Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Churg-Strauss syndrome (CSS) is the least common of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, which also include microscopic polyangiitis and granulomatosis with polyangiitis (Wegener's). CSS has been recently renamed as eosinophilic granulomatosis with polyangiitis, EGPA (Churg-Strauss) [1]. Everlasting messages from history The first well-described vasculitis in medical history was periarteritis nodosa in 1866, by Kussmaul and Maier, who reported “a hitherto undescribed peculiar disease of the arteries which is accompanied by Bright's disease and a rapid progressive paralysis of themuscles” [2]. Thirteenyears later, Ehrlich discovered the eosinophil leukocyte [3]. The first published case of EGPA was that of Albert Lamb in 1914 [4] under the heading of polyarteritis nodosa. The 26-year-old patient he reported had asthma, eosinophils up to 7.7 G/L, and he died 1month after admission to the hospital. Autopsy disclosed especially myocarditis with periarterial eosinophilia and glomerulonephritis with epithelial crescents. Several reports and short series were further published in the following years, until Churg and Strauss [5] eventually reported a well-studied series of 13 cases with extended autopsy in nine. They emphasized the severity of asthma, and the manifestations of cardiac failure, renal damage, and nervous involvement. The characteristic histopathologic features that they described mainly consisted of necrotizing arteritis, eosinophil infiltration, and granulomatosis with giant cells. Up to the 1950s almost all patients with EGPA died and autopsy studies could thus describe the entity in detail. After corticosteroids had become available, improvement in EGPA was obtained; however it was only in the 1980s that cytotoxic drugs (especially cyclophosphamide and azathioprine) were combined with corticosteroids, and that the prognosis of EGPA eventually improved with long-lasting remission and eventual healing. Diagnostic criteria: a protracted challenge Surprisingly, up to now no consensual diagnostic criteria have been established for EGPA. Lanham et al. [6] reported 16 cases and reviewed the literature based on diagnostic criteria including asthma, eosinophils greater than 1.5 G/L, and systemic vasculitis involving two or more extrapulmonary organs. Masi et al. [7] reported the American College of Rheumatology criteria for the classification of CSS which have often inappropriately been used as diagnostic criteria. This was quite inadequate, as for example a patient with idiopathic chronic eosinophilic pneumonia with asthma and paranasal sinusitis could fit such criteria and therefore be called CSS. Furthermore, the Chapel Hill nomenclature was convened as a nomenclature and neither as a classification system nor as a diagnostic system [8]. From nomenclature to diagnostic criteria The 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides [1] decided to rename CSS as EGPA (Churg-Strauss), a terminology that reminds the user that EGPA is indeed a vasculitis. In recent years, distinct phenotypes have emerged from the largest series of CSS [9,10] with a vasculitic phenotype (with patients having more frequently ANCA, glomerulonephritis, alveolar hemorrhage, and/or biopsy-proven vasculitis) and a tissular phenotype (with patients having more frequently cardiomyopathy, but no ANCA). Members of the European Respiratory Society CSS-Task Force (listed below as authors) prepared recommendations for the diagnosis of EGPA, including a definition of detailed criteria of vasculitis (or surrogates of vasculitis) in patients with asthma and blood eosinophils greater than 1.5 G/L (box 1). The CSSTask Force further proposed that patients with asthma and blood eosinophils greater than 1.5 G/L without ANCA, vasculitis, or surrogates of vasculitis be called hypereosinophilic asthma with systemic manifestations (HASM), non-vasculitic (box 2). Epidemiology and triggers The prevalence of EGPA in the general population is about 11 to 13 per million inhabitants. There is no sex predominance and the mean age is about 50 years. Drugs, vaccinations, allergic hyposensitization and infectious agents have been reported as possible triggers. More recently, leukotriene-receptor antagonists have been suspected to enhance CSS, however this has not been established. Clinical manifestations Data about EGPA mainly result from a limited number of large series, [9-16]. Fatigue, fever, malaise and weight loss are common initial features. Pulmonary manifestations Asthma is present in almost all patients (it may occasionally be replaced by severe cough or cough-variant asthma). It usually precedes vasculitis for several years, and is often associated with rhinitis, nasal polyposis, or sinusitis. An increase in blood eosinophils is common for months or years before vasculitis develops. High resolution computed tomography (HRCT) features demonstrate pulmonary opacities in a majority of patients. These mainly consist of alveolar opacities (ground-glass attenuation, consolidation), or airway opacities (centrilobular nodules, V- or Y-shaped branching opacities, bronchial wall thickening) due to bronchial and bronchiolar eosinophilic involvement. Alveolar hemorrhage blood is very rare, manifesting as hemoptysis, drop in haemoglobin level, and alveolar opacities at imaging. Bronchoalveolar lavage in alveolar hemorrhage shows a bloody aspirated fluid, and the diagnosis of alveolar hemorrhage should not be made only on the finding of siderophages at Perls staining as these are common in conditions such as chronic heart failure. Pleural effusion when present mainly results from cardiac failure (transudate), however eosinophilic exudates may be present. Cardiac manifestations The cardiac manifestations of CSS mainly consist of myocarditis and pericarditis. Cardiac failure may develop rapidly, with markedly reduced ejection fraction at echocardiography. These may improve very rapidly with corticosteroids, however chronic heart failure may persist as a sequela. Coronary vasculitis is rare and myocardial infarction is unusual. Nervous manifestations Mononeuritis multiplex resulting from vasculitic involvement of the vasa nervorum (mostly affecting the common peroneal nerve) is a characteristic feature of systemic vasculitis. Polyneuropathy and central nervous involvement are uncommon and less characteristic of EGPA. Other manifestations Skin manifestations may consist of vasculitis (vascular palpable purpura especially), or subcutaneous granulomatous nodules. Gastrointestinal manifestations are occasionally severe with hemorrhage or bowel perforation. Abdominal pain, nausea, vomiting, diarrhea may be present. Renal manifestations are uncommon (less than 20% of cases), however crescentic glomerulonephritis (a typical vasculitis feature) may develop with ensuing acute renal failure. All organs may be involved by CSS including the eye, the urinary tract, etc. Diagnosis The diagnosis of EGPA first requires a history of asthma, and the demonstration of a high level of eosinophils in blood cell count (> 1-1.5 G/L). Rarely asthma is not present and replaced by severe cough (cough-variant asthma). Blood eosinophils may drop dramatically after corticosteroid treatment (even within 24 hours), so that blood cell count should always be made before initiation of any corticosteroid treatment (or after stopping corticosteroids if possible). Antineutrophil cytoplasmic autoantibodies (ANCA) are present in about 40% of patients with CSS, consisting usually of perinuclear antibodies on immunofluorescence, and with antimyeloperoxidase (MPO) specificity in most cases. Diagnosis usually relies on the characteristic clinical manifestations and ANCA when present. Confirmation by biopsy is necessary in only a minority of patients; biopsies of skin, nerve, and muscle have the best sensitivity. Treatment and prognosis Whereas almost all patients died within a few months before corticosteroids were available, these have dramatically changed the prognosis. Cytotoxic drugs (especially cyclophosphamide) have further markedly improved the rate of remission. Maintenance therapy mainly relies on azathioprine. Rituximab for obtaining remission and/or preventing relapses might prove to be a major component of EGPA treatment.