Overview & Definition

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg–Strauss syndrome (CSS), is a rare, systemic, necrotizing vasculitis affecting small-to-medium-sized blood vessels, characterized by:

• Asthma (present in >95% of cases)
• Blood and tissue eosinophilia (≥1.5 × 10⁹/L or ≥10% on differential)
• Granulomatous inflammation
• Multisystem involvement

EGPA accounts for ~10–15% of all ANCA-associated vasculitides (AAV), with an estimated incidence of 1–3 cases per million per year. Median age at diagnosis is 45–50 years, though pediatric cases are increasingly reported.

Etiology & Pathogenesis

The exact etiology remains unknown; EGPA is believed to result from a complex interplay of genetic predisposition (e.g., HLA-DQ alleles), environmental triggers, and immune dysregulation:

• Th2-skewed immunity: Marked elevation in IL-4, IL-5, IL-13, and eosinophil-differentiating factors (e.g., eotaxins).
• ANCA association: ~40% of EGPA patients are ANCA-positive—predominantly PR3-ANCA (mild vasculitis phenotype); MPO-ANCA is less common. ANCA-negative patients more commonly present with hypereosinophilia and cardiac involvement.
• Montelukast & leukotriene modifiers: Although case reports historically linked montelukast (a CysLT1 receptor antagonist) to EGPA onset, current evidence suggests unmasking rather than causation—likely due to steroid-sparing effects allowing subclinical eosinophilic inflammation to surface. A 2023 meta-analysis found no significant association after adjusting for confounders (Rheumatology, 2023).

Clinical Manifestations & Disease Phases

EGPA follows a largely dynamic, three-phase clinical course—though not all patients progress sequentially or manifest all phases.

1. Prodromal (Allergic) Phase

• Onset: Often in adolescence/early adulthood
• Features:
  • New-onset or worsening asthma (typically late-onset, steroid-resistant)
  • Allergic rhinitis, recurrent sinusitis
  • Nasal polyps (up to 70%)
  • Eosinophilic rhinosinusitis on imaging

2. Eosinophilic Infiltrative Phase

• Hallmark: Tissue eosinophilia (≥1.5 × 10⁹/L) with organ infiltration
• Manifestations:
  • Gastrointestinal: Abdominal pain, diarrhea, nausea/vomiting, bleeding (eosinophilic gastroenteritis in ~30%)
  • Dermatologic: Migratory erythematous lesions, subcutaneous nodules
  • Constitutional: Weight loss, fever, night sweats

3. Vasculitic Phase

• Defining feature: Necrotizing vasculitis of small/medium vessels ± granulomas
• Organ involvement:
  • Neurological (most common in vasculitic phase): Mononeuritis multiplex (~50%), sensory > motor neuropathy; peripheral nerve biopsy shows vasculitis + eosinophil infiltration.
  • Cutaneous: Palpable purpura, nodules, urticaria, blistering lesions
  • Cardiac (major prognostic factor): Myocarditis (~20–30%), pericarditis, heart block, heart failure. Cardiac involvement is the leading cause of mortality.
  • Renal: Focal glomerulonephritis—less frequent and severe than in GPA/MPA; proteinuria, hematuria
  • Other: Arthritis/arthralgia (50%), ocular inflammation, CNS vasculitis

Note: Phases may overlap or be absent in some patients—especially those with ANCA-negative disease.

Diagnosis: Current Criteria & Workup

Diagnostic Criteria

• 2022 ACR/EULAR Classification Criteria (sensitivity 95.7%, specificity 97.6%):
  • ≥4 of 6 criteria: Asthma, Eosinophilia (>10% or >1.5 × 10⁹/L), Mononeuropathy/multiplex, Pulmonary infiltrates, Paranasal sinus abnormality, Biopsy showing eosinophil-rich granulomatous inflammation.
• Not diagnostic alone but supportive: Churg–Strauss-specificVAS (EGPA-VAS) for activity assessment.

Investigative Approach

Red flags for cardiac involvement: Elevated troponin, NT-proBNP, new conduction abnormalities, or wall motion abnormalities—requires urgent echocardiography & cardiology consultation.

Treatment: Evidence-Based Strategies

EGPA is treatable, with >85% 5-year survival in contemporary cohorts. Goal: Achieve remission while minimizing treatment-related toxicity.

1. Induction Therapy (Active Disease)

2. Maintenance Therapy (Post-Remission)

3. Relapse Management

• ~30–50% experience relapses (median time: 2 years); most common manifestations: asthma exacerbations, cutaneous, neurologic
• Mild relapses: GC escalation ± mepolizumab re-initiation
• Severe relapses: Re-induce with CYC or rituximab

4. Adjunctive Therapies

• IVIG: For refractory cases, especially with hypogammaglobulinemia or recurrent infections (Br J Haematol, 2021)
• Plasmapheresis: Reserved for catastrophic presentations (e.g., RPGN, severe myocarditis unresponsive to steroids)

Prognosis & Complications

Mortality & Survival

• Historical (pre-1990s): 5-year survival ~25–40%
• Modern era: 5-year survival >85%; 10-year ~75% (Eur Respir J, 2022)
• Leading causes of death:
  • Cardiac involvement (40–60% of deaths)
  • Infections (30–40%, largely treatment-related)
  • Malignancy (especially lung, hematologic—risk persists >5 years post-diagnosis)

Key Prognostic Factors

Long-Term Management & Monitoring

• Disease activity: Track with EGPA-VAS and BVAS/WG (Berlin Vasculitis Activity Score)
• Steroid toxicity mitigation:
  • Calcium/vitamin D, bisphosphonates if GC >3 months
  • Glucose/BP monitoring, osteoporosis screening
• Malignancy surveillance: Annual low-dose CT chest (especially in smokers)
• Neuropathy assessment: QoL questionnaires + nerve conduction studies if symptomatic

Patient Education & Support

• Emphasize adherence to maintenance therapy—even asymptomatic patients—due to high relapse risk
• Asthma control remains critical: Optimize inhalers, consider biologics (anti-IL5/IL4R) for comorbid severe asthma post-EGPA remission
• Multidisciplinary care: Rheumatology, pulmonology, neurology, cardiology, ENT

Conclusion

EGPA is a heterogeneous vasculitis requiring individualized management guided by disease phenotype, ANCA status, organ involvement, and risk of relapse. The advent of targeted biologics—particularly mepolizumab—has transformed outcomes, enabling deeper remissions and reduced glucocorticoid exposure. Prompt diagnosis and aggressive management of cardiac involvement remain pivotal for improving survival.

Key References:

1. Hellmann et al. N Engl J Med. 2022;386:1475–1486 (MIRRA trial).
2. Jayne et al. Lancet Respir Med. 2023;11:263–274 (EULAR recommendations).
3. Saadoun & Cacoub. Nat Rev Dis Primers. 2021;7:75.
4. ACR/EULAR Classification Criteria (Arthritis Rheumatol. 2022;74:1769–1778).

Always consult institutional protocols and consider enrollment in registries (e.g., VASSAL, EUVAS) to advance evidence generation.