Aetiology

The aetiology of EGPA is unknown. A proposed mechanism that may underlie disease development includes exposure to an unidentified antigen (inhalant, drug, vaccine, or virus) that triggers an immune response.

Various medications have been linked to EGPA, including macrolide antibiotics and quinidine. However, the most notable are the leukotriene receptor antagonists (montelukast and zafirlukast). Although a pathogenic role has not yet been excluded, it is likely that leukotriene receptor antagonists unmask the previously unrecognised disease state by allowing the tapering of systemic corticosteroids.[18][19][20]

Pathophysiology

The underlying pathogenesis of EGPA is unknown. There are three disease phases that typically occur sequentially. The first phase is that of allergic rhinitis, sinusitis, and asthma. This is then typically followed by a second phase of tissue infiltration by eosinophils, which may manifest as eosinophilic pneumonia. The third phase is vasculitic inflammation of the organ system involved. The vasculitic phase of the disease is typically associated with circulating anti-neutrophil cytoplasmic autoantibodies (ANCA).[21]

Consistent with a disease with an allergic component, increased levels of serum immunoglobulin (Ig) E and immune complexes containing IgE have been noted, particularly during flare-ups of EGPA.[22] The role played by the T helper cell 2 (Th2) in the asthma inflammatory response in the development of EGPA is still being evaluated. The Th2 cytokine interleukin (IL)-5 has been documented to be increased in both sera and bronchoalveolar lavage fluid in active EGPA. Levels are influenced by treatment of EGPA. IL-5 plays a key role in eosinophilic maturation and activation.[23] Eosinophils, in turn, are known to have direct pathogenic effects due to the release of their cytotoxic proteins, including ribonucleases and eosinophil major basic protein. Cardiac involvement in EGPA is associated with a higher degree of eosinophilia; this eosinophilic inflammation is likely to be the primary driver behind the cardiotoxicity seen in both EGPA and hypereosinophilic syndrome.[24]

ANCA are also thought to have a pathogenic role in EGPA, particularly with the development of vasculitis. A pathogenic role for anti-myeloperoxidase antibodies, which are synonymous with perinuclear-ANCA, has been demonstrated in animal models.[25] ANCA-positive patients have a higher incidence of severe vasculitic manifestations, including glomerulonephritis, alveolar haemorrhage, and mononeuritis multiplex. They may represent a specific subset of patients.[16][17][26][27] The pathogenesis of vasculitis in ANCA-negative patients remains unclear.

Classification

Nomenclature of systemic vasculitides[1]

The primary systemic vasculitides are divided based on the size of blood vessels predominantly targeted.

  • Large-vessel vasculitis

    • Takayasu arteritis

    • Giant cell arteritis

  • Medium-vessel vasculitis

    • Polyarteritis nodosa

    • Kawasaki disease

  • Small-vessel vasculitis

    • ANCA-associated vasculitis (granulomatosis with polyangiitis [formerly known as Wegener's granulomatosis], microscopic polyangiitis, EGPA [Churg-Strauss syndrome])

    • Immune complex vasculitis

    • Anti-glomerular basement membrane disease

    • Cryoglobulinaemic vasculitis

    • IgA vasculitis (Henoch-Schonlein)

    • Hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis)

  • Variable vessel vasculitis

    • Behcet's disease

    • Cogan’s syndrome

American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 classification criteria for EGPA[2]

These criteria should be applied to classify a patient as having EGPA when a diagnosis of small- or medium-vessel vasculitis has been made.

Clinical criteria

  • Obstructive airway disease (+3)

  • Nasal polyps (+3)

  • Mononeuritis multiplex (+1)

Laboratory and biopsy criteria

  • Blood eosinophil count ≥1 x 10⁹/L (+5)

  • Extravascular eosinophilic-predominant inflammation on biopsy (+2)

  • Positive test for cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA) or anti-proteinase 3 (anti-PR3) antibodies (-3)

  • Haematuria (-1)

A score of ≥6 is needed for the classification of vasculitis as EGPA.

Chapel Hill consensus conference (CHCC2012) definition of eosinophilic granulomatosis with polyangiitis[1]

Eosinophil-rich and and necrotising granulomatous inflammation often involving the respiratory tract, and necrotising vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.

Forme fruste eosinophilic granulomatosis with polyangiitis[3]

Defined as eosinophilic granulomatosis with polyangiitis (previously referred to as Churg-Strauss syndrome), in which the vasculitis is suppressed secondary to corticosteroids that are being used to treat the underlying asthma, hence delaying the definitive diagnosis.

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