Churg-Strauss Disease 

Churg-Strauss disease (CSD) is one of three important fibrinoid, necrotizing, inflammatory leukocytoclastic systemic small-vessel vasculitides that are associated with antineutrophil cytoplasm antibodies (ANCAs). Of these three conditions, Churg-Strauss disease is the least commonly encountered. The others are Wegener granulomatosis (WG) and microscopic polyangiitis (MPA). Although these conditions are not thought to be directly infectious, microbial superantigens may play a role in provoking the onset of the dysregulated immune response that gives rise to these conditions.^[1]

Sir William Osler possibly described the clinical aspects of Churg-Strauss disease in 1900. However, it was not until 1951 that Jacob Churg and Lotte Strauss of Sweden clearly identified the clinical and pathological findings as representative of a distinct entity, setting it apart from polyarteritis nodosa (PAN). They reported 13 individuals who initially manifested severe asthma and subsequently developed fever, eosinophilia, cardiac and renal failure, and peripheral neuropathy.^[2] Most also developed pulmonary infiltrates, sinusitis, hypertension, abdominal pain, bloody diarrhea, and skin changes including purpura and subcutaneous nodules. That 11 of the 13 individuals described by Churg and Strauss in their 1951 paper had died of Churg-Strauss disease is not surprising since corticosteroids were only introduced into medical practice in 1951 and did not become readily available for use in medicine until suitable synthetic preparations were prepared.

Because most of the individuals they described had died, Churg and Strauss concentrated particular attention on the distinctive histologic features of CSD. Chumbley and associates used the criteria of Churg and Strauss in their Mayo Clinic series.^[3]

Subsequent attempts to refine diagnostic criteria have incorporated more clinical features.^{[4, 5, 6]} The fact that 3 or more sets of criteria are in existence reflect the fact that no single clinical feature is pathognomonic and no discrete measurable biological marker has been identified for this condition. As noted, histologic distinction of Churg-Strauss from a condition that it closely resembled clinically, polyarteritis nodosa (PAN), was particularly important in establishing CSD as a discrete entity. Pathological investigation has established that PAN predominantly affects both medium-sized blood vessels and some small arteries, though it tends to spare capillaries, arterioles, and venules. This tendency is shared with Kawasaki disease.

Churg-Strauss disease chiefly affects small vessels (capillaries, venules, arterioles) by the development of eosinophil-rich granulomatous inflammation of the respiratory tract and small vessels.^[6] However, Lie^[7] has emphasized the fact that Churg-Strauss disease (and for that matter WG and MPA) may not be restricted to small-vessel vasculitis, a histological fact that is also acknowledged in the Jennette et al^[6] "international consensus criteria", which state that CSD, WG, and MPA may involve the medium-sized vessels that are more characteristic targets of PAN.

The identification of antineutrophil cytoplasmic antibodies (ANCA)^[1] provided a sensitive, although nonspecific, marker for a particular group of systemic vasculitides including CSD. ANCA with a cytoplasmic staining pattern (cANCA), largely specific for the immunogenic epitopes of antiproteinase 3, was shown to have 98% sensitivity and high specificity for active clinically identified cases of Wegener granulomatosis.^[8] ANCA with a perinuclear staining pattern (pANCA) was also identified and shown to have antigenic specificity for epitopes expressed by myeloperoxidase (MPO) as well as other possible epitopes. pANCA is an important marker for CSD,^{[9, 10]} though not as specific as cANCA is for WG. pANCA may also be found in WG, MPA, and PAN.^{[8, 9, 11, 10]}

ANCA provides considerable value in supporting the diagnosis of clinically classified ANCA-related illnesses. Thus, for example, the finding of pANCA in a systemic vasculitic condition arising initially as an asthmatic condition and found to also manifest tissue and blood eosinophilia makes a strong case for the diagnosis of CSD (which invariably involves the lungs).

CSD also has a reasonably characteristic disease evolution, and histologic demonstration of the distinctive pattern of eosinophilic vasculitis of small and some medium-sized vessels results in an even more secure diagnosis. Nonetheless, note that occasional examples of diseases that straddle the boundaries between PAN, WG, MPA, and Churg-Strauss disease are encountered for which it is difficult with certainty which label is most appropriate. For this reason, a recent classification system by Watts and Scott combined these particular entities under the general heading primary systemic vasculitides.^[12]

ANCA assays have an even more definitive role in distinguishing the ANCA-related vasculitides from non-ANCA immune complex–associated small-vessel vasculitides such as Schönlein-Henoch purpura (SHP), essential cryoglobulinemic vasculitis (ECV), lupus vasculitis, serum sickness vasculitis, and infection-induced immune complex vasculitis. Churg-Strauss disease also has considerable overlap with idiopathic hypereosinophilic syndrome. In such instances, the distinction of Churg-Strauss from these various other conditions, particularly those that share ANCA positivity, is usually made on the basis of prodromal asthma indicative of Churg-Strauss disease. In instances where the kidney is involved, ANCA-positive vasculitides also share, in distinction to other small-vessel vasculitides, the presence of pauci-immune crescentic glomerulonephritis.

Idiopathic hypereosinophilic syndrome (IHES) closely resembles Churg-Strauss disease, differing particularly in that the prodromal asthmatic phase is absent. IHES is defined by (1) peripheral eosinophil count greater than 1500/µL for at least 6 months, (2) evidence of characteristic organ involvement, and (3) absence of other known cause. It affects men aged 20-50 years.

The initial manifestations of IHES are cardiac, consisting of eosinophilic myocarditis with endocardial damage and confirmed by endomyocardial biopsy. Restrictive cardiomyopathy may ensue as thrombosis develops, promoted by the damaged endocardial surface. Fibrosis then occurs. Mitral or tricuspid incompetence may develop as a result of fibrotic degeneration of the chordae tendineae. In some instances, dilated cardiomyopathy develops.

Cardioembolic disease in IHES may produce neurologic manifestations, but a primary encephalopathy has also been described. Sensory or mixed sensorimotor peripheral polyneuropathy, closely resembling that found in Churg-Strauss disease, may develop in a symmetrical or asymmetrical distribution. Mononeuropathy multiplex may also develop. Although prodromal asthma is not a feature, as many as 40% of patients with IHES manifest a persistent, dry cough at some stage of illness. Pulmonary dysfunction may result from cardiac failure or cardiogenic pulmonary embolism.

Pulmonary infiltrates may be found in as many as 30% of cases of IHES, tending not to be peripheral. Parenchymal eosinophilic infiltration may be found and, rarely, eosinophilic pleural effusions develop. Diarrhea complicates about 20% of cases, while eosinophilic gastritis, enteritis, or colitis occasionally has been reported. Dermatologic manifestations may include urticaria, angioedema, or erythematous pruritic papules and nodules. Raynaud phenomenon, arthralgias, or joint effusions are occasional complications.

The pathophysiology of Churg-Strauss disease, particularly the triggering circumstances, is not well understood. In their original description of ANCAs, Daives and associates^[1] suggested that arboviral infection-related superantigens might stimulate the production of ANCAs that attacked host tissues because of molecular mimicry or some other abnormality of immune tolerance. Triggering of these vasculitides by infection has remained a pathophysiological consideration.^[13] ANCAs in part mediate vascular endothelial injury in Churg-Strauss disease, as they do in PAN, MPA, and WG. In these various conditions, ANCAs may promote polymorphonuclear (PMN) cell adherence to vascular endothelial cells, with ensuing lytic vascular endothelial injury. An independent or adjuvant role in this activation may be played by tumor necrosis factor (TNF).

Studies of affected peripheral nerve tissues show that once the stage of epineural necrotic vasculitis has been achieved, activated cytotoxic T-lymphocyte clones (CD8⁺ suppressor and cytotoxic and CD4⁺ helper cells) begin to outnumber eosinophils and predominate in the inflammatory exudate. Occasionally, CD20⁺ B lymphocytes are found in the inflammatory exudate, and less prominent deposits of immunoglobulin (IgG), immunoglobulin E (IgE), and C3d antibodies may also be detected.

Cytokines undoubtedly participate in this autoimmune process. Patients with CSD have markedly increased serum levels of interferon alpha and interleukin 2 (IL-2) and moderate increases of TNF-alpha and interleukin 1 beta (IL-1beta) similar to those observed in PAN. Elevations of serum interleukin 6 (IL-6) concentrations have been shown to precede the rise in serum rheumatoid factors that may accompany the onset of an exacerbation of Churg-Strauss vasculitis. Thus, IL-6 may be an important triggering factor. The rheumatoid factors are chiefly of IgG and immunoglobulin M (IgM) classes, rather than immunoglobulin A (IgA) or IgE.

Typically (approximately 70% of clinically ascertained cases), pANCAs (directed against myeloperoxidase) are found in patients with Churg-Strauss disease. These perinuclear deposits appear as azurophilic granules. pANCA titers in individuals with CSD have been shown to correlate with disease severity; falling titers have been used as indicators of the success or failure of immunosuppressive treatments and, conversely, rising titers have been regarded as indicative of disease exacerbation.^[14]

Antibodies with this pattern of staining and similar antigenic specificity are also found in the uncertainly classified entity microscopic polyangiitis (MPA). Recent work suggests that a mutation in exon 11 of the CD18 gene may be permissive of the elaboration of antimyeloperoxidase antibodies in either of these 2 conditions.

In Wegener granulomatosis, on the other hand, the presence of cANCAs with antigenic specificity for proteinase-3 is characteristic. A case of one patient with pANCAs directed against myeloperoxidase and cANCAs against proteinase-3 has been reported; the patient manifested a combination of clinical characteristics suggesting both Churg-Strauss disease and temporal arteritis.

These immunologic disturbances may provoke the translocation of proteinase-3 from within the azurophilic granules of PMN cells to the surface of the cell membrane. The attachment of PMN cells to the endothelial surface likely is enhanced by cytokine-mediated induction of adhesion molecules (eg, lymphocyte function-associated protein 1, IL adhesion molecule 1, endothelial-leukocyte adhesion molecule 1). Anti-endothelial cell antibodies, detectable in many different primary vasculitic conditions as well as in systemic autoimmune disease with a vasculitic component, may play a role in Churg-Strauss disease.

Abnormal expression of CD95 cellular receptors (producing a soluble splice variant rather than the usual membrane-bound isoform) may participate in the pathogenesis of Churg-Strauss disease. The result is impairment of normal apoptotic processes whereby lymphocytes and eosinophils are eliminated. This permits abnormal oligoclonal expansion of specific T-cell clones, which may mediate cellular injury. The soluble CD95 isoform has been termed eosinophil survival factor.

CSD onset has been associated with immunotherapy for asthma in epidemiologic studies. Immunization with allergen extracts has been suggested to provoke onset of CSD. A particularly important form of immunotherapy in asthma has been the use of drugs designed to reduce leukotriene-mediated airway obstruction.^{[15, 16, 17]} Onset of CSD after the use of antileukotrienes for the treatment of asthma has suggested that these agents may provoke an idiosyncratic drug-induced form of CSD. In particular, an association has been detected with the use of cysteinyl leukotriene receptor type-1 (CysLT1) antagonists (eg, zafirlukast, pranlukast, montelukast) and onset of CSD.^[18] However, some authorities appear to regard this association as the result of the "unmasking" of preexisting CSD, as the introduction of leukotriene inhibitors permits corticosteroid doses to be reduced.^{[19, 18, 20, 17, 21, 22]}

On the other hand, zafirlukast treatment has been associated with idiosyncratic development of drug-induced lupus; hence, a primary role for such agents in induction of CSD must also be considered.^[23] Despite some continued degree of etiologic uncertainty, it can be said that it remains particularly important to consider unmasked CSD as the underlying cause of CSD-related deterioration in patients with severe asthma undergoing steroid dosage-reduction during a period of antileukotriene therapy–associated improvement in pulmonary disease.

Antiasthmatic agents, such as beclomethasone, cromolyn sodium, or other drugs, may provoke pulmonary eosinophilia. However, it is important to carefully distinguish pulmonary eosinophilia from CSD. Pulmonary disease with eosinophilia has been associated with the use of crack-cocaine.^{[24, 25]}

Pathology

Unlike most noninfectious vasculitides, Churg-Strauss disease is fairly distinctive in its pathology, owing to the abundance of eosinophils in the inflammatory perivenular exudate. However, CSD is a condition with a wide variety of presentations and associated signs and symptoms and other entities may provoke eosinophilic vasculitis. Therefore, CSD remains a clinicopathologic rather than a histopathologic entity.

Eosinophilic infiltration of the upper respiratory tracts and lungs is the most common finding in CSD, while similar infiltrative pathology is also often found in the gastrointestinal tract. The infiltrative appearance may change into eosinophilic vasculitis with worsening disease. Such clinical manifestations as weight loss, fever, and myalgia are common diagnostic clues to the possibility that CSD is in evolution. These manifestations are found in more than half of all individuals with CSD. Sinusitis has similar prevalence. The characteristic vasculopathy of CSD is predominantly an arteriopathy, tending to affect small- and medium-sized arteries much more than arterioles, veins, or capillaries. This predilection is also found in PAN and some other conditions. However, the predominance of eosinophils sets CSD apart from these other conditions. Epithelioid and giant cells are also found in the inflammatory exudate of patients with CSD.

The inflammatory arteriopathy evolves into granulomatous fibrinoid necrosis of the vascular media. The result of this process includes the development of collagenolytic or necrobiotic noninfectious granulomata. The granulomatous material surrounds altered vascular elastic fibers and collagen as well as acellular pigmented debris, which is helpful in pathologically distinguishing one form of granulomatous vasculitis from another. CSD is associated with "red" collagenolytic granulomas.

The lungs are the chief organs involved in patients with Churg-Strauss vasculopathy, and they almost invariably develop regions of angiopathy as the disease progresses. In a series of 96 individuals with CSD, asthma was the first evidence of CSD in 92%; one third developed asthma severe enough to require oral corticosteroid administration.^[26] Typical manifestations include granuloma formation, which occurs within vascular walls and in adjacent pulmonary tissues. Similar angiopathic changes develop in the heart (approximately 85%), skin (70%), peripheral nervous system (66%), central nervous system (60%), kidneys (40%), gastrointestinal tract (40%), and musculoskeletal system (20%).

Vasculitic involvement of the heart was found in as many as 85% of cases described in early reports, typically manifesting as low-output congestive cardiac failure. However, myocardial involvement (which was associated with poor prognosis) was identified in only 14% of the large series of patients with CSD reported by Guillevin et al.^[26] Churg-Straus disease should be considered in adults with asthma and eosinophilia who develop chest pain, shortness of breath, and cardiogenic shock.^[27]

• Cardiac evaluation may demonstrate eosinophilic pericarditis, cardiomegaly, restrictive cardiomyopathy/perimyocarditis, diminished myocardial contractility due to myocardial or endocardial eosinophilic vasculitis or associated tissue infarction. These changes and pericardial effusion are important prognostic factors that obviously bear upon the degree and time course of CSD-associated heart failure.
• Both systolic and diastolic dysfunction may be discerned.
• Steady decline in myocardial shortening fraction often follows.
• Heart failure is an important cause of death in Churg-Strauss disease and is a major determinant of prognosis. In the series by Guillevin et al, 8% of patients with CSD died from cardiac disease in the acute phase of the illness.^[26]

Skin and nervous tissues are the systems next most commonly involved in patients with Churg-Strauss disease.

• The skin is involved in 65-70% of cases that have progressed to the systemic vasculitic phase. The pathology most commonly encountered in skin biopsies is small-vessel leukocytoclastic vasculitis with ensuing blood vessel necrosis of either small or large vessels. The cutaneous vasculopathy may be associated with the development of purpura, nodules, or areas of infarction. Similar pathological changes account for mononeuropathy multiplex and myositis due to CSD and are also found in kidneys if glomerulonephritis develops.
• Eosinophilic granulomatous changes in the gallbladder wall may result in obstructive jaundice or pain and require cholecystectomy.^[28]
• Approximately 64-80% of patients in the systemic phase of Churg-Strauss disease develop peripheral neuropathy, usually in the pattern of mononeuritis multiplex.^[26] Mononeuritis multiplex is the second most common initial manifestation of systemic vasculitis in adults with Churg-Strauss disease.
• Initial mononeuritic findings often progress to asymmetrical polyneuropathy, which is restricted to the limbs. As with PAN, both motor and sensory deficits are detectable, especially in the legs; thus, the sciatic nerves (including peroneal and tibial branches) are involved more frequently than radial, median, or cubital nerves.
• Sensory disturbances may include hypoesthesia or hyperesthesia, allodynia, and pain.
• Polyneuropathy may regress with treatment.
• Vasculitis of muscle develops in slightly more than 20% of patients.

Approximately 60% of adults with Churg-Strauss disease develop CNS vasculitis. This is unlike PAN, in which CNS manifestations are rare. However, CNS vasculitis has not been reported in children with Churg-Strauss disease. It does occur in adolescents, albeit rarely.

• Manifestations include intellectual and motor disturbances. These may be abrupt in onset, and seizures may occur.
• Acute cerebral hemorrhage is among the important causes of sudden death in Churg-Strauss disease. In some but not all instances, hemorrhage occurs in individuals who have hypertension.

Gastrointestinal dysfunction develops in 30-60% of individuals with CSD (prevalence higher in earlier series than in more recent case series). Most commonly, this takes the form of mesenteric vasculitis, similar to that seen in PAN. The most common manifestations are bloody diarrhea and abdominal pain.

Arteritis of medium-sized blood vessels of the kidneys develops in 20-50% of cases. However, hypertension is less common in Churg-Strauss disease than in PAN.

• As in PAN, the predominant renal pathology is eosinophilic interstitial pauci-immune segmental glomerulonephritis.^[28]
• Crescentic necrotic glomerulopathy may develop in some instances, as is also found in microscopic polyangiitis.
• IgA glomerulonephropathy may develop, as also is the case in microscopic polyangiitis, but rarely. This is a pathological change that is more typical of Schönlein-Henoch purpura.
• In early reports of Churg-Strauss disease, uremia was an occasional cause of death. Current management has considerably reduced the risk of uremia, and, in most cases of Churg-Strauss disease, renal involvement is mild. Even if the renal involvement is severe, renal disease usually responds well to corticosteroid treatment.

Testicular pain, with or without epididymitis, may occur in men with Churg-Strauss disease.

Frequency

United States

Churg-Strauss disease is said to account for slightly more than 2% of all vasculitic illnesses. The various primary systemic vasculitides (Churg-Strauss disease, PAN, microscopic polyangiitis, Wegener granulomatosis) together are estimated by Watts et al to affect 15-25 individuals per million individuals in North America annually.^[12]

International

Little information is available concerning international variation in the prevalence or incidence of Churg-Strauss disease.

Mortality/Morbidity

• Most (85%) of the index cases reported by Churg and Strauss in 1951 had died from their illness. The development of effective strategies for treatment in ensuing decades (particularly oral corticosteroids) has improved survival considerably, though the disease remains a serious one. To some extent, improved survival may relate to recognition of milder cases. The 5-year survival rate reported in the 30 patient series of CSD that Chumbley and associates reported in 1977 was 62%.^[3] In 1999, Guillevin and associates reported a 72% 6-year survival rate in a series of 96 patients with CSD.^[26] Elderly patients may have as much as 50% greater risk of death from their CSD and compared to middle-aged or young individuals with this disease.^[29]
• Morbidity is chiefly cardiopulmonary. Painful arthritis, arthralgia, neuritis, and myalgia are common troublesome and recurrent manifestations. Abdominal pain, diarrhea, gastrointestinal bleeding, and bowel perforation are less common but important complications. Necrotizing glomerulonephritis occurs in fewer than half of patients. It tends to affect older patients, who as a group have particularly poor outcomes. Early diagnosis of this renal complication improves outcome.^[30] Leukopenia due to immunosuppressive therapy enhances risk for sepsis and death and therefore should be avoided.^[30] The chief neurologic morbidity is, as in PAN, peripheral neuropathy.
• The chief causes of mortality related to Churg-Strauss disease are severe asthma, cardiopulmonary failure, or gastrointestinal complications. In general, the long-term outcome of Churg-Strauss disease does not differ greatly from that of PAN. In addition to overall severity of CSD, both myocardial disease and severe gastrointestinal disease were found by Guillevin et al to be independent predictors of poor prognosis.^[26]

Race

Few data are available regarding racial variations in occurrence or severity of Churg-Strauss disease. In some studies, no racial predilection has been suggested; in others, without clear documentation, it has been suggested that Churg-Strauss disease shares with other systemic vasculitides (eg, Wegener granulomatosis) a tendency toward greater prevalence in whites or individuals of Nordic ancestry.^[29] Clearly additional data are necessary, using data of greater refinement entailing the casting of a wide socioeconomic and geographic net and greater precision in characterizing populations at risk than what may be based upon such tentative and possibly irrelevant indirect genetic markers as skin pigmentation. Nonetheless, there is some support in selected diseases for the notion that disease prevalence or severity for certain autoimmune conditions may be greater in individuals with heavier skin pigmentation.

Sex

As with a number of other primary systemic vasculitides, males are slightly more likely than females to develop Churg-Strauss disease. The male-to-female ratio for Churg-Strauss disease is estimated by some to be approximately 1.4:1, similar to the sex-related risk ratio for the combined class of Churg-Strauss disease, PAN, microscopic polyangiitis, and Wegener granulomatosis.

A higher risk ratio for males is found for one of the important differential considerations, hypereosinophilic syndrome (HES). HES is likely a heterogeneous collection of very severe diseases that are very rare and tend to occur in persons aged 20-50 years, with a male-to-female ratio of 9:1. It is not linked with asthma, but pulmonary disease may be found particularly on the basis of cardiac disease or pulmonary embolization.

Age

Most individuals with Churg-Strauss disease experience the onset of disease in the age range of 15-69 years. Peak risk for vasculitic manifestations is in the middle of the fourth decade of life. Thus, the vasculitic stages of Churg-Strauss disease tend to develop at earlier ages than other primary systemic vasculitides, for which the average age of occurrence is about 60-65 years.

• Churg-Strauss disease is chiefly a disease of adults, occurring in individuals with adult-onset asthma. The vasculitic stages of Churg-Strauss disease seldom, if ever, manifest in small children, although they may in teenagers. On the other hand, the premonitory asthmatic stage of Churg-Strauss disease may manifest in children as young as 3 years.
• Although occurrence of the subsequent vascular stages of illness has been regarded as rare even in adolescents, some data suggest that as many as 20% of patients may manifest vasculitic findings in the second decade of life, often preceded by bronchial asthma during the first decade.
• Childhood-onset Churg-Strauss disease is less likely to be complicated by central nervous system vasculitis than cases that develop in middle-aged individuals.