Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)

Etiology

In recent years, efforts have been made to subclassify clinical phenotypes of EGPA based on the presence or absence of vasculitis, which is somewhat counterintuitive to the nomenclature itself.[4]

Patients who are ANCA-positive (approximately 30%-40% of all EGPA patients) typically exhibit a vasculitic phenotype, often presenting with myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement, such as crescentic or necrotizing glomerulonephritis.[5][6][7] Conversely, patients who are ANCA-negative tend to have an eosinophilic phenotype with a higher incidence of myocarditis.

The presence of ANCA alone is not an absolute indicator of vasculitis. In one study, about 47% of patients had vasculitis without seropositivity for ANCA, while 29% tested positive for myeloperoxidase (MPO) ANCA without evidence of vasculitis. Approximately 41% of patients had eosinophilic tissue infiltrates and involvement without vasculitis.[8] This group, therefore, suggests the need to identify and recognize a specific subgroup with features of vasculitis, such as defined in the study.

Vasculitic Phenotype

Definitive features of vasculitis include:

• Biopsy-proven necrotizing vasculitis in any organ
• Biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis
• Palpable purpura
• Alveolar hemorrhage
• Coronary arteritis causing myocardial infarction

Surrogates of vasculitis include:

• Hematuria with red casts greater than 10%, dysmorphic RBC, or 2+ protein
• Leukocytoclastic capillaritis
• Mononeuritis
• Presence of ANCA

The remaining patients fall into the eosinophilic asthma phenotype. Notably, it is crucial to recognize this subgroup early, especially in cases where myocarditis is present without other evidence of vasculitis. Depending heavily on the presence of vasculitis to diagnose EGPA may lead to overlooking patients with eosinophilic asthma, who could benefit from early, targeted therapy.

The primary trigger in the pathogenesis at the cellular level appears to be an aberrant T-helper (Th)-cell pathway.

Role of the T_H2-Cell Lineage

Various theories have been proposed regarding what triggers the abnormal T_H2-type immune response in EGPA. Allergies, infections, and medications have all been considered potential factors. Rolla et al suggested a superantigen theory, proposing that certain T-cell subsets undergo oligoclonal expansion.[9] Evidence also suggests colonization of airways by Aspergillus or Actinomyces. Several medications, including sulfonamides, macrolides, and diphenylhydantoin, have also been reported as potential triggers.[10][11][12][13][14][15] Furthermore, several cases have been described after massive inhalation of antigens from grain dust or pigeon exposure.[7]

The pathogenic role of T lymphocytes in this aberrant immune response has been supported by the presence of specific clonally expanded T-cell subpopulations and an increased frequency of related HLA alleles, such as HLA-DRB1:04 and HLA-DRB1:07.[16][17] In addition, an increased serum presence of interleukin 10 (IL-10) exists, which mediates the inhibition of T_H1 response, thus favoring the differentiation of T_H2 cells. This phenomenon is particularly common in the ANCA-negative phenotype of EGPA.[18]

Epidemiology

The estimated prevalence of the disease is approximately 1 to 3 per million adults worldwide.[6] The mean age of onset, as reported, ranges between 38 and 54, with a median of 40. However, cases have also been reported in extremes of age, from as young as 4 to as high as 74. Gender prevalences are similar between males and females.[19]

In contrast to certain small vessel vasculitides, such as immunoglobulin A (IgA) vasculitis and Kawasaki disease, with a preponderance in childhood, AAV is rare in children. However, regardless of age, both adult and childhood EGPA present with highly elevated IgE and eosinophil levels.[7] About 40% of adults with EGPA have a positive ANCA, whereas 25% of children are seropositive for this.

Clinically, childhood EGPA has a higher incidence of cardiomyopathy and pneumonic infiltrates, with a lower occurrence of mononeuritis multiplex. The increased prevalence of cardiac disease contributes to higher mortality in childhood EGPA, similar to that seen in adult cases.[2]

Pathophysiology

The pathogenesis and clinical phenotype of EGPA follow a dichotomy of either eosinophil-mediated damage or ANCA-induced endothelial injury.

Eosinophils

An initial T_H2-mediated immune response triggers the margination of eosinophils. Their presence in active disease likely results from increased synthesis, enhanced extravasation, and prolonged survival in target tissues. IL-3 and IL-5, produced by T_H2 lymphocytes, are key regulators of eosinophil maturation, release, and survival in the bloodstream. Serum levels of IL-5 consistently correlate with disease activity and decrease with the initiation of immunosuppressive therapy.[20][21][22] 

Eosinophils release proteins such as eosinophil cationic protein (ECP), eosinophil peroxidases, eosinophil-derived neurotoxins, and eosinophil granule major basic protein, which are directly involved in mediating tissue damage. Histological findings in EGPA typically show eosinophilic infiltrates in the walls of small- and medium-sized blood vessels and in extravascular tissue spaces. During acute pulmonary exacerbations of EGPA, bronchoalveolar lavage fluid is also rich in eosinophils, similar to what is seen in acute or chronic eosinophilic pneumonia. Additionally, extravascular eosinophilic granulomas are often observed, particularly in the gastrointestinal tract.[23]

IL-5 mediates eosinophilic tissue infiltration, as shown by the persistence of tissue major basic protein despite therapy with mepolizumab, which leads to complete downregulation of IL-5 titers. IL-4 and IL-13, other potent cytokines associated with the T_H2 immune response, may also play a significant role in tissue infiltration and degranulation of eosinophils.[24] Peripheral blood eosinophils in EGPA exhibit activation markers such as CD69 and CD25, along with elevated serum levels of IL-5 and ECP.[25][26]

Antineutrophil cytoplasmic autoantibody

In EGPA, approximately 60% of patients are ANCA-negative, around 35% are MPO-positive, and about 5% are PR3-positive. The presence of ANCA correlates with a higher incidence of glomerulonephritis, mononeuritis, and biopsy-proven vasculitis. Alveolar hemorrhage is also more commonly observed in ANCA-positive patients.[6]

Infusion of anti-MPO-ANCA in wild-type and Rag2 knockout mice resulted in severe necrotizing and crescentic glomerulonephritis.[27] The hypothesis of two clinical subsets in EGPA has been further supported by recent findings showing an increased frequency of HLA-DRB4 in ANCA-positive EGPA patients. Additionally, emerging evidence suggests that T_H17 lymphocytes play a role in the occurrence and maintenance of the vasculitis response, particularly concerning the balance between T_H17 and Treg cells.[28] However, endothelial injury in AAV is primarily mediated by neutrophils through the generation of reactive oxygen species and proteolytic enzymes from cytoplasmic granules.[29][30][31]

In their retrospective study of 74 EGPA patients, Keogh and Specks reported an increased prevalence of neuropathy and central nervous system (CNS) involvement in ANCA-positive patients.[32] Since then, increased efforts have been made to identify clinical phenotypes associated with ANCA positivity. Several studies have shown that the presentations of ANCA-positive and ANCA-negative EGPA differ significantly. Patients with ANCA positivity are more likely to have constitutional symptoms, mononeuritis, crescentic glomerulonephritis, and pulmonary capillaritis. Patients who are ANCA-negative are more likely to have higher levels of eosinophilic pulmonary infiltration and cardiac disease (of note, cardiac disease is a primary cause of mortality in patients with refractory EGPA).[33][34][35]

History and Physical

The clinical features of EGPA follow 2 main patterns—eosinophilic tissue infiltration and small- to medium-vessel vasculitis. The clinical course is characterized by 3 phases, as mentioned below, although not every patient experiences all phases, and they may overlap in an individual's disease course.

In the initial prodromal phase, nonspecific symptoms such as malaise, fever, migrating polyarthralgia, and weight loss are common, often accompanied by a severe adult-onset form of asthma that is refractory to conventional treatment. Diffuse myalgia and polyarthralgia have been reported in 37% to 57% of EGPA patients, particularly at the onset of disease. Upper respiratory symptoms frequently include chronic rhinosinusitis (47%-93%) and nasal polyps (62%-77%); however, unlike in GPA, nasal granulomas, erosion, crusting, or epistaxis are typically absent.

The second phase is characterized by eosinophilic infiltrates in end organs along with peripheral eosinophilia. Common manifestations include patchy peripheral nodular pulmonary infiltrates, eosinophilic gastroenteritis, and serosal effusions.

The third phase is characterized by the onset of vasculitis, which can develop 3 to 9 years after the initial onset of asthma. Neurological symptoms are a hallmark of this phase.

Organ System Involvement

Respiratory and pulmonary manifestations: Asthma is nearly ubiquitous in the prodromal phase, reported in 96% to 100% of patients. The mean age of onset is between 35 and 50, typically occurring 3 to 9 years before the onset of vasculitis, despite variability in clinical manifestations.

Debate exists regarding whether asthma medications like leukotriene receptor antagonists, montelukast and zafirlukast may precipitate the onset of EGPA. However, some argue that these medications might only unmask the underlying vasculitides by helping steroid-dependent patients taper off steroids.

Patients with EGPA often present with adult-onset asthma featuring an eosinophilic phenotype, and it is characterized by rhinitis, sinusitis, and nasal polyposis. Chronic rhinitis, the most common extrathoracic manifestation, occurs in about 75% of cases. Asthma in these patients is typically progressive, frequently becoming steroid-dependent. Up to 75% of patients require systemic corticosteroid therapy to control their asthma before an EGPA diagnosis is made.

Even when other systemic manifestations of the disease are controlled with therapy, asthma often remains uncontrolled, significantly impacting the quality of life. Beyond upper airway allergic manifestations and eosinophilic asthma, pulmonary manifestations of the disease can also be related to parenchymal eosinophilic infiltration and the vasculitic process. In the first 2 clinical phases described, transient pulmonary infiltrates and eosinophilia are common. In the vasculitic phase, necrotizing vasculitis and granuloma formation become more prevalent. Alveolar hemorrhage is more frequently reported in the ANCA-positive subset, although its incidence is lower compared to that in GPA patients.

Cardiac disease: Cardiac involvement is observed in about 62% of cases, but symptomatic manifestation occurs in only 26%. This involvement results from mediators released by activated eosinophils and vasculitis lesions affecting the myocardium and coronary arteries. Myocarditis can lead to post-inflammatory fibrosis and restrictive cardiomyopathy, which may progress to congestive heart failure. The spectrum of clinical manifestations includes coronary artery disease, primary arrhythmias, cardiomyopathy, acute constrictive pericarditis, myocarditis, and eosinophilic pericardial effusion. Cardiac disease is more strongly associated with the absence of ANCA and eosinophilia.[36]

Echocardiography and cardiac magnetic resonance imaging (MRI) have proven effective in detecting cardiac abnormalities, even beyond the active phase of the disease, including non-reversible chronic fibrosis and cardiomyopathy. Untreated cardiac changes are associated with poor prognosis and increased mortality.[36]

Gastrointestinal Involvement

Eosinophilic gastroenteritis and mesenteric vasculitis often occur together in gastrointestinal tract involvement. These conditions lead to nonspecific symptoms such as abdominal pain, nausea, vomiting, and diarrhea. They can also result in severe complications such as bleeding or intestinal obstruction due to submucosal nodular masses. Mesenteric vasculitis predisposes to ischemic bowel, mucosal ulceration, and even perforation, potentially requiring exploratory laparotomy. Serosal involvement can cause eosinophilic ascites and peritonitis. Rare manifestations include necrotizing acalculous cholecystitis, pancreatitis, and eosinophilic liver disease.[37] Gastrointestinal involvement is more common with EGPA than with GPA or MPA.[7]

Renal Involvement

Renal involvement occurs in approximately 25% of patients with EGPA, making it less common compared to other medium vessel vasculitides such as GPA.[38] The most frequent manifestation is necrotizing crescentic glomerulonephritis, but focal sclerosing disease, IgA nephropathy, and eosinophilic interstitial nephritis can also be observed. Biopsy features are not pathognomonic and are often indistinguishable from other vasculitis unless accompanied by eosinophilic asthma, eosinophilia, or other systemic manifestations. Hypertension is present in 10% to 30% of patients with EGPA and may indicate renal involvement.[23]

Neurologic Involvement 

Neurologic involvement in EGPA often presents as mononeuritis multiplex or mixed sensorimotor peripheral neuropathy, with wrist or foot drop being common symptoms. The most frequently affected nerves are the common peroneal and internal popliteal nerves, although the radial and ulnar nerves in the upper limbs can also be involved.[31] Peripheral neuropathy is seen in 75% to 80% of cases. Additionally, 10% to 39% of neurological manifestations may involve CNS vasculitis, leading to cerebral infarctions or hemorrhages.[39]

Cranial nerve palsies are uncommon in EGPA, but the involvement of cranial nerves II, III, VI, and VIII has been described. Ischemic optic neuritis is the most frequently reported cranial neuropathy. Autonomic neuropathies may contribute to cardiac dysrhythmias observed in EGPA patients.[40] While CNS vasculitis can lead to significant neurological symptoms, most other neurological manifestations typically respond well to standard therapy.

Other Organs

Dermatological manifestations occur in approximately one-half to two-thirds of patients. Extravascular granulomas and changes consistent with leukocytoclastic vasculitis are observed in the skin. The most common skin manifestations include nonthrombocytopenic palpable purpura, scalp nodules, urticarial rashes, skin infarcts, and livedo reticularis. Less commonly affected organ systems include central retinal artery and venous occlusion, thromboembolic disease, salivary gland involvement, and vasculitis of the breasts.[41][42]

Evaluation

Due to its protean manifestations and lack of a single diagnostic test of choice, the diagnosis of EGPA relies more on clinical features than histopathology or laboratory testing. When eosinophilic asthma is present, clinicians should identify a pattern of multisystem involvement and seek additional supportive findings.

The scoring system developed by the ACR and European Alliance of Associations for Rheumatology (ACR-EULAR) in 2022 for diagnosing EGPA includes:[43]

• Maximum eosinophil count of 1×10⁹ cells/L or higher (+5) 
• Obstructive airway disease (+3)
• Nasal polyps (+3)
• ANCA or anti-proteinase 3-ANCA positivity (−3) 
• Extravascular eosinophilic predominant inflammation (+2)
• Mononeuritis multiplex or motor neuropathy not due to radiculopathy (+1)
• Hematuria (−1)

After excluding conditions that mimic vasculitis, a patient with small- or medium vessel vasculitis can be classified as having EGPA if the cumulative score is 6 or more points. In validation testing, these criteria demonstrated a sensitivity of 85% and a specificity of 99%.[43]

Other Criteria

Peripheral blood eosinophilia (>10% on differential white blood cell count or >1500 cells/dL) is a well-recognized lab hallmark of the disease. Elevated serum IgE is also observed in about 75% of patients. Other laboratory abnormalities are nonspecific and may include elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), normocytic normochromic anemia, and extrapulmonary rheumatoid factor in approximately 60% of patients.[7][44]

As mentioned, ANCA positivity in EGPA is observed in approximately 30% to 40% of cases. The most common ANCA immunofluorescence pattern is perinuclear, with specificity for MPO. Patients who are positive for PR3 ANCA often exhibit more clinical features overlapping with GPA.[45]

Serum IgG4 levels and CCL17 levels correlate with disease activity.[46][47]

Computed tomography (CT) of the chest often shows asymmetric diffuse bilateral peripheral ground-glass infiltrates along with bronchial wall thickening. It can sometimes be migratory. Bilateral bronchocentric nodular infiltrates can also occur, but unlike GPA, they do not cavitate. Pleural effusion is present in 20% to 30% of cases.

CT of the sinuses is characterized by the thickening of the paranasal sinus and nasal mucosa without any evidence of bony erosion, as seen in GPA.

Airflow obstruction is present in pulmonary function tests in 70% of patients. Although FEV₁ may transiently improve with corticosteroid therapy, variable degrees of airflow obstruction persist in 40% of patients.[48]

Given that cardiac disease indicates a poor prognosis, early detection through cardiac MRI is recommended even in the absence of clinical symptoms once a diagnosis of EGPA is made. Any patient with suspected EGPA should undergo a comprehensive evaluation of cardiac performance and coronary status.

Sural nerve biopsy is considered the gold standard for documenting peripheral neuropathy. The most common finding is axonal degeneration, while necrotizing vasculitis and perineural eosinophilic infiltration are confirmed in only about half of the cases.

Skin biopsy is the most convenient procedure to perform. While none of the findings are exclusive to EGPA, evidence of small vessel vasculitis in the appropriate clinical context may be sufficient for diagnosis. In cases involving the kidneys, biopsy typically reveals focal necrosis, crescentic deposits, and a paucity of immunoglobulin deposits, which are the characteristic findings.

Treatment / Management

The ACR-EULAR organizations are currently developing treatment criteria for AAV. Based on new clinical trial data, recent recommendations distinguish between GPA/MPA as one treatment group and EGPA as a separate group.[45] Early recognition and the effective use of corticosteroids and immunosuppressants have significantly altered the natural history of EGPA, leading to improved prognosis and overall survival. Treatment involves 2 stages: induction of remission, defined as the absence of active disease symptoms, and maintenance therapy.

Current treatment choices are based on classifying patients by the extent of involvement in limited or severe disease. Severe disease constitutes a life-threatening or organ-threatening disease, which includes active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, gastrointestinal bleeding, pericarditis, orbital pseudotumor, or myocarditis. Non-organ or life-threatening disease includes manifestations such as asthma, rhinosinusitis, cutaneous disease, or mild arthirtis.[7][45](B3)

Corticosteroids help reduce the burden of eosinophils in blood and tissues and inhibit the prolonged survival of eosinophils in extravascular tissues. For non-severe disease, the initial dose of therapy typically involves 1 mg/kg of oral prednisone. However, remission induction in severe cases is often more effectively achieved with pulse doses of methylprednisolone, with or without cyclophosphamide.

The Five Factor Score (FFS) is used for the prognostic assessment of EGPA.[49][50] (A1)

The 5 factors associated with higher mortality are:

• Proteinuria (>1 g/d)
• Renal insufficiency (Cr >1.58 mg/dL)
• Cardiomyopathy
• Gastrointestinal tract involvement
• CNS involvement [51][52]
(A1)

These factors became the basis of the FFS used to define a poor prognosis and higher mortality in EGPA. The absence of any of these 5 factors (FFS=0) indicates a good prognosis, while the presence of 2 or more increases the risk of mortality. Among these factors, cardiomyopathy is an independent risk factor in EGPA.

Multiple studies indicate that maintaining remission while managing a high incidence of relapses is challenging. Although effective agents have been well established, the ideal treatment duration and the sequence for discontinuing medications remain unclear and are not well standardized.

The 2022 EULAR Recommendations for the Treatment of EGPA and Results of the French Vasculitis Study [7][45] (B3)

1) For new-onset or relapsing EGPA with organ/life-threatening manifestations, high-dose glucocorticoids plus either cyclosporine or rituximab is recommended. Although earlier evidence suggested that induction with rituximab may be especially useful in ANCA-positive EGPA, results of the REOVAS trial found no significant differences between cyclophosphamide and rituximab.[53] After remission is achieved after 6 pulses of cyclosporine, glucocorticoid doses can be lowered for maintenance treatment. Asthma or ear/nose/throat involvement requires prolonged tapering of glucocorticoids. Although not definitively supported by studies, pulse steroids are often given in these cases at a dose of 7.5 to 15 mg/kg/day IV for 3 days, followed by oral corticosteroids. The French Vasculitis Study suggests a taper over 12 to 18 months with reference doses of 20 mg/day, 10 mg/day, and 5 mg/day at 3 months, 6 months, and 1 year, respectively. However, treatment should be individualized to account for each patient's response.[7] (B3)

For patients with FFS ≥1, corticosteroids with IV cyclophosphamide is preferred. The French Vasculitis Study guidelines recommend a dose of 0.6 g/m² per infusion on days 1, 15, and 29, followed by a bolus dose of 0.7 mg/m² per infusion every 3 weeks, with a maximum dose of 1.2 g per infusion for a total of 6 boluses. If after 6 boluses, only partial remission is achieved, 3 additional boluses (every 3 weeks) can be given, and the disease should be reassessed after 9 boluses.[54][53] Patients with impaired kidney function or patients who are older than 65 years should be given an IV bolus of cyclophosphamide at a fixed dose of 0.5 g on days 1, 15, and 29, then every 21 days (for a total of 6 boluses). The benefit of this has been demonstrated in the CORTAGE trial. Maintenance therapy should be started between 2 to 4 weeks after the last cyclophosphamide bolus. This therapy should be accompanied by hydration, antiemetics, and 2-mercaptoethanesulfonate sodium (MESNA) prophylaxis to limit bladder toxicity.[53](B3)

2) According to the French Vasculitis Study group, if complete remission is not achieved after the above cyclophosphamide boluses, this treatment can continue at a dose of 2 mg/kg/day of cyclophosphamide (maximum 200 mg/day) until complete remission is achieved.[53]

3) For new-onset or relapsing EGPA without organ/life-threatening disease, treatment with glucocorticoids alone is recommended. Glucocorticoids alone achieve remission in over 90% of cases. Although relapses are common with this treatment, adding other agents has not been proven to improve outcomes. The recommended dose is 1 mg/kg/day or 60 mg/day maximum for 2 to 3 weeks, followed by a taper.[7] (B3)

If FFS=0, but corticosteroids alone are not adequately controlling symptoms, an additional immunosuppressant agent can be added. Azathioprine orally at 2 to 3 mg/kg/day or methotrexate subcutaneously or orally at 0.3 mg/kg/week can be administered for 12 to 18 months.[53]

4) For induction in relapsing or refractory EGPA without organ/life-threatening disease, mepolizumab (an IL-5 inhibitor) is recommended by the 2022 EULAR guidelines. Other IL-5 or IL-5 receptor inhibitors (eg, reslizumab, bevacizumab, depemokimab) have shown efficacy in small trials, but more robust data are lacking. Theoretically, IL-5 inhibitors may be more effective in ANCA-negative EGPA patients who have more of an eosinophilic presentation, but this has not been proven.[55]

5) For maintaining remission in relapsing EGPA after induction for non–organ-threatening or non–life-threatening disease, mepolizumab is recommended. If organ- or life-threatening disease was present, maintenance with methotrexate, azathioprine, mepolizumab, or rituximab is considered, as the efficacy of mepolizumab in this situation has not been established.[45] One small study showed that maintenance rituximab (500 mg every 6 months) reduced the relapse rate compared to patients treated with rituximab 1 gram once relapse occurred. Cyclophosphamide is not used for maintenance due to its toxicity.[55]

Refractory Disease

Treatment strategies for frequent relapses or severe refractory disease often depend on end-organ involvement. Plasmapheresis is effective and preferred in rapidly progressive glomerulonephritis or alveolar hemorrhage. Intravenous immunoglobulin (IVIG), on the other hand, is considered for neuropathy or cardiomyopathy, which is refractory to conventional therapy.[56] Rituximab and tumor necrosis factor (TNF) inhibitors are alternative options based on smaller case series and evidence of success in other AAVs.[57] (B2)

Interferon-alfa (3 million IU subcutaneously, 3 times weekly) has also shown some success in inducing remission in 7 EGPA patients refractory to cyclophosphamide. This treatment downregulates the expression of IL-5 and IL-13 and modulates eosinophil-activating cytokines. However, interferon-alfa was unable to reduce the relapse rate after 1 year of follow-up.

Recent reports highlight the successful use of mepolizumab (an anti-IL-5 monoclonal antibody) and omalizumab (a recombinant humanized monoclonal anti-IgE antibody) in refractory EGPA. Both drugs have shown evidence of success in treating moderate-to-severe persistent asthma with allergic phenotypes.[58][59](B3)

Multiple studies highlight the challenge of maintaining remission due to the high incidence of relapses. While the choice of agents has been well established, the ideal treatment duration and the order in which drugs should be discontinued are still not well standardized.

Differential Diagnosis

The differential diagnosis should consider conditions stemming from the 2 principal phenotypes of EGPA—eosinophilic lung disease and systemic small- and medium vessel vasculitis.

Eosinophilic Lung Diseases

• Acute and chronic eosinophilic pneumonia
• Allergic bronchopulmonary aspergillosis
• Bronchocentric granulomatosis
• Löffler syndrome
• Idiopathic hypereosinophilic syndrome

Small- and Medium-Vessel Vasculitis

• Granulomatosis with polyangiitis
• Polyarteritis nodosa
• Microscopic polyangiitis

Most eosinophilic lung diseases are distinguished from EGPA by the absence of multisystem involvement, except for idiopathic hypereosinophilic syndrome. In idiopathic hypereosinophilic syndrome, peripheral eosinophilia exceeds 1500 cells/mm³ and persists for over 6 months. ANCA is completely absent in hypereosinophilic syndrome, and late-onset asthma is very uncommon. Recent molecular genetic testing has identified specific mutations to idiopathic hypereosinophilic syndromes, such as FIP1-like 1–platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) and T-cell antigen receptor rearrangements. Reactive hypereosinophilic syndrome (with non-clonal eosinophils) and neoplastic hypereosinophilic syndrome (with clonal eosinophils) are also considerations which must be ruled out.

For differentiation from other small- and medium vessel vasculitides, renal involvement is more common in GPA, which also often presents with cavitary lung lesions or necrotizing upper airway lesions. Septal nasal perforation, frequently seen in GPA, does not occur in EGPA.

Prognosis

EGPA has a favorable prognosis following timely detection and treatment, with a 5-year survival rate of 90%.[60] The relapse rate is estimated at approximately 20% to 30%, often presenting with fever, joint pain, and constitutional symptoms.

Certain risk factors for relapse include:

• A sudden rise in eosinophil count
• Persistent ANCA positivity
• Gastrointestinal tract involvement
• An increase in ANCA titers

Just as peripheral eosinophilia is a hallmark of diagnosis, an association exists between the degree of eosinophilia and the severity of vasculitis. A sudden rise in eosinophil count also precedes a relapse of the disease.

The Birmingham Vasculitis Activity Score (BVAS) is a detailed 66-question tool to assess vasculitic organ involvement and is widely used in clinical trials.[57] The Vasculitis Damage Index (VDI) is a valuable tool for assessing accumulated organ damage resulting from both the disease and its treatment. This tool correlates strongly with mortality and morbidity.[61]

Factors associated with a poor prognosis include:

• Severe gastrointestinal tract involvement
• Cardiomyopathy
• CNS vasculitis
• Renal failure [4][62]

Cardiac involvement is the most frequent cause of mortality in patients with poor response to therapy, primarily through myocarditis and coronary arteritis.[34]

Complications

Although early detection and treatment of the disease lead to a favorable prognosis, asthma often remains refractory and significantly impacts the quality of life. The persistence of severe asthma symptoms typically requires a prolonged course of systemic corticosteroids compared to other small vessel vasculitides, leading to a high prevalence of corticosteroid-induced adverse effects, such as diabetes mellitus, myopathy, osteoporosis, vertebral fractures, and osteonecrosis of the femoral head.[63] Moreover, nearly all patients with EGPA may develop long-lasting steroid-refractory neuralgia and myopathy.