Practice Essentials
Eosinophilic granulomatosis with polyangiitis (EGPA) or, as it was formerly known, Churg-Strauss syndrome, is one of the antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides. It is a rare systemic necrotizing granulomatous vasculitis that affects small- to medium-sized vessels and can result in life-threatening multiorgan damage. [1, 2, 3]
The hallmark features of EGPA, eosinophilia and asthma along with organ damage from granulomatous inflammation (eg, heart or kidney failure, peripheral neuropathy), were first described in 1951 by Churg and Strauss, who reported on autopsy analyses in 13 patients. [4] In 1990, the American College of Rheumatology (ACR) proposed the following criteria for the classification of EGPA [5] :
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Asthma (wheezing, expiratory rhonchi)
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Eosinophilia of more than 10% on a differential white blood cell count (WBC)
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Paranasal sinusitis
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Pulmonary infiltrates (may be transient)
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Histologic proof of vasculitis with extravascular eosinophils
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Mononeuritis multiplex or polyneuropathy
The presence of four or more criteria yields a sensitivity of 85% and a specificity of 99.7%. [5]
In 2022 the ACR and the European Alliance of Associations for Rheumatology (EULAR) updated the classification with a score that uses weighted criteria and also includes ANCA serology testing. [6] The criteria and points assigned are as follows:
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Maximum eosinophil count ≥1×109/L (5 points)
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Obstructive airway disease (3 points)
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Nasal polyps (3 points)
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Extravascular eosinophilic-predominant inflammation (2 points)
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Mononeuritis multiplex/motor neuropathy not due to radiculopathy (1 point)
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Hematuria (-1 point)
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Cytoplasmic ANCA (c-ANCA) or anti–proteinase 3 ANCA (PR3-ANCA) positivity (-3 points)
A score of 6 or higher (positive minus negative points) has a sensitivity of 85% and a specificity of 99% for diagnosis of EGPA. [6] When measured against a benchmark of EGPA patients from the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) database, the 2022 ACR-EULAR criteria showed a sensitivity of 75%, whereas the 1990 ACR criteria had a sensitivity of 44%. However, both criteria sets retained their high specificity of 99%. [6]
It is essential to recognize that the negative points for hematuria (-1) and c-ANCA (-3), in the 2022 ACR-EULAR criteria do not mean that their presence excludes EGPA. Rather, it serves to signify their infrequency in EGPA. If either criterion is present, the clinician should definitively rule out other small-vessel vasculitides, in particular granulomatosis with polyangiitis (GPA), before settling on EGPA as the diagnosis. Clinicians should also be aware that such classification sets are used to create a homogeneous population for research studies and are not representative of the wide heterogeneous phenotypic presentations of EGPA.
Note that the ACR and ACR-EULAR criteria were developed for the purpose of classification; they were not intended for diagnosis and should not be used as diagnostic criteria. [2] A proposed but unvalidated approach, used in the pivotal Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial, bases the diagnosis of EGPA on the presence of asthma and eosinophilia (> 1000 cells/mm3 or > 10% of WBC), along with at least two of the following criteria [7] :
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Biopsy showing histopathologic evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil–rich granulomatous inflammation
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Neuropathy, mono or poly (motor deficit or nerve conduction abnormality)
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Pulmonary infiltrates, non–fixed
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Sinonasal abnormality
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Cardiomyopathy (established by echocardiography or MRI)
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Glomerulonephritis (hematuria, red cell casts, proteinuria)
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Alveolar hemorrhage (by bronchoalveolar lavage)
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Palpable purpura
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Positive test for ANCA (MPO or PR3)
See Presentation and Workup.
Treatment
Systemic corticosteroid therapy is the cornerstone of management of EGPA, with the agent and dosage selected on the basis of disease severity. Other therapeutic options include immunosuppressive agents (eg, rituximab, cyclophosphamide) for severe disease, and the interleukin-5 inhibitors mepolizumab and benralizumab. Patients also require management of asthma, using the same approach as for asthma in the general population. See Treatment and Medication.
Pathophysiology
The pathophysiology of EGPA is primarily attributed to a dysregulation of the cell-mediated adaptive immune system. The CD4 T-helper cells are highly up-regulated—especially Th2 lymphocytes, but also Th17 and Th1. The T cells are most likely activated by an antigen-presenting cell presenting a foreign antigen from the respiratory system, as asthma is a major feature of EGPA, found in 96-100% of cases. [8, 9]
The Th2 subset of CD4 is responsible for the secretion of interleukin-5 (IL-5), which prompts a vigorous eosinophilic response. IL-5 enhances the production, maturation, and activation of eosinophils and prolongs eosinophil survival, mainly by inhibiting apoptosis. [8] The importance of IL-5 is demonstrated by the efficacy of mepolizumab and benralizumab (monoclonal antibodies that serve as IL-5 inhibitors) in the treatment of EGPA. [7, 9]
The increased population of Th1 results in increased interferon-gamma production, which is responsible for the granulomatous formation in EGPA. [8] The reason for the development of granulomas in EGPA remains unclear; they might form in order to isolate and contain a chronic irritant/antigen/microbe or, as suggested by Fijoek et al, they may be intended to provide protection against the harsh cytotoxic effects of eosinophils. [8, 10]
The cytotoxicity of eosinophils is attributed to their pre-formed primary and secondary granules. [8] The primary granules, also known as Charcot-Leyden crystals, appear as hexagonal double-pointed crystals and are highly associated with eosinophilic inflammation. [8, 10] These crystalline structures are formed from a protein called galectin-10 within eosinophils. Once tissue eosinophils are activated, they begin a process of cell death resulting in the extrusion of their intracellular crystalline contents to the extracellular milieu, prompting a powerful inflammasome reaction, a process known as extracellular trap cell death (ETosis). [11, 12]
The secondary granules contain a variety of pre-formed proinflammatory cytokines such as major basic proteins (MBP), eosinophilic cationic proteins (ECP), eosinophilic peroxidases (EPO), and eosinophilic-derived neurotoxins (EDN). These can cause catastrophic organ damage in EGPA. [8]
Normally, Th17 (proinflammatory) and Treg (anti-inflammatory) co-exist in a careful balance; however, in EGPA the regulatory function of Treg is significantly decreased, leaving Th17 unchecked. This results in the continued secretion of pro-inflammatory cytokines such as IL-17 and IL-22. [8, 13] Th17 can also promote B-cell class switching, resulting in elevated levels of IgE antibodies. [13]
Finally, newer research highlights the involvement of the innate immune system in EGPA. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine that functions as an alarmin (ie, a self-derived molecule that recruits and activates the immune system), is released in the respiratory system in response to an infectious, environmental, or inflammatory insult. TSLP can provoke a powerful immune response by directly activating the Th2 pathway. [8]
Etiology
The majority of EGPA cases are idiopathic and are attributed to a complex interplay of polygenic risk factors and environmental exposures. Genetic analysis in a small population of EGPA patients found an association with HLA-DRB 1*04 and HLA-DRB 1*07, whereas HLA-DRB 1*03 and HLA-DRB1*13 proved to be protective. [2, 14] A genome-wide association study (GWAS) by Lyons et al demonstrated genetic differences between myeloperoxidase (MPO)-ANCA–positive EGPA compared with ANCA-negative EGPA, suggesting that those may be two distinct disease entities. [14]
MPO-ANCA–positive EGPA typically has vasculitic features, such as neuropathy and glomerulonephritis, and is strongly associated with the HLA-DQ genes, which are responsible for encoding the cell surface protein receptors found on antigen-presenting cells. [14, 15] Those genetic and clinical features are also characteristic of MPO-ANCA–positive microscopic polyangiitis (MPA). [14]
In contrast, ANCA-negative EGPA has a very different genetic signature. It is less strongly associated with HLA-DQ but rather has an increased presentation of glycoprotein A33 (GPA33) and thymic stromal lymphopoietin (TSLP). GPA33 is integral in maintaining the intestinal barrier function, and decreased expression of GPA33 is associated with inflammatory bowel diseases. [14] A variant of GPA33 in EGPA is expressed in bronchial tissue, suggesting that loss of these tight junctions may play a role in the pathogenesis of EGPA. [14] TSLP, a cytokine released by various epithelial cells of the pulmonary and intestinal system, is a potent driver of Th2. It is highly associated with asthma, nasal polyps, and allergic rhinitis. Variants of the TSLP gene are also associated with other eosinophilic syndromes.
Research has identified several environmental risk factors for EGPA. Maritati et al evaluated environmental exposures in 111 patients with EGPA and reported that the odds ratio of farming exposure in EGPA was 2.68, and exposure to silica had an odds ratio of 3.26. The combination of both exposures increased the odds ratio for EGPA to 7.49. [16]
Asthma in particular tends to have very strong environmental associations, with dust mites, cockroaches, grass, molds, and pets being the most commonly listed exposures [17] ; however only 33% of EPGA patients test positive for an allergen exposure. There are a few documented cases of massive inhalational exposures to harvest grain dust, flour, and pigeon droppings resulting in EGPA. [8]
Infections may serve as triggers for vasculitides. However, this is not characteristic of EGPA. [18]
A few cases of drug-induced EGPA have been reported. These have included mesalazine-induced EGPA in a patient with Crohn disease and sclerosing cholangitis, [19] clarithromycin-induced EGPA in a patient with chronic pneumonia, [20] and dupilumab-induced EGPA in a patient with refractory asthma. [21]
An EGPA-like syndrome is a rare complication that develops in steroid-dependent patients with asthma who have their oral steroid dose reduced after they start treatment with a leukotriene receptor antagonist (eg, montelukast, zafirlukast). [1] This syndrome is most often thought to represent unmasking of EGPA by corticosteroid withdrawal, but its occurrence in patients with no prior history of oral corticosteroid use and resolution after discontinuation of the leukotriene receptor antagonist suggests a causal relationship in some cases. [1, 22]
Epidemiology
The incidence and prevalence of EGPA is approximately 1.7 and 14.25 cases per million persons, respectively, making EGPA the least common of all the ANCA vasculitides. In comparison, the incidence and prevalence of GPA per million persons is 9.0 and 96.8 cases, respectively, and that of MPA is 5.9 and 39.2 cases. [23, 24]
The country with the highest overall incidence is the United States, at 4 cases per million persons. The prevalence is highest in Norway, with 30.4 cases per million persons, and within Europe, Norway has the highest incidence at 2.5 cases per million persons. [23, 24] There are very few cases to determine the true incidence and prevalence of EGPA in the global south; however, a nationwide population-based study from Korea reported an increase in the incidence per million persons from 1.1 in 2007 to 1.6 in 2017, and increase in prevalence over that time from 1.1 to 11.2. [25]
The prevalence of EGPA is equal in men and women. Onset occurs most often between the ages of 40-60 years, with the mean age at diagnosis being 50 years. [23, 24]
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Transient pulmonary infiltrates in a patient with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome)
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Eosinophilic granuloma in a patient with eosinophilic granulomatosis with polyangiitis (EGPA)
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The skin rashes of eosinophilic granulomatosis with polyangiitis (EGPA). The biopsy of this rash showed eosinophilic leukocytoclastic angiitis with poorly formed granulomas.
