Summary
Eosinophilia may be responsible for cardiac injuries of widely varying severity, from acute myocarditis to endomyocardial fibrosis. In this review, we present both the molecular mechanisms that are responsible for these lesions and their clinical and paraclinical aspects. Numerous aetiologies can lead to severe eosinophilia, but these are mainly represented by hypersensitivity reactions, rheumatological diseases and hypereosinophilic syndrome. Because cardiac involvement may be extremely severe, echocardiography should be always performed in the context of eosinophilia and appropriate therapeutics should be started rapidly in order to limit the progression of the disease.
Résumé
Une hyperéosinophilie peut être responsable de lésions cardiaques dont la sévérité est très variable, allant de la myocardite aiguë jusqu’à la fibrose endomyocardique. Nous présentons, à travers cette revue de la littérature, les mécanismes moléculaires qui entraînent ces différentes lésions ainsi que leurs aspects cliniques et paracliniques. Si de nombreuses étiologies peuvent être responsables d’hyperéosinophilie, les réactions d’hypersensibilité, les maladies rhumatologiques et le syndrome d’hyperéosinophilie en sont les principales causes. Parce que l’atteinte cardiaque peut être extrêmement sévère, une échocardiographie doit être systématiquement réalisée en cas d’hyperéosinophilie et un traitement approprié doit être débuté rapidement afin de limiter la progression des lésions.
Introduction
Eosinophilic cardiac disease is a relatively rare condition that was first described in 1936 by Wilhelm Löffler, who called it ‘fibroplastic parietal endocarditis with blood eosinophilia’ . Also known as Löffler’s endocarditis, eosinophilic endomyocardial fibrosis (EMF) is an uncommon cause of restrictive cardiomyopathy. In fact, several types of cardiac damage may be encountered in the context of eosinophilia, from acute myocarditis to EMF. All result from toxicity of infiltrating eosinophils into cardiac tissue. The aim of this review is to present both the mechanisms that underlie these lesions and their clinical aspects, imaging features and specific treatments.
Physiology and pathophysiology of eosinophils
Eosinophils are normally found in the blood and in certain tissues. These granulocytes are involved in normal antimicrobial immunity . They have surface proteins for immunoglobulin (Ig)E binding to IgE antigen complexes by which phagocytosis and release of granules is triggered. Indeed, when stimulated, eosinophils possess the ability to elaborate substances that are toxic to a wide variety of parasites that are too large to phagocytose . Their usual location in the body (respiratory tract, gastrointestinal tract and skin) is therefore explained by this antiparasitic activity. They measure 12–15 μm in diameter and are characterized by a bilobed nucleus and numerous eosin-staining specific granules in their cytoplasm . These granules contain high concentrations of hydrolases and cationic and basic proteins ( Fig. 1 ).
Production and kinetics
Along with the other polymorphonuclear leukocytes, eosinophils are produced by the bone marrow, where they represent up to 6% of the resident nucleated cells . Under the influence of several cytokines, the haematopoietic stem cells gradually differentiate into eosinophilic myelocytes and then into mature eosinophils ( Fig. 1 ). This maturation process takes approximately 8 days. The main cytokines responsible for the increase in eosinophil number are granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5. IL-5 – produced by T helper 2 lymphocytes – is specific for the production of eosinophils and is considered to be their major growth factor . It is also involved in survival, chemotaxis and degranulation. Eosinophils remain in the peripheral blood for 8–12 hours before migrating preferentially to certain tissues where they are concentrated: the respiratory tract, the gastrointestinal tract, the skin and the urogenital tract (in females). Eosinophils survive for 1–2 weeks unless apoptosis is prevented by cytokines (GM-CSF, IL-3, IL-5) .
Composition
The cytoplasm of eosinophils is filled with many eosin-staining specific and non-eosinophilic granules. As eosinophils are involved in the inflammation process and in innate and adaptive immunity, the specific granules are capable of inducing tissue damage and dysfunction by degranulation following activation by an immune stimulus. They contain cationic proteins: major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO) ( Fig. 1 ). These proteins have several effects including production of free radicals, cell necrosis and apoptosis induction. These eosinophilic constituents are very deleterious to the endothelial cells and are capable of activating platelets and impairing the anticoagulant effects of thrombomodulin . Finally, the endocardium appears to be very sensitive to the release of these cardiotoxic agents, especially MBP and ECP .
Definition of eosinophilia
Eosinophils are present in the blood in small numbers: the normal count of circulating eosinophils is ≤ 350/mm 3 , for both adults and children. Mild eosinophilia is defined by a level of 500–1500 eosinophils/mm 3 . A count of 1500–5000 eosinophils/mm 3 is considered as moderate and > 5000 eosinophils/mm 3 is a significant eosinophilia .
Cardiac toxicity
The degree of damage associated with eosinophilic infiltration of tissue appears to be related to the stimulus attracting the eosinophils, the duration of eosinophilia and the degree of eosinophil activation. Indeed, deleterious effects on tissues, particularly on the heart, are more common in cases of profound eosinophilia (> 5000/mm 3 ). According to Gottdiener et al. , three phases are classically described. The first stage is due to eosinophilic infiltration into the tissues and leads, after the release of granular proteins, to cells necrosis. When biopsies are performed, they consistently show deposits of MBP, ECP and EPO. The second phase is represented by thrombosis formation. Because the cationic proteins of eosinophils bind to the anion-binding exosite of thrombomodulin, the complex thrombomodulin-thrombin cannot form and it loses its anti-thrombotic role. Indeed thrombomodulin, by binding to the circulating thrombin, is a potent physiological inhibitor of coagulation ( Fig. 2 ). The third stage corresponds to fibrotic scarring. In the final stage, cardiac endothelium and valves become fibrotic and thickened, resulting in a non-compliant ventricle, initially defined as Löffler’s fibroplastic endocarditis .
Causes of eosinophilia
Many diseases may be responsible for eosinophilia but not all cause profound eosinophilia. The most common aetiologies are reported in Table 1 . The first step is to exclude reactive eosinophilia . Indeed, some drugs (anticonvulsants, non-steroidal anti-inflammatory drugs, antimicrobial agents, sulfonamides) are well known to trigger an abnormal production of eosinophils. Eosinophilia may be the sole manifestation of a drug-induced hypersensitivity reaction. When a drug-related eosinophilia is associated with a morbilliform eruption and severe tissue damage, this condition is called drug rash with eosinophilia and systemic symptoms (DRESS) syndrome . Withdrawal of the offending drug usually results in normalization of the eosinophil count within 7–10 days . Cases of post-vaccination eosinophilic myocarditis (after smallpox or diphtheria/tetanus/pertussis vaccines) have also been reported . Thereby, in the presence of significant eosinophilia, an empirical anti-helminthic drug therapy should be started immediately. Other aetiologies are mainly represented by systemic diseases, malignancies and hypereosinophilic syndrome (HES).
| Reactive eosinophilia |
| Drugs (hypersensitivity) |
| Anticonvulsants |
| Non-steroidal anti-inflammatory drugs |
| Antimicrobial agents |
| Sulfonamides |
| Infections |
| Helminths |
| Human immunodeficiency virus |
| Human T-lymphocyte virus I |
| Tuberculosis |
| Allergic diseases |
| Systemic diseases |
| Crohn’s disease |
| Churg-Strauss syndrome |
| Wegener’s granulomatosis |
| Polyarteritis nodosa |
| Rheumatoid arthritis |
| Cholesterol crystal embolism |
| Malignancies |
| Hodgkin lymphoma |
| Non-Hodgkin lymphoma |
| Acute leukaemia |
| Systemic mastocytosis |
| Hypereosinophilic syndrome |
| Lymphocytic variant |
| Myeloproliferative variant |
Hypereosinophilic syndrome
HES is a heterogeneous group of rare haematological disorders characterized by unexplained and sustained blood eosinophilia. Chusid et al. defined HES as an eosinophilia > 1500/mm 3 for longer than 6 months, without any secondary cause and with evidence of organ involvement. HES is consecutive to a clonal proliferation of myeloid precursor cells. It occurs in several myeloproliferative disorders associated with tyrosine kinase mutations or translocations. Although more common between 20 and 50 years of age, this entity is sometimes encountered in children and is more common in males . Whereas dermatological, pulmonary and gastrointestinal involvement seems to be more common, the involvement of the cardiovascular system represents the major source of morbidity and mortality . In children, HES is commonly associated with chromosomal abnormalities. A new classification, introducing the concepts of variants, was recently proposed . As their clinical presentations, treatments and prognoses are different, two subtypes of HES must be recognized: a lymphocytic variant of HES (L-HES) and a myeloproliferative variant or chronic eosinophilic leukaemia. Bone marrow cytogenetic analysis and fluorescent in-situ hybridisation are essential for their diagnosis. Indeed, an FIP1L1-PDGFRA (FP) fusion gene, created by an 800-kb deletion at the 4q12 locus, was discovered in the majority of myeloproliferative variants . Thus, patients with FP mutation are likely to have the myeloproliferative variant of HES as opposed to L-HES. The product of this fusion gene is a constitutively active protein-tyrosine kinase capable of transforming haematopoietic cells into eosinophil precursors. It explains the fact that a well-known tyrosine kinase inhibitor, imatinib, is completely effective in 88% of FP-positive patients . However, some patients with myeloproliferative variant are FP-negative and therefore do not respond to imatinib. The L-HES variant is characterized by a deregulation of the lymphocyte homeostasis, resulting in an increased secretion of cytokines (IL-5). In this case, corticosteroids are the first-line therapeutic agents. For the resistant forms, an anti-IL-5 therapy (mepolizumab) is recommended . Whereas the L-HES variant is less deleterious for the heart, the transformation into acute leukaemia seems to be more common, especially for children .
Eosinophilic cardiac injuries
The heart is one of the most frequently involved organs in cases of sustained eosinophilia . In the Löffler’s post-mortem examination of two patients with chronic eosinophilia, cardiac involvement was characterized by fibrosis that obliterated the ventricles . It is now recognised that EMF is the ultimate form of eosinophilic cardiac disease. Classically, cardiac injuries of eosinophilia are divided into three chronological phases: eosinophilic infiltration, thrombosis and fibrosis .
Endomyocardial injuries: three successive phases
Eosinophilic myocarditis (acute necrotic stage)
The early phase is characterized by an eosinophilic endomyocarditis with eosinophil and lymphocyte infiltration . When infiltrating cardiac tissues, eosinophils degranulate and release toxic cationic proteins, thus inducing necrosis and apoptosis. However, patients generally have no cardiac symptoms during this stage and they may present only non-specific signs . Clinical and in vivo recognition of eosinophilic myocarditis is infrequent, whereas it accounts for up to 0.5% of unselected myocarditis autopsy series . Electrocardiography (ECG) may show sinus tachycardia, supraventricular tachycardia, non-specific ST-segment anomalies or conduction delays, but is often unremarkable. Echocardiography reveals an increased left ventricular wall thickness because of interstitial myocardial oedema ( Fig. 3 A , Video 1 ). Endomyocardial biopsy is necessary to make the diagnosis and to differentiate eosinophilic myocarditis from other types of myocarditis. Indeed, histological sections show eosinophilic infiltration of the endocardium and subendocardial interstitium, evidence of myocardial necrosis and sometimes eosinophilic granulomas ( Fig. 4 ) . At this stage of the disease, the aim of treatment is to rapidly lower the eosinophil count in order to limit myocardial necrosis.
