Omalizumab-associated eosinophilic granulomatosis with polyangiitis: cause or coincidence?

Background

Omalizumab is a recombinant monoclonal antibody that binds circulating IgE and is an effective treatment option for severe allergic asthma. Eosinophilic granulomatosis with polyangiitis (EPGA) is a rare vasculitis, affecting small to medium-sized vessels, the clinical features can include asthma, eosinophilia and pulmonary infiltrates.1 An association between omalizumab and EGPA has been recognised; however, it remains unclear whether this treatment may have a causative or, conversely, a therapeutic role in EPGA.

This case report describes the development of cardiac involvement in EGPA after commencing omalizumab.

Case presentation

A 60-year-old man presented acutely with global weakness, altered sensation and a progressive petechial rash on his lower limbs. Prior to his admission, he had presented to his general practitioner with transient left eye ptosis and unilateral arm weakness. This had been preceded by a 2-month history of night sweats and lethargy.

He had a known history of severe asthma, two unprovoked pulmonary emboli, nasal polyposis, hypertension and poststreptococcal glomerulonephritis from which he had recovered fully. He had been commenced on omalizumab therapy for severe asthma 10 weeks prior to the admission and had not reported any worsening of his respiratory symptoms.

He was diagnosed with asthma in his 20s, controlled with salbutamol therapy and subsequently a steroid inhaler in his thirties. After turning 40, his asthma became more difficult to control, he was exacerbating more than four times a year and was referred to our local severe asthma service in 2015.

Baseline results at the time of referral included an IgE level of 257 kU/L, IgE to house dust mite 43.2 kU/L (grade 4), antineutrophil cytoplasmic antibody (ANCA) negative, eosinophils 1.37 10⁹/L, fractional exhaled nitric oxide (FeNO) 45 ppb. His inhaled therapy was optimised and a trial of a leukotriene receptor antagonist was commenced, which showed some initial benefit, but this was not a lasting effect and was subsequently discontinued. Due to the frequent exacerbations and the impact on his quality of life at the time of referral, the decision was made with the patient to commence low-dose maintenance oral corticosteroid therapy (5 mg prednisolone/day), which was started in 2016. He initially had a good response to maintenance steroids with an improvement in his day-to-day asthma control; however, in 2017, he had five exacerbations requiring 40 mg prednisone each time. His case was discussed at our regional severe asthma MDT, and the outcome was to start a 16 week trial of omalizumab at a dose of 600 mg every 4 weeks and to change over to mepolizumab if the trial was unsuccessful. At the start of the trial, his ACQ-7 (asthma control questionnaire) was 0.9 and eosinophil count 0.62 10⁹/L.

Ten days after receiving his first dose of omalizumab, the patient reported feeling light headed and noted that his pulse was irregular. He attended his GP practice and was diagnosed with atrial fibrillation (see figure 1) and commenced on a calcium channel blocker with a plan for an outpatient echocardiogram and cardiology review. He received two further doses of omalizumab prior to the admission, 10 weeks following the start of treatment. He did not experience any asthma exacerbations requiring an increase in his baseline steroids dose during this time. On admission, examination revealed reduced right upper and left upper limb power (4/5) and in the left and right lower limb (between 3 and 4/5). Altered sensation in L5/S1 dermatomes was also noted. There was no joint swelling observed. Auscultation of his chest was clear.

Figure 1

ECG on presentation showing atrial fibrillation.

Blood results revealed a troponin 403 ng/L (normal range 0–13), creatine kinase 870 IU/L (24–195 IU/L) and eosinophils 6.85×10⁹/L.

To investigate the cause of the elevated cardiac biomakers and ECG findings, an echocardiography was performed. This demonstrated a severely dilated left atrium, global hypokinesis of the left ventricle and a severely impaired ejection fraction of approximately 33%. A dilated right atrium with mild tricuspid regurgitation was also noted.

The neurological findings and eosinophilia found on admission prompted a vasculitic process to be considered as part of the differential diagnosis, and autoimmune testing for ANCA, antinuclear antibodies and anti-double-stranded DNA antibodies were performed and were negative. A CT scan of his chest abdomen and pelvis revealed no malignancy to explain his presenation. He was reviewed by the local rheumatology, neurology, cardiology and respiratory team; a clinical diagnosis of ANCA-negative EGPA was agreed on.

Investigations

A chest X-ray on admisison (figure 2) revealed a raised left hemidiaphragm, which was not present on chest X-ray 2 months previously. CT thorax (figure 3) revealed no ground-glass changes, small bilateral effusions, left lower lobe atelectasis and a raised left hemidiaphragm. There were no endobronchial secretions or lesions to account for this latter finding and clinically it was thought to be secondary to left phrenic nerve palsy secondary to EGPA and the small bilateral effusions attributed to his cardiac failure.

Figure 2

Initial chest X-ray on admission showing a raised left hemidiaphragm (note lung apex was not within the field of view).

Figure 3

Coronal CT chest image showing a raised left hemidiaphragm and left basal atelectasis.

A cardiac MRI (figure 4) performed later showed subepicardial and diffuse myocardial fibrosis on the basalo mid inferolarteral wall resulting in global hypokinesia more pronounced in the basal inferolateral wall. Moderate left ventricular dysfunction (ejection fraction 42%) as well as mild concentric left ventricular hypertrophy was noted. Aortic root dimensions were normal and moderate tricuscipd regurgitation and severe right atrial dilatation were identified. The features were in keeping with an eosinophilic myocarditis.

Figure 4

Cardiac MRI showing subepicardial and diffuse myocardial fibrosis on the basalo mid inferolarteral wall.

Nerve conduction studies were performed, which showed a decrease in sensory and motor response of the lower limbs with asymmetry in the amplitude in the ulnar nerve distribution, consistent with findings of mononeuritis multiplex. Muscle biopsy was inconclusive for a diagnosis of EGPA.

Differential diagnosis

An initial clinical impression of cervical myelopathy was made and an MRI brain and spine were performed. His MRI brain was reported as normal. An MRI spine showed large central C5–6 disc herniation causing encroachment on the spinal canal changes thought to be long standing and could have been due to chronic venous congestion associated with cervical canal stenosis.

In the lumbar area, degenerative spondylolistheses were observed at the L5–S1 level associated with significant L5–S1 disc bulging, which was causing compression of the L5 nerve roots bilaterally.

The 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides defines EGPA as an ‘eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract and necrotising vasculitis predominantly affecting small to medium vessels and associated with asthma and eosinophilia. Nasal polyps are common. ANCA is more frequent when glomerulonephritis is present… Granulomatous and nongranulomatous extravascular inflammation, such as nongranulomatous eosinophil-rich inflammation of lungs, myocardium, and gastrointestinal tract, is common’.2 Prior to initiation of omalizumab only asthma and nasal polyposis were present; but following its initiation multisystem involvement (including neurological, cardiological and systemic upset) then developed, suggesting this to be a likely trigger for his condition.

Treatment

He was commenced on a 5-day course of intravenous methyprednisolone followed by a weaning protocol of prednisolone from 60 mg to 15 mg in a 3-month period. This is consistent with recommendations from current guidance.3 He was subsequently started on azathioprine and weaned on regular steroids.

Outcome and follow-up

Our patient has shown a very good clinical response to therapy. A cardiac MRI 10 months later showed an improved ejection fraction to 51% with some resolution of myocardial fibrosis and New York Heart Association class 1. He remains under our follow-up for control of his asthma and has a persistent eosinophilia and an exacerbation rate of 2/year. At 6 months postdischarge, a repeat antibody screen was negative and repeated chest radiograph showed persistent elevation of the left hemidiaphragm.