Chapter 34. Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

• Asthma, eosinophilia, and systemic vasculitis are the hallmarks of eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome).
• Classic clinical features include the following:
  • Allergic rhinitis and nasal polyposis.
  • Reactive airway disease.
  • Peripheral eosinophilia (10–60% of all circulating leukocytes).
  • Fleeting pulmonary infiltrates and occasional alveolar hemorrhage.
  • Vasculitic neuropathy.
  • Congestive heart failure.
• Approximately 50% of patients with EGPA have antineutrophil cytoplasmic antibodies (ANCAs), usually with a specificity for myeloperoxidase (MPO).

In 1951, Churg and Strauss reported a series of 13 patients with “periarteritis nodosa” (see Chapter 35) who demonstrated severe asthma and an unusual constellation of other symptoms: “fever…hypereosinophilia, symptoms of cardiac failure, renal damage, and peripheral neuropathy, resulting from vascular embarrassment….” The investigators termed this new disease “allergic angiitis and allergic granulomatosis,” and specified three histologic criteria for the diagnosis: (1) the presence of necrotizing vasculitis, (2) tissue infiltration by eosinophils, and (3) extravascular granuloma.

In 1990, an American College of Rheumatology panel liberalized the criteria for the classification of this disease, dropping the requirements for histopathologically proven vasculitis and granuloma (Table 34–1). The Chapel Hill Consensus Conference on nomenclature of the vasculitides subsequently defined the Churg-Strauss syndrome as a disorder characterized by eosinophil-rich, granulomatous inflammation of the respiratory tract and necrotizing vasculitis of small- to medium-sized vessels, associated with asthma and eosinophilia. In 2012, the Revised Chapel Hill Consensus Conference Nomenclature of Vasculitides recommended the term “eosinophilic granulomatosis with polyangiitis (EGPA)” for this disease. The purpose for this recommendation was twofold: (1) to emphasize certain cardinal features of the condition, and (2) for consistency with the names preferred for two related disorders, granulomatosis with polyangiitis (formerly Wegener granulomatosis)(see Chapter 32) and microscopic polyangiitis (see Chapter 33).

EGPA is a rare disease—significantly less common than the other forms of ANCA-associated vasculitis. The annual incidence of EGPA is approximately 2.4 cases per million individuals. The distribution of cases is roughly equal between men and women. In recent years, associations between the use of leukotriene antagonists and EGPA have been reported. Rather than causing the disease, however, it is more likely that these medications permit the tapering of glucocorticoids, thereby “unmasking” the vasculitic phase of EGPA.

Symptoms and Signs

After the diagnosis of EGPA has been made, three disease phases are often recognizable: the prodrome, eosinophilia/tissue infiltration, and vasculitis.

The prodrome phase is characterized by the presence of allergic disease (typically asthma or allergic rhinitis). This phase often lasts for several years.

During the eosinophilia/tissue infiltration phase, striking peripheral eosinophilia may occur. Tissue infiltration by eosinophils is observed in the heart, lung, gastrointestinal tract, and other tissues.

In the third phase, vasculitis, systemic necrotizing vasculitis affects a wide range of organs, ranging from the heart and lungs to the peripheral nerves and skin (Figure 34–1).

Nose and Sinuses

Upper airway disease in EGPA usually takes the form of nasal polyps or allergic rhinitis. A surprisingly high percentage of patients with EGPA have histories of nasal polypectomies, usually long before suspicion of an underlying disease is raised. Although pansinusitis occurs frequently, destructive upper airway disease is not characteristic of EGPA.

Ears

Middle ear granulation tissue with eosinophilic infiltrates occurs in some patients, leading to conductive hearing loss. Cases of sensorineural hearing loss (see Chapter 68) have also been reported.

Lungs

More than 90% of patients with EGPA have histories of asthma. Typically, the asthma represents either adult-onset reactive airway disease or, less commonly, a significant worsening of long-standing disease. Upon encroachment of the vasculitic phase of EGPA, patients’ asthma may improve substantially, even before therapy for vasculitis has begun. Following successful treatment of the vasculitic phase, however, glucocorticoid-dependent asthma persists in many patients.

The pathologic features of lung disease in EGPA vary according to the disease phase. In the early phases, there may be extensive eosinophilic infiltration of the alveoli and interstitium. During the vasculitic phase, necrotizing vasculitis and granuloma may be evident. In the current era, when many patients with asthma are treated with systemic glucocorticoids, lung biopsy specimens showing all three histologic hallmarks of this disease are unusual.

Peripheral Nerves

Mononeuritis multiplex occurs with a remarkable frequency in EGPA, with often devastating effects. Vasculitic neuropathy was evident in 74 (77%) of the 96 patients in one series. Nerve infarctions may appear several weeks after the start of appropriate treatment, but do not always indicate the need to intensify therapy, particularly if treatment with both high-dose prednisone and cyclophosphamide has already been initiated. This may be due to continued disease activity but is more likely secondary to thrombosis of vessels that have become severely compromised by previously active inflammation. Clinically, nerve infarctions are heralded by the abrupt occurrence of a foot drop, wrist drop, or some other focal nerve lesion. Muscle wasting secondary to nerve infarctions may continue to appear for weeks after the disease has been brought under control (Figure 34–2).

Heart

Cardiac involvement also occurs with a disproportionate frequency in EGPA, and is a common cause of death. Some form of cardiac involvement occurred in 12.5% of patients in one large series. Congestive heart failure is the most common cardiac manifestation, although coronary arteritis and valvular abnormalities have also been reported.

Skin

Skin disease in EGPA takes many forms, none of which is specific: Palpable purpura, papules, ulcers, and vesiculobullous lesions are common. Nodular skin lesions are usually “Churg-Strauss granuloma” (cutaneous extravascular necrotizing granuloma). These tend to occur on the extensor surfaces of the elbows and other pressure points. Skin biopsy specimens in EGPA reveal eosinophilic infiltration of blood vessel walls. Splinter hemorrhages, digital ischemia, and gangrene associated with inflammation in medium-sized digital arteries are often present at the time of diagnosis.

Kidneys

EGPA is less likely to cause end-stage renal disease than are other forms of ANCA-associated vasculitis. Acute kidney injury may be caused by an eosinophil-mediated interstitial nephritis. When glomerulonephritis does occur, however, the histopathologic findings are often indistinguishable from those of other forms of pauci-immune vasculitis (eg, granulomatosis with polyangiitis [formerly Wegener granulomatosis], microscopic polyangiitis, and renal-limited vasculitis).

Joints

Nonspecific arthralgias and frank arthritis often occur early in the course of EGPA. The arthritis of EGPA is migratory in nature and may assume a variety of joint patterns, from a pauciarticular syndrome of lower extremity joints to a polyarthritis of the small joints of the hands.

Laboratory Findings

Eosinophilia (before treatment) is a sine qua non of EGPA. Eosinophil counts may comprise as much as 60% of the total white blood cell count. Eosinophil counts are usually sensitive markers of disease flares, but generally respond very quickly to treatment with high doses of glucocorticoids. Most patients with EGPA also have elevated serum IgE levels. Serum complement levels are usually normal. Immune complexes are not believed to play a primary role in this disease. The erythrocyte sedimentation rate, serum C-reactive protein level, and eosinophil count can be useful in the longitudinal evaluation of disease activity. The reported percentages of EGPA patients with ANCA are variable, with most figures in the literature in the range of 50% (see Chapter 32 for a full discussion of ANCA). Antibodies to either proteinase-3 or MPO (but not to both) may be found. Of the two vasculitis-specific ANCAs, which include antibodies to MPO and proteinase-3, those to MPO are more common in EGPA. MPO-ANCAs usually produce a perinuclear-ANCA (P-ANCA) pattern on serum immunofluorescence testing. Patients who are ANCA-negative tend to have more cardiopulmonary complications, while patients who are ANCA-positive tend to have more of the classic vasculitic manifestations of this disease, although there is considerable overlap between these two groups.

Imaging Studies

Pulmonary infiltrates are evident in approximately one third of patients with EGPA. These lesions are usually migratory infiltrates that occur bilaterally. Pulmonary hemorrhage is unusual but has been reported. Nodular or cavitary lesions suggest the alternative diagnoses of granulomatosis with polyangiitis (formerly Wegener granulomatosis), infection, or malignancy. Among patients with cardiac involvement, echocardiography or cardiac MRI may confirm poor cardiac function consistent with cardiomyopathy or demonstrate findings compatible with regional myocardial fibrosis.

The major disease entities in the differential diagnosis of EGPA are shown in Table 34–2. There are many diseases in which patients occasionally demonstrate mild eosinophilia (eg, a peripheral blood eosinophilia on the order of 10% or so in asthma or parasitic infections). Only a handful of diseases, however, can cause eosinophilia as high as 20–60%, as is occasionally observed with EGPA and its related conditions. Strongyloides infection, which can cause both high levels of eosinophilia and asthma, should be considered in endemic areas, which include the southeastern United States. EGPA must also be distinguished from other hypereosinophilic disorders: Löffler syndrome, chronic eosinophilic pneumonia, eosinophilic gastroenteritis, hypereosinophilic syndrome, eosinophilic fasciitis, IgG4-related disease, and eosinophilic leukemia.

The fleeting pulmonary infiltrates of the Löffler syndrome and the peripheral infiltrates of chronic eosinophilic pneumonia may both mimic EGPA closely.

Differentiating EGPA from hypereosinophilic syndrome may be the biggest challenge, however. Clinically, hypereosinophilic syndrome is rarely associated with reactive airway disease. Laboratory tests for the F1P1L1-PDGFR gene translocation or elevated serum tryptase levels (both of which are associated with hypereosinophilic syndrome) may also be helpful in the evaluation of such patients.

Many other forms of systemic vasculitis are high on the differential diagnosis for EGPA. Granulomatosis with polyangiitis, polyarteritis nodosa, microscopic polyangiitis, Goodpasture syndrome (antiglomerular basement membrane disease), cryoglobulinemia, and other vasculitic disorders have clinical features that overlap with those of EGPA. However, the finding of eosinophilia superimposed upon a history of allergy or asthma usually permits the clear distinction of EGPA from these other disorders.

In contrast to other forms of ANCA-associated vasculitis, many patients with EGPA may be treated effectively with glucocorticoids alone. Nevertheless, certain disease complications, particularly the presence of vasculitic neuropathy or glomerulonephritis, should trigger the use of cyclophosphamide (2 mg/kg/d orally, decreased in the setting of renal dysfunction or advanced age) as part of the remission induction strategy. Cyclophosphamide should also be considered with other complications of EGPA that pose immediate threats to the function of vital organs (eg, the heart). Appropriate cautions are paramount when using this medication (see Chapter 32). Whenever possible, the duration of cyclophosphamide therapy should be limited to 6 months or less. Milder cases may be treated with azathioprine (2 mg/kg/d), methotrexate (15–25 mg/wk), or mycophenolate mofetil (2–3 g/d in divided doses). For patients whose disease remains active despite the combination of glucocorticoids and a cytotoxic agent, interferon-α and rituximab have been used with some success in a limited number of cases. The bronchospastic component of this disease rarely responds to glucocorticoid-sparing agents, and should be managed with conventional bronchodilators (including leukotriene inhibitors) and, if necessary, glucocorticoids.

Substantial morbidity and death may result from EGPA. The major sources of morbidity are the disease itself and its therapies. Because the disease begins with a long prodrome of comparatively mundane problems (eg, atopic symptoms and asthma), the diagnosis is often overlooked until the occurrence of significant damage. The complications of vasculitic neuropathy are particularly devastating in this regard. Crippling nerve dysfunction may occur to varying degrees in all four distal extremities, leading to enormous disabilities. The recovery of function in infarcted nerves generally requires months, and in many cases the return of function is minimal. Recovery is likely dependent partly on the age of the patient and on the severity and extent of nerve damage.

Treatment regimens for EGPA that include prolonged courses of high-dose glucocorticoids and (often) cyclophosphamide are associated with a high incidence of adverse effects, some of which may be permanent or fatal. Following the remission of vasculitis, many patients have persistent, glucocorticoid-dependent asthma. The long-term use of even moderately low-dose glucocorticoids brings many unwanted side effects. More dangerous, however, is the intensive immunosuppression associated with the combination of glucocorticoids and cytotoxic agents. Even with careful monitoring, opportunistic infections, myelosuppression, infertility, bladder toxicity, and (in the long term) an increased risk of certain malignancies are all major concerns.

Although clinical remissions may be obtained in more than 90% of patients with EGPA, disease recurrences are common upon cessation of therapy. In the largest series reported to date, flares were detected in more than 25% of the patients. In most cases, relapses are heralded by the return of eosinophilia. In an even higher percentage of patients, following the resolution of the vasculitic phase of EGPA, glucocorticoid-dependent asthma remains an issue requiring ongoing management.