Individuals affected by IHS may be asymptomatic, but those that develop LE often report fever, chills and chest pain. Physical examination during that stage of the disease may reveal lymphadenopathy and splenomegaly.
Impaired diastolic compliance is associated with exacerbating dyspnea, cough, congestion of neck veins and generalized edema. Patients lose weight, claim fatigue and intolerance to exercise. During auscultation, a third heart sound and murmurs due to atrioventricular regurgitation may be perceived.
Of note, the above described first and second stages of the disease may not be well distinguishable. Severe eosinophilia may provoke rapid aggravation of endocarditis and patients may present with symptoms of advanced cardiac disease before reporting any other issues.
Because thromboembolism is a potential complication of LE, symptoms related to cerebral, myocardial or renal infarction or pulmonary embolism may prompt patients that did not experience any of the aforementioned symptoms to seek medical attention.
Moreover, it has to be noted that IHS is a systemic disease that may also cause pulmonary, dermatological and neurological disorders. In that context, patients may present with an indolent rash or with symptoms evoked by pneumonia, Wegener's granulomatosis, vasculitis or central nervous system vasculitis. These may even dominate the clinical picture.
Diagnosis of LE is based on cardiological examination, identification of characteristic alterations of the endocardium, and exclusion of differential diagnoses that may explain eosinophilia.
With regards to the former, echocardiography is the technique of choice to visualize the presence of often large mural thrombi, thickening of endocardium and valves, atrioventricular regurgitation, reduced diastolic ventricular filling, and further signs of restrictive cardiomyopathy. If echocardiography yields pathologic findings, cardiac magnetic resonance imaging or computed tomography may be conducted to better assess heart function. An elevated ventricular filling pressure may be measured during cardiac catheterization. Despite the undisputed utility of the aforementioned diagnostic measures, verification of endomyocardial fibrosis and eosinophilic infiltrates requires an endomyocardial biopsy. Here, abundant connective tissue within the endocardium, with possible extensions into the myocardium are generally seen. Eosinophilic infiltrates are diagnostic, but not always present. Histopathological analysis of biopsy samples is of particular importance in patients that don't present peripheral eosinophilia , but because LE does not necessarily comprise the whole endocardium, false-negative results are possible.
Of note, echocardiographic examinations should be carried out regularly in patients diagnosed with IHS in order to detect possible cardiac involvement as early as possible .
If laboratory analyses of blood samples reveal persistent eosinophilia, the following differential diagnoses should be considered and ruled out:
As has been mentioned above, peripheral eosinophilia is characteristic for LE but should not be considered an exclusion criterion. Nevertheless, eosinophil cell counts should be monitored in all IHS and LE patients.
Because in general, a direct correlation between duration and severity of eosinophilia and the extent of endocardial lesions exists, remediation of eosinophilia is the primary aim of IHS and LE treatment. This measure may even be considered causative treatment of LE and is carried out by administration of immunosuppressive drugs like corticosteroids and/or imatinib  . Such medication generally causes complete resolution of eosinophilia and may significantly improve the condition of the endocardium. However, advanced stages of endomyocardial fibrosis may be irreversible, which is the main reason for the overall poor prognosis of LE patients. If endomyocardial fibrosis provoked permanent cardiac insufficiency, standard treatments comprising diuretics, angiotensin-converting-enzyme inhibitors, and/or inotropics are indicated.
Surgical interventions may be undertaken if patients don't respond to drug therapy. Endocardiectomy is most commonly carried out in patients suffering from advanced endomyocardial fibrosis and depending on valve involvement, repair or replacement of these structures may become necessary. Although these interventions carry a considerable risk, it is not recommended to delay them unnecessarily. In fact, the curative effect of endocardiectomy will be much more pronounced while connective tissue proliferation does not yet involve the underlying myocardium. Thus, surgery should take place before myocardial involvement occurs.
Prognosis depends on the extent of endocardial damage at the time of initial diagnosis. If eosinophilia is detected and treated before fibrotic remodeling processes take place, complete resolution is possible . Unfortunately, LE is often diagnosed in patients that already present restrictive cardiomyopathy and imminent heart failure. Here, diagnosis is poor. The disease follows a progressive course and premature death may occur due to cardiac dysfunction or thromboembolic phenomena. In a retrospective study comprising almost 250 IHS patients, the overall mortality was 10% .
It has been proposed to classify IHS as a myeloproliferative disorder induced by a mutation on chromosome 4 . As a result of sequence deletions, fusion of those genes encoding for FIP1-like 1 protein and platelet-derived growth factor receptor-α (PDGFRA) occurs in affected individuals and yields a constitutively active tyrosine kinase. This hypothesis is supported by the fact that IHS and LE patients may respond to treatment with imatinib, a tyrosine kinase inhibitor, when tested positive for the FIP1L1-PDGFRA fusion. A considerable share of patients doesn't show this genetic defect and in these cases, IHS and possible LE are still considered idiopathic.
IHS is a rather broad term relating to a variety of conditions that may be associated with cardiac lesions  and as per definition, both IHS in general and LE in particular are associated with persistent eosinophilia that may or may not be related to the aforedescribed chromosomal aberration. Approximately half of the patients with IHS present with cardiac complications and LE has been proposed to be caused by hypersensitivity reactions to drugs or environmental factors, autoimmune disorders, infestations with parasites, eosinophilic leukemia, lymphoma or carcinoma . Some of these pathologies tend to follow a chronic course and are associated with persistently increased eosinophil counts. Indeed, diseases characterized by permanent eosinophilia have repeatedly been related to LE-like findings. However, LE has also been diagnosed in patients who overcame eosinophilia years ago or who were never diagnosed with this condition . Here, it is still unclear how LE is caused.
LE incidence is highest in tropical regions of South America, Africa and Asia. Patients who present with LE in temperate climates often report to have immigrated from or traveled to such regions and this observation supports the theory of an infectious disease underlying LE. It has to be noted though that this is not an exclusion criterion for LE and patients may develop this type of endocarditis without ever having been to the tropics .
Males and females are both affected by LE, but a slight male predilection has been reported. Patients pertaining to all age groups may develop the disease. Although the majority of LE patients are young adults, the disease has been diagnosed in pediatric patients and elderly individuals .
Cytologic examination of samples obtained from LE patients revealed phenotypic anomalies in eosinophil granulocytes, a fact that indicates previous stimulation and maturation. Although it is not clear why eosinophils preferentially infiltrate heart, lungs, skin or central nervous system, degranulation of these cells is assumed to initiate cell damage in these organs. Major basic protein and eosinophil cationic protein, two of many types of protein contained in cytoplasmatic vesicles of eosinophil granulocytes, seem to exert particularly detrimental effects . Binding of these proteins to the anionic endothelial protein thrombomodulin may hinder the anticoagulant activity of the latter and thus favor thrombus formation . In case of more extensive lesions, exposure of subendothelial structures results in adherence of von Willebrand factor, and this protein is able to capture and activate platelets. Adhesion of thrombocytes to endothelial lesions is the first step of primary hemostasis and thrombus formation. Furthermore, eosinophils also release reactive oxygen species that promote inflammation and coagulation. LE also predisposes for endomyocardial fibrosis and restrictive heart failure. In a recent case report, endocardial eosinophilic infiltrates was referred to as an "endocardiac eosinophilic mass", "layers of intraventricular thrombus", and an increased left ventricular mass were described in a patient diagnosed with IHS .
Accordingly, three stages are distinguished in LE pathogenesis :
Because little is known about the disease' etiology, no specific measures can be recommended to prevent LE.
The designation idiopathic hypereosinophilic syndrome (IHS) describes distinct systemic diseases of unknown etiology who are characterized by elevated cell counts of eosinophil granulocytes that don't diminish over the course of months . In general, eosinophilia may be triggered by hypersensitivity reactions, autoimmune disorders, parasitoses or hematological malignancies, but in IHS patients, none of these pathologies can be identified as the cause of persistent eosinophilia. Thus, diagnosis of IHS is based on repeated measurements of eosinophil counts, exclusion of the aforementioned differential diagnoses and possibly detection of IHS-associated diseases.
While some IHS patients remain asymptomatic, most eventually show symptoms of cardiac, pulmonary, skin or central nervous system involvement, whereby a typical cardiac manifestation is Loeffler endocarditis (LE). Functionally, LE is classified as a type of restrictive cardiomyopathy, i.e., impaired compliance during diastole interferes with with ventricular filling. Although contractility and systolic function remain unaltered, the stroke volume is diminished.
The causal relation between eosinophilia, endocarditis and pathologies affecting other internal organs has first been described by the Swiss internist Wilhelm Löffler in 1936 . He also observed that his patients had higher risks of thromboembolism and endomyocardial fibrosis. Today, the pathophysiological mechanisms behind endocarditis-related thromboembolism are well understood and they are not specific for LE. However, considerable knowledge gaps remain regarding the pathogenesis of endomyocardial fibrosis.
This complicates LE treatment. In current practice, immunosuppressive drugs are administered to reduce eosinophilia. Anticoagulants are prescribed to prevent formation of thrombi and detrimental consequences like pulmonary embolism or cerebral infarction. Nevertheless, LE therapy is still challenging and cardiac failure and thromboembolism account for about 50% of IHS-related deaths .
Loeffler endocarditis (LE) refers to an inflammation of the endocardium - the inner layer of the heart - that may be observed in patients suffering from idiopathic hypereosinophilic syndrome. The latter may manifest in pulmonary, skin or central nervous system symptoms, too.
Eosinophilia is assumed to be the direct cause of LE, although some cases have been described where no alteration in eosinophil cell counts has been observed. Eosinophilia may be triggered by hypersensitivity reactions, autoimmune disorders, infestation with parasites or hematological malignancies, and these pathologies may indeed cause LE-like lesions. However, LE may also develop years after successful treatment of such a condition. It is therefore deemed idiopathic, i.e., arising from an unknown cause.
During the initial stage of the disease, common symptoms are fever, chills and chest pain. LE takes a progressive course and the more it interferes with cardiac function, the more patients suffer from fatigue, intolerance to exercise, breathing difficulties and cough. The may lose weight and develop an indolent rash.
Diagnosis relies on repeated analyses of blood samples in order to confirm persistent eosinophilia and thorough cardiac examination. The latter is of particular importance since not all LE patients present elevated eosinophil cell counts.
Initially, cardiac function will be elevated by means of electrocardiography, i.e., cardiac sonography. This technique allows for the detection of intracardial thrombi, thickening of endocardium and valves, atrioventricular dysfunction and signs of restrictive cardiomyopathy. In some cases, heart function evaluation requires additional magnetic resonance imaging or computed tomography scans.
So as to confirm LE, it is necessary to obtain a tissue sample - an endomyocardial biopsy - for histopathological analysis.
Because eosinophilia is assumed to aggravate endocardial lesions, LE patients are prescribed immunosuppressive drugs like corticosteroids or imatinib. In order to avoid thrombi formation, anticoagulants are administered.
There is no drug therapy against endomyocardial fibrosis, an irreversible complication of LE. Standard treatments to improve cardiac function may relieve related symptoms, but in some cases, surgery may be necessary.