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.)

REFERENCES

1. CHURG J, STRAUSS L. Allergic granulomatosis, allergic angiitis, and

periarteritis nodosa. Am J Pathol 1951; 27:277.

2. Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Pathol 1983;

14:868.

3. Sinico RA, Bottero P. Churg-Strauss angiitis. Best Pract Res Clin Rheumatol
2009; 23:355.

4. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin

Rheumatol 2007; 19:25.

5. Keogh KA, Specks U. Churg-Strauss syndrome. Semin Respir Crit Care Med
2006; 27:148.

6. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study

and long-term follow-up of 96 patients. Medicine (Baltimore) 1999; 78:26.

7. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma
and eosinophilia: a clinical approach to the Churg-Strauss syndrome.
Medicine (Baltimore) 1984; 63:65.

8. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology
1990 criteria for the classification of Churg-Strauss syndrome (allergic
granulomatosis and angiitis). Arthritis Rheum 1990; 33:1094.

9. Szczeklik W, Jakieła B, Adamek D, Musiał J. Cutting edge issues in the Churg-

Strauss syndrome. Clin Rev Allergy Immunol 2013; 44:39.
10. Schwartz RA, Churg J. Churg-Strauss syndrome. Br J Dermatol 1992; 127:199.

11. Conron M, Beynon HL. Churg-Strauss syndrome. Thorax 2000; 55:870.

12. Mouthon L, Le Toumelin P, Andre MH, et al. Polyarteritis nodosa and Churg-
Strauss angiitis: characteristics and outcome in 38 patients over 65 years.
Medicine (Baltimore) 2002; 81:27.

13. Abril A, Calamia KT, Cohen MD. The Churg Strauss syndrome (allergic
granulomatous angiitis): review and update. Semin Arthritis Rheum 2003;
33:106.

14. Zwerina J, Eger G, Englbrecht M, et al. Churg-Strauss syndrome in childhood: a

systematic literature review and clinical comparison with adult patients.
Semin Arthritis Rheum 2009; 39:108.

15. Gendelman S, Zeft A, Spalding SJ. Childhood-onset eosinophilic

granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): a
contemporary single-center cohort. J Rheumatol 2013; 40:929.

16. Iudici M, Puéchal X, Pagnoux C, et al. Brief Report: Childhood-Onset Systemic

Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study
Group Registry. Arthritis Rheumatol 2015; 67:1959.

17. Harrold LR, Andrade SE, Go AS, et al. Incidence of Churg-Strauss syndrome in
asthma drug users: a population-based perspective. J Rheumatol 2005;
32:1076.

18. Sada KE, Amano K, Uehara R, et al. A nationwide survey on the epidemiology
and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-
Strauss) in Japan. Mod Rheumatol 2014; 24:640.

19. Hellmich B, Ehlers S, Csernok E, Gross WL. Update on the pathogenesis of

Churg-Strauss syndrome. Clin Exp Rheumatol 2003; 21:S69.
20. Zwerina J, Axmann R, Jatzwauk M, et al. Pathogenesis of Churg-Strauss
syndrome: recent insights. Autoimmunity 2009; 42:376.

21. Schmitt WH, Csernok E, Kobayashi S, et al. Churg-Strauss syndrome: serum

markers of lymphocyte activation and endothelial damage. Arthritis Rheum
1998; 41:445.

22. Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and

autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci 2005; 1051:121.

23. Tsurikisawa N, Saito H, Tsuburai T, et al. Differences in regulatory T cells

between Churg-Strauss syndrome and chronic eosinophilic pneumonia with
asthma. J Allergy Clin Immunol 2008; 122:610.

24. Vaglio A, Martorana D, Maggiore U, et al. HLA-DRB4 as a genetic risk factor for
Churg-Strauss syndrome. Arthritis Rheum 2007; 56:3159.

25. Wieczorek S, Hellmich B, Arning L, et al. Functionally relevant variations of the

interleukin-10 gene associated with antineutrophil cytoplasmic antibody-
negative Churg-Strauss syndrome, but not with Wegener's granulomatosis.
Arthritis Rheum 2008; 58:1839.

26. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia,
and cardiomyopathy following corticosteroid withdrawal in patients with
asthma receiving zafirlukast. JAMA 1998; 279:455.

27. Franco J, Artés MJ. Pulmonary eosinophilia associated with montelukast.

Thorax 1999; 54:558.

28. Green RL, Vayonis AG. Churg-Strauss syndrome after zafirlukast in two
patients not receiving systemic steroid treatment. Lancet 1999; 353:725.

29. Kinoshita M, Shiraishi T, Koga T, et al. Churg-Strauss syndrome after

corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J
Allergy Clin Immunol 1999; 103:534.
30. Martin RM, Wilton LV, Mann RD. Prevalence of Churg-Strauss syndrome,
vasculitis, eosinophilia and associated conditions: retrospective analysis of
58 prescription-event monitoring cohort studies. Pharmacoepidemiol Drug
Saf 1999; 8:179.

31. Wechsler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in

patients receiving montelukast as treatment for asthma. Chest 2000;
117:708.

32. Hauser T, Mahr A, Metzler C, et al. The leucotriene receptor antagonist

montelukast and the risk of Churg-Strauss syndrome: a case-crossover study.
Thorax 2008; 63:677.

33. D'Cruz DP, Barnes NC, Lockwood CM. Difficult asthma or Churg-Strauss
syndrome? BMJ 1999; 318:475.

34. Le Gall C, Pham S, Vignes S, et al. Inhaled corticosteroids and Churg-Strauss

syndrome: a report of five cases. Eur Respir J 2000; 15:978.

35. Cooper SM, Libman BS, Lazarovich M. Churg-strauss syndrome in a group of

patients receiving fluticasone for asthma. J Rheumatol 2002; 29:2651.

36. Tuggey JM, Hosker HS. Churg-Strauss syndrome associated with

montelukast therapy. Thorax 2000; 55:805.

37. Katsura T, Yoshida F, Takinishi Y. The Churg-Strauss syndrome after

pranlukast treatment in a patient not receiving corticosteroids. Ann Intern
Med 2003; 139:386.

38. Nathani N, Little MA, Kunst H, et al. Churg-Strauss syndrome and leukotriene
antagonist use: a respiratory perspective. Thorax 2008; 63:883.

39. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation,

antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists.
Am J Med 2003; 115:284.

40. Specks, U. Pulmonary vasculitis. In: Interstitial Lung Disease, 5th, Schwarz, MI,
King, TE Jr (Eds), People's Medical Publishing House, Shelton, CT, USA 2011.
p.765.

41. Keogh KA. Leukotriene receptor antagonists and Churg-Strauss syndrome:

cause, trigger or merely an association? Drug Saf 2007; 30:837.

42. Bibby S, Healy B, Steele R, et al. Association between leukotriene receptor

antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS
database. Thorax 2010; 65:132.

43. Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-strauss

syndrome in patients treated with omalizumab. Chest 2009; 136:507.

44. Ruppert AM, Averous G, Stanciu D, et al. Development of Churg-Strauss

syndrome with controlled asthma during omalizumab treatment. J Allergy Clin
Immunol 2008; 121:253.

45. Nazir S, Tachamo N, Fareedy SB, et al. Omalizumab-associated eosinophilic

granulomatosis with polyangiitis (Churg-Strauss syndrome). Ann Allergy
Asthma Immunol 2017; 118:372.

46. Orriols R, Muñoz X, Ferrer J, et al. Cocaine-induced Churg-Strauss vasculitis.

Eur Respir J 1996; 9:175.

47. Wiesner O, Russell KA, Lee AS, et al. Antineutrophil cytoplasmic antibodies
reacting with human neutrophil elastase as a diagnostic marker for cocaine-
induced midline destructive lesions but not autoimmune vasculitis. Arthritis
Rheum 2004; 50:2954.

48. Peikert T, Finkielman JD, Hummel AM, et al. Functional characterization of

antineutrophil cytoplasmic antibodies in patients with cocaine-induced
midline destructive lesions. Arthritis Rheum 2008; 58:1546.
49. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod
Pathol 2001; 14:1284.

50. Katzenstein AL. Diagnostic features and differential diagnosis of Churg-

Strauss syndrome in the lung. A review. Am J Clin Pathol 2000; 114:767.

51. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis
syndromes. American College of Rheumatology Subcommittee on
Classification of Vasculitis. Arthritis Rheum 1990; 33:1074.

52. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in Churg-Strauss

syndrome. Am J Kidney Dis 2006; 47:770.

53. Clutterbuck EJ, Evans DJ, Pusey CD. Renal involvement in Churg-Strauss
syndrome. Nephrol Dial Transplant 1990; 5:161.

54. Neumann T, Manger B, Schmid M, et al. Cardiac involvement in Churg-Strauss

syndrome: impact of endomyocarditis. Medicine (Baltimore) 2009; 88:236.

55. Kawakami T, Soma Y, Kawasaki K, et al. Initial cutaneous manifestations

consistent with mononeuropathy multiplex in Churg-Strauss syndrome. Arch
Dermatol 2005; 141:873.

56. Churg A, Brallas M, Cronin SR, Churg J. Formes frustes of Churg-Strauss

syndrome. Chest 1995; 108:320.

57. Hueto-Perez-de-Heredia JJ, Dominguez-del-Valle FJ, Garcia E, et al. Chronic

eosinophilic pneumonia as a presenting feature of Churg-Strauss syndrome.
Eur Respir J 1994; 7:1006.

Topic 4363 Version 11.0

© 2019 UpToDate, Inc. All rights reserved.