Eosinophilic Granulomatosis With Polyangiitis

AUTHORS: Alison DeDent, MD, and Erica Farrand, MD

Definition

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (CSS) or as allergic granulomatosis and angiitis, refers to a multisystem, necrotizing, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis affecting small and medium-sized vessels characterized by asthma and eosinophilia. ANCA reactivity may be positive or negative.¹ Universal consensus for diagnostic criteria is lacking. Classification and proposed diagnostic criteria for EGPA are described in Table E1.²^,³

TABLE E1 Classification and Diagnostic Criteria for EGPA ²^,³

Classification Criteria ∗		Diagnostic Criteria
American College of Rheumatology (preferred; requires 4 of 6)		Lanham (requires all 3)
Asthma Eosinophilia (>10% total WBC count) Neuropathy (mono- or polyneuropathy) Pulmonary infiltrates (migratory or transitory) Paranasal sinus abnormality (pain, tenderness, or radiologic abnormality) Extravascular eosinophils (in a biopsy containing an artery, arteriole, or venule)		Asthma Eosinophilia (>10% WBC count or >1.5 × 109) Systemic vasculitis affecting at least two or more extrapulmonary sites

EGPA, Eosinophilic granulomatosis with polyangiitis; WBC, white blood cell.

^∗Classification criteria constitutes a unique set of uniform characteristics among groups of patients for the purpose of further study. Though not intended for individual-level diagnosis, it is frequently applied for these purposes. The new classification criteria published in 2022 was established for use in research and was not intended to be used for diagnostic purposes.

Adapted from Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

EGPA, Eosinophilic granulomatosis with polyangiitis; WBC, white blood cell.

Synonyms

Allergic angiitis

Allergic granulomatosis

Allergic granulomatosis and angiitis

Churg-Strauss syndrome

EGPA

ICD-10CM CODE
M30.1		Polyarteritis with lung involvement (Churg-Strauss)

Epidemiology & Demographics

Epidemiology varies based on geographic location and applied classification criteria. Incidence and prevalence range from 0.18 to 4.0 cases per million person-yr and 2 to 30.4 per million person-yr, respectively.
Rarest of the ANCA-associated vasculitides.
Median age of onset is 49 to 59 yr.
No sex predominance.

Physical Findings & Clinical Presentation

The clinical picture of EGPA typically consists of three partially overlapping phases, which may or may not be sequential. See Table E2 for organ-specific manifestations.
1. Prodromal/allergic phase ⁷:
  1. Main manifestation is asthma, present in 95% to 100% of patients
  2. Upper respiratory manifestations are common
  3. May precede development of systemic vasculitis by several years
2. Eosinophilic/tissue infiltration phase ⁷:
  1. Characterized by peripheral eosinophilia and eosinophilic tissue infiltration leading to organ-specific signs and symptoms, most commonly with pulmonary, cardiac, and/or GI involvement
3. Systemic vasculitic phase ⁷:
  1. Onset of necrotizing vasculitis leading to constitutional and organ-specific signs and symptoms, typically with cutaneous, renal, and nervous system manifestations
The presence of ANCA reactivity leads to distinct phenotypes that influence the frequency of organ-specific involvement.⁷ (see Table E2).

TABLE E2 Organ-Specific Manifestations and Phenotypes of EGPA ³^,^5-8^,¹⁰^,^13-15

Organ Involvement	Disease Manifestations ∗	Phase	ANCA+ Phenotype	ANCA - Phenotype	Pathology
Ear, nose, and throat	Allergic rhinitis Sinusitis Nasal polyposis	Prodromal			Eosinophilic infiltrates
Pulmonary	Asthma Pulmonary infiltrates (transient) or nodules Pleural effusions Alveolar hemorrhage (rare)	Prodromal, eosinophilic, vasculitis		x	Eosinophilic infiltration Extravascular granulomas Necrotizing vasculitis
Cardiovascular	Cardiomyopathy Pericarditis Myocarditis Myocardial infarction Arrhythmia Valvular defects Endomyocardial fibrosis Intracavitary thrombus Arterial & venous thromboembolism	Eosinophilic, vasculitis		x	Endomyocardial and pericardial eosinophilic infiltration Coronary vasculitis (rare)
Gastrointestinal	Abdominal pain Bleeding Mesenteric vasculitis	Eosinophilic, vasculitis			Eosinophilic infiltration Vasculitis
Renal	Microscopic hematuria Proteinuria Elevated creatinine Rapidly progressive glomerulonephritis (less common)	Vasculitis	x		Crescentic and pauci-immune focal segmental necrotizing glomerulonephritis Eosinophils and granulomas uncommon
Nervous System	Peripheral nervous system: Mononeuritis multiplex Polyneuropathy Central nervous system (rare): Cerebral hemorrhage or infarct	Vasculitis	x		Necrotizing vasculitis Eosinophilic infiltration less common
Skin	Purpura Dermal and subcutaneous nodules and papules Ecchymosis Livedo racemosa and/or hemorrhagic bullae Urticaria Ulcers	Vasculitis	x		Red granulomas Dermal and subcutaneous vessel vasculitis Eosinophilic infiltration

ANCA, Antineutrophil cytoplasmic antibodies.

^∗Spectrum of signs, symptoms, and syndromes described in patients with EGPA.

Etiology

Etiology unknown; however, pathophysiology involves both T- and B-cell responses and eosinophil activation, with influence from genetic and environmental factors.⁶^,⁷

Diagnosis ⬆ ⬇

The American College of Rheumatology (ACR) has established classification criteria for EGPA (see Table E1). The presence of four or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7% for EGPA. For patients with vasculitis, the presence of asthma and eosinophilia is 90% sensitive and 99% specific for EGPA.²

Differential Diagnosis ¹

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
Allergic bronchopulmonary aspergillosis (ABPA)
Chronic eosinophilic pneumonia (CEP)
Hypereosinophilic syndrome (HES)
IgG4-related disease

EGPA can be distinguished from the above diagnoses by the following:

In contrast to the other ANCA-associated vasculitides, including MPA and GPA, EGPA is associated with asthma and eosinophilia.
Kidney involvement, nasal/paranasal sinus bone erosions, and pulmonary nodule cavitation are much less common in EGPA compared to GPA.
CEP and ABPA are limited to lung involvement.
ANCAs, asthma, nasal polyps, and vasculitis are not features of HES, in contrast to EGPA.
The clinical characteristics of IgG4-related disease may mimic EGPA; however, vasculitis and eosinophilic granulomas are not seen on pathology.

Workup & Laboratory Tests

Initial testing focuses on diagnosing EGPA and excluding alternative diseases

CBC with differential: Eosinophilia >10% is an American College of Rheumatology -(ACR) classification criterion.
C-Reactive protein and erythrocyte sedimentation rate are often elevated during the active phase.
Immunoglobulin E (IgE) is commonly elevated.
ANCA positivity is found in 30% to 47% of patients, and myeloperoxidase (MPO) antibody positivity with a perinuclear staining pattern (p-ANCA) is most common. Negative ANCA does not rule out EGPA.
Hypereosinophilia (eosinophils >1.5 × 10⁹) necessitates a comprehensive evaluation for causes of eosinophilia.
Presence of asthma and an elevated IgE suggest possible ABPA, and serum Aspergillus antibodies should be obtained.

Once EGPA is diagnosed, subsequent testing should screen for organ-specific involvement:

Cardiac: Brain natriuretic peptide (BNP) and troponin may be elevated, suggesting cardiac involvement. ECG may be abnormal, and echocardiogram may show wall motion abnormalities, left ventricular dysfunction, and effusions.
Renal: Creatinine may be mildly elevated, and urinalysis may show mild hematuria or proteinuria, suggesting renal involvement.

Imaging Studies ⁵ ⁷ ⁸ ¹⁰

Chest radiograph may show bilateral, patchy, and migratory opacities.
Computed tomography (CT) scan is more sensitive and is the preferred imaging modality, though findings are nonspecific and may show ground-glass opacities or consolidation, bronchial wall thickening, centrilobular nodules, and pleural effusions (Fig. E1).
Paranasal sinus films may reveal sinusitis, which is an ACR classification criterion.
Organ-specific symptoms warrant additional testing and may include angiography, pulmonary function tests, abdominal imaging, cardiac MRI, and/or electromyogram and nerve conduction studies (EMG/NCS).

Figure E1 EGPA.

Thin-section CT scan at carina shows multifocal patchy ground-glass opacity around the patchy consolidation showing halo sign (arrow). Bronchial wall thickening is evident. CT, Computed tomography. (From Choi YH et al: Thoracic manifestation of Churg-Strauss syndrome: radiologic and clinical findings, Chest 117[1]:117-124, 2000.)

Treatment ⬆ ⬇

Pharmacologic Therapy

The five-factor score [FFS] may be used to guide immunosuppressive therapy. One point is assigned for each of the following risk factors present at the time of diagnosis. Higher scores indicate a worse prognosis ⁹:

Proteinuria >1 g/day
Cardiomyopathy
GI involvement
Renal insufficiency (creatinine >1.58 mg/dl)
Central nervous system involvement

NOTE: The FFS was updated in 2011 to include age ≥65 yr and absence of ear, nose, throat (ENT) manifestations,¹¹ replacing the presence of proteinuria and central nervous system involvement; however, the original criteria listed earlier are more commonly used.

Acute General Rx: Remission Induction Therapy ¹²

Active, nonsevere disease (without life- or organ-threatening characteristics):

Mepolizumab (300 mg SC every 4 wk) and glucocorticoids (prednisone 1 mg/kg/day) are initiated as first-line therapy over methotrexate, azathioprine, or mycophenolate mofetil, though individual manifestations of vasculitis may influence preferential selection of these therapies. Glucocorticoid monotherapy is not recommended.

Active, severe disease (with life- or organ-threatening characteristics):

First-line therapy includes glucocorticoids (IV methylprednisolone 500 to 1000 mg/day for 3 to 5 days or prednisone 1 mg/kg/day, or IV/PO equivalent) and either cyclophosphamide (up to 2 mg/kg/day PO for 3 to 6 mo or IV pulses) or rituximab. Cyclophosphamide is suggested with cardiac involvement or ANCA-negative cases with GI and severe neurologic involvement. Rituximab may be selected in the setting of ANCA-positivity, active glomerulonephritis, prior cyclophosphamide treatment, or for patients at risk for gonadal toxicity from cyclophosphamide. Mepolizumab is not recommended.

Chronic Rx: Maintenance Therapy ¹²

Once remission is achieved, maintenance therapy is initiated using azathioprine (2 mg/kg/day), methotrexate (up to 25 mg/wk, SC or PO), or mycophenolate mofetil (up to 1500 mg PO twice daily) for those with life-threatening or organ-specific disease manifestations. Tapering of prednisone is continued until withdrawal or the minimal effective dose is achieved. Patients with uncontrolled asthma may require long-term oral corticosteroids even in the absence of active vasculitis.

Relapse Therapy ¹²

For nonsevere disease, the addition of mepolizumab to glucocorticoid monotherapy or treatment with methotrexate, azathioprine, or mycophenolate mofetil is recommended.
For severe disease, rituximab is recommended for remission reinduction therapy after initial induction with cyclophosphamide or rituximab. However, cyclophosphamide is recommended in the setting of cardiac involvement.
Other therapeutic considerations:¹²
Leukotriene inhibitors for the treatment of asthma or sinonasal disease are not contraindicated.
Prophylaxis for Pneumocystis jiroveci pneumonia is recommended in the setting of cyclophosphamide or rituximab.

Disposition ⁶ ¹⁰

Clinical remission is obtained in >81% to 92% of patients after treatment, though relapse rates are common (∼26%).
5- and 10-yr survival with treatment is favorable, with rates between 88% and 97% and 78% and 89%, respectively.
Death is uncommon; however, older age and cardiac involvement at the time of diagnosis increase the risk of mortality.

Referral

A pulmonary referral for diagnosis and management is appropriate.
Patients should be followed closely by rheumatology.

Pearls & Considerations ⬆ ⬇

Comments

EGPA is an ANCA-associated vasculitis distinguished by the hallmark findings of asthma and eosinophilia and is composed of three overlapping phases of disease affecting multiple organ systems, most notably the lungs.
The presence of four of six American College of Rheumatology Classification Criteria is often used for diagnosing patients with EGPA. A biopsy is optimal, but not required, and diagnosis of EGPA is not excluded in the absence of ANCA reactivity.
For active, nonsevere disease, mepolizumab and corticosteroids are first-line treatment. For active, severe disease, glucocorticoids and cyclophosphamide or rituximab are recommended for induction therapy, and maintenance therapy is initiated with methotrexate, azathioprine, or mycophenolate mofetil once remission is achieved.
Remission rates are high, though relapse is common. Long-term survival with treatment is favorable. Cardiac involvement represents the leading cause of mortality.⁸

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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