Eosinophilic granulomatosis with polyangiitis …

Davide Maimone MD PhD

Neuroimmunology

Updated 02.18.2024
Released 11.08.1996
Expires For CME 02.18.2027

Eosinophilic granulomatosis with polyangiitis

Author: Davide Maimone MD PhD

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Editor: Francesc Graus MD PhD

Eosinophilic granulomatosis with polyangiitis

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Introduction

Overview

Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) is a rare systemic vasculitis almost invariably associated with allergic disorders, such as asthma and rhinosinusitis. It involves the small vessels of the lungs, peripheral nerves, skin, and, less frequently, the heart and the gastrointestinal tract. Nervous system involvement is mostly represented by mononeuritis multiplex, but cranial neuropathies, cerebral ischemic infarcts, or hemorrhages may also occur. Laboratory abnormalities include marked eosinophilia and the presence of ANCA. Increased serum levels of cytokines imply that the systemic activation of the immune system and perturbation of the balance of Th1 and Th2 cytokines may contribute to the heterogeneous spectrum of clinical phenotypes. Increased serum levels of IgG4 and the presence of infiltrating IgG4-positive plasma cells in the peripheral nerve of a subgroup of patients may suggest a relationship with IgG4-related disorders. Pathologic hallmarks are necrotizing vasculitis and extravascular granulomas, consisting of infiltrating eosinophils and lymphocytes. If untreated, eosinophilic granulomatosis with polyangiitis may be fatal in 50% of cases within 3 months, with a survival rate of 3% at 5 years. However, progress made in the management of this disorder has dramatically changed the prognosis of these patients, who are now achieving a median survival time longer than 10 years. The judicious use of corticosteroids and immunosuppressants can prevent serious consequences, including death, and lead to remission in more than 90% of patients. Aggressive forms may require induction protocols, including intravenous high-dose methylprednisolone, cyclophosphamide, or rituximab. Intravenous immunoglobulin, tumor necrosis factor-alpha blockers, anti-IL5 monoclonal antibody (mepolizumab), or autologous hematopoietic stem cell transplantation may be beneficial for refractory forms.

Key points

	• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is a rare systemic vasculitis associated with eosinophilia and asthma.
	• Vasculitic infiltrates are responsible for multiple organ involvement, including lung, gut, heart, kidney, nervous system, and skin.
	• The main neurologic complication of eosinophilic granulomatosis with polyangiitis is a mononeuropathy multiplex, but cerebral hemorrhages or infarcts may also occur.
	• Histological confirmation is mandatory for the definitive diagnosis of eosinophilic granulomatosis with polyangiitis.
	• Corticosteroids are the mainstay of treatment, but immunosuppressants (eg, cyclophosphamide or methotrexate) and biological drugs (TNF-alpha receptor blockers or monoclonal antibodies to CD20 positive B-cells or to interleukin 5) may be needed to obtain remission in more severe cases.

Historical note and terminology

In 1951, Jacob Churg and Lotte Strauss described 13 patients with asthma, fever, hypereosinophilia, and “symptoms of vascular embarrassment in various organ systems,” particularly the heart, gastrointestinal tract, kidney, skin, and peripheral nerves (21). At postmortem, they found not only a systemic arteritis, but also generalized, extravascular, granulomatous lesions. The latter distinguished these patients from those with polyarteritis nodosa ("periarteritis nodosa" at the time) and Wegener granulomatosis. Previous examples of arteritis associated with asthma had been considered variants of polyarteritis nodosa (108), but Churg and Strauss believed their findings delineated a distinct clinical entity. Although they named the disorder “allergic granulomatosis and angiitis”, it was known until recently as “Churg-Strauss syndrome.”

The 2012 international nomenclature categorizes the systemic vasculitides according to the size of vessels affected and the nature of the pathology. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is defined by “eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia” (61). Marked eosinophilia in tissue specimens is not diagnostic of eosinophilic granulomatosis with polyangiitis and can be seen in other vasculitides. Eosinophilic granulomatosis with polyangiitis, along with granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis, are classified as small vessel vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA). The addition of a prefix to the name is recommended to indicate antineutrophil cytoplasmic antibody reactivity (ie, ANCA positive or negative). The ANCA most often found in eosinophilic granulomatosis with polyangiitis are the antimyeloperoxidase type (p-ANCA) and are more frequent in patients with renal disease of any type and in 100% of those with necrotizing glomerulonephritis.

Clinical manifestations

Presentation and course

The key clinical features of eosinophilic granulomatosis with polyangiitis are eosinophilia with asthma and variable signs of systemic vasculitis, most commonly affecting peripheral nerves. Untreated, this is a serious disease with high mortality; therefore, early diagnosis and treatment are essential. Classification criteria for eosinophilic granulomatosis with polyangiitis were updated in 2022 by an expert consensus from the American College of Rheumatology and the European Alliance of Associations for Rheumatology and validated for the purpose of classification of vasculitis, but not for use in establishing a diagnosis of small- or medium-vessel vasculitis (41). Alternate diagnoses mimicking vasculitis should be excluded prior to applying the criteria. According to the Table 1, a score of greater than or equal to 6 is needed for classification of eosinophilic granulomatosis with polyangiitis.

Table 1. Criteria for Eosinophilic Granulomatosis with Polyangiitis

Clinical Criteria
Obstructive airway disease	+3
Nasal polyps	+3
Mononeuritis multiplex	+1
Laboratory and Biopsy Criteria
Blood eosinophil count ≥ 1x109/liter	+2
Positive test for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) or antiproteinase 3 (anti-PR3) antibodies	-3
Hematuria	-1

However, evidence-based guidelines developed by a panel of experts underscore that the diagnosis of eosinophilic granulomatosis with polyangiitis should still be based on highly suggestive clinical features, objective evidence of vasculitis, and the presence of ANCA (32). Eosinophilic granulomatosis with polyangiitis often progresses in three overlapping phases. The first prodromal period may last up to 30 years and is respiratory, beginning with allergic rhinitis or nasal polyposis, frequently followed by asthma. The second phase (eosinophilic phase) consists of peripheral and tissue eosinophilia, with eosinophilic pneumonia, or gastroenteritis. During this second phase, the disease may also wax and wane for years before the third (vasculitic) phase begins. This last phase develops a mean of 3 years after the onset of asthma. Shorter intervals between onset of asthma and vasculitis are associated with a poor prognosis. The three phases do not always progress in this order (19).

Table 2 summarizes the clinical features of eosinophilic granulomatosis with polyangiitis as reported in the largest dataset to date (23). The overall percentage of patients with a systemic clinical feature is given (eg, lung manifestations, 91.4%), but only some of the subcategories are provided.

Lhote and Guillevin reviewed and tabulated the clinical features of eosinophilic granulomatosis with polyangiitis (74). Asthma, as one of the defining clinical features, is seen in nearly 100% of patients. In contrast to common asthma, the asthma of eosinophilic granulomatosis with polyangiitis is later in onset, at a mean age of 35 years (71). Asthma may increase in severity until the vasculitic phase begins, when it actually may remit. Development of eosinophilic granulomatosis with polyangiitis may be masked by steroid treatment for asthma. Upper-airway signs include allergic rhinitis, nasal polyps, and sinusitis. Chest radiographs are abnormal in 60% to 70% of patients. The most common pattern is of transient, patchy infiltrates without a lobar distribution, in an alveolar pattern, but other patterns may be observed. Eosinophil-rich pleural effusions also occur.

Intermittent or chronic fever and weight loss are present in about 70% of cases, and often herald the onset of the vasculitic phase. Skin lesions are found in about two thirds of patients and provide an accessible tissue to biopsy. Purpura is found in about half of patients, and about one third of patients have subcutaneous nodules, commonly on the scalp and extremities.

Cardiac disease is often a significant cause of morbidity and mortality. Cardiac involvement reflects infiltration of the myocardium, or coronary vasculitis, and is manifest as pericardial effusion, congestive heart failure, or myocardial infarction. Approximately one half the patients in Lanham's review died of cardiac disease (71).

Gastrointestinal symptoms result from either mesenteric vasculitis or eosinophilic infiltration of the bowel wall. Patients present with abdominal pain, diarrhea, and bleeding. Mesenteric vasculitis can lead to bowel perforation; infiltration by eosinophils can cause obstruction.

The most common renal lesion in eosinophilic granulomatosis with polyangiitis is similar to that in other ANCA positive syndromes: focal segmental glomerulonephritis with necrotizing features. Although generally milder than in other vasculitic syndromes, it can be severe enough to require dialysis.

Eosinophilic granulomatosis with polyangiitis is important for the neurologist because a majority of patients develop neurologic signs and symptoms. Indeed, in most series, the peripheral nervous system is the most commonly affected, apart from the respiratory involvement that defines the disorder (55). Peripheral neuropathy is present in 60% to 92% of cases of eosinophilic granulomatosis with polyangiitis. The most common form is mononeuritis multiplex, but an apparently symmetrical, distal pattern can also occur. In a study of 28 patients with peripheral neuropathy and eosinophilic granulomatosis with polyangiitis, the typical pattern at onset was a mononeuropathy multiplex, with eventual evolution toward a more or less symmetrical pattern (50). This study was one of the first descriptions of the neuropathy of eosinophilic granulomatosis with polyangiitis as a distinct entity from other systemic necrotizing vasculitides. At presentation, patients were typically ill with fever, weight loss, arthralgias, and fatigue. The common peroneal nerve was the most often involved (96%), followed by tibial, sural, and median nerves (all greater than 40% and less than 60%). Nerve pathology was consistent with ischemic damage. Both myelinated and unmyelinated nerve fibers were lost, and occluded or recanalizing vessels were frequently seen. Transmural, necrotizing epineurial vasculitis was seen in just over one half of the biopsies. Granulomas were seen in only 4 out of 28 cases, and eosinophils were prominent in only 7, usually in the outer zones of inflammation. Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the myeloperoxidase (MPO)-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs. 14.6%, p < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (ie, destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels (p < 0.01) and epineurial vessels occluded by intraluminal eosinophils (p < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group (p < 0.01).

The predominant infiltrating cells were invariably both CD4 and CD8 T lymphocytes. Infiltrates contained few B cells, and little or no complement, immunoglobulin, or eosinophil cationic protein. The type of T lymphocyte infiltration differs from that seen in polyarteritis nodosa, rheumatoid arthritis, and isolated vasculitis of nerve and muscle, where CD8 cells predominate. IgG4-positive plasma cell infiltrates are also found in the epineurium of a subgroup (46%) of patients, and their number correlates with the degree of fibrosis (100). The initial presentation may also be that of a sensory neuropathy with neuropathic pain as the main clinical symptom coupled with skin denervation and cutaneous vasculitis (17). Peripheral neuropathy is more frequent at presentation (up to 60% of cases) and its clinical picture is often more severe in patients with eosinophilic granulomatosis with polyangiitis than in those with other systemic vasculitides (14; 149). The presence versus the absence of serum antimyeloperoxidase or p-ANCA may help to identify two subgroups of patients with peripheral neuropathy: the first with upper limb symptoms at onset, higher serum C-reactive protein levels, and vasculitic findings in epineurial vessels, and the second with eosinophils occluding the lumen of epineurial vessels and infiltrating the endoneurium (97). The burden of neurologic involvement can be assessed by the Overall Disability Sum Score that measures limb functionality, and patients display an early clinical response to therapy with significant decrease in score, but only a slow decrease in the long term, suggesting the existence of a brief therapeutic window (102).

Cranial neuropathies are infrequent, but the most common manifestation is ischemic optic neuropathy (63; 143). Oculomotor, trochlear, and abducens palsies, trigeminal sensory neuropathy, and paralysis of facial, spinal accessory, and hypoglossal nerves have also been reported only in a few patients (71).

Table 2. Clinical Features of Eosinophilic Granulomatosis with Polyangiitis

• Number of patients: 383 • Gender ratio (M/F): 1.08 • Age at diagnosis (years):
	- 50.3 ± 15.7 (mean ± SD)
• Clinical features:
	- asthma: 91.1% - duration of asthma at diagnosis (years): 9.3 ± 10.8 (mean ± SD)
• Systemic symptoms:
	- weight loss: 49.3% - fever: 38.9% - myalgias: 38.9% - arthralgias: 29.8%
• ENT manifestations (48.0%):
	- rhinitis: 17.0% - sinusitis/polyposis: 41.8%
• Lung manifestations (91.4%):
	- chest pain: 7.3% - lung nodule(s): 5.2% - lung infiltrates: 38.6% - pleural effusion: 8.9% - alveolar hemorrhage: 4.2%
• Cutaneous manifestations (39.7%):
	- purpura 22.5% - pseudo-urticarial rash, hives: 9.9% - subcutaneous nodule(s): 9.7% - Livedo reticularis: 3.9% - gangrenous necrotic lesions: 3.7%
• Neurologic symptoms (55.1%):
	- peripheral neuropathy: 51.4% - mononeuritis multiplex: 46.0% - CNS involvement: 5.2% - cranial nerve involvement: 3.1%
• Cardiovascular manifestations (27.4%):
	- Raynaud phenomenon: 1.6% - cardiomyopathy: 16.4% - pericarditis: 15.1% - deep venous thrombosis/pulmonary embolism: 7.6%
• Gastrointestinal involvement (23.2%):
	- abdominal pain: 20.4% - surgical abdomen: 5.7%
• Eye involvement: 6.5% • Renal manifestations: 21.7% • Laboratory features:
	- proteinuria > 0.4 gm/24 h: 12.8% - creatinine > 140 µmoles/liter: 4.3% - eosinophilia: 97.4% - ANCA: 31% - perinuclear ANCA: 20.6% - proteinase 3 ANCA: 5.1%
• Pathologic features:
	- vasculitis: 61.0% - eosinophil infiltrate: 61.3% - granuloma: 33.3%
Adapted from (23)

Central nervous system involvement may occur in up to 17.3% of patients, and in the majority of cases, the involvement is revealed when eosinophilic granulomatosis with polyangiitis is diagnosed (03; 39; 76). The most common clinical manifestations are motor deficits, cranial nerve involvement, loss of visual acuity, psychiatric disorders, and headache. Neuroradiological findings that occur more frequently are unilateral or bilateral cerebral infarcts, involving cerebral hemispheres, basal ganglia, medulla oblongata, and spinal cord, posterior reversible encephalopathy syndrome, and hemorrhagic lesions (76). Cerebral hemorrhage may account for up to 16% of deaths (71). The pathologic basis for both hemorrhage and infarction remains, for the most part, undocumented. It is likely vasculitic, although hypertension may contribute. Two reports document isolated vasculitis of the choroid plexus with intraventricular hemorrhage (16; 73).

Cardioembolic strokes may occur, given the high incidence of cardiac disease in eosinophilic granulomatosis with polyangiitis (124; 44). Subcortical brain damage could also occur asymptomatically in patients with eosinophilic granulomatosis with polyangiitis. A detailed neuropsychological evaluation may be required to detect mild deficits in abstract reasoning, mental speed, and nonverbal memory (82). Psychosis or dementia, responsive to corticosteroids, has been described (44).

Among 47 patients with eosinophilic granulomatosis with polyangiitis seen at the Mayo clinic, 62% had neurologic involvement (124). Peripheral neuropathy was found in 25 out of 47. Of these, 17 had mononeuropathy multiplex, seven a distal symmetric polyneuropathy, and one an asymmetric polyneuropathy. Three patients had cerebral infarctions, including one young patient in whom the mechanism was almost surely cardioembolic. One each had a polyradiculopathy, ischemic optic neuropathy, and symmetric trigeminal sensory neuropathy. Myalgias are reported in 50% to 60% of patients. Frank myositis is rare.

Very rarely eosinophilic granulomatosis with polyangiitis may occur in the pediatric population. In children, the organ systems most frequently involved are respiratory tract, skin, digestive tract, and heart, whereas neurologic and renal involvement are rare (35). The delay between asthma and systemic symptoms is shorter than in adults, and mortality is more substantial (152).

According to the Consensus Task Force for Evaluation and Management of Eosinophilic Granulomatosis with Polyangiitis, the absence of systemic manifestation defines a remission status whereas the new appearance or recurrence or worsening of systemic symptoms characterizes a relapse status, requiring the addition, change, or dose increase of glucocorticoids or immunosuppressants (42). The distinction of isolated exacerbations of asthma and ear, nose, and throat manifestations from systemic vasculitic relapses is recommended as the therapeutic approach may be different (32). Systemic relapses should also be differentiated between severe and non-severe as the former (ie, those with relapsing peripheral neuropathy, glomerulonephritis, cardiomyopathy, or gastroenteritis) need a more timely and aggressive treatment. A revision of 157 patients based on the presence or absence of definite vasculitic features or ANCA status supports the existence of different disease phenotypes for eosinophilic granulomatosis with polyangiitis and suggests the identification of two distinct subcategories (26). Common features for both subcategories are asthma, eosinophilia, and at least one system organ manifestation (other than asthma, pulmonary, or ENT involvement) directly attributable to eosinophilic granulomatosis with polyangiitis.

The true phenotype with polyangiitis is identified by at least one of the following criteria:

	(1) definite vasculitis feature as defined: biopsy-proven necrotizing vasculitis of any organ, biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis, alveolar hemorrhage, palpable purpura, myocardial infarction due to confirmed coronary arteritis and related to the systemic disease
	(2) strong surrogate of vasculitis as defined: hematuria associated with red casts or > 10% dysmorphic erythrocytes, or hematuria and 2+proteinuria on urinalysis related to the systemic disease, no biopsy; and any organ manifestation other than ENT or bronchopulmonary manifestation associated with a biopsy demonstrating leukocytoclastic capillaritis or eosinophilic infiltration of the arterial wall
	(3) mononeuritis multiplex
	(4) ANCA at ELISA with at least one extrathoracic non-ENT manifestation of disease

The alternative phenotype is better defined as hypereosinophilic asthma with systemic manifestation and is characterized by: (1) any systemic manifestation other than definite polyangiitis or surrogate of vasculitis or mononeuritis; AND (2) absence of ANCA.

Patients showing the true polyangiitic phenotype more frequently have fever, weight loss, myalgia, arthralgia, renal disease, mononeuritis multiplex, and ANCA. In contrast, patients not fulfilling the criteria for polyangiitis tend to have more frequently myocarditis.

Prognosis and complications

Prior to the use of corticosteroid therapy, patients with eosinophilic granulomatosis with polyangiitis had a 50% mortality rate at 3 months, and a 5-year survival rate of only 3%. Since the use of these agents, survival times have improved dramatically. Remission rates range from 81% to 92%, and 40% of patients need only steroids as maintenance treatment (44; 128). Relapses may occur in up to 81% of patients and their frequency is not related to the ANCA status (31). Relapse-free survival rates at 5 years reach 64%, and high eosinophil counts at onset and azathioprine maintenance therapy are independent factors of lower relapse risk, whereas high immunoglobulin E level at onset is a risk factor for relapse (119). Survival rates can now reach 93% at 6 years (31). Myocardial or severe gastrointestinal dysfunction correlates significantly with a poor clinical outcome. A prognostic “5 factor score” based on the presence of severe proteinuria, elevated creatinine, severe gastrointestinal myocardial, or central nervous system involvement has been derived (44). A score of greater than or equal to 1 at diagnosis is associated with a significant higher risk of relapse in the following 2 years (65). Those with scores of 0 to 1 had about a 90% 5-year survival rate; with higher scores, survival rates fell to approximately 60%. Fortunately, greater than 80% of patients were in the former category. In a series of 60 patients with necrotizing vasculitis who died within the first year from diagnosis, including nine with eosinophilic granulomatosis with polyangiitis, the clinical signs predictive of death were renal involvement, central nervous system involvement, and cardiomyopathy. The presence of ANCA is also associated with more neurologic and renal morbidity (31), but their absence correlates with an increased mortality (23; 51). The involvement of ear, nose, and throat is a protective factor for renal and cardiac morbidity (31). Insufficient or inappropriate treatment was significantly associated with early deaths (13). A prompt diagnosis may also affect the prognosis, as a delay of 2 weeks is associated with a more severe course of the disease, a higher hospitalization rate, higher corticosteroids dose requirements, and the need for additional immunosuppressive therapy (127). Infection is a major burden in patients with antineutrophil cytoplasmic antibody-associated vasculitis with a risk up to seven times higher than the general population, which remains significant after 8 years of follow-up (120). Patients with eosinophil granulomatosis with polyangiitis have a higher risk of developing squamous cell carcinomas, but its relationship with the use of immunosuppressants is still unclear (52).

Clinical vignette

A 30-year-old woman developed nasal congestion and recurrent sinusitis at the age of 12 years, followed by asthma at the age of 19 years. The asthma gradually worsened, eventually requiring low-dose prednisolone for control, and frequent hospital admissions for attacks precipitated by infection. During one of such admissions, marked blood eosinophilia and pulmonary infiltrates were noted. The vasculitic phase of her illness began with abdominal pain, diarrhea, myalgias, and generalized weakness. A papular hemorrhagic rash developed on the palms and arms, and later spread to the trunk and legs. This was followed shortly by left ulnar nerve palsy and sensory loss in both feet. Following the onset of severe dyspnea and hemoptysis, a chest x-ray showed opacification of the right lung, eventually attributed to vasculitic pulmonary hemorrhage. Eosinophil count at this time was 6000/mm³. She was treated with plasma exchange and prednisolone 60 mg/day and made a good recovery. Skin biopsy showed vasculitis with fibrinoid necrosis of vessel walls and extensive infiltration by eosinophils (71).

Biological basis

	• Eosinophilic granulomatosis with polyangiitis is a multisystemic disorder characterized by hypereosinophilia and antineutrophil cytoplasmic antibody-associated vasculitis.
	• Eosinophilic proliferation and vessel inflammation are the hallmarks of disease and the effectors of organ damage.
	• Two distinct phenotypes of disease may be identified based on the antineutrophil cytoplasmic antibody status: the antineutrophil cytoplasmic antibody negative subset with eosinophil driven manifestations as in analogous Th2-mediated diseases and the antineutrophil cytoplasmic antibody positive subset with vasculitic features.

Etiology and pathogenesis

The cause of eosinophilic granulomatosis with polyangiitis is not known. An infectious etiology has not been formally ruled out. Guillevin and colleagues suggested that vaccination or allergen desensitization might be precipitating factors (45). Several reports have repeatedly linked leukotriene receptor antagonists and omalizumab (humanized anti-IgE antibody) to the development of eosinophilic granulomatosis with polyangiitis (62; 130; 30; 07; 114). Because these agents are used to treat asthma, a prominent early symptom of eosinophilic granulomatosis with polyangiitis, the association may be an example of confounding by indication (ie, attributing causation to a drug used to treat early symptoms of a disease) (34). Furthermore, the administration of leukotriene antagonist or omalizumab is also used to spare corticosteroids, which often undergo a concomitant tapering. Indeed, a more robust association is found between systemic corticosteroid tapering during asthma treatment and the development of eosinophilic granulomatosis with polyangiitis (145). These findings suggest that the disorder may go unrecognized during systemic corticosteroid use and be unmasked on drug withdrawal (98).

The key clinical features of eosinophilia, respiratory hypersensitivity, and vascular inflammation suggest that eosinophilic granulomatosis with polyangiitis results from an infection, autoimmunity, or both. Allergic inflammation may be triggered by an infectious agent or an inhaled allergen, resulting in asthma and rhinosinusitis. Circulating and tissue eosinophilia may follow, leading to eosinophilic pneumonia or gastroenteritis. Finally, vascular inflammation can develop from endothelial-cell adhesion and leucocyte activation, leading to necrotizing vasculitis in various organs (98).

Immunology. Two immunophenotypes characterize eosinophilic granulomatosis with polyangiitis based on the presence or absence of ANCA (136). The phenotype with ANCA is associated with vasculitic manifestations, whereas the one without ANCA is identified by eosinophilic (allergic) features. Three interconnected inflammatory processes are ongoing in eosinophilic granulomatosis with polyangiitis: endothelial activation of eosinophils by eotaxin-3, T helper cell 2 drivers, and B cell activation leading to autoantibody production. Findings indicate that eotaxin-3, an eosinotactic chemokine, is expressed on endothelium of inflamed tissues in patients with eosinophilic granulomatosis with polyangiitis and may be responsible for sustained accumulation of eosinophils (105). Serum eotaxin-3 levels are elevated in relapsing patients and may help to rule out other eosinophilic diseases or small vessel vasculitides (151). Eosinophil granules contain a number of potentially cytotoxic substances, such as major basic proteins, eosinophil cationic proteins, eosinophil peroxidase, and lysophospholipase. Deposition of some of these granule proteins induces tissue damage and granulomatous inflammation (147). Infiltrating eosinophils also stain intensely for vascular endothelial growth factor, and this cytokine may enhance vascular permeability at the inflamed sites (83). In addition, VGEF serum levels are increased in patients with eosinophilic granulomatosis with polyangiitis and have been proposed as a screening marker to allow distinction from patients with asthma (83). Eosinophils infiltrating tissues undergo a type of cell death termed ETosis, which leads to the release of net-like eosinophil extracellular traps, free galectin-10, and membrane-bound intact granules, contributing to local inflammation. Increased serum granule proteins and galectin-10 levels correlate with disease activity (36).

Studies of Th2 cells in the airways and in the circulation of patients with active eosinophilic granulomatosis with polyangiitis revealed an increased production of eosinophil-specific mediators, including interleukin-5, interleukin-4, interleukin-10, and interleukin-13 (58). Th2-associated cytokines may precipitate severe eosinophilia. CCL17/thymus and activation-regulated chemokine and interleukin-25 are soluble factors involved in the recruitment of Th2 cells and the enhancement of Th2 cytokine production, respectively. Serum levels of both factors are increased, and their presence is identified in vasculitic lesions of patients with active disease (27; 131). Peripheral blood mononuclear cells also secrete increased amounts of Th1 (ie, interleukin-2 and interferon gamma), confirming the systemic activation of the immune system in eosinophilic granulomatosis with polyangiitis. A perturbation of the balance of Th1 and Th2 cytokines may contribute to the variable clinical spectrum of the disease, ranging from a Th1-mediated generalized vasculitis with granulomas to a Th2-mediated systemic hypereosinophilia (53). Furthermore, relapses in eosinophilic granulomatosis with polyangiitis may be linked to a decreased number of T regulatory cells producing IL-10 and TGF-beta and a parallel increase in T helper cells producing IL-17 and IL-25 (118). Patients with frequent relapses also exhibit decreased counts of CD4+/FOXP3+ T reg cells and increased percentages of CD80+, CD27+, or CD95+ activated B cells, suggesting an influence of these lymphocyte subsets on the course of the disease (139). CD8+ T cells may participate in the pathogenesis of eosinophilic granulomatosis with polyangiitis given that the CD8+ effector memory T cell subset is expanded in the circulation and expresses cytotoxic markers such as NKG2D and CD107a (11). Moreover, CD8+ T cells are clonally expanded, as demonstrated by an increased frequency of T cell receptor beta-variable chain expansions and show a proinflammatory phenotype with increased CCR5 and CXCR3 expression and elevated production of IFN gamma and TNF alpha (10). A number of circulating cytokines are increased during active disease in patients with eosinophilic granulomatosis with polyangiitis, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin-6, interleukin-15, and s-interleukin-2Ra, and their levels may help the differentiation from other vasculitis (113). Increased levels of other circulating cytokines such as Axl, a receptor tyrosine kinase, and YKL-40, serum chitinase-3-like 1 protein, are also found in patients with eosinophilic granulomatosis with polyangiitis and have been proposed as biomarkers of active disease (01; Ma et el 2021).

The involvement of B-cells in the pathogenesis of eosinophilic granulomatosis with polyangiitis is mostly supported by the presence of autoantibodies and the efficacy of CD20+ B-cell-depleting treatment with rituximab. Approximately one half to two thirds of patients with eosinophilic granulomatosis with polyangiitis have elevated antineutrophil cytoplasmic antibody levels, especially p-ANCA. A few also have antiproteinase 3 antibodies (c-ANCA). The production of ANCA may be related to a disordered regulation of neutrophil extracellular traps (94). Incomplete degradation of neutrophil extracellular traps allows the exposure of cryptic epitopes of myeloperoxidase, which are recognized by the immune system in the presence of susceptible major histocompatibility complex class II genotypes. The use of leukotriene receptor antagonists prior to the diagnosis of eosinophilic granulomatosis with polyangiitis is associated with positivity for ANCA, suggesting a role for innate immunity in autoantibodies production (122). There is as yet no proof that the ANCA cause any vasculitic syndrome, and they are seen in a wide variety of other conditions (25). When activated by tumor necrosis factor-alpha, neutrophil granules containing myeloperoxidase and proteinase 3 move to the cell membrane, where they can then be recognized by extracellular antibodies. This interaction of ANCA with the neutrophil proteins leads to further neutrophil activation with degranulation, nitric oxide production, increased cell adhesion molecule expression, and binding to endothelium, resulting in vascular damage (49). Antilactoferrin antibodies are a subgroup of ANCA, and they are detected in a minority of patients with eosinophilic granulomatosis with polyangiitis (125). Antilactoferrin antibodies associate with disease activity and may contribute to neutrophil activation by enhanced neutrophil trap formation (125). Alternative factors of neutrophil activation may exist as the serum of patients with eosinophilic granulomatosis with polyangiitis promotes neutrophil extracellular trap formation independently from the presence of ANCA (95). Endothelial cell activation is suggested by the finding of increased circulating levels of soluble vascular cell adhesion molecule-1 (121). ANCA may drive endothelial cells to produce tissue factors, and this promotes inflammation and thrombosis. Animal models and in vitro observations also support the notion that antineutrophil cytoplasmic antibody cause neutrophils to release factors that activate the alternate pathway of complement (59). The presence or lack of ANCA may help distinguish two pathogenetic mechanisms underlying different clinical phenotypes (116; 126). Patients with ANCA are more prone to develop vasculitis and show a higher incidence of renal involvement, alveolar hemorrhages, and mononeuritis multiplex, whereas patients without ANCA exhibit a higher incidence of heart disease (eg, pericarditis or cardiomyopathy) and pleural effusion but have a lower frequency of vasculitis at biopsy. ANCA are often negative in children with eosinophilic granulomatosis with polyangiitis (38).

Patient without ANCA may have other autoantibodies like those directed to alpha-enolase, which are associated with skin involvement (72). Increased IgG4 levels and IgG4/IgG ratios can be found in active cases of eosinophilic granulomatosis with polyangiitis, supporting the notion that the disorders may belong to the growing list of IgG4-related diseases (141). Quantitative analysis of targeted circulating proteins by selected reaction monitoring mass spectrometry identified tissue inhibitor of metalloproteinase 1 as the best biomarker of disease activity, whereas increased transketolase, CD93 and tenascin C levels, reflected organ involvement and, therefore, disease severity (57). Serum periostin levels are modestly increased in eosinophilic granulomatosis with polyangiitis with greater disease severity and may help discriminate from other eosinophilic conditions like asthma (110). Elevated peripheral type 2 innate immune cell count and serum interleukin-33 concentration are markers of innate and type 2 response involvement in eosinophilic granulomatosis with polyangiitis, and they correlate with disease activity (138). In addition, increased serum levels of interleukin-33 may suggest the presence of active vasculitis more than a simple peripheral or tissue eosinophilia.

Pathology. The pathological hallmarks of eosinophilic granulomatosis with polyangiitis were defined as eosinophilic infiltration, necrotizing vasculitis, and extravascular granuloma formation. However, these findings were often observed on autopsy (20). The early phase (eosinophilic phase) is characterized by extravascular tissue infiltration by eosinophils of several organs. Up to 70% of cases of eosinophilic granulomatosis with polyangiitis have pulmonary infiltrates at some points in their course. Intense eosinophilic infiltrates may also be seen in gastrointestinal biopsies. The vasculitic phase is characterized by an eosinophil rich vasculitis with fibrinoid necrosis involving small arteries, arterioles, venules, and veins and necrotizing granulomas centered on necrotic eosinophils. The vasculitic process is systemic and any organ may be affected. It must be mentioned that the use of glucocorticoid therapy may alter the pathologic picture by reducing the intensity of eosinophilic infiltrates, transforming vasculitis in a nonnecrotizing type, and markedly reducing the number of granulomas on biopsy (20).

Genetics. The search for genetic risk factors has demonstrated that the frequency of HLA-DRB4 is significantly higher in patients with eosinophilic granulomatosis with polyangiitis than in controls, and its presence may help to identify asthmatic patients at risk for this disease (12). In addition, the presence of the HLA-DRB4 allele strongly correlates with the number of vasculitis symptoms (140). The interleukin-10.2 haplotype associated with increased IL-10 expression and the CD226 Gly307Ser polymorphism may also be predisposing factors (148). A genome-wide association study revealed at least eight loci associated with eosinophilic granulomatosis with polyangiitis and helped in understanding the ANCA-based dichotomy (77). Variants associated with eosinophilia contribute to disease susceptibility and, after stratification based on the presence or absence of ANCA, two genetically and clinically distinct syndromes may be identified. HLA-DQ association with antineutrophil cytoplasmic antibody positivity in eosinophilic granulomatosis with polyangiitis may point toward a true eosinophilic autoimmune disease. Conversely, GPA33 and IL-5 variant association with antineutrophil cytoplasmic antibody negativity may identify a mucosal/barrier dysfunction with increased eosinophil infiltration (77). Genetically distinct subsets in eosinophilic granulomatosis with polyangiitis could require different treatment strategies, as patients with antineutrophil cytoplasmic antibody may be more likely to respond to rituximab, whereas patients without antineutrophil cytoplasmic antibody, but with IL-5-dependent hypereosinophilia, may be more susceptible to mepolizumab (135). One study that included 130 patients with eosinophilic granulomatosis with polyangiitis found that relapse-free survival was significantly shorter in carriers of the Fc-gamma receptor 3B (FCGR3B) haplotype NA1/NA1 (02). A subgroup analysis showed a significant association was maintained in the myeloperoxidase ANCA-positive patients, whereas no association was observed in those who were myeloperoxidase ANCA-negative.

Differential diagnosis

Confusing conditions

Polyarteritis nodosa and granulomatosis with polyangiitis (Wegener granulomatosis) are the disorders most similar clinically and pathogenically to eosinophilic granulomatosis with polyangiitis. Polyarteritis nodosa also commonly causes mononeuritis multiplex but should be distinguishable by the absence of pulmonary symptoms, ANCA, and eosinophilia.

“Microscopic polyangiitis,” the term for microscopic polyarteritis nodosa (60), is associated with peripheral nerve involvement in 15% to 20% of cases, and all cases have rapidly progressive glomerulonephritis. Myeloperoxidase p-ANCA and occasionally proteinase 3 (c) ANCA are elevated in most cases of microscopic polyangiitis. More than half of the cases have pulmonary involvement.

Granulomatosis with polyangiitis (Wegener granulomatosis) should be clinically distinguishable from eosinophilic granulomatosis with polyangiitis by the absence of asthma, allergy, and eosinophilia, and by the presence of the pathologic hallmark: necrotizing granulomas of the upper respiratory tract. Peripheral nerve involvement is relatively infrequent in granulomatosis with polyangiitis; however, kidney involvement is more common in eosinophilic granulomatosis with polyangiitis. When granulomatosis with polyangiitis affects the nervous system, it is usually by direct granulomatous invasion from the sinuses into cranial nerves. Although ANCA elevations occur also in granulomatosis with polyangiitis, these are more typically the proteinase 3 variety (c-antineutrophil cytoplasmic antibodies), rather than the p-ANCA seen in most patients with eosinophilic granulomatosis with polyangiitis.

Chronic eosinophilic pneumonia usually does not affect nonrespiratory sites, and granulomas and vasculitis do not occur.

Hypereosinophilic syndrome is characterized by cardiac disease, thrombocytopenia, and persistent marked systemic and blood eosinophilia but is not associated with asthma, allergy history, vasculitis, or granulomas. Other mononeuropathy multiplex syndromes and chronic inflammatory demyelinating polyneuropathy states lack the pulmonary and allergic manifestations, eosinophilia, vasculitis, and granulomas.

Parasitic, viral, and fungal infections, including Toxocara, Strongyloides stercoralis, HIV, and Aspergillus, should be excluded, as these can be responsible for hypereosinophilia (42). Atheroemboli can cause multiorgan disease and eosinophilia and should be considered in elderly patients (04; 05).

In selected cases, eosinophilic granulomatosis with polyangiitis could represent a diagnostic challenge with coronavirus disease 2019 (COVID-19), as the two conditions may share similarities in clinical and imaging findings and may present with respiratory distress. A history of asthma and eosinophilia are useful clues to discriminate COVID-19 mimickers (101).

Diagnostic workup

The clinical picture of asthma and allergic rhinitis with eosinophilia (defined as greater than 1500 eosinophils/mm³), mononeuritis multiplex, pulmonary infiltrates, and other systemic signs and symptoms should strongly suggest the diagnosis of eosinophilic granulomatosis with polyangiitis. Diagnostic tests may be grouped into “baseline investigations” and “investigations to be performed in selected cases,” which are tests to be ordered on the basis of specific disease manifestations (Table 3) (32).

Table 3. Eosinophilic Granulomatosis with Polyangiitis Diagnostic Work-up

Investigations for all patients
Baseline investigations			Screening/Diagnostic aims
	Routine laboratory investigations
		• Routine serum chemistry • Complete blood count • Urinalysis, 24h proteinuria • Sputum culture • D-dimer, troponin, BNP • Fecal occult blood • C-reactive protein • LDH, tryptase, vitamin B12	General/hematological assessment Kidney involvement screening Infectious disease screening Cardiac involvement screening Intestinal involvement screening Disease activity assessment Screening for myeloproliferative forms
	Immunological and allergic tests (ANCA, IgG, IgA, IgM, IgE, IgG4)		EPGA-related immune parameters
	Infectious tests (stool cultures for parasites), HIV serology		Screening for parasitic and viral infections
	Hematological tests
		• Blood smear (dysplastic eosinophils or blasts) • FIL1L1 fusion proteins	Screening for hematology forms or hypereosinophilia
	Imaging studies and other procedures
		• Chest x-ray and/or HRCT	Lung involvement screening
	Pulmonary function test		Lung involvement screening
	ENT consultation (with nasal endoscopy)		ENT involvement screening
	Echocardiography		Cardiac involvement screening
	Abdominal ultrasonography		Screening for hepatosplenomegaly
Investigations for selected patients
Indications			Procedure(s)
	Peripheral neuropathy		EMG-ENG (sural nerve biopsy)
	Renal function impairment, urinary abnormalities		Kidney biopsy
	GI symptoms and/or bleeding		Endoscopy
	ENT abnormalities (eg, polyps, sino-nasal obstruction symptoms, hearing loss)		Audiometry Sinus CT scan FESS
	Lung infiltrates/pleural effusion		BAL, pleural puncture, lung biopsy
	Clinical signs of allergic bronchopulmonary aspergillosis		Aspergillus-specific IgE and/or IgG sputum (or BAL) cultures for Aspergillus app
	Purpura		Skin biopsy
	Clinical or echocardiogram signs of cardiomyopathy		Cardiac MRI (endomyocardial biopsy)
	Vascular events and/or high CV risk		Arterial and venous Doppler ultrasonography
	CNS manifestations		Brain and/or spinal cord MRI (CSF analysis)
	Other hematological manifestations		T-cell immunophenotyping Bone marrow biopsy
Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; BAL, broncho-alveolar lavage; BNP, brain natriuretic peptide; CNS, central nervous system; CSF, cerebrospinal fluid; CV, cardiovascular; EMG-ENG, electromyography-electroneurography; ENT, ear-nose-throat; FESS, functional endoscopy sinus surgery; GI, gastrointestinal; HRCT, high-resolution CT; LDH, lactate dehydrogenase

Final diagnosis is achieved by tissue biopsy, and further investigations should follow to detect involvement of visceral organs and peripheral nerves.

A complete clinical evaluation should include careful cutaneous examination. The eosinophilia of eosinophilic granulomatosis with polyangiitis fluctuates, so serial counts may be needed before this essential feature is recognized (71).

For the neurologist, the most common clinical presenting syndrome is that of mononeuritis multiplex or asymmetrical peripheral neuropathy. Electrophysiologic studies are mandatory to define the nature and extent of the neuropathy, as it may not be readily apparent by clinical examination. Patients should undergo brain magnetic resonance imaging when central nervous system involvement is suspected or in case of stroke-like episodes, cranial neuropathies, or meningeal symptoms. Multifocal enhancing cortical lesions may occasionally be found, reflecting the presence of granulomatous eosinophilic vasculitis (48). As in other vasculitides affecting the central nervous system, the use of diffusion-weighted imaging may help to assess the degree of brain involvement by revealing small and active ischemic lesions that go undetected on conventional MRI (90).

ANCA (usually myeloperoxidase or p-ANCA, but occasionally proteinase 3, c-ANCA) are detected in one half to two thirds of patients with eosinophilic granulomatosis with polyangiitis. The frequency of ANCA is higher in active disease, and antibody titer tends to correlate with disease activity and glucocorticoid treatment (64). Patients with ANCA display more frequently vasculitis features, including glomerulonephritis, neuropathy, and skin lesions, but this finding is not specific enough to allow a subclassification in vasculitic or eosinophilic form of disease or to orientate therapeutic decisions to immunosuppressants rather than glucocorticoids (85). Monitoring of ANCA is useful solely when they were present at disease onset (85). However, caution should be used in interpreting this test because assays for ANCA are not standardized, and ANCA are present in disorders other than vasculitis, including infections (25). The perinuclear (p) pattern of ANCA staining is sometimes produced by antibodies against proteins other than myeloperoxidase, and in these cases, its clinical significance is less clear. Antibodies to proteinase 3, c-ANCA, are rarely found, but they may be typical of a subgroup of patients with a different form of vasculitis, characterized by less asthma and peripheral neuropathy and more frequent skin involvement, pulmonary nodules, and lower eosinophil counts (104). The use of sensitive immunoenzymatic assays for the screening phase of ANCA followed by confirmatory immunofluorescence assays seems to offer the best results in terms of diagnostic accuracy and cost-effectiveness (115). ANCA may be found in the sputum, rather than in the blood, of patients with eosinophilic granulomatosis with polyangiitis with severe asthma (91). Consider testing for hepatitis B infection, IgE levels (elevated in 75% of patients with eosinophilic granulomatosis with polyangiitis), cryoglobulins, rheumatoid factor, antinuclear antibody titer, erythrocyte sedimentation rate, C-reactive protein level, and renal, pancreatic, and hepatic function studies. Rheumatoid factor levels may allow the distinction of two groups of patients: one with high levels (above 75 IU/mL) who also show absence of antimyeloperoxidase antibodies, higher eosinophil count, and frequent involvement of gastrointestinal tract; and another with low levels (below 75 IU/mL) who exhibit antimyeloperoxidase antibodies, lower eosinophil count, and involvement of heart and kidney (56). Consideration should be given to examination of stool and sputum for parasites. To rule out infectious causes of hypereosinophilia serology for Toxocara, HIV, and Aspergillus may be obtained, whereas paraneoplastic eosinophilia should be investigated by lactate dehydrogenase level, chest x-ray, abdominal ultrasound, and thoracoabdominal CT scan (42). Screening for vitamin B12 and tryptase levels is sensitive for neoplastic eosinophilia, including chronic eosinophilic leukemia and other myeloid neoplasms (42).

Angiography is not usually helpful. Occasional patients with eosinophilic granulomatosis with polyangiitis will present in a manner suggestive of giant cell or temporal arteritis. Positive temporal artery biopsies have been obtained (44; 33).

Definitive diagnosis of eosinophilic granulomatosis with polyangiitis rests on tissue diagnosis. Choice of the biopsy site should, of course, be directed by clinical findings. Palpable purpura or subcutaneous nodules, if present, are generally amenable to biopsy, but are not always specific. Nerve and muscle biopsy is often the main resource for a confirmatory diagnosis. The combined use of both tissues increases the sensitivity compared to that obtained with nerve biopsy alone, leading to positive findings in 62.5% to 80% of cases of vasculitis with neuropathy (117; 142). The electrophysiologic examination is helpful in the selection of the most appropriate nerve and muscle to biopsy. The important pathologic findings in peripheral nerve have been discussed earlier in this summary and were reviewed by Lanham and Churg (70).

Once the diagnosis of eosinophilic granulomatosis with polyangiitis is reached the possible involvement of lung, kidney, heart, gastrointestinal tract, and peripheral nerves needs to be investigated. Pulmonary evaluation includes high-resolution CT scans and spirometry; cardiac assessment requires electrocardiography, transthoracic echocardiography, N-terminal pro-brain natriuretic peptide, and troponin; gastrointestinal tract evaluation by abdominal CT scans or endoscopy is indicated only in symptomatic patients; renal function tests and urine analysis should be obtained at diagnosis and regularly during follow-up, to detect asymptomatic kidney disease or drug toxicity (eg, cyclophosphamide) (42).

Management

	• Immunosuppressive therapy has substantially changed the prognosis of eosinophilic granulomatosis with polyangiitis, allowing to obtain a remission in the majority of patients.
	• A stepwise approach includes the use of glucocorticoids and oral immunosuppressants at first followed by intravenous immunosuppressants when required.
	• The advent of monoclonal antibodies like anti-CD20 and anti-IL5 has made it possible to control even the most aggressive and refractory cases.

The goal of treatment is to achieve remission of clinical symptoms and to maintain this condition with the lowest dose of glucocorticoids or immunosuppressants. Clinical remission is considered as the absence of clinical signs or symptoms attributable to active disease, with a Birmingham Vasculitis Activity Score (BVAS) of zero (92). Remission-induction treatment should be tailored according to the clinical manifestations with prognostic implications.

In patients with non-severe disease, ie, without generalized systemic vasculitis (renal, cardiac, or gastrointestinal disease), corticosteroids alone are the drug of choice. A multicenter trial on patients with eosinophilic granulomatosis with polyangiitis without poor-prognosis factors showed that remission can be achieved in 93% of cases by using corticosteroid monotherapy (111). For relatively uncomplicated eosinophilic granulomatosis with polyangiitis without severe systemic complications, corticosteroid treatment should begin with a daily dose of 1 mg/kg of prednisone or equivalent. If the patient responds, (usually within the month), steroids can be slowly tapered. A low dose is often needed to control asthma, but a slower taper from this low dose should be attempted. Those who fail to respond, those who relapse on tapering of corticosteroids, or those with intolerable corticosteroid side effects should be treated with alternative immunosuppressants, such as azathioprine or cyclophosphamide. Anti-IL5 and anti-IL5 receptor monoclonal antibodies, including mepolizumab, reslizumab, and benralizumab, are now included in the therapeutic strategy for eosinophilic granulomatosis with polyangiitis as they increase the percentage of patients achieving remission, prolong the duration of remissions, and reduce the relapse rate (146; 129; 80). Mepolizumab effectiveness may be predicted by elevated eosinophil numbers at diagnosis (137), and it is also helpful as a steroid-sparing treatment or in refractory forms of the disease (66; 54; 129). In patients with severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis, a subgroup may be identified as “super-responders” to biological treatments, and these individuals are characterized by worse clinical baseline features but greater improvement in asthma exacerbations and glucocorticoid dose reduction after mepolizumab or benralizumab therapy (106). Mepolizumab at 300 mg every 4 weeks is approved for the treatment of eosinophilic granulomatosis with polyangiitis, but it may still be effective at a reduced dose of 100 mg (09) and in patients with refractory peripheral neuropathies (93). Mepolizumab alone or in combination with glucocorticoids is recommended in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis without organ- or life-threatening manifestations (32). Pulmonary function, erythrocyte sedimentation rate, C-reactive protein, and possibly ANCA titers may be of value to follow response because peripheral nerve lesions will respond slowly. Decreasing serum vascular endothelial growth factor levels can also parallel drug-induced remissions (83). During follow-up, eosinophil count is the most accurate biomarker to detect disease activity and to predict relapses (40).

The occurrence of organ-threatening manifestations as in the Five Factor Score (renal insufficiency, proteinuria, cardiomyopathy, gastrointestinal tract, and central nervous system involvement) as well as peripheral neuropathy should prompt more aggressive treatment to induce remission (32). Boluses of intravenous methylprednisolone (500 to 1000 mg/day over 3 days) followed by high doses oral glucocorticoids may be used. As an alternative, these patients and those who do not respond or cannot tolerate prednisone could be treated with cyclophosphamide or anti-CD20 positive B-cell monoclonal antibody (rituximab). Disease control may be obtained in patients with eosinophilic granulomatosis with polyangiitis and at least one of five poor-prognosis factors by adding a 12-pulse regimen of cyclophosphamide to oral prednisone (22). Early treatment with monthly intravenous cyclophosphamide in addition to corticosteroids is also effective to achieve a rapid control of peripheral nerve symptoms (18). Rituximab is becoming a useful alternative to cyclophosphamide in the treatment of severe forms of ANCA-associated vasculitis, and it has also demonstrated therapeutic efficacy in refractory patients with eosinophilic granulomatosis with polyangiitis (69; 112; 134). Rituximab is more effective in ANCA-positive patients and may become the treatment of choice for patients with renal involvement or severe refractory disease, or also for patients in whom traditional cytotoxic agents are contraindicated or undesirable (84). Azathioprine (2 mg/kg) or methotrexate (7.5 to 15 mg once a week) may also be used alone or in combination with steroids as maintenance therapy.

Therapeutic strategy also differs in patients with severe eosinophilic granulomatosis with polyangiitis and those with non-severe disease. Rituximab is recommended to maintain remission in patients with unfavorable factors, whereas mepolizumab can be used during remission maintenance in subjects without major organ involvement to control asthma and to reduce glucocorticoids exposure (32).

Alternative treatments with intravenous IgG or plasmapheresis may be useful in those cases of eosinophilic granulomatosis with polyangiitis that are refractory to glucocorticoids (43; 28; 109). Intravenous immunoglobulin can also ameliorate muscle strength in patients with residual peripheral neuropathy even after remission has been achieved (67). Interferon-alpha is able to induce a high rate of remission and maintenance and may be used as steroid sparing agent (123). Anecdotal reports suggest that treatments with tumor necrosis factor-alpha blockers, such as etanercept or infliximab, could be considered in selected patients (06). Autologous hematopoietic stem cell transplantation may be tried in patients who failed to respond to glucocorticoids and immunosuppressants (68). Omalizumab, an anti-IgE monoclonal antibody, is effective in some patients with uncontrolled asthma, but it shows less efficacy in those having vasculitis (15). Dupilumab, an inhibitor of IL-4 and IL-13 cytokine-induced responses, may be helpful in eosinophilic granulomatosis with polyangiitis with refractory asthma or ear, nose, and throat manifestations (86). Imatinib mesylate, a tyrosine kinase inhibitor, has been successfully used to treat refractory eosinophilic granulomatosis with polyangiitis, and this therapeutic approach appears promising (08).

Outcomes

Since the advent of glucocorticoid or immunosuppressant treatment the outcome of eosinophilic granulomatosis with polyangiitis has substantially changed. Patients without poor prognosis factors achieve remission in 93% of cases by using glucocorticoid monotherapy, and survival rates at 1 and 5 years are respectively 100% and 97% (111). In a trial including patients with poor prognostic factors, 92% of patients were still alive at 8-year follow-up (Cohen at al 2007). In addition, a monocentric retrospective analysis on 150 patients showed that survival rates at 5 and 10 years were 97% and 89%, respectively (87). In patients with nonsevere eosinophilic granulomatosis with polyangiitis, the combination of glucocorticoids with azathioprine may result in good overall 1-year survival, but vasculitic relapses and asthma/rhinosinusitis exacerbations may occur in the following years requiring other preventive treatments (107). Effective therapies to induce remission in glucocorticoid-refractory patients are represented by biological agents such as rituximab or mepolizumab. The use of these agents is also helpful in avoiding the potential side effects of glucocorticoids or cyclophosphamide (including sepsis and myelosuppression). Rituximab may induce persistent remission in 34% of patients after the first course of treatment and a second infusion may increase this percentage up to 49%, preventing relapses during a 3-year follow-up (Thiel at el 2013; 84). B cell repopulation within the first year after rituximab is often incomplete in patients with eosinophilic granulomatosis, and polyangiitis and significant hypogammaglobulinemia may occur (133). Mepolizumab use in glucocorticoid-resistant or relapsing patients achieves remission in 80% of cases, but its discontinuation is associated with 50% incidence of relapses (88). However, immunosuppressive treatments increase the risk of opportunistic infections, which are the main cause of death in patients with ANCA-associated vasculitis (37). Alternative treatments for cases that failed to respond to glucocorticoids and immunosuppression include high-dose intravenous immunoglobulins in combination with plasma exchange, cyclophosphamide, and glucocorticoids (28).

References

01: Ahn SS, Yoon T, Park YB, et al. Serum chitinase-3-like 1 protein is a useful biomarker to assess disease activity in ANCA-associated vasculitis: an observational study. Arthritis Res Ther 2021;23(1):77. PMID 33685523
02: Alberici F, Bonatti F, Adorni A, et al. FCGR3B polymorphism predicts relapse risk in eosinophilic granulomatosis with polyangiitis. Rheumatology (Oxford) 2020;59(11):3563-6. PMID 32375167
03: André R, Cottin V, Saraux JL, et al. Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): report of 26 patients and review of the literature. Autoimmun Rev 2017;16(9):963-9.** PMID 28709761
04: Anonymous. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-1986. A 74-year-old man with azotemia, eosinophilia, and peripheral cyanosis and mottling. N Engl J Med 1986;315(5):308-15. PMID 2873510
05: Anonymous. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-2000. A 25-year-old man with asthma, cardiac failure, diarrhea, and weakness of the right hand. N Engl J Med 2000;343(13):953-61. PMID 11006372
06: Arbach O, Gross WL, Gause A. Treatment of refractory Churg-Strauss syndrome by TNF-alpha blockade. Immunobiology 2002;206:496-501. PMID 12607724
07: Bargagli E, Rottoli P. Omalizumab treatment associated with Churg-Strauss vasculitis. Int Arch Allergy Immunol 2008;145(3):268. PMID 17921677
08: Beketova TV, Volkov MY, Naryshkin EA, Novoselova TM, Nabokov EL. Imatinib mesylate use in refractory eosinophilic granulomatosis with polyangiitis: a literature review and a case report. Clin Rheumatol 2018;37(6):1729-35. PMID 29564565
09: Bettiol A, Urban ML, Dagna L, et al. Mepolizumab for eosinophilic granulomatosis with polyangiitis: a European multicenter observational study. Arthritis Rheumatol 2022;74(2):295-306. PMID 34347947
10: Boita M, Guida G, Circosta P, et al. The molecular and functional characterization of clonally expanded CD8+ TCR BV T cells in eosinophilic granulomatosis with polyangiitis (EGPA). Clin Immunol 2014;152(1-2):152-63. PMID 24632064
11: Boita M, Rolla G, Mallone R, et al. Expression of NKG2D and CD107 in CD8(+) effector memory lymphocytes in Churg-Strauss syndrome. Clin Exp Rheumatol 2012;30(1 Suppl 70):S57-61. PMID 22640649
12: Bottero P, Motta F, Bonini M, et al. Can HLA-DRB4 help to identify asthmatic patients at risk of Churg-Strauss syndrome? ISRN Rheumatol 2014;2014:843804. PMID 24734195
13: Bourgarit A, Le Toumelin P, Pagnoux C, et al. Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine 2005;84:323-30. PMID 16148732
14: Cattaneo L, Chierici E, Pavone L, et al. Peripheral neuropathy in Wegener's granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis. J Neurol Neurosurg Psychiatry 2007;78(10):1119-23. PMID 17299018
15: Celebi Sozener Z, Gorgulu B, Mungan D, et al. Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases. World Allergy Organ J 2018;11(1):39. PMID 30524647
16: Chang Y, Kargas SA, Goates JJ, Horoupian DS. Intraventricular and subarachnoid hemorrhage resulting from necrotizing vasculitis of the choroid plexus in a patient with Churg-Strauss syndrome. Clin Neuropathol 1993;12(2):84-7. PMID 8097441
17: Chao CC, Hsieh ST, Shun CT, Hsieh SC. Skin denervation and cutaneous vasculitis in eosinophilia-associated neuropathy. Arch Neurol 2007;64(7):959-65. PMID 17620485
18: Cho HJ, Yune S, Seok JM, et al. Clinical characteristics and treatment response of peripheral neuropathy in the presence of eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome): Experience at a single tertiary center. J Clin Neurol 2017;13(1):77-83. PMID 28079316
19: Chumbley LC, Harrison EG, DeRemee RA. Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc 1977;52:477-84. PMID 18640
20: Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol 2001;14(12):1284-93. PMID 11743052
21: Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951;27:277-301. PMID 14819261
22: Cohen P, Pagnoux C, Mahr A, et al; French Vasculitis Study Group. Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum 2007;57(4):686-93. PMID 17471546
23: Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum 2013;65(1):270-81. PMID 23044708
24: Connolly JO, Lanham JG, Partridge MR. Fulminant pregnancy-related Churg-Strauss syndrome. Br J Rheumatol 1994;33:776-7. PMID 8055209
25: Conron M, Beynon HL. Churg-Strauss syndrome. Thorax 2000;55(10):870-7. PMID 10992542
26: Cottin V, Bel E, Bottero P, et al. Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). A study of 157 patients by the Groupe d’Etudes et de la Recherche sur les Maladies Orphelines Pulmonaires and the European Respiratory Society Taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Autoimmun Rev 2017;16(1):1-9. PMID 27671089
27: Dallos T, Heiland GR, Strehl J, et al. CCL17/thymus and activation-related chemokine in Churg-Strauss syndrome. Arthritis Rheum 2010;62(11):3496-503. PMID 20669282
28: Danieli MG, Cappelli M, Malcangi G, Logullo F, Salvi A, Danieli G. Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis 2004;63:1649-54. PMID 15547090
29: Debby A, Tanay A, Zakut H. Allergic granulomatosis and angiitis (Churg-Strauss vasculitis) in pregnancy. Int Arch Allergy Immunol 1993;102:307-8. PMID 8219786
30: DuMouchel W, Smith ET, Beasley R, et al. Association of asthma therapy and Churg-Strauss syndrome: an analysis of postmarketing surveillance data. Clin Ther 2004;26:1092-104. PMID 15336474
31: Durel CA, Berthiller J, Caboni S, Jayne D, Ninet J, Hot A. Long-term follow-up of a multicentre cohort of 101 patients with eosinophilic granulomatosis with polyangiitis (EGPA). Arthritis Care Res (Hoboken) 2016;68(3):374-87. PMID 26315340
32: Emmi G, Bettiol A, Gelain E, et al. Evidence-based guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nat Rev Rheumatol 2023;19(6):378-93. PMID 37161084
33: Endo T, Katsuta Y, Kimura Y, et al. A variant form of Churg-Strauss syndrome: initial temporal non-giant cell arteritis followed by asthma- is this a distinct clinicopathologic entity. Hum Pathol 2000;31(9):1169-71. PMID 11014587
34: Eustace JA, Nadasdy T, Choi M. The Churg Strauss syndrome. J Am Soc Nephrol 1999;10:2048-55. PMID 10477159
35: Fina A, Dubus JC, Tran A, et al. Eosinophilic granulomatosis with polyangiitis in children: Data from the French RespiRare® cohort. Pediatr Pulmonol 2018;53(12):1640-50. PMID 29943913
36: Fukuchi M, Kamide Y, Ueki S, et al. Eosinophil ETosis-mediated release of galectin-10 in eosinophilic granulomatosis with polyangiitis. Arthritis Rheumatol 2021;73(9):1683-93. PMID 33750029
37: Garcia-Vives E, Segarra-Medrano A, Martinez-Valle F, Agraz I, Solans-Laque R. Prevalence and risk factors for major infections in patients with antineutrophil cytoplasmic antibody-associated vasculitis: influence on the disease outcome. J Rheumatol 2020;47(3):407-14. PMID 31203229
38: Gendelman S, Zeft A, Spalding SJ. Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): a contemporary single-center cohort. J Rheumatol 2013;40(6):929-35. PMID 23637321
39: Graf J. Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis. Rheum Dis Clin North Am 2017;43(4):573-8. PMID 29061243
40: Grayson PC, Monach PA, Pagnoux C, et al. Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis. Rheumatology 2015;54(8):1351-9. PMID 25406357
41: Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis. Ann Rheum Dis 2022;81(3):309-14. PMID 35110334
42: Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management. Eur J Int Med 2015;26(7):545-53. PMID 25971154
43: Gross WL. Systemic necrotizing vasculitis. Baillieres Clin Rheumatol 1997;11:259-84. PMID 9220078
44: Guillevin L, Cohen P, Gayraud M, Lhote F, Jarousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long term followup of 96 patients. Medicine 1999;78:26-37. PMID 9990352
45: Guillevin L, Guittard T, Bletry O, Godeau P, Rosenthal P. Systemic necrotizing angiitis with asthma: causes and precipitating factors in 43 cases. Lung 1987;165:165-72. PMID 3108593
46: Guillevin L, Lhote F, Amouroux J, Gherardi R, Callard P, Casassus P. Antineutrophil cytoplasmic antibodies, abnormal angiograms and pathological findings in polyarteritis nodosa and Churg-Strauss syndrome: indications for the classification of vasculitides of the polyarteritis nodosa group. Br J Rheumatol 1996;35:958-64. PMID 8883433
47: Haas C, Geneau C, Odinot JM, et al. Allergic angiitis with granulomatosis: Churg-Strauss syndrome. Retrospective study of 16 cases. Ann Med Interne (Paris) 1991;142:335-42. PMID 1952511
48: Hagiwara K, Tominaga K, Shida N, Yamashita Y. Multifocal enhancing cortical lesions in a patient with Churg-Strauss syndrome. Neurology 2008;71(19):1546-8. PMID 18981377
49: Harper L, Savage CO. Pathogenesis of ANCA-associated systemic vasculitis. J Pathol 2000;190:349-59. PMID 10685069
50: Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. Brain 1999;122:427-39. PMID 10094252
51: Healy B, Bibby S, Steele R, Weatherall M, Nelson H, Beasley R. Antineutrophil cytoplasmic autoantibodies and myeloperoxidase autoantibodies in clinical expression of Churg-Strauss syndrome. J Allergy Clin Immunol 2013;131(2):571-6. PMID 22920496
52: Heijl C, Westman K, Höglund P, Mohammad AJ. Malignancies in patients with antineutrophil cytoplasmic antibody-associated vasculitis: a population-based cohort study. J Rheumatol 2020;47(8):1229-37. PMID 31474595
53: Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci 2005;1051:121-31. PMID 16126951
54: Herrmann K, Gross WL, Moosig F. Extended follow-up after stopping mepolizumab in relapsing/refractory Churg-Strauss syndrome. Clin Exp Rheumatol 2012;30(1 Suppl 70):S62-5. PMID 22512988
55: Imboden JB. Involvement of the peripheral nervous system in polyarteritis nodosa and antineutrophil cytoplasmic antibodies-associated vasculitis. Rheum Dis Clin North Am 2017;43(4):633-9. PMID 29061248
56: Inamo J, Kaneko Y, Ota y, Takeuchi T. Subtypes of eosiniphilic granulamatosis with polyangiitis classified according to rheumatoid factor. Clin Rheumatol 2019;38(12):3493-9. PMID 31317422
57: Ishizaki J, Takemori A, Suemori K, et al. Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther 2017;19(1):218. PMID 28962592
58: Jakiela B, Szczeklik W, Plutecka H, et al. Increased production of IL-5 and dominant Th2-type response in airways of Churg-Strauss syndrome patients. Rheumatology 2012;51(10):1887-93. PMID 22772323
59: Jennette JC, Falk RJ. New insight into the pathogenesis of vasculitis associated with antineutrophil cytoplasmic autoantibodies. Curr Opin Rheumatol 2008;20(1):55-60. PMID 18281858
60: Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37:187-92. PMID 8129773
61: Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65(1):1-11. PMID 23045170
62: Josefson D. Asthma drug linked with Churg-Strauss syndrome. BMJ 1997;315(7104):330. PMID 9270450
63: Kattah JC, Chrousos GA, Katz PA, McCasland B, Kolsky MP. Anterior ischemic optic neuritis in Churg -Strauss syndrome. Neurology 1994;44:2200. PMID 7969987
64: Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophilic cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 2003;115:284-90. PMID 12967693
65: Kim DS, Song JJ, Park YB, Lee SW. Five factor score of more than 1 is associated with relapse during the first 2 year-follow up in patients with eosinophilic granulomatosis with polyangiitis. Int J Rheum Dis 2017; 20(9):1261-8. PMID 28261989
66: Kim S, Marigowda G, Oren E, Israel E, Wechsler ME. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol 2010;125:1336-43. PMID 20513524
67: Koike H, Akiyama K, Saito T, Sobue G, The Research Group for IVIg for EGPA/CSS in Japan. Intravenous immunoglobulin for chronic residual peripheral neuropathy in eosinophilic granulomatosis with polyangiitis /Churg-Strauss syndrome): a multicenter, double-blind trial. J Neurol 2015;262(3):752-9. PMID 25577176
68: Kotter I, Daikeler T, Amberger C, Tyndall A, Kanz L. Autologous stem cell transplantation of treatment-resistant systemic vasculitis--a single center experience and review of the literature. Clin Nephrol 2005;64:485-9. PMID 16370165
69: Koukoulaki M, Smith KG, Jayne DR. Rituximab in Churg-Strauss syndrome. Ann Rheum Dis 2006;65(4):557-9. PMID 16531558
70: Lanham JG, Churg J. Churg-Strauss syndrome. In: Churg A, Churg J, editors. Systemic vasculitides. New York: Igaku-Shoin, 1991:101-20.
71: Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine 1984;63:65-81. PMID 6366453
72: Laskari K, Hellmich B, Adamus G, Csernok E. Autoantibody profile in eosinophilic granulomatosis and polyangiitis: predominance of anti-alpha-enolase antibodies. Clin Exp Rheumatol 2021;39 Suppl 129(2):83-87. PMID 33200729
73: Lee PC, Gocke CD, Harris ED Jr, et al. 47-year-old woman with six-week history of lower extremity weakness and eosinophilia. West J Med 1992;156(5):517-22. PMID 1595277
74: Lhote F, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical aspects and treatment. Rheum Dis Clin North Am 1995;21:911-47. PMID 8592743
75: Lima F, Buchanan N, Froes L, Kerslake S, Khamashta MA, Hughes GR. Pregnancy in granulomatous vasculitis. Ann Rheum Dis 1995;54:604-6. PMID 7668907
76: Liu S, Guo L, Fan X, et al. Clinical features of central nervous system involvement in patients with eosinophilic granulomatosis with polyangiitis: a retrospective cohort study in China. Orphanet J Rare Dis 2021;16(1):152. PMID 33789679
77: Lyons PA, Peters JE, Alberici F, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun 2019;10(1):5120. PMID 31719529
78: Ma J, Dong C, Wei S, et al. Serum cytokine profiling identifies Axl as a new biomarker candidate for active eosinophilic granulomatosis with polyangiitis. Front Mol Biosci 2021;8:653461. PMID 33987203
79: Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalence of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum 2004;51(1):92-9. PMID 14872461
80: Manka LA, Guntur VP, Denson Jl, et al. Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis. Ann Allergy Asthma Immunol 2021;126(6):696-701. PMID 33548468
81: Martin RM, Wilton LV, Mann RD. Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: prospective analysis of 58 prescription-event monitoring cohort studies. Pharmacoepidemiol Drug Saf 1999;8(3):179-89. PMID 15073927
82: Mattioli F, Capra R, Rovaris M, et al. Frequency and patterns of subclinical cognitive impairment in patients with ANCA-associated small vessel vasculitides. J Neurol Sci 2002;30:161-6. PMID 11897248
83: Mitsuyama H, Matsuyama W, Iwakawa J, et al. Increased serum vascular endothelial growth factor level in Churg-Strauss syndrome. Chest 2006;129:407-11. PMID 16478859
84: Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Ann Rheum Dis 2016;75(2):396-401. PMID 25467294
85: Moiseev S, Bossuyt X, Arimura Y, et al. International consensus on ANCA testing in eosinophilic granulomatosis with polyangiitis. Am J Respir Crit Care Med 2020. [Epub ahead of print] PMID 32584187
86: Molina B, Padoan R, Urban ML, et al. Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study. Ann Rheum Dis 2023;82(12):1587-93. PMID 37734881
87: Moosig F, Bremer JP, Hellmich B, et al. A vasculitis centre based management strategy leads to improve outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EPGA): monocentric experiences in 150 patients. Ann Rheum Dis 2013;72(6):1011-7. PMID 22887848
88: Moosig F, Gross WL, Herrmann K, Bremer JP, Hellmich B. Targeting interleukin-5 in refractory and relapsing Churg-Strauss syndrome. Ann Intern Med 2011;155(5):341-3. PMID 21893636
89: Morishita KA, Moorthy LN, Lubieniecka JM, et al. Early outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2017;69(7):1470-9. PMID 28371513
90: Moritani T, Hiwatashi A, Shrier DA, Wang HZ, Numaguchi Y, Westesson PL. CNS vasculitis and vasculopathy: efficacy and usefulness of diffusion-weighted echoplanar MR imaging. Clin Imaging 2004;28:1261-70. PMID 15246475
91: Mukherjee M, Thomas SR, Radford K, et al. Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis. Am J Respir Crit Care Med 2019;199(2):158-70. PMID 30179583
92: Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis 2009;68(12):1827-32. PMID 19054820
93: Nakamura Y, Fukutomi Y, Sekiya K, et al. Low-dose mepolizumab is effective as an add-on therapy for treating long-lasting peripheral neuropathy in patients with eosinophilic granulomatosis with polyangiitis. Mod Rheumatol 2022;32(2):387-95. PMID 34910206
94: Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol 2019;15(2):91-101. PMID 30542206
95: Natorska J, Zabczyk M, Siudut J, Krawiec P, Mastalerz L, Undas A. Neutrophil extracellular traps formation in patients with eosinophilic granulomatosis with polyangiitis: association with eosinophilic inflammation. Clin Exp Rheumatol 2017;35 Suppl 103(1):27-32. PMID 28229830
96: Nilsen AT, Karlsen C, Bakland G, Watts R, Luqmani R, Koldingsnes W. Increasing incidence and prevalence of ANCA-associated vasculitis in Northern Norway. Rheumatology 2020;59(9):2316-24. PMID 31859355
97: Nishi R, Koike H, Ohyama K, et al. Differential clinicopathological features of EGPA-associated neuropathy with and without ANCA. Neurology 2020;94(16):e1726-37. PMID 32217776
98: Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. Lancet 2003;361(9357):587-94. PMID 12598156
99: Ogasawara M, Kajiura S, Inagaki H, Sasa H, Aoki K, Yagami Y. Successful pregnancy in a Churg-Strauss syndrome patient with a history of intrauterine fetal death. Int Arch Allergy Immunol 1995;108:200-2. PMID 7549510
100: Ohyama K, Koike H, Takahashi M, et al. Immunoglobulin G4-related pathologic features in inflammatory neuropathies. Neurology 2015;85(16):1400-7. PMID 26408495
101: Özdemir B, Erden A, Güven SC, et al. COVID-19 and eosinophilic granulomatosis with polyangiitis or COVID-19 mimicking eosinophilic granulomatosis with polyangiitis? Rheumatol Int 2021;41(8):1515-21. PMID 34032896
102: Padoan R, Marconato M, Felicetti M, et al. Overall disability sum score for clinical assessment of neurological involvement in eosinophilic granulomatosis with polyangiitis. J Clin Rheumatol 2018;24(4):197-202. PMID 29652700
103: Pagnoux C, Le Guern V, Goffinet F, et al. Pregnancies in systemic necrotizing vasculitides: report on 12 women and their 20 pregnancies. Rheumatology (Oxford) 2011;50(5):953-61. PMID 21183452
104: Papo M, Sinico RA, Teixeira V, et al. Significance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Rheumatology 2021;60(9):4355-60. PMID 33347592
105: Polzer K, Karonitsch T, Neumann T, et al. Eotaxin-3 is involved in Churg-Strauss syndrome–a serum marker closely correlating with disease activity. Rheumatology (Oxford) 2008;47(6):804-8. PMID 18397958
106: Portacci A, Campisi R, Buonamico E, et al. Real-world characteristics of "super-responders" to mepolizumab and benralizumab in severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis. ERJ Open Res 2023;9(5):00419-2023. PMID 37908397
107: Puéchal X, Pagnoux C, Baron G, et al. Non-severe eosinophilic granulomatosis with polyangiitis: long-term outcomes after remission-induction trial. Rheumatology (Oxford) 2019;58(12):2107-16. PMID 31056661
108: Rackemann FM, Greene JE. Periarteritis nodosa and asthma. Trans Assoc Am Physicians 1939;54:112-8.
109: Raffray L, Guillevin L. Treatment of eosinophilic granulomatosis with polyangiitis: a review. Drugs 2018;78(8):809-21. PMID 2976639
110: Rhee RL, Holweg CT, Wong K, et al. Serum periostin as a biomarker in eosinophilic granulomatosis with polyangiitis. PLoS One 2018;13(10):e0205768. PMID 30308057
111: Ribi C, Cohen P, Pagnoux C, et al; French Vasculitis Study Group. Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 2008;58(2):586-94. PMID 18240234
112: Roccatello D, Sciascia S, Rossi D, et al. Long-term effects of rituximab added to cyclophosphamide in refractory patients with vasculitis. Am J Nephrol 2011;34(2):175-80. PMID 21757891
113: Rodriguez-Pla A, Warner RL, Cuthbertson D, et al. Evaluation of potential serum biomarkers of disease activity in diverse forms of vasculitis. J Rheumatol 2020;47(7):1001-10. PMID 31474593
114: Ruppert AM, Averous G, Stanciu D, et al. Development of Churg-Strauss syndrome with controlled asthma during omalizumab treatment. J Allergy Clin Immunol 2008;121(1):253-4. PMID 18206510
115: Russell KA, Wiegert E, Schroeder DR, Homburger HA, Specks U. Detection of anti-neutrophilic antibodies under actual clinical testing conditions. Clin Immunol 2002;103:196-203. PMID 12027425
116: Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005;143:632-8. PMID 16263885
117: Said G, Lacroix-Ciaudo C, Fujimura H, Blas C, Faux N. The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol 1988;23:461-5. PMID 2839104
118: Saito H, Tsurikisawa N, Tsuburai T, Oshikata C, Akiyama K. The proportion of regulatory T cells in the peripheral blood reflects the relapse or remission status of patients with Churg-Strauss syndrome. Int Arch Allergy Immunol 2011;155 Suppl 1:46-52. PMID 21646795
119: Saku A, Furuta S, Hiraguri M, et al. Longterm outcomes of 188 Japanese patients with eosinophilic granulomatosis with polyangiitis. J Rheumatol 2018;45(8):1159-66. PMID 29907668
120: Sarica SH, Dhaun N, Sznajd J, et al. Characterizing infection in anti-neutrophil cytoplasmic antibody-associated vasculitis: results from a longitudinal, matched-cohort data linkage study. Rheumatology 2020;59(10):3014-22. PMID 32159801
121: Schneeweis C, Rafalowicz M, Feist E, et al. Increased levels of BLyS and sVCAM-1 in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitides (AAV). Clin Exp Rheumatol 2010;28(1 Suppl 57):62-6. PMID 20412705
122: Schroeder JW, Folci M, Losappio LM, et al. Anti-neutrophil cytoplasmic antibodies positivity and anti-leukotrienes in eosinophilic granulomatosis with polyangiitis: a retrospective monocentric study on 134 Italian patients. Int Arch Allergy Immunol 2019;180(1):64-71. PMID 31189169
123: Seeliger B, Försyter M, Happe J, et al. Interferon-α for induction and maintenance of remission in eosinophilic granulomatosis with polyangiitis: a single-center retrospective observational cohort study. J Rheumatol 2017;44(6):806-14. PMID 28412705
124: Sehgal M, Swanson JW, DeRemee RA, Colby TV. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc 1995;70:337-41. PMID 7898138
125: Shida H, Nakazawa D, Tateyama Y, et al. The presence of anti-lactoferrin antibodies in a subgroup of eosinophilic granulomatosis with polyangiitis patients and their possible contribution to enhancement of neutrophil extracellular trap formation. Front Immunol 2016;7:636. PMID 28066444
126: Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005;52(9):2926-35. PMID 16142760
127: Sokolowska B, Szczeklik W, Mastalerz L, et al. Effect of delayed diagnosis on disease course and management of Churg-Strauss syndrome: a retrospective study. Clin Rheumatol 2013;32(3):349-54. PMID 23192420
128: Solans R, Bosch JA, Perez-Bocanegra, et al. Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology 2001;40:763-71. PMID 11477281
129: Steinfeld J, Bradford ES, Brown J, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol 2019;143(6):2170-7. PMID 30578883
130: Stirling RG, Chung KF. Leukotriene antagonists and Churg-Strauss syndrome: the smoking gun. Thorax 1999;54:865-6. PMID 10491447
131: Terrier B, Bièche I, Maisonobe T, et al. Interleukin-25: a cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome. Blood 2010;116(22):4523-31. PMID 20729468
132: Thiel J, Hässler F, Salzer U, Voll RE, Venhoff N. Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Arthritis Res Ther 2013;15(5):R133. PMID 24286362
133: Thiel J, Rizzi M, Engesser M, et al. B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther 2017b;19(1):101. PMID 28521808
134: Thiel J, Troilo A, Salzer U, et al. Rituximab as induction therapy in eosinophilic granulomatosis with polyangiitis refractory to conventional immunosuppressive treatment: a 36-month follow-up analysis. J Allergy Clin Immunol Pract 2017a;5(6):1556-63.** PMID 28916432
135: Trivioli G, Marquez A, Martorana D, et al. Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management. Nat Rev Rheumatol 2022;18(10):559-74. PMID 36109667
136: Trivioli G, Terrier B, Vaglio A. Eosinophilic granulomatosis with polyangiitis: understanding the disease and its management. Rheumatology 2020;59(Suppl 3):iii84-iii94. PMID 32348510
137: Tsurikisawa N, Oshikata C, Watanabe M, et al. Clinical features of patients with active eosinophilic granulomatosis with polyangiitis successfully treated with mepolizumab. Int Arch Allergy Immunol 2021;182(8):744-56. PMID 33887721
138: Tsurikisawa N, Oshikata C, Watanabe M, Tsuburai T, Kaneko T, Saito H. Innate immune response reflects disease activity in eosinophilic granulomatosis with polyangiitis. Clin Exp Allergy 2018;48(10):1305-16. PMID 29908086
139: Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K. Decreases in the numbers of peripheral blood regulatory T cells, and increases in the levels of memory and activated B cells, in patients with active eosinophilic granulomatosis and polyangiitis. J Clin Immunol 2013;33(5):965-76. PMID 23624693
140: Vaglio A, Martorana D, Maggiore U, et al; Secondary and Primary Vasculitis Study Group. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum 2007;56(9):3159-66. PMID 17763415
141: Vaglio A, Strehl JD, Manger B, et al. IgG4 immune response in Churg-Strauss syndrome. Ann Rheum Dis 2012;71(3):390-3. PMID 22121132
142: Vital A, Vital C, Viallard JF, Ragnaud JM, Canron MH, Lagueny A. Neuro-muscular biopsy in Churg-Strauss syndrome: 24 cases. J Neuropathol Exp Neurol 2006;65:187-92. PMID 16462209
143: Vitali C, Genovesi-Ebert F, Romani A, Jeracitano G, Nardi M. Ophthalmological and neuro-ophthalmological involvement in Churg-Strauss syndrome: a case report. Graefes Arch Clin Exp Ophthalmol 1996;234(6):404-8. PMID 8738708
144: Watts RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis. A ten-year study in the United Kingdom. Arthritis Rheum 2000;43(2):414-19. PMID 10693883
145: Weller PF, Plant M, Taggart V, Trontell A. The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 2001;108(2):175-83. PMID 11496231
146: Wechsler ME, Akhutota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017;376(20):1921-32.** PMID 28514601
147: White JPE, Dubey S. Eosinophilic granulomatosis with polyangiitis: A review. Autoimmun Rev 2022:103219. PMID 36283646
148: Wieczorek S, Holle JU, Epplen JT. Recent progress in the genetics of Wegener’s granulomatosis and Churg-Strauss syndrome. Curr Opin Rheumatol 2010;22:8-14. PMID 19864953
149: Wolf J, Schmitt V, Palm F, Grau AJ, Bergner R. Peripheral neuropathy as initial manifestation of primary systemic vasculitides. J Neurol 2013;260(4):1061-70. PMID 23212754
150: Zielonka TM, Dabrowski A, Droszcz W. Efficacy of slow-release betamethasone in Churg-Strauss syndrome. Apropos of a case. Rev Pneum Clin 1994;50(2):77-9. PMID 7839055
151: Zwerina J, Bach C, Martorana D, et al. Eotaxin-3 in Churg-Strauss syndrome: a clinical and immunogenetic study. Rheumatology (Oxford) 2011;50(10):1823-7. PMID 21266446
152: Zwerina J, Eger G, Englbrecht M, Manger B, Schett G. Churg-Strauss syndrome in childhood: a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 2009;39:108-15. PMID 18639318

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

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Davide Maimone MD PhD

Dr. Maimone of Garibaldi Hospital in Catania, Italy, has no relevant financial relationships to disclose.
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Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Former Authors

James Garbern (original author) and James Warne Schmidley MD

Patient Profile

Age range of presentation: 2 to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none
Occupation groups selectively affected: none selectively affected

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Eosinophilic granulomatosis with polyangiitis

Associated Disorders

Asthma
Seasonal allergies

Differential Diagnosis

polyarteritis nodosa
granulomatosis with polyangiitis
Wegener granulomatosis
microscopic polyangiitis
chronic eosinophilic pneumonia
- hypereosinophilic syndrome
- mononeuropathy multiplex syndromes
- chronic inflammatory demyelinating polyneuropathy
- parasitic, viral, and fungal infections
- atheroemboli

Also Relevant

Cerebral arteriopathies
Granulomatosis with polyangiitis
Multiple cranial neuropathies
Stroke in young adults
Systemic small-vessel vasculitis
- Traumatic cranial neuropathy
- Vasculitic neuropathies

Clinical Categories

Neuroimmunology

Web References

Clinical Trials

NIH: Churg-Strauss Syndrome

Eosinophilic granulomatosis with polyangiitis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Criteria for Eosinophilic Granulomatosis with Polyangiitis

Table 2. Clinical Features of Eosinophilic Granulomatosis with Polyangiitis

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Table 3. Eosinophilic Granulomatosis with Polyangiitis Diagnostic Work-up

Management

Outcomes

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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