Eosinophilic granulomatosis with polyangiitis (EGPA)—or, as it was traditionally termed, Churg-Strauss syndrome—is a rare systemic necrotizing vasculitis that affects small-to-medium-sized vessels and is associated with severe asthma and blood and tissue eosinophilia.[1, 2] Like granulomatosis with polyangiitis (Wegener granulomatosis), and the microscopic form of periarteritis (ie, microscopic polyangiitis), EGPA is an antineutrophil cytoplasmic antibody (ANCA)–associated vasculitide.[3, 4, 5, 6]
In 1951, Churg and Strauss first described the syndrome in 13 patients who had asthma, eosinophilia, granulomatous inflammation, necrotizing systemic vasculitis, and necrotizing glomerulonephritis.[4] In 1990, the American College of Rheumatology (ACR) proposed the following six criteria for the diagnosis of Churg-Strauss syndrome[7] :
The presence of four or more criteria yields a sensitivity of 85% and a specificity of 99.7%. The 1994 Chapel Hill consensus conference on the classification of vasculitides did not modify the ACR criteria.[8]
A new set of classification criteria for EGPA, based on the Diagnosis and Classification of Vasculitis Study (DCVAS) dataset of 226 EGPA patients, has been published by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology. The new criteria set is intended for use when a diagnosis of small-vessel or medium-vessel vasculitis has been made, and has sensitivity of 85% and specificity of 99%. A total score of 6 or higher (positive points minus negative points) is needed for classification of EGPA. Criteria and scores are as follows[9] :
A 2017 study by the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires—conducted in 157 patients with asthma, eosinophilia, and at least one systemic organ manifestation attributable to systemic disease—found that 41% of patients had definite vasculitis manifestations (37%) or strong surrogates of vasculitis (4%), of whom only 53% had ANCA. This group proposed a new entity termed hypereosinophilic asthma with systemic (non-vasculitic) manifestations. The image below depicts transient pulmonary infiltrates.[10]
See Vasculitis: Case Presentations, a Critical Images slideshow, for more information on clinical, histologic and radiographic imaging findings in various forms of vasculitis.
EGPA is a granulomatous small-vessel vasculitis. The cause of this allergic angiitis and granulomatosis is unknown.[11] No data have been reported regarding the role of immune complexes or cell-mediated mechanisms in this disease, although autoimmunity is evident with the presence of hypergammaglobulinemia, increased levels of immunoglobulin E (IgE), rheumatoid factor, and ANCA. However, only a minority (30%) of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO).[12]
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).[13] It has also been reported in patients in whom withdrawal of oral steroids is facilitated by use of inhaled steroids.
This complication is probably related to steroid withdrawal, which unmasks underlying EGPA,[14, 15, 16] rather than to the drugs themselves. However, in rare cases, this syndrome has developed when a leukotriene receptor antagonist has been substituted for inhaled steroids ini patients without a history of oral steroid withdrawal.[17]
HLA-DRB4 positivity may be a genetic risk factor for the development of EGPA, and may increase the likelihood of vasculitic manifestations of the disease.[18]
A genome-wide association study (GWAS) of 676 EGPA cases identified 11 loci associated with EGPA. When the patients were differentiated by MPO ANCA status, the researchers reported that EGPA has two genetically and clinically distinct subtypes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease with clinical features and an HLA-DQ association similar to MPO+ ANCA-associated vasculitis. In individuals with ANCA-negative EGPA, the association with genes affecting barrier function (including GPA33) implies a role for mucosal dysfunction.[12]
ANCA status may affect the organ-specific manifestations of EGPA. A systematic review found that, compared with patients with ANCA-negative EGPA, patients with ANCA-positive EGPA had higher risks of peripheral neuropathy (odds ratio [OR], 1.701), kidney involvement (OR, 5.097), and cutaneous purpura (OR, 1.746) and lower risks of pulmonary infiltrates (OR, 0.589) and cardiac involvement (OR, 0.427).[19]
Causes of EGPA are unknown.[11] EGPA is possibly an allergic or autoimmune reaction to an environmental agent or drug.
Several case reports have described drug-induced forms of EGPA. Mesalazine-induced EGPA has been reported in a patient with Crohn disease and sclerosing cholangitis.[20] Publications have addressed the association between propylthiouracil, methimazole, and vasculitides, including EGPA. One report is available on the association of freebase cocaine and EGPA.[21] New-onset ANCA and ANCA flares have been reported following vaccination with messenger RNA COVID-19 vaccines, although some of these cases may represent coincidence rather than causality.[22]
The incidence of EGPA in the United States is 1-3 cases per 100,000 adults per year.[23] The international incidence of EGPA is approximately 2.5 cases per 100,000 adults per year.
EGPA is slightly more common in males than in females. The age at onset varies from 15-70 years, with a mean age of approximately 38 years. EGPA in pediatric patients is well described, but mostly as case reports.[24] The mean age at diagnosis is around 50 years.
Overall, without treatment, the 5-year survival rate in EGPA is about 25%. With treatment, the 1-year survival rate is 90% and the 5-year survival rate is 62%.[3, 25]
The principal causes of morbidity and mortality in EGPA are myocarditis and myocardial infarction secondary to coronary arteritis.[26] Other causes of death associated with EGPA include the following:
Eosinophilic granulomatosis with polyangiitis (EGPA) has three phases, as follows:
The vasculitic phase usually develops within 3 years after the onset of asthma, although it may be delayed for several decades. The most prominent symptoms and signs are those related to pulmonary, cardiac, dermatologic, renal, and peripheral nerve involvement. Mononeuritis multiplex is a major clinical finding.
The following symptoms and signs of the disease were reported by Guillevin et al in their case series[3] :
Constitutional symptoms - Malaise, fatigue, flulike symptoms, weight loss (70%), fever (57%), myalgias (52%)
Asthma symptoms - Asthma is a central feature of EGPA, occurring in 97% of patients. Asthma may precede vasculitis by up to 10 years or, less frequently, may coincide with the appearance of vasculitis. Asthma symptoms are usually persistent; therefore, patients are usually treated with steroids. This, in turn, might mask other features of the syndrome.[27]
Paranasal sinusitis (61%) - Usually responds to oral steroids
Allergic rhinitis - This is a common symptom. Additionally, recurrent sinusitis and polyposis are seen, but unlike in granulomatosis with polyangiitis [Wegener granulomatosis], necrotizing lesions of the upper airway are unusual.
Pulmonary symptoms (37%), including cough and hemoptysis
Arthralgias (40%)
Skin manifestations (49%)
Purpura - Skin nodules, urticarial rash, necrotic bulla, digital ischemia
Cardiac manifestations - Symptoms related to heart failure, myocarditis, pericarditis, constrictive pericarditis, and myocardial infarction
Gastrointestinal (GI) symptoms (31%) - Symptoms related to GI vasculitis, eosinophilic gastritis, or colitis; these include abdominal pain (59%), diarrhea (33%), and GI bleeding (18%).
Peripheral neuropathy - Mononeuritis multiplex (most frequent form, occurring in as many as 77% of patients)
Less frequent symptoms - Symptoms related to stroke, ophthalmologic involvement, and other rare symptoms
Except for fever, the physical findings in EGPA are specific to organ-system involvement. Pulmonary involvement is the most prominent. In fact, a pneumonitis plus eosinophilia warrants consideration of this syndrome and a search for evidence of systemic vasculitis elsewhere.[3] In addition to asthma and eosinophilia, a dermato-pulmonary-renal syndrome is the feature of this disease. Mononeuritis multiplex is common.
Skin involvement (60%) may include the following:
Upper respiratory involvement may include the following:
Lower respiratory system physical findings are related to the following:
Cardiovascular findings may include the following:
Renal findings may include the following:
Gastrointestinal findings may include the following:
Nervous system findings may include the following:
In a study of 15 ANCA-positive and 35 ANCA-negative patients with EGPA, ANCA-positive patients had a significantly higher incidence of renal involvement, skin involvement, and peripheral neuropathy in the form of mononeuritis multiplex at the time of diagnosis. Over the entire follow-up period, ANCA-negative patients had significantly more frequent cardiac manifestations. ANCA-positive patients required significantly higher steroid doses to maintain remission.[28]
Other problems to be considered in the differential diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) are as follows:
European guidelines from the EGPA Consensus Task Force recommend the following for the workup of eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome)[2] :
Additional investigations should be guided by patient-specific clinical findings and an extensive search for causes of hypereosinophilia.[2]
The EGPA Consensus Task Force encourages obtaining biopsies from patients with suspected EGPA. In the correct clinical context (asthma with eosinophilia or systemic manifestations, or even eosinophilia with extrapulmonary disease), a biopsy showing small- or medium-vessel vasculitis, a strong clinical surrogate of vasculitis, or both strongly supports a diagnosis of EGPA.[2]
In patients with EGPA, the complete blood cell count (CBC) with differential typically demonstrates eosinophilia, usually with at least 10% eosinophils (or 5000-9000 eosinophils/µL), and anemia. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are usually elevated.
In patients with renal involvement, blood urea nitrogen (BUN) and serum creatinine levels are elevated. Urinalysis demonstrates abnormal urine sediment, proteinuria, microscopic hematuria, and red blood cell casts.
Antineutrophil cytoplasmic antibodies (ANCAs) are present in approximately 40% of patients with EGPA. Most of these patients are perinuclear-ANCA (p-ANCA)–positive (antimyeloperoxidase antibodies).[29]
Other immunologic test results are as follows:
On bronchoalveolar lavage (BAL), eosinophilia is evident in 33% of cases.
The laboratory tests that might correlate with disease activity include ESR and peripheral blood eosinophilia. In some patients, ANCA titers are related to disease activity.
Imaging studies used in the workup of patients with EGPA include chest radiography and chest computed tomography (CT). Other imaging studies are indicated for the complications of the disease and specific organ-system involvement, including abdominal CT scanning for pancreatitis, coronary angiography for myocardial ischemia and infarction, and echocardiography for congestive heart failure (CHF).
Chest radiography findings are as follows[30, 31] :
In the limited number of reported cases of EGPA studied with CT scanning, findings included peripheral areas of parenchymal consolidation with ground-glass attenuation similar to that of chronic eosinophilic pneumonia.[32, 33] Much less commonly, parenchymal nodules (from 5 mm to 3.5 cm), with cavitation or air bronchograms, can be observed. Bronchial dilatation and bronchial wall thickening may also be visible.
High-resolution CT scanning of chest produces findings that include significant enlargement of peripheral pulmonary arteries with stellate and irregular configuration—a vasculitis pattern.
Diffuse subendocardial fibrosis or past myocarditis was seen on cardiovascular magnetic resonance imaging in both ANCA-positive and ANCA-negative patients with EGPA in a study that included 28 EGPA patients, but the incidence and amount of fibrosis was significantly higher in ANCA-negative patients. Acute cardiac lesions were observed in all ANCA-negative patients with active disease and acute cardiac symptoms but in only one asymptomatic ANCA-positive patient with active disease. During 2 years of follow-up, one third of the EGPA patients with diffuse subendocardial fibrosis developed deterioration in left ventricular dysfunction.[34]
The following studies are indicated for specific organ-system involvement:
The characteristic pathologic changes in EGPA, found especially in the lung,[35, 36] include small necrotizing granulomas, as well as necrotizing vasculitis involving small arteries and venules. The granulomas are composed of a central eosinophilic core surrounded radially by macrophages and epithelioid giant cells. EGPA affects medium-sized and small vessels.
Glomerulonephritis is not as common or severe as in granulomatosis with polyangiitis (Wegener granulomatosis), but, when present, it is usually focal and segmental and indistinguishable from other forms of so-called pauci-immune (without significant tissue deposition of immune complexes) glomerulonephritis.[37, 38]
If local organ involvement exists, obtaining a biopsy of that organ is most helpful in confirming the diagnosis. Biopsies of the following may be considered:
If no localizing finding exists, obtaining nerve or muscle biopsy may be considered. Sural nerve biopsy is the most feasible procedure. In the case of renal involvement, kidney biopsy results may show focal or crescentic glomerulonephritis; however, this pathological change is only consistent with, but not diagnostic of, EGPA.
Glucocorticoids alone are usually adequate for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome).[40, 41] Cytotoxic drugs are necessary in fewer than 20% of patients.
Rituximab, which is approved for use in granulomatosis with polyangiitis and microscopic polyangiitis, has proved useful in treatment of steroid-resistant cases, as well as for prevention and treatment of relapse.[42] However, its efficacy is greatly reduced in ANCA-negative patients with EGPA.[43, 12]
The anti-IgE monoclonal antibody omalizumab has demonstrated a corticosteroid-sparing effect in refractory or relapsing EGPA, but reducing steroid doses may also increase the risk of severe EGPA flares.[44] Case reports have described infliximab therapy in patients with steroid-dependent EGPA.[45]
Major life-threatening organ involvement may require treatment with pulse doses of intravenous corticosteroids and other cytotoxic agents. Cyclophosphamide is typically given in intravenous pulses for 3 months; afterward, patients are converted to oral mycophenolate, azathioprine, or methotrexate for maintenance therapy.
Plasma exchange has been studied in EGPA and other ANCA-positive vasculitides, without a clear benefit.[46] A meta-analysis of 140 patients with glomerulonephritis and EGPA and microscopic polyangiitis confirmed that plasma exchanges offered no added benefit.[47] One case report is available on intravenous immune globulin for treatment of EGPA in pregnancy.[48]
Mepolizumab was approved for use in adult patients with EGPA by the US Food and Drug Administration in 2017. Mepolizumab is an interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells. It was previously approved in 2015 as an add-on maintenance treatment in patients with severe asthma that has an eosinophilic phenotype. Approval for EGPA was based on a 52-week multicenter, double-blind, parallel-group, phase III trial in patients with relapsing or refractory EGPA who had received glucocorticoid treatment for at least 4 weeks. Patients were randomized to either receive mepolizumab or placebo once every 4 weeks while continuing corticosteroid therapy.
More patients in the mepolizumab group than the placebo group remained in remission for < 24 weeks (28% versus 3%, respectively). Failure to achieve remission occurred in 47% of patients in the mepolizumab group, as compared with 81% of patients in the placebo group. A higher percentage of participants in the mepolizumab group than in the placebo group had remission at both week 36 and week 49 (32% vs. 3%). Moreover, significantly more patients who received mepolizumab achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study.[49]
Benralizumab, an IL-5α antagonist monoclonal antibody, is approved for use in severe asthma and has orphan drug designation for EGPA. A study by Koga et al in 41 patients with mepolizumab-refractory EGPA and intractable cardiac and neuropathy complications reported that after the initiation of benralizumab therapy, oral corticosteroids could be reduced to 10 mg/day or less in all patients and to less than 5 mg/day at least 80%. More than 40% of patients were able to discontinue corticosteroids.[50]
Inpatient medications include the following:
Prednisone: Start at 0.5-1 mg/kg/d PO.
Methylprednisolone is administered in intravenous (IV) form at higher doses in patients with major organ involvement, including cardiac, pulmonary (hemorrhage), renal, or neuropathy.
Cyclophosphamide is administered in patients with severe or life-threatening complications.[51, 52] The single IV dose is 500 mg/m2 of body-surface area. The dose should be reduced in patients with renal failure.
Other medications include azathioprine, mycophenolate mofetil, and intravenous immune globulin administered similarly as in microscopic polyangiitis or granulomatosis with polyangiitis (Wegener granulomatosis).[53]
Plasmapheresis is probably not helpful.[47]
Interferon alpha might be helpful in treatment.[54, 55]
EGPA is a systemic vasculitis that involves multiple organ systems; the type of support and care depends on the type of organ system involvement. Consultation with a rheumatologist is generally indicated. Specific organ-system involvement may require consultation with one or more of the following specialists:
Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome) cases must be followed up very closely at a rheumatology clinic or another specialty clinic. Patients with this syndrome usually need long-term immunosuppressive medications.
The patient's clinical status, erythrocyte sedimentation rate, and eosinophil count should be monitored. In EGPA patients with antineutrophil cytoplasmic antibodies (ANCAs), the ANCA level does not correlate well with disease activity.[56]
European guidelines from the EGPA Consensus Task Force recommend the following for the workup of eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome)[2] :
Additional investigations should be guided by patient-specific clinical findings and an extensive search for causes of hypereosinophilia.[2]
The EGPA Consensus Task Force encourages obtaining biopsies from patients with suspected EGPA. In the correct clinical context (asthma with eosinophilia or systemic manifestations, or even eosinophilia with extrapulmonary disease), a biopsy showing small- or medium-vessel vasculitis, a strong clinical surrogate of vasculitis, or both strongly supports a diagnosis of EGPA.[2]
The American College of Rheumatology and the European Alliance of Associations for Rheumatology have published classification criteria for EGPA.[9] Diagnostic criteria and assigned points are as follows:
Once mimics of vasculitis have been excluded, patients with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if their cumulative score was 6 points or higher.[9]
The American College of Rheumatology/Vasculitis Foundation has published a guideline for the management of ANCA-associated vasculitis, including EGPA. The guideline contains recommendations and ungraded position statements; all the recommendations are conditional, as the level of supporting evidence ranges from very low to low.[57]
Remission induction for active, severe EGPA
Remission induction for active, nonsevere EGPA
Remission maintenance
Treatment of relapse
Other considerations
Glucocorticoids are the cornerstone of therapy for eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome).[2] For life- or organ-threatening disease, glucocorticoids are combined with other immunosuppressant drugs, such as cyclophosphamide, for induction of remission, and maintenance therapy is provided with azathioprine or methotrexate.[2] The monoclonal antibody mepolizumab is approved for use in EGPA. Rituximab and omalizumab are often used off-label, especially in steroid-refractory or relapsing cases.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the immune response to diverse stimuli.
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Oral prednisone is usually sufficient to control disease activity.
These agents inhibit cell growth and proliferation. They are reserved for cases resistant to corticosteroids.
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which interferes with growth of rapidly proliferating cells.
Eosinophils produce proinflammatory mediators, such as eosinophilic cationic protein (ECP) and leukotrienes. IL-5 promotes eosinophil differentiation and activation, as well as trafficking into the lungs. Monoclonal antibodies against IL-5 have been developed to target eosinophilic inflammation.
Humanized IgG1 kappa monoclonal antibody specific for IL-5; binds IL-5, and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. By inhibiting IL-5 signaling, mepolizumab reduces the production and survival of eosinophils.
Overview
What is eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome)?
What are the diagnostic criteria for EGPA (Churg-Strauss syndrome)?
What is the pathophysiology of EGPA (Churg-Strauss syndrome)?
What causes EGPA (Churg-Strauss syndrome)?
What is the incidence of EGPA (Churg-Strauss syndrome)?
What is the epidemiology of EGPA (Churg-Strauss syndrome)?
What is the prognosis of EGPA (Churg-Strauss syndrome)?
Presentation
What are the phases of EGPA (Churg-Strauss syndrome)?
How is the vasculitic phase of EGPA (Churg-Strauss syndrome) characterized?
What are the signs and symptoms of EGPA (Churg-Strauss syndrome)?
What are the physical findings in EGPA (Churg-Strauss syndrome)?
What are the dermatologic findings in EGPA (Churg-Strauss syndrome)?
What are the upper respiratory system findings in EGPA (Churg-Strauss syndrome)?
What are the lower respiratory system findings in EGPA (Churg-Strauss syndrome)?
What are the cardiovascular findings in EGPA (Churg-Strauss syndrome)?
What are the renal findings in EGPA (Churg-Strauss syndrome)?
What are the GI findings in EGPA (Churg-Strauss syndrome)?
What are the neurologic findings in EGPA (Churg-Strauss syndrome)?
How are ANCA-positive and ANCA-negative EGPA (Churg-Strauss syndrome) differentiated?
DDX
Workup
What are the guidelines on the workup of EGPA (Churg-Strauss syndrome)?
What lab study findings are associated with EGPA (Churg-Strauss syndrome)?
Which imaging studies are indicated in the workup of EGPA (Churg-Strauss syndrome)?
What are the chest radiography findings in EGPA (Churg-Strauss syndrome)?
What are the CT findings in EGPA (Churg-Strauss syndrome)?
What are the histologic findings in EGPA (Churg-Strauss syndrome)?
What is the role of biopsy in the workup of EGPA (Churg-Strauss syndrome)?
Treatment
Which drugs are used in the treatment of EGPA (Churg-Strauss syndrome)?
Which medications are used in the inpatient treatment of EGPA (Churg-Strauss syndrome)?
Which specialist consultations are indicated in the treatment of EGPA (Churg-Strauss syndrome)?
What are the monitoring procedures for patients with EGPA (Churg-Strauss syndrome)?
Guidelines
Medications
What is the cornerstone of therapy for EGPA (Churg-Strauss syndrome)?