Pathologic Quiz Case: A Young Woman With Eosinophilia and Heart Failure

A 29-year-old African woman, living in Canada for 3 years, presented with 3 weeks of dysphagia, cervical lymphadenopathy, and a productive cough that failed to respond to 2 courses of antibiotics. She complained of progressive chest heaviness, dyspnea, orthopnea, fever, chills, night sweats, generalized weakness, nausea, and vomiting. She denied arthralgia, myalgia, rashes, or joint pain. Her past history included remote tuberculosis, successfully treated; multiple hereditary osteochondromatoses; and eosinophilic pneumonia. Previous investigations did not find a satisfactory etiology for the eosinophilia. She had no history of atopy or asthma.Physical examination showed heart rate of 122 beats per minute, blood pressure of 97/64 mm Hg, and tachypnea. She had bilateral pulmonary rales, a third and fourth heart sound, and jugular venous distension. There was no pulsus paradoxus, murmurs, or pedal edema.Her chest radiograph showed right middle and lower lobe pulmonary infiltrates and cardiomegaly. Electrocardiogram showed sinus tachycardia. Radionuclide ventriculogram demonstrated mild to moderate left ventricular cavity dilatation, decreased left ventricular ejection fraction (38%), and moderate apical hypokinesis. Her leukocyte count was 9900/μL (normal range, 4000–11 000/μL), with an elevated eosinophil count of 2970/μL (normal range, 40–440/μL). Prior elevated eosinophil counts of greater than 7000/μL had been observed during a 2- to 3-year period. Serum creatine kinase was elevated, at 453 IU/L (normal range, 20–160 IU/L), and troponin T was elevated as well, at 5.80 μg/L (normal, <0.01 μg/L). Anti-neutrophil cytoplasmic antibody screen was negative, but rheumatoid factor was elevated, at 161 kIU/L (normal, <20 kIU/L).The patient was given inotropic support and diuretics, and when stable, she underwent a right ventricular endomyocardial biopsy. The biopsy showed mild fibrosis and severe active eosinophilic myocarditis (Figure, A) with myocyte necrosis and eosinophilic granulomas (Figure, B). The endocardium had a severe lympho-eosinophilic inflammatory infiltrate with organizing thrombus with fibroblasts. Bone marrow aspirate showed eosinophilic hyperplasia with a moderate increase in eosinophilic precursors.The patient developed a pruritic papular rash and severe submandibular pain and fullness. High-dose prednisone therapy resulted in dramatic improvement in all symptoms. The dose was tapered slowly. Attempts to stop the steroid resulted in recurrent episodes of eosinophilic pneumonia that were responsive to therapy.What is your diagnosis?The hypereosinophilic syndrome was clearly described in 1968 by Hardy and Anderson.1 The incidence of hypereosinophilic syndrome (HES) is estimated at 1 to 2 cases per 200 000 people per year. Whites are affected more than blacks, and men more often than women (9:1). The condition typically affects individuals aged 20 to 50 years. Hypereosinophilic syndrome may affect any organ system. Eosinophils release toxic substances, including eosinophil-derived neurotoxin, cationic protein, major basic protein, reactive oxygen species, and arachidonic acid derivatives. These may cause endothelial and myocyte damage, resulting in thrombosis, fibrosis, and infarction.The differential diagnosis includes hypereosinophilia secondary to malignant disease, parasitic infection, atopy or allergy, eosinophilic leukemia, chronic eosinophilic pneumonia, and Churg-Strauss syndrome.2 Churg-Strauss may involve the same organ systems seen in HES, but the absence of asthma, clinically evident vasculitis, and renal disease likely excludes this condition in the current patient.Proposed diagnostic criteria for idiopathic HES include blood eosinophilia >1500/μL for more than 6 consecutive months, absence of an identifiable cause, and evidence of multiorgan damage/dysfunction.3 Hypereosinophilic syndrome affects a wide range of organs and has been given different names depending on the predominant presentation: Loeffler syndrome, Loeffler endocarditis parietalis fibroplastica, disseminated eosinophilic collagen vascular disease, and eosinophilic leukemia.4 The lungs, heart, liver, skin, and nervous system are most frequently involved. Although the condition is thought to result in early mortality, the hallmark of this disease is its great clinical heterogeneity, ranging from minimally symptomatic to rapidly fatal.Cardiac manifestations are seen in more than 60% of patients with HES and are generally referred to as "Loeffler endocarditis." Endomyocardial fibrosis, ventricular hypertrophy, cardiomegaly, atrial enlargement, and pericardial effusion are described. Serious sequelae include myocardial infarction, arrhythmias, ventricular failure, and restrictive cardiomyopathy. The evolution of the pathology of myocardial hypereosinophilia involves a necrotic stage, often asymptomatic; a thrombotic stage with mural thrombi; and finally a fibrotic stage with endomyocardial fibrosis, often with valve immobility and heart failure.In a 9-year retrospective study of patients with cardiac manifestations of HES, echocardiography was a sensitive method to detect disease.5 Echocardiography detected 82% of affected individuals, often preclinically, compared with 55% who had electrocardiogram, radiograph, or clinically evident disease. The diagnostic gold standard remains endomyocardial biopsy.Echocardiography may demonstrate atrioventricular valve regurgitation secondary to thrombus and fibrosis of valvular leaflets, chords, or papillary muscles. Decreased ventricular compliance and impaired diastolic filling are seen with restrictive cardiomyopathy. An association between atherosclerotic coronary artery disease and Loeffler endocarditis has been postulated. Coronary artery disease should be considered as a cause of angina in these relatively young HES patients.5Chronically, marked fibrosis may involve the endocardium and the adjacent myocardium. There may be granulation tissue, and superficial regions may show fibrin, thrombus, calcium, and a large number of eosinophils. Intramural coronary vessels may have thrombosis, fibrinoid change, and perivascular inflammatory cell infiltrates.5 Eosinophils often extend deep in the myocardium. Endomyocardial biopsies from patients with advanced disease may show only endomyocardial fibrotic thickening, with few or no eosinophils.5Corticosteroids, with or without hydroxyurea, have been found to potentially stabilize or delay ultimate progression to heart failure. Myeloproliferative and lymphocytic variants of HES have been identified.4 Imatinib myselate, a tyrosine-kinase inhibitor, can suppress clinical disease in some patients. This has led to the identification of a constitutively active tyrosine-kinase fusion protein, PDGFRα-FIL1L1, in a subset of imatinib myselate–responsive patients.6 This may represent the underlying molecular aberration responsible and may be a potential therapeutic target for some forms of HES.478 Elucidation of the molecular and genetic features of this disease is leading to a growing disregard for the term idiopathic and may result in targeted pharmacologic therapy.

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