Eosinophilic Granulomatosis with Polyangiitis

Overview

EGPA (formerly Churg-Strauss syndrome) is a rare, small-to-medium vessel necrotizing vasculitis characterized by asthma, eosinophilia, and extravascular granulomas. It commonly affects the lungs, skin, peripheral nerves, and heart. Annual incidence: ~1–3 per million; peak onset in 40s–60s; no significant gender bias. Strongly associated with MPO-ANCA positivity in ~40–60% of patients; others are ANCA-negative.

Physiology

Eosinophil Function

• Primary role: Defense against parasites and involvement in allergic and eosinophilic inflammatory responses
• Cytotoxic action via release of:
  • Major Basic Protein (MBP) – damages parasites, host tissue
  • Eosinophil Cationic Protein (ECP) – antiviral, cytotoxic
  • Eosinophil Peroxidase (EPO) – generates reactive oxygen species
  • Eosinophil-Derived Neurotoxin (EDN) – neurotoxic effects
• Contribute to tissue damage and fibrosis in diseases like EGPA, asthma, and eosinophilic esophagitis
• Regulate local immune response by releasing cytokines, chemokines, and lipid mediators (e.g., leukotrienes)

Key Cytokines in Eosinophil Production and Activation
Cytokine	Function
IL-5	Most important; stimulates eosinophil growth, differentiation, activation, and survival in tissues
IL-3	Promotes early eosinophil progenitor development from bone marrow
GM-CSF	Enhances eosinophil activation and prolongs survival
IL-4 / IL-13	Promote Th2 differentiation, leading to more IL-5 production
Eotaxins (CCL11, CCL24)	Chemokines that recruit eosinophils to sites of inflammation (especially in lungs and GI tract)

Aetiology and Risk Factors

Aetiology

• Idiopathic; suspected immune dysregulation with eosinophilic activation
• Hypersensitivity response to allergens or autoantigens
  

Risk Factors

• History of asthma or allergic rhinitis
• Atopy, nasal polyposis
• Certain medications (e.g., leukotriene receptor antagonists like montelukast, though likely unmasking latent disease)
  

Pathophysiology

• Phase 1: Prodromal (Allergic phase)
  • Chronic rhinosinusitis, asthma, nasal polyps
  • Eosinophilic asthma 
• Phase 2: Eosinophilic phase
  • Marked blood and tissue eosinophilia → eosinophilic pneumonitis, gastroenteritis
• Phase 3: Vasculitic phase
• Necrotizing vasculitis ± granulomas of small/medium vessels; systemic organ damage (nerves, skin, heart)

Clinical Manifestations

• ENT & Respiratory
  • Adult-onset asthma (nearly universal)
  • Nasal polyps, allergic rhinitis
  • Pulmonary infiltrates (transient, patchy)
  • Pleural effusion, hemoptysis (rare)
• Mononeuritis multiplex (~70%): foot drop, wrist drop
• Skin: Palpable purpura, nodules, livedo reticularis
• Cardiac: Myocarditis, pericarditis, heart failure; leading cause of death
• Renal: Mild proteinuria, hematuria. Glomerulonephritis less common than in GPA/MPA
• Eosinophilic gastroenteritis
  

Diagnosis

Classification Criteria (2022 ACR/EULAR)

Entry Requirement: A diagnosis of small- or medium-vessel vasculitis has been made (biopsy), and other mimicking conditions have been excluded.
Variables	GPA	MPA	EGPA
Clinical criteria
Nasal passage involvement	+3	−3	—
Cartilaginous involvement	+2	—	—
Conductive or sensorineural hearing loss	+1	—	—
Obstructive airway disease	—	—	+3
Nasal polyp	—	—	+3
Mononeuritis multiplex	—	—	+1
Laboratory criteria
PR3-ANCA (or C-ANCA) positivity	+5	−1	−3
MPO-ANCA (or P-ANCA) positivity	−1	+6	—
Serum eosinophil ≥1000/µL	−4	−4	+5
Hematuria	—	—	−1
Histological criteria
Granuloma, granulomatous inflammation, or giant cells	+2	—	—
Pauci-immune glomerulonephritis	+1	+3	—
Extravascular eosinophilic-predominant inflammation	—	—	+2
Radiological criteria
Pulmonary nodules, mass, or cavitation on chest imaging	+2	—	—
Fibrosis or ILD on chest imaging	—	+3	—
Nasal/paranasal sinusitis or mastoiditis on imaging	+1	—	+1
Total Score Cut-off for Classification	≥5	≥5	≥6

Investigations

• Eosinophilia ≥10%
• ANCA panel: MPO-ANCA positive (~40–60%)
• ESR/CRP: elevated
• IgE: usually elevated
• Imaging: CT chest (transient infiltrates, effusions)
• Biopsy (skin, nerve, lung): eosinophilic infiltration ± granulomas
  

Differential Diagnoses

Diagnosis	Key Differences
Eosinophilic asthma	Chronic airway inflammation with mild to moderate eosinophilia. Only lung involvement, no systemic vasculitis.
Hypereosinophilic syndrome	Persistent eosinophilia without vasculitis or parasitic infection
Allergic bronchopulmonary aspergillosis	Asthma + eosinophilia, but lacks systemic vasculitis

Treatment

Phase	Treatment
Mild (non-severe)	Glucocorticoids taper ± Mepolizumab
Severe (organ/life-threatening)	High-dose glucocorticoids + cyclophosphamide or rituximab
Maintenance	Glucocorticoid taper + Mepolizumab, azathioprine, methotrexate, or rituximab

Supportive

• Pneumocystis prophylaxis (e.g. TMP-SMX)
• Cardiac monitoring if involvement suspected
• Vaccinations (influenza, pneumococcal, shingles)
  

Complications and Prognosis

Complications

• Heart failure (due to myocarditis)
• GI perforation
• Relapsing neuropathy
• Steroid toxicity
  

Prognosis

• 5-year survival ~80–90%
• Poor prognostic factors (Five-Factor Score):
  
  • Proteinuria >1g/day
  • Renal insufficiency
  • GI involvement
  • Cardiomyopathy
  • CNS involvement
    

References

1. Groh M et al. JAMA. 2013;309(20):2068–2075.
   
2. Jennette JC et al. Kidney Int. 2013;83(2):227–234.
   
3. Robson JC et al. Ann Rheum Dis. 2022;81(3):309–320.
   
4. Comarmond C et al. Arthritis Rheum. 2013;65(11):3176–3182.
   
5. Samson M et al. Eur Respir Rev. 2017;26(145):170083.