What are the pathophysiology, signs, and symptoms of Eosinophilic Granulomatosis with Polyangiitis (eGPA)?

Pathophysiology, Signs, and Symptoms of Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare small-vessel vasculitis characterized by eosinophil-rich granulomatous inflammation of the respiratory tract and necrotizing vasculitis, with a pathophysiology driven by dysregulated Th2 immune responses and eosinophilic infiltration causing tissue damage across multiple organ systems. 1

Pathophysiology

Immunological Mechanisms

• Genetic factors: Associated with HLA-DRB1*04 and *07 alleles, HLA-DRB4, and HLA-DQ (particularly in MPO-ANCA positive patients) 1
• Cellular mechanisms:
  • Eosinophils are central to disease pathogenesis, mediating tissue damage 1
  • T-cell dysregulation with predominant Th2 responses producing IL-4, IL-13, and IL-5 1
  • Late-stage disease shows involvement of Th1 and Th17 cells producing IL-17a 1
  • Type 2 innate lymphoid cells promote vascular permeability and eotaxin secretion 1

Pathogenic Cascade

1. Endothelial and epithelial cells produce eotaxin-3, contributing to eosinophilic tissue infiltration 1
2. Activated eosinophils release eosinophilic cationic protein causing tissue damage 1
3. Eosinophils secrete IL-25, which elicits further Th2 responses, creating a self-perpetuating inflammatory cycle 1
4. B-cell dysregulation leads to ANCA production (in ~40% of cases) and increased IgG4 levels 1

Environmental Triggers

• Exposure to allergens, drugs, vaccinations, and pulmonary infections may initiate the inflammatory cascade 1
• Silica, organic solvents, and farming exposure increase risk, while cigarette smoking is associated with lower risk 1

Clinical Presentation

Disease Evolution

EGPA typically evolves through three phases (though they often overlap and may not follow this sequence) 1:

1. Prodromic "allergic" phase:

   • Can last several years
   • Characterized by asthma and chronic rhinosinusitis

2. Eosinophilic phase:

   • Marked by peripheral eosinophilia
   • Initial organ involvement appears

3. Vasculitic phase:

   • Small-vessel vasculitis manifestations develop
   • Features like mononeuritis multiplex and glomerulonephritis appear

Clinical Phenotypes Based on ANCA Status

ANCA-positive (30-40% of patients, mostly MPO-ANCA) 1:

• More frequent vasculitic manifestations:
  • Glomerulonephritis
  • Peripheral neuropathy
  • Purpura
  • More common histopathological evidence of vasculitis

ANCA-negative (60-70% of patients) 1:

• More frequent eosinophilic manifestations:
  • Cardiac involvement
  • Eosinophilic gastroenteritis

Signs and Symptoms by Organ System

1. Respiratory system (>90% of patients) 1:

   • Adult-onset asthma (hallmark feature)
   • Non-fixed pulmonary infiltrates
   • Alveolar hemorrhage (rare but severe)

2. Ear, nose, and throat (60-80% of patients) 1:

   • Severe rhinitis
   • Nasal polyps
   • Chronic rhinosinusitis

3. Neurological 1:

   • Mononeuritis multiplex or polyneuropathy
   • Central nervous system involvement (rare)

4. Cutaneous 1:

   • Purpura
   • Skin nodules
   • Urticaria

5. Cardiovascular 1:

   • Cardiomyopathy (more common in ANCA-negative)
   • Pericarditis
   • Myocarditis
   • Heart failure

6. Renal 1:

   • Glomerulonephritis (more common in ANCA-positive)
   • Proteinuria
   • Renal insufficiency

7. Gastrointestinal 1:

   • Eosinophilic gastroenteritis
   • Abdominal pain
   • Diarrhea

Diagnostic Criteria

According to the American College of Rheumatology, at least four of these six criteria must be present 1:

1. Asthma history
2. Blood eosinophilia >10%
3. Mono- or polyneuropathy
4. Non-fixed pulmonary infiltrates
5. Paranasal sinus abnormalities
6. Biopsy showing accumulated eosinophils in extravascular tissue

Laboratory Findings

• Peripheral eosinophilia (key feature)
• ANCA positivity in 30-40% of cases (predominantly MPO-ANCA)
• Elevated IgG4 and IgG4/IgG ratios 1
• Elevated inflammatory markers (ESR, CRP)

Common Pitfalls in Diagnosis

• Delayed recognition: The three phases may develop over years, delaying diagnosis
• Misdiagnosis: Often initially diagnosed as severe asthma or allergic disease
• Incomplete evaluation: Failure to assess for multi-organ involvement
• Overlooking ANCA-negative disease: Remember that most EGPA cases are ANCA-negative

Clinical Pearls

• Adult-onset asthma with eosinophilia should raise suspicion for EGPA
• Cardiac involvement is the most common cause of death in EGPA
• The disease may present initially as localized in the upper respiratory tract before systemic manifestations appear
• Histopathological findings typically include a mix of eosinophilic infiltrates, granulomas, and necrotizing vasculitis