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Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, complex, multisystem antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by allergic, eosinophilic, and vasculitic phases. The disorder affects multiple organ systems, including the lungs, heart, kidneys, nervous system, skin, and gastrointestinal tract. Only 30% to 40% of patients are ANCA positive, reflecting variability in immune dysregulation and disease phenotype. Clinical manifestations range from asthma, sinusitis, and peripheral eosinophilia in early stages to systemic vasculitis with neuropathy, cardiac involvement, and renal dysfunction in advanced stages. Delayed recognition increases the risk of irreversible organ damage, underscoring the importance of timely diagnosis through laboratory evaluation, imaging, and tissue biopsy. Management involves corticosteroids and immunosuppressive therapy, tailored to disease severity, while ongoing monitoring for relapse or complications is essential. Accurate assessment of disease activity and organ involvement requires a comprehensive understanding of EGPA pathophysiology and clinical progression. This educational activity equips clinicians with evidence-based knowledge and practical skills to identify, evaluate, and effectively manage EGPA. Participants learn to interpret laboratory markers, ANCA status, imaging results, and histopathology to differentiate EGPA from other vasculitides. The activity emphasizes individualized treatment planning, including the selection and titration of corticosteroids and immunosuppressants, as well as monitoring strategies to prevent relapse and organ damage. Collaborative care with an interprofessional team—including pulmonologists, cardiologists, neurologists, nephrologists, dermatologists, and allergists—enhances patient outcomes by ensuring coordinated evaluation, timely interventions, and comprehensive patient education. Objectives: Identify the key clinical features of eosinophilic granulomatosis polyangiitis to aid in diagnosis. Implement tailored treatment strategies for eosinophilic granulomatosis with polyangiitis, considering the eosinophilic phenotype and antineutrophil cytoplasmic autoantibody-associated phenotype. Select appropriate immunosuppressive therapies based on the severity of eosinophilic granulomatosis with polyangiitis and the presence of poor prognostic factors.

Implement tailored treatment strategies for eosinophilic granulomatosis with polyangiitis, considering the eosinophilic phenotype and antineutrophil cytoplasmic autoantibody-associated phenotype. Select appropriate immunosuppressive therapies based on the severity of eosinophilic granulomatosis with polyangiitis and the presence of poor prognostic factors. Collaborate with an interprofessional healthcare team to optimize the management of eosinophilic granulomatosis with polyangiitis, ensuring a comprehensive approach to patient care. Access free multiple choice questions on this topic.

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a specific variant within a group of diseases characterized by necrotizing vasculitis of small- and medium-sized systemic blood vessels. This is one of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), alongside granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). EGPA is distinguished from the other AAVs by its association with asthma, rhinosinusitis, and peripheral eosinophilia.[1] History Jacob Churg and Lotte Strauss first described EGPA in 1951, based on autopsy findings from a case series of 13 patients. All the patients exhibited a similar pattern of severe asthma, fever, blood eosinophilia, and autopsy evidence of granulomatous necrotizing vasculitis.[1] They named the condition allergic granulomatosis and angiitis. Their classic definition and diagnosis of the disease required the presence of the following 3 key features: Eosinophilic infiltration Necrotizing vasculitis of small- and medium-sized vessels Extravascular granuloma formation However, because individuals often presented with varying combinations of these features, and rarely all 3, more clinically relevant diagnostic criteria were later developed. Lanham et al proposed a definition based on slightly different characteristics, as mentioned below: Bronchial asthma Blood eosinophilia of more than 1500 eosinophils per mL Vasculitis involving at least 2 extrapulmonary organs [2] An unintended drawback of these diagnostic criteria was that they often led to delayed diagnosis, as they required the involvement of 2 or more organ systems. This delay in diagnosis was unfavorable because early treatment can prevent complications. In 1990, the American College of Rheumatology (ACR) proposed new classification criteria for EGPA, which require the presence of 4 out of 6 features, as listed below, for diagnosis.[3] These criteria demonstrated a specificity of 99.7% and a sensitivity of 85% for diagnosis. Asthma Migratory infiltrates in the lung Paranasal sinus abnormalities Mono- or polyneuropathy Peripheral blood eosinophilia (>10% of total leukocyte count) Eosinophilic tissue infiltrates in the biopsy

In 1990, the American College of Rheumatology (ACR) proposed new classification criteria for EGPA, which require the presence of 4 out of 6 features, as listed below, for diagnosis.[3] These criteria demonstrated a specificity of 99.7% and a sensitivity of 85% for diagnosis. Asthma Migratory infiltrates in the lung Paranasal sinus abnormalities Mono- or polyneuropathy Peripheral blood eosinophilia (>10% of total leukocyte count) Eosinophilic tissue infiltrates in the biopsy At the Chapel Hill Consensus Conference in 1994, EGPA was defined as "eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels, associated with asthma and eosinophilia."[3] This definition was significant because it excluded biopsy as a necessity for diagnosis, facilitating the early recognition of cases characterized solely by asthma and eosinophilia in tissue or blood. In current clinical practice, the 2022 ACR and European Alliance of Associations for Rheumatology classification criteria for EGPA are used. These criteria should be used when a diagnosis of small to medium vasculitis has been made and mimicking diagnoses have been ruled out.[4] Clinical criteria Obstructive airway disease: +3 Nasal polyps: +3 Mononeuritis multiplex: +1 Laboratory criteria Blood eosinophilia count >1x10(9)/L: +5 Extravascular eosinophilic-predominant inflammation on biopsy: +2 positive test for cytoplasmic antineutrophilic antibodies (cANCA): -3 Hematuria: -1 Sum the scores for 7 items if present. A score of greater than 6 is required for the classification of EGPA.

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.[5] Patients who are ANCA-positive (approximately 30%–40% of all patients with EGPA) typically exhibit a vasculitic phenotype, often presenting with myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement, such as crescentic or necrotizing glomerulonephritis.[6][7][8] 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, ~47% of patients had vasculitis without seropositivity for ANCA, while 29% tested positive for myeloperoxidase ANCA without evidence of vasculitis. Approximately 41% of patients had eosinophilic tissue infiltrates and involvement without vasculitis.[9] This group, therefore, suggests the need to identify and recognize a specific subgroup with features of vasculitis, 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 red blood cells, 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 TH2-Cell Lineage

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 TH2-Cell Lineage Several theories have been proposed regarding the triggers of the abnormal TH2-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.[10] Evidence also suggests colonization of airways by Aspergillus or Actinomyces. Several medications, including sulfonamides, macrolides, and diphenylhydantoin, have also been reported as potential triggers.[11][12][13][14][15][16] Furthermore, several cases have been described after massive inhalation of antigens from grain dust or pigeon exposure.[8] 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.[17][18] Additionally, an increased serum presence of interleukin-10 exists, which mediates the inhibition of the TH1 response, thereby favoring the differentiation of TH2 cells. This phenomenon is widespread in the ANCA-negative phenotype of EGPA.[19]

The estimated prevalence of the disease is approximately 1 to 3 per million adults worldwide.[7] The reported mean age of onset ranges between 38 and 54, with a median of 40. However, cases have also been reported in individuals of all ages, ranging from 4 to 74. Sex prevalences are similar between males and females.[20] In contrast to certain small vessel vasculitides, such as immunoglobulin A vasculitis and Kawasaki disease, with a preponderance in childhood, AAV is rare in children. However, regardless of age, both adult and childhood EGPA are characterized by high levels of immunoglobulin E and eosinophils.[8] Approximately 40% of adults with EGPA have a positive ANCA, whereas 25% of children are seropositive for this condition. 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]

The pathogenesis and clinical phenotype of EGPA follow a dichotomy between eosinophil-mediated damage and ANCA-induced endothelial injury. Eosinophils An initial TH2-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. Interleukin (IL)-3 and IL-5, produced by TH2 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.[21][22][23] 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 reveal eosinophilic infiltrates in the walls of small- and medium-sized blood vessels, as well as 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.[24] IL-5 mediates eosinophilic tissue infiltration, as evidenced by the persistence of tissue major basic protein despite therapy with mepolizumab, which results in the complete downregulation of IL-5 titers. IL-4 and IL-13, other potent cytokines associated with the TH2 immune response, may also play a significant role in tissue infiltration and degranulation of eosinophils.[25] Peripheral blood eosinophils in EGPA exhibit activation markers such as CD69 and CD25, along with elevated serum levels of IL-5 and ECP.[26][27] Antineutrophil cytoplasmic autoantibody In EGPA, approximately 60% of patients are ANCA-negative, around 35% are myeloperoxidase (MPO)-positive, and about 5% are proteinase 3-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 individuals.[7]

In EGPA, approximately 60% of patients are ANCA-negative, around 35% are myeloperoxidase (MPO)-positive, and about 5% are proteinase 3-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 individuals.[7] Infusion of anti-MPO-ANCA in wild-type and Rag2 knockout mice resulted in severe necrotizing and crescentic glomerulonephritis.[28] 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 TH17 lymphocytes play a role in the occurrence and maintenance of the vasculitis response, particularly concerning the balance between TH17 and Treg cells.[29] However, endothelial injury in AAV is primarily mediated by neutrophils through the generation of reactive oxygen species and proteolytic enzymes from cytoplasmic granules.[30][31][32] In their retrospective study of 74 EGPA patients, Keogh and Specks reported an increased prevalence of neuropathy and central nervous system involvement in ANCA-positive patients.[33] 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).[34][35][36]

Histopathological features of EGPA have three main findings: Necrotizing vasculitis in small to medium-sized vessels Extravascular granulomatous inflammation Tissue eosinophilia Biopsies can come from any affected organ. The most frequently biopsied site is the skin due to its accessibility. Lung, renal, and peripheral nerve biopsies may also be performed.[37][38][39] Rarely, an endomyocardial biopsy is implemented.[40]

The clinical features of EGPA follow 2 main patterns—eosinophilic tissue infiltration and small- to medium-vessel vasculitis. Three phases, as mentioned below, characterize the clinical course. Although not every patient experiences all phases, 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 patients with EGPA, particularly at the onset of disease. Upper respiratory symptoms frequently include chronic rhinosinusitis (47%–93%) and nasal polyps (62%–77%); however, unlike in granulomatosis with polyangiitis, 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, affects approximately 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.

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, affects approximately 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 patients with GPA.[41] Cardiac involvement 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 vasculitic 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.[42]

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 vasculitic 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.[42] A recent study by Liu et al discusses the heterogeneity of cardiac disease in EGPA, specifically examining EGPA-eosinophilic myocarditis (EGPA-EM), EGPA-chronic inflammatory cardiomyopathy (EGPA-ICM), and EGPA control. The study identified several differences between the groups, noting that the rate of onset in EGPA-EM was significantly faster (12 days) compared to EGPA-ICM (7.1 months). EGPA-EM had higher markers of cardiac injury and a lower ejection fraction (EF), whereas EGPA-ICM had a relatively preserved EF. [43] They have proposed a screening tool to differentiate these types called the LATE EAST score, consisting of 7 items with a maximum score of 9 points, which follows: L: No lung infiltration (0.5 point) A: CA negative (0.5 point) T: Elevated troponin I (1 point for above normal upper limit, 2 points for >1.9 ng/ml) E: Elevated eosinophil count (0.5 point for >6.38 × 109/l, 1 point for >9.91 × 109/l) E: Myocardial edema (pathological or MRI evidence of myocardial oedema or active inflammation, 2 points) A: Abnormal LVEF (1 point for below normal lower limit, 2 points for <40%) ST: ST-T abnormalities (1 point)

T: Elevated troponin I (1 point for above normal upper limit, 2 points for >1.9 ng/ml) E: Elevated eosinophil count (0.5 point for >6.38 × 109/l, 1 point for >9.91 × 109/l) E: Myocardial edema (pathological or MRI evidence of myocardial oedema or active inflammation, 2 points) A: Abnormal LVEF (1 point for below normal lower limit, 2 points for <40%) ST: ST-T abnormalities (1 point) Patients with scores of less than 2.3 had more than an 80% probability of being in the control group, with 4 points as the cut-off value for differentiating EGPA-EM and ICM. The area above the curve was 0.85 (95% CI, 0.78–0.92), with a sensitivity of 0.78 and a specificity of 0.86. Ninety % of those with scores greater than 4.3 were individuals with EGPA-EM. This score has an overall prediction accuracy of 83%.[43] Echocardiography and cardiac magnetic resonance imaging (MRI) have proven effective in detecting cardiac abnormalities, even beyond the active phase of the disease, including nonreversible chronic fibrosis and cardiomyopathy. Untreated cardiac changes are associated with poor prognosis and increased mortality.[42] 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.[44] Gastrointestinal involvement is more common with EGPA than with GPA or microscopic polyangiitis.[8] Renal 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.[44] Gastrointestinal involvement is more common with EGPA than with GPA or microscopic polyangiitis.[8] Renal involvement Renal involvement occurs in approximately 25% of patients with EGPA, which is less common compared to other medium vessel vasculitides, such as GPA.[45] The most frequent manifestation is necrotizing crescentic glomerulonephritis; however, focal sclerosing disease, immunoglobulin A nephropathy, and eosinophilic interstitial nephritis can also be observed. Biopsy findings are not pathognomonic and frequently resemble those of other vasculitides unless evaluated in the context of eosinophilic asthma, peripheral eosinophilia, or other systemic manifestations. Hypertension is present in 10% to 30% of patients with EGPA and may indicate renal involvement.[24] Neurologic involvement Neurologic involvement in EGPA often presents as mononeuritis multiplex or mixed sensorimotor peripheral neuropathy, with wrist or foot drop being a common symptom. 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.[32] Peripheral neuropathy is seen in 75% to 80% of cases. Additionally, 10% to 39% of neurological manifestations may involve central nervous system vasculitis, leading to cerebral infarctions or hemorrhages.[46]

Neurologic involvement in EGPA often presents as mononeuritis multiplex or mixed sensorimotor peripheral neuropathy, with wrist or foot drop being a common symptom. 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.[32] Peripheral neuropathy is seen in 75% to 80% of cases. Additionally, 10% to 39% of neurological manifestations may involve central nervous system vasculitis, leading to cerebral infarctions or hemorrhages.[46] Cranial nerve palsies are uncommon in EGPA; however, involvement of cranial nerves II, III, VI, and VIII has been reported. Ischemic optic neuritis is the most frequently reported cranial neuropathy. Autonomic neuropathies may contribute to cardiac dysrhythmias observed in EGPA patients.[47] While central nervous system 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.[48][49]

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: 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) [4] 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%.[4] Other Criteria Peripheral blood eosinophilia (>10% on differential white blood cell count or >1500 cells/dL) is a well-recognized laboratory hallmark of the disease. Elevated serum IgE levels are also observed in approximately 75% of patients. Other laboratory abnormalities are nonspecific and may include an elevated erythrocyte sedimentation rate and C-reactive protein, as well as normocytic normochromic anemia, and extrapulmonary rheumatoid factor in approximately 60% of patients.[8][50] 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 that overlap with those of GPA.[51] Serum IgG4 levels and CCL17 levels correlate with disease activity.[52][53] Computed tomography (CT) of the chest often reveals 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.

Computed tomography (CT) of the chest often reveals 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.[54] 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 has been made. Any patient with suspected EGPA should undergo a comprehensive evaluation of cardiac performance and coronary status. A sural nerve biopsy is considered the gold standard for diagnosing 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.

In 2024, EULAR updated its treatment recommendations for ANCA-associated vasculitis (ANCA-AAV), which were first published in 2022. Based on recent trial data, the 2022 recommendations distinguish between GPA/MPA as one treatment group and EGPA as a separate group.[51] Early recognition and the effective use of corticosteroids and immunosuppressants have significantly altered the natural course of EGPA, resulting in 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, distinguishing between limited and 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. Nonorgan or life-threatening diseases include manifestations such as asthma, rhinosinusitis, cutaneous disease, or mild arthritis.[8][51](B3) Corticosteroids help reduce the burden of eosinophils in the 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, either alone or in combination with cyclophosphamide. The Five Factor Score (FFS) is used for the prognostic assessment of EGPA.[55][56](A1) The 5 factors associated with higher mortality are: Proteinuria (>1 g/d) Renal insufficiency (creatinine >1.58 mg/dL) Cardiomyopathy Gastrointestinal tract involvement Central nervous system involvement [57][58](A1)

Corticosteroids help reduce the burden of eosinophils in the 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, either alone or in combination with cyclophosphamide. The Five Factor Score (FFS) is used for the prognostic assessment of EGPA.[55][56](A1) The 5 factors associated with higher mortality are: Proteinuria (>1 g/d) Renal insufficiency (creatinine >1.58 mg/dL) Cardiomyopathy Gastrointestinal tract involvement Central nervous system involvement [57][58](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. Results from 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 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.[59] After remission is achieved after 6 pulses of cyclosporine, glucocorticoid doses can be lowered for maintenance treatment. Asthma or involvement of the ear/nose/throat requires prolonged tapering of glucocorticoids.

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.[59] After remission is achieved after 6 pulses of cyclosporine, glucocorticoid doses can be lowered for maintenance treatment. Asthma or involvement of the ear/nose/throat 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 intravenously (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.[8](B3) For patients with FFS of 1 or greater, corticosteroids with IV cyclophosphamide are 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 (administered every 3 weeks) can be given, and the disease should be reassessed after a total of 9 boluses.[59][60][59] Patients with impaired kidney function or those older than 65 should receive an IV bolus of cyclophosphamide at a fixed dose of 0.5 g on days 1, 15, and 29, followed by 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.[59](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.[59]

Patients with impaired kidney function or those older than 65 should receive an IV bolus of cyclophosphamide at a fixed dose of 0.5 g on days 1, 15, and 29, followed by 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.[59](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.[59] 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 a maximum of 60 mg/day for 2 to 3 weeks, followed by a taper.[8](B3) If the 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.[59] 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; however, more robust data are lacking. Theoretically, IL-5 inhibitors may be more effective in ANCA-negative EGPA patients who present with a more eosinophilic phenotype, but this has not been proven.[61]

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; however, more robust data are lacking. Theoretically, IL-5 inhibitors may be more effective in ANCA-negative EGPA patients who present with a more eosinophilic phenotype, but this has not been proven.[61] 5) For maintaining remission in relapsing EGPA after induction for non–organ-threatening or non–life-threatening disease, mepolizumab is recommended. If organ-threatening or life-threatening disease is present, maintenance with methotrexate, azathioprine, mepolizumab, or rituximab is considered, as the efficacy of mepolizumab in this situation has not been established.[51] 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.[61] Refractory Disease Treatment strategies for frequent relapses or severe refractory disease often depend on end-organ involvement. Plasmapheresis is an effective and preferred treatment for rapidly progressive glomerulonephritis or alveolar hemorrhage. Intravenous immunoglobulin, on the other hand, is considered for neuropathy or cardiomyopathy that is refractory to conventional therapy.[62] Rituximab and tumor necrosis factor inhibitors are alternative options based on smaller case series and evidence of success in other AAVs.[63](B2) Interferon-alfa (3 million international units 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.

Interferon-alfa (3 million international units 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 demonstrated efficacy in treating moderate to severe persistent asthma with allergic phenotypes.[64][65](B3) Results from 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 remain poorly standardized.

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 more than 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 that 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.

EGPA has a favorable prognosis following timely detection and treatment, with a 5-year survival rate of 90%.[66] 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 is a detailed 66-question tool to assess vasculitic organ involvement and is widely used in clinical trials.[63] The Vasculitis Damage Index 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.[67] Factors associated with a poor prognosis include: Severe gastrointestinal tract involvement Cardiomyopathy Central nervous system vasculitis Renal failure [5][68] Cardiac involvement is the most frequent cause of mortality in patients with poor response to therapy, primarily through myocarditis and coronary arteritis.[35]

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.[69] Moreover, nearly all patients with EGPA may develop long-lasting steroid-refractory neuralgia and myopathy.

As EGPA is a multisystem disease, multiple specialists are typically involved depending on patient presentation. Neurology, pulmonology, cardiology, rheumatology, nephrology, dermatology, and allergy may be involved.

Deterrence and patient education are vital for managing EGPA, as mentioned below. EGPA, formerly known as Churg-Strauss syndrome, is a multisystem immune disorder. Persistent, poorly controlled asthma with sinus and nasal symptoms, especially when accompanied by high blood eosinophil counts, should raise suspicion for this condition. Early initiation of treatment with steroids and other immunosuppressants usually leads to a favorable outcome and prolonged life expectancy. Bronchial asthma and some muscle and nerve weakness may persist. Regular screening for corticosteroid-induced adverse effects is crucial due to the potential need for long-term treatment with high-dose steroids over months. Adherence to diagnostic procedures and treatment recommendations is essential, and regular follow-up with healthcare providers should continue after diagnosis.

EGPA, previously known as Churg-Strauss syndrome, presents as a systemic vasculitis with 2 main manifestations: eosinophilic damage and ANCA-associated small- and medium-vessel injury. The dichotomy of EGPA complicates the establishment of a gold standard for diagnosis and contributes to variable prognoses. Effective pharmacological treatment, irrespective of the mechanism of injury, depends on early recognition of EGPA. Immunomodulators, plasma exchange, and IVIG are reserved for more refractory cases. EGPA generally responds well to treatment and has a high remission rate. However, patients often experience persistent, difficult-to-control asthma and systemic manifestations that impact their quality of life.

When an asthmatic individual experiences recurrent exacerbations despite conventional therapy, it is crucial to recognize patterns of recurrence or persistence. Expanding suspicion and correlating with initial blood tests, such as cell differential, erythrocyte sedimentation rate, C-reactive protein, and IgE, can be beneficial. Additionally, if other organ systems are involved, such as cardiomyopathy, renal disease, or gastrointestinal symptoms, these should be considered in a unified diagnosis such as EGPA. In cases of eosinophilic asthma with multisystem involvement, discontinuing leukotriene receptor antagonists should also be evaluated due to their potential role in pathogenesis. Prompt recognition and treatment are essential for improving prognosis and life expectancy in diseases like EGPA. Finally, awareness of the likelihood of prolonged steroid dependence and its adverse effects postdiagnosis and treatment is crucial. A routine care plan for the disease includes periodic screening of glycemic status, bone density, fall prevention, and infection prevention. An interprofessional healthcare team, comprising primary care clinicians, specialists, nurse practitioners, and pharmacists, is essential for enhancing care. Prompt referral is essential. Pharmacists assess dosing, check for drug interactions, and provide patient education. Nurses administer treatments, monitor for adverse effects, educate patients and families, and relay information to the team. Coordination among these disciplines will help enhance patient outcomes.