Churg–Strauss syndrome (CSS), also called granulomatous and allergic angiitis is a necrotizing systemic vasculitis, which was first described in 1951 by the pathologists J. Churg and L. Strauss in an autopsy series of patients with severe asthma.1 These patients had hypereosinophilia and systemic vasculitis with the histological examination showing extravascular granulomas, tissue eosinophilia and necrotizing vasculitis.

Further case reports led to an improvement in the definition; the American College of Rheumatology (ACR) classification criteria in patients with biopsy proven vasculitis is the most widely used today.2 These criteria include asthma, greater than 10% peripheral eosinophilia, mono or polyneuropathy, migratory pulmonary infiltrates, sinus anomalies and extravascular eosinophils in the biopsy. The presence of four of these criteria in a patient with biopsy proven vasculitis has a sensitivity of 85% and a specificity of 99.7% for CSS.2

CSS is a very rare disease, with an incidence of 1–7 cases per million per year.3,4 The disease affects both genders equally and can present at any age, with an average age of 50 at presentation.5,6

The etiology of CSS is unknown. Proposed hypotheses include an auto-immune process, possibly associated with genetic and environmental factors.7

In the last decade, the leukotriene receptor antagonists (LTRAs), including zafirlukast and montelukast have been reported to be associated with the development of CSS. This is probably related to steroid withdrawal after starting LTRAs in patients with hitherto attenuated CSS or the prescription of LTRAs to patients with worsening asthma which was actually unrecognized worsening CSS.8,9 In fact there have been reports of CSS after starting inhaled steroids10 and omalizumab11 and a recent case crossover study showed that several asthma control medications are associated with the onset of CSS, supporting the hypothesis that an aggravation of asthma is associated with CSS onset, rather than a specific drug.12

The pathophysiology of CSS is not sufficiently well known. A particular feature of the disease is the prominent blood and tissue eosinophilia which is related to the activity of the disease.13 In patients with active disease, eosinophils express surface markers of activation14 and secrete proteins that lead to tissue injury.15 The eosinophilia seems to be maintained by increased release of IL-5, produced mainly by activated Th2 lymphocytes.16 In effect, the anti-IL5 antibody mepolizumab turned out to be effective in refractory CSS in a recent study.17 Although CSS is mainly associated with a Th2 profile, recent studies have also shown possible imbalances in the activity of Th1,18 T regulatory19 and Th17 lymphocyte lineages.20 Anti-neutrophil cytoplasmic antibodies (ANCAs), specifically anti-myeloperoxidase antibodies seem to have a pathogenic role in the vasculitic lesions, possibly through the activation of neutrophils leading to the release of reactive oxygen species and proteolytic enzymes.21 The proposed roles of eosinophils and ANCAs in disease pathogenesis are in agreement with the recent reports of different disease manifestations in ANCA-positive and ANCA-negative patients.

The clinical manifestations of CSS are generally described in three stages.

The first stage (prodromal stage) can last for several years. Atopic asthma and rhinitis are the predominant features, usually difficult to control.

In the second stage (eosinophilic stage), an intense tissue infiltration by eosinophils is seen in various organs, including the lungs and gastro-intestinal (GI) tract, eventually evolving into Loeffler's syndrome or eosinophilic gastroenteritis.

The third (vasculitic) stage of the disease is characterized by an intense systemic vasculitis, with general symptoms usually predating the involvement of various organs by this process.22

One of the systems that is frequently affected by the vasculitis is the peripheral nervous system, with involvement of the vasa vasorum and development of mononeuritis multiplex.23 The GI tract is also affected, with abdominal pain, gastroenteritis or even full-blown acute abdomen as symptoms.24 Cardiac involvement can present as myocarditis, heart failure, pericarditis, or even coronary vasculitis and consequent myocardial ischemia. About half of all the CSS associated deaths are caused by cardiac lesions.25The respiratory system is involved in virtually all patients, not only with asthma in the first clinical stage, but also with infiltrates in the chest X-ray, that are present in 37–77% of patients. Pleural effusion can also be seen in up to a third of the patients.26–28

Clinically significant renal disease is both less frequent and serious in CSS than in other types of vasculitis.24

Recent studies have demonstrated the existence of two discrete CSS patient populations. ANCA positive patients (40% in these studies) present more frequently with vasculitis related manifestations, including renal and peripheral nervous system involvement as well as alveolar hemorrhage, purpura and vasculitis in the biopsy. ANCA negative patients more frequently have manifestations related to eosinophil infiltration, including cardiac, pulmonary and systemic symptoms. It is still unclear how relevant these new findings are for the therapy and prognosis of CSS.29

The diagnosis of CSS is generally dependent on histological analysis, although this may not be needed if the patient has eosinophilia and the typical clinical manifestations. The most frequent tissue samples come from the GI tract (eosinophilic enterocolitis with necrotizing or granulomatous vasculitis), and from the skin, where several patterns of lesion can be seen (even in the same patient), including extravascular granulomas, leukocytoclastic vasculitis and cutaneous polyarteritis nodosa.

Nerve biopsies frequently demonstrate necrotizing epineural vasculitis. The lung is also frequently sampled, revealing patterns of bronchial asthma, eosinophilic pneumonia and extravascular granulomatosis.30–32

The two most suggestive and frequent histological findings of CSS are necrotizing vasculitis and extravascular necrotizing granulomas, with eosinophilic infiltrates. These findings, however, are not pathognomonic.33

Blood tests show a significant increase in inflammation markers and intense peripheral eosinophilia. The titers of IgE and rheumatoid factor are also frequently elevated. ANCAs are typically present (40–70% of patients), showing a perinuclear pattern in almost all cases (p-ANCAs).5

The differential diagnosis includes hypereosinophilic idiopathic syndrome, chronic eosinophilic pneumonia and various other forms of systemic vasculitis.5,34,35

The treatment of CSS is similar to various other small-vessel vasculitis. High dose steroids are the mainstay of treatment and generally begin with a dose of 1mg/Kg/day (max 60mg/day) of prednisolone, maintained until symptoms are controlled and then slowly tapered (for one year). In patients with factors which have a poor prognosis (central nervous system, renal, cardiac or gastro-intestinal involvement), the combination of steroids and cyclophosphamide produced better control and sustained remission rates,6 compared to steroids alone and is therefore included for remission induction in the European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. In non-organ threatening or non-life threatening disease, the same document recommends the use of methotrexate as a less toxic alternative to cyclophosphamide. For remission maintenance, the combination of low-dose steroids and azathioprine, leflunomide or methotrexate is used.36

Patients not responding or who relapse despite appropriate therapy are managed with different therapies, including mycophenolate mofetil,37 human intravenous immunoglobulin,38 and biological agents including rituximab39, interferon-alpha,40,41 and mepolizumab.17,42

In the absence of treatment, CSS can be rapidly fatal after vasculitis has set in. Treatment with steroids leads to a significant response in 90% of patients, although about 20% will need additional cytotoxic therapy.

Treatment dramatically changes the prognosis of CSS patients (over 90% survival in one year). Nevertheless, following suspension of steroids, recurrent disease is observed in up to 25% of patients in the first five years, with asthma and sinusitis being the most frequent manifestations.43 Most recurrences show a good response to steroids. The leading cause of chronic morbidity in patients with CSS is neurological disease.37,43

Mortality in CSS patients is usually the result of cardiac or GI involvement, with myocarditis, heart failure, pericarditis, or even coronary vasculitis in the former and hemorrhage, perforation or entero-colic necrosis in the latter. Hemorrhagic stroke can also be a cause of death.

Through the analysis of a large number of CSS cases, Guillevin et al. recognized five factors associated with a worse prognosis, if they are present at the time of diagnosis (cardiomyopathy, CNS involvement, severe GI disease, renal failure with creatinine over 1.58mg/dl and proteinuria over 1g/day).44

Four patients were included (2M/2F), with an average age of 48 years (34–60) at diagnosis.

Description of case seriesClinical characteristics

The patients’ clinical characteristics are summarized in Table 1.

Table 1.

Patients clinical characteristics at the time of diagnosis.

Patient	1	2	3	4
Age	46	34	60	53
Gender	F	M	F	M
Asthma (years)	+ (2)	+ (4)	+ (9)	+ (3)
Sinusitis	+	+	+	+
Systemic symptoms	+	+	+	+
Peripheral nervous system	MM	PN	PN	RP
Gastrointestinal	+	−	+	+
Cardiovascular	−	−	−	+
Renal	−	−	−	−
Skin	+	+	−	+

MM: mononeuritis multiplex, PN: polyneuropathy, RP: radiculopathy.

All patients had systemic, pulmonary and nervous system involvement. Systemic symptoms included fever, weight loss and diffuse myalgia. All patients had asthma, and two also had complaints of worsening dyspnea and productive cough. Although only two patients complained of paresthesia, on examination all had neurological abnormalities, including muscle weakness in two patients and hypoesthesia in all four. The GI tract was affected in three patients, with diarrhea and abdominal pain.

Skin changes were found in three patients (signs of vasculitis in the lower limbs).

Only one patient had cardiac involvement, which was most likely prior to CSS, since it had started before all symptoms except for asthma and was probably associated with chronic alcohol abuse. No renal, ophthalmic or joint abnormalities were reported in any patient. Neither was CNS involvement described.

Past medical history

Past medical history was significant for previously diagnosed asthma in all patients, two of them medicated with LTRAs. One patient also had dilated myocardiopathy with severe heart failure, probably due to chronic alcohol abuse.

Laboratory abnormalities

The summary of laboratory characteristics of all patients is presented in Table 2.

Table 2.

Patients laboratory characteristics.

Patient	1	2	3	4
Peripheral leukocytes (cells/mm3)	26,500	19,100	44,200	15,800
Peripheral eosinophils (cells/mm3)	10,600	8800	35,300	7800
ESR (mm)	56	53	17	82
CRP (mg/dl)	N/A	5.9	3	9
Rheumatoid factor (UI/ml)	N/A	0	2650	301
IgE (UI/ml)	N/A	8950	0	2,320
ANCAs	N/A	Neg	Neg	Neg

ESR: erythrocyte sedimentation rate, CRP: C reactive protein−normal<0.5, IgE: total immunoglobulin E, N/A: not available.

All patients had leukocytosis and eosinophilia at the time of diagnosis, with the peripheral blood eosinophils varying between 7800 and 35,000G/L. Erythrocyte sedimentation rate was elevated in three patients. The levels of IgE were quantified in three patients and were elevated in two of them. Three patients were tested for ANCAs, but none was positive.

Three of the patients had relevant changes in the chest X-ray, although only one showing migratory infiltrates generally associated with CSS. Chest CT was performed in three patients revealing abnormalities in both the interstitium and the large bronchi (Fig. 1).

Figure 1.

High resolution computer tomography of patient 1 showing a parenchymal infiltrate in the lingula and left inferior lobe as well as peribronchovascular interstitial thickening.

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Histological analysis

All patients had a histological confirmation of the vasculitis diagnosis. Two had skin biopsy, one had colonic mucosal biopsy and the fourth had both skin and colonic mucosal biopsies. Biopsies of the colonic mucosa showed aspects of active eosinophilic colitis (Fig. 2) and skin biopsies revealed aspects of eosinophilic vasculitis in two patients and typical aspects of the Churg–Strauss granuloma in another.

Figure 2.

Colonic (left) and skin (right) biopsies showing a dense infiltrate of eosinophils both in the colon mucosa and in the walls of skin vessels (HE 400×).

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Treatment

All patients received treatment with high doses of systemic steroids (≥1mg/kg/day of prednisolone or equivalent).

An immediate and relevant response to the treatment was seen in all patients, with improvement in all but the neurological complaints within two to four days. Troublesome neurological symptoms required the addition of another drug in three patients, namely cyclophosphamide in one case, gabapentine in another and gabapentine and cyclophosphamide, followed by gabapentine and human immunoglobulin in another.

Follow-up

None of the patients died while in hospital. Three were free of symptoms when discharged from hospital, 12–46 days after admission. The other patient continued to suffer from serious neurological complaints (upper limb paresthesia with loss of function).

One of the patients disappeared from follow-up after 3 years. Another died two weeks after discharge, at home, probably due to worsening severe chronic heart failure secondary to dilated myocardiopathy which had been present before diagnosis of CSS. The other two patients are still in follow-up; one of them (patient 3) still suffers from asthma and intense upper member paresthesia which only improved after 6 cycles of endovenous human immunoglobulin. The other patient (patient 2) only suffers from asthma.

Relapses

Only one relapse was recorded, in patient 1, three years after diagnosis, characterized by complaints of polyarthralgias and cutaneous lesions, and leukocytosis with eosinophilia, which all responded well to treatment with prednisolone and cyclophosphamide.