Myopericarditis as a presentation of eosinophilic granulomatosus with polyangiitis (EGPA)

Abstract

A 60-year-old woman was admitted to the hospital with worsening dyspnoea, cough and chest pain. This was on a background of weight loss, decreased appetite, mononeuritis multiplex, chronic eosinophilia and a single episode of a non-blanching rash. Investigations demonstrated a raised troponin and ischaemic changes on ECG, and she was therefore initially treated for a presumed myocardial infarction. However, her symptoms failed to improve with treatment for the acute coronary syndrome. A coronary angiogram revealed no significant flow-limiting disease, and further investigations yielded confirmation of raised eosinophils and a positive perinuclear antineutrophil cytoplasmic antibody test. An echocardiogram demonstrated a pericardial effusion, and subsequent cardiac magnetic resonance features were compatible with myopericarditis. In light of these findings, the patient was diagnosed with eosinophilic granulomatous with polyangiitis and commenced on high-dose intravenous methylprednisolone and cyclophosphamide. She made an excellent recovery and remains in remission on azathioprine and a tapering dose of corticosteroids.

Background

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a rare multisystem necrotising vasculitis, affecting small-to-medium-sized vessels.¹ EGPA is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly involving myeloperoxidase ANCA, also known as a perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^{2 3} Incidence rates have been reported as 2.7/million in the UK.⁴ The disease is characterised by asthma, blood hypereosinophilia, tissue infiltration with eosinophils, and granulomatous inflammation and vasculitis.⁵ Commonly involved organ systems include the nervous system, lungs and skin. However, EGPA can affect almost any part of the body, including the cardiovascular system.⁶

Cardiac involvement in EGPA can occur in up to 60% of patients and is an indicator of poor prognosis, with 48% of deaths attributable to cardiac disease.⁷ Cardiovascular disease complicated by EGPA is more challenging to treat than a stand-alone disease. Presentations of cardiovascular disease in EGPA may include eosinophilic vasculitis, pericarditis, pericardial effusion, cardiac valve disease, cardiomyopathy and myocarditis, as well as acute myocardial infarction and cardiac failure.⁸

Here, we present a case of myopericarditis as the first presentation of EGPA. The case demonstrates several aspects of this multisystem disease, including the need for thorough clinical history and knowledge of prior presentations to other specialties, involvement of the multidisciplinary team (MDT) and prompt intervention once the disease is identified, especially given the severity of symptoms at the time of presentation.

Case presentation

A 60-year-old female financial adviser presented to the accident and emergency (A&E) department with worsening difficulty in breathing, cough and non-radiating central chest pain. This was on a background of worsening respiratory symptoms over the preceding 2 months. Specifically, she had a persistent cough with breathlessness on minimal exertion. In addition, she reported reduced appetite, and 12 kg weight loss in 2 months. In addition, on further questioning, the patient reported one episode of a non-blanching rash over her ankles 2 weeks prior to admission, as well as intermittent but worsening numbness of the lower limbs.

She was given a diagnostic label of asthma in her 40s, and had a history of recurrent sinus infections. The patient had previously undergone resection of her uterus, ovaries and cervix. In light of ongoing breathlessness and cough, the patient had recently undergone a bronchoscopy with broncheo-alveolar lavage (BAL), which yielded nil significant findings, including negative tests for IgE-specific and IgG-specific antibodies to Aspergillus. Of note, she was noted to have persistent eosinophilia in the month preceding this acute presentation.

She was a never-smoker, and there was nil significant family or travel history. While she had previously been independent with activities of daily living and mobility, she reported requiring increasing help from family members with these. The patient reported being low in mood over the past 2 months, especially with regards lack of energy, low appetite, and worsening chest symptoms despite multiple antibiotics. The numbness in her feet was also leading to unsteadiness and increased falls.

On examination, she was hypoxic (oxygen saturation of 90% at room air), tachycardic (113 bpm) and apyrexial, although intermittent fevers were reported over the preceding days. Examination of the chest demonstrated decreased air entry and fine crepitations bibasally. Heart sounds were normal with no murmurs or adventitious sounds audible. Neurological examination demonstrated bilateral lower limb weakness with patchy areas of numbness and unsteady gait, consistent with mononeuritis multiplex.

Investigations

An ECG in A&E showed new T-wave inversion in leads V₂–V₆. Both Nt-pro-brain natriuretic peptide levels (1890 pg/mL; normal range, <125) and sequential troponin-I levels (284 and 403 ng/L; normal range, 0–14) were elevated. In light of these findings, the patient was treated for a non-ST-elevation myocardial infarction, with decompensated heart failure.

A D-dimer test was raised at 1.79 mg/L (0.01–0.49), prompting a CT pulmonary angiogram (CTPA) to rule out pulmonary emboli (PE). This was negative for PE, but a small left-sided basal pleural effusion was noted, as well as extensive hilar lymphadenopathy. An echocardiogram showed preserved left ventricular systolic function and normal valvular function, with a 0.5 cm pericardial effusion. A coronary angiogram revealed normal epicardial coronary arteries, with no significant flow-limiting disease. In light of these results, combined with chest pain, raised troponins and intermittent fevers, a cardiac magnetic resonance imaging (CMRI) scan was performed (figure 1). This confirmed the presence of a moderate circumferential pericardial effusion, most prominent adjacent to the lateral wall of the left ventricle (LV). Late gadolinium enhancement imaging revealed patchy hyperenhancement in the anterior and lateral segments of the LV in a non-infarct pattern. The CMRI features were consistent with a diagnosis of myopericarditis.⁹

Figure 1.

Cardiac MRI findings. Cine images in (A) long-axis and (B) short-axis orientations demonstrating a circumferential pericardial effusion (white arrows) most prominent, adjacent to the lateral wall of the left ventricle. Short-axis LGE images demonstrating (dashed white arrows) a focal area of high signal intensity in the mid-wall of the anterior segment and more diffuse areas of high signal intensity in the lateral segments (note—‘nulled’ dark appearance of ‘normal’ myocardium in the interventricular septum for comparison). Pericardial effusion (white arrows) also appears dark in LGE images. LGE, late gadolinium enhancement.

Full blood count demonstrated a white cell count (WCC) of 24.5×10⁹/L and eosinophils of 17×10⁹/L (0–0.8), on a background of 1 month’s preceding eosinophilia. Renal function was normal, although microscopic haematuria was noted on urine dipstick testing.

Electrophysiological studies showed abnormalities consistent with length-dependent non-confluent multiple mononeuropathy with a patchy myogenic abnormality, consistent with a mononeuritis multiplex.

In light of these results and to confirm a probable diagnosis of eosinophilic granulomatosus with polyangiitis (EGPA), a vasculitis screen was requested, which yielded p-ANCA level of 15 IU/mL (<3.5), along with a total IgE of 643 kU/L (<100).

Differential diagnosis

The patient was reviewed extensively by the cardiology, respiratory and rheumatology teams early in admission. She was treated as having the acute coronary syndrome in the emergency department, in light of her cardiological parameters and ECG. However, this failed to explain her severe and worsening respiratory symptoms, systemic symptoms of weight loss, fever and decreased appetite, as well as rash and new neurological findings and high eosinophil count.

This patient’s eosinophilia had many possible causes. A recent BAL had ruled out Aspergillus (a cause of high IgE and eosinophilia), and bronchoscopy and CTPA had confidently ruled out a lung carcinoma and lymphoma, which may give rise to a paraneoplastic eosinophilia. Eosinophilia is also seen in certain parasitic infections, but the patient denied a recent history of foreign travel, rarely leaving her immediate geographical area. In light of the extensive hilar lymphadenopathy noted on CTPA, fulminant respiratory symptoms and evidence of possible fibrosis on CMRI, a diagnosis of sarcoidosis was considered. However, a serum ACE level was within the normal range and no granulomata were seen on CT scan of the chest.

Based on this, her cardiac imaging results, and following combined review by the MDT, the patient was diagnosed as having myopericarditis secondary to EGPA. In addition to her presenting signs and symptoms on admission, her history of chronic sinus infections, previous diagnosis of asthma, raised p-ANCA titre and total IgE, and mononeuritis multiplex gave support to this conclusion.

Treatment

Approximately 1 week after admission, the patient was commenced on high-dose (1 g) intravenous methylprednisolone, followed by a course of oral corticosteroids and intravenous cyclophosphamide, with proton pump inhibitor and bisphosphonate therapy for prophylaxis against steroid-induced side effects. This was in accordance with the CYCLOPS regime detailed in the current national and international guidelines for the treatment of ANCA-associated vasculitis.¹⁰

Almost immediately on commencing treatment, the patient reported increased appetite and energy levels, improved mood and decreased peripheral neuropathy with improved mobility, aided by physiotherapy intervention.

Outcome and follow-up

The patient’s respiratory and neurological symptoms continued to improve over the week following commencement of corticosteroids and cyclophosphamide, including improvements in balance and mobility through physiotherapy. She was successfully discharged 2 weeks after admission.

She continues to be followed-up in the cardiology, rheumatology and respiratory clinics. A repeat echocardiogram at 6 months revealed a small effusion around the lateral wall of the right ventricle, which has continued to remain minimal in size, with good left ventricular systolic function. WCC, including eosinophil count, remains within the normal range. She has remained in remission on azathioprine and a tapering dose of prednisolone. She continues to have intermittent respiratory infections, but, overall, her breathlessness is much improved. Motor strength is normal, aside from mild weakness in right ankle dorsiflexion, and there is some residual distal sensory disturbance.

Discussion

Cardiac involvement is present in 60% of patients with EGPA and is the leading cause of death in patients with EGPA,^{3 11 12} accounting for 50% of fatalities. Cardiac manifestations include cardiomyopathy, myocarditis, myocardial infarction and congestive cardiac failure. ANCA-positive patients have a propensity to have renal disease, peripheral nervous system disturbance and/or alveolar haemorrhage, whereas the ANCA-negative phenotype more commonly has cardiac involvement, lung infiltrates and/or systemic manifestations.¹³ However, further analyses demonstrated no relationship between ANCA and outcomes of myopericarditis. Early stages of cardiac involvement may remain subclinical for long periods of time, subsequently presenting with fulminant clinical signs.

To our knowledge, few cases exist in the literature specifically detailing myopericarditis as a presenting feature of EGPA. In all reported cases, patients consistently have a pre-existing diagnosis of asthma. One group reported a case of fatal myopericarditis in a 51-year-old man, diagnosed with asthma and noted to have eosinophilia, 6 weeks prior to death.¹⁴ Death due to myocarditis alone is highly unusual, which prompted a postmortem investigation in this case, highlighting the importance of further investigation for a secondary cause in patients presenting systemically unwell with symptoms refractory to standard therapy. A second group detailed a case of cardiac tamponade leading to a new diagnosis of EGPA, even rarer than myopericarditis, and indicative of increased severity of disease.¹⁵ In all cases, the increasingly recognised role for CMRI is highlighted^{7 16} although this does not form part of the official guidelines for the management of EGPA, and more extensive studies are certainly warranted for its use in this setting, especially given the paucity of data, mostly derived from individual case reports.

In all of the above cases, including ours, patients in fact fulfilled all of the American College of Rheumatology guidelines for diagnosis of EGPA at the time of presentation¹⁷ (four of the following six required: asthma; eosinophilia >10%; migratory pulmonary infiltrates; mononeuropathy or polyneuropathy; sinusitis, nasal polyps or rhinitis; histological demonstration of extravascular eosinophils in biopsy samples), highlighting a need to consider this diagnosis in patients presenting systemically unwell on a background of respiratory disease.

The European League Against Rheumatism have published extensive guidelines on the management of EGPA, including those with multiorgan involvement.¹⁰ For new-onset, organ-threatening or life-threatening ANCA-associated vasculitis, it is recommended to commence glucocorticoids with cyclophosphamide or rituximab for remission induction. These should be administered alongside prophylaxis against osteoporosis and gastritis side-effects of high-dose glucocorticoids, as well as prophylaxis against infection in cases of leucopenia. For remission maintenance, low-dose glucocorticoids with azathioprine are recommended. Although oral cyclophosphamide would be an option for remission maintenance, its toxicity in the long term and the equivalent efficacy of azathioprine makes this the superior option.^{18 19} Remission maintenance is then recommended for at least 24 months following induction of remission although there are as yet no published randomised-controlled trials to compare the duration of maintenance regimens. It is, however, known that early therapy cessation increases the risk of relapse.

There was no indication to deviate from the above guidelines, thus, our patient was treated in accordance with recommended practice. However, few data exist on the management of cardiac involvement in EGPA, which, given the prevalence of morbidity and mortality associated with this organ system, indicates a need for further investigations particularly into avoiding late diagnoses (and therefore acute cardiovascular presentations of EGPA). This includes indications for the use of imaging methods such as cardiac MRI.

In summary, we present a case of acute myopericarditis leading to a new diagnosis of EGPA. This case highlights the need to consider this diagnosis in patients presenting with asthma-like symptoms and chronic lung or sinus pathology refractory to standard therapy, as well as persistent eosinophilia of unknown cause. It also demonstrates the benefit of the prompt intervention, through the rapid improvement seen in the patient’s disease and illness experience, following the commencement of high-dose immunosuppression.

Learning points.

• Patients with a history of difficult and persistent asthma and nasal polyposis, and/or those with persistent eosinophilia, should be screened for eosinophilic granulomatosis with polyangiitis (EGPA) with antineutrophil cytoplasmic antibodies, as the presentation may be indolent and variable.

• Patients with the above presentation and those diagnosed with EGPA with low disease activity should be followed-up closely for disease evolution.

• Acute cardiac pathology may herald the first presentation of EGPA.

• Prompt intervention with high-dose corticosteroids and cyclophosphamide induces remission in most cases of EGPA and should not be delayed due to irreversible and rapid organ damage that can otherwise occur.

• EGPA is a multisystem disorder, optimally managed with the input of the multidisciplinary team.