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

INTRODUCTION — Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), abbreviated EGPA, previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a chronic inflammatory disorder characterized by multisystem manifestations, most commonly asthma, chronic rhinosinusitis with or without polyposis, pulmonary involvement, and peripheral blood eosinophilia [1-8]. EGPA is classified as a vasculitis of the small- and medium-sized arteries, although the vasculitis, when present, may be difficult to diagnose depending on the ability to obtain biopsies off treatment or in locations where affected vessels can be obtained.

The most commonly involved organ is the lung. However, EGPA can affect any organ system, including the upper respiratory, cardiovascular, gastrointestinal, kidney, and peripheral 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)".)

●(See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)

●(See "Approach to the patient with unexplained eosinophilia".)

●(See "Overview of pulmonary 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]. There is increasing recognition of different presentations of antineutrophil cytoplasmic antibody (ANCA)-positive EGPA as compared with ANCA-negative EGPA.

Natural history — Historically, the clinical features of EGPA have been described as occurring in sequential phases. In practice, however, these phases are not always distinguishable [10,11], and some patients present acutely with vasculitis.

●Prodromal phase – This designation, typically applied retrospectively to patients diagnosed with EGPA, describes the development of adult-onset atopic disease, including allergic rhinitis, asthma, and chronic rhinosinusitis (with or without polyposis). This phase may precede or occur simultaneously with the observation of peripheral blood eosinophilia.

●Eosinophilic phase – In the absence of systemic glucocorticoids or anti-eosinophilic biologic therapy for asthma treatment, most patients with EGPA develop significant peripheral blood eosinophilia as well as eosinophilic infiltration of affected organs, such as the lung and gastrointestinal tract. For example, in one case series, 97 percent of patients presented with blood eosinophil counts ≥500 cells/microL (mean 7,500 ± 6,428 cells/microL) regardless of ANCA status [8].

●Vasculitic phase – Clinically apparent vasculitis is characterized by development of organ- or life-threatening systemic vasculitis of the medium and small vessels. Biopsies of affected organs may show vascular and extravascular granulomatosis [6] or perivascular eosinophils [12]. The vasculitic phase may be heralded by nonspecific constitutional symptoms and signs, especially fever, weight loss, and malaise.

Asthma and lung disease — Asthma is the cardinal clinical feature of EGPA, present in more than 90 percent of patients [8,9]. Asthma usually precedes frank vasculitis by approximately 8 to 10 years [6,13]. (See 'Natural history' above.)

EGPA is typically suspected in patients whose respiratory symptoms become increasingly difficult to control despite use of high-dose combination inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) and long-acting beta-agonists (LABA) therapy; many patients diagnosed with EGPA require frequent or long-term courses of systemic glucocorticoids to control their asthma [14]. Asthma severity and the number of exacerbations often increase prior to an eventual diagnosis. Prolonged treatment of asthma with systemic glucocorticoid therapy may partially or completely suppress clinical signs of untreated EGPA, including peripheral blood eosinophilia, as well as result in inconclusive biopsy proof of EGPA. The disease may therefore not become evident until systemic glucocorticoids are reduced or stopped [14-16]. Asthma biologic therapies, particularly anti-interleukin-5 or interleukin-5 receptor therapies, may also partially or completely treat EGPA, preventing diagnosis during ongoing biologic use.

Other pulmonary findings, including pulmonary opacities with eosinophilia, pleural effusion (often eosinophilic), and noncavitary nodules, are reported in 50 to 70 percent of patients [3]. Alveolar hemorrhage is rare and is usually associated with ANCA positivity [17].

Upper airway and ear disease — Otolaryngologic manifestations are reported in 70 to 85 percent of EGPA patients and include allergic rhinitis, recurrent sinusitis, nasal polyposis, nasal obstruction, and more rarely serous otitis media or subglottic stenosis [8,18-22]. Common presenting symptoms include nasal discharge (88 percent), nasal congestion (84 percent), and/or facial pain or pressure (84 percent) [23]. In a series of 29 patients with EGPA, nasal polyposis was detected in 60 percent [19]. Abnormalities of smell may also occur. In the absence 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 may reflect the severity of rhinosinusitis [20,24,25]. 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) [3,26-28]. 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, extensive ecchymosis, livedo reticularis, bullous lesions, or urticaria [29].

Cardiovascular — Cardiac involvement is one of the more serious manifestations of EGPA, accounting for approximately one-half of deaths attributable to EGPA [30,31]. Clinical manifestations include clinical signs of heart failure, myocarditis, pericarditis, and cardiac rhythm abnormalities [30,32-34]. Cardiac involvement is more frequent in patients with higher eosinophil counts at the time of diagnosis [30,35].

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 [30]. Endomyocardial involvement was found in 12 patients based on cardiac magnetic resonance imaging (MRI) findings of mural thrombus and a positive endomyocardial biopsy [30]. 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 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 with and without ANCA positivity [36].

Neurologic — 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 [3,6,33,37-42]. Untreated, this may progress to a symmetric or asymmetric polyneuropathy [43]. Severe neuropathic pain may accompany the peripheral neuropathy [39]. Mononeuritis multiplex and peripheral neuropathy can occur equally in patients with and without ANCA positivity [9]. A more detailed description of vasculitic neuropathy is presented separately. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Multiple mononeuropathy'.)

Though more rare, EGPA-related central nervous system manifestations have been reported, including subarachnoid and cerebral hemorrhage, cerebral infarction, cranial nerve palsies, and cortical blindness [6,42,44-46]. Ophthalmic manifestations can include central retinal artery or vein occlusion, ischemic optic neuropathy, conjunctival nodules, and orbital myositis [47].

Kidney — The frequency of kidney involvement varies among studies [8,48-50]. In the largest series of 383 patients with EGPA, kidney 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 kidney injury (plasma creatinine concentration >1.4 mg/dL [>124 micromol/L]), while the others had isolated proteinuria or microscopic hematuria [49]. Sixteen patients underwent kidney 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 kidney involvement (see 'Antineutrophil cytoplasmic antibodies' below). In another study of 157 patients with EGPA (48 ANCA-positive, 109 ANCA-negative), biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis was diagnosed in eight ANCA-positive patients (17 percent) and in only one ANCA-negative patient (1 percent) [9].

Systemic hypertension affects approximately 10 to 30 percent of patients with EGPA and may reflect kidney involvement with EGPA or be a complication of glucocorticoid therapy [6,10,44].

Gastrointestinal tract — Eosinophilic gastritis or enteritis, 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. Patients who are ANCA-positive may present with more severe manifestations of perforation and mesenteric ischemia, whereas ANCA-negative patients may have disease presentation similar to that seen in eosinophilic gastrointestinal diseases without EGPA. In our experience, gastroparesis may also be seen in active EGPA affecting the stomach. Additional extra-intestinal manifestations may include eosinophilic cholecystitis or hepatitis. (See 'Natural history' above and "Eosinophilic gastrointestinal diseases".)

Musculoskeletal — Myalgias, migratory polyarthralgias, and frank arthritis may affect 40 to 50 percent of patients with vasculitis but are also residual symptoms after treatment [6]. Although rare, myositis may be a presenting manifestation [51,52].

Lymphadenopathy — Eosinophilic lymphadenopathy has been noted in 30 to 40 percent of patients [16]. Prominent cervical and axillary lymphadenopathy has been reported, with individual lymph nodes up to 3 cm in diameter.

EVALUATION

When to suspect the diagnosis — For most patients, EGPA is suspected based on a combination of clinical findings, such as progressive or difficult-to-control asthma, chronic rhinosinusitis, and peripheral blood eosinophilia ≥1000 cells/microL. A diagnosis of EGPA is often delayed and difficult to confirm due to the following factors:

●Individual manifestations of EGPA can occur in isolation.

●Systemic glucocorticoid treatment or biologic therapies for asthma or asthma exacerbations may partially treat disease manifestations and lower peripheral eosinophil counts.

●Lung parenchymal involvement is not universal.

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

●Vasculitis is frequently absent on biopsy. Although EGPA is classified as a vasculitis, only 30 to 40 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 [53]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

Occasionally skin rash, mononeuropathy multiplex, acute kidney injury, or proteinuria are the most salient initial clinical features, leading to a work-up for vasculitis. For those diagnosed with small or medium-sized vessel vasculitis by biopsy, clinical and laboratory features most suspicious for EGPA include the presence of asthma, nasal polyps, and peripheral or tissue eosinophilia as well as the absence of antiproteinase 3 antibodies [54]. (See 'Vasculitis classification criteria' below.)

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, serum immunoglobulin E (IgE) level, and inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein (CRP). Eosinophilia, if present, requires further evaluation to determine the cause. In addition, we usually obtain ANCA testing, although the sensitivity and specificity are low, as noted below. The presence of c-ANCA antibodies is unusual enough to suggest consideration of granulomatous polyangiitis as an alternative diagnosis. (See 'Antineutrophil cytoplasmic antibodies' below.)

Eosinophilia — Peripheral blood eosinophilia is the most characteristic laboratory finding for those with EGPA. Absolute blood eosinophil counts ≥1000 cells/microL (or greater than 10 percent of the total leukocyte count) should prompt suspicion for the diagnosis [10,55,56]. Eosinophilia, however, is occasionally missed because of glucocorticoid-induced reductions or fluctuations in eosinophil counts. Tissue eosinophilia can still be found in patients with low peripheral blood eosinophil counts.

Patients with an absolute eosinophil count ≥1500 cells/microL or additional clinical suspicion for other causes of hypereosinophilia should be evaluated for evidence of organ system involvement guided by presenting symptoms (table 1), including the following [57-61] (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 likely exposures

●Radiographic imaging of suspected organ involvement

●Immunoassay for human immunodeficiency virus (HIV) infection

●Serum vitamin B12 and serum tryptase with additional hematologic evaluation if elevated

●Peripheral blood smear to identify blasts or dysplastic eosinophils

●Urinalysis, blood urea nitrogen, serum creatinine

Further information on the work-up of eosinophilia and hypereosinophilic syndromes may be found elsewhere. (See "Approach to the patient with unexplained eosinophilia" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Immunoglobulin E (IgE) — EGPA frequently results in higher serum levels of total IgE compared with the general population (table 2). Up to 75 percent of patients with EGPA have elevated serum IgE [11]. Given its lack of specificity, IgE is most useful to confirm a type 2 inflammatory process and to identify patients with highly elevated levels of IgE (>1000 international units/mL) who would benefit from further testing for other conditions that may have similar presentations as EGPA. High IgE levels should prompt clinical evaluation for endemic and travel-associated parasitic infections, as well as testing for possible allergic bronchopulmonary aspergillosis (ie, specific IgG and IgE antibodies to Aspergillus). (See 'Differential diagnosis' below and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

Antineutrophil cytoplasmic antibodies — ANCA are found in approximately 30 to 40 percent of patients with EGPA [8,9,13,37,62-64]. The majority of ANCA-positive EGPA patients (96 percent, in one study) have antibodies directed against myeloperoxidase with a perinuclear staining pattern (called MPO-ANCA or p-ANCA) (picture 2) [9,33,64-67]. Antibodies to proteinase 3 (PR3) are unusual [9,61]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

EGPA disease manifestations may differ between ANCA-positive and ANCA-negative patients based on several retrospective case series [8,9,11,61,64].

●A retrospective European multicenter cohort of 734 patients with known ANCA status found that 508 (69 percent) were ANCA-negative, 210 (29 percent) had positive MPO-ANCA, and 16 (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 [68].

●In a separate series of 157 consecutive patients with EGPA, 49 (31 percent) were ANCA-positive [9]. ANCA positivity was associated with weight loss, myalgias, arthralgias, mononeuritis multiplex, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of the arterial wall on biopsy, and other kidney disease. However, a significant minority (approximately 20 percent) of those with definite vasculitis or multiple mononeuropathy were ANCA-negative. In terms of ANCA types, 96 percent were specific for myeloperoxidase, and 4 percent were specific for PR3.

●Additional cohorts have also found more frequent vasculitic features (peripheral neuropathy, kidney involvement, or biopsy-proven vasculitis) in ANCA-positive patients, but more frequent cardiac involvement in those who were ANCA-negative [8,64].

Acute phase reactants — Tests of inflammation such as the erythrocyte sedimentation rate (ESR) and CRP are nonspecific and may not differentiate between flares of EGPA and infections (eg, sinusitis, pneumonia). Their usefulness in predicting relapses of EGPA is unclear [69]. They are most useful to confirm systemic inflammation in those with otherwise more localized symptoms (eg, difficult-to-treat asthma). (See "Acute phase reactants", section on 'Laboratory evaluation'.)

Other laboratory tests — There are no definitive biomarkers that reliably assess EGPA activity or treatment response [61]. Nonspecific laboratory abnormalities that may be observed in EGPA include [6,10]:

●Normochromic, normocytic anemia

●Leukocytosis

●Hypergammaglobulinemia

●Elevated IgG4 [70]

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

●Elevated complement (C3, C4, CH50) levels

Imaging — Evidence of EGPA may be present on chest radiograph, typically in the form of bilateral patchy opacities. Because pulmonary infiltrates due to EGPA may frequently be missed on radiography (over 30 percent in one small series [71]), high-resolution computed tomography (HRCT) should be performed in those with normal chest radiographs and suspected disease. Additional imaging may reveal extensive sinus disease, but the findings are not specific for EGPA.

●Chest radiograph – The most common chest radiographic abnormalities in patients with EGPA consist of transient, often migratory, patchy opacities without lobar or segmental distribution or persistent bilateral peripheral consolidation (image 1 and image 2) [71-73]. Less common findings include reticulonodular opacities, pleural effusion, and, occasionally, lung nodules [72,74-76]. Pleural effusions are found in approximately 9 percent of patients and are usually exudative and eosinophilic [8].

●High-resolution CT – Typical HRCT findings in EGPA consist of ground-glass opacities and areas of consolidation that are peripheral or randomly located (image 3) and (image 4) [71]. Interlobular septal thickening, bronchial wall thickening, bronchial dilation, pulmonary nodules, and pleural fluid can also be seen. One series described parenchymal consolidation or ground-glass opacification on the computed tomography (CT) scans of 10 of 17 patients [76]. In another study of 31 patients, CT demonstrated parenchymal opacification (ground-glass and/or consolidation) in 17, bronchial wall thickening in 15, interlobular septal thickening in 5, pleural effusion in 4, and a nodule in 1 [77]. The interlobular septal thickening in EGPA may be due to cardiac involvement leading to interstitial pulmonary edema or infiltration of the septa by eosinophils [78]. These findings are not specific for EGPA but may guide choice of a location for bronchoalveolar lavage (BAL) 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 with the corresponding bronchi) in combination with a stellate and irregular configuration of some pulmonary arteries (referred to as the vasculitis sign) (image 5) [75].

●Sinus CT – Sinus CT features include thickening of sinus and nasal mucosa, sinus opacification of all sinuses, obstruction of the ostiomeatal complex, polypoid tissue, mastoiditis, and serous or thick mucoid impaction of the middle ear [79].

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

Pulmonary function testing — We perform spirometry in patients with suspected EGPA if this has not previously been performed. 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. Patients presenting with dysphonia and vocal cord abnormalities or subglottic stenosis may also have detectable abnormalities on spirometry flow-volume loops. When lung parenchymal involvement occurs, there may be additional possible restriction on spirometry or reduction in lung volumes or diffusion capacity (eg, total vital capacity and forced vital capacity), if performed. (See "Overview of pulmonary function testing in adults" and "Pulmonary function testing in asthma" and "Presentation and diagnostic evaluation of non-life-threatening and nonmalignant subglottic and tracheal stenosis in adults".)

Bronchoalveolar lavage (BAL), in select patients with pulmonary infiltrates — BAL may be 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) [80,81]. However, this finding is not specific nor required for a diagnosis of EGPA and would only be present in the event of active pneumonitis (table 3). (See "Overview of pulmonary eosinophilia" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Biopsy, when possible — Histologic confirmation of EGPA is desirable but sometimes not possible. A biopsy site should be 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 [43]. (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 [22], 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 in which none of the extrapulmonary sites are 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. Biopsies obtained using transbronchial cryobiopsy may be larger [82]; however, the role for this technique in EGPA has not be systematically assessed. (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

Surveillance testing — We typically obtain serum levels of NT-proBNP and cardiac troponin, an electrocardiogram (ECG), and a transthoracic echocardiogram (looking for wall motion abnormalities, mural or valvular thrombi) as part of the initial evaluation of a patient with a suspected diagnosis of EGPA even in the absence of symptoms suggesting cardiac disease [32,61,83,84]. 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 [8,30,32]. We use this initial testing to guide further imaging and decisions about endomyocardial biopsy.

The most common echocardiographic finding in EGPA with cardiac involvement is wall motion abnormalities, which were found in 41 percent of patients in one case series [32]. Other findings include valvular abnormalities (eg, mitral or aortic regurgitation), pericardial effusion, mural thrombi, and pulmonary hypertension.

Subsequent work-up, for those with abnormalities — If abnormalities suspicious for EGPA cardiac involvement are noted on ECG or echocardiogram, we perform cardiovascular magnetic resonance imaging (CMR) with gadolinium enhancement if kidney function is adequate [85]. Some patients may also require endomyocardial biopsy. Gadolinium should be used with caution in patients with acute kidney injury or chronic kidney disease (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'.)

●Cardiovascular magnetic resonance imaging (CMR) – Gadolinium enhancement on CMR has been reported to correlate with endomyocardial biopsy evidence of eosinophilic infiltration [86]. Assessment of late gadolinium enhancement (LGE) images may reveal myocardial edema, necrosis or fibrosis [35,87], as well as the distribution of the findings in a coronary pattern that may suggest a coronary vasculitis, especially if the presentation was consistent with an acute coronary syndrome. CMR may be a useful tool for EGPA risk stratification and treatment individualization [88,89], although additional testing may be needed to differentiate active disease from fibrosis [61]. ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake has been evaluated as one possible method to differentiate inflammation and fibrosis in a small study [85] but has not been more broadly validated.

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 [32].

●Endomyocardial biopsy – An endomyocardial biopsy may be considered when EGPA is suspected based on noninvasive testing and documentation of cardiac involvement would affect the choice of therapy. (See "Endomyocardial biopsy" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

DIAGNOSIS — In most patients, the diagnosis of EGPA is based on a combination of hypereosinophilia (≥1000 cells/microL), typical clinical characteristics (eg, asthma, rhinosinusitis with or without polyposis, mononeuritis multiplex), and histopathology from affected tissues (eg, skin, lung, peripheral nerve, gastrointestinal tract) showing eosinophilic infiltration with or without vasculitis (picture 3A). (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)

The biopsy site should be selected from among the most accessible sites (eg, skin, kidney, peripheral nerve, lacrimal gland, conjunctiva) that are likely to yield a diagnosis (based on disease activity of the site and known diagnostic yield of the given tissue). Lung biopsy may be considered when none of the extrapulmonary sites are appropriate for biopsy and a CT scan shows pulmonary parenchymal involvement. (See 'Biopsy, when possible' above.)

Among patients with small- or medium-vessel vasculitis, diagnostic criteria have been proposed by the American College of Rheumatology to differentiate patients with EGPA from those with other forms of vasculitis. (See 'Vasculitis classification criteria' below.)

When histopathology is not available or is inconclusive, a presumptive diagnosis of EGPA can be made in patients with suggestive clinical features and peripheral eosinophilia after excluding alternative diagnoses. (See 'Differential diagnosis' below.)

VASCULITIS CLASSIFICATION CRITERIA — Several classification criteria have been used over the years to select for patients with EGPA from those with other vasculitides with high specificity in clinical trials [7,10,54,56,66]. None of them perform well to differentiate EGPA from other eosinophilic disorders in the absence of proven vasculitis. (See "Overview of and approach to the vasculitides in adults", section on 'Classification criteria'.)

In 2022, the American College of Rheumatology and European Alliance of Associations for Rheumatologic (EULAR) revised the classification system to identify EGPA among patients with small- or medium-sized vessel vasculitis [54]. In this revised system (table 4), a score of 6 or more had a sensitivity of 85 percent and a specificity of 99 percent for EGPA compared with expert consensus:

●Blood eosinophil count ≥1000 cells/microL (+5 points)

●Asthma (a history of wheezing or the finding of diffuse high-pitched wheezes on expiration; +3 points)

●Nasal polyps (+3 points)

●Extravascular eosinophilic predominant inflammation on biopsy (picture 3A-B) (+2 points)

●Multiple mononeuropathy (+1 point)

●Hematuria (minus 1 point)

●Elevated cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) or anti-proteinase 3 antibody (minus 3 points)

Classification of patients for clinical trials without definite evidence of vasculitis is more controversial. One proposal encompassing some of these patients is to classify those with asthma, peripheral eosinophilia (blood eosinophils ≥1500 cells/microL or ≥10 percent of leukocytes), and one or more of the following as having EGPA [9]:

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

●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 kidney disease, abdominal pain)

DIFFERENTIAL DIAGNOSIS — The main diseases to consider in the differential diagnosis of EGPA are aspirin-exacerbated respiratory disease (AERD), eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypereosinophilic syndromes, 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 anti-inflammatory drugs (NSAIDs) characterized by bronchoconstriction, nasal congestion, and rhinorrhea. These patients may also have hypereosinophilia but do not have eosinophilic pneumonia or other organ system involvement seen in EGPA. Coronary vasospasm may also be seen in AERD [90]. It may be difficult to differentiate these conditions early in the course of disease, and patients with EGPA may have coincident NSAID sensitivity [91]. (See "Aspirin-exacerbated respiratory disease".)

●Chronic eosinophilic pneumonia – Chronic eosinophilic pneumonia is characterized by pulmonary symptoms, bronchoalveolar eosinophilia, and interstitial or alveolar infiltrates on histopathology. Granulomas are generally not seen on biopsy, although a nonnecrotizing eosinophilic vasculopathy has been rarely reported [92]. Clinically, imaging confirms eosinophilic lung involvement with pulmonary opacities, but unlike other systemic eosinophilic syndromes, organs other than the lungs are not involved [93,94].

Occasionally, eosinophilic pneumonia may precede the other manifestations of EGPA, making it difficult to differentiate EGPA from chronic eosinophilic pneumonia. These patients should be monitored closely for development of additional organ involvement that would indicate a diagnosis of EGPA. (See 'Natural history' above and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

●Allergic bronchopulmonary aspergillosis – ABPA is also associated with asthma, Aspergillus sensitization, radiographic pulmonary opacities, and IgE elevation and peripheral blood eosinophilia in the context of type 2 inflammation. Although the pulmonary symptoms may overlap with EGPA, the predominant bronchial involvement with mucoid impaction differentiates ABPA from EGPA. Additional radiologic features typical of ABPA include tree-in-bud peripheral opacities as well as "finger in glove" appearance. Central bronchiectasis is part of the diagnostic criteria. Testing for sensitization to mycoses or demonstration of hyphae on biopsies is not a feature of EGPA. Like AERD, ABPA does not typically affect extrapulmonary organs, although allergic fungal rhinosinusitis may co-occur with ABPA and has a characteristic appearance on imaging. (See "Overview of pulmonary eosinophilia" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Allergic fungal rhinosinusitis".)

●Hypereosinophilic syndrome – Differentiating hypereosinophilic syndromes (HES) from EGPA can be difficult. Pulmonary involvement is not uncommon in HES, with 25 to 67 percent of patients having pulmonary involvement, with 10 to 40 percent presenting with cough [95]. Testing for molecular abnormalities associated with HES is important to rule out myeloid malignancies that could be treated with targeted therapies. Elevated serum vitamin B12 and tryptase levels may be seen in myeloid variants 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 lungs, 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 antimyeloperoxidase, whereas in granulomatosis with polyangiitis it is more likely antiproteinase 3. (See "Overview of and approach to the vasculitides in adults".)

●Other eosinophilic diseases – Drug-induced eosinophilia (table 5), toxocariasis, strongyloidiasis, HIV infection, and paraneoplastic eosinophilia are in the differential diagnosis of EGPA [61]. Depending on the patient’s travel, geographic residence, exposure history, and symptom pattern, serologic testing for Toxocara and Strongyloides and/or empiric treatment, testing for HIV infection, serum vitamin 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".)

POSTDIAGNOSTIC TESTING — 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.

●Glomerular disease – Kidney involvement is assessed with urinalysis (to assess for hematuria, proteinuria, or red blood cell casts), blood urea nitrogen, and serum creatinine. Antineutrophil cytoplasmic antibodies (ANCA) are positive in 75 to 100 percent of patients with glomerulonephritis due to EGPA [96]. (See 'Kidney' above.)

●Cardiovascular involvement – Initial cardiovascular testing, which we perform once the diagnosis is suspected, typically includes serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin, an electrocardiogram (ECG), and a transthoracic echocardiogram [97]. Cardiac MRI may help with demonstration of cardiac involvement. Further testing is based on the results of these tests and is described above. (See 'Cardiovascular tests' above.)

●Gastrointestinal testing, in those with symptoms – Evaluation for gastrointestinal involvement is guided by the specific symptoms (eg, upper abdominal pain, diarrhea, hematochezia) and laboratory testing but may include upper or lower endoscopy with biopsies. Elevated liver enzymes may suggest gallbladder or liver involvement. (See 'Gastrointestinal tract' above.)

●Survey of peripheral nerves – 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 if vasculitis has already been demonstrated. In some situations, the diagnosis of EGPA is demonstrated via nerve biopsy. (See 'Biopsy, when possible' above and "Clinical manifestations and diagnosis of vasculitic neuropathies".)

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 – 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. The exact etiology of EGPA is unknown. (See 'Introduction' above.)

●Clinical features

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

•Upper airway and ear disease – Otolaryngologic 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.)

•Neuropathy – 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.)

•Skin – Two-thirds of EGPA patients have skin involvement; findings include palpable purpura, subcutaneous nodules, and macular or papular erythematous rashes. (See 'Skin' above.)

•Cardiac – 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 1000/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 peripheral or patchy parenchymal consolidation or ground-glass opacification; interlobular septal thickening, nodules, and pleural effusions may also be noted. (See 'Imaging' above.)

•Biopsy, when possible – A biopsy site should be 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 are appropriate for biopsy and the HRCT shows lung parenchyma involvement. (See 'Biopsy, when possible' above.)

●Diagnosis – In most patients, the diagnosis of EGPA is based on a combination of hypereosinophilia (≥1000 cells/microL), typical clinical characteristics (eg, asthma, rhinosinusitis with or without polyposis, mononeuritis multiplex), and histopathology showing eosinophilic infiltration with or without vasculitis. When histopathology is not available or is inconclusive, a presumptive diagnosis can be made in patients with suggestive clinical features and peripheral eosinophilia after excluding alternative diagnoses. (See 'Diagnosis' above.)

●Vasculitis classification criteria – Patients with a new diagnosis of vasculitis on biopsy may have variable systemic manifestations and serologic testing. For these patients, criteria have been developed to distinguish those with EGPA from those more likely to have other vasculitides (table 4). (See 'Vasculitis classification criteria' above.)

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

●Postdiagnostic testing – 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 'Postdiagnostic testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Talmadge E King, Jr, MD, who contributed to earlier versions of this topic review.