SLIDE 1 - Title Slide

SLIDE 2 - Historical Background & Nomenclature

• First described in 1951 by Jacob Churg and Lotte Strauss who reported necrotizing vasculitis in multiple organs with eosinophilic tissue inflammation and extravascular granulomas in asthmatic patients with fever and peripheral eosinophilia
• Earlier in 1939, Rackemann and Greene had described a subgroup of polyarteritis nodosa patients with concomitant allergic disease
• Renamed from "Churg-Strauss Syndrome" (CSS) to EGPA by the 2012 Revised International Chapel Hill Consensus Conference Nomenclature for vasculitides
• Belongs to the ANCA-associated vasculitides (AAV) group, alongside Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)

Sources: Harrison's 22E; Fishman's Pulmonary; Scott-Brown's ENT

SLIDE 3 - Epidemiology

• Uncommon but may be underdiagnosed due to variable clinical presentation
• Can occur at any age except infants

Sources: Harrison's 22E; Fishman's Pulmonary; Murray & Nadel

SLIDE 4 - Classification (Where EGPA Sits)

ANCA-Associated Vasculitides
├── Granulomatosis with Polyangiitis (GPA) — c-ANCA/PR3
├── Microscopic Polyangiitis (MPA) — p-ANCA/MPO
└── Eosinophilic GPA (EGPA) — p-ANCA/MPO (~40-50%)

• Prominent asthma (nearly universal, 96-100%)
• Marked peripheral eosinophilia (>10% or >1000 cells/µL)
• ANCA is only positive in ~40-50% of cases (vs. higher rates in GPA/MPA)
• Lower rate of renal involvement compared to GPA and MPA
• Unique cardiac involvement not typical of other AAV

Sources: Harrison's 22E; Fitzpatrick's Dermatology; Braunwald's Heart Disease

SLIDE 5 - Pathology & Pathogenesis

1. Necrotizing vasculitis - involving small to medium vessels with fibrinoid necrosis
2. Eosinophilic tissue infiltration - diffuse infiltration of tissues by eosinophils
3. Extravascular granulomas - palisaded granulomas, often present within vessel walls; differ from GPA granulomas in that they generally lack multinucleated giant cells and have an eosinophil-rich core

• Strong association with asthma and atopy points to aberrant immunologic phenomena
• Eosinophils release major basic protein and eosinophil-derived neurotoxin causing direct tissue injury (especially cardiac)
• Th2 immune skewing with IL-4, IL-5, IL-13 elevation drives eosinophilia
• IL-5 is central - drives eosinophil production, survival, and activation
• ANCA (anti-MPO) present in ~40-50% - may contribute to neutrophil activation
• Increased rates of arterial and venous thrombosis linked to dense eosinophilic infiltrates

• ANCA-positive (p-ANCA/MPO): Higher incidence of renal involvement, peripheral nerve disease, alveolar hemorrhage; features more like "classic" AAV vasculitis
• ANCA-negative: More likely to have cardiopulmonary complications (myocarditis, cardiomyopathy)

Sources: Harrison's 22E; Andrews' Diseases of the Skin; Braunwald's Heart Disease; Fishman's Pulmonary

SLIDE 6 - The Three Clinical Phases

Phase 1: Prodromal / Allergic Phase

• Duration: Months to many years (typically 8-10 years before EGPA recognition; up to 30 years reported)
• Features: Allergic rhinitis, nasal polyposis, late-onset asthma (mean onset age 35 years, unlike childhood allergic asthma), drug sensitivities
• The asthma is often severe, poorly controlled, and adult-onset
• Asthma typically precedes vasculitis by 3-6 years

Phase 2: Eosinophilic Phase

• Remarkably high peripheral blood eosinophilia (can reach 20-90%)
• Eosinophilic tissue infiltration of: lungs (eosinophilic pneumonia), GI tract, skin, and other organs

Phase 3: Vasculitic Phase

• Systemic necrotizing vasculitis affecting multiple organs
• Heralded by constitutional symptoms: fever, malaise, weight loss, arthralgias, myalgias
• Onset typically ~3 years after initial symptoms
• Asthma may persist, worsen, or temporarily improve during this phase

Important: Phases overlap and may not appear in strict order; asthma/rhinosinusitis rarely arise after vasculitic manifestations.

Sources: Goldman-Cecil Medicine; Andrews' Diseases of the Skin; Fishman's Pulmonary; Scott-Brown's ENT

SLIDE 7 - Clinical Manifestations (System-by-System)

Pulmonary (Most Dominant - Nearly Universal)

• Asthma: Present in 96-100%; the most consistent feature
• Pulmonary infiltrates: Present in 30-70% on chest X-ray (transient, migratory, bilateral)
• Eosinophilic pneumonia
• Diffuse alveolar hemorrhage (DAH) is rare in EGPA (<5%)
• Pleural effusions (less common)

Chest radiograph showing pulmonary infiltrates in EGPA - Scott-Brown's Otorhinolaryngology

Neurological (2nd Most Common)

• Mononeuritis multiplex: Occurs in up to 63-93% of patients; most common form of neuropathy
• Acute, painful, asymmetrical peripheral neuropathy
• Involves both sensory and motor fibers
• Mechanism: necrotizing vasculitis of the vasa nervorum (identical to polyarteritis nodosa histologically, but with more intense eosinophilic infiltration)
• Cranial nerve involvement is less common

ENT / Upper Airway

• Allergic rhinitis and sinusitis: Up to 61% of patients; often the first manifestation
• Nasal polyps: ~50% of patients; characteristically recur after surgery unless immunosuppressive therapy is given
• Paranasal sinusitis present in ACR classification criteria

Cardiac (Major Cause of Mortality)

• Occurs in 14-60% of patients (variable by series)
• Spectrum includes: pericarditis, myocarditis, coronary arteritis, myocardial infarction, restrictive/dilated/congestive cardiomyopathy, valvular dysfunction, arterial thrombosis
• Mechanism: Eosinophilic infiltration of myocardium + granulomatous inflammation + direct toxicity from major basic protein and eosinophil-derived neurotoxin
• Cardiomyopathy from ischemia secondary to arteritis of intramyocardial arteries
• Cardiac disease is the most frequent cause of death (responsible for 39% of mortality)
• ANCA-negative patients are at greater risk for cardiac complications

Skin (~51-78% of patients)

• Palpable purpura: ~50% (reflects vasculitis histologically)
• Subcutaneous nodules: ~30%, on extensor surfaces of extremities and scalp
• Eosinophilic dermatitis, granulomatous dermatitis producing erythematous macules, papules, nodules
• Urticaria, livedo reticularis, solar urticaria
• Plaques resembling Wells syndrome (eosinophilic cellulitis)
• Firm, nontender papules on fingertips (may mimic septic emboli)
• Skin biopsy: small-vessel vasculitis with intense eosinophilic infiltrate; palisaded granulomas with eosinophil-rich core (no multinucleated giant cells)

Renal

• Less common than in GPA or MPA
• Focal segmental necrotizing glomerulonephritis (with or without crescents)
• Renal insufficiency in a subset of patients
• More common in ANCA-positive patients

Gastrointestinal

• Abdominal pain, diarrhea, GI bleeding
• Eosinophilic gastroenteritis
• GI involvement is a poor prognostic factor

Constitutional

• Fever, malaise, anorexia, weight loss (nonspecific but characteristic of multisystem disease)

Sources: Harrison's 22E; Braunwald's Heart Disease; Adams & Victor's Neurology; Fishman's Pulmonary; Andrews' Diseases of the Skin; Fitzpatrick's Dermatology

SLIDE 8 - Laboratory Findings

• ANCA+: More renal, peripheral nerve, DAH involvement
• ANCA-: More cardiac, pulmonary involvement

Sources: Harrison's 22E; Fishman's Pulmonary; Braunwald's Heart Disease; Washington Manual

SLIDE 9 - Diagnostic Criteria (ACR 1990 Classification)

1. Asthma
2. Peripheral blood eosinophilia
3. Clinical features consistent with vasculitis

Note: The 2022 ACR/EULAR classification criteria (updated) are now used in research settings; the diagnosis remains clinical in practice.

Sources: Harrison's 22E; Scott-Brown's ENT; Andrews' Diseases of the Skin

SLIDE 10 - Differential Diagnosis

Sources: Braunwald's Heart Disease; Adams & Victor's; Fishman's

SLIDE 11 - Prognosis - Five Factor Score (FFS)

1. Renal insufficiency (serum creatinine >1.58 mg/dL)
2. Clinically significant GI disease (bleeding, perforation, infarction, pancreatitis)
3. Cardiac symptoms (cardiomyopathy, infarction)
4. Age ≥65 years
5. Absence of upper airway (ENT) involvement (its presence is protective - indicates a more limited phenotype)

• Cardiac or GI involvement = worse prognosis
• Without treatment: 5-year survival 25%
• With treatment: 78-month actuarial survival 72%; remission in >90% of patients

Sources: Murray & Nadel; Fishman's Pulmonary; Harrison's 22E

SLIDE 12 - Treatment Overview

General Principle

Step 1: Induction of Remission

• Prednisone 1 mg/kg/day (typically 40-60 mg/day) orally, or IV methylprednisolone pulses for severe disease
• Achieves remission in >80-90% of patients as monotherapy for mild-moderate disease
• Tapering is often limited by persistent asthma

• Indicated when: neurological involvement, cardiac involvement, renal involvement, severe GI disease, CNS involvement
• Oral daily or IV pulse cyclophosphamide + prednisone
• After remission (3-6 months), replace CYC with azathioprine or methotrexate

Step 2: Maintenance of Remission

• Azathioprine or Methotrexate (or leflunomide) as steroid-sparing agents
• Rituximab - increasingly used especially in ANCA-positive patients with glomerulonephritis or severe small-vessel vasculitis (data still emerging for EGPA specifically)
• Mycophenolate mofetil (MMF) - alternative option

Step 3: Biologic Therapy - Anti-IL-5 Agents (MAJOR ADVANCE)

Mepolizumab (Anti-IL-5 monoclonal antibody)

• FDA-approved for EGPA (2017)
• Dose: 300 mg subcutaneously every 4 weeks
• Phase 3 RCT: More weeks in remission (28% vs 3%), higher remission rate (32% vs 3%) vs. placebo
• Significantly reduces oral glucocorticoid requirements
• Should NOT be used for severe/life-threatening disease
• Best role: Relapsing or resistant asthma requiring glucocorticoids, sinus disease, mild-moderate eosinophilic disease, mild vasculitis

Benralizumab (Anti-IL-5Rα monoclonal antibody) - 2024 NEJM MANDARA Trial

• Dose: 30 mg subcutaneously every 4 weeks
• Phase 3 RCT (MANDARA, 2024, NEJM, PMID 38393328): Benralizumab was noninferior to mepolizumab for induction of remission in relapsing/refractory EGPA
  • Remission at weeks 36 and 48: Benralizumab 59% vs. Mepolizumab 56%
  • Complete oral glucocorticoid withdrawal in 41% (benralizumab) vs. 26% (mepolizumab) - advantage for benralizumab
  • Eosinophil counts reduced to near-zero with benralizumab (32 vs 72/µL at week 52)
  • Serious adverse events: 6% (benralizumab) vs. 13% (mepolizumab)

Omalizumab (Anti-IgE)

• Beneficial for EGPA with predominantly asthma and sinonasal disease

Other agents used in refractory/special cases:

• IFN-α, IVIG - used in some refractory cases
• Leukotriene receptor antagonists - may be beneficial but note association with EGPA unmasking
• Anti-TNF agents (infliximab, etanercept) - limited reports

Treatment Summary Table

Sources: Harrison's 22E; Goldman-Cecil; Andrews' Diseases of the Skin; Washington Manual; Braunwald's Heart Disease; PMID 38393328 (NEJM 2024); PMID 37161084 (Nat Rev Rheumatol 2023)

SLIDE 13 - Cardiac Management (Special Focus)

• Echocardiography + 12-lead ECG should be performed in ALL newly diagnosed patients
• Cardiac MRI is the most sensitive tool for myocardial involvement
• Endomyocardial biopsy if diagnosis is in doubt (low yield due to patchy disease)
• Common echo findings: LV dilatation in 30%, reduced shortening fraction, increased wall echogenicity
• High-dose glucocorticoids typically produce good cardiac response (90% remission)
• For severe cardiac involvement: pulsed IV cyclophosphamide is first choice
• Congestive heart failure from granulomatous myocardial inflammation = most frequent cause of death
• Increased risk of arterial and venous thrombosis - consider anticoagulation

Sources: Braunwald's Heart Disease; Harrison's 22E

SLIDE 14 - Neurological Manifestations (Special Focus)

• Neuropathy occurs in ~three-quarters of patients
• Mononeuritis multiplex is the most common pattern: acute, painful, asymmetrical
• Histology: vasculitic changes in nerve biopsies similar to PAN, but more intense eosinophilic infiltration
• Fever and weight loss typically precede neuropathy
• c-ANCA/p-ANCA found in >50% of cases (note: Adams & Victor states c-ANCA but most current sources favor p-ANCA/MPO)
• Distinguishing from Hypereosinophilic Syndrome (HES): HES causes diffuse nerve infiltration by eosinophils (not vasculitis), producing a painful diffuse sensorimotor neuropathy
• Association with leukotriene receptor antagonist (zafirlukast) use has been reported - may be drug-triggered or unmasking of disease
• Treatment: corticosteroids initially; rituximab, AZA, MTX, cyclophosphamide for fulminant/refractory neuropathy

Sources: Adams & Victor's Neurology 12E

SLIDE 15 - Association with Asthma Medications

• The development of EGPA has been associated with several asthma therapies:
  • Leukotriene receptor antagonists (LTRAs): e.g., zafirlukast, montelukast
  • 5-lipoxygenase inhibitors
  • Inhaled glucocorticoids
  • Omalizumab
  • Macrolide antibiotics (e.g., azithromycin), estrogen, carbamazepine
• Debated mechanism: These steroid-sparing agents may unmask pre-existing EGPA by allowing reduction of systemic corticosteroid dose, rather than directly causing the disease
• A short duration between asthma onset and vasculitis is associated with increased severity of vasculitis

Sources: Fishman's Pulmonary; Adams & Victor's Neurology

SLIDE 16 - Prognosis & Follow-Up

• Untreated: 5-year survival ~25% (poor prognosis)
• With treatment: >90% achieve clinical remission; 78-month actuarial survival ~72%
• Relapses occur in 25-40%, usually heralded by:
  • Return of peripheral blood eosinophilia
  • Worsening asthma during steroid taper
• Most patients cannot fully discontinue glucocorticoids primarily due to persistent asthmatic symptoms
• 5-year mortality by FFS: 0 = ~11%, 1 = ~26%, ≥2 = ~46%
• Main cause of death: Myocardial involvement (39% of deaths)
• Monitoring: Serial eosinophil counts, ESR/CRP, renal function, echo (cardiac monitoring), clinical assessment of asthma and neuropathy
• 2023 Nature Reviews Rheumatology guidelines (PMID 37161084) recommend a multidisciplinary approach, with 16 evidence-based statements covering diagnosis, staging, treatment, and follow-up

Sources: Harrison's 22E; Goldman-Cecil; Murray & Nadel; PMID 37161084

SLIDE 17 - Summary Slide

SLIDE 18 - References (Key Sources)

• Fauci AS et al. Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Ch. on Vasculitis
• Goldman L. Goldman-Cecil Medicine, International Ed. (2025)
• Zipes DP. Braunwald's Heart Disease, 12th Ed. - Cardiovascular manifestations of EGPA
• Weedon D. Andrews' Diseases of the Skin, 13th Ed. - Cutaneous vasculitis
• Fishman AP. Fishman's Pulmonary Diseases and Disorders, 6th Ed. - EGPA chapter
• Murray JF. Murray & Nadel's Textbook of Respiratory Medicine, 7th Ed.
• Ropper AH. Adams and Victor's Principles of Neurology, 12th Ed.
• Cummings CW. Scott-Brown's Otorhinolaryngology Head & Neck Surgery

1. Emmi G et al. "Evidence-Based Guideline for the diagnosis and management of EGPA." Nature Reviews Rheumatology, 2023. PMID 37161084
2. Wechsler ME et al. "Benralizumab versus Mepolizumab for EGPA (MANDARA Trial)." NEJM, 2024;390:911-921. PMID 38393328
3. Solans-Laqué R et al. "Red flags for clinical suspicion of EGPA." Eur J Intern Med, 2024. PMID 38880725

Tips for Your PPT

1. Use the three-phase diagram as a visual on Slide 6 - draw an arrow timeline with phases labeled; it's the most frequently tested concept
2. Highlight the ANCA phenotype split (ANCA+ vs. ANCA-) on Slides 5 and 8 - this is a high-yield distinction
3. Cardiac involvement deserves its own slide - examiners love asking about the most common cause of death
4. Include the FFS table with 5-year mortality - makes for a clean, memorable slide
5. The MANDARA 2024 trial (benralizumab vs. mepolizumab, NEJM) is very recent and will impress your audience - include the key numbers (59% vs. 56% remission, 41% vs. 26% glucocorticoid withdrawal)
6. Use the CXR image from Scott-Brown's (above) showing bilateral infiltrates to illustrate the pulmonary phase
7. Distinguish from GPA with a comparison table - commonly tested in rheumatology exams