Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

INTRODUCTION — Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated EGPA, which was previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia [1-9]. EGPA is classified as a vasculitis of the small and medium sized arteries, although the vasculitis is often not apparent in the initial phases of the disease.

The most involved organ is the lung, followed by the skin. EGPA, however, can affect any organ system, including the cardiovascular, gastrointestinal, renal, and central nervous systems. Vasculitis of extrapulmonary organs is largely responsible for the morbidity and mortality associated with EGPA.

The epidemiology, pathogenesis, and pathology of EGPA will be reviewed here. The clinical features, diagnosis, treatment and prognosis of this disorder, as well as the approach to patients with vasculitis and/or eosinophilia are discussed separately. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis" and "Overview of and approach to the vasculitides in adults" and "Approach to the patient with unexplained eosinophilia".)

EPIDEMIOLOGY — The epidemiology of EGPA remains unclear because of the uncertainties related to diagnosis [10]. Approximately 10 percent of patients with a major form of vasculitis are recognized to have EGPA. Among the three anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (EGPA, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis), EGPA is least common [5]. Prevalence in Europe ranges from 10.7 to 14/million. In the United States, the prevalence is approximately 18/million. The highest prevalence reported is from Australia, at 22.3 cases/million [11]. (See "Overview of and approach to the vasculitides in adults".)

The mean age at diagnosis of EGPA is 40 years [12]. EGPA is an uncommon cause of vasculitis in people older than 65 years, accounting for 5 percent of histologically proven vasculitis among 38 older adult patients with various systemic forms of angiitis [13,14]. EGPA is also rare in children and adolescents; when it does occur in this age group, it appears to follow a more aggressive course with prominent pulmonary and cardiovascular manifestations [15-17].

EGPA does not exhibit sex predominance [12,18].

A cross-sectional nationwide survey in Japan estimated the prevalence of EGPA at 17.8/1,000,000 [19]. The mean age at onset was 55 ± 14 years (± SD). Among the patients tested for myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (p-ANCA), 50 percent were positive; however, only 2.5 percent were positive for proteinase3 (PR3) c-ANCA. There was female predominance (2:1).

PATHOGENESIS

Abnormal immune function — The exact pathogenesis of EGPA is unknown. Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60 percent of patients, and EGPA is classified among the ANCA-positive vasculitides [12,19-22]. However, it is not known whether ANCAs have a pathogenic role in EGPA or whether they just reflect one end of the spectrum of EGPA manifestations. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Antineutrophil cytoplasmic antibodies' and "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)

In addition, EGPA is characterized by several other abnormalities in immune function [23-26]:

●The prominence of allergic features (allergic rhinitis, asthma, and positive skin tests) suggests heightened Th2 immunity [25].

●Pulmonary angiocentric granulomatosis suggests heightened Th1 immunity [26].

●The number of peripheral blood CD4+CD25+ T cells (T regulatory cells) that produce IL-10 were decreased in patients with EGPA compared with asthma or chronic eosinophilic pneumonia and were increased in patients with EGPA in remission [27]. These observations suggest that T regulatory cells may influence which patients with asthma and chronic eosinophilic pneumonia will develop active EGPA.

●Abnormal eosinophil function is likely due to a combination of increased eosinophil recruitment by Th2 cytokines and decreased eosinophil apoptosis [23].

●Altered humoral immunity is suggested by hypergammaglobulinemia, especially IgE, and rheumatoid factor positivity in some patients.

Genetic factors — Genetic factors may also play a role. In a study of 48 patients and 350 healthy controls, both HLA-DRB1*07 and HLA-DRB4 were more prevalent among patients with EGPA and HLA-DRB4 correlated with the number of vasculitic manifestations [28].

A genome wide association study (GWAS) that included 676 patients with EGPA and 6809 healthy controls identified genetic distinctions between ANCA-myeloperoxidase positive (MPO+) and ANCA-negative disease, correlating with different clinical features [21]. Variants in the regions of BCL2L11, LPP, C5orf56-IRF1-IL5, and 10p14 were associated with EGPA, consistent with a polygenic disease and suggesting a role for susceptibility to eosinophilia in EGPA pathogenesis. When comparing MPO+ patients with MPO- patients, the study noted an association with HLA-DQ in MPO+ EGPA that was not present in MPO- EGPA, suggesting two potential subtypes of EGPA: an eosinophilic autoimmune (MPO+) disease and a mucosal barrier dysfunction (MPO-) subtype.

Polymorphisms in the interleukin (IL)-10 gene have been associated with EGPA. In a study of 103 patients with EGPA, genotyping identified three single nucleotide polymorphisms (SNPs) relating to the interleukin (IL)-10 gene [29]. The IL-10 -3575/-1082/-592 TAC haplotype (part of IL 10.2) was strongly associated with EGPA (OR=2.16) and negatively associated with granulomatosis with polyangiitis (GPA). Three-fourths of the patients were ANCA negative. (See "Genetics of asthma".)

ASSOCIATION WITH MEDICATIONS — Several medications have been associated with the appearance of EGPA. In the case of asthma therapies such as leukotriene modifying agents, inhaled glucocorticoids, and omalizumab, it appears that this is more likely an unmasking of underlying disease rather than a causal relationship, as described below.

Leukotriene modifying agents — EGPA has been reported as a rare complication in patients with systemic glucocorticoid-dependent asthma who were treated with a leukotriene modifying agent (LTMA; eg, zafirlukast, montelukast, pranlukast, zileuton), usually in the setting of reduction in the dose of oral glucocorticoids [30-43].

It is believed that LTMAs may unmask underlying EGPA in the following ways [44,45]:

●Glucocorticoid withdrawal is facilitated by LTMA therapy, leading to elaboration of EGPA disease manifestations.

●Patients who have undiagnosed but escalating EGPA are prescribed a LTMA because of worsening symptoms. The LTMA is insufficient to control EGPA and the disease becomes manifest (ie, confounding by indication).

However, it is difficult to completely exclude the possibility that LTMAs play a causal role in the development of EGPA in some patients [30-42,46].

Inhaled glucocorticoids — The onset of clinical evidence of EGPA has also occurred when the addition or increase in inhaled glucocorticoids allowed reduction in the dose of systemic glucocorticoids, which in turn led to an "unmasking" of EGPA symptoms as described above [38].

Omalizumab — EGPA has also been noted in patients receiving omalizumab (a humanized anti-IgE antibody) for treatment of severe asthma [47-49]. The appearance of EGPA symptoms preceded treatment with omalizumab or coincided with tapering of systemic glucocorticoids, suggesting that omalizumab had been added in the setting of escalating EGPA or that it allowed "unmasking" of underlying EGPA. It remains unclear whether or not omalizumab can be used in the treatment of EGPA [50]. (See "Anti-IgE therapy", section on 'Other issues'.)

Cocaine — An unusual EGPA-like vasculitis has been associated with the use of free base cocaine [51]. The diagnosis of EGPA in patients who use cocaine is a complicated issue because both acute and chronic eosinophilic pneumonia are manifestations of cocaine toxicity and antineutrophil cytoplasmic antibodies are detected in the majority of patients with cocaine-induced midline destructive lesions of the nose [52]. (See "Pulmonary complications of cocaine use", section on 'Acute pulmonary toxicity and crack lung' and "Pulmonary complications of cocaine use", section on 'Chronic toxicity'.)

The anti-neutrophil cytoplasmic antibodies (ANCAs) associated with cocaine-induced midline destructive lesions appear to be different from those associated with EGPA. ANCAs from patients with cocaine-induced midline destructive lesions typically recognize human neutrophil elastase as the target antigen, although autoantibodies to proteinase 3 and other serine proteases are also seen [53]. In contrast, ANCAs from patients with EGPA commonly react to myeloperoxidase and not human neutrophil elastase [52]. Sera from patients with granulomatosis with polyangiitis (GPA) typically react with proteinase 3, but not human neutrophil elastase. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Antineutrophil cytoplasmic antibodies'.)

PATHOLOGY

The major histopathologic findings of EGPA from any affected organ includes the following, although they may not all be present (especially in patients who have been partially treated) [54-56]:

●Eosinophilic infiltration

●Prominent and sometimes quite extensive areas of necrosis

●An eosinophilic, giant cell vasculitis, especially of the small arteries and veins

●Interstitial and perivascular necrotizing granulomas (picture 1)

Pathologic findings in different organs include:

●In the lung, asthmatic bronchitis, eosinophilic pneumonia, extravascular granulomas, or vasculitis (affecting arteries, veins, or capillaries) may be seen. In some cases, the inflammatory lesions extend along the pleura and interlobular septa. The granulomas in EGPA typically have a border of palisading histiocytes and multinucleated giant cells surrounding a central necrotic zone consisting of the necrotic eosinophils. The vascular infiltrates are often composed of chronic inflammatory cells, eosinophilic infiltrates, epithelioid histiocytes, multinucleated giant cells and/or neutrophils. Diffuse pulmonary hemorrhage and capillaritis may be seen.

●In the kidney, necrotizing crescentic glomerulonephritis is the most common finding, but eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal segmental glomerulosclerosis are also seen [57,58].

●Endomyocardial biopsies typically reveal eosinophilic infiltration and endomyocarditis, but not vasculitis [59].

●Skin biopsy typically reveals a leukocytoclastic vasculitis with eosinophil infiltration [60]. Palisading granulomas and/or eosinophilic infiltration of dermal nerve fibers may also be noted.

The histopathologic findings may vary with the phase of disease [61,62]. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Phases of disease'.)

●During the prevasculitic phase, tissue infiltration by eosinophils may be present without overt vasculitis.

●During the vasculitic phase, a nondestructive infiltration of vessel walls is noted and may be more common than a necrotizing vasculitis.

●In the postvasculitic phase, healed vascular lesions resembled organized thrombi, but are associated with extensive destruction of the elastica. In this later phase, eosinophilic infiltration may be absent.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated EGPA, which was previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia. (See 'Introduction' above.)

●The exact etiology is unknown. Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60 percent of patients and EGPA is classified among the ANCA-positive vasculitides. Several other abnormalities in immunologic function occur in EGPA, including heightened Th1 and Th2 lymphocyte function, increased eosinophil recruitment and decreased eosinophil apoptosis. (See 'Pathogenesis' above.)

●Genetic factors such as human leukocyte antigen (HLA) class and certain interleukin-10 polymorphisms may play a role in EGPA pathogenesis. (See 'Genetic factors' above.)

●Several asthma medications, such as the leukotriene modifying agents, inhaled glucocorticoids, and omalizumab, have been associated with the appearance of EGPA. However, it appears that the association is most likely due to unmasking of the underlying disease or intensification of therapy in a patient with escalating EGPA, rather than a causal relationship. (See 'Association with medications' above.)

●A EGPA-like illness can rarely occur after the use of free base cocaine. However, the ANCAs associated with cocaine use recognize different target proteases than the typical ANCAs associated with EGPA. (See 'Cocaine' above.)

●The major histopathologic findings of EGPA from any affected organ include the following, although they may not all be present: eosinophilic infiltration; prominent and sometimes extensive areas of necrosis; an eosinophilic, giant cell vasculitis, especially of the small arteries and veins; and also interstitial and perivascular necrotizing granulomas (picture 1). (See 'Pathology' above.)