Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

INTRODUCTION — Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), abbreviated EGPA, which was previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia [1-8]. EGPA is classified as a vasculitis of the small and medium sized arteries, although the vasculitis is often not apparent in the initial phases of the disease.

The most commonly involved organ is the lung, followed by the skin. EGPA, however, can affect any organ system, including the cardiovascular, gastrointestinal, renal, and central nervous systems. Vasculitis of extrapulmonary organs is largely responsible for the morbidity and mortality associated with EGPA.

The clinical features and diagnosis of EGPA will be reviewed here. The epidemiology, pathogenesis, treatment, and prognosis of this disorder, as well as the approach to patients with vasculitis and/or eosinophilia are discussed separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis" and "Overview of and approach to the vasculitides in adults" and "Approach to the patient with unexplained eosinophilia".)

CLINICAL FEATURES — The most common presenting features of EGPA are asthma, nasal and sinus symptoms, and peripheral neuropathy [6,8,9]. EGPA is a multiorgan system disease and other manifestations that may be present initially or develop over the course of the disease include weight loss, fever, myalgia, arthralgia, skin involvement, pulmonary opacities, cardiomyopathy, kidney disease, and gastrointestinal involvement. The mean age at diagnosis is 50 years [8].

Phases of disease — The clinical features of EGPA typically develop in several sequential phases, although these phases are not always clearly distinguishable [10,11]:

●Prodromal phase – The prodromal phase occurs among individuals in the second and third decades of life and is characterized by atopic disease, allergic rhinitis, and asthma.

●Eosinophilic phase – Features of the eosinophilic phase include peripheral blood eosinophilia and eosinophilic infiltration of multiple organs, especially the lung and gastrointestinal tract. Almost 40 percent of patients with EGPA present with pulmonary opacities, asthma, and peripheral eosinophilia prior to the development of a systemic vasculitis (polyangiitis) [10].

●Vasculitic phase – The vasculitic phase is characterized by a life-threatening systemic vasculitis of the medium and small vessels frequently occurs, that is often associated with vascular and extravascular granulomatosis [6]. The vasculitic phase may be heralded by nonspecific constitutional symptoms and signs, especially fever, weight loss, malaise, and lassitude.

Asthma and lung disease — Asthma is the cardinal clinical feature of EGPA and is present in more than 90 percent of patients [8,9]. Asthma usually precedes the vasculitic phase by approximately 8 to 10 years [6,12]. (See 'Phases of disease' above.)

EGPA is typically suspected in patients whose asthma is poorly controlled on moderate doses of inhaled glucocorticoids; many patients diagnosed with EGPA require frequent or long-term courses of systemic glucocorticoids to control their asthma [13]. As the vasculitic phase begins, asthma severity and the number of exacerbations may increase. Rarely, the asthma symptoms lessen in the early stages of the vasculitic phase.

Prolonged treatment of asthma with glucocorticoid therapy may partially or totally suppress the usual clinical signs of untreated EGPA. The disease may therefore not become evident until glucocorticoids are reduced or stopped [13-15].

Other pulmonary findings are reported in 50 to 70 percent and include pulmonary opacities with eosinophilia, pleural effusion (often eosinophilic), and nodules that are rarely cavitary [3]. Alveolar hemorrhage is rare and usually associated with antineutrophil cytoplasmic antibody (ANCA) positivity [16]. In one series, venous thromboembolic disease was noted in 8 percent [8].

Upper airway and ear disease — Ear, nose, and throat involvement, including serous otitis media, allergic rhinitis, nasal obstruction, recurrent sinusitis, and nasal polyposis, is reported in 70 to 85 percent patients with EGPA [8,17-21]. Common presenting symptoms include nasal discharge (88 percent), nasal congestion (84 percent), and/or facial pain or pressure (84 percent) [22]. In a series of 29 patients with EGPA, nasal polyposis was detected in 60 percent [18]. Prior to the onset of eosinophilic infiltration of the lung or other organs, the characteristics of these patients overlap considerably with those associated with aspirin-exacerbated respiratory disease. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'CRS with nasal polyposis' and "Aspirin-exacerbated respiratory disease".)

Chronic serous otitis media and sensorineural hearing loss are occasionally seen in EGPA and likely reflect the severity of rhinosinusitis [19,23,24]. Necrotizing lesions of the nasopharynx and upper airway are more characteristic of granulomatosis with polyangiitis (GPA), and are unusual in EGPA. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

Skin — Skin involvement is one of the most common features of the vasculitic phase of EGPA. Half to two-thirds of patients with EGPA have skin lesions, which usually appear as tender subcutaneous nodules on the extensor surfaces of the arm, particularly the elbows, hands, and legs (picture 1) [3,25-27]. Biopsy of these lesions usually reveals granulomas. The pathology of cutaneous EGPA is discussed in greater detail separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

Skin lesions can also appear as a macular or papular erythematous rash or hemorrhagic lesions, including petechiae, palpable purpura, and extensive ecchymosis [28].

Cardiovascular — Cardiac involvement is one of the more serious manifestations of EGPA, accounting for approximately one-half of deaths attributable to EGPA [29,30]. Clinical manifestations include clinical signs of heart failure or pericarditis and cardiac rhythm abnormalities [29,31-33]. Patients with cardiac involvement typically have a shorter duration of EGPA related symptoms than those without. Cardiac involvement is more frequent in patients with higher eosinophil counts at the time of diagnosis [29,34].

In a series of 383 patients with EGPA, 16 percent had a cardiomyopathy and 15 percent had pericarditis [8]. In a separate series of 22 patients with evidence of cardiac involvement, cardiac abnormalities included an abnormal electrocardiogram (ECG) in all patients; valvular insufficiency, pericardial effusion, and heart failure were noted in 73, 50, and 41 percent, respectively [29]. Endomyocardial involvement was found in 12 patients based on cardiac magnetic resonance imaging (MRI) findings of mural thrombus and a positive endomyocardial biopsy [29]. The majority of patients improved with treatment, although two of the patients with endomyocardial disease died of heart failure. Patients with cardiac involvement were less likely to have a positive antineutrophil cytoplasmic antibody (ANCA) and more likely to have higher peripheral blood eosinophil counts than other EGPA patients.

The use of various cardiovascular tests to evaluate myocardial EGPA and the typical biopsy findings seen on endomyocardial biopsy are discussed separately. (See 'Cardiovascular tests' below and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

Thromboembolic disease — Patients with EGPA appear to be at increased risk for venous thromboembolism (VTE), similar to that seen in other systemic vasculitides. In a retrospective study of 232 patients with EGPA, the risk of VTE was 8 percent and did not differ significantly between those who were ANCA positive or not [35].

Neurologic — A peripheral neuropathy, usually affecting at least two separate nerve areas (multiple mononeuropathy, also called mononeuritis multiplex), is seen in up to 75 percent of patients with EGPA and presents with pain, numbness, and/or weakness [3,6,32,36-41]. Untreated, this may progress to a symmetric or asymmetric polyneuropathy [42]. Severe neuropathic pain may accompany the peripheral neuropathy [38]. Patients with mononeuritis multiplex are more likely to have a positive ANCA [9]. A more detailed description of vasculitic neuropathy is presented separately. (See "Clinical manifestations and diagnosis of vasculitic neuropathies".)

In addition, EGPA-related central nervous system manifestations have been reported, including subarachnoid and cerebral hemorrhage, cerebral infarction, cranial nerve palsies, and cortical blindness [6,41,43-45]. Ophthalmic manifestations can include central retinal artery or vein occlusion, ischemic optic neuropathy, conjunctival nodules, and orbital myositis [46].

Renal — The frequency of renal involvement varies among studies [8,47-49]. In the largest series of 383 patients with EGPA, renal involvement was found in 83 patients (22 percent) [8]. Similar findings were noted in a series of 116 patients in which one-half had rapidly progressive or acute renal insufficiency (plasma creatinine concentration >1.4 mg/dL [>124 micromol/L]), while the others had isolated proteinuria or microscopic hematuria [48]. Sixteen patients underwent renal biopsy, which demonstrated necrotizing glomerulonephritis in 11 patients. A positive test for ANCA was found in all patients with glomerulonephritis, compared with 26 percent of patients without renal involvement. (See 'Antineutrophil cytoplasmic antibodies' below.)

Systemic hypertension affects approximately 10 to 30 percent of patients with EGPA and may reflect renal involvement with EGPA or be a complication of glucocorticoid therapy [6,10,43].

Gastrointestinal tract — An eosinophilic gastroenteritis, characterized by abdominal pain (59 percent of patients), diarrhea (33 percent), gastrointestinal bleeding (18 percent), and colitis, may precede or coincide with the vasculitic phase of EGPA. (See 'Phases of disease' above and "Eosinophilic gastrointestinal diseases".)

Musculoskeletal — Myalgias, migratory polyarthralgias, and frank arthritis are less common, but may affect 40 to 50 percent of patients in the vasculitic phase of the disorder [6]. Although rare, myositis may be a presenting manifestation [50,51]. (See 'Phases of disease' above.)

Lymphadenopathy — Eosinophilic lymphadenopathy has been noted in 30 to 40 percent of patients [15]. Prominent cervical and axillary lymphadenopathy has been reported with individual lymph nodes up to 3 cm in diameter.

EVALUATION — EGPA is typically suspected based on a combination of clinical findings, such as difficult-to-control asthma, chronic rhinosinusitis, and eosinophilia ≥1500/microL. However, confirming the diagnosis is often difficult because of the following confounding factors:

●Individual manifestations of the syndrome can occur in isolation.

●Lung parenchymal involvement is not universal.

●Some manifestations can exist for many years before additional features become clinically apparent. (See 'Phases of disease' above.)

●Although EGPA is classified as a vasculitis, only 30 to 60 percent of patients with EGPA have antineutrophil cytoplasmic antibodies (ANCA). In addition, many biopsies do not show a necrotizing vasculitis or granuloma, but rather an apparently nondestructive infiltration of vessel walls by eosinophils [52]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

Laboratory tests — There are no laboratory tests that are specific for EGPA, although eosinophilia is characteristic. For patients who have suspected EGPA, initial testing includes a complete cell count with differential, an absolute eosinophil count, and a serum immunoglobulin E (IgE) level. Eosinophilia, if present, requires further evaluation to determine the cause. In addition, we usually obtain an ANCA test, although the sensitivity and specificity are low, as noted below. (See 'Antineutrophil cytoplasmic antibodies' below.)

Eosinophilia — Peripheral blood eosinophilia (usually 5000 to 9000 eosinophils/microL) is the most characteristic finding, although absolute eosinophil counts ≥1500 cells/microL (or greater than 10 percent of the total leukocyte count) should prompt suspicion for EGPA [10,53,54]. Eosinophilia, however, is occasionally missed because of rapid spontaneous, or glucocorticoid-induced reductions or fluctuations in eosinophil counts. Tissue eosinophilia can still be found in patients in whom peripheral blood eosinophilia is absent.

Patients with an absolute eosinophil count ≥1500 cells/microL should be evaluated for causes of hypereosinophilia other than EGPA (table 1) and for evidence of extrapulmonary involvement with EGPA [55-59] (see 'Differential diagnosis' below):

●Serum cardiac troponin

●Serum N-terminal pro-brain natriuretic peptide (NT-proBNP)

●Serology for Toxocara, Strongyloides, filaria, Trichinella, and other parasites depending on the locale

●Immunoassay for human immunodeficiency virus (HIV) infection

●Serum vitamin B12

●Serum tryptase

●Peripheral blood smear to identify blasts or dysplastic eosinophils

●Urinalysis, blood urea nitrogen, serum creatinine

(See "Approach to the patient with unexplained eosinophilia" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Antineutrophil cytoplasmic antibodies — ANCA are found in 30 to 60 percent of patients with EGPA [8,9,12,36,60-62]. The majority of ANCA-positive EGPA patients (70 to 75 percent) have antibodies directed against myeloperoxidase with a perinuclear staining pattern (called MPO-ANCA or P-ANCA) (picture 2) [32,62-65]. Antibodies to proteinase-3 (PR3) are unusual in EGPA [59]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

EGPA disease manifestations may differ between ANCA-positive and ANCA-negative patients, although confirmatory data are needed [8,9,11,59,62].

●In a series of 157 consecutive patients with EGPA, 49 (31 percent) were ANCA positive [9]. ANCA-positivity was associated with weight loss, myalgias, arthralgias, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of the arterial wall on biopsy, and other renal disease. However, 18 percent of those with definite vasculitis were ANCA-negative. Mononeuritis multiplex was associated with systemic vasculitis and ANCA-positivity, although 22 percent of patients with mononeuritis multiplex were ANCA-negative. In terms of ANCA types, 96 percent were specific for myeloperoxidase and 4 percent were specific for PR3.

●Among 383 patients with EGPA, those who were ANCA-positive had clinical vasculitis manifestations, such as peripheral neuropathy or renal involvement, more frequently than ANCA-negative patients, but less frequently had cardiomyopathy [8].

●In a series of 112 patients with newly diagnosed EGPA, a positive ANCA at diagnosis was associated with renal involvement, peripheral neuropathy, and biopsy-proven vasculitis, whereas a negative ANCA was associated with heart disease and fever [62].

●A retrospective European multicenter cohort of 734 patients with known ANCA status found that 508 (69.2 percent) were ANCA-negative, 210 (28.6 percent) had positive MPO-ANCA, and 16 (2.2 percent) had positive PR3-ANCA. At baseline, PR3-ANCA positive patients had less frequent active asthma and peripheral neuropathy, more frequent cutaneous manifestations and pulmonary nodules, and lower median eosinophil count compared with those who were MPO-ANCA-positive or ANCA-negative. Vasculitis relapse-free survival was shorter for PR3-ANCA and MPO-ANCA patients compared with ANCA-negative patients [66].

●In a retrospective review of 242 Korean patients with EGPA, those who were PR3-ANCA positive at disease diagnosis exhibited peripheral eosinophilia less frequently, experienced relapse more often, and had lower cumulative relapse-free survival rate compared with those without PR3-ANCA [67].

Acute phase reactants — Tests of inflammation such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are nonspecific and do not differentiate between flares of EGPA and infections (eg, sinusitis, pneumonia). Their usefulness in EGPA is unclear. (See "Acute phase reactants", section on 'Clinical use'.)

Other laboratory tests — There are no biomarkers that reliably assess EGPA activity, although CCCL17/TARC, immunoglobulin (Ig)G4 and CCL26/eotaxin-3 are being evaluated [59].

Nonspecific laboratory abnormalities that may be observed in EGPA include [6,10]:

●Normochromic, normocytic anemia

●Leukocytosis

●Serum IgE is frequently elevated (75 percent) and may vary with the activity of the vasculitic process [68]

●Hypergammaglobulinemia

●A positive rheumatoid factor or antinuclear antibody test at low titer

●Normal or elevated complement (C3, C4, CH50) levels

Imaging — Chest radiographs are typically obtained during a flare of asthma or to evaluate peripheral eosinophilia. Chest high resolution computed tomography (HRCT) is obtained to evaluate persistent or unexplained dyspnea, an abnormal chest radiograph, or gas transfer abnormalities, such as a low diffusion capacity or low pulse oximetry, and is more sensitive than a conventional radiograph. In a series of 15 patients with EGPA, HRCT identified lung disease in 5 patients with a normal chest radiograph [69].

●Chest radiograph – Chest radiographic abnormalities in patients with EGPA are diverse and include transient, patchy opacities (75 percent of patients) without lobar or segmental distribution, symmetrical opacities in an axillary and peripheral distribution, diffuse or miliary opacities, and bilateral nodular disease without cavitation (image 1A-B) [70-73]. Pleural effusions are found in approximately 30 percent of patients and are usually exudative and eosinophilic [71].

●HRCT – Typical HRCT findings in EGPA include patchy, non-fixed ground glass opacities and consolidations that are peripheral or randomly located [69]. Pulmonary micronodules, interlobular septal thickening, bronchial wall thickening, bronchial dilation, and pleural fluid can also be seen. One series described parenchymal consolidation or ground glass opacification on the CT scans of 10 of 17 patients [73]. These findings are not specific for EGPA, but may guide choice of a location for bronchoalveolar lavage or lung biopsy and help in the assessment of the extent of disease. (See "High resolution computed tomography of the lungs".)

A less common HRCT feature is a significant enlargement of the peripheral pulmonary arteries (when compared to the corresponding bronchi) in combination with a stellate and irregular configuration of some pulmonary arteries (referred to as the vasculitis sign) (image 2) [72].

●Sinus CT – Sinus CT features include thickening of sinus and nasal mucosa, nasal polyps, and absence of bony erosion.

●Cardiac magnetic resonance imaging (MRI) – Cardiac MRI is discussed below. (See 'Cardiovascular tests' below.)

Pulmonary function tests — Spirometry typically shows variable airflow limitation (obstruction) consistent with asthma [10]. Some patients may have a component of irreversible airflow limitation noted on spirometry or peak expiratory flow. When lung parenchymal involvement occurs, lung volume measurements (eg, total vital capacity and forced vital capacity) may be decreased. In addition, gas transfer abnormalities may be manifest by a low pulse oximetry at rest or with exertion, or by a decrease in the diffusion capacity. (See "Overview of pulmonary function testing in adults" and "Pulmonary function testing in asthma".)

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) is typically performed in patients with interstitial opacities on radiographic imaging to evaluate for eosinophilia, infection, alveolar hemorrhage, or malignancy. In EGPA, BAL fluid typically has a high percentage of eosinophils (usually greater than 30 percent) [74,75]. However, this finding is not specific for EGPA and would only be present in a patient with active pneumonitis (table 2). (See "Overview of pulmonary eosinophilia" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Biopsy — Histologic confirmation of EGPA is desirable, but not always possible. The biopsy site is selected from among the least invasive options (eg, skin, kidney, peripheral nerve, lacrimal gland, conjunctival) that is most likely to yield a diagnosis. As an example, when either skin disease or peripheral neuropathy is present, biopsy of one of these less invasive sites is often preferred to a lung biopsy. In one study, 15 of 28 patients with a peripheral neuropathy and EGPA had evidence of a necrotizing vasculitis on a peripheral nerve biopsy [42]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Diagnostic evaluation'.)

Nasal cytology demonstrates eosinophilia in approximately 60 percent of patients with chronic rhinosinusitis due to EGPA [21], which can be supportive but not diagnostic. In a series that included 23 patients who underwent nasal or sinus mucosal biopsies, the sensitivity for EGPA was 35 percent [8]. Sinus biopsy is generally obtained at the time of sinus surgery to relieve obstruction.

Lung biopsy is reserved for situations where none of the extrapulmonary sites is appropriate for biopsy, the HRCT scan shows lung parenchyma involvement, and therapeutic decisions would be altered by the results. Lung biopsy is obtained from an area of HRCT abnormality. In general, thoracoscopic or open surgical biopsy is preferred over transbronchial lung biopsy, which does not provide a sufficient sample size. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

The lung histopathology in EGPA may show asthmatic bronchitis, eosinophilic pneumonia, extravascular granulomas, or vasculitis (affecting arteries, veins, or capillaries). The histopathologic findings of EGPA are discussed in more detail separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

Cardiovascular tests — We typically obtain serum levels of NT-proBNP and cardiac troponin, an electrocardiogram, and a transthoracic echocardiogram (looking for wall motion abnormalities, mural thrombi, and valvular thrombi) as part of the initial evaluation of a patient with a diagnosis of EGPA even in the absence of symptoms suggesting cardiac disease [31,59,76,77]. The rationale for this routine testing is that cardiac involvement is the leading cause of mortality due to EGPA, and approximately 40 percent of asymptomatic patients with a normal ECG have evidence of cardiac involvement with EGPA on echocardiogram [8,29,31]. We use this initial testing to guide further imaging and decisions about endomyocardial biopsy.

●Transthoracic echocardiogram – The most common echocardiographic finding in EGPA is wall motion abnormalities, which were found in 41 percent of patients in one case series [31]. Other findings include valvular abnormalities (eg, mitral or aortic regurgitation), pericardial effusion, mural thrombi, and pulmonary hypertension.

●Cardiovascular magnetic resonance imaging (CMR) – If abnormalities are noted on ECG or echocardiogram, we perform CMR with gadolinium enhancement, if renal function is adequate [78]. Gadolinium should be used with caution in patients with acute kidney injury or advanced renal insufficiency (eg, estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m²), because of the risk of inducing nephrogenic systemic fibrosis. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging", section on 'Approach to preventing nephrogenic systemic fibrosis'.)

Gadolinium enhancement on CMR has been reported to correlate with endomyocardial biopsy evidence of eosinophilic infiltration [79]. Assessment of late images may reveal myocardial necrosis or fibrosis [34,80]. CMR may be a useful tool for EGPA risk stratification and treatment individualization [81,82], although additional testing may be needed to differentiate active disease from fibrosis [59].

The exact sensitivity and specificity of CMR for myocardial involvement with EGPA is not known. A comparison of echocardiography and CMR in a small group of patients found that echocardiography had a sensitivity and specificity of 83 and 80 percent, respectively, for abnormalities on CMR, while CMR had a sensitivity and specificity of 88 and 72 percent, respectively, for echocardiographic abnormalities [31].

●Fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) – FDG-PET has been evaluated as a method to determine whether delayed myocardial enhancement on CMR is due to fibrosis or inflammation. Among 14 patients with EGPA in remission and delayed myocardial enhancement on CMR, FDG-PET uptake was reduced in 10, increased in 2, and normal in 2 [78]. FDG-PET uptake was also normal in six patients with normal CMR findings. As this study evaluated a small number of patients and the outcomes of alterations in therapy based on FDG-PET results were not assessed, further study is needed to determine the most appropriate role for FDG-PET in the evaluation of EGPA.  

●Endomyocardial biopsy – An endomyocardial biopsy is performed selectively when EGPA is suspected, the noninvasive testing suggests endomyocarditis, and the documentation of cardiac involvement would affect the decision about whether to initiate immunosuppressive therapy. (See "Endomyocardial biopsy" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

DIAGNOSTIC CRITERIA — A number of different sets of criteria for the diagnosis of EGPA have been proposed [7,10,54,64]. The classifications used most commonly are the American College of Rheumatology (ACR, preferred) and the Lanham criteria [10,54]. Revised criteria from the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) and ACR have been developed for use in clinical trials but not for diagnosis [83]. (See "Overview of and approach to the vasculitides in adults", section on 'Classification criteria'.)

In 1990, the ACR established six criteria for the classification of EGPA in a patient with documented vasculitis [54]. The presence of four or more of these criteria had a sensitivity of 85 percent and a specificity of 99.7 percent for EGPA:

●Asthma (a history of wheezing or the finding of diffuse high pitched wheezes on expiration)

●Greater than 10 percent eosinophils on the differential leukocyte count

●Mononeuropathy (including multiplex) or polyneuropathy

●Migratory or transient pulmonary opacities detected radiographically

●Paranasal sinus abnormality

●Biopsy containing a blood vessel showing the accumulation of eosinophils in extravascular areas (picture 3A-B)

The Lanham criteria include asthma, peak peripheral blood eosinophilia in excess of 1500 cells/microL, and systemic vasculitis involving two or more extra-pulmonary organs [10]. In this classification, all three criteria must be met for a diagnosis of EGPA.

A question that arises in the categorization of patients with suspected EGPA is how to classify patients with asthma and blood eosinophilia >1500 cells/microL and/or ≥10 percent of leukocytes, but without definite evidence of vasculitis outside the lungs, nose, and sinuses. One proposal is to reserve the designation of EGPA for patients with asthma and blood eosinophils ≥1500 cells/microL (1.5 G/L) and/or ≥10 percent of leukocytes and one or more of the following [9]:

●Definite polyangiitis: Biopsy showing necrotizing vasculitis, biopsy showing necrotizing or crescentic glomerulonephritis, alveolar hemorrhage, palpable purpura, or myocardial infarction due to proven coronaritis

●Definite surrogates for vasculitis: Hematuria associated with red cell casts or >10 percent dysmorphic erythrocytes; hematuria with 2+ proteinuria; leukocytoclastic vasculitis/eosinophilic infiltration of an arterial wall on biopsy

●Mononeuritis or mononeuritis multiplex

●Antineutrophil cytoplasmic antibody (ANCA) and systemic manifestations (eg, myocarditis, pericarditis, peripheral neuropathy, other renal disease, abdominal pain)

This proposal suggests creating a new category called “hypereosinophilic asthma with systemic manifestations” for patients with asthma, hypereosinophilia (≥1500 cells/microL and/or ≥10 percent of leukocytes), and any systemic manifestation, but without ANCA, definite polyangiitis, a surrogate of polyangiitis, or mononeuritis.

DIAGNOSIS AND POSTDIAGNOSTIC TESTING — In practice, the diagnosis of EGPA is based on a combination of eosinophilia (≥1500 cells/microL), asthma, rhinosinusitis, and histopathology from the lung or other affected tissues (eg, skin, peripheral nerve, gastrointestinal tract) showing eosinophilic infiltration with or without vasculitis (see 'Diagnostic criteria' above and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'). Alternatively, after excluding processes in the differential diagnosis, a presumptive diagnosis of EGPA can be made in patients with these clinical features and peripheral eosinophilia when histopathology is not available. (See 'Differential diagnosis' below.)

Once EGPA has been diagnosed, patients should be evaluated for possible kidney, heart, gastrointestinal, or peripheral nerve involvement (if not already performed), as these are associated with a poor prognosis.

●Renal involvement is assessed with urinalysis (eg, hematuria, proteinuria, red blood cell casts), blood urea nitrogen, serum creatinine. The antineutrophil cytoplasmic antibody (ANCA) is almost always positive in patients with glomerulonephritis due to EGPA.

●Initial cardiovascular testing typically includes serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin, an electrocardiogram, and possibly a transthoracic echocardiogram [84]. Further testing is based on the results of these tests and is described above. (See 'Cardiovascular tests' above.)

●Evaluation for gastrointestinal involvement is guided by the specific symptoms (eg, upper abdominal pain, diarrhea, hematochezia), but may include upper or lower endoscopy with biopsy. Patients with ascites should have the fluid sampled. (See 'Renal' above and 'Cardiovascular' above and 'Gastrointestinal tract' above and 'Neurologic' above.)

●Peripheral nerve involvement is evaluated with a focused history and physical examination, followed, as indicated, by nerve conduction studies, and electromyogram (NCS/EMG). Biopsy is generally not needed in a patient with a known systemic vasculitis like EGPA. (See 'Neurologic' above and "Clinical manifestations and diagnosis of vasculitic neuropathies".)

DIFFERENTIAL DIAGNOSIS — The main diseases to consider in the differential diagnosis of EGPA are aspirin-exacerbated respiratory disease (AERD), the eosinophilic pneumonias, allergic bronchopulmonary aspergillosis, the hypereosinophilic syndrome, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis. The following observations may help to narrow the differential diagnosis:

●Aspirin-exacerbated respiratory disease – AERD refers to the combination of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin (acetylsalicylic acid [ASA]) and other COX-1 inhibiting nonsteroidal antiinflammatory drugs (NSAIDs) characterized by bronchoconstriction, nasal congestion, and rhinorrhea. These patients may also have eosinophilia, but do not have eosinophilic pneumonia or the other organ system involvement seen in EGPA. However, AERD may evolve into EGPA [85]. (See "Aspirin-exacerbated respiratory disease".)

●Chronic eosinophilic pneumonia – Chronic eosinophilic pneumonia usually lacks granulomas on biopsy and generally does not involve organs other than the lung [86,87].

Occasionally, an episode of eosinophilic pneumonia may precede the other manifestations of EGPA, making it difficult to differentiate EGPA from chronic eosinophilic pneumonia. These patients are monitored closely for development of evidence of additional organ involvement that would secure the diagnosis of EGPA. (See 'Phases of disease' above and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

●Allergic bronchopulmonary aspergillosis – Allergic bronchopulmonary aspergillosis is another cause of asthma, radiographic pulmonary opacities, and eosinophilia, but does not affect extrapulmonary organs other than the nose and sinuses. (See "Overview of pulmonary eosinophilia".)

●Hypereosinophilic syndrome – While some patients with the hypereosinophilic syndrome (HES) may have a cough, a minority have pulmonary opacities, and asthma is rare. When a clear differentiation cannot be made on clinical grounds, molecular testing for the FIP1L1/PDGFRalpha mutation may be helpful as this mutation is suggestive of HES. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Hematologic evaluation'.)

●Other vasculitides – Granulomatosis with polyangiitis, microscopic polyangiitis, and EGPA can all affect the lung, although the degree of eosinophilia and presence of asthma are typical of EGPA and not usually seen in the other two. The type of ANCA seen in EGPA is more typically anti-myeloperoxidase, whereas in granulomatosis with polyangiitis it is more likely anti-proteinase 3. (See "Overview of and approach to the vasculitides in adults".)

●Other eosinophilic diseases – Drug-induced eosinophilia (table 3), toxocariasis, strongyloidiasis, human immunodeficiency virus (HIV) infection, and paraneoplastic eosinophilia are in the differential diagnosis of EGPA [59]. Depending on the patient’s travel, residence, and exposure history and symptom pattern, serologic testing for Toxocara and Strongyloides and/or empiric treatment, testing for HIV infection, serum B12, and serum tryptase levels may be appropriate. (See "Approach to the patient with unexplained eosinophilia" and "Eosinophil biology and causes of eosinophilia" and "Toxocariasis: Visceral and ocular larva migrans" and "Strongyloidiasis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Background – Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), abbreviated EGPA, which was formerly called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia (≥ 1500 cells/microL and/or >10 percent eosinophils on differential leukocyte count). The exact etiology of EGPA is unknown. (See 'Introduction' above.)

●Clinical features

•Asthma is the cardinal feature of EGPA (occurring in more than 95 percent of patients) and usually precedes the vasculitic phase by approximately 8 to 10 years. (See 'Asthma and lung disease' above.)

•Ear, nose, and throat involvement, including serous otitis media, allergic rhinitis, nasal obstruction, recurrent sinusitis, and nasal polyposis, is reported in 70 to 85 percent patients with EGPA. (See 'Upper airway and ear disease' above.)

•A peripheral neuropathy, usually mononeuritis multiplex, is seen in up to 75 percent of patients with EGPA. Central nervous system manifestations may include subarachnoid and cerebral hemorrhage, cerebral infarction, cranial nerve palsies, and loss of visual acuity. (See 'Neurologic' above.)

•Two-thirds of EGPA patients have skin involvement; findings include palpable purpura, subcutaneous nodules, and macular or papular erythematous rashes. Skin biopsy is often helpful for confirming the diagnosis. (See 'Skin' above.)

•Cardiac involvement is one of the more serious manifestations of EGPA, accounting for approximately one-half of deaths attributable to EGPA. It should be suspected in the presence of refractory dyspnea, clinical evidence of heart failure, or cardiac rhythm abnormalities, but can also be asymptomatic. (See 'Cardiovascular' above.)

●Evaluation

•Blood eosinophilia – Most patients with EGPA have blood eosinophilia (typically above 1500/microL, often 5000 to 9000/microL), although this may be obscured by use of systemic glucocorticoids to control asthma. (See 'Eosinophilia' above.)

•Antineutrophil cytoplasmic antibodies (ANCAs) – ANCAs are noted in 30 to 60 percent of EGPA patients. The majority of ANCAs associated with EGPA are directed against myeloperoxidase with a perinuclear staining pattern (called MPO-ANCA or P-ANCA). (See 'Antineutrophil cytoplasmic antibodies' above.)

•Imaging – Typical findings on chest high resolution computed tomography (HRCT) include patchy parenchymal consolidation or ground glass opacification; nodules may also be noted. (See 'Imaging' above.)

•Bronchoalveolar lavage – Bronchoalveolar lavage (BAL) fluid from patients with EGPA typically has a high percentage of eosinophils (usually greater than 30 percent), although this is a nonspecific finding (table 2). (See 'Bronchoalveolar lavage' above.)

●Diagnosis – The diagnosis of EGPA is suggested by the combination of asthma, rhinosinusitis, and blood eosinophilia (≥1500 cells/microL), but should be confirmed by biopsy whenever possible. The biopsy site is selected from among the least invasive options (eg, skin, kidney, peripheral nerve, lacrimal gland, conjunctival) that is most likely to yield a diagnosis. Lung biopsy is reserved for situations where none of the extrapulmonary sites is appropriate for biopsy and the HRCT shows lung parenchyma involvement. (See 'Biopsy' above.)

Once EGPA has been diagnosed, patients should be evaluated for possible kidney, heart, gastrointestinal, or peripheral nerve involvement (if not already assessed), as these are associated with a poor prognosis. (See 'Diagnosis and postdiagnostic testing' above.)

●Diagnostic criteria – Two sets of diagnostic criteria are commonly used; the American College of Rheumatology (ACR) criteria for the classification of EGPA in a patient with documented vasculitis and the Lanham criteria. (See 'Diagnostic criteria' above.)

●Differential diagnosis – The main diseases to consider in the differential diagnosis of EGPA are aspirin-exacerbated respiratory disease, the eosinophilic pneumonias, allergic bronchopulmonary aspergillosis, the hypereosinophilic syndrome, granulomatosis with polyangiitis, and microscopic polyangiitis. (See 'Differential diagnosis' above.)