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

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

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:

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

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.

Epidemiology

Eosinophilic granulomatosis with polyangiitis is a rare disease, but its frequency may be higher in the subgroup of patients with asthma. In the general population, the frequency of the disorder can be estimated at 2.4 to 10.7 per 1.000.000 patient-years, but among patients with asthma, this number increases to 64.4 (81; 144; 79). The use of registries for vasculitis allows a more accurate data capture with an annual incidence of 2.7 cases per 1,000,000 and a prevalence of 32.9 per 1,000,000 (96). Eosinophilic granulomatosis with polyangiitis affects all racial groups, but subjects of European ancestry appear more susceptible to the disease as they are affected 2 times more frequently than non-Europeans (79). The age of presentation has ranged from 3.5 to 75 years (46), with male to female ratios ranging from 0.8 to 3 (47; 124).

Prevention

No means of preventing eosinophilic granulomatosis with polyangiitis are known.

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

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

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).

Special considerations

Eosinophilic granulomatosis with polyangiitis is rare in pediatric age, but patients tend to show more active disease and experience damage to various organ systems at early stages (89).

Pregnancy

Most reports describe aggravation of the disease by pregnancy (29; 24; 75), but one report documents improvement (150). Eosinophilic granulomatosis with polyangiitis, as well as other systemic necrotizing vasculitides, may be associated with an increased incidence of miscarriages, pre-term births, and premature rupture of membranes. Patients with heart or kidney involvement are at risk for life-threatening complications (103). Successful outcomes have been reported (99), but pregnancies should be carefully planned to prevent teratogenic effects by suspending toxic immunosuppressants at least 6 months before conception (103).