Introduction
Background
Churg-Strauss syndrome (CSS), or allergic granulomatous angiitis, is a rare syndrome that affects small- to medium-sized arteries and veins. Wegener granulomatosis, Churg-Strauss syndrome, and the microscopic form of periarteritis (ie, microscopic polyangiitis) are three closely related vasculitic syndromes that affect medium- and small-sized vessels and are associated with antibodies to neutrophil cytoplasmic antigens (ANCAs).1,2,3,4
In 1951, Churg and Strauss first described the syndrome in 13 patients who had asthma, eosinophilia, granulomatous inflammation, necrotizing systemic vasculitis, and necrotizing glomerulonephritis.2
The American College of Rheumatology (ACR) has proposed 6 criteria for the diagnosis of Churg-Strauss syndrome.5 The presence of 4 or more criteria yields a sensitivity of 85% and a specificity of 99.7%. These criteria include (1) asthma (wheezing, expiratory rhonchi), (2) eosinophilia of more than 10% in peripheral blood, (3) paranasal sinusitis, (4) pulmonary infiltrates (may be transient), (5) histological proof of vasculitis with extravascular eosinophils, and (6) mononeuritis multiplex or polyneuropathy.
The 1994 Chapel Hill consensus conference on the classification of vasculitides did not modify the ACR criteria.6
Pathophysiology
Churg-Strauss syndrome is a granulomatous small-vessel vasculitis. The cause of this allergic angiitis and granulomatosis is unknown.7 No data have been reported regarding the role of immune complexes or cell-mediated mechanisms in this disease, although autoimmunity is evident with the presence of hypergammaglobulinemia, increased levels of immunoglobulin E (IgE), rheumatoid factor, and ANCA.
A Churg-Strauss syndrome–like syndrome develops as a rare complication in people with asthma who are steroid-dependent and who are treated with leukotriene receptor antagonists (eg, montelukast, zafirlukast) upon reduction in their oral steroid dose.8 The Churg-Strauss syndrome–like complication is reported in people whose withdrawal of oral steroids is also facilitated by inhaled steroids. This complication is probably related to steroid withdrawal, which unmasks underlying Churg-Strauss syndrome,9,10,11 rather than to the drugs themselves. However, in rare cases, this syndrome has developed when a leukotriene receptor antagonist has been substituted for inhaled steroids without a history of oral steroid withdrawal.
HLA-DRB4 positivity may be a genetic risk factor for the development of Churg-Strauss syndrome and may increase the likelihood of vasculitic manifestations of the disease.12
Frequency
United States
The incidence of Churg-Strauss syndrome in the United States is 1-3 cases per 100,000 adults per year.13
International
The international incidence of Churg-Strauss syndrome is approximately 2.5 cases per 100,000 adults per year.
Mortality/Morbidity
* The principal causes of morbidity and mortality in Churg-Strauss syndrome are myocarditis and myocardial infarction secondary to coronary arteritis.14
* With treatment, the 1-year survival rate is 90% and the 5-year survival rate is 62%.1,15
Sex
Churg-Strauss syndrome is slightly more common in males than in females.
Age
The age at onset varies from 15-70 years, with a mean age of approximately 38 years. Churg-Strauss syndrome in pediatric patients is well described, but mostly as case reports. The mean age at diagnosis is around 50 years.
Clinical
History
Churg-Strauss syndrome (CSS) has 3 phases— allergic rhinitis and asthma; eosinophilic infiltrative disease, such as eosinophilic pneumonia or gastroenteritis; and systemic medium- and small-vessel vasculitis with granulomatous inflammation. The vasculitic phase usually develops within 3 years of the onset of asthma, although it may be delayed for several decades. The most prominent symptoms and signs are those related to pulmonary, cardiac, dermatologic, renal, and peripheral nerve involvement. Mononeuritis multiplex is a major clinical finding.
The following list includes the symptoms and signs of the disease as reported by Guillevin et al (1999) in their case series:1
* Constitutional symptoms - Malaise, fatigue, flulike symptoms, weight loss (70%), fever (57%), myalgias (52%)
* Asthma symptoms (Asthma is a central feature of Churg-Strauss syndrome, occurring in 97% of patients. Asthma may precede vasculitis by up to 10 years or, less frequently, may coincide with the appearance of vasculitis. Asthma symptoms are usually persistent; therefore, patients are usually treated with steroids. This, in turn, might mask other features of the syndrome.)
* Paranasal sinusitis (61%) - Usually responds to oral steroids
* Allergic rhinitis (This is a common symptom. Additionally, recurrent sinusitis and polyposis are seen. But, unlike in Wegener granulomatosis, necrotizing lesions of the upper airway are unusual.)
* Pulmonary symptoms (37%), including cough and hemoptysis
* Arthralgias (40%)
* Skin manifestations (49%)
* Purpura
o Skin nodules
o Urticarial rash
o Necrotic bullae
o Digital ischemia
* Cardiac manifestations - Symptoms related to heart failure, myocarditis, pericarditis, constrictive pericarditis, and myocardial infarction
* Gastrointestinal symptoms (31%) - Symptoms related to GI vasculitis, eosinophilic gastritis, colitis (This includes abdominal pain [59%], diarrhea [33%], and GI bleeding [18%].)
* Peripheral neuropathy - Mononeuritis multiplex (most frequent form, occurring in as many as 77% of patients)
* Less frequent symptoms - Symptoms related to stroke, ophthalmologic involvement, and other rare symptoms
Physical
The physical findings in Churg-Strauss syndrome are specific to organ-system involvement. Pulmonary involvement is the most prominent. In fact, a pneumonitis plus eosinophilia warrants consideration of this syndrome and a search for evidence of systemic vasculitis elsewhere.1 In addition to asthma and eosinophilia, a dermato-pulmonary-renal syndrome is the feature of this disease. Mononeuritis multiplex is common.
* Fever
* Skin involvement (60%)
o Leukocytoclastic angiitis with palpable purpura
o Livedo reticularis, skin necrosis and gangrene, digital ischemia, urticaria, and subcutaneous nodules
The skin rashes of Churg-Strauss syndrome. The bi...
The skin rashes of Churg-Strauss syndrome. The biopsy of this rash showed eosinophilic leukocytoclastic angiitis with poorly formed granulomas.
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The skin rashes of Churg-Strauss syndrome. The bi...
The skin rashes of Churg-Strauss syndrome. The biopsy of this rash showed eosinophilic leukocytoclastic angiitis with poorly formed granulomas.
* Upper respiratory involvement
o Allergic rhinitis
o Paranasal sinusitis
o Nasal polyposis
* Lower respiratory system physical findings related to the following:
o Asthma (ie, wheeze), expiratory rhonchi
o Pneumonitis
o Hemoptysis secondary to pulmonary alveolar hemorrhage (alveolar capillaritis)
* Cardiovascular system
o Myocarditis and signs related to heart failure
o Myocardial infarction secondary to coronary vasculitis
* Renal system
o Hypertension
o Signs of uremia and advanced renal failure
* Gastrointestinal system
o GI bleeding
o Bowel ischemia and perforation
o Gastroenteritis
o Appendicitis
o Pancreatitis
* Nervous system
o Peripheral neuropathy (includes mononeuritis multiplex [77%])
o Central nervous system (includes stroke [5%])
Causes
Causes of Churg-Strauss syndrome are unknown.7 Churg-Strauss syndrome is possibly an allergic or autoimmune reaction to an environmental agent or drug.
Several case reports have described drug-induced forms of Churg-Strauss syndrome. Mesalazine-induced Churg-Strauss syndrome has been reported in a patient with Crohn disease and sclerosing cholangitis16 ; 4 publications have addressed the association between propylthiouracil, methimazole, and vasculitides, including Churg-Strauss syndrome. One report is available on the association of freebase cocaine and Churg-Strauss syndrome.Differential Diagnoses
Acute Mesenteric Ischemia
Goodpasture Syndrome
Antiglomerular Basement Membrane Disease
Hypereosinophilic Syndrome
Asthma
Infective Endocarditis
Cryoglobulinemia
Leukocytoclastic Vasculitis
Eosinophilia
Microscopic Polyangiitis
Eosinophilic Gastroenteritis
Pneumonia, Bacterial
Eosinophilic Pneumonia
Polyarteritis Nodosa
Glomerulonephritis, Crescentic
Wegener Granulomatosis
Other Problems to Be Considered
Segmental glomerulonephritis
Acute nephritis
Allergic bronchopulmonary aspergillosis
Asthma
Other vasculitis syndromes (including Wegener granulomatosis)
Medication-induced eosinophilia
Other causes of pulmonary infiltration with eosinophilia (PIE)
Workup
Laboratory Studies
* Hematology
o Eosinophilia, usually at least 10% eosinophils (or 5000-9000 eosinophils/µL)
o Anemia
* Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels
* Renal tests
o Elevated serum BUN and creatinine levels in cases of renal involvement
o Abnormal urine sediment, proteinuria, microscopic hematuria, and RBC casts
* Antineutrophil cytoplasmic antibodies: ANCA is present in approximately 40% of patients with Churg-Strauss syndrome (CSS). Most of these patients are perinuclear-ANCA (p-ANCA)–positive (antimyeloperoxidase antibodies).18
* Elevated serum IgE levels
* Hypergammaglobulinemia
* Positive results for rheumatoid factor at low titer
* Other immunologic tests
o Levels of eosinophil cationic protein (ECP), soluble interleukin-2 receptor (sIL-2R), and soluble thrombomodulin (sTM), which is a marker of endothelial cell damage, are elevated.
o Elevated sIL-2R and ECP levels in Churg-Strauss syndrome indicate an immunoregulatory defect associated with vasculitis and eosinophilia.
* Eosinophilia in bronchioalveolar lavage (BAL), evident in 33% of cases
Imaging Studies
* Chest radiography19,20
o Pulmonary opacities can be found in 26%-77% of cases of Churg-Strauss syndrome, and films demonstrate no abnormalities in approximately 25% of patients.20
o Localized parenchymal opacities usually are bilateral, peripheral, and patchy.
o Cavitation is rare.
o Pulmonary infiltrates may be transient. Occasionally, infiltrates are similar to those observed in patients with chronic eosinophilic pneumonia, or they may be nodular.
Transient pulmonary infiltrates in a patient with...
Transient pulmonary infiltrates in a patient with Churg-Strauss syndrome (CSS).
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Transient pulmonary infiltrates in a patient with...
Transient pulmonary infiltrates in a patient with Churg-Strauss syndrome (CSS).
o Extensive air-space opacities in the setting of a drop in hemoglobin levels suggest massive intra-alveolar hemorrhage as a result of pulmonary alveolar capillaritis. Hemoptysis is present in only 45%-66% of cases.
o Pleural effusions are observed in 5%-30% of cases and can be eosinophilic.
o Hilar nodal enlargement has occasionally been reported.
* CT scanning21,22
o In the limited number of patients with Churg-Strauss syndrome studied with CT scanning, findings include peripheral areas of parenchymal consolidation with ground-glass attenuation similar to that of chronic eosinophilic pneumonia.
o Much less commonly, parenchymal nodules (from 5 mm to 3.5 cm), with cavitation or air bronchograms, can be observed.
o Bronchial dilatation and bronchial wall thickening may also be visible.
o High-resolution CT scanning of chest produces findings that include significant enlargement of peripheral pulmonary arteries with stellate and irregular configuration—a vasculitis pattern.
* Other imaging studies are indicated for the complications of the disease and specific organ-system involvement, including abdominal CT scanning for pancreatitis, coronary angiography for myocardial ischemia and infarction, and echocardiography for congestive heart failure (CHF).
Other Tests
* The following tests are for specific organ-system involvement:
o ECG for cardiac manifestations
o Gastrointestinal endoscopy for GI bleeding
o Electromyelography (EMG) and nerve conduction studies for peripheral neuropathies
Procedures
* Biopsy: If local organ involvement exists, obtaining a biopsy of that organ is most helpful in confirming the diagnosis. However, if no localizing finding exists, obtaining nerve or muscle biopsy may be considered. Sural nerve biopsy is the most feasible procedure. In the case of renal involvement, kidney biopsy results may show focal or crescentic glomerulonephritis; however, this pathological change is consistent with, but not diagnostic of, Churg-Strauss syndrome.
o Skin
o Lung - Open or video-assisted thoracoscopic biopsy preferred over transbronchial
o Renal
o Nerve
o Muscle
Histologic Findings
The characteristic pathologic changes in Churg-Strauss syndrome, found especially in the lung,23,24 include small necrotizing granulomas, as well as necrotizing vasculitis involving small arteries and venules. The granulomas are composed of a central eosinophilic core surrounded radially by macrophages and epithelioid giant cells. Churg-Strauss syndrome affects medium- and small-sized vessels.
Glomerulonephritis is not as common or severe as in Wegener granulomatosis, but, when present, it is usually focal and segmental and indistinguishable from other forms of so-called pauci-immune (without significant tissue deposition of immune complexes) glomerulonephritis.25,26
Eosinophilic granuloma in a patient with Churg-St...
Eosinophilic granuloma in a patient with Churg-Strauss syndrome (CSS)Treatment
Medical Care
Churg-Strauss syndrome (CSS) is a systemic vasculitis that involves multiple organ systems; the type of support and care depends on the type of organ system involvement.
Consultations
* Consultation with a rheumatologist
* Specific organ-system involvement may require the following:
o Consultation with a pulmonologist for the management of hemoptysis and respiratory failure secondary to pulmonary alveolar capillaritis
o Consultation with a cardiologist for management of myocardial infarction, myocarditis, and heart failure
o Consultation with a nephrologist for the management of renal failure
o Consultations with a gastroenterologist and neurologist
Diet
Adjust nutritional requirements according to the particular clinical situation (eg, renal failure, heart failure).
Medication
Glucocorticoids alone are usually adequate for the treatment of Churg-Strauss syndrome (CSS).27,28 Cytotoxic drugs are necessary in fewer than 20% of patients. Case reports have described infliximab therapy in patients with steroid-dependent Churg-Strauss syndrome. Major life-threatening organ involvement may require treatment with pulse doses of intravenous corticosteroids and other cytotoxic agents. Cyclophosphamide is typically given in intravenous pulses for 3 months; afterward, patients are converted to either oral mycophenolate or azathioprine.
Other treatments include intravenous immune globulin, interferon alpha, rituximab, and plasma exchange. Plasma exchange, which has not improved the course of the disease, has been used but has not added benefit to the treatment of patients who were treated with prednisone or cyclophosphamide. This is based on a meta-analysis of 140 patients with glomerulonephritis and Churg-Strauss syndrome and microscopic polyangiitis. One case report is available on intravenous immune globulin for treatment of Churg-Strauss syndrome in pregnancy.29
The laboratory tests that might correlate with disease activity include ESR and peripheral blood eosinophilia. In some patients, ANCA titers are related to disease activity.
Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the immune response to diverse stimuli.
Prednisone (Deltasone, Orasone, Sterapred)
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Oral prednisone is usually sufficient to control disease activity.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
0.5-1.5 mg/kg/d or 40-60 mg/d PO, taper over 6-12 wk as symptoms resolve; long-term low doses may be required indefinitely
Pediatric
0.5-1 mg/kg/d PO initially and taper as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with estrogens or ketoconazole may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, aminoglutethimide, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; increases toxicity of anticoagulants and theophylline; cholestyramine decreases effects; decreases effect of salicylates
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; severe bacterial, viral, or fungal infection; peptic ulcer disease; diabetes mellitus
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Observe patients for weight increase, edema, hypertension, and excessive potassium excretion; abrupt discontinuation of glucocorticoids may cause adrenal crisis; monitor for negative nitrogen balance resulting from protein catabolism; other symptoms may include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis
Cytotoxic agents
These agents inhibit cell growth and proliferation. They are reserved for cases resistant to corticosteroids.
Cyclophosphamide (Cytoxan, Neosar)
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which interferes with growth of rapidly proliferating cells.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1-2 mg/kg/d PO
May also be administered in pulsed doses of 500-1000 mg/m2 IV qmo
Dose is adjusted according to clinical response, hematologic response, and toxicity
Single IV dose of 500 mg/m2 in patients with normal renal function and 350 mg/m2 in patients with CrCl of <10 is an alternative option for the short-term management of life-threatening events, including alveolar hemorrhage or gastrointestinal bleeding
Pediatric
Administer as in adultsFollow-up
Further Inpatient Care
* Churg-Strauss syndrome (CSS) cases must be followed up very closely at a rheumatology clinic or another specialty clinic. Patients with this syndrome usually need long-term immunosuppressive medications.
* The patient's clinical status, ESR, and eosinophilia should be monitored. The ANCA level does not correlate well with disease activity.30
Inpatient & Outpatient Medications
* Inpatient medications include the following:
o Prednisone: Start at 0.5-1 mg/kg/d PO.
o Methylprednisolone is administered in intravenous form at higher doses in the presence of major organ involvement, including cardiac, pulmonary (hemorrhage), renal, or neuropathy.
o Cyclophosphamide is administered in patients with severe or life-threatening complications.31,32 The single intravenous dose is 500 mg/m2 of body-surface area. The dose should be reduced in patients with renal failure.
o Other medications include azathioprine, mycophenolate mofetil, and intravenous immune globulin administered in similar fashion as it is used in microscopic polyangiitis or Wegener granulomatosis.33
o Plasmapheresis is probably not helpful.34
o Interferon alpha might be helpful in treatment.35,36
Complications
* Complications of vasculitis depend on the specific organ system involvement.
Prognosis
* Overall, without treatment, the 5-year survival rate in Churg-Strauss syndrome is about 25%.
* With treatment, the 1-year survival rate is 90% and the 5-year survival rate is 62%.
* Causes of death associated with Churg-Strauss syndrome include the following:
o Cardiac failure, myocardial infarction, or both (most common cause)
o Renal failure
o Cerebral hemorrhage
o Gastrointestinal bleeding
o Status asthmaticus
Miscellaneous
Medicolegal Pitfalls
* In all syndromes of vasculitis that involve medium- and small-sized vessels, including Churg-Strauss syndrome (CSS), recognizing the severity of the disease and avoiding overtreatment or undertreatment is prudent.
* Treatment with cyclophosphamide is associated with major adverse effects, including transitional cell carcinoma of the bladder, which should be considered in choosing the treatment plan.
