Churg-Strauss Disease

Updated: Jul 21, 2020
  • Author: Nir Shimony, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
  • Print
Overview

Background

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]

Next:

Pathophysiology

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.

Previous
Next:

Epidemiology

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]

Previous