1. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis)
Eugene Choo, MD, FAAAAI, FACAAI
Allergy & Asthma Associates, Houston, Texas
Past-Assistant Professor of Medicine, Division of Allergy/Immunology, National Jewish Health, Denver, Colorado
Dennis Ledford, MD, FAAAAI, FACAAI
Allergy, Asthma & Immunology Associates of Tampa Bay
Ellsworth and Mabel Simmons Professor of Allergy/Immunology
Past-President of Medical Faculty
University of South Florida College of Medicine

2. Patient History Chief Complaint: worsening asthma, new lung lesion
HPI: 47yo female with asthma, chronic sinusitis, allergic rhinitis, atopic dermatitis, and GERD presented as consultation for further evaluation of lung disease and lesion
Quit smoking after 23 pack years
Asthma since 19yo but sx worsening over recent years
Systemic signs\symptoms over recent months: fatigue, fever/chills/night sweats, abdominal pain, intermittent nonpruritic rash on bilateral thighs and buttocks, bilateral hand numbness, bilateral thigh pain

3. Evaluation prior to referral
1y prior to presentation, had CT chest after fall: incidentally found 3mm RML pulmonary nodule, no LAD
CT chest 7 months later: RML nodule stable but new 4 x 3.1 cm LLL pulmonary mass-like lesion
Initial IgE 7375 kU/L, 14,000 WBC/uL, 6-8% eosinophils (later peaked at 15.4%); negative ANCAs and PPD
Aspergillus fumigatus-specific precipitins and specific-IgG/IgE eventually negative
Transbronchial biopsy: inflamed granulomatous lesion with occasional multinucleated giant cells; no malignancy, AFB, fungus, Pneumocystis.

4. Evaluation prior to referral
Started intravenous methylprednisolone as inpatient, discharged home with oral prednisone 40 mg daily
Symptoms dramatically improved
CT chest 1 month later: LLL lung mass decreased from 4x3.1 cm to 2.3x2.1 cm, no bronchiectasis
2 months later: given improvement in CT and systemic symptoms, prednisone tapered off

5. Medications Current medications:
Fluticasone/salmeterol 500/50 1 inhalation BID
Levalbuterol HFA 2 puffs BID
Loratidine 10 mg daily
Omeprazole 20 mg daily
Gabapentin 300 mg BID
Estradiol 2 mg daily
Bupropion 150 mg BID
Clobetasol/tacrolimus topical PRN
No known drug allergies

6. Physical Examination Normal vital signs, not hypertensive
Minimal dry eczematoid areas on bilateral forearms, no rash
Mildly inflamed nasal mucosa without sores
Remainder of exam unremarkable, no neurologic findings

7. Pulmonary function testing
FVC 2.76 L (83%) -> 2.93L (88%)
FEV L (78%) -> 2.29L (86%); 10% increase after albuterol
FEV1/FVC > 0.78
TLC 5.74 L (127%) -> 5.62L (124%)
FRC 2.95 L (117%) -> 2.89L (114%)
RV 2.51 L (233%) -> 2.42L (225%)
Raw 6.5 (458%) -> 4.17 (294%); 36% decrease after albuterol
sGaw (19%) -> (30%); 59% increase after albuterol
DLCO/VA 5.87 (109%)
Summary: hyperinflation, airflow limitation, conductance improved with albuterol

8. Laboratory data 5.5% eosinophils (300 cells/uL); was 15.3% 1 yr ago
IgE 2012 kU/L (3234 kU/L 1 yr ago)
Other labs unremarkable:
CMP, urinalysis
ESR, CRP, rheumatoid factor, angiotensin converting enzyme
ANA, anti-centromere Ab, Anti-SCL70 Ab, Jo-1 Ab, anticardiolipin Ab
C-ANCA, P-ANCA
L-myeloperoxidase, L-protease 3, L-cryoglobulin Ab
Fungal Ab for Histo/Blasto/Aspergillus/Coccidioides
Cystic fibrosis mutation analysis

9. CT chest
CT chest: 2.3 x 2.1 cm LLL lung mass (was 4 x 3.1 cm 1 month ago)
2 months later: focal dense linear LLL lesion, associated bronchiectasis; appearance suggestive of resolving inflammatory/infectious process with residual scarring, not mass

10. Radiographic data CT chest (2 months after prior exams): CT sinus:
New bilateral multifocal ground glass areas suggestive of infection/inflammation
Differential diagnosis: hemorrhage, eosinophilic lung disease, vasculitis, eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss vasculitis)
CT sinus:
Mild-moderate chronic ethmoid sinusitis

11. Transbronchial biopsy
Bronchial wall with moderate eosinophilic inflammation (see arrow) & thickened sub-basal lamina
Centrally necrotizing granulomas, air space eosinophils and neutrophils, airway fibrin deposition
Ddx: fungal/parasitic, drugs, collagen vascular disease, severe asthma, hematopoietic malignancy, idiopathic

12. Patient summary Worsening asthma symptoms Allergic rhinitis
Chronic sinusitis
Systemic symptoms (fever/chills, fatigue)
Eosinophilia, negative ANCAs
Pulmonary ground glass opacities, granulomatous LLL lesion with eosinophilic infiltration, negative cultures, no malignancy
Symptoms and LLL lesion improved with prednisone
No travel abroad

13. Differential diagnosis
Infection (fungal, parasitic)
Chronic eosinophilic pneumonia
Drug reaction
Severe asthma
Hematopoietic malignancies
Idiopathic disease
Vasculitis or autoimmune diseases (e.g. EGPA, microscopic polyangiitis, anti-glomerular basement membrane antibody disease)

14. Differential diagnosis
Infection (fungal, parasitic)
But cultures negative x 2, no travel abroad, prolonged significant clinical improvement with prednisone
Chronic eosinophilic pneumonia
But patients usually very ill, have different lung involvement (bilateral peripheral/pleural-based infiltrates)
Drug reaction
Not suggested by history
Severe asthma
But ground glass opacities would be atypical

15. Differential diagnosis
Hematopoietic malignancies
But BAL negative for malignancy x2
Langerhans cell histiocytosis typically has diabetes insipidus, bone involvement, mid-upper lobe reticulonodular pulm lesions
ABPA
Patient has asthma, peripheral eosinophilia, elevated IgE
But negative Aspergillus-specific IgG/IgE & ST, bronchiectasis not central
Immunologic lung diseases/vasculitis
Anti-glomerular basement membrane antibody disease
Granulomatosis with polyangiitis (GPA or Wegener vasculitis): but nasal ulcerations common
Microscopic polyangiitis (MP): but granulomas uncommon
EGPA
Goodpasture’s: antiglomerular basement membrane Ab, crescentic glomerulonephritis, diffuse pulm hemorrhage.
Wegener’s: triad granulomas, necrosis, vasculitis upper & lower resp tract. But 70-80% focal segmental necrotizing glomerulonephritis, 75-90% c-ANCA +, nasal ulcers common. MP: Small-vessel vasculitis involving lung & kidney. But not assoc w granulomas

16. EGPA: Diagnostic criteria
American College of Rheumatology criteria:
1. Asthma
2. Eosinophilia (>10% blood white cells)
3. Mono/polyneuropathy
4. Migratory/transient pulmonary opacities on imaging
5. Paranasal sinus abnormality
6. Biopsy containing blood vessel showing eosinophil accumulation in extravascular areas (if lung, surgical >> transbronchial)
If 4+ criteria present, sensitivity 85%, specificity 99.7%
Lanham criteria (need all 3):
asthma, peak peripheral eosinophilia > 1500 cells/uL, systemic vasculitis involving 2+ extrapulmonary organs
Diagnostic criteria not intended for routine clinical application but for identifying patients for clinical trials
1. 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.

17. This patient
Meets at least 4/6 ACR criteria for the diagnosis of EGPA:
1. Asthma
2. Eosinophilia > 10% (peak was 15.3%)
3. Migratory/transient pulmonary opacities
4. Sinus disease
5. Had history suggestive of neuropathy

18. EGPA: Background
Previously allergic granulomatosis and angiomatosis, Churg-Strauss vasculitis
First described as syndrome of “asthma, eosinophilia, fever, and accompanying vasculitis of various organ systems”
Syndrome occurring almost exclusively in patients with asthma and AR; characterized by systemic vasculitis with eosinophilia
Similar in many clinical and pathological respects to polyarteritis nodosa, but distinguished by granulomas and eosinophilia
1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 1951; 27:

19. EGPA: Pathogenesis Hypothesis of overproduction of Th2-type cytokines
Evidence for ANCA amplification of inflammatory signals in vitro suggests ANCA contributes to pathogenesis
Association between freebase cocaine use and EGPA-like vasculitis
Role of leukotriene antagonists controversial
1. Adkinson, et al. Middleton’s Allergy: Principles and Practice, 7th edition Mosby. Chapter 54: Immunologic non-asthmatic diseases of the lung.
2. Nathani N, Little MA, Kunst H, Wilson D, Thickett DR. Churg–Strauss syndrome and leukotriene antagonist use: a respiratory perspective. Thorax 2008;63:

20. EGPA: Clinical features
Multisystem disorder, but pulmonary features predominant
Asthma defining feature (90-100%); typically precedes vasculitis (median time between asthma onset and EGPA diagnosis 4 years)
Lung parenchyma involved in 40-60% of patients
Lung nodules, granulomatous mass lesions may be present, but capillaritis with alveolar hemorrhage rare
Paranasal sinuses often involved, but severe necrosis rare
Can present with leukocytoclastic vasculitis as involvement occurs with multiple sized vessels
1. King Jr, TE. Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

21. EGPA: Laboratory features
Prototypical finding: peripheral eosinophilia (80-100% patients), usually 5-9k
Inflammatory markers (ESR, CRP, fibrinogen, α2-globulins), IgE commonly elevated
Anemia, leukocytosis, hypergammaglobulinemia, circulating immune complexes, rheumatoid factor may be present
40-75% patients develop p-ANCA (antimyeloperoxidase), <5% c-ANCA (anti-proteinase-3)
1. King Jr, TE. Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

22. EGPA: Other features
Radiographic features: Transient patchy opacities (75% pts), pleural effusions (30% pts, exudative and eosinophilic), hilar lymphadenopathy, pulmonary hemorrhage, bilateral nodular disease, granulomas
Pathologic features: eosinophilic infiltration of tissue, necrotizing granulomatous inflammation, necrotizing small-vessel vasculitis
Pathognomonic lesion: allergic granuloma (necrotizing granuloma surrounded by eosinophilic inflammatory infiltrate)
Small-vessel vasculitis: fibrinoid necrosis, eosinophilic inflammation, granuloma formation typically in/adjacent to vessel wall
1. King Jr, TE. Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

23. So how might EGPA present in your office?
Asthmatic with any of the below findings:
Foot drop
Peripheral blood eosinophilia and pulmonary infiltrates
Severe eosinophilic upper airway disease (ear, sinus)
Eosinophilic pleural or pericardial effusion
Palpable purpura

24. EGPA: Treatment Primary option: corticosteroids
May respond to corticosteroids alone
Typical dose: mg/kg/day for 6-12 weeks (or resolution of disease)
Higher dose oral/IV corticosteroids in vasculitis, fulminant multiorgan disease
Late relapses after treatment uncommon
May require long-term low dose oral/inhaled corticosteroids for asthma control
Monitoring regimen: eosinophil counts, ESR (ANCA persistence not helpful)
HTN: Treat in typical manner (but control may be difficult)
1. King Jr, TE. Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

25. EGPA: Other treatment options
Reported benefit in patients unresponsive to corticosteroids or with severe fulminant disease:
Cyclophosphamide
Azathioprine
Methotrexate
Rituximab
Mycophenalate mofetil
Controversial:
Plasma exchange
IVIG
Interferon-alpha + corticosteroids
Omalizumab
Mepolizumab (anti-IL5)
1. King Jr, TE. Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

26. EGPA: Prognosis If untreated: 25% 5-year survival
50% died within 3 months before corticosteroid use
If treated: 72% survival rate over 78 months
Most deaths due to vasculitis complications:
Myocardial infarction / congestive heart failure
Intracranial hemorrhage
Renal failure
Gastrointestinal bleed
Status asthmaticus
Earlier vasculitis onset after asthma onset associated with worse prognosis
1. King Jr, TE. Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). In: UpToDate, Flaherty KR, et al (Ed), UpToDate, Waltham, MA. (Accessed on February 17, 2014.)

27. EGPA: Prognosis 5 clinical factors associated with adverse prognosis:
Cardiac manifestations
GI disease
Renal insufficiency (creatinine >1.6)
Proteinuria (>1g/day)
CNS involvement
5-yr mortality based on presence/absence of above:
12% if 0 present
26% if 1 present
46% if 3+ present
1. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75:17.
2. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001; 44:666.
3. Moosig F, Bremer JP, Hellmich B, et al. A vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA): monocentric experiences in 150 patients. Ann Rheum Dis 2013; 72:1011.
4. Samson M, Puéchal X, Devilliers H, et al. Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials. J Autoimmun 2013; 43:60.

28. Patient follow-up
At last contact, doing well on only inhaled corticosteroids
Was not requiring systemic corticosteroids or immunomodulatory treatment

29. EGPA: summary
1. Occurs almost entirely in patients with asthma and allergic rhinitis
2. Characterized by systemic vasculitis with eosinophilia
3. Pulmonary symptoms predominate, but virtually any organ system can be affected
4. Gold standard for diagnosis is biopsy showing tissue eosinophilia with predilection to blood vessels
5. Corticosteroids effective in most patients and therefore mainstay of treatment