Eosinophilic granulomatosis

Notes

Overview

Eosinophilic granulomatosis with polyangiitis is a small to medium vessel vasculitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is one of the anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) that is characterised by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia.

Among the three AAVs (see below), EGPA is the least common with a prevalence in Europe between 10.7-14.1 cases per million population. The mean age of diagnosis is around 40 years old and there is no gender predominance. 

ANCA associated vasculitis

AAV is an umbrella term for three conditions:

  • Microscopic polyangiitis (MPA)
  • Granulomatosis with polyangiitis (GPA): previously known as Wegener’s granulomatosis
  • Eosinophilic granulomatosis with polyangiitis (EGPA): previously known as Churg-Strauss syndrome

These conditions are all small vessel vasculitides that can affect arterioles, capillaries and venules. While MPA and GPA are similar conditions, EGPA has different predilection of organ involvement (predominantly pulmonary and cutaneous involvement) and also affects medium-sized vessels. 

Collectively, these conditions are characterised by a positive ANCAs. The change in terminology of the conditions reflects the movement away from honorific eponyms linked to Nazi Germany. 

Aetiology

EGPA is linked to the development of ANCA positivity, but the exact pathogenesis of the condition is unknown.

Genetic risk

Development of EGPA has been linked with several human leucocyte antigens (HLA), which are involved in antigen processing by the immune system. These include HLA-DRB1 and HLA-DRB4.

Medications linked to EGPA

Several medications have been linked with development of EGPA. However, whether they are important in the pathogenesis or simply unmask the underlying disease is unclear.

  • Leukotriene modifying agents (e.g. montelukast)
  • Inhaled corticosteroids: possibly unmask the condition by being able to withdraw systemic corticosteroids for the control of asthma
  • Omalizumab: monoclonal antibody directed against IgE used to treat severe asthma

ANCA

ANCA antibodies are important in the classification of small vessel vasculitis.

ANCA antibodies may be seen in a variety of immune-mediated conditions.

In AAV, they have characteristic staining patterns and associate with antigen targets myeloperoxidase and proteinase 3. In other immune-mediated disorders, the staining pattern is variable and the target antigen may be different including lactoferrin or elastase, among others.

ANCA antigen targets

The two ANCA antigen targets associated with AAV are:

  • Myeloperoxidase (MPO): typically associated with p-ANCA due to the perinuclear staining pattern on immunofluorescence
  • Proteinase 3 (PR3): typically associated with c-ANCA due to the cytoplasmic staining pattern on immunofluorescence

These ANCA-antigen targets help to define the likely AAV:

  • MPA: almost 90% of patients are ANCA positive with the vast majority MPO-ANCA (p-ANCA)
  • GPA: approximately 90% ANCA positive. Of these, 80-90% have PR3-ANCA (c-ANCA). A small majority have MPO-ANCA (p-ANCA).
  • EGPA: approximately 50% are ANCA positive. MPO-ANCA (p-ANCA) is more common, but PR3-ANCA (c-ANCA) can also be seen. The frequencies vary depending on study.

It is unclear whether ANCA positivity is central to the pathogenesis of EGPA or part of the manifestations of the disease.

Pathophysiology

EGPA is characterised by the presence of an allergic type immune reaction

The immune reaction is a predominant Th2 helper cell response with a high eosinophil level. Typical pathological findings include eosinophil infiltration, predominant eosinophilic vasculitis in small vessels and perivascular necrotising granulomas.

These pathological changes may occur in the lungs, kidneys, skin and even heart. In the lungs, it can cause asthmatic bronchitis and eosinophilic pneumonia. In the kidneys, it may lead to a variety of findings but a necrotising glomerulonephritis is most common. In the skin there is evidence of vasculitis with eosinophil infiltration. In the heart there may be evidence of eosinophil infiltration with endomyocarditis in the absence of vasculitis.

Clinical features

EGPA is characterised by an adult-onset asthma, which subsequently develops into vasculitis.

Disease phases

  1. Prodromal phase: characterised by asthma and allergic rhinitis. Asthma occurs in 97% of patients. Usually precedes vasculitic phase by 3 years but may be delayed up to 10 years. 
  2. Eosinophilic phase: eosinophils infiltrate a variety of tissue without overt vasculitis. May see marked eosinophilia on full blood count.
  3. Vasculitic phase: multi-system involvement with granulomatous inflammation. Can be life-threatening.

Constitutional symptoms

  • Lethargy
  • Flu-like illness
  • Weight loss
  • Fever

Ear, nose, throat

Up to 85% of patients have ENT involvement. 

  • Sinusitis: facial pain, fever
  • Allergic rhinitis: runny nose, post-nasal drip, congestion
  • Nasal polyps
  • Otitis media: ear pain, fever, fullness (may be chronic)

Pulmonary

EGPA should be suspected in patients with poorly controlled, adult-onset asthma. Severity of symptoms usually increases as the vasculitic process begins. Opacities and pleural effusions may be seen on imaging

  • Cough
  • Dyspnoea
  • Wheeze
  • Haemoptysis (rare)

Cardiac

Cardiac involvement in EGPA is associated with high mortality. Features include heart failure, pericarditis +/- pericardial effusion and arrhythmias. 

Cutaneous

Up to two thirds have evidence of cutaneous involvement with tender subcutaneous nodules on extensor surfaces.

Neurological 

Up to 75% of patients may have peripheral nervous system involvement that can present as mononeuritis multiplex. This refers to an asymmetrical and asynchronous (occurring at different times) motor or sensory neuropathy involved ≥2 nerve areas.

Kidneys

Involvement of the renal system is variable and usually characterised by necrotising glomerulonephritis. This may present with asymptomatic haematuria or nephritic syndrome (haematuria, proteinuria, renal impairment and hypertension).

Other

  • Gastrointestinal: bleeding, abdominal pain and diarrhoea
  • Musculoskeletal: myalgia, arthralgia and arthritis  

Diagnosis criteria

Traditionally, diagnosis was based on the American College of Rheumatology (ACR) diagnostic criteria.

ACR criteria

This criteria was developed in 1990 and was composed of six criteria of which ≥4 needed to be present for a diagnosis of EGPA. We have summarised this below:

  • Asthma
  • > 10% eosinophils on differential count
  • Peripheral neuropathy (mono-/poly-/mononeuritis multiplex)
  • Migratory or transient pulmonary opacities (on imaging)
  • Paranasal sinus abnormality
  • Confirmation of extravascular eosinophil infiltration on biopsy

Lanham criteria

This criteria is formed of three components, which all need to be met for the diagnosis of EGPA:

  • Asthma
  • Peak peripheral eosinophil count >1500 cells/microL (>1.5 x10^9/L)
  • Systemic vasculitis (with ≥2 extra-pulmonary organ involvement)

NOTE: a revised criteria in association with the European League Against Rheumatism (EULAR) and ACR are currently ongoing.

Work-up

EGPA is suggested by a raised peripheral eosinophil count, difficult to control asthma and other typical clinical findings.

Bedside

  • Urinalysis: assessment of blood and protein
  • Red cell casts: seen under microscopy. Suggestive of glomerulonephritis

Routine bloods

  • FBC + film (to assess for blasts or abnormal eosinophils)
  • ESR/CRP
  • U&E
  • LFT
  • Bone profile
  • Troponin and NT-proBNP: if cardiac involvement suspected
  • Coagulation

Vasculitis screen

  • ANCA: positive in around 50%
  • ANA
  • Rheumatoid factor
  • Complement
  • Anti-GBM
  • Hepatitis B and C serology
  • HIV
  • +/- Cryoglobulins

Allergic testing

This refers to the identification of an allergic response (e.g. raised IgE) and testing for other causes of an eosinophilia (e.g. parasitic infection).

  • Serum IgE and immunoglobulins
  • Serology of parasitic infections: Toxocara, Strongyloides, filaria, Trichinella +/- others
  • Testing for aspergillus (IgE/IgG, sputum samples)
  • Tryptase and vitamin B12 levels

Imaging

  • Chest x-ray: look for infiltrates, consolidation, effusions
  • CT chest: better at assessing degree of pulmonary involvement compared to chest x-ray
  • CT sinuses: may be used to look for sinus involvement
  • Echocardiography and cardiac MRI: if cardiac involvement suspected

Special

  • Pulmonary function tests
  • Biopsy of affected tissue (usually nasal, skin or kidneys)
  • Nasoendoscopy
  • Bronchoscopy +/- bronchoalveolar lavage

Management

The primary treatment for EGPA is systemic corticosteroids and less commonly other immunosuppressive agents.

Induction therapy

This refers to the initial treatment with the primary intention of achieving disease remission.

Choice of treatment depends on the severity of vasculitis. Systemic corticosteroids are usually initiated in the first instance (e.g. prednisolone at 0.5-1.0 mg/kg/day). Methylprednisolone 1g daily for three days may be used for more extensive disease.

Cyclophosphamide, which is an alkylating chemotherapeutic agent used in systemic inflammatory conditions, may be added for severe multi-system disease or an inadequate response to steroids. 

Maintenance therapy

This can be initiated after induction therapy to maintain disease remission over long periods of time. The choice of agents may include azathioprine or methotrexate, but there are many other options. 

Asthma management

Patients with EGPA usually have difficult to control asthma and treatment should follow the usual asthma guidelines.

Complications

The overall five year survival is estimated at 70-90%.

Major complications associated with EGPA include:

  • Cardiac failure and/or myocardial infarction
  • Cerebral haemorrhage
  • Severe acute kidney injury 
  • Gastrointestinal bleeding
  • Severe exacerbation of asthma

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