiopathic hypereosinophilic syndrome suggest that the suppression of eosinophils is an important mechanism by which interferon-α exerts its beneficial effect in these two conditions. In accord with this, in vitro studies have shown that interferon-α suppresses the proliferation of eosinophil colony-forming bone marrow cells and inhibits the release of eosinophil granule constituents from mature eosinophils. These constituents are thought to be important mediators of tissue injury in the eosinophilic disorders [7]. A receptor for interferon-α was recently identified on eosinophils, suggesting that eosinophils are under the direct control of interferon-α [18].

In conclusion, these preliminary observations suggest that high doses of interferon-α can effectively treat the Churg-Strauss syndrome, particularly in patients who have incomplete response to cyclophosphamide or have infectious complications. Although it is impossible to predict from these observations whether interferon-α can also be used to induce remission in patients who are resistant to corticosteroids, the role of interferon-α in maintenance therapy merits more detailed examination.