Churg-Strauss Disease

Churg-Strauss syndrome or disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is a specific variant of the group of diseases characterized by necrotizing vasculitis of small- and medium-sized systemic blood vessels. This type of vasculitis includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and polyarteritis nodosa (PAN). The classic distinction of CSD/EGPA from the other diseases in the category is the coexistence of asthma, rhinosinusitis, and presence of peripheral eosinophilia.[2]  Although these conditions are not thought to be directly infectious, microbial superantigens may play a role in provoking the onset of the dysregulated immune response that gives rise to these conditions.[1]

Sir William Osler possibly described the clinical aspects of CSD in 1900. However, it was not until 1951 that Jacob Churg and Lotte Strauss of Sweden clearly identified the clinical and pathological findings as representative of a distinct entity, setting it apart from PAN. They reported 13 individuals who initially manifested severe asthma and subsequently developed fever, eosinophilia, cardiac and renal failure, and peripheral neuropathy.[2]  Most also developed pulmonary infiltrates, sinusitis, hypertension, abdominal pain, bloody diarrhea, and skin changes including purpura and subcutaneous nodules. That 11 of the 13 individuals described by Churg and Strauss in their 1951 paper had died of CSD is not surprising since corticosteroids were only introduced into medical practice in 1951 and did not become readily available for use in medicine until suitable synthetic preparations were prepared. In their paper they named the disease allergic granulomatosis and angiitis. Although not presented in all the patients they summarized the classic diagnosis of the disease as 3 required parameters that need to be present at diagnosis: eosinophilic infiltration, necrotizing vasculitis of small- and medium-sized vessels, and extravascular granuloma formation.

The classic definition was hard to work with since patients tend to present with a wide variance of these features. Most of the patients rarely present with all three. This triggered the need for more clinically relevant diagnostic criteria. In 1982, Lanham et al proposed a definition that includes: bronchial asthma, blood eosinophilia more than 1500/microliter, and vasculitis involving at least 2 extrapulmonary organs.[100]  The main problem with this definition was delayed diagnosis of the disease, waiting until 2 or more organ systems were involved. 

Subsequent attempts to refine diagnostic criteria have incorporated more clinical features.[4, 5, 6]  The fact that 3 or more sets of criteria are in existence reflect the fact that no single clinical feature is pathognomonic and no discrete measurable biological marker has been identified for this condition. 

The American College of Rheumatology proposed new classification criteria in 1990 where 4 out of 6 features needed to be identified:[101]

• Asthma
• Migratory infiltrates in lung
• Paranasal sinus abnormalities
• Mono or polyneuropathy
• Peripheral blood eosinophilia (greater than 10% total leucocyte count)
• Eosinophilic tissue infiltrates in the biopsy

This new classification system rendered a 99.7% specificity and 85% sensitivity for diagnosis. In 1994, Jennette et al published "The Chapel Hill consensus conference" where they came up with a definition of EGPA as "eosinophil-rich and granulomatous inflammation involving respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels associated with asthma and eosinophilia."[6]  The old assumption that EGPA chiefly affects small vessels (capillaries, venules, arterioles) by the development of eosinophil-rich granulomatous inflammation of the respiratory tract and small vessels has slowly been replaced since Lie et al[7]  as well as Jennette et al[6]  have shown that EGPA may not be restricted to small-vessel vasculitis. Besides this important distinction, the other significant change in the consensus published by Jennette et al was the exclusion of biopsy as a necessity for diagnosis and therefore its ability to recognize early cases with only asthma and tissue and blood eosinophilia.[6]

The pathophysiology of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), particularly the triggering circumstances, is not well understood and still under investigation. In their original description of antineutrophil cytoplasmic antibodies (ANCAs), Daives et al[1]  suggested that arboviral infection-related superantigens might stimulate the production of ANCAs that attack host tissues because of molecular mimicry or some other abnormality of immune tolerance. Triggering of these vasculitides by infection has remained a pathophysiological consideration.[13]  ANCAs in part mediate vascular endothelial injury in CSD/EGPA, as they do in polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Wegener's granulomatosis (WG). In these various conditions, ANCAs may promote polymorphonuclear (PMN) cell adherence to vascular endothelial cells, with ensuing lytic vascular endothelial injury. An independent or adjuvant role in this activation may be played by tumor necrosis factor (TNF).

The major change that occurred over the years is the understanding that not every patient with different types of EGPA has overt vasculitis. Hence, there have been efforts in recent years to sub-classify the clinical phenotypes based on the presence or absence of vasculitis, somewhat counterintuitive to the nomenclature itself.[102]

The vasculitic phenotype is more common among patients with positive ANCA. ANCA is positive in close to 40% of patients suffering from EGPA. These patients more commonly have myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement either as crescentic or necrotizing glomerulonephritis.[101]  For patients with negative ANCA, the dominant phenotype is not vasculitis but rather eosinophilia with much higher incidence of myocarditis.

The presence of ANCA was proven to suggest vasculitis but not necessarily for diagnosis. In 2017, Cottin et al found that almost half of patients with overt vasculitis (47%) had negative ANCA results. They also found that in almost 30% of cases, the seropositivity of ANCA did not correlate with vasculitis.[103]  Due to this, they suggested a new categorization of EGPA based on phenotypes at presentation.

Vasculitic Phenotype

Definitive vasculitis features

• biopsy-proven necrotizing vasculitis of any organ
• biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis
• palpable purpura
• alveolar hemorrhage
• coronary arteritis causing myocardial infarction

Surrogates of vasculitis

• hematuria with red casts greater than 10%, dysmorphic RBC, and/or 2+ protein
• leucocytoclastic capillaritis

Mononeuritis

Presence of ANCA

Asthma phenotype

It is customary to define all cases that are not of the vasculitic phenotype as asthma related. The motivation behind early diagnosis of this specific phenotype is treatment. Patients can benefit from early recognition and targeted treatment. Hence, cases that have myocarditis with no other evidence of vasculitis should receive the same attention as patients with the asthma phenotype.

The primary trigger in pathogenesis at the cellular level seems to be an aberrant T-helper cell pathway.[101]

Role of the T-helper pathway in diagnosis and differentiation

The pathogenic role of T cells in EGPA was shown to have specific clonally expanded subpopulations of T cells as well as increased frequency of related HLA alleles.[104, 105] In EGPA there is high serum level of IL-10, which leads to suppression of Th-1 cells, thus leading to relative elevation of serum Th-2. This is the main subgroup currently associated with the diagnosis of EGPA (Th-2 Cell subgroup). It was previously found that this subgroup has abnormal activity in EGPA and the hypothesis in regard to the pathophysiology included allergies, infections, and specific medications. Yet, none of these potential triggers were found to be significant enough in previous studies.[101] Some previous publications found association between EGPA and airway colonization with Aspergillus or Actinomyces. Allergy was found to be a factor in only in 30% of cases of EGPA. Bibby et al reviewed the US FDA database from 1996 to 2003 to report 181 cases of EGPA in which a pharmacological trigger was suspected. They found high correlation to leukotriene receptor antagonists in 90% of the cases. However, others disagree with this finding.[106] Onset of EGPA after the use of anti-leukotrienes for the treatment of asthma has suggested that these agents may provoke an idiosyncratic drug-induced form of EGPA. In particular, an association has been detected with the use of cysteinyl leukotriene receptor type-1 (CysLT1) antagonists (eg, zafirlukast, pranlukast, montelukast) and onset of EGPA as mentioned above.[19]  However, some authorities appear to regard this association as the result of the "unmasking" of preexisting EGPA, as the introduction of leukotriene inhibitors permits corticosteroid doses to be reduced.[18, 19, 20, 21, 22, 23]

On the other hand, zafirlukast treatment has been associated with idiosyncratic development of drug-induced lupus; hence, a primary role for such agents in induction of EGPA must also be considered.[24]  Despite some continued degree of etiologic uncertainty, it can be said that it remains particularly important to consider unmasked EGPA as the underlying cause of EGPA-related deterioration in patients with severe asthma undergoing steroid dosage-reduction during a period of anti-leukotriene therapy–associated improvement in pulmonary disease.

Anti-asthmatic agents, such as beclomethasone, cromolyn sodium, or other drugs, may provoke pulmonary eosinophilia. However, it is important to carefully distinguish pulmonary eosinophilia from EGPA. Others suggested theories of activation of certain lines of T-cell subsets as possible immunology involvement in the development of EGPA.[108] Studies of affected peripheral nerve tissues show that once the stage of epineural necrotic vasculitis has been achieved, activated cytotoxic T-lymphocyte clones (CD8+ suppressor and cytotoxic and CD4+ helper cells) begin to outnumber eosinophils and predominate in the inflammatory exudate. Occasionally, CD20+ B lymphocytes are found in the inflammatory exudate, and less prominent deposits of immunoglobulin (IgG), immunoglobulin E (IgE), and C3d antibodies may also be detected.

Eosinophils-mediated damage

Serum level of IL-5 highly correlates with disease progression and activity. IL-5 as well as IL-3 are produced by the Th-2 cells and are significant for the maturation of eosinophils. These two factors are also important in the survival of eosinophilic cells and hence their levels correlate well with the level of activity of the eosinophils.[109, 110, 111] Histological findings in EGPA are characterized by eosinophilic infiltrates in walls of small- and medium-sized blood vessels as well as extravascular tissue spaces. Hence, when tissue diagnosis is obtained, either by bronchoalveolar lavage or intestinal biopsy, the sample is usually observed to have significant eosinophilic load.[27] Different cytokines and chemokines are involved in the associated immune response in EGPA. For example, when epithelial and endothelial cells are activated by the Th-2 cytokines, they secrete a series of chemokines (eg, CCL26, CCL17, CCL22)[112, 113] that act on CCR4 in order to facilitate more eosinophilic recruitment in the end organs and thus augment the immune cascade. As a result, like with IL-5, some of these chemokines can be used as disease activity markers.[114] Eosinophils in turn secrete many cytokines that, like IL-5, augment in return the function of the eosinophils. IL-4 and IL-13 are two other potent cytokines of Th-2 profile immune response and may play an important role in tissue infiltration and degranulation of eosinophils.[107]

Other cytokines participate in the autoimmune process that is seen in the development of EGPA. Patients with EGPA have markedly increased serum levels of interferon alpha and interleukin 2 (IL-2) and moderate increases of TNF-alpha and interleukin 1 beta (IL-1beta) similar to those observed in PAN. Elevations of serum interleukin 6 (IL-6) concentrations have been shown to precede the rise in serum rheumatoid factors that may accompany the onset of an exacerbation of the EGPA’s vasculitis phenotype. Thus, IL-6 may be an important triggering factor. The rheumatoid factors are chiefly of IgG and immunoglobulin M (IgM) classes, rather than immunoglobulin A (IgA) or IgE.[14]

ANCA

Elevated perinuclear ANCA (p-ANCA) with myeloperoxidase (MPO)+ is the most common finding in terms of ANCA, yet less than 50% are positive. Rarely a cytoplasmic pattern with specificity for neutrophil proteinase 3 (c- ANCA) is seen.

Presence of ANCA correlates with an increased incidence of glomerulonephritis, alveolar hemorrhage, mononeuritis, and biopsy-proven vasculitis. Yet, the level of p-ANCA correlates poorly with the disease activity. Endothelial injury in ANCA-associated vasculitis is, however, neutrophil-mediated with the generation of reactive oxygen species and proteolytic enzymes from cytoplasmic granules.[115, 116, 117]

The 2 subset hypothesis in clinical phenotyping of EGPA has been further substantiated by a recent demonstration of increased frequency of HLA- DRB4 in EGPA patients with ANCA positivity. There has been some evidence of the role of Th17 lymphocytes in the occurrence and maintenance of vasculitis response in the disease, particularly with regards to the balance between Th17 and Treg cells.[120]  Some reports have suggested that Th17 cells are associated with vasculitis, as occurs in giant cell arteritis,[118]  Henoch-Schönlein purpura,[119]  ANCA-associated vasculitis,[120] granulomatosis polyangiitis or Wegener’s granulomatosis,[121] and EGPA.[111, 123, 124]

Pathology

Unlike most noninfectious vasculitides, EGPA is fairly distinctive in its pathology, owing to the abundance of eosinophils in the inflammatory perivenular exudate. However, EGPA is a condition with a wide variety of presentations and associated signs and symptoms and other entities may provoke eosinophilic vasculitis. Therefore, EGPA remains a clinicopathologic rather than a histopathologic entity.

Eosinophilic infiltration of the upper respiratory tracts and lungs is the most common finding in EGPA, while similar infiltrative pathology is also often found in the gastrointestinal tract. The infiltrative appearance may change into eosinophilic vasculitis with worsening disease. Such clinical manifestations as weight loss, fever, and myalgia are common diagnostic clues to the possibility that EGPA is in evolution. These manifestations are found in more than half of all individuals with EGPA. Sinusitis has similar prevalence. The characteristic vasculopathy of EGPA is predominantly an arteriopathy, tending to affect small- and medium-sized arteries much more than arterioles, veins, or capillaries. This predilection is also found in PAN and some other conditions. However, the predominance of eosinophils sets EGPA apart from these other conditions. Epithelioid and giant cells are also found in the inflammatory exudate of patients with EGPA.

The inflammatory arteriopathy evolves into granulomatous fibrinoid necrosis of the vascular media. The result of this process includes the development of collagenolytic or necrobiotic noninfectious granulomata. The granulomatous material surrounds altered vascular elastic fibers and collagen as well as acellular pigmented debris, which is helpful in pathologically distinguishing one form of granulomatous vasculitis from another. EGPA is associated with "red" collagenolytic granulomas.

The lungs are the chief organs involved in patients with EGPA vasculopathy, and they almost invariably develop regions of angiopathy as the disease progresses. In a series of 96 individuals with EGPA, asthma was the first evidence of EGPA in 92%; one third developed asthma severe enough to require oral corticosteroid administration.[27]  Typical manifestations include granuloma formation, which occurs within vascular walls and in adjacent pulmonary tissues. Similar angiopathic changes develop in the heart (approximately 85%), skin (70%), peripheral nervous system (66%), central nervous system (60%), kidneys (40%), gastrointestinal tract (40%), and musculoskeletal system (20%).

Vasculitic involvement of the heart was found in as many as 85% of cases described in early reports, typically manifesting as low-output congestive cardiac failure. However, myocardial involvement (which was associated with poor prognosis) was identified in only 14% of the large series of patients with EGPA reported by Guillevin et al.[27]  EGPA should be considered in adults with asthma and eosinophilia who develop chest pain, shortness of breath, and cardiogenic shock.[28]

Cardiac evaluation may demonstrate eosinophilic pericarditis, cardiomegaly, restrictive cardiomyopathy/perimyocarditis, and diminished myocardial contractility due to myocardial or endocardial eosinophilic vasculitis or associated tissue infarction. These changes and pericardial effusion are important prognostic factors that obviously bear upon the degree and time course of EGPA-associated heart failure.[29]

• Both systolic and diastolic dysfunction may be discerned.
• Steady decline in myocardial shortening fraction often follows.
• Heart failure is an important cause of death in EGPA and is a major determinant of prognosis. In the series by Guillevin et al, 8% of patients with EGPA died from cardiac disease in the acute phase of the illness. ^[27]

Skin and nervous tissues are the systems next most commonly involved in patients with EGPA.

• The skin is involved in 65%–70% of cases that have progressed to the systemic vasculitic phase. The pathology most commonly encountered in skin biopsies is small-vessel leukocytoclastic vasculitis with ensuing blood vessel necrosis of either small or large vessels. The cutaneous vasculopathy may be associated with the development of purpura, nodules, or areas of infarction. Similar pathological changes account for mononeuropathy multiplex and myositis due to EGPA and are also found in kidneys if glomerulonephritis develops.
• Eosinophilic granulomatous changes in the gallbladder wall may result in obstructive jaundice or pain and require cholecystectomy. ^[30]
• Approximately 64%–80% of patients in the systemic phase of EGPA develop peripheral neuropathy, usually in the pattern of mononeuritis multiplex. ^[27]  Mononeuritis multiplex is the second most common initial manifestation of systemic vasculitis in adults with EGPA.
• Initial mononeuritic findings often progress to asymmetrical polyneuropathy, which is restricted to the limbs. As with PAN, both motor and sensory deficits are detectable, especially in the legs; thus, the sciatic nerves (including peroneal and tibial branches) are involved more frequently than radial, median, or cubital nerves.
• Sensory disturbances may include hypoesthesia or hyperesthesia, allodynia, and pain.
• Polyneuropathy may regress with treatment.
• Vasculitis of muscle develops in slightly more than 20% of patients.

Approximately 60% of adults with EGPA develop CNS vasculitis. This is unlike PAN, in which CNS manifestations are rare. However, CNS vasculitis has not been reported in children with EGPA. It does occur in adolescents, albeit rarely.

• Manifestations include intellectual and motor disturbances. These may be abrupt in onset, and seizures may occur.
• Acute cerebral hemorrhage is among the important causes of sudden death in EGPA. In some but not all instances, hemorrhage occurs in individuals who have hypertension.

Gastrointestinal dysfunction develops in 30%–60% of individuals with EGPA (prevalence higher in earlier series than in more recent case series). Most commonly, this takes the form of mesenteric vasculitis, similar to that seen in PAN. The most common manifestations are bloody diarrhea and abdominal pain.

Arteritis of medium-sized blood vessels of the kidneys develops in 20%–50% of cases. However, hypertension is less common in EGPA than in PAN.

• As in PAN, the predominant renal pathology is eosinophilic interstitial pauci-immune segmental glomerulonephritis. ^[30]
• Crescentic necrotic glomerulopathy may develop in some instances, as is also found in microscopic polyangiitis.
• IgA glomerulonephropathy may develop, as also is the case in microscopic polyangiitis, but rarely. This is a pathological change that is more typical of Schönlein-Henoch purpura.
• In early reports of EGPA, uremia was an occasional cause of death. Current management has considerably reduced the risk of uremia, and, in most cases of EGPA, renal involvement is mild. Even if the renal involvement is severe, renal disease usually responds well to corticosteroid treatment.

Testicular pain, with or without epididymitis, may occur in men with EGPA.

The estimated prevalence of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is 10.7 to 14 per million adults worldwide. There is no gender difference in the incidence of the disease.[125] The age distribution is wide with reports of patients as young as 4 years and as old as 74 years; median age at presentation is 40 years old.[125] In general, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is quite rare in the pediatric population. Close to 40% of adults have a positive ANCA, whereas only 25% of the pediatric population are positive for it.[101] Yet, the clinical manifastation in the pediatric population has much more involvement of cardiac manifestation and hence high mortality rates.[100] Across the years there has been a constant decrease in the mortality rate of patients who suffered from EGPA. Most (85%) of the index cases reported by Churg and Strauss in 1951 had died from their illness. The development of effective strategies for treatment in ensuing decades (particularly oral corticosteroids) has improved survival considerably, though the disease remains a serious one. To some extent, improved survival may relate to recognition of milder cases. The 5-year survival rate reported in the 30-patient series of EGPA that Chumbley et al reported in 1977 was 62%.[3]  In 1999, Guillevin et al reported a 72% 6-year survival rate in a series of 96 patients with EGPA.[27]  Elderly patients may have as much as 50% greater risk of death from their EGPA and compared to middle-aged or young individuals with this disease.[31]  Yet, as mentioned, the mortality among the young population does not differ much from the adult population because of relatively high prevalence of cardiac involvement. In most cases of EGPA, morbidity is chiefly cardiopulmonary. Painful arthritis, arthralgia, neuritis, and myalgia are common troublesome and recurrent manifestations. Abdominal pain, diarrhea, gastrointestinal bleeding, and bowel perforation are less common but important complications. Necrotizing glomerulonephritis occurs in fewer than half of patients. It tends to affect older patients, who as a group have particularly poor outcomes. Early diagnosis of this renal complication improves outcome.[32]  Leukopenia due to immunosuppressive therapy enhances risk for sepsis and death and therefore should be avoided.[32]  The chief neurologic morbidity is, as in PAN, peripheral neuropathy.

The chief causes of mortality related to EGPA are severe asthma, cardiopulmonary failure, or gastrointestinal complications. In general, the long-term outcome of EGPA does not differ greatly from that of PAN. In addition to overall severity of EGPA, both myocardial disease and severe gastrointestinal disease were found by Guillevin et al to be independent predictors of poor prognosis.[27]

Clinical features of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), follow two-pronged themes of eosinophilic tissue infiltration or small- and medium-vessel vasculitis. Lanham divided the clinical evolution of EGPA into 3 phases.[4]  Yet, the clinical course of a specific patient does need to include all of them. They may even overlap in the natural history of an individual’s disease.

First phase

The initial prodromal phase commonly includes nonspecific symptoms of malaise, fever, migrating polyarthralgia, and weight loss along with a severe adult-onset form of asthma that is refractory to conventional treatment. The bronchial asthma is the initial disease manifestation in as many as 80%–90% of cases of EGPA.[27]  The asthma is severe in as many as one third of all patients. An additional 6% will develop asthma within a year of onset of manifestations in other organ systems. In most series, bronchial asthma is the first clinical feature and is the nearly constant finding of the first phase, preceding fever or eosinophilia. Some authors have estimated that less than 3% of all individuals who develop EGPA have no asthma as an element of their presentation.

• Additional findings that often precede or accompany the first phase of EGPA include allergic rhinitis, nasal polyposis, sinusitis, and recurrent bronchitis, or pneumonia. Nasal rhinitis and polyposis, in particular, are likely to precede the onset of reactive airway disease. Upper respiratory symptoms are more common with chronic rhinosinusitis (47%–93%) and nasal polyps (62%–77%). However nasal granulomas, erosion, and crusting or epistaxis as seen in GPA are absent here.
• An additional historical fact of importance is the recent addition of leukotriene receptor antagonists to the treatment regimen for asthma. This association is found in perhaps half of cases; in three quarters of these patients, the addition of those drugs was made within 3 months prior. ^[33]
• The presence of an asthmatic condition (usually steroid-dependent) is the historical feature that most commonly prompts consideration of EGPA in individuals who manifest any of the many vasculitic abnormalities of various other organ systems that may be present in ensuing stages of the disease.
• Recurrent fevers of unclear etiology and weight loss, either of which may occur in the first phase of illness in more than half of individuals developing EGPA, enable the careful clinician to suspect that EGPA underlies the allergic and asthmatic manifestations. Another clue is the fact that the reactive airway component of EGPA tends to develop at a later age (commonly, the fourth decade of life) than is typical for idiopathic asthma. However, fairly typical early childhood-onset asthma may presage the development of the vasculitic stages of EGPA in adolescence.
• Diffuse myalgia and polyarthralgia have been reported in 37%–57% of EGPA patients, particularly at the onset of disease. ^[101]
• Exceedingly rarely, EGPA pathogenesis may result in development of the systemic vasculitic stages of EGPA in individuals who do not have either asthma or eosinophilia.
• However, also remember that it is possible for asthmatic individuals to develop vasculitic or inflammatory diseases other than EGPA as explanations for the disease of either pulmonary or nonpulmonary organ systems. The occurrence of tissue and blood eosinophilia provides an additional important clue in the individual who has asthma and abnormalities of sudden onset in several organ systems that EGPA is the likely cause of the various organ system disease manifestations noted below as comprising the systemic vasculitic stages of EGPA.
• The duration of the first phase, prior to progression of illness, averages about 28 months (range, 4–72 mo). However, a few patients remain in the prodromal stage of illness for 30 years or more before the second or third phase of EGPA manifests.
• The frequency of CSD–related reactive airway disease increases and the severity of the disease worsens, as the vasculitic stage of EGPA is reached. In some cases, an unexpected remission of asthma occurs with the onset of vasculitic manifestations of the second phase of EGPA.

Second phase

During the second phase of illness, eosinophilic infiltrates are seen in end organs along with peripheral eosinophilia. Patchy peripheral nodular pulmonary infiltrates, eosinophilic gastroenteritis, serosal effusion, are common. Hence, hypereosinophilia of blood develops in association with tissue eosinophilia and Loeffler syndrome. During this phase, the eosinophils comprise on average 40% of the WBC count on peripheral blood film (range, 18%–65%). Particularly characteristic complications of this phase of illness are chronic eosinophilic pneumonia and eosinophilic gastroenteritis. Hemoptysis may occur. Patients experience a relapsing and remitting course of eosinophilic infiltrative disease and blood eosinophilia.

In some instances, the second phase of illness consists of the combination of chest pain, shortness of breath, and development of cardiogenic shock. ECG may suggest myocardial infarction, although coronary arteries may appear normal on angiography. Valvular insufficiency and segmental or global hypokinesis of the myocardium may be found. These findings suggest EGPA myocarditis.[28]

Fever always is present during periods of exacerbation.

Third phase

This is a late phase that can present 3 to 9 years after the onset of the initial asthma. It is characterized by systemic vasculitis and neurologic sequela.

Before the presence of this phase, the patient has intermittent bouts of symptoms that were mentioned in the two previous phases. Patients with continued reactive airway manifestations may experience remission, often to a remarkable extent, at the onset of this third phase of the disease. As vasculitis develops and worsens, weight loss may be noted.

In some fulminant cases, systemic vasculitic manifestations may develop without a prior second phase of relapsing-remitting complications. In other cases, the second and third phases of EGPA develop simultaneously. The interval between first and third phases of EGPA is prognostically significant. As might be expected, the shorter the duration of that interval, the worse the prognosis.

Signs and symptoms may include any of the following:

• Symptoms related to congestive heart failure ranging from congestive heart failure to cardiogenic shock. ECG may suggest myocardial infarction, although coronary arteries may appear normal on angiography. Valvular insufficiency and segmental or global hypokinesis of the myocardium may be found, all in keeping with EGPA myocarditis.
• Neurologic findings are most commonly peripheral polyneuropathy, usually mononeuritis multiplex pattern with motor and sensory deficits unexplainable by a single central lesion. Deficits tend to be asymmetrically distributed, involving individual peripheral nerves without reference to specific fiber types. The distribution is not in the "glove-stocking" distribution suggestive of toxic neuropathies. Peripheral muscle stretch reflexes may be diminished or lost. Sensory disturbances may include hypoesthesia, hyperesthesia, allodynia, or other forms of pain. Pain and paresthesia tend to involve the legs. However, other manifestations may result in vasculitic disease of the brain with stroke or hemorrhage. These may result in abrupt onset of motor, intellectual, or sensory deficits, brainstem signs, stupor, or coma. Seizures may occur.
• Eosinophilic gastroenteritis may result in abdominal pain, weight loss, or bloody diarrhea.
• Skin changes may include the development of petechiae and palpable purpura.
• Acute renal failure, developing rapidly over several weeks, is a characteristic feature of the rapidly progressive glomerulonephritis of EGPA. Gross hematuria or pyuria may be found. These findings, due to inflammatory glomerulonephritis, may be misinterpreted as urinary tract infection.
• Testicular pain may occur in men with EGPA.

Organ system involvement

Different organs are affected by the disease, and many of the manifestations are related to vasculitis and hence hemorrhages or thrombosis-related symptoms (e.g., retinal artery or vein occlusion).[126]

Respiratory and pulmonary manifestations

Asthma in the prodromal phase is seen nearly in all the cases, and it is reported in 96% to 100% patients. The mean age of onset of asthma is 35 to 50 years. As mentioned above there is debate about whether some asthma medications from the leukotriene receptor antagonists family, montelukast as well as omalizumab, can trigger the eruption of EGPA. The asthma tends to be severe and progressive with up to 75% of patients becoming steroid-dependent even before the diagnosis of EGPA is achieved. 

EGPA patients tend to present with adult-onset asthma with an eosinophilic phenotype. The asthma is accompanied by upper airways manifestations like rhinitis, sinusitis, and nasal polyposis. Chronic rhinitis is the most common extra-thoracic manifestation occurring in about 75% of cases.

Asthma tends to be the last manifestation, if at all, to respond to treatment. Even when most of the symptoms are under control, asthma tends to stay active. The involvement of the respiratory system involves parenchymal eosinophilic infiltration as well as the vasculitic process, upper respiratory allergic response, and eosinophilic asthma. During the first two clinical phases described, transient pulmonary infiltrates and eosinophilia is common, whereas in the vasculitic phase, necrotizing vasculitis and granuloma are more common. Alveolar hemorrhage is reported more often in ANCA-positive cases and hence is less common among EGPA patients than in GPA patients.

Cardiac involvement

The cardiac manifestation of EGPA can be devastating. The cardiac injury can include coronary artery disease, primary arrhythmias, cardiomyopathy, acute constrictive pericarditis, myocarditis, and eosinophilic pericardial effusion. The cardiac involvement happens in about two-thirds of cases, yet most will not be symptomatic. It is caused by both mediators released from activated eosinophils as well as vasculitis lesions in the myocardium and coronary arteries. The myocarditis can lead to post inflammatory fibrosis and restrictive cardiomyopathy. Cardiac changes are associated with a poor prognosis and high mortality if left untreated.[127]

Gastrointestinal involvement

The involvement of the gastrointestinal system is related to infiltrates as well as the eosinophilic response. Gastroenteritis can evolve as a result of eosinophilic reaction, usually with prodrome of abdominal pain, nausea, vomiting, and diarrhea or more severe complications like bleeding or intestinal obstruction (mediated by submucosal nodular masses). In some cases the gastroenteritis is accompanied by mesenteric vasculitis. The vasculitis can lead to ischemic bowel, mucosal ulceration, and even perforation necessitating exploratory laparotomy. Serosal involvement can cause eosinophilic ascites and peritonitis. In rare cases the gastroenteric system will have manifestations of necrotizing acalculous cholecystitis, pancreatitis, and eosinophilic liver disease.[40]

Renal involvement

Renal involvement is seen in 25% of patients. The renal manifestations can include necrotizing crescentic glomerulonephritis, focal sclerosing disease, IgA nephropathy, or eosinophilic interstitial nephritis. Necrotizing crescentic glumeronephritis is the most common. Biopsy alone is not enough to establish diagnosis in many cases. Hypertension is seen in up to one third of cases and might reflect early renal involvement in EGPA.[27]

Neurologic involvement 

Neurologic injury can involve the peripheral (up to 80% of cases) as well as the central nervous systems (up to 40% of cases). The injury involves different kinds of neuropathies as well as possible brain vasculitis that can lead to brain infarcts and hemorrhages in some cases.[129] The peripheral injury usually includes mononeuritis multiplex or mixed sensorimotor peripheral neuropathy. Common peroneal and internal popliteal nerves are most commonly involved in lower limbs, while radial and ulnar nerves in upper limbs are usually affected in those cases that have upper limbs involvement.[117]  Cranial nerve palsies can be found in some cases and usually will include the optic nerves. The neurologic injury in EGPA, although quite common, is usually efficiently treated with the regular systemic treatment of EGPA.

Skin involvement

Up to two thirds of cases will have skin manifestations. Palpable purpura without thrombocytopenia is the most common finding as well as extravascular granulomas, scalp nodules, urticarial rashes, skin infarcts, livedo reticularis, and other changes that are consistent with leukocytoclastic vasculitis.

In the first phase of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), examination reveals nasal polyposis, intermittent fever, and findings consistent with sinusitis, allergic rhinitis, and bronchial asthma. The signs of reactive airway disease gradually worsen over time.

During the systemic vasculitic phase, examination of the skin, heart, abdomen, joints, peripheral nerves, and muscles may reveal evidence for the various characteristic changes of EGPA as noted in History. Two thirds of patients in this advanced state of illness are found to have cutaneous purpura or nodules.

Cardiopulmonary findings that are consistent with congestive heart failure, low-output state, or pericardial effusion may be discerned.

Abdominal tenderness and evidence for gastrointestinal bleeding may be found on examination. Occasionally, the examination reveals evidence of bowel obstruction. The findings of acute abdomen develop in patients with bowel perforation.

Arthritis may be noted; any joint may be involved.

Neurologic examination

In patients in the systemic vasculitic phase of illness, neurologic examination may reveal evidence of peripheral neuropathy limited to the extremities. At first, the pattern usually is that of mononeuritis multiplex, but with progression of illness, asymmetrical sensory and motor polyneuropathy is found (legs > arms).

Neurologic findings tend to develop late. Pulmonary manifestations with eosinophilia usually establish the diagnosis of EGPA prior to the development of neurologic disease.

The examination may disclose CNS manifestations due to intraparenchymal or subarachnoid brain hemorrhages.

Optic neuritis, cranial neuritis, and psychosis have been described in adults with EGPA.

Children seldom manifest CNS findings. One girl with EGPA, who was in the early years of the second decade of her life, developed chorea.

Genetic factors

Several lines of evidence suggest a genetic predisposition to Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), which may entail an inherited tendency to dysregulation of the cellular immune system. The features of this dysregulation are discussed in Pathophysiology.

The variation in age at onset of illness is not understood, but this variation suggests the possibility that secondary factors, such as environmental influences, may hasten the onset of disease for some individuals.

Environmental factors

Environmental factors may contribute to the development of EGPA. For example, the inhalation of fungal spores, such as those produced by actinomycetes and Aspergillus species, has been implicated in the pathogenesis of some cases.

Exposure to pigeons and the molds associated with their roosts may provoke the development of EGPA.

Smoking free-base cocaine was documented carefully as a circumstance preceding individual bouts of an illness similar to or identical to EGPA in one individual. The illness in that case was not sustained endogenously, recurring only with additional episodes of cocaine smoking.[26]

In summary, some environmental factors appear to provoke transient effects that resemble EGPA, but do not represent a chronic and self-perpetuating disease.

Drugs

Carbamazepine, macrolide antibiotics, and cysteinyl leukotriene-receptor antagonists have been implicated as provocative causes of EGPA. Leukotriene-receptor antagonists may be especially important in terms of provoking chronic EGPA that does not resolve with discontinuation of the inciting drug.

Leukotriene-receptor antagonists are used in some patients who are undergoing withdrawal of steroid treatment for asthma. This has prompted some clinicians to ascribe the onset of EGPA to steroid withdrawal rather than to direct effects of the leukotriene-receptor antagonist. They propose that EGPA manifestations were masked or perhaps prevented by the higher steroid doses. However, several patients who were not in the midst of a steroid taper have developed EGPA after administration of leukotriene-receptor antagonists. Some authorities now recommend the use of inhaled steroids rather than leukotriene-receptor antagonists when attempting to taper systemically administered steroid treatment of asthma.

EGPA has developed in the wake of Basedow disease with autoimmune thyroiditis; whether this is a chance association is not known.

Diagnosis of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is in many cases a process comprised of several tests, clinical visits, and high suspicion. The main reason for this relatively cumbersome diagnosis process is that many of the symptoms and signs change over time, hence delaying clear diagnosis. There is no gold standard diagnostic tool. For all these reasons EGPA diagnosis is mainly clinical with support of lab work and sometimes histopathology and biopsy. As such, when a patient presents with eosinophilic asthma, the clinician must look for a pattern of multisystem disease and investigate for other supportive findings.

Peripheral blood eosinophilia (greater than 10% on differential white blood cell count or greater than 1500 /dl) is the best-known lab hallmark of the disease. Elevated serum IgE is also found in 75% of patients.[101]

The first (prodromal) phase of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), consists of asthma usually in association with other typical allergic features, which may include eosinophilia. During the second phase, the clinical presentation with EGPA, eosinophilia is characteristic (see below) and ANCAs with perinuclear staining pattern (pANCAs) are detected.

Where possible, the diagnosis is confirmed by demonstration of angiographic abnormalities in affected organs and by pathognomonic biopsy findings (see Histologic Findings).

According to the American College of Rheumatology criteria, clinical diagnosis is established when 4 of the following manifestations are documented: (1) allergic history, (2) asthma, (3) eosinophilia, (4) migratory pulmonary infiltrates, (5) paranasal sinus abnormality, (6) mononeuropathy or polyneuropathy, and (7) demonstration of extravascular eosinophilic infiltration of tissues on biopsy.

Eosinophil count

Once the second phase of EGPA is reached, eosinophilia (> 1500/µL or > 10% of total peripheral WBCs) is found on the peripheral blood film of at least 90% of untreated patients.

Mean values for absolute eosinophil counts are in the range of 5,000–9,000/µL, but, in rare instances, counts may exceed 100,000/µL. Thus, the history of asthma with the ensuing development of eosinophilia is highly suggestive of EGPA.

Treatment of asthmatic manifestations of the first stage of EGPA with corticosteroids may promptly resolve this characteristic finding. The prompt resolution of eosinophilia with corticosteroid treatment is itself characteristic of EGPA.

Intermittent elevations of eosinophil counts during the third phase of EGPA may presage a relapse of systemic vasculitis.

Other features

Elevations of ANCA titers are found in 40% of cases of EGPA; these are predominantly pANCAs directed against myeloperoxidase epitopes.[27]

Enzyme-linked immunosorbent assays specific for antimyeloperoxidase antibodies were positive in 10 of 11 patients in whom this test was performed by Guillevin et al.[27]

Serum IgE concentrations are elevated in three quarters of patients in the second or third phase of Churg-Strauss disease.

Erythrocyte sedimentation rate (ESR) and other indices suggestive of the presence of acute-phase reactants may be elevated. Abnormality of sedimentation rate may rapidly (and characteristically, as is also true of eosinophilia) disappear within a few days of treatment with corticosteroids.

Testing for rheumatoid factor is positive in approximately 70% of cases.

False-positive precipitin test results for syphilis have been reported.

Lactate dehydrogenase (LDH) level may be elevated and, as with eosinophilia and elevated sedimentation rate, may correct within a day or a few days after initiation of corticosteroid treatment.

Blood urea nitrogen and creatinine levels may be elevated in individuals who develop ANCA-associated renal vasculitis. Gross or microscopic hematuria and pyuria may be found and are due to inflammatory glomerulonephritis, although they may be misinterpreted as representing urinary tract infection. Dysmorphic red cells or red-cell casts in the urine sediment are consistent with the presence of glomerulonephritis; high-grade proteinemia is also suggestive, although the absence of proteinuria does not exclude glomerulonephritis.

Vasculitis, neurological, and renal manifestations are more common among ANCA-positive patients.[131, 132, 137, 138]  

Serum IgG4 levels and CCL17 levels correlate with disease activity.[133, 113]

Chest radiographs

Chest radiographs demonstrate pulmonary infiltrates in at least half of the patients in the second phase of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), and a greater percentage in the third phase of the disease. Typically, these are transient patchy alveolar infiltrates, usually without preferential, lobar, or segmental distribution. In some instances, a diffuse interstitial infiltrative pattern may be apparent.

Lungs may be hyperinflated.

Nonsegmental reticulonodular opacities without cavitation may be found. These may be solitary but may be multiple in more advanced cases. In some patients with advanced disease, striking bilateral reticulonodular opacities are observed.

Bronchial walls may be thickened.

Enlarged intrapulmonary lymph nodes may be found in some cases. This unusual finding suggests EGPA in asthmatic patients who have no history of heavy smoking.

Pleural effusions are not common. Pulmonary hemorrhage is a particularly suggestive and ominous sign in EGPA.

Imaging of the heart may reveal cardiomegaly or pericardial effusion.

CT scan of the lungs

CT scan of the lungs demonstrates the above-mentioned findings of EGPA even more clearly. In most cases of advanced disease, thin-section lung CT scan also reveals the highly suggestive finding of bilateral, ground-glass pulmonary opacity.

Subpleural airspace consolidation is an additional feature in about half of cases, whereas more widespread consolidation is discerned occasionally.

Occasional finding of centrolobular nodular densities within the background ground-glass opacity is highly suggestive of EGPA. This change is much more apparent on CT scan than on plain radiographs, as is the thickening of interlobular septi and bronchial wall.

Increased vascular wall caliber also may be discerned.

Enlarged hilar or mediastinal lymph nodes also are apparent on pulmonary thin-section CT scan in many patients with EGPA, representing an opportunity for diagnostic biopsy.

Pleural or pericardial effusions can be seen in up to 30% of the cases.

Other imaging studies

Results of abdominal or renal angiography usually are negative in EGPA. However, EGPA may account for less than 5% of all cases of ANCA-associated renal vasculitis, whereas microscopic polyangiitis (MPA) accounts for approximately half, and Wegener granulomatosis (WG) approximately one third of such cases.

MRI of the brain in patients with CNS manifestations may reveal vascular territory infarction, with or without hemorrhage. Areas of bright signal on T2-weighted MRI suggestive of vasculitis may be found.[34]

Upper respiratory obstruction is present in respirometry  in up to 70% of the cases, and can be persistent after treatment in up to 40% of the cases.[103]

Because of the devastating results of untreated cardiac manifestations, cardiac investigation including MRI should be considered in some of the cases.

Electrophysiological studies

Electrophysiological studies of peripheral nerves may reveal deficits referable to both myelinated and unmyelinated sensory and motor fibers, especially those subserving the lower extremities.

Abnormalities in the findings of electrophysiological studies of the sciatic nerve (including tibial and peroneal branches) typically are more profound than those in the radial, median, and cubital nerves. The absence of conduction blocks may be helpful in distinguishing Churg-Strauss mononeuritis multiplex from chronic inflammatory demyelinating polyneuropathy.

Patients may be found to manifest acute-onset reduction or absence of sensory nerve action potentials.

Procedures that may be valuable in the diagnosis of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), have been reviewed and include the following:

• Biopsy specimens of skin, hilar lymph nodes, lung parenchyma, or peripheral nerve demonstrate the characteristic vasculitis. Kidney biopsy sample may show segmental necrotizing glomerulonephritis with crescent formation, possibly including highly characteristic eosinophilic infiltration of the renal interstitium.

• Electrophysiological studies of peripheral nerves.

Biopsy

Biopsy results in Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), may demonstrate eosinophilic vasculitis, especially involving the outer zone of the adventitia of medium (10–150 μ m) to small (30–50 μ m) arteries. However, it may be found that infiltrating cells are predominantly lymphocytic while eosinophils may be less prominent or even rare. Vascular wall necrosis with loss of inner elastic vascular lamina and associated hyaline degeneration may be observed. Involved vessels often show occlusion and recanalization. Granuloma formation is rare. The region of arteriopathic change chiefly consists of a central eosinophilic core surrounded by an inflammatory exudate consisting of macrophages, epithelioid cells, and giant cells. Similarly constituted inflammatory exudate may infiltrate the perivascular surround. Fibrinoid necrosis of the vascular media may be discerned.

Nerve biopsy specimens may show similar vascular changes in the epineural space in as many as half of all cases with EGPA neuropathy. Sural nerve biopsy is hence the gold standard test in documenting peripheral neuropathy. Evidence of axonal degeneration is the most common finding, and necrotizing vasculitis and perineural eosinophilic infiltration can only be confirmed in half of the cases. Focal loss of myelinated nerves and subperineural edema is characteristic. Immunohistochemical changes on biopsy specimens may confirm the presence of CD4-, CD45 RO- or CD8+ T cells, CD3+ Pan-T lymphocytes, or CD-68 positive macrophages. MHC-class I cells (beta2-microglobulin positive) and MHC class II cells (HLA-DR) may be found—the later particularly in the endoneurium, accompanied by CD68+ macrophages. CD20+ B cells are comparatively rare as are deposits of IgG or C3d complement.

Histopathologic studies of a biopsy specimen of affected skin areas reveal small-vessel arteriopathy with granuloma formation in the vascular walls. Enlarged intrapulmonary, hilar, or mediastinal lymph nodes or pulmonary nodules, if biopsied, may reveal similar characteristic histologic abnormalities.

Biopsy of lung parenchyma may show tissue injury and eosinophilia without necrotizing vasculitis or the presence of extravascular granulomata.

Nerve biopsies reveal vasculitic epineural necrosis in more than half of patients with clinical neuropathy. As has been noted, the predominant cell type within the epineural inflammatory exudate is lymphocytes expressing CD8+ or CD4+ T-cell markers. Lesser numbers of eosinophils are found, with small numbers of CD20+ B cells. Scarce deposits of IgG, IgE, and C3d antibodies may be detected.

Kidney biopsy may reveal eosinophilic interstitial pauci-immune segmental glomerulonephritis. Occasionally, glomerulonephritis with IgA deposition is found.

Medical management of cardiovascular, cardiac, renal, and gastrointestinal complications of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), falls under the purview of subspecialty consultation. Drugs used in the treatment of EGPA  are described in Medication.

Surgical procedures in patients with Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), most commonly entail biopsy of affected tissues.

In addition, surgical intervention may be indicated in patients who experience catastrophic complications, such as acute abdomen or intracranial hemorrhage.

Consultations for patients with ofChurg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), depend on the manifestations of the disease. The cardiopulmonary manifestations typically are most important. Consultations with the following may be required:

• Pulmonologist

• Cardiologist

• Rheumatologist

• Gastroenterologist

• Urologist

No dietary factors are clearly known to assist in the management of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), except as are related to the management of congestive heart failure, renal failure, or gastrointestinal complications. The management of these factors falls under the purview of subspecialists involved in the care of these organ systems.

No clear evidence suggests that particular activities influence the course of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), once it is established. Environmental exposures and medical treatment of asthma that may influence the chances for development of EGPA are discussed in Causes.

The mainstay of treatment of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is combination of steroids and immunosuppressants agents. Corticosteroids assist in lowering the eosinophilia burden as well as diminished the tissue infiltrates. For most patients, EGPA is a readily treatable illness, and reports over the past few decades have shown better outcomes than were demonstrated in earlier case series. In part, this may be due to the inclusion of milder cases due to improved recognition. In particular, diagnostic sensitivity has been greatest for individuals whose initial presentation is with asthma (90% of cases in some case series). However, a major factor has been the availability of corticosteroids. Milder EGPA may respond well to orally administered corticosteroids.

The recommended initial medications for treatment of severe manifestations of EGPA, including patients with EGPA–related peripheral neuritis, are corticosteroids, which are administered at high doses. In mild disease 1 mg/kg of Prednisone can be  initiated. In more severe cases the use of intravenous methylprednisolone at doses of 15 mg/kg on 1-3 successive mornings is a better option. Rapid correction of eosinophilia, leukocytosis, and elevations of sedimentation rate and LDH are characteristic of EGPA. Failure to provoke such corrections early in the course of therapy is associated with elevated risk for poor long-term outcome.

Intravenous treatment is followed by oral prednisone at a dose of approximately 1 mg/kg/d (usual, but absolute maximal daily dose should not exceed 80 mg/d), with ensuing taper once clinical improvement is noted.

Many patients with EGPA manifest a favorable response to this monotherapeutic approach within a few days; however, in many cases, persistence of asthma prevents oral prednisone from being tapered to doses lower than 10-15 mg/d. In milder cases, initial treatment can be undertaken with the administration of oral corticosteroids at doses of 1 mg/kg/d (60 mg/d is the usual but not absolute maximal dose).

Corticosteroid treatment, whether oral or intravenous, has been combined with plasma exchange or plasmapheresis for cases that were difficult to treat. This combination appears to have conferred benefit in some patients. Some patients have demonstrated marked clinical improvement, accompanied by declining circulating pANCA titers, after treatment with intravenous immunoglobulin (IVIg). Some patients have been treated, either initially or during a subsequent phase of therapy, with the combination of daily oral prednisone and cyclophosphamide. This approach may enhance disease control and may have a sparing effect upon steroid dosage, thus diminishing steroid-related adverse effects. Prednisone taper in patients responding to the combined therapy can be undertaken after approximately 2 weeks.

The combination of high-dose corticosteroids and dapsone has been used in patients with severe Churg-Strauss disease and has proven effective in instances of Churg-Strauss myocarditis.[28]  Corticosteroid doses may be reduced after improvement in myocarditis is achieved. IVIg is considered in neuropathy or cardiomyopathy refractory to conventional therapy.[134]

Cyclophosphamide treatment (titrated to the neutrophil count) generally is continued for 6-12 months after remission is established. Pulse intravenous cyclophosphamide therapy in combination with corticosteroids appears to diminish the risk for various adverse effects seen in patients receiving oral cyclophosphamide daily. This form of therapy is also considered in patients whose disease responds poorly to corticosteroids. Dose, frequency, and total number of cyclophosphamide pulses are adjusted to disease response, blood counts, and renal function. Efficacy of this form of therapy is not, as yet, fully established.

Usually, collaborating with physicians specializing in renal medicine is the best way to undertake this form of therapy. Protocols must be utilized to ensure that renal function is preserved with regard to additionally administered medications and hydration. These protocols entail intense hydration and coadministration of 2-mercaptoethanesulfonate (mesna). Some studies have used initial pulse intravenous cyclophosphamide at doses as high as 0.6 g/m2 of body surface, but this dose must be reduced in accordance with the degree of impairment of renal function exhibited by the patient.

Azathioprine, methotrexate, or ribavirin have possible roles in the treatment of CSD, but these drugs require additional study and should not be used without the participation of a subspecialist who can provide recommendations concerning dosage, anticipated benefits, and adverse effects.

The suggestion has been made that males with CSD might attain some benefit from treatment with thalidomide. This approach requires considerable additional study and the participation of an expert who can provide information concerning appropriate dosage, anticipated benefits, and adverse effects. The use of thalidomide is contraindicated in women of childbearing age. None of the drugs noted in this paragraph should be used without the collaboration of subspecialists skilled in their use and familiar with the relative indications, dosage adjustments, potential benefits, and adverse effects. Therefore, none of these agents are reviewed in the following Medication section because the complex issues entailed with their use fall beyond the scope of this article.

Summary for treatment perspectives in EGPA can be:[135]

Induction of remission

Mild disease

Oral prednisone: 1 mg/kg daily for 3 weeks, then tapering 5 mg every 10 days to 0.5 mg/kg. Then taper 2.5 mg every 10 days to the minimal effective dosage, or until definite withdrawal

Or

Intravenous methylprednisolone pulse (15 mg/kg) followed by oral prednisone as above. This option can be used in all cases or selectively in the more severe presentations

Relapse

Oral azathioprine 2/mg/kg daily for at least 6 months

Or

Cyclophosphamide pulses (600 mg/m2) every 2 weeks for 1 month, then every 4 weeks after that

Severe disease in presentation

Three consecutive methylprednisolone pulses (15 mg/kg) on day 1 to 3 plus oral prednisone 

Plus

Either 12 cyclophosphamide pulses (600 mg/m2) every 2 weeks for 1 month, then every 4 weeks after that

Or

Short-course of cyclophosphamide (oral 2 mg/kg) for 3 months or 6 cyclophosphamide pulses (600 mg/m2) every 2 weeks for 1 month, then every 4 weeks after that, followed by azathioprine 2 mg/kg for 1 year or more

Maintenance of remission

Methotrexate (10–25 mg per week)

Cyclosporin A (1.5–2.5 mg/kg per day)

Azathioprine (2 mg/kg per day)

Refractory disease

Plasma exchange

IVIG (0.4 g/kg per day for 5 days)

Interferon-alpha (3 million IU 3 times per week subcutaneously). Interferon-alpha as well as Rituximab (anti-CD20) are especially good for ANCA related vasculitis[136]  

TNF inhibitors: Infliximab, etanercept, adalimumab

Rituximab (325 mg/m2 for 4 consecutive weeks)

Class Summary

These medications decrease the activity of the immune system in inflammatory reactions. The immune system is of critical importance in the pathophysiology of this disease.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Moderate or severe cases often treated for 1-3 d with IV methylprednisolone (or equivalent dose of some other anti-inflammatory corticosteroid). Administer initial dose under close supervision, since rare instances of anaphylaxis after initial dose have been reported.

Prednisone (Sterapred)

Useful in initial management of mild cases (especially for asthma) and in taper and maintenance phases of therapy for Churg-Strauss disease.

Class Summary

These agents inhibit cell growth and proliferation, reducing the activity of the immune system.

Cyclophosphamide (Cytoxan)

Synthetic drug, chemically related to nitrogen mustards, developed as antineoplastic agent. Biotransformed in liver, where constituent alkylating metabolites activated. These activated compounds interfere with growth of susceptible rapidly proliferating cells. Mechanism of action with regard to tumor cells may involve cross-linking of tumor cell DNA.

Administration of antacids or histamine-blocking agents to reduce the risk for gastrointestinal hemorrhage should be continued for as long as patients are administered oral corticosteroids.

Long-term corticosteroid administration entails risk for electrolyte disturbances, infections, and fractures because of diminished bone mass. These risks must be reassessed continually during the course of therapy.

Alternative steroid-sparing anti-inflammatory therapies, selected from among the options noted in the Medication section, should be considered in patients requiring long-term corticosteroid therapy.

Patients hospitalized for treatment of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), should be assessed, as should any hospitalized patient, for the risk of deep vein thrombosis, pulmonary embolus and, if cardiac dysfunction has been noted, cardiogenic embolus.

Treatment with steroids entails risks for gastrointestinal hemorrhage, electrolyte disturbance, and infection, which must be considered. When steroids are administered, antacids or appropriate histamine-blocking agents should be administered to reduce the risk for gastrointestinal hemorrhage.

A number of authorities believe that the administration of cysteinyl leukotriene-receptor antagonists for the treatment of asthma may provoke development of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), in some individuals. The use of inhaled steroids, rather than cysteinyl leukotriene-receptor antagonists, during the taper phase of steroid treatment of an acute exacerbation of asthma may be a valuable alternative for avoiding this potentially provocative circumstance.

Particularly characteristic complications of the second phase of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), are chronic eosinophilic pneumonia and eosinophilic gastroenteritis.

Abdominal pain, diarrhea, gastrointestinal bleeding, and bowel perforation are important complications.

Raynaud phenomenon, arthralgias, or joint effusions are occasional complications.

Treatment-related complications include those associated with immunosuppression (eg, risk for infection) and other effects of anti-inflammatory medications such as Cushing ulcer with or without gastrointestinal perforation.

Once an appropriate therapeutic intervention is undertaken, a good response usually is achieved within 4 weeks. Thereafter, Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), can usually be well controlled with low maintenance steroid doses.

Most individuals who showed favorable response to corticosteroid treatment of EGPA associated neuropathy do not manifest disease relapse within the ensuing 8 months.

Individuals with neuropathy associated with EGPA who show poor response to initial corticosteroid treatment may experience improvement once cyclophosphamide is administered.

With modern therapy, the outlook for EGPA appears to be much better than in early reports. More than 90% of patients achieve remission after initial steroid treatment. Whether the apparently improved outlook, as compared to earlier reports, represents a change in the average severity of disease, improved recognition and diagnosis of milder cases, or improvements in therapy is not well understood. Patients demonstrating a favorable response usually retain an independent existence on steroid maintenance therapy. The relapse rate is approximately 25%–30%.

Characteristically, patients with severe systemic vasculitis have a poor response to the initial phases of treatment. Both systolic and diastolic dysfunction associated with cardiomyopathy may improve with steroid therapy, although very low myocardial shortening fractions may not improve with this therapy. The outlook for patients with severe systemic vasculitis is guarded because they have a considerable risk for dependent existence and progressive decline or premature death. The overall mortality rate may be as high as 25% within 5 years of diagnosis, half of these patients dying directly from vasculitis and half from secondary complications of vasculitis. The patients at highest risk for death or severe morbidity are those with severe myocardial or gastrointestinal vasculitis.