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Large Vessel Vasculitis Online Monograph

Eosinophilic Granulomatosis
with Polyangiitis

Carmen E. Gota, MD

Eosinophils are multifunctional cells involved in the pathogenesis of atopic disease and in the host defense against parasitic infections. Interleukin-5, interleukin-3, and GM-CSF all play a role in differentiation, survival, chemotaxis, local tissue expansion, and activation of eosinophils. Eosinophilia, defined as elevated eosinophil count in the peripheral blood, is associated with atopic disease, drug allergies, and infectious, autoimmune, and malignant conditions. These include eosinophilic pulmonary disease, hypereosinophilic syndrome, and eosinophilic granulomatosis with polyangiitis (EGPA).

The EGPA syndrome, formerly known as Churg-Strauss vasculitis syndrome, is defined as a multisystem disorder characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia. It is considered to be an ANCA-associated vasculitis, classified as a vasculitis of the small and medium-sized arteries, although the vasculitis is often not apparent in the initial disease phases.

The Churg-Strauss name was given in honor of Jacob Churg, MD, and Lotte Strauss, MD, pathologists at Mount Sinai Hospital in New York City who were the first to publish a description of the syndrome and its pathological findings.1

The clinical course of EGPA evolves in three phases, which can be consecutive or overlapping:

  1. allergic atopic phase with adult onset asthma, allergic sinusitis/rhinitis, and nasal polyposis.
  2. tissue eosinophilic infiltrative phase that can affect various organs, but most commonly including the lungs (fleeting infiltrates histologically indistinguishable from eosinophilic pneumonia) and the heart (eosinophilic cardiomyopathy leading to heart failure).
  3. vasculitic phase with evidence of mononeuritis multiplex and pauci-immune glomerulonephritis (Table 1)2,3.
Table 1. Classification criteria for EGPA (CSS): ACR 1990 criteria and 2012 Chapel Hill Consensus Conference definition.2,3
ACR 1990 CHCC 2012
Asthma Asthma
Eosinophilia >10% Eosinophilia
Neuropathy Necrotizing vasculitis, small to medium
Pulmonary infiltrates, nonfixed Eosinophilic, granulomatous infiltrates often involving the respiratory tract
Paranasal sinus disease  
Extravascular eosinophilia  
≥4/6 criteria  

The prevalence of EGPA is reported at 1.3 per 100.000 population; it affects both sexes equally, and usually occurs at 48 to 50 years of age.4

The initial stages of EGPA are under the influence of a Th1-type immune response, with engagement of IL-4, IL-5, and IL-13 leading to activation of B cells and eosinophils and ensuing release of eosinophil enzymes and tissue damage. The vasculitic stage is a Th1- and Th17-driven response involving IL-2, IFN-gamma, and IL-17 leading to granuloma formation, vasculitis, and tissue damage.

No causative agent is known. Although many case reports described the onset of EGPA after the use of leukotriene-receptor antagonists or use of beta-2 agonists or glucocorticoid inhalers to treat severe asthma, it is believed that these drugs decrease the need for oral glucocorticosteroids, which, in turn, facilitates the clinical expression of EGPA.

Laboratory data indicate an elevated eosinophil count, at least 10% of the total white cell count and often elevated IgE. Up to 40% of patients are ANCA-positive, predominantly pANCA/MPO ANCA. The ANCA positivity is associated with a predominantly vasculitic picture with pauci-immune glomerulonephritis, mononeuritis multiplex, pulmonary hemorrhage, and purpura.

Patients who are ANCA-negative are more likely to have an eosinophilic infiltrative presentation with eosinophilic endomyocarditis, fever, gastrointestinal involvement, and pulmonary infiltrates. This is a more severe disease with lower survival rates.

Other necessary tests include urinalysis and urine sediment analysis to screen for glomerulonephritis, pulmonary imaging to evaluate for possible lung involvement, and echocardiogram to evaluate the heart function as cardiac involvement remains the most important negative prognostic factor. In a study of 150 EGPA patients from 1990 through 2009,5 46% had heart disease, 18% renal disease, and 10% lung involvement. Of the patients treated with cyclophosphamide, the 10-year survival rate was 89%. Only patients with EGPA and heart failure had increased mortality (SMR 3).

The differential diagnosis of EGPA is difficult in the prevasculitic stage and includes other hypereosinophilic-related conditions such as Loffler's syndrome, acute and chronic eosinophilic pneumonias, hypereosinophilic syndrome, and allergic bronchopulmonary aspergillosis. The bronchoalveolar lavage indicates elevated eosinophil counts in all these conditions (normal is less than 2% eosinophils in BAL) (Table 2).

Table 2. Differential diagnosis of EGPA
  EGPA Loffler's syndrome Eosinophilic pneumonia acute/chronic Hypereosinophilic syndrome (HES) Allergic bronchopulmonary aspergillosis
Description vasculitis transient pulmonary eosinophilia due to parasitic infections, drugs or idiopathic acute/chronic eosinophilic pneumonia myeloproliferative HES-clonal expansion of eosinophils lymphocytic HES- clonal expansion of T cells leading to overproduction of eosinophilo-poetic cytokines hypersensitivity to aspergillus colonization
eosinophilia yes, high yes no/yes yes, high yes, high
asthma yes no no/yes no yes
other organs yes no no yes yes
tests ANCA     F/P fusion gene*; CHIC2 locus**, abnormal lymphocyte phenotypes Aspergillus in BAL; Aspergillus specific IgE Antibody
eosinophilic lung infiltrates yes yes yes yes yes
necrotizing vasculitis yes no no no no
necrotizing granuloma yes no no no yes

*F/P fusion gene= FIP1L1-PDGFRA – chromosomal rearrangement resulting in fusion of two genes, due to an 800 KB deletion on chromosome 4, leading to a fusion gene that encodes F/P protein with constitutive tyrosine kinase activity.

** CHIC 2 locus- absence of the locus is a surrogate marker for the presence of the F/P fusion.

The choice of treatment of EGPA is determined by the severity of organ involvement. A modified five-factor score (FFS) for EGPA developed in 20116 includes the following:

  • age >65 years.
  • creatinine level >150 mcmol/L.
  • specific gastrointestinal involvement.
  • specific cardiomyopathy.
  • absence of ENT manifestations.

Patients with a FFS of zero can be treated with glucocorticoids alone, adding another immunosuppressant in case of glucocorticoid failure. Patients with FFS ≥1, however, require combined therapy with glucocorticoids and another immunosuppressant. The evidence for these recommendations comes from several studies. Of 72 newly diagnosed EGPA patients with an FFP of zero treated with glucocorticoids alone, 92% achieved remission and 35% relapsed in the first year of therapy.7 Remission maintenance required continuation of glucocorticoids in 79% of patients with a survival rate of 100% at 1 year and 97% at year 5.

A study of 48 EGPA patients with FFS ≥1 treated with glucocorticoids and cyclophosphamide (CYC) IV pulses either 6 or 12 showed that 87.5% achieved remission, more in the 6 pulse CYC regimen.8 The relapse rate in this study was high — 74%, and glucocorticoid therapy could be stopped in only 11% of patients. Relapse rates were higher in ANCA-positive patients than in ANCA-negative patients — 35.2% vs 22.5%, respectively.

Biologics have not been extensively studied in EGPA, although some data suggest a benefit for rituximab. A retrospective study of 30 EGPA refractory/relapsing patients treated with rituximab resulted in 86% remission rate at 6 months. Other drugs being studied include omalizumab (binds free IgE and membrane-bound IgE on B cells) and mepolizumab (targets IL-5, blocks IL-5 binding to the IL-5 receptor on eosinophil surface).

It is important to note that even in remission, many EGPA patients continue to suffer from asthma attacks, which should not be confused with vasculitis flares.

Further studies are needed to determine the best treatments for EGPA customized on the factors that determine treatment response, such as FFS and ANCA positivity.

Summary

EGPA, formerly known as Churg Strauss Syndrome, is a small- to medium-vessel vasculitis. The disease follows three stages: allergic (asthma, allergies and nasal polyposis), infiltrative (presence of eosinophils in various organs), and vasculitic.

The most suggestive clinical manifestations are adult onset asthma, chronic sinusitis, recurrent nasal polyposis, fleeting lung infiltrates, eosinophilic endomyocarditis, mononeuritis multiplex, and pauci-immune glomerulonephritis and purpura.

Laboratory data show eosinophilia of ≥10% of the total white cell count and elevated IgE. Up to 40% of patients are ANCA positive. ANCA-positive cases are more likely to have symptoms that resemble vasculitis; ANCA-negative cases have more severe manifestations, such as cardiac involvement, that are more similar to the hypereosinophilic syndrome.

Treatment depends on the severity of organ involvement. Patients with an FFS of zero can be managed with steroids alone, while patients with an FFS ≥1 require an associated immunosuppressant.

Patients with heart failure have higher mortality rates; patients who are ANCA positive have a higher relapse rate.

Leonard Calabrese, DO

Editor's Comment

Leonard Calabrese, DO

Eosinophilic granulomatosis with polyangiitis (EGPA) — is it always vasculitis?

While the 2012 Revised Chapel Hill Consensus statement on vasculitis nomenclature2 reminds us that EGPA is indeed a vasculitis syndrome, clinicians caring for such patients know that this is often difficult to document.

The large prospective series noted by Dr. Gota has clearly demonstrated both vasculitic and tissular phenotypes.5 A recent European Respiratory Society task force9 proposed a new variant for patients with asthma, blood eosinophils greater than 1500/ml without ANCA, and documented vasculitis or surrogates of vasculitis to be called hypereosinophilic asthma with systemic manifestations (HASM). Such patients should have at least one of the following: myocarditis, pericarditis, peripheral neuropathy other than mononeuritis multiplex, and any other organ system manifestation related to eosinophilic disease. I believe that the concept of HASM is useful, as evidenced by my practice where I find this variant to be quite common. It does not clarify exactly how similar or dissimilar we should therapeutically approach such patients. I generally treat them with the same drugs and base intensity and duration on the severity of the target organ involvement encountered.

 

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