Churg-Svauss Syndrome

EPOS 395-397

8.7.3. Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) (previously Churg Strauss Syndrome)(329, 392), is a rare form
of vasculitis characterised by adult onset asthma, severe rhinitis, nasal polyps and other systemic manifestations as
a result of widespread eosinophilic granulomatous infiltration of tissues.
The Chapel Hill consensus defined it as ‘eosinophil-rich granulomatous inflammation of the respiratory tract and
necrotizing vasculitis of small to medium-sized vessels, associated with eosinophilia’. However, the nomenclature
has been challenged as only 59% of patients with this diagnosis have evidence of polyangiitis(393).
8.7.3.1. Epidemiology
The overall prevalence of the condition ranges from 10.7-13 cases/million inhabitants with an annual incidence of
0.5-6.8 new cases/million inhabitants(394). However, among asthma patients the incidence is as high as 67 per
million(395).
8.7.3.2. Pathophysiology
The aetiology is unknown though it is probably an idiopathic autoimmune Th2 mediated disease affecting
eosinophils, endothelial cells and lymphocytes. It has been suggested that exposure to certain allergens, drugs,
vaccinations, corticosteroid withdrawal, and pulmonary infection may initiate the inflammatory cascade (396-398). It
has been suggested that antileukotriene antagonists such as zafirlukast and montelukast(396) when used for asthma in
some patients, could unmask EGPA. However, the consensus is that these drugs may be used if needed in EGPA,
as the onset was either coincidental or resulted when symptoms of EGPA were unmasked after oral
glucocorticosteroids were tapered and/or withdrawn(399, 400). Other drugs implicated in triggering EGPA include
antibiotics (macrolides), oestrogen replacement therapy, and carbamazepine suggesting a hypersensitivity reaction.
There is also some evidence for a genetic predisposition in respect of the HLA-DRB1*04 and *07 alleles and the
related HLADRB4(401, 402). In EGPA the anti-myeloperoxidase ANCA may be associated with HLA-DQ(341).
Eosinophilic infiltration and endothelial damage are likely the most important pathophysiological mechanisms.
Peripheral T-cell lines from EGPA patients can produce Th2 associated cytokines such as IL4 and IL13 and IL5 is
upregulated in active disease, offering therapeutic possibilities(403). However, an exaggerated Th2 response cannot
account for all the manifestations of EGPA and there is evidence of involvement of Th1 and Th17 cells secreting
large amounts of IL-17a in the late stages of the disease. Eoxtaxin-3 produced by endothelial and epithelial cells
may contribute to eosinophilic tissue infiltration and further tissue damage may be caused by eosinophilic cationic
protein from activated eosinophils. They also secrete large amounts of IL25 which elicits Th2 responses,
maintaining a vicious circle(403).
Increased levels of IgG4 and IgG4/IgG ratios in EGPA have led to the suggestion that EGPA may be part of the
IgG4 disease spectrum(404).
As with GPA, it is thought that localised early forms of EGPA may exist, particularly in the upper respiratory
tract(403).
8.7.3.3. Diagnosis and differential diagnosis
According to the American College of Rheumatology criteria(405), at least four out of six criteria must be present:
1) A medical history of asthma
2) Eosinophilia >10%
3) Mono- or polyneuropathy
4) Nonfixed pulmonary infiltrates
5) Paranasal sinus abnormalities
6) Biopsy including an artery, arteriole or venule showing accumulated eosinophils in the extravascular tissue.

Clinical (Table 8.7.2.)

The male to female ratio in the literature ranges from 58:43 to 39:54 with mean age of between 49-52 years in the
28 studies included in a systematic review by Goldfarb(406). It can manifest between 7-74 years with a mean age of
onset of 38-54 years(403). No ethnic predisposition has been determined(407).
The condition often follows three clinical stages. The prodromal stage is characterised by allergic rhinitis, CRS
with or without polyps and asthma(408, 409). This stage may predate the overt vasculitis by months to many years
(mean eight years)(396).
The second ‘eosinophilic’ stage is characterised by tissue and peripheral eosinophilia.
The final ‘vasculitic’ phase involves extrapulmonary disease with vasculitis, associated with severe and fatal
manifestations including polyneuropathies, myocarditis, cerebral haemorrhage, ischaemic strokes and bowel
perforations.
In a systematic review(406) of 1175 patients with EGPA, 48-96% presented with head and neck manifestations,
which are often sinonasal(410). These include nasal obstruction (95%), crusting (75%), bleeding (60%), rhinorrhoea
(95%), facial pain, loss of smell (90%) and sneezing (80%) associated with allergic rhinitis (43%) and chronic
rhinosinusitis with (54%) and without nasal polyposis (70%). In addition to nasal crusting, hypertrophy of the
inferior turbinates, mucosal oedema, synechia and nasal polyps may be seen on endoscopy(411, 412). Olfactory testing
using Sniffin’ sticks in 62 subjects showed normosmia in 79%, hyposmia in 11%, anosmia in 29% and dysosmia in
40%(412). Anterior rhinomanometry in 86 subjects showed severe nasal obstruction in a third. A mean SNOT-22 of
41.5 has been found, comparable to patients with CRS without vasculitis(410).
As a consequence, patients are frequently seen by the ENT community who may not appreciate the potential for a
more serious systemic disease but are in a unique position to make an early diagnosis and prevent late
complications of the condition(413). EGPA should be considered in any patient with severe nasal polyposis who is
not responding to conventional therapy. ENT and systemic manifestations are shown in Table 8.7.2. In one series
the mean delay between diagnosis and presenting to the physician with worsening symptoms was 18.5 months
(range 1-71 months, SD 21.6)(410) whereas a mean delay from diagnosis of asthma to diagnosis of EGPA of 11.8+/-
18.2 years has been reported(414).
Investigations (Table 8.7.3.)
Active EGPA is characterised by marked peripheral eosinophilia (usually >1500 cells/ul or >10%)(403). There is
usually a non-specific increase in IgE if the patients are not taking systemic steroids for their asthma.
EGPA is one of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Immunofluorescent
patterns with ELISA detecting antibodies to myeloperoxidase (MPO) is the most common EGPA ANCA-positivity
finding but figures for p-ANCA positivity vary. Between 26-48% have been reported to have a positive p-ANCA
but this increases to 75% with renal involvement(415) and other studies quote 35-77% so a negative ANCA does not
rule out EGPA and a positive ANCA may not be essential for the diagnosis in the head and neck phenotype(329, 395,
416-419).Overall pANCA-positive patients are more likely to have peripheral neuropathy, glomerulonephritis and

purpura (due to small vessel vasculitis) as compared to those with myocardial, respiratory and gastrointestinal
involvement who are more often pANCA negative(416, 420).
Other biomarkers have been investigated including serum TARC/CCL17, eotaxin-3, IgG4 and IgG4/IgG ratio but
none were useful in discriminating between active disease and remission(421).
Imaging
Sinus CT does not show anything other than what would be expected in diffuse polypoid rhinosinusitis i.e. pan-
opacification(422). Mean Lund-Mackay scores of 9-17 have been reported in large cohorts of EGPA(412, 422).
Expansion and bone erosion may be seen in the ethmoid complex with widening of the intercanthal distance. In
addition, there may be evidence of mucocele formation, notably in the fronto-ethmoidal region.
High resolution CT of the chest is recommended to demonstrate atypical ‘fluffy’ or nodular migratory pulmonary
infiltrates which would only be seen in 64% of plain chest x-rays(423). Peripheral nodules (25%), ground glass
opacities (86%) and bronchial wall thickening and bronchiectasis (66%) are also found on CT.
Histopathology
Histopathologically the condition is characterised by eosinophilic inflammation and infiltration, extravascular
granulomas and necrotizing vasculitis in the presence of asthma. However, in studies where sinonasal tissue was
examined, eosinophilic infiltration was seen in 35-100%, whilst necrotising vasculitis and eosinophilic granulomas
were not seen(408, 424).
Although the histology is important, this combined with clinical criteria are required to make the diagnosis and a
low threshold of suspicion is required in any patient with eosinophilic diseases i.e. significant adult-onset asthma,
recurrent CRSwNP and allergic rhinitis. Once EGPA is diagnosed, investigation for lung, kidney, heart,
gastrointestinal and peripheral nerve involvement is recommended as these are associated with poor prognosis (394).
This can include imaging, biopsy, bronchoalveolar lavage, renal and cardiac function tests.
Differential diagnosis
The differential diagnosis is from other eosinophilic pneumonias, idiopathic hypereosinophilic syndrome, c-ANCA
positive granulomatosis and microscopic polyangiitis, sarcoid, allergic bronchopulmonary aspergillosis and
parasitic infections. Thus in addition to ANCA, the EGPA Consensus Task Force recommended as a minimum
initial differential diagnostic work-up the following: serologic testing for toxocariasis, HIV, specific IgE and IgG
for Aspergillus spp, a search for Aspergillus spp in sputum and/or bronchoalveolar lavage fluid, tryptase and
vitamin B12, full blood count and CT of the chest(394). However, EGPA can usually be distinguished from other
primary systemic vasculitides by the presence of asthma and a marked blood eosinophilia.
8.7.3.4. Treatment
In 2009, the European League Against Rheumatism (EULAR) published treatment recommendations for small to
medium sized vessel vasculitides. Without treatment, the mortality rate is high once the vasculitis phase is
reached(425, 426). A multidisciplinary management is widely recommended in the literature(394) and with appropriate
treatment, survival rates are comparable to GPA(426).
Long –term studies have shown that overall remission rates are good, ranging from 81-92% but over a quarter do
relapse either within the first year of treatment or much later(427). This is higher in MPO /pANCA positive patients.
Overall mortality in treated patients who relapsed was only 3.1%.
Factors predicting poor outcome are: cardiomyopathy (an independent risk factor) or two features of the ‘five-
factor’ score (FFS) (creatininemia >140umoles/litre; proteinuria >1g/day; involvement of central nervous system,
gastrointestinal or heart)(426, 428). If one of these factors is present at onset, the five year mortality is 25.9%, when
two or more are present, this increases to 46% at five years(428). Survival at one and five years was 100% if the
score was 0. The FFS was revisited in 2011 by the French Vasculitis Study group as follows: 1) age >65yrs; 2)
cardiac symptoms; 3) gastrointestinal involvement; 4) renal insufficiency characterised by a serum creatinine >150
umol/l; 5) absence of ENT manifestations. With each factor accorded one point, a revised FFS of 0, 1 and 2 is
associated with a five-year mortality rate of 9%, 21% and 40% respectively(429). A subsequent study showed that
age >65 years was the only factor associated with higher risk of death during follow-up(427).
Systemic
In most patients, disease control is achieved with immunosuppressant therapy, usually oral prednisolone +/-
cytotoxic drugs such as pulsed cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate
dependent on the severity of the disease at presentation. Patients without poor prognostic factors can often be
managed with glucocorticoids alone. Additional systemic treatments include intravenous immunoglobulin,
leflunomide, anti-TNFa, interferon-a and plasma exchange(430).
Rituximab is now frequently being used in selected ANCA-positive patients with renal involvement or refractory
disease though the evidence is less robust that in GPA(394, 431-434) and other new biologic therapies may be helpful e.g.
anti-IL 5 (mepolizumab)(435-437) or anti-IgE (omalizumab) monoclonal antibodies(438, 439).
Nasal
Alkaline/saline nasal irrigations, topical intranasal corticosteroids and nasal lubricants are the mainstay of
treatment (Level IV).
Endoscopic surgery can be successfully undertaken in those whose CRS with nasal polyps do not respond to
systemic and local steroids. The numbers of reported EGPA surgical cases in the literature is small(440) and surgery is
often associated with a high recurrence rate though patients may still obtain benefit(422). A number of patients
develop paranasal sinus mucoceles which may also be dealt with endoscopically. In a series of 25 patients, 48%
had undergone endoscopic sinus surgery, often multiple times(410).