Churg-Strauss Syndrome

A. Characteristics

Also called "allergic granulomatosis"
Polyarteritis nodosa (PAN) related leukocytoclastic vasculitis
Components of Syndrome
1. Asthma required for diagnosis (asthma usually severe) with clear lung involvement
2. Patients usually with allergies (atopy) as well (but not required)
3. Hypereosinophilia occurs and may be marked
4. Vasculitis must be present
Incidence is ~2.4 per 1 million patients per year overall
May occur in patients on leukotriene antagonists who are tapering glucocorticoids [4]
Antineutrophil cytoplasmic antibodies (ANCA) present in majority of cases
Mechanism [10]
1. The ANCA may be directly involved in endothelial cell damage in some types of vasculitis
2. Infection or other inflammatory stimuli stimulates production of TNFa and other cytokines
3. These cytokines stimulate neutrophils and endothelial cells
4. PR3 and MPO are stimluated to move from neutrophil azurophilic granules to surface
5. In setting of inflammation, PR3 and MPO become immunogenic, with ANCA forming
6. ANCA bind to targets on neutrophil surfaces, and Fc region of ANCA stimulate neutrophil
7. ANCAs induce firm adhesion (not rolling) of neutrophils to endothelial surface
8. ANCA induce release of reactive oxygen species and proteolytic enzymes from neutrophils
9. ANCA-activated neutrophils also secrete proinflammatory cytokines
10. Together, these effects cause neutrophil mediated endothelial damage

B. Symptoms [5,6]

Severe Asthma
1. Nearly always requires systemic glucocorticoids
2. CSS should be considered in any case of severe asthma, particularly with eosinophilia
3. In asthmatics, incidence of CSS is ~64 per million per year
Neurologic Symptoms
1. Present in >60% of patients
2. Multiple mononeuropathy (mononeuritis multiplex) is most common
3. Mononeuritis multiplex with asthma and eosinophilia essentially confirms CSS diagnosis
4. Distal symmetric polyneuropathy can also occur
5. Cerebral infarctions can occur
Sinusitis and other sinus problems
Arthritis - usually polyarticular, moderately inflammatory
Skin Lesions
1. Common and usually purpuric
2. Erythematous, maculopapular, or pustular lesions
3. Palpable purpura can occur (non-thrombocytopenic)
4. Skin lesions and mononeuritis are more common in CSS than PAN
5. Skin lesions show leukocytoclastic vasculitis
Cardiac Disease
1. Leading cause of mortality and fairly common in CSS
2. Eosinophilic endomyocarditis
3. Coronary vasculitis
4. Valvular heart disease
5. Pericarditis
6. Congestive heart failure may occur
Renal Involvement
1. Commonly found
2. Acute glomerulonephritis, usually does not progress rapidly
3. Tubulointerstitial nephritis with eosinophilia may be present
CSS may be "unmasked" by use of leukotriene inhibitors in patients with moderate or severe asthma as glucocorticoids are withdrawn

C. Diagnosis

Eosinophilia
1. Peripheral eosinophil count elevated, must be >10% of total cells
2. Extravascular eosinophils are commonly seen
Pulmonary
1. Asthma, usually moderate to severe, must be present
2. Non-fixed pulmonary infiltrates on chest radiograph
3. Eosinophil-rich, granulomatous inflammation in lung biopsy
Necrotizing (granulomatous) vasculitis with small-medium sized vessels
Serum IgE is often elevated
Neutrophilia with leukopenia often present
Antineutrophil Cytoplasmic Antibody (ANCA) [9]
1. Peripheral pattern in 40-70% of cases
2. Antibodies to myeloperoxidase (anti-MPO Abs) in 90% of ANCA+ cases (pANCA)
3. Remainder of ANCA+ cases have cANCA (mainly proteinase III)
Clinical Syndromes in ANCA+ and ANCA- CSS [9]
1. CSS appears to differ based on ANCA status
2. ANCA+ CSS associated with renal involvement, peripheral neuropathy, vasculitis
3. ANCA- CSS associated with heart disease and fever
Chapel Hill Consensus Disease Definition [1,7]
1. Includes both pathological and clinical findings
2. Eosinophil-rich and granulomatous inflammation involving respiratory tract
3. Necrotizing vasculitis affecting small-to-medium sized vessels
4. Asthma and eosinophilia
5. Lanham's and American College of Rheumatology criteria differ slightly
6. Overall, ~90% of patients with very likely CSS meet one of the three criteria

D. Differential Diagnosis

Eosinophilia / Hypereosinophilic Syndrome (HES)
1. Asthma and elevated IgE very uncommon in HES
2. Sinus involvement is rare in HES
3. Restrictive cardiomyopathy and endocardial fibrosis more common in HES
4. Palpable purpura is not typically seen in HES
Purpura and Petechiae [6]
1. Normal blood vessels: thrombocytopenia, primary platelet dysfunction, coagulation defects, infections (meningococcemia, Rocky Mountain Spotted Fever)
2. Injured blood vessels: small vessel vasculitis, type 1 cryoglobulinemia, polyarteritis nodosa

E. Treatment [1]

Glucocorticoids
1. Severe asthma nearly always requiring systemic glucocorticoids
2. Rapid reduction in peripheral and organ eosinophil counts
3. Prednisone 40-60mg qd x 1 month then with gradual taper
4. Glucocorticoids alone may be acceptable for good prognosis patients
5. Standard precautions and osteoporosis prophylaxis for patients on glucocorticoids
Cytotoxic Agents for Severe Disease
1. Cyclophosphamide is usually combined with glucocorticoids
2. Cyclophosphamide given as oral (2mg/kg/d) or intravenous pulse 0.6mg/m2 monthly
Consider azathioprine or methotrexate for glucocorticoid-sparing effects
Interferon alpha (IFNa) [8]
1. May be effective in patients with resistant or recurrent disease
2. Initial dose is 3 million units 3 times weekly (tiw) subcutaneously
3. May increase dose to 10 million units tiw during relapse
4. Reduces eosinophilia very well
5. Permitted reduction in doses of all other agents including glucocorticoids
6. Consider use in patients who relapse with cytotoxics, or prior to cyclophosphamide
Other Alternatives
1. Cyclosporin A 150mg po bid may be used in resistant cases
2. Intravenous immunoglobulin (IVIg) 400mg/kg/d x 5 days each month
Unclear if standard asthma medications are effective in CSS
1. Asthma is relatively refractory to bronchodilators
2. Glucocorticoids are always required
Prognosis of CSS is better than that for PAN

References