An 8-year-old patient presented to the Emergency Department of the Children's Clinical University Hospital (CCUH) in the late evening in August 2021, complaining of an acute febrile illness for 3 weeks with an intermittent febrile body temperature above 38  C, accompanied by submandibular oedema, abdominal pain, loose stools, joint pain, and pain and tightness in her chest. The general practitioner had previously diagnosed an Epstein-Barr virus infection clinically, but the EBV IgM was negative, while the EBV IgG was positive. The patient was treated with amoxicillin/clavulanate for a week and has since then developed persistent diarrhoea. The patient had a diagnosis of bronchial asthma for 1 year with a need for the intermittent use of inhalation with salbutamol and fluticasone propionate due to a dry cough, but with no severe asthmatic episodes. On admission, her body temperature was 37.7 C, tachycardia 165 beats/minute, normal arterial pressure 110/50 mmHg, no cardiac murmurs or pulmonary rales audible, a respiratory rate 40 times per minute, SpO2 96%, no hepatomegaly and negative meningeal symptoms. The patient's blood tests showed HES, fulfilling the criteria: severe leucocytosis WBC 102.34 x103 uL, eosinophilia 24.9%, absolute eosinophilia 25.53x103/uL, thrombocytopenia 72x103/ uL, erythrocytes 4.32x106/ microL, CRP 87 mg/L, LDH 994 U/L, ferritin 1306 ng/mL, total IgE > 2000 U/mL, EGA 48 mm/h, pANCA and cANCA negative, ANA positive 1:1280, EBV IgM positive, troponin I 1880.4 pg/ml (acute myocardial involvement/myocarditis suspected) and ProBNP 6786 pg/ml. While at the emergency department, the child complained about generalized pain in her body and was not able to move her right hand or her right leg. The computed tomography (CT) of the head without contrast showed no signs of haemorrhages but thickened mucous membranes in all paranasal sinuses. Magnetic resonance imaging (MRI) of the head was performed and revealed: acute cerebral infarcts of various sizes, localized in the cerebellum, in all lobes of the large hemispheres in the anterior, posterior, and inferior border basins. The finding might be consistent with hypereosinophilia syndrome.
To exclude the diseases of the hematopoietic system, blood tests for flow cytometry and cytogenetics of peripheral blood were sent to the laboratory at Vilnius Hospital and excluded the myeloproliferative process. No significant findings related to HES were found by flow cytometry in the peripheral blood and bone marrow. No signs of clonality in TCRB, TCRG or TCRD genes were detected. In the bone marrow biopsy, hypercellularity was found with a predominance of eosinophils, but no atypical eosinophils, platelets or increased blast count were found, corresponding to secondary HES.
Serology of the blood was performed to exclude parasitic diseases (toxoplasma, toxocara, taenia solium, trichinella or echinococcus), and cryptococcus antigens in the blood were excluded. Other probable causes such as tuberculosis, entero and coxacki, and HIV viruses were excluded. The patient had positive Toxocara canis IgA and a subsequent positive Western blot test. She, therefore, also received treatment with albendazole to treat the possible cause of hypereosinophilic syndrome.
Echocardiography showed a normal cardiac anatomy with slightly decreased functioning of the right ventricle (TAPSE 14 mm), hypertrophy of the right ventricle (RV) (RV free wall 11 mm), normal functioning of the left ventricle, but mild hypertrophy of the ventricular septum.
Her cardiac MRI was consistent with a presentation of acute myocarditis: late gadolinium enhancement, subendocardially diffuse in the right ventricle, and also in the inferior and lateral wall of the left ventricle, ejection fraction (EF) of the left ventricle of 41%, hypokinesia in the apex and posterior wall of the left ventricle, hypertrophy of the free wall of the right ventricle and severe hypertrophy of the apex of the right ventricle, diffuse oedema of the right ventricle and local oedema in the anterior and posterior walls of the left ventricle.
A thoracic CT showed right-sided pleural effusion up to 1.5 cm, small infiltrates in the right lower lobe segments S8 and S9. No evident hyperplasia of the intrathoracic lymph nodes.
Abdominal ultrasound and ophthalmological examinations were without pathology.
The patient's treatment was discussed in a multidisciplinary consilium together with paediatric haematologists, paediatric rheumatologists, pneumonologists, cardiologists, neurologists, and immunologists. The diagnosis was hypereosinophilic syndrome with ischemic stroke and suspected eosinophilic myocarditis (the myocardial biopsy was not taken because of possible complications), but EGPA was considered as a possible differential diagnosis, as was the possibility of development of a myeloproliferative disorder.
Based on the "Guidelines for the Investigation and Treatment of Eosinophilia": the patient received methylprednisolone bolus intravenously followed by oral methylprednisolone 40 mg (14 days), then 36 mg (7 days) and 32 mg (7 days), with slow weaning then according to the scheme. Long term treatment with Medrol (slowly weaning during the next 3 months as suggested by the rheumatologist) led to the development of exogenous Cushing's syndrome (initially the patient's weight was 49 kg (+2.42z, BMI 25.4 kg/m2, but her weight increased afterwards to 74 kg (+3.24z, BMI 33.3 kg/m2). With this acute episode, the patient was treated in the CCUH for 41 days. She received a low molecular weight heparin (enoxaparin) therapeutic dose for 7 days, then a prophylactic dose which was changed to oral rivaroxaban for 6 months. Due to initial persistent tachycardia, myocardial hypertrophy, and inflammation, she received carvedilol 3.125 mg twice a day in the long term. The patient underwent rehabilitation and the paresis of the right leg already disappeared during the hospital stay, and after discharge, her right hand function improved fully within the next 3 months (the patient regained her right handwriting skills).
The patient's progress was followed up by a cardiologist, haematologist, pneumonologist and neurologist. In the echocardiography, hypertrophy of the right ventricle had decreased. Two months after her discharge from the hospital, her blood count showed eosinophilia 0% and absolute numbers of eosinophilia 0x103/uL.
The follow-up MRI of the heart performed on February 2022, 6 months after the first MRI, showed significant improvement in both ventricular functions, with left and right ventricular volumes within normal limits and without enlargement. Myocardial hypertrophy was still visualized in the right ventricle and was more pronounced in the distal segment of the apical region, where the residual abnormal myocardial gadolinium enhancement with a subendocardial oedema had markedly decreased but was still persistent. The myocardial morphological lesion had markedly regressed.
At the end of May 2022, the patient developed an oedema of the right upper eye lid. Tobradex (eye drops containing tobramycin and dexamethasone) were prescribed, but the oedema spread over the right side of the face and especially the right orbita during the next five days. The patient was hospitalized at the CCUH. Blood analyses showed eosinophilia 16.7%, leukocytes 10.74 x 103, erythrocytes 5x106 micro/L, thrombocytes 460 x 103 micro/L and CRP 1.61 mg/L. The ophthalmologist noted that the right eye was sensitive to the left and left downward view, and that there was restriction of movement to the upward view, but the left eye was mobile to a lesser extent. The left eye had a full range of movement. A conclusion of right sided pre-septal and post-septal cellulitis was made. The otolaryngologist detected that the mucous membrane was pink and slightly oedematous.
To clarify the inpatient diagnosis, the patient underwent a biopsy of the inflammatory foci: in the ethmoid tissue there was constant lymphohistiocytic and eosinophilic inflammation with 30-50% eosinophilic ipsilateral infiltrate cells; granulomatous and chronic perivascular inflammation with eosinophils was found in the striated muscle tissue, which might be consistent with EGPA. Based on scientific articles, the early use of steroids (this patient received Medrol therapy) for a brief period could help to shorten hospitalization and prevent the progress of the inflammation. As the patient had Cushing's syndrome, and according to the bone marrow and blood tests, the consensus was to continue treatment with prednisolone (Medrol) orally 60 mg/day and, in parallel, to initiate pathogenetic therapy with anti-Il-5 antibody mepolizumab subcutaneously due to the relapsing course of the disease, long-lasting corticosteroid side effects and the suitability of the drug for idiopathic HES, L-HES phenotype and HES-eosinophilic granulomatosis with polyangiitis overlap.