Churg–Strauss syndrome associated with elevated levels of serum interleukin-5 and T cell receptor-Cβ gene rearrangement

A 58-year-old woman was diagnosed with Churg–Strauss syndrome (CSS) based on the symptoms of bronchial asthma, eosinophilia, mononeuritis multiplex and histological examination of the right sural nerve. Prior to treatment, the serum interleukin (IL)-5 level was high, and rearrangement of the T cell receptor (TCR) gene was identified. This is the first report of TCR gene rearrangement in a patient with CSS. The expanded T cell clone may be responsible for the overproduction of IL-5. Further studies are warranted to disclose a prevalence of TCR gene rearrangement in CSS patients and its pathophysiological roles in the development of this disease.     

The lung in systemic vasculitis

Pulmonary vasculitis is usually caused by one of three disorders: (1) Wegener's granulomatosis (WG); (2) Churg-Strauss syndrome (CSS), or allergic angiitis and granulomatosis; or (3) a nonspecific small vessel systemic necrotizing vasculitis (SNV), or microscopic polyarteritis. WG, the most common cause of lung vasculitis, has features of a granulomatous vasculitis of the upper airway and lung and widespread small vessel vasculitis involving the kidneys and other organs. The features of pulmonary WG overlap with those of malignancy and infectious granulomatous lung disease; accurate diagnosis generally requires open lung biopsy. CSS is defined by the triad of asthma, eosinophilia, and systemic vasculitis. Easily accessible tissues should be biopsied, but the clinical features are so distinctive that tissue biopsy is not invariably required for diagnosis. CSS must be differentiated from other diseases that cause pulmonary infiltrates with eosinophilia, including infections. Nonspecific SNV causes diffuse alveolar hemorrhage due to pulmonary capillaritis. Concomitant segmental necrotizing glomerulonephritis is almost always present. Diagnosis is made by renal biopsy, compatible extrarenal features, exclusion of nonimmune causes of lung hemorrhage, and exclusion of WG to the extent possible.     

ANCA-assoziierte Vaskulitiden (AAV)

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a rare systemic disease that affects small and medium-sized arteries and is potentially life threatening. AAV comprises Wegner’s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). These diseases are closely associated with antineutrophil cytoplasmic antibodies (ANCA) and are also characterized by a pauci-immune histology. The diagnosis is based on history, current clinical presentation and technical analysis. However, histology remains the gold standard of diagnostics. Cardiovascular manifestations are the main reason for an unfavourable outcome in CSS, although any major organ involvement might be potentially life threatening. Therapy should be guided by the disease stage and activity. The standard therapy remains the application of glucocorticoids and cyclophosphamide.     

Churg–Strauss syndrome associated with leukotriene receptor antagonists (LTRA)

Churg–Strauss syndrome (CSS) is a rare vasculitic disorder that generally occurs in patients with bronchial asthma. CSS is being increasingly recognized in asthmatic patients treated with leukotriene receptor antagonists. However, the nature of this relationship remains to be elucidated. The present report describes three asthmatic patients who developed clinical manifestations highly suggestive of CSS, although one patient lacked the presence of eosinophilia. The patient, however, exhibited biopsy-proven cutaneous necrotizing vasculitis, which improved after withdrawal of montelukast. The second patient presented with systemic constitutional signs including fever, malaise, arthralgias, clinical jaundice, peripheral blood eosinophilia, and biopsy-proven eosinophilic hepatitis. The third patient also had circulating eosinophilia, scleritis, and arthritis. All patients improved after discontinuation of the leukotriene receptor antagonist (montelukast).     

Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy.

Churg-Strauss syndrome (CSS) is characterized by the presence of asthma, eosinophilia, and small-vessel vasculitis with granuloma. It is a distinct entity, as determined from all classifications of systemic vasculitis. The poor prognostic factors in CSS are renal insufficiency, cardiomyopathy, severe gastrointestinal (GI) tract, and central nervous systems (CNS) involvement. The initial management of CSS should include a high dose of a corticosteroid: prednisone at 1 mg/kg/day or its equivalent for methylprednisolone with tapering over 6 months. In patients with severe or rapidly progressing CSS, the administration of methylprednisolone pulse at 1 g/body/day for 3 days is recommended. When corticosteroid therapy does not induce remission, or when patients have poor prognostic factors, immunosuppressive cytotoxic therapy is indicated. However, some patients with severe CSS often show resistance to conventional treatment. We think that IVIG therapy is a hopeful candidate for second-line treatment for CSS patients, particularly in the case of neuropathy and/or cardiomyopathy, which are resistant to conventional therapy. However, there is not much evidence supporting the effectiveness of IVIG in CSS, and the mechanisms underlying the action of IVIG remain unclear. Now we are performing clinical trials of IVIG therapy for CSS patients who are resistant to conventional treatment, through a nationwide double-blinded placebo-controlled study in Japan.     

CCL17/thymus and activation–related chemokine in Churg‐Strauss syndrome

Objective

Churg‐Strauss syndrome (CSS) is a Th2‐mediated systemic vasculitis characterized by eosinophilic infiltration, blood eosinophilia, and high IgE levels. CCL17/thymus and activation–regulated chemokine (TARC) is a chemokine responsible for the recruitment of Th2 cells. This study was undertaken to explore a possible role of CCL17/TARC in CSS.

Methods

CCL17/TARC levels in serum from patients with active or inactive CSS, hypereosinophilic syndrome, systemic small‐vessel vasculitis other than CSS, other types of eosinophilia, and healthy controls were determined by enzyme‐linked immunosorbent assay. Biopsy samples of affected tissue from CSS patients were examined by immunohistochemical staining for Th2 infiltration and CCL17/TARC expression.

Results

Serum CCL17/TARC levels were significantly elevated in CSS patients with active disease (mean ± SEM 1,122.0 ± 422.7 pg/ml) compared with controls (220.6 ± 27.9 pg/ml) and patients with inactive disease (388.9 ± 72.6 pg/ml) (P < 0.001 and P < 0.05, respectively). These levels correlated with the clinical disease course of CSS and with absolute eosinophil counts as well as IgE levels. Infiltrating Th2 cells in active CSS lesions were evidenced by CD294 staining. CCL17/TARC in the affected tissue of CSS patients was readily identified by immunohistochemical analysis. Elevated CCL17/TARC levels were also noted in patients with hypereosinophilic syndrome (794.5 ± 294.8 pg/ml) and other disorders associated with eosinophilia (1,096.0 ± 345.3 pg/ml) (both P < 0.005 versus controls).

Conclusion

CCL17/TARC may contribute to CSS pathogenesis by recruitment of Th2 cells into affected tissue. Serum CCL17/TARC levels reflect disease activity, and further studies to validate its use as an activity marker in CSS are warranted.

     

Inhibition of atherogenesis in LDLR knockout mice by systemic delivery of adeno-associated virus type 2-hIL-10

Atherosclerosis is an inflammatory disease of the arteries. Interleukin-10 (IL-10) is known to be an anti-inflammatory cytokine which might be useful for counteracting the development of atherosclerosis. As long-term systemic cytokine delivery is prohibitively expensive, gene therapy might be a suitable approach. To test this idea, low-density lipoprotein receptor (LDLR) knockout mice were injected with recombinant adeno-associated virus type 2 (AAV)/interleukin-10 virus or AAV/granulocyte macrophage-colony stimulating factor (GM-CSF) virus and then put on a high-cholesterol diet. Upon harvesting the animals at 18 weeks, elevated blood lipids could be documented and AAV/IL-10 and AAV/GM-CSF DNA and mRNA could be found in various mouse organs. The mice receiving the AAV/IL-10 virus had significantly lower levels of atherogenesis (Sudan IV-staining and histology) than the untreated or the AAV/GM-CSF-treated animals, dropping from 53% to 17% (p < 0.05). The aortas of the AAV/IL-10-treated animals displayed higher IL-10 expression and lower CD68 and nitrotyrosine expression. These data are similar to those of Yoshioka et al. [Yoshioka, T, Okada, T, Maeda, Y, et al. Adeno-associatedvirus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther 2004;11:1772-9] in which AAV/IL-10 was delivered into the tibial muscle of ApoE-deficient mice, instead of tail vein injection used here. These data indicate that systemic AAV/IL-10 gene delivery, with resulting inhibition of inflammation and oxidative stress, was able to limit atherogenesis, and suggest that this approach is worthy of further study.     

Circulating cytokines and soluble CD23, CD26 and CD30 in ANCA-associated vasculitides

OBJECTIVE: To assess circulating immunoregulatory cytokines and soluble surface markers of T and B cell activation in the plasma of patients with Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA) during active and inactive disease, in order to establish their value in discriminating between disease entities and as markers of disease activity. METHODS: Plasma levels of IL-4, IL-5, IL-10, IL-12, IL-13, IFN-gamma and soluble CD23, CD26 and CD30 were determined by enzyme-linked immunosorbent assay in patients with WG (n = 21), CSS (n = 19) and MPA (n = 14) during active disease and remission. RESULTS: Concerning cytokines, no differences were observed for IFN-gamma, IL-4, IL-5 and IL-13. Plasma levels of IL-12 were decreased in all subgroups of patients. On the contrary, IL-10 levels were significantly elevated only in patients with CSS. Levels of sCD30 were significantly increased in patients with active generalized WG and CSS, but not in those with MPA and localized WG, correlating with the disease extent and activity. sCD26 levels were markedly decreased in patients with generalized WG, CSS and MPA and increased towards remission. sCD23 levels were slightly, but not significantly increased in CSS and generalized WG. CONCLUSION: Regarding the investigated immunoregulatory cytokines (Th1/Th2 type), only the measurement of plasma levels of IL-10 discriminated CSS from WG and MPA. The reported data could indicate a similar status of T cell activation in generalized WG and CSS, and possibly a shift in peripheral immunity towards a more humoral dominated immune response. The differences observed between patients with the localized and generalized forms of WG seem to reflect the clinically known biphasic course of this disease.     

Evaluation of the Sørensen diagnostic criteria in the classification of systemic vasculitis

OBJECTIVES: To evaluate the use of the diagnostic criteria for Wegener's granulomatosis (WG) and microscopic polyangiitis (mPA) proposed by S?rensen et al. in the classification of primary systemic vasculitis (PSV). METHODS: We applied to our cohort of PSV patients the American College of Rheumatology (ACR) criteria for WG, Churg-Strauss syndrome (CSS) and polyarteritis nodosa (PAN), the Chapel Hill Consensus Conference (CHCC) definitions for WG, mPA and CSS, the Hammersmith criteria for CSS and the S?rensen criteria for WG and mPA. RESULTS: Ninety-nine PSV cases were identified. Fifty-six fulfilled criteria for WG (ACR), 60 for PAN (ACR) and 15 for CSS (ACR). Four fulfilled the Hammersmith criteria for CSS. Thirty-nine were defined as mPA (CHCC). Fifty-three patients fulfilled the S?rensen criteria for WG and three for mPA. Five of six patients classified as WG (ACR) who did not meet the S?rensen criteria were excluded by eosinophilia. Six patients who did not fulfil WG (ACR) met the S?rensen criteria for WG. CONCLUSION: The classification of systemic vasculitis is complicated and many cases fulfil more than one set of criteria. The S?rensen criteria for WG is limited by its exclusion of eosinophilia despite reports of an association. We recommend that tissue eosinophilia or peripheral eosinophilia of <1.5x10(9)/l should not exclude a diagnosis of WG. With this modification, the S?rensen criteria for WG may be a useful method of classification, especially in confirming the classification of WG in patients who fulfil both WG (ACR) and mPA (CHCC). Few patients fulfilled the S?rensen criteria for mPA which suggests that they are not of value in classification.     

Churg-Strauss syndrome revealed by granulomatous acute pericarditis: two case reports and a review of the literature

BACKGROUND: Churg-Strauss syndrome (CSS) is a necrotizing systemic vasculitis with extravascular granulomas and eosinophilic infiltrates of small vessels. CSS is usually revealed by nonspecific signs of necrotizing vasculitis in a context of late-onset asthma and blood eosinophilia. It is considered a systemic vasculitis with the highest prevalence of cardiac involvement and can lead to rapid-onset heart failure due to specific cardiomyopathy. Pericardial effusion may also occur during CSS and is usually well tolerated. OBJECTIVE: The objective of these case reports was to indicate that CSS may present as tamponade, with or without other visceral involvement. METHODS: Among CSS patients treated during the past 10 years at 2 French university hospitals, we have identified and described 2 cases revealed by tamponade with pericardial biopsy-proven granulomatous vasculitis. We have also reviewed the international medical literature in PubMed on cardiac involvement in CSS. RESULTS: The first case report describes a 66-year-old man who had an isolated cardiac tamponade with both inflammatory syndrome and eosinophilia. Long-term remission was obtained with corticosteroids. The second case report describes a 46-year-old woman whose CSS presented with tamponade and associated central nervous system and myocardial involvement. Remission was obtained with corticosteroids and cyclophosphamide. In both cases, CSS was assessed by histological analysis of a pericardial sample. CONCLUSIONS: CSS may present as isolated cardiac tamponade. Whereas pericarditis with myocardial injury warrants immunosuppressive therapy, isolated pericarditis without other visceral involvement of poor prognosis only requires corticosteroid therapy.     

Interleukin-5 mRNA in three T-cell lymphomas with eosinophilia

The objective of this controlled pilot study was to determine if mRNA coding for interleukin-5 (IL-5), a cytokine that promotes eosinophil differentiation, growth, and migration, could be detected in three T-cell lymphomas that were infiltrated extensively by eosinophils. To detect mRNA coding for IL-5, we performed an RNA polymerase chain reaction on mRNA extracted from three T-cell lymphomas with eosinophilia and from 29 positive and negative validation controls. Using this procedure, we detected a 293-base pair, IL-5-specific amplification product in the three cases of T-cell lymphoma with eosinophilia and in 11 of 12 positive validation controls, including 10 cases of Hodgkin's disease with eosinophilia. IL-5 mRNA was not detectable in the 17 negative validation controls. This preliminary study suggests that IL-5 mRNA is detectable by polymerase chain reaction in three cases of T-cell lymphoma with eosinophilia. © 1993 Wiley-Liss, Inc.     

Adult T cell leukemia associated with eosinophilia: analysis of eosinophil-stimulating factors produced by leukemic cells.

The mechanism of eosinophilia in a patient with adult T cell leukemia (ATL) was investigated. A 61-year-old woman with ATL presented marked eosinophilia. No parasite infections or allergic diseases were found in this patient. The number of eosinophils fluctuated in parallel with that of ATL cells during her clinical course. The patient's serum and the culture supernatant of ATL cells showed eosinophil colony-stimulating activity. Northern blot analysis of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5), which are known eosinophil CSFs, showed that only GM-CSF but not IL-3 or IL-5 was expressed in freshly separated and cultured ATL cells. Since neutrophil and monocyte numbers did not increase, it is suggested that GM-CSF and unknown cytokines other than IL-3 and IL-5 produced by ATL cells synergistically stimulated eosinophil precursors in the present case.     

The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis)

Criteria for the classification of Churg-Strauss syndrome (CSS) were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. For the traditional format classification, 6 criteria were selected: asthma, eosinophilia greater than 10% on differential white blood cell count, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on roentgenography, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The presence of 4 or more of these 6 criteria yielded a sensitivity of 85% and a specificity of 99.7%. A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. Advantages of the traditional format compared with the classification tree format, when applied to patients with systemic vasculitis, and their comparison with earlier work on CSS are discussed.     

Acute painless monocular visual loss due to central retinal artery occlusion in a patient with Churg–Strauss vasculitis

Ocular involvement in Churg–Strauss syndrome (CSS) is infrequent. We describe a case of a 50-year-old woman, with blood eosinophilia, involvement of the respiratory tract, skin, and peripheral nervous system, fulfilling the American College of Rheumatology criteria for CSS, who presented with left foot drop followed by left acute painless visual loss. Central retinal artery occlusion was diagnosed by fundoscopic findings (retinal whitening with a cherry-red spot). CSS was confirmed by sural nerve biopsy. Despite treatment with high-dose corticosteroids, cyclophosphamide, and anticoagulant therapy, visual acuity was not substantially improved. Acute blindness in CSS has been rarely described. Even more rarely, central retinal artery occlusion has been found to be the underlying cause of this infrequent clinical manifestation in CSS.     

Allergic angiitis with granulomatosis: Churg-Strauss syndrome. Retrospective study of 16 cases

Sixteen patients with Churg-Strauss syndrome (CSS), a disorder characterized by hypereosinophilia and systemic vasculities which complicate preexisting asthma, were analyzed. The mean duration of asthma before CSS was 8 years; peripheral blood eosinophilia was always greater than 1,900/microliters and exceeded 5,000/microliters in 14 cases. The clinical manifestations were the following: 16 in generally poor condition with fever; 12 peripheral neuropathies; 11 cutaneous lesions; 9 pericardial or myocardial involvement; 9 digestive disorders; 9 muscular or articular diseases; 5 renal involvement, all associated with the vasculitis; 7 upper respiratory tract disorders. Chest radiographs showed pleuropulmonary or cardiac anomalies in 11 patients. The diagnosis was confirmed histologically in 11 cases, however, no clinical, biological or evolutive differences were observed between these patients and those with negative biopsies (5). Follow-up for 6.35 +/- 5.55 years was characterized by relapses always preceded by increased eosinophilia. Fourteen patients were successfully treated with corticosteroids, associated with cyclophosphamide in 7 of them. Five-year survival was 87%. Four deaths occurred, all CSS-associated, two because of a poorly adapted therapeutic regimen. The need for rapid and effective treatment must be stressed. The diagnosis can be made based on clinical manifestations alone before histological confirmation can be obtained.     

Eosinophil active cytokines and surface analysis of eosinophils in Churg-Strauss syndrome.

There are few reports regarding the measurement of cytokines and surface analysis of eosinophils in Churg-Strauss syndrome (CSS). To examine the pathophysiology of CSS, concentrations of cytokines in serum and bronchoalveolar lavage fluid (BALF), and surface antigens on peripheral blood eosinophils were analyzed in five patients with CSS. Concentrations of cytokines (interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), interleukin-5 (IL-5) and granulocyte/macrophage colony stimulating factor (GM-CSF) were measured using ELISA. Surface antigens on eosinophils in peripheral blood were analyzed using flow cytometry. A concentration of interleukin-5 (IL-5) and TNF-alpha in serum was detected in five cases; however IL-1 beta, GM-CSF, and IL-3 were detected in 3 of 5, 2 of 5, and 1 of 5 patients, respectively. In BALF, TNF-alpha and IL-5 were detected in 2 of 3 and 1 of 3 patients, respectively; however, neither IL-1 beta, GM-CSF, nor IL-3 was detected in any. Newly expressed surface antigens such as CD25, CD4, and CD69 were observed on peripheral blood eosinophils in five cases. CD54 and HLA-DR were expressed in 4 of 5 and 3 of 5 patients, respectively. Eosinophils in peripheral blood are activated to various degrees, possibly depending on cytokine stimulation. This eosinophil activation may be related to the clinical stage of CSS.     

Rare manifestations of Churg–Strauss syndrome: coronary artery vasospasm, temporal artery vasculitis, and reversible monocular blindness—a case report

Churg–Strauss syndrome (CSS) is a rare illness with clinical findings characterized by asthma, eosinophilia, and vasculitis affecting medium and small-sized arteries and veins in a variety of organs. Involvement of the temporal arteries by non-giant cell eosinophilic vasculitis in CSS is quite rare and has only been published as isolated case reports or small patient series. Myocardial infarction due to coronary artery vasospasm is an unusual manifestation of CSS. We describe a case of a 39-year-old woman who had two myocardial infarctions due to severe coronary artery vasospasm and was diagnosed with CSS based on a temporal artery biopsy. During the course of her treatment, she also had another rare manifestation of CSS, monocular blindness reversible with immunosuppressive therapy.