Are You Confident of the Diagnosis?
What you should be alert for in the history
Most often patients have an antecedent history of asthma and/or severe allergic rhinitis with elevated eosinophil counts. Skin lesions may present as palpable purpura, papules on the extensor extremities, persistent urticarial lesions, livedo, nodules or ulceration (Figure 1). Skin lesions most often present after or simultaneously with systemic symptoms or signs. Approximately 50% of EGPA patients have skin lesions at some point.
Characteristic findings on physical examination
Characteristic findings on physical examination include small papules with a propensity for the extensor aspects of the fingers and hands, elbows or knees. These papules are often referred to as Churg Strauss papules but are not entirely specific for EGPA, as they can be seen in eosinophilic granulomatosis with polyangiitis (GPA; formerly known as Wegener’s granulomatosis) and other disorders at times. Palpable purpura, nodules and livedo can also be seen in the skin of EGPA patients, most often involving the lower extremities. Persistent urticarial lesions can be located on the truncal area, head and neck or extremities.
Expected results of diagnostic studies
Diagnostic studies most often show an elevated eosinophil count and serum IgE. Depending on organ involvement, there may be fever, arthralgias or peripheral edema. Pulmonary infiltrates are commonly seen. Other organs may be involved including the nervous system with mononeuritis multiplex as a characteristic finding. Systemic abnormalities can include renal dysfunction and less commonly cardiac dysfunction.
Diagnosis confirmation rests upon careful clinical and pathologic correlation. The definition of EGPA includes antecedent asthma, eosinophilia, allergic rhinitis/sinusitis or polyposis, pulmonary infiltrates, mononeuritis multiplex and biopsy confirming vasculitis (Figure 2 and Figure 3). Most often four of these six criteria must be present over time.
Antineutrophil cytoplasmic antibody tests (ANCA) may be positive (approximately 50%), typically not the Proteinase 3-cytoplasmic ANCA (c-ANCA/PR3) seen in GPA but most often the perinuclear pattern (p-ANCA) and may react with myeloperoxidase (MPO). Pulmonary nodules are more often seen in GPA than in EGPA as “patchy” pulmonary infiltrates are more often seen in EGPA. Palpable purpura with the corresponding microscopy of leukocytoclastic vasculitis (LCV) may be seen in GPA and EGPA.
The characteristic EGPA papule microscopically shows foci of degeneration of collagen surrounded by dust and debris typical of collagen damage by eosinophil degranulation surrounded in turn by a histiocytic infiltrate. EGPA may show more eosinophilic change when compared to GPA but this is not an absolute criterion for differentiation and requires clinical correlation. As is true with all forms of vasculitis and especially with granulomatous vasculitides, infection must always be considered in the differential diagnosis and appropriate tissue and serum studies should be done to exclude infection.
Who is at Risk for Developing this Disease?
Churg Strauss disease is thought to represent an autoimmune process developing in those at risk. Most often patients have had “allergic” diseases with increase in eosinophils prior to onset, including asthma, allergic rhinitis, nasal polyps and sinus or upper respiratory infections. Adults of both genders are most often affected, with the average age at onset in the late 40s.
What is the Cause of the Disease?
The etiology is likely an autoimmune and genetic diathesis combined with certain infectious and allergic illnesses characterized by elevated eosinophils and IgE.
Pathophysiology is linked most closely to other antineutrophil cytoplasmic antibody (ANCA) associated disease. EGPA most often involves the upper airways and the lungs and tends to be associated with eosinophilia and less often presents with renal disease when compared to GPA or microscopic polyangiitis (MPA). Immune complex deposition, proinflammatory chemokines and cytokines and direct damage to affected blood vessels and tissue by degranulation and release of eosinophilic contents all play a role in pathogenesis.
Systemic Implications and Complications
Associated systemic disorders are frequent and include pulmonary infiltrates (more so than nodules), upper airway disease including polyposis of the sinuses, nervous system disease, gastrointestinal and renal disease, cardiac disease and eye involvement in descending order of frequency. Initial tests include a complete blood count (CBC) with differential count, serum IgE level, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum antineutrophilic cytoplasmic antibodies (ANCA), chest x-ray, blood chemistry tests, urinalysis with microscopy. Further evaluation most often requires imaging of the chest and most often direct imaging by endoscopy of the upper airways and bronchi.
Cardiac function evaluation is important as cardiac involvement and damage are more commonly seen in EGPA than in GPA and may portend a poorer prognosis. Biopsy of affected organs may lead to confirmation of the diagnosis and skin biopsy may be very helpful if involved. Biopsies of affected organs may be required to confirm the diagnosis. Infection as a possible cause of patient symptoms and signs or resulting as a complication of therapy must always be considered. Appropriate cultures and tests must be done to rule out infection.
EPGA patients do not all develop vasculitis suggesting additional classification criteria may be helpful. ANCA positivity is associated with vasculitis or vasculitis associated symptoms while EPGA patients lacking ANCA are more likely to develop myocarditis.
Once the diagnosis has been confirmed the treatment of EGPA requires a coordinated effort amongst specialists who are both familiar with the disease and with the various organs involved. Systemic therapy is required to bring the disease into remission as quickly as possible to limit organ damage and to induce remission. Skin lesions most often respond in parallel to improvement in other organs.
Topical therapy may be of help in those patients with ulcerations or painful skin lesions to reduce pain, prevent secondary infection and hasten the healing process. Antiseptic wet compresses may be useful in patients with ulcerated skin lesions. EGPA papules may not require specific topical therapy.
Systemic corticosteroids comprise the mainstay of therapy for EGPA, doses similar to those used in GPA, 1 mg/Kg/day, and with slow taper over months depending on response. Cyclophosphamide may be used in patients with more severe disease, in those with consequential multiple organ involvement or in those not responding to prednisone alone.
Optimal Therapeutic Approach for this Disease
Therapy requires a thorough assessment of organ involvement and a coordinated approach in concert with those specialists familiar with the disease. EGPA like GPA can be a fatal disease and requires expert care.
Prednisone is most often used as the first-line therapy for EGPA. Cyclophosphamide may be added if needed or required according to severity of organ involvement. Mycophenolate mofetil has been shown to be effective in some forms of ANCA associated vasculitis and other larger controlled trials are underway.
Recent studies have looked at Rituximab in addition to or as an alternative to intravenous or oral cyclophosphamide in ANCA-associated vasculitis. Rituximab was given in a dosage of 375mg/m2 once weekly for 4 weeks. Patients in the Rituximab arm did as well as patients in the arm where both drugs were given, suggesting that Rituximab could be an alternative treatment for induction of remission in patients with severe disease. Mepolizumab, an anti–interleukin-5 monoclonal antibody, is known to reduce serum eosinophil levels and is also under investigation for treatment of EGPA. Prednisone is most often used as the first-line therapy for EGPA. Cyclophosphamide may be added if needed or required according to severity of organ involvement.
Management requires follow-up of the clinical abnormalities noted at the time of diagnosis, primarily pulmonary parameters and function. Skin lesions tend to respond along with improvement in other organ systems.
Unusual Clinical Scenarios to Consider in Patient Management
Management of airway disease and pulmonary function is critical. Asthmatic symptoms may be difficult to control and require expert guidance and follow up. Diabetes or secondary infection may develop as a result of the medications used to treat the disease and close monitoring for such complications is essential.
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