Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss)

• Th2-mediated immune dysregulation and eosinophil activation: EGPA fundamentally involves aberrant Th2 cell differentiation and increased production of IL-4, IL-5, and IL-13, which promote class switching to IgE, eosinophil production in bone marrow, and enhanced eosinophil survival and tissue homing. IL-5 is particularly critical, acting on eosinophil precursors and mature eosinophils to increase proliferation and activate tissue eosinophils. Activated eosinophils release granule proteins (major basic protein, eosinophil peroxidase, eosinophil cationic protein) that directly damage vascular endothelium and surrounding tissues. Elevated serum IgE levels (often >1000 IU/mL) and allergen-specific IgE further amplify mast cell and basophil degranulation, perpetuating the Th2 response. This eosinophil-centric pathology distinguishes EGPA from the predominantly neutrophil-mediated vasculitis seen in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

• ANCA generation and neutrophil activation: Approximately 40–60% of EGPA patients develop myeloperoxidase (MPO)-ANCA (also called p-ANCA), and rarely proteinase-3 (PR3)-ANCA is detected; ANCA-negative disease is more common in EGPA than in other vasculitides. The mechanism of ANCA generation remains incompletely understood but likely involves molecular mimicry with pathogens, epitope spreading during tissue inflammation, or genetic predisposition. MPO-ANCA activates neutrophils through cross-linking of Fcγ receptors, leading to respiratory burst, degranulation, and release of neutrophil elastase and other proteases that damage vessel walls. Notably, ANCA seropositivity correlates with more severe systemic disease (particularly renal involvement), whereas ANCA-negative patients more frequently present with cardiac and pulmonary manifestations. This ANCA heterogeneity suggests that EGPA may represent a spectrum of disease with variable pathogenic mechanisms.

• Granulomatous inflammation and necrotizing vasculitis: Unlike the fibrinoid necrosis of medium-sized vessels seen primarily in polyarteritis nodosa, EGPA exhibits distinctive granulomatous inflammation, often with striking eosinophilic infiltration of vessel walls and surrounding tissues. Activated tissue macrophages and dendritic cells drive Th2 differentiation through IL-4 production, while granulomatous lesions contain epithelioid histiocytes and multinucleated giant cells interspersed with eosinophilic infiltrates. The vasculitis affects small vessels (capillaries, venules, arterioles) and small-to-medium arteries; necrotizing vasculitis of coronary arteries is particularly characteristic and contributes significantly to EGPA-related mortality. Eosinophil-derived neurotoxin and other mediators promote vascular remodeling, myocardial infiltration, and endocardial fibrosis, explaining the disproportionate cardiac involvement in this disease.

• Genetic predisposition and HLA associations: Genome-wide association studies have identified polymorphisms in genes related to immune regulation (e.g., HLA-DRB1, PTPN22, CTLA4) that increase susceptibility to EGPA. The **HLA-DRB1*04:01 and HLA-DRB1*07:01** alleles are enriched in EGPA populations, suggesting antigen presentation-dependent activation of autoreactive T cells. However, genetic factors alone are insufficient for disease; environmental triggers (infections, drug exposure, allergen sensitization) are likely required to initiate disease in genetically predisposed individuals.

• Drug-induced EGPA and leukotriene receptor antagonist (LTRA) association: A subset of EGPA cases occur in temporal association with LTRA use (montelukast, zafirlukast) in asthmatic patients, though causality remains debated. The proposed mechanism involves disease unmasking—as asthma control improves with LTRAs, corticosteroid doses are reduced, unmasking previously subclinical vasculitis. Alternatively, LTRAs may directly alter immune tolerance or reduce Th1-mediated suppression of Th2 responses. Nonetheless, EGPA has been reported without LTRA exposure, and LTRAs are not uniformly present in EGPA cases, indicating that drug association is epidemiologically associated but not causally obligatory.

• Asthma as prodromal disease and risk factor: The vast majority (>90%) of EGPA patients have preceding or concurrent asthma, which frequently precedes systemic vasculitis by months to years. This asthma often exhibits atypical features—late-onset (age 30–50), severe despite optimal inhaled corticosteroid therapy, and associated with prominent blood and tissue eosinophilia. The prolonged asthma prodrome reflects progressive Th2 skewing and eosinophilic airway inflammation that eventually extends systemically. Asthma severity at EGPA onset predicts overall disease severity and organ involvement.

• Leukotriene receptor antagonist (LTRA) exposure: Temporal association between LTRA initiation and EGPA presentation has been documented in multiple case reports and series; published estimates suggest 1–2% of EGPA patients have preceding LTRA use. The mechanism likely involves corticosteroid dose reduction unmasking underlying vasculitis rather than direct drug toxicity. Patients requiring LTRA therapy should be monitored for unexplained systemic symptoms, eosinophilia, and vasculitis features; however, LTRA use should not be withheld from patients with legitimate asthma indications based solely on EGPA risk.

• Infection and molecular mimicry: Preceding respiratory tract infections, particularly those caused by respiratory viruses (parainfluenza, RSV, influenza), have been noted in disease onset timelines, suggesting that infection-induced epitope spreading or direct viral triggering of immune dysregulation may initiate disease in susceptible individuals.

• Environmental allergen exposure and sensitization: Enhanced IgE responses to environmental allergens (elevated total IgE, allergen-specific IgE) are typical; chronic allergen exposure may perpetuate the Th2 environment favoring disease progression.

Phase 1: Prodromal Phase (Allergic Phase)

• Severe asthma with unusual features: Patients present with new-onset or worsening asthma typically in adulthood (age 30–50), often refractory to standard inhaled corticosteroids. Dyspnea and wheezing are accompanied by cough, sometimes with hemoptysis. Pulmonary function tests show obstructive defect with reduced FEV1/FVC ratio.
• Allergic rhinitis and sinusitis: Chronic rhinosinusitis with nasal polyposis occurs in 50–70% of patients. Patients report nasal congestion, purulent rhinorrhea, loss of smell, and recurrent sinus infections refractory to antibiotics. Computed tomography (CT) of sinuses reveals opacification and polyps.
• Otitis media: Serous otitis media and conductive hearing loss may occur due to eustachian tube obstruction.
• Eosinophilia: Peripheral blood eosinophilia develops, typically >1500 cells/μL but often >4000 cells/μL; eosinophils may comprise >30% of WBC differential.

Phase 2: Systemic Phase (Vasculitic Phase)

• Fever and constitutional symptoms: Low-grade fever, malaise, weight loss, and fatigue reflect systemic inflammation and vasculitis.
• Arthralgias and arthritis: Non-erosive arthritis and arthralgia occur in 60–70% of patients, commonly affecting knees, ankles, elbows, and wrists. Joint involvement is typically oligoarticular and migratory. Morning stiffness is common but usually <1 hour duration.
• Skin manifestations: Palpable purpura (typically on lower extremities and buttocks), urticarial rash, nodules, and livedo reticularis reflect small vessel vasculitis of skin. Histology typically shows necrotizing vasculitis with eosinophilic infiltration. Cutaneous involvement occurs in 40–50% of patients.
• Peripheral neuropathy: Mononeuritis multiplex is the most common neurologic manifestation, occurring in 50–70% of patients. Patients report asymmetric weakness, foot drop, or wrist drop corresponding to single nerve territories (e.g., radial, peroneal, ulnar nerves). Distal sensorimotor polyneuropathy also occurs. Electromyography/nerve conduction studies confirm axonal damage with demyelinating features.
• Pulmonary involvement: Pulmonary hemorrhage with hemoptysis occurs in 5–15% of patients. Infiltrates on chest X-ray are typically fleeting and migratory, often described as "transient pulmonary opacities." Dyspnea worsens despite asthma treatment.
• Gastrointestinal involvement: Abdominal pain, diarrhea, and gastrointestinal bleeding reflect vasculitis of mesenteric vessels and bowel wall eosinophilic infiltration. Abdominal pain may be severe and may precede other systemic features.
• Renal involvement: ANCA-positive patients more commonly develop glomerulonephritis, manifesting as hematuria, proteinuria, and rising creatinine. Rapidly progressive glomerulonephritis with crescents can develop. Renal involvement predicts worse overall prognosis and is associated with higher mortality.

Phase 3: Organ-Specific Phase

• Cardiac involvement (most significant prognostic factor): Myocarditis, pericarditis, and myocardial infarction from coronary vasculitis occur in 20–50% of EGPA patients and account for the majority of disease-related mortality. Patients may present with chest pain, dyspnea from congestive heart failure, arrhythmias (including sudden cardiac death), or fulminant cardiogenic shock. Troponin elevation, ST-segment changes on electrocardiogram (ECG), reduced ejection fraction on echocardiography, and delayed gadolinium enhancement on cardiac magnetic resonance imaging (CMR) support myocardial involvement. Cardiac troponin elevation and reduced left ventricular ejection fraction (LVEF <40%) are major prognostic variables; endomyocardial fibrosis can develop, mimicking restrictive cardiomyopathy.

• Renal vasculitis and glomerulonephritis: Rapidly progressive glomerulonephritis with crescent formation causes acute kidney injury; patients present with hematuria, proteinuria, and rising serum creatinine. Renal biopsy shows necrotizing glomerulonephritis with crescent formation, often with eosinophilic infiltration of interstitium.

• Neurologic involvement: In addition to mononeuritis multiplex, central nervous system vasculitis (stroke, intracranial hemorrhage) and encephalitis can occur, though less frequently than peripheral neuropathy.

• Pulmonary hemorrhage: Diffuse alveolar hemorrhage presents with acute dyspnea, hemoptysis, and respiratory failure requiring mechanical ventilation.

Physical Examination Findings

• Palpable purpura on lower extremities and buttocks (hallmark finding)
• Asymmetric motor deficits (foot drop, wrist drop) from mononeuritis multiplex
• Peripheral edema (particularly lower extremities) from myocarditis and heart failure
• Cardiac arrhythmia or murmur from myocarditis/pericarditis
• Nasal polyps visible on nasal endoscopy
• Decreased breath sounds or crackles from pulmonary infiltration
• Hepatomegaly or splenomegaly (less common)
• Hypertension from renal vasculitis

Clinical Variants and Presentations

• ANCA-positive versus ANCA-negative disease: ANCA-positive patients more frequently present with systemic disease affecting kidneys, whereas ANCA-negative patients more often have cardiac and pulmonary predominant disease.
• Fulminant presentation: Rare patients present with rapidly progressive multiorgan involvement (renal failure, myocarditis, pulmonary hemorrhage) requiring immediate immunosuppression.
• Cardiac-predominant EGPA: Presents with acute myocarditis or recurrent arrhythmias; may progress to cardiomyopathy without prominent systemic features initially.

Clinical History and Risk Assessment

• Characterize asthma onset (adult-onset, severity, corticosteroid responsiveness) and evolution to systemic features
• Document timeline of constitutional symptoms, rash, arthralgia, neurologic symptoms, and organ-specific symptoms
• Obtain detailed medication history focusing on LTRA use, timing of initiation, and corticosteroid dosing
• Assess for antecedent infections and allergen exposures

Laboratory Testing

• Complete blood count with differential: Peripheral eosinophilia is nearly universal; absolute eosinophil count typically >1500/μL (normal <500/μL), often >4000/μL. Eosinophils typically comprise ≥10% of WBC differential. Mild normocytic anemia may reflect chronic inflammation; thrombocytosis is common.

• ANCA serology: Test for MPO-ANCA (p-ANCA pattern) and PR3-ANCA (c-ANCA pattern). MPO-ANCA positivity occurs in 40–60% of EGPA and correlates with renal involvement and systemic disease severity. ANCA-negative patients comprise 40–60% of cases and are associated with more favorable short-term outcomes and more cardiac involvement. ANCA testing should include both standard immunofluorescence and ELISA-based antigen-specific testing for optimal sensitivity.

• Inflammatory markers: Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) reflect systemic inflammation; however, normal values do not exclude active disease, and normalization may lag behind clinical improvement.

• Comprehensive metabolic panel and renal function: Serum creatinine and urinalysis assessment are essential to detect glomerulonephritis early. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m² at diagnosis predicts worse renal outcomes. Proteinuria and hematuria are markers of renal involvement.

• Cardiac biomarkers: Troponin I or T elevation indicates myocardial injury; troponin elevation is a major prognostic marker associated with increased mortality. B-type natriuretic peptide (BNP) or N-terminal pro-BNP elevation suggests myocardial dysfunction and heart failure.

• Immunoglobulin E (IgE): Total serum IgE is markedly elevated (often >1000 IU/mL, normal <150 IU/mL) and supports diagnosis. Allergen

Immediate stabilisation (severe disease)

• Pulse IV glucocorticoids: methylprednisolone for alveolar hemorrhage, fulminant myocarditis, rapidly progressive glucomerulonephritis, or progressive mononeuritis multiplex — rapidly suppresses eosinophil survival and vascular inflammation while definitive immunosuppression takes effect.
• Airway/hemodynamic support: mechanical ventilation for diffuse alveolar hemorrhage; ICU care and heart-failure management for cardiogenic shock. Cardiac involvement drives most EGPA mortality, so troponin, ECG, and echocardiography are obtained up front.

Remission induction

• Severe disease — glucocorticoids plus a cytotoxic/B-cell agent: ACR/VF recommends cyclophosphamide or rituximab added to high-dose oral prednisone with taper. Rituximab is often favored in ANCA-positive (MPO-ANCA) patients and in those wishing to preserve fertility.
• Non-severe disease — glucocorticoids plus anti–IL-5 therapy: mepolizumab, an anti–IL-5 monoclonal antibody, is FDA-approved for EGPA and is conditionally recommended by ACR/VF as add-on therapy; it starves eosinophils of their key survival cytokine and is markedly steroid-sparing. Benralizumab (anti–IL-5 receptor α) is also now approved for EGPA.
• Plasma exchange: not routine. Following PEXIVAS, ACR/VF conditionally recommends against it, reserving consideration for severe glomerulonephritis or concomitant anti-GBM disease.

Maintenance

• Steroid-sparing agents: azathioprine, methotrexate, or mycophenolate; rituximab for maintenance after rituximab induction. Continue asthma controller therapy (inhaled corticosteroid/LABA).

Cautions and contraindications

• Avoid abrupt glucocorticoid withdrawal — vasculitis may be unmasked as steroids are tapered.
• Cyclophosphamide: give mesna and hydration; avoid in pregnancy; counsel on gonadotoxicity.
• Rituximab: screen HBsAg/anti-HBc before dosing; live vaccines are contraindicated during immunosuppression.
• PJP prophylaxis with trimethoprim-sulfamethoxazole during cyclophosphamide/high-dose steroid therapy.

Disease-related complications

• Cardiac vasculitis and eosinophilic myocarditis (emergency): eosinophil granule proteins and coronary arteritis produce myocarditis, arrhythmia, infarction, and endomyocardial fibrosis with a restrictive physiology. Signalled by troponin elevation, falling ejection fraction, or late gadolinium enhancement on cardiac MRI. This is the leading cause of EGPA death and includes sudden cardiac death.
• Diffuse alveolar hemorrhage (emergency): capillaritis of the alveolar bed; suggested by hemoptysis, diffuse infiltrates, and a falling hematocrit with rising DLCO.
• Rapidly progressive glomerulonephritis (emergency): pauci-immune crescentic GN, more common in MPO-ANCA-positive patients; signalled by dysmorphic hematuria, RBC casts, and a rising creatinine over days.
• Mesenteric vasculitis with bowel infarction or perforation (emergency): severe abdominal pain out of proportion to exam, GI bleeding, or peritonitis.
• Mononeuritis multiplex with permanent deficit: vasa nervorum occlusion causes axonal infarction; foot drop or wrist drop that persists after remission because axonal regrowth is slow and incomplete.
• Venous thromboembolism: active vasculitis and eosinophil-driven procoagulant activity raise VTE risk.
• CNS involvement: ischemic or hemorrhagic stroke from cerebral vasculitis.

Treatment-related complications

• Glucocorticoid toxicity: hyperglycemia, osteoporosis with fragility fracture, avascular necrosis of the femoral head, cataracts, and adrenal suppression on taper.
• Cyclophosphamide: acrolein-mediated hemorrhagic cystitis (hematuria; prevented with mesna and hydration), late bladder carcinoma, myelodysplasia/leukemia, and premature ovarian failure or azoospermia.
• Rituximab: hypogammaglobulinemia with recurrent sinopulmonary infection, hepatitis B reactivation, and rare progressive multifocal leukoencephalopathy.
• Opportunistic infection (potentially emergent): Pneumocystis jirovecii pneumonia presenting as hypoxemia with a relatively clear chest film — the reason TMP-SMX prophylaxis accompanies intensive immunosuppression.

• The classic triad: adult-onset, steroid-dependent asthma + peripheral eosinophilia >10% of the differential + mononeuritis multiplex (foot drop/wrist drop). This trio in a vignette is EGPA until proven otherwise.
• The single best next step in a newly diagnosed patient is cardiac assessment — troponin, ECG, and echocardiography (cardiac MRI if equivocal). Cardiac involvement, not renal disease, is the dominant cause of EGPA mortality, and it can be clinically silent.
• The serology examiners test: MPO-ANCA (p-ANCA), positive in only about half of patients. A negative ANCA does not exclude EGPA — ANCA-negative disease skews toward cardiac and pulmonary involvement, ANCA-positive toward glomerulonephritis and neuropathy.
• Biopsy buzzword: necrotizing vasculitis of small vessels with extravascular eosinophilic granulomas and dense tissue eosinophilia.
• The drug association: leukotriene receptor antagonists (montelukast) preceding disease onset — best explained as unmasking during steroid taper, not direct drug toxicity. Do not answer that montelukast is contraindicated in all asthmatics.
• Treatment split: severe/organ-threatening disease gets glucocorticoids plus rituximab or cyclophosphamide; non-severe disease gets glucocorticoids plus mepolizumab (anti–IL-5), per the 2021 ACR/Vasculitis Foundation guideline.

Distractors to avoid

• Granulomatosis with polyangiitis: PR3-ANCA/c-ANCA, destructive upper-airway disease with saddle-nose deformity and cavitary nodules — asthma and eosinophilia are absent.
• Microscopic polyangiitis: MPO-ANCA with pulmonary-renal syndrome but no asthma, no granulomas, no eosinophilia.
• Hypereosinophilic syndrome: eosinophilia and cardiac damage but no vasculitis and no ANCA; the FIP1L1-PDGFRA fusion variant responds to imatinib.
• Polyarteritis nodosa: medium-vessel, ANCA-negative, hepatitis B–associated, spares the lungs.