Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)

Etiology

In recent years, there have been efforts to sub-classify clinical phenotypes of eosinophilic granulomatosis with polyangiitis based on the presence or absence of vasculitis, somewhat counterintuitive to the nomenclature itself.[4]

Patients who are ANCA positive (reported around 40% of all patients with EGPA) tend to have a vasculitic phenotype and are more common to have myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement either as crescentic or necrotizing glomerulonephritis.

Conversely, patients without ANCA positivity tend to have an eosinophilic phenotype with a higher incidence of myocarditis.

The presence of ANCA alone, however, is not the absolute correlate to vasculitis. About 47% of patients in a study by Cottin et al. had vasculitis without seropositivity for ANCA, while 29% were positive for myeloperoxidase ANCA without the presence of vasculitis. 

About 41% of patients in the same series by Cottin et al.[5] did not have vasculitis but rather an eosinophilic tissue infiltrate and involvement.

They, therefore, suggested isolating and recognizing a subgroup with features of vasculitis to be defined here.

Vasculitic Phenotype

Definitive vasculitis features

• Biopsy-proven necrotizing vasculitis of any organ
• Biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis
• Palpable purpura
• Alveolar hemorrhage
• Coronary arteritis causing myocardial infarction

Surrogates of vasculitis

• Hematuria with red casts greater than 10%, dysmorphic RBC, and/or 2+ protein
• Leukocytoclastic capillaritis

Mononeuritis

Presence of ANCA

The rest of the patients will fall into the eosinophilic asthma phenotype. It is important to recognize that subgroup early, particularly in the presence of myocarditis with no other evidence of vasculitis. Overly depending on the presence of vasculitis to diagnose EGPA may result in missing those patients with eosinophilic asthma who may otherwise benefit from early targeted therapy.

The primary trigger in pathogenesis at the cellular level seems to be an aberrant T-helper cell pathway.

Role of the Th2 Cell Lineage

There have been various theories about what prompts an abnormal Th-2 type immune response in the first place. Allergies, infections, medications have all been considered. The allergy theory has not been substantiated despite a high prevalence of IgE levels, as studies show that hypersensitivity to currently tested allergens is present only in 30% of CSS cases. Rolla et al. suggested a superantigen theory in CSS, which activated the oligoclonal expansion of certain T cell subsets[6]. There has also been some evidence of colonization of airways with Aspergillus or Actinomyces. Several medications have also been reported, including sulfonamides, macrolide, and diphenylhydantoin.[7][8][9][10][11][12] However, none of them has been as strong as a possible association between the onset of EGPA and the use of leukotriene inhibitors montelukast and zafirlukast. Bibby et al. reviewed the USFDA database from 1996 to 2003 to report 181 cases of EGPA  in which a pharmacological trigger was suspected. 90% involved leukotriene receptor antagonists. Although some argue that it could merely be the unmasking of disease following the ability to wean off steroids in severe asthma after initiation of leukotriene inhibitors.[13]

The pathogenic role of T cells in the aberrant immune response of this disease has been further proven by the presence of specific clonally expanded subpopulations of T cells as well as increased frequency of related HLA alleles like HLA- DRB1 04 and HLA-DRB1 07.[14][15] 

There is an increased serum presence of IL-10, which mediates inhibition of Th-1 response, thus tilting the scale towards differentiation of Th2 cells. This phenomenon is particularly common in the ANCA negative phenotype of EGPA.[16]

Epidemiology

The estimated prevalence of the disease is 10.7 to 14 per million adults worldwide. The mean age of onset, as reported, is between 38 to 54 years, with a median of 40. However, it has been reported in extremes of age as well, from as low as 4 to as high as 74. There is no gender difference in incidence.[17]

In contrast to certain small vessel vasculitis with a preponderance in childhood (Henoch-Schonlein purpura, Kawasaki disease), ANCA-associated vasculitis is rare in children. Regardless of age, adult and childhood EGPA both present with highly elevated IgE and eosinophil levels. About 40% of adults have a positive ANCA, while 25% of children are seropositive.

Clinically, however, childhood EGPA has a higher incidence of cardiomyopathy, pneumonic infiltrates with a rarer occurrence of mononeuritis multiplex. A higher prevalence of cardiac disease increases the mortality in childhood EGPA, just as in adult disease.[2]

Pathophysiology

The pathogenesis and clinical phenotype follow a dichotomy of either eosinophil-mediated damage or ANCA-induced endothelial injury.

Eosinophils

An initial TH2-mediated immune response provokes the margination of eosinophils. Eosinophilic presence in active disease is likely a consequence of increased synthesis, enhanced extravasation, and prolonged survival in target tissues. IL-3 and IL-5, produced by TH-2 lymphocytes, are the key regulators in the maturation and release of eosinophils, as well as their survival in blood. Serum levels of IL-5 correlate consistently with disease activity and go down with the initiation of immunosuppressive therapy.[18][19][20] 

When activated by Th-2 type cytokines, Epithelial and endothelial cells also secrete eosinophil-specific chemokines like eotaxin 3(CCL26), CCL17, and CCL22. They act on CCR4 receptors to facilitate the recruitment of eosinophils and effector Th2 cells to the end organs–thus amplifying the immune response.[21][22]  Martorana et al. demonstrated serum levels of CCL26 as a reliable marker for disease activity in CSS.[23]

Eosinophils, in turn, release the cationic proteins like eosinophil cationic protein (ECP), eosinophil peroxidases, eosinophil-derived neurotoxins, and eosinophil granule major basic protein which is directly involved in mediating tissue damage.

Eosinophils also secrete cytokines like IL- 1, IL-3, IL-5, TGF- beta, and vascular endothelial growth factor. IL-5, in turn, plays an active role in the maturation, differentiation, and survival of eosinophils.

Histological findings in EGPA are characterized by eosinophilic infiltrates in walls of small and medium-sized blood vessels and extravascular tissue spaces. In EGPA with acute pulmonary exacerbations, Bronchoalveolar lavage fluid is also rich in eosinophils, similar to acute or chronic eosinophilic pneumonia. Extravascular eosinophilic granulomas are also observed, particularly in the gastrointestinal tract.[24]

IL- 5 is not the only mediator of eosinophilic tissue infiltration, as evidenced by the persistence of tissue  Major Basic Protein (MBP) despite therapy with mepolizumab causing complete downregulation of IL5 titers. IL-4 and IL-13 are two other potent cytokines of Th-2 profile immune response and may play an important role in tissue infiltration and degranulation of eosinophils.[25]

Peripheral blood eosinophils in EGPA express surface markers of activation like CD69 and CD25 along with a concomitant increase in serum IL-5 and ECP.[26][27]

ANCA

Elevated p- ANCA levels with antibodies in a perinuclear pattern are seen in approximately 40% of patients with EGPA. Rarely a cytoplasmic pattern with specificity for neutrophil proteinase 3 (c- ANCA) is seen.

The presence of ANCA correlates with an increased incidence of glomerulonephritis, mononeuritis, and biopsy-proven vasculitis. Alveolar hemorrhage is also found more often in this group of patients.

Infusion of MPO- ANCA in wild-type and Rag2 knockout mice resulted in severe necrotizing and crescentic glomerulonephritis. [28] The 2 subset hypothesis in clinical phenotyping of EGPA has been further substantiated by a recent demonstration of increased frequency of HLA- DRB4 in EGPA patients with ANCA positivity. There has been some recent evidence of the role of Th17 lymphocytes in the occurrence and maintenance of vasculitis response in the disease, particularly regarding the balance between Th17 and Treg cells.[29]

However, endothelial injury in ANCA associated vasculitis is neutrophil-mediated with the generation of reactive oxygen species and proteolytic enzymes from cytoplasmic granules.[30][31][32]

History and Physical

Clinical features of the disease follow 2-pronged themes of eosinophilic tissue infiltration or small and medium vessel vasculitis.

The clinical course is characterized by 3 phases, which do not necessarily always present in every patient. They may even overlap in the natural history of an individual’s disease.

In the initial prodromal phase, nonspecific symptoms of malaise, fever, migrating polyarthralgia, and weight loss are common, along with a severe adult-onset form of asthma that is refractory to conventional treatment. Diffuse myalgia and polyarthralgia have been reported in 37% to 57% of CSS patients, particularly at the onset of disease. Upper respiratory symptoms are more common with chronic rhinosinusitis (47% to 93%) and nasal polyps (62% to 77%). However, nasal granulomas, erosion, and crusting or epistaxis, as seen in GPA, are absent.

The second phase is characterized by eosinophilic infiltrates in end organs along with peripheral eosinophilia. Patchy peripheral nodular pulmonary infiltrates, eosinophilic gastroenteritis, serosal effusion, are common.

An onset of vasculitis characterizes the third phase, and it may take anywhere between 3 to 9 years since the onset of asthma. Neurological symptoms are a hallmark of this phase.

Organ System Involvement

Respiratory and Pulmonary Manifestations

However, variable the clinical manifestations may be, asthma in the prodromal phase seems nearly ubiquitous, reported in 96% to 100% of patients. The mean age of onset of asthma is 35 to 50 years, and it precedes the onset of vasculitis by 3 to 9 years.

There has been some debate about certain asthma medications like leukotriene receptor antagonists, montelukast, and omalizumab precipitating the onset of CSS. However, others believe that they simply help steroid-dependent patients taper off steroids, thereby unmasking the underlying vasculitides successfully.

Patients with Churg-Strauss syndrome tend to present with adult-onset asthma with an eosinophilic phenotype. It is accompanied by rhinitis, sinusitis, and nasal polyposis more often. Chronic rhinitis is the most common extrathoracic manifestation occurring in about 75% of cases.

Asthma is progressive and often ends up being steroid-dependent asthma. Up to 75% of patients require systemic corticosteroid therapy for asthma control before a diagnosis of EGPA is achieved.

Even when other systemic manifestations of the disease are brought under control with therapy, asthma tends to remain uncontrolled, thus detrimentally affecting the quality of life. Apart from upper airway allergic manifestations and eosinophilic asthma, pulmonary manifestations of the disease can also be related to parenchymal eosinophilic infiltration as well as the vasculitic process. During the first 2 clinical phases described, transient pulmonary infiltrates and eosinophilia is common, whereas, in the vasculitic phase, necrotizing vasculitis and granuloma are more common. Alveolar hemorrhage is reported more often in ANCA positive subset, although its incidence is lower than in GPA patients.

Cardiac Disease

Cardiac involvement may be present in 62% of cases, although it is symptomatically manifest in only 26%. It is caused by both mediators released from activated eosinophils and vasculitis lesions in the myocardium and coronary arteries. Myocarditis, in turn, leads to post-inflammatory fibrosis and restrictive cardiomyopathy, followed by congestive cardiac failure. The spectrum of clinical manifestations varies from coronary artery disease, primary arrhythmias, cardiomyopathy, acute constrictive pericarditis and myocarditis, and eosinophilic pericardial effusion. The absence of ANCA and eosinophilia correlates better with cardiac disease.

The use of echocardiography and cardiac MRI has helped detect cardiac abnormalities even beyond an active phase of the disease like nonreversible chronic fibrosis and cardiomyopathy.

Cardiac changes are associated with poor prognosis and high mortality if left untreated.[33]

Gastrointestinal Involvement

Eosinophilic gastroenteritis and mesenteric vasculitis often seem to coincide as far as gastrointestinal tract involvement is concerned. They result in nonspecific symptoms of abdominal pain, nausea, vomiting, and diarrhea to more severe complications like bleeding or intestinal obstruction caused by submucosal nodular masses. Mesenteric vasculitis predisposes to ischemic bowel, mucosal ulceration, and even perforation necessitating exploratory laparotomy. Serosal involvement can cause eosinophilic ascites and peritonitis. Rare manifestations include necrotizing acalculous cholecystitis, pancreatitis, and eosinophilic liver disease.[34]

Renal Involvement

Renal involvement is seen in 25% of patients and is less common than other medium vessel vasculitides like GPA.[35] The most common manifestation is necrotizing crescentic glomerulonephritis, although focal sclerosing disease, IgA nephropathy, or eosinophilic interstitial nephritis can also be seen. The biopsy features are not pathognomonic and often indistinguishable in isolation from other vasculitis diseases unless combined with the spectrum of eosinophilic asthma, eosinophilia, or other system manifestations.

Hypertension is seen in 10% to 30% of patients with EGPA, and its presence, many reflect the renal involvement.[24]

Neurologic Involvement 

A wrist or a foot drop resulting from mononeuritis multiplex or mixed sensorimotor peripheral neuropathy is reported. Common peroneal and internal popliteal nerves are most commonly involved. Radial and ulnar nerves in the upper limbs may also be involved.[32] Peripheral neuropathy can be present in 75% to 80% of cases. 10% to 39% of neurological involvements can be in the form of CNS vasculitis causing cerebral infarctions or hemorrhages.[36]

Cranial nerve palsies are uncommon, but the involvement of cranial nerves 2, 3, 6, and 8 have been described. Ischemic optic neuritis is the most common cranial neuropathy.

Autonomic neuropathies have also been proposed to be the root cause of cardiac dysrhythmia in EGPA patients [37]

Apart from CNC vasculitis, most neurologic symptoms tend to reverse well to standard therapy.

Other Organs

Dermatological manifestations are present in half to two-thirds of patients.

Extravascular granulomas are seen in the skin, as are changes consistent with leukocytoclastic vasculitis. Nonthrombocytopenic palpable purpura is the most common skin manifestation, along with scalp nodules, urticarial rashes, skin infarcts, and livedo reticularis.

Among other less common organ system involvements, central retinal artery and venous occlusion, thromboembolic disease, salivary gland involvement, or vasculitis involvement of breasts have also been seen.[38][39]

Evaluation

Because of its protean manifestations and lack of a single diagnostic test of choice, the diagnosis of EGPA is based on clinical features more than histopathology or lab testing. With eosinophilic asthma, the clinician must recognize a pattern of multisystem disease and investigate for other supportive findings.

Peripheral blood eosinophilia (greater than 10% on differential white blood cell count or greater than 1500 /dl) is the best-known lab hallmark of the disease. Elevated serum IgE is also found in 75% of patients.

The rest of the laboratory abnormalities are nonspecific, including elevated ESR, CRP, normocytic normochromic anemia, and extrapulmonary rheumatoid factor in 60% of patients.[40]

As mentioned before, the prevalence of ANCA positivity in EGPA is seen in approximately 40% of cases. The common ANCA immunofluorescence pattern is perinuclear, with specificity for myeloperoxidase (MPO).

In their retrospective study of 74 Churg-Strauss syndrome patients, Keogh and Specks reported an increased prevalence of neuropathy and central nervous system involvement in ANCA-positive patients.[41] There have been increasing efforts since then to identify clinical phenotypes correlating with ANCA positivity. Sable–Fourtassou and colleagues from the French vasculitis study group showed a higher prevalence of renal disease, microliter vasculitis, and peripheral neuropathy in the ANCA positive subgroup of their 112 Churg-Strauss Syndrome patients. Similarly, Sinico and colleagues showed a similar end-organ involvement pattern along with alveolar hemorrhage in the ANCA positive subgroup. In both studies, vasculitis was less frequent in ANCA negative patients, with a higher prevalence of cardiomyopathy and systemic manifestations like malaise and fever.[42][43][44]

Serum IgG4 levels and CCL17 levels correlate with disease activity.[45][22]

CT chest shows asymmetric diffuse bilateral peripheral ground-glass infiltrates along with bronchial wall thickening. It can sometimes be migratory. Bilateral bronchocentric nodular infiltrates can also occur, but unlike GPA, they do not cavitate. Pleural effusion is present in 20% to 30% of cases.

CT sinuses are characterized by paranasal sinus thickening along with thickening of nasal mucosa without any evidence of bony erosion (seen in granulomatosis with polyangiitis).

Airflow obstruction is present in pulmonary function tests in 70% of patients. Even though FEV1 may transiently improve with corticosteroid therapy, airflow obstruction in variable degrees persist in 40% of patients.[46]

Since cardiac disease portends a poor prognosis, early detection with cardiac MRI is being advocated even in the absence of clinical symptoms once the disease diagnosis is made. Any patient with suspected EGPA should undergo a thorough evaluation of cardiac performance and coronary status.

Sural nerve biopsy is the gold standard test in documenting peripheral neuropathy. Evidence of axonal degeneration is the most common finding, and necrotizing vasculitis and perineural eosinophilic infiltration can only be confirmed in half of the cases.

Skin biopsy is the most convenient to perform. Although none of the findings are exclusive to EGPA, evidence of small vessel vasculitis in an appropriate clinical setting may be enough to make a diagnosis. If the kidney is involved and biopsied, focal necrosis, crescentic deposits, and the paucity of immunoglobulin deposits are the characteristic findings.

Treatment / Management

Early recognition and ability to use corticosteroids and immunosuppressants have significantly changed the natural history of EGPA, improving prognosis, and overall survival.

Corticosteroids help reduce eosinophil burden in blood and tissues and inhibit the prolongation of eosinophil survival in extravascular tissues.

While the initial dose of therapy for a non-severe disease has been 1 mg/kg of oral prednisone, induction of remission in severe disease is often better achieved with pulse dose methylprednisolone with or without cyclophosphamide.

Two randomized controlled trials by the French vasculitis study group established a standardized treatment regimen based on a 5-factor score.[47][48] In patients without poor prognostic factors, corticosteroid alone was able to achieve remission in 93% of patients. However, relapses happened more commonly and during tapering of steroids prompting the addition of cyclophosphamide or azathioprine for maintenance. There is an overview of the treatment plan based on a study by Ribi et al. below.(A1)

Multiple studies show that maintaining remission with a high incidence of relapses is challenging. Although agents of choice have been well established, the ideal treatment duration and which drugs to stop first are still not well standardized.

Refractory Disease

Treatment strategy for frequent relapse or severe refractory disease somewhat depends on end-organ involvement.

Plasmapheresis is effective and preferred in rapidly progressive glomerulonephritis or alveolar hemorrhage.

Intravenous immunoglobulin, on the other hand, is considered in neuropathy or cardiomyopathy refractory to conventional therapy.[49](B3)

Based on smaller case series and well-evidenced success with other ANCA-associated vasculitides, rituximab (anti CD 20) and tumor necrosis factor inhibitors (TNF) are considered an alternative option.[50] (B2)

There has also been some success with interferon-alfa (3 million IU 3 times weekly subcutaneously) to induce remission in seven CSS patients refractory to cyclophosphamide. It down-regulates the expression of IL-5 (known to have an increased titer in CSS) and IL-13, apart from modulating eosinophil activating cytokines in CSS. However, it was unable to reduce the rate of relapses after one year of follow-up.

There have also been recent reports of successful use of mepolizumab–an anti-IL-5 monoclonal antibody and omalizumab (recombinant humanized monoclonal anti-IVIG E antibody) in refractory EGPA. Both drugs have already been in use for moderate to severe persistent asthma with allergic phenotypes.[51][52](B3)

As evident in multiple studies, the challenge is to maintain remission with a high incidence of relapses. Although agents of choice have been well established, the ideal treatment duration and which drugs to stop first are still not well standardized.

Treatment Strategies for Eosinophilic Granulomatosis with Polyangiitis[47](A1)

Induction of Remission

Without Poor Prognosis (FFS greater than 1)

• Oral prednisone: 1 mg/kg daily for 3 weeks, then tapering 5 mg every 10 days to 0.5 mg/kg. Then taper 2.5 mg every 10 days to the minimal effective dosage, or until definite withdrawal.

Or

• Intravenous methylprednisolone pulse (15 mg/kg) followed by oral prednisone as above.

Relapse

• Oral azathioprine 2/mg/kg daily for at least 6 months

Or

• Cyclophosphamide pulses (600 mg/m2) every 2 weeks for 1 month, then every 4 weeks afterward

With Poor Prognosis

• Three consecutive methylprednisolone pulses (15 mg/kg) on day 1 to 3 plus oral prednisone (see above)

Plus

• Either 12 cyclophosphamide pulses (600 mg/m2) every 2 weeks for 1 month then every 4 weeks after that

Or

• Short-course of cyclophosphamide (oral 2 mg/kg) for 3 months  or 6 cyclophosphamide  pulses (600 mg/m2) every 2 weeks for 1 month, then every 4 weeks after that, followed by azathioprine 2 mg/kg for 1 year or more

Maintenance of Remission

• Methotrexate (10 to 25 mg per week)
• Cyclosporin A (1.5 to 2.5 mg/kg per day)
• Azathioprine (2 mg/kg per day)

Refractory Disease

• Plasma exchange
• IVIG (0.4 g/kg per day for 5 days)
• Interferon-alfa (3 million IU 3 times per week subcutaneously)
• TNF inhibitors: infliximab, etanercept, adalimumab
• Rituximab (325 mg/m^2 for 4 consecutive weeks)

Differential Diagnosis

Conditions that need to be considered in the differential stems from the 2 principal phenotypes of EGPA – eosinophilic lung disease and systemic small and medium vessel vasculitis.

Eosinophilic Lung Diseases

• Acute and chronic eosinophilic pneumonia
• Allergic bronchopulmonary aspergillosis
• Bronchocentric granulomatosis
• Loffler’s syndrome
• Idiopathic hypereosinophilic syndrome

Small and Medium Vessel Vasculitis

• Granulomatosis with polyangiitis
• Polyarteritis nodosa
• Microscopic polyangiitis

Most eosinophilic lung diseases are distinguished from EGPA by lack of multisystem involvement except idiopathic hypereosinophilic syndrome, where peripheral eosinophilia is more than 1500/cubic mm is a chronic phenomenon lasting beyond 6 months. ANCA is completely absent in hypereosinophilic syndrome, and late-onset asthma is very uncommon. Recent molecular genetic testing has helped identify mutations specific to idiopathic hypereosinophilic syndromes, such as FIP1-like 1-platelet-derived growth factor receptor–alpha or T-cell antigen receptor rearrangements.

As far as differentiation from other small and medium vessel vasculitides is concerned, renal involvement is much more common in granulomatosis with polyangiitis (GPA), as is evidence of cavitary lung lesions or necrotizing upper airway lesions. Septal nasal perforation often reported in GPA does not occur in EGPA.

Prognosis

Following timely detection and treatment, CSS has a favorable prognosis with a 5-year survival of 90%.[53]    

The relapse rate is estimated at approximately 20% to 30% and is often minor with fever, joint pain, and constitutional symptoms.

Certain risk factors for relapse include:

• The sudden rise in eosinophil count
• Persistent ANCA positivity
• Gastrointestinal tract (GI) involvement
• The rise in ANCA titers

Just as peripheral eosinophilia is a hallmark of diagnosis, there is an association between the degree of eosinophilia and the extent of vasculitis disease. A sudden rise in eosinophil count also precedes a relapse of vasculitis.

Guillevin et al. identified 5 factors associated with higher mortality[54][55]:

• Proteinuria (greater than 1 gm per day)
• Renal insufficiency (Cr greater than  1.58 mg/dl)
• Cardiomyopathy
• GI tract involvement
• CNS involvement

They became the basis of the Five-Factor Score (FFS) used to define a poor prognosis and higher mortality in EGPA. The absence of any of the five factors carries a good prognosis (RR 0.52; 95% CI, 0.42 to 0.62; P <0.03), and the presence of 2 or more increases the risk of mortality (RR 1.36; 95% CI, 1.10 to 1.62; P <0.001). Of the 5 factors, cardiomyopathy is an independent risk factor in CSS (hazard ratio 3.39; 95% CI, 1.6 to 7.3).

The Birmingham Vasculitis Activity Score (BVAS) is a detailed 66 question tool to assess vasculitic organ involvement and is widely used in clinical trials.[50] 

Vasculitis Damage Index (VDI) assesses accumulated organ damage and is a very useful assessment of organ injury due to both disease itself and its treatment. It correlates well with mortality and morbidity.[56]

Some factors associated with a poor prognosis are[57][4]:

• Evidence of severe GI tract involvement
• Cardiomyopathy
• CNS vasculitis
• Renal failure

Cardiac involvement is the most frequent cause of mortality in patients with poor response to therapy.

Complications

Even though the disease has a favorable prognosis with early detection and treatment,  asthma often remains refractory and impacts the quality of life. The persistence of severe asthma symptoms often necessitates a much longer course of systemic corticosteroids than is necessary for other small vessel vasculitides. As reported by Solans et al., there is, therefore, an expected high prevalence of corticosteroid-induced side effects, including diabetes mellitus, myopathy, osteoporosis, and vertebral fractures, osteonecrosis of the femoral head, etc.[58] 

Moreover, almost all patients with EGPA develop long-lasting steroid-refractory neuralgia and myopathy, as well.