Vasculitis: Churg Strauss Syndrome

Does this patient have eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)?

There are many challenges in making the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome. It is one of the rarest systemic small vessel vasculitis with symptoms that may evolve over decades until the diagnosis is clinically apparent. Multiple complications leading to significant morbidity and mortality may result from this disease once established, thus the importance of prompt recognition and treatment.
EGPA has been traditionally described as having an initial long prodromal phase characterized by asthma, rhinitis, sinusitis and/or nasal polyposis (allergic ear, nose and throat [ENT] manifestations), or eosinophilic gastroenteritis. A second phase follows later on when pulmonary infiltrates and peripheral eosinophilia predominate. Then the disease culminates in a third phase with vasculitic manifestations such as polyneuropathies, skin lesions, gastrointestinal (GI) ischemia, glomerulonephritis (GN). However, being stuck to this concept of a triphasics disease may delay the diagnosis and treatment in many patients as clinical manifestations frequently overlap and may occur at different times during the course of disease, not in a particular sequence.
The most common clinical manifestations of EGPA are asthma, rhinitis and sinus disease, polyneuropathy and skin lesions. Although GI and cardiac disease are less common, they may be associated with significant morbidity and mortality.

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Patients with EGPA typically develop asthma at adult age or may present with worsening symptoms of long standing asthma that had been well controlled in the past. Asthma may be present for over ten years before onset of another symptom, a fact which has contributed to the concept of EGPA as a triphasic illness. About 90% of patients have asthma at the time of diagnosis and the remaining usually develop symptoms of asthma after the diagnosis.
EGPA may be a difficult diagnosis to establish in patients with late-onset asthma and peripheral eosinophilia in the absence of any other organ-system involvement, but should be considered. Even in patients that in addition to late-onset asthma, present with sinus and/or nasal disease and pulmonary infiltrates, physicians often feel unsure about confirming the diagnosis when the vasculitic component is missing. Therefore, treatment is often delayed until the patient develops symptoms or signs of vasculitis and significant morbidity may result. Limited disease or “forms frustes” (asthma, eosinophilia and other non-vasculitic manifestations) have been increasingly recognized and represent a major diagnostic challenge.
Skin lesions are very common and the most frequently seen is palpable purpura. Other lesions include subcutaneous nodules, ulcers, urticaria and digital ischemia.
Gastrointestinal symptoms range from mild abdominal pain, nausea and vomiting to intestinal necrosis due to mesenteric ischemia.
EGPA has some characteristic features that are very particular to this disease and knowledge of these helps in making the diagnosis. Lung infiltrates are common and usually have a fleeting and migratory pattern. They may be associated with significant hypoxia, or may cause little or no symptoms. The infiltrates initially can be confused with infection, congestive heart failure (although often are peripheral), or allergic pneumonitis. Polyneuropathies, in particular mononeuritis multiplex are very common in EGPA and can be rapidly progressive with devastating morbidity (e.g. motor loss) if not aggressively treated at the outset. In contrast, GN is not as frequent in EGPA as compared to granulomatosis with polyangiitis (GPA – former Wegener’s granulomatosis) or microscopic polyangiitis (MPA), and most patients have an indolent course without developing end-stage renal disease. Cardiac disease is a very important clinical manifestation to recognize as cardiomyopathy is the main predictor of mortality in EGPA.
The differential diagnosis of EGPA includes other systemic small vessel vasculitis such as GPA and MPA, upper and lower chronic respiratory infections, parasitic infections, hypereosinophilic syndromes (HES) and chronic eosinophilic pneumonia. Asthma and allergic rhinitis are not clinical manifestations of other systemic small vessel vasculitis. The distinction between EGPA and HES may be very difficult in patients without ENT involvement. ENT manifestations are not usually part of HES. There is a significant overlap of organ-system involvement in these two entities and they both typically present with peripheral and tissue eosinophilia.

What tests to perform?

Laboratory tests may show anemia, leukocytosis thrombocytosis, an elevated erythrocyte sedimentation rate and/or C-reactive protein but these are all non-specific findings. A high eosinophil count is expected in all patients, however it may be absent as a result of corticosteroid (CS) therapy for the asthma. It may be helpful to obtain test results from before CS treatment. The antineutrophil cytoplasmic antibodies (ANCA) occur in only 30% to 40% of patients, and thus are not critically important for diagnosis. The main antigen is myeloperoxidase (MPO-ANCA) and its presence may be associated with certain clinical features more than others. Laboratory tests, in particular the complete blood cell count, are important in monitoring cytotoxic therapy. Alveolar hemorrhage may present without hemoptysis and thus when suspected, hemoglobin/hematocrit should be closely monitored. These patients can rapidly deteriorate due to recurrent alveolar bleeding before the appearance of hemoptysis.
Imaging tests are useful for diagnosis and monitoring of response to treatment. A chest X-ray (CXR) is the initial test of choice for lung evaluation, followed by computerized tomography (CT) if more detailed parenchymal evaluation is needed. Pulmonary infiltrates are common, usually migratory and recurrent. Alveolar hemorrhage is infrequent in EGPA but may present as infiltrates or alveolar consolidation. It is important to remember that infectious processes may have the exact same appearance on lung imaging studies and should always be considered. That is particularly important if lung nodules/cavities are present as these are rare in EGPA and an alternative etiology should always be pursued. Other imaging tests should be ordered as indicated by the presence of specific clinical features such as GI symptoms. Despite the lack of specific guidelines regarding cardiac imaging (i.e. echocardiography and/or magnetic resonance imaging) in the absence of suggestive symptoms, given the high mortality associated with these manifestations most experts recommend cardiac evaluation with echocardiogram at the time of diagnosis for all patients.
Histologic confirmation is preferred but not always feasible. Eosinophilic infiltrates may be seen in cutaneous or parenchymal lesions or blood vessel walls, where there may also be fibrinoid necrosis. Tissue granulomas were described by Churg and Strauss but are not always present and not necessary for diagnosis. In trying to make a distinction between HES and EGPA, biopsy of affected tissue is usually obtained but not always diagnostic. Nerve biopsy is usually unnecessary in patients with confirmed EGPA who present with limb pain, paresthesias, sensory and/or motor loss. Electromyography is used for diagnosis of polyneuropathies but treatment should not be delayed as nerve damage can be disabling.
The diagnosis of EGPA is primarily based on suggestive clinical manifestations supported by laboratory testing showing eosinophilia, abnormal imaging studies and tissue biopsy when needed and feasible. Patients with EGPA follow different courses of disease and while some patients may achieve long sustained remissions with minimal therapy, a large number of patients have chronic or relapsing disease requiring multiple courses of therapy.

How should patients with eosinophilic granulomatosis with polyangiitis be managed?

The treatment of EGPA is determined by severity and extension of disease, and must be individualized. It always includes the use of corticosteroids (CS), as monotherapy or in combination with another immunosuppressive agent. Patients with mild disease or in the absence of poor prognostic factors may be treated with CS alone. Following a course of treatment and achieving disease remission, CS may be discontinued and some patients are just monitored on a regular basis without any therapy. Patients with severe disease often require the addition of a cytotoxic agent to CS. Cyclophosphamide (CP) is usually the first option for severe disease. Intravenous pulse of solumedrol at doses of 1g per day for three days may be given to patients with rapidly progressive or severe disease (i.e. alveolar hemorrhage, acute severe neuropathy, mesenteric ischemia, cardiac involvement, or glomerulonephritis with renal insufficiency).
Poor prognostic factors have been used as the main indication for the use of CP and they include central nervous system, cardiac, renal with elevated creatinine, and severe GI involvement. Moreover, disease that may be associated with permanent morbidity, such as mononeuritis multiplex should also be treated more aggressively with CP. Other treatment options for less severe disease include methotrexate, azathioprine, or mycophenolate mofetil when a second agent is needed.

The use of Mepolizumab, an anti-interleukin-5 monoclonal antibody in a randomized trial resulted in higher rates of remission and lower requirements of CS. However, even on the Mepolizumab group, the rate of remission was no higher than 50%. Anecdotal evidence from case series suggest that Rituximab may be effective in EGPA and prompted the ongoing phase III study comparing rituximab with conventional therapy for induction of remission.

What happens to patients with eosinophilic granulomatosis with polyangiitis?

Following a diagnosis of EGPA, patients should be evaluated for any possible trigger factors, which should be eliminated when possible (e.g. leukotriene-receptor antagonists, omalizumab, environmental agents).
Prognosis of EGPA has improved significantly with increased awareness of disease and its associated poor prognostic factors, which now result in the early use of cytotoxic therapy.
Clinical features associated with the presence of vasculitis such as mesenteric ischemia, palpable purpura or GN may be controlled without much difficulty with aggressive therapy while manifestations of asthma, allergic rhinitis, sinusitis, nasal or sinus polyposis tend to be relapsing or chronic and may be quite difficult to suppress. Patients may require chronic low dose CS to control asthma symptoms, which may persist after control of all other features of disease. Chronic CS use frequently results in multiple drug-induced morbidity such as infections, osteoporosis with fractures and diabetes. These complications are common reasons for hospital admissions and should always be considered in patients on long-term use of CS.
Morbidity from polyneuropathies or heart failure may be permanent and very disabling, thus early aggressive cytotoxic therapy should not be delayed.
It is important to remember that at the time of diagnosis as well as during evaluation of possible recurrences, infection is a common complication of immunosuppressive therapy and may occur concomitantly with a flare of EGPA. A new pulmonary infiltrate or skin lesions in patients with EGPA may be clinically or radiologic indistinguishable from infection. When in doubt, always exclude an infectious process before intensifying immunosuppressive therapy. Obtaining tissue for cultures may be necessary.
Patients with EGPA should always be evaluated for cardiac disease, not just in the presence of severe symptoms but also in the presence of more subtle clinical presentations. In patients who present with cough and persistent pulmonary infiltrates, heart disease may be easily missed.

How to utilize team care?

A multispecialty team is important for best care of patients with EGPA. Patients may require tissue biopsies for diagnosis and for exclusion of other complications (e.g. infections) during times of clinical exacerbations. Not infrequently dermatologists are needed for skin biopsies and pulmonologists for bronchoscopy, transbronchial biopsies and additional treatment for asthma. Occasionally patients need open lung biopsies performed by thoracic surgeons.

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