Epidemiology, pathogenesis, and pathology of

eosinophilic granulomatosis with polyangiitis

(Churg-Strauss)
Author: Talmadge E King, Jr, MD
Section Editors: Kevin R Flaherty, MD, MS, Richard J Glassock, MD, MACP, Bruce S Bochner, MD
Deputy Editor: Helen Hollingsworth, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Oct 2019. | This topic last updated: Feb 23, 2018.

INTRODUCTION

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated EGPA,

which was previously called the Churg-Strauss syndrome (CSS) or allergic
granulomatosis and angiitis, is a multisystem disorder characterized by allergic
rhinitis, asthma, and prominent peripheral blood eosinophilia [1-9]. EGPA is
classified as a vasculitis of the small and medium sized arteries, although the
vasculitis is often not apparent in the initial phases of the disease.

The most commonly involved organ is the lung, followed by the skin. EGPA,
however, can affect any organ system, including the cardiovascular,
gastrointestinal, renal, and central nervous systems. Vasculitis of extrapulmonary
organs is largely responsible for the morbidity and mortality associated with
EGPA.

The epidemiology, pathogenesis, and pathology of EGPA will be reviewed here.

The clinical features, diagnosis, treatment and prognosis of this disorder, as well
as the approach to patients with vasculitis and/or eosinophilia are discussed
separately. (See "Clinical features and diagnosis of eosinophilic granulomatosis
with polyangiitis (Churg-Strauss)" and "Treatment and prognosis of eosinophilic
granulomatosis with polyangiitis (Churg-Strauss)" and "Overview of and approach
to the vasculitides in adults" and "Approach to the patient with unexplained
eosinophilia".)

EPIDEMIOLOGY

The epidemiology of EGPA remains unclear because of the uncertainties related to

diagnosis [10]. Approximately 10 percent of patients with a major form of
vasculitis are recognized to have EGPA. Among the three anti-neutrophil
cytoplasmic antibodies (ANCA)-associated vasculitides (EGPA, granulomatosis
with polyangiitis (Wegener's), and microscopic polyangiitis), EGPA is least
common [5]. (See "Overview of and approach to the vasculitides in adults".)

The mean age at diagnosis of EGPA is 40 years [11]. EGPA is an uncommon cause
of vasculitis in people older than 65 years, accounting for 5 percent of
histologically proven vasculitis among 38 elderly patients with various systemic
forms of angiitis [12,13]. EGPA is also rare in children and adolescents; when it
does occur in this age group, it appears to follow a more aggressive course with
prominent pulmonary and cardiovascular manifestations [14-16].

EGPA does not exhibit gender predominance [11,17].

A cross-sectional nationwide survey in Japan estimated the prevalence of EGPA at

17.8/1,000,000 [18]. The mean age at onset was 55 ± 14 years (± SD). Among the
patients tested for myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody
(p-ANCA), 50 percent were positive; however, only 2.5 percent were positive for
proteinase3 (PR3) c-ANCA. There was female predominance (2:1).

PATHOGENESIS
Abnormal immune function — The exact pathogenesis of EGPA is unknown.
Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60
percent of patients and EGPA is classified among the ANCA-positive vasculitides
[11]. However, it is not known whether ANCAs have a pathogenic role in EGPA or
whether they just reflect one end of the spectrum of EGPA manifestations. (See
"Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis
(Churg-Strauss)", section on 'Antineutrophil cytoplasmic antibodies' and
"Pathogenesis of granulomatosis with polyangiitis and related vasculitides".)

In addition, EGPA is characterized by several other abnormalities in immune

function [19-22]:

● The prominence of allergic features (allergic rhinitis, asthma, and positive skin
tests) suggests heightened Th2 immunity [21].

● Pulmonary angiocentric granulomatosis suggests heightened Th1 immunity

[22].

● The number of peripheral blood CD4+CD25+ T cells (T regulatory cells) that

produce IL-10 were decreased in patients with EGPA compared with asthma
or chronic eosinophilic pneumonia and were increased in patients with EGPA
in remission [23]. These observations suggest that T regulatory cells may
influence which patients with asthma and chronic eosinophilic pneumonia will
develop active EGPA.

● Abnormal eosinophil function is likely due to a combination of increased

eosinophil recruitment by Th2 cytokines and decreased eosinophil apoptosis
[19].

● Altered humoral immunity is suggested by hypergammaglobulinemia,

especially IgE, and rheumatoid factor positivity in some patients.
Genetic factors — Genetic factors may also play a role. In a study of 48 patients
and 350 healthy controls, both HLA-DRB1*07 and HLA-DRB4 were more prevalent
among patients with EGPA and HLA-DRB4 correlated with the number of vasculitic
manifestations [24].

Polymorphisms in the interleukin (IL)-10 gene have been associated with EGPA. In
a study of 103 patients with EGPA, genotyping identified three single nucleotide
polymorphisms (SNPs) relating to the interleukin (IL)-10 gene [25]. The IL-10
-3575/-1082/-592 TAC haplotype (part of IL 10.2) was strongly associated with
EGPA (OR=2.16) and negatively associated with granulomatosis with polyangiitis
(Wegener's). Three-fourths of the patients were ANCA negative. (See "Genetics of
asthma".)

ASSOCIATION WITH MEDICATIONS

Several medications have been associated with the appearance of EGPA. In the
case of asthma therapies such as leukotriene modifying agents, inhaled
glucocorticoids, and omalizumab, it appears that this is more likely an unmasking
of underlying disease rather than a causal relationship, as described below.

Leukotriene modifying agents — EGPA has been reported as a rare complication

in patients with systemic glucocorticoid-dependent asthma who were treated with
a leukotriene modifying agent (LTMA; eg, zafirlukast, montelukast, pranlukast,
zileuton), usually in the setting of reduction in the dose of oral glucocorticoids [26-
39].

It is believed that LTMAs may unmask underlying EGPA in the following ways
[40,41]:

● Glucocorticoid withdrawal is facilitated by LTMA therapy, leading to

elaboration of EGPA disease manifestations.
 ● Patients who have undiagnosed but escalating EGPA are prescribed a LTMA
because of worsening symptoms. The LTMA is insufficient to control EGPA
and the disease becomes manifest (ie, confounding by indication).

However, it is difficult to completely exclude the possibility that LTMAs play a

causal role in the development of EGPA in some patients [26-38,42].

Inhaled glucocorticoids — The onset of clinical evidence of EGPA has also

occurred when the addition or increase in inhaled glucocorticoids allowed
reduction in the dose of systemic glucocorticoids, which in turn led to an
"unmasking" of EGPA symptoms as described above [34].

Omalizumab — EGPA has also been noted in patients receiving omalizumab (a

humanized anti-IgE antibody) for treatment of severe asthma [43-45]. The
appearance of EGPA symptoms preceded treatment with omalizumab or
coincided with tapering of systemic glucocorticoids, suggesting that omalizumab
had been added in the setting of escalating EGPA or that it allowed "unmasking" of
underlying EGPA. (See "Anti-IgE therapy", section on 'Other issues'.)

Cocaine — An unusual EGPA-like vasculitis has been associated with the use of
free base cocaine [46]. The diagnosis of EGPA in patients who use cocaine is a
complicated issue because both acute and chronic eosinophilic pneumonia are
manifestations of cocaine toxicity and antineutrophil cytoplasmic antibodies are
detected in the majority of patients with cocaine-induced midline destructive
lesions of the nose [47]. (See "Pulmonary complications of cocaine abuse",
section on 'Acute pulmonary toxicity and crack lung' and "Pulmonary
complications of cocaine abuse", section on 'Chronic toxicity'.)

The anti-neutrophil cytoplasmic antibodies (ANCAs) associated with cocaine-

induced midline destructive lesions appear to be different from those associated
with EGPA. ANCAs from patients with cocaine-induced midline destructive lesions
typically recognize human neutrophil elastase as the target antigen, although
autoantibodies to proteinase 3 and other serine proteases are also seen [48]. In
contrast, ANCAs from patients with EGPA commonly react to myeloperoxidase
and not human neutrophil elastase [47]. Sera from patients with granulomatosis
with polyangiitis (Wegener's) typically react with proteinase 3, but not human
neutrophil elastase. (See "Clinical features and diagnosis of eosinophilic
granulomatosis with polyangiitis (Churg-Strauss)", section on 'Antineutrophil
cytoplasmic antibodies'.)

PATHOLOGY

The major histopathologic findings of EGPA from any affected organ includes the
following, although they may not all be present (especially in patients who have
been partially treated) [49-51]:

● Eosinophilic infiltration

● Prominent and sometimes quite extensive areas of necrosis

● An eosinophilic, giant cell vasculitis, especially of the small arteries and veins

● Interstitial and perivascular necrotizing granulomas (picture 1)

Pathologic findings in different organs include:

● In the lung, asthmatic bronchitis, eosinophilic pneumonia, extravascular

granulomas, or vasculitis (affecting arteries, veins, or capillaries) may be
seen. In some cases, the inflammatory lesions extend along the pleura and
interlobular septa. The granulomas in EGPA, also called allergic granulomas,
typically have a border of palisading histiocytes and multinucleated giant cells
surrounding a central necrotic zone consisting of the necrotic eosinophils.
The vascular infiltrates are often composed of chronic inflammatory cells,
eosinophilic infiltrates, epithelioid cells, multinucleated giant cells and/or
neutrophils. Diffuse pulmonary hemorrhage and capillaritis may be seen.
 ● In the kidney, necrotizing crescentic glomerulonephritis is the most common
finding, but eosinophilic interstitial nephritis, mesangial glomerulonephritis,
and focal segmental glomerulosclerosis are also seen [52,53].

● Endomyocardial biopsies typically reveal eosinophilic infiltration and

endomyocarditis, but not vasculitis [54].

● Skin biopsy typically reveals a leukocytoclastic vasculitis with eosinophil

infiltration [55]. Palisading granulomas and/or eosinophilic infiltration of
dermal nerve fibers may also be noted.

The histopathologic findings may vary with the phase of disease [56,57]. (See
"Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis
(Churg-Strauss)", section on 'Phases of disease'.)

● During the prevasculitic phase, tissue infiltration by eosinophils may be

present without overt vasculitis.

● During the vasculitic phase, a nondestructive infiltration of vessel walls is

noted and may be more common than a necrotizing vasculitis.

● In the postvasculitic phase, healed vascular lesions resembled organized

thrombi, but are associated with extensive destruction of the elastica. In this
later phase, eosinophilic infiltration may be absent.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries

and regions around the world are provided separately. (See "Society guideline
links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

● Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated
EGPA, which was previously called the Churg-Strauss syndrome (CSS) or
allergic granulomatosis and angiitis, is a multisystem disorder characterized
by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia. (See
'Introduction' above.)

● The exact etiology is unknown. Antineutrophil cytoplasmic antibodies (ANCA)

are detected in about 40 to 60 percent of patients and EGPA is classified
among the ANCA-positive vasculitides. Several other abnormalities in
immunologic function occur in EGPA, including heightened Th1 and Th2
lymphocyte function, increased eosinophil recruitment and decreased
eosinophil apoptosis. (See 'Pathogenesis' above.)

● Genetic factors such as human leukocyte antigen (HLA) class and certain
interleukin-10 polymorphisms may play a role in EGPA pathogenesis. (See
'Genetic factors' above.)

● Several asthma medications, such as the leukotriene modifying agents,

inhaled glucocorticoids, and omalizumab, have been associated with the
appearance of EGPA. However, it appears that the association is most likely
due to unmasking of the underlying disease or intensification of therapy in a
patient with escalating EGPA, rather than a causal relationship. (See
'Association with medications' above.)

● A EGPA-like illness can rarely occur after the use of free base cocaine.
However, the ANCAs associated with cocaine use recognize different target
proteases than the typical ANCAs associated with EGPA. (See 'Cocaine'
above.)

● The major histopathologic findings of EGPA from any affected organ include
the following, although they may not all be present: eosinophilic infiltration;
prominent and sometimes extensive areas of necrosis; an eosinophilic, giant
 cell vasculitis, especially of the small arteries and veins; and also interstitial
and perivascular necrotizing granulomas (picture 1). (See 'Pathology' above.)

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