Hypereosinophilia and Löffler’s Endocarditis: A Systematic Review

Löffler endocarditis is an uncommon, but known complication of hypereosinophilic syndrome (HES). It is a relatively rare entity, and remains poorly understood. To this point in time, the compendium of knowledge about this disease consists of various case reports, prospective studies and review articles. We aim to present a scoping study about this disease. Our goals are to identify the characteristic features found in case reports to identify characteristic features found in patients with Löffler endocarditis as a result of hypereosinophilic syndrome. An analysis of the 26 case reports showed a mean age of 41.6 years with a standard deviation of 17.1 years. Dyspnea was the most common presenting complaint (64%) followed by fatigue (23%), cough (19%), fever (19%), orthopnea/paroxysmal nocturnal dyspnea (19%), stroke related symptoms (15%), chest pain (15%) and lower extremity edema (15%). The most common cardiac structure affected was the mitral valve (65%), followed by the tricuspid valve (42%), left ventricle (23%), with 35% of cases having involvement of two valves. The most common therapeutic modality was immunosuppression (85%), followed by anticoagulation (73%) and mitral valve replacement (23%). Death was reported in 19% of the cases. Löffler’s endocarditis continues to be associated with high morbidity and mortality. Further research must aim to develop guidelines for management of this uncommon manifestation of hypereosinophilic syndrome.


Introduction
Hypereosinophilic syndrome is a group of rare disorders which are characterized by the presence of increased amounts of serum and tissue eosinophils. It was defined in 1975 by Chusid et al. [1] with the following criteria: (1) Sustained serum eosinophilia (>1.5 x 10 9/L) for >6 months (2) No identifiable cause, including blood and parasitic disorders (3) signs and symptoms of organ involvement. Hypereosinophilic syndromes are varied in their clinical presentation and severity and are associated with the level of organ involvement. [2] Löffler endocarditis was first described in 1936, as an acute form of fibrinous restrictive pericarditis. [3] Histologically, it is described as the migration of eosinophils into the myocardium with, tissue damage and fibrosis resulting from eosinophil degranulation. [4] Löffler endocarditis is a rare manifestation of hypereosinophilic syndrome. Clinical signs and symptoms include fever, weight loss, rash, symptoms of heart failure and arrhythmias. [5,6]

Methods
On April 1st 2019, a literature search of Pubmed, Google Scholar, CINAHL, Cochrane CENTRAL and Web of Science databases was conducted using the search phrases "Lüffler's endocarditis" and "hypereosinophilic syndrome" to identify cases of Löffler endocarditis related to hypereosinophilic syndrome. A total of 26 cases were identified (Table 1). References in the aforementioned cases were reviewed to identify additional cases. Demographic date, vitals, complete blood counts (CBC), echocardiograms, computed tomography imaging, magnetic resonance imaging and management protocols were reviewed.

Discussion
As described by Chusid et al in 1975, hypereosinophilic syndromes are described as persistent marked elevations in blood eosinophil counts (>1.5 x 10 9/L) with no discernable primary cause, and the presence of end organ involvement. [1] It is a relatively rare entity, with an age adjusted incidence rate of 0.036 cases per 100,000 person years. [31] Cardiovascular involvement in hypereosinophilic disorders were initially thought to be as prevalent as 84%, however recent studies have shown the frequency to be around 40-50%. [32,33] Cardiovascular involvement in HES is most commonly associated with Löffler endocarditis, a form of restrictive cardiomyopathy associated with the degranulation of eosinophils in the myocardium, resulting in tissue damage and fibrosis. [23] The progression of cardiac involvement in HES follows a stepwise pattern that can be described in three stages: acute necrosis, thrombosis and fibrosis. The necrotic stage describes the infiltration of the myocardium by the eosinophils. The eosinophils undergo degranulation and release toxic cationic proteins, which cause myocardial necrosis. This acute phase is usually subclinical, with minimal electrocardiographic or echocardiographic changes. [34] It is followed by the thrombotic phase, which is a result of damage to the endomyocardial surface. It is also believed that eosinophils also contribute to thrombus formation by binding to thrombomodulin and impairing the inherent anticoagulant properties of the endothelial membrane. [35] Fibrosis follows after the thrombotic phase which has been described to occur after 24.5 months of hypereosinophilia. [36] Most of the patients with this condition tend to present with scarring of the chordae tendinae and endocardium. It leads to a restrictive or dilated cardiomyopathy with progressive valvulopathy. [37] Cardiac manifestations of HES have been described as signs and symptoms of heart failure, ventricular thrombus formation, myocardial ischemia, arrhythmias and pericarditis. A prospective study of 25 patients done in 1979 by Parrillo JE et al. [33] showed the most common presenting symptom was dyspnea (42%), chest pain (27%), heart failure symptoms (38%), cough (12%), palpitations (8%) and embolic events (4%). Echocardiography is the mainstay of diagnostic imaging and surveillance for Löffler endocarditis caused by HES. Classic findings in HES are myocardial thickening, apical thrombus formation, and valvulopathy. An NIH study of 22 HES patients who had echocardiographs showed that 68% had left ventricular wall thickening, 37% had increased left atrial transverse dimension and 27% had in increase in right ventricular transverse dimension. [33] A Mayo clinic study consisting of 55 patients with hypereosinophilic syndromes and echocardiograms showed that 12% had endocardial thickening, 24% had left ventricular apical thrombus, 20% had right ventricular apical thrombus, 20% had posterior mitral leaflet involvement, 10% had tricuspid involvement, 16% had hyperdynamic LV, 10% had LV hypertrophy, 14% had LV dilation and 18% had pericardial effusion. [38] The mean age in this study was 45 ± 17 years; mean eosinophil count × 10 9 /L was 18.6 ± 29.7 with a p value of 0.05. Seventy eight percent of the patients in the study were males, and 33% of the patients died.
Management of hypereosinophilic syndrome consists of heart failure management using established guidelines, immunosuppression with the aim of decreasing eosinophil counts and anticoagulation if there is the presence of thrombus. Routine anticoagulation is not recommended, unless there is the presence of an intracardiac thrombus or valve replacement. Most of the literature shows that warfarin is the predominant anticoagulation regimen and the direct acting anticoagulants have not been significantly used in these patients. Due to the complications associated with anticoagulation, the use of anticoagulation must be correlated to the presence of endomyocardial disease. [34] Valvulopathy as a result of Löffler endocarditis is common and bio-prosthetic valve replacement is preferred, as mechanical valves are associated with thrombus formation. [39,40,41] Current immunosuppressive regimens for Löffler endocarditis are dictated by the level of disease present. It consists of the use of corticosteroids, interferon, hydroxyurea, tyrosine kinase inhibitors and other cytotoxic medication. [23] Consensus guidelines have not been established for the management of Löffler endocarditis.

Conclusion
Based on our review, the majority of the primary eosinophilic syndrome patients who presented with Löffler endocarditis were young adult females and most of them presented with heart failure symptoms such as shortness of breath. These patients had a low prevalence of cardiovascular risk factors among them and nearly 1/3 were diagnosed with heart failure. Mitral valve was the most common valve affected followed by the tricuspid valve and one third of the patient's had two valve endocarditis. These patients had elevated WBC count and high eosinophil count. Medical management strategies included immunosuppression and anticoagulation. Nearly 30% of the patient's had valvular replacement. A high mortality rate was noted in these patients.  Table 3.  Table 4.