Loeffler Endocarditis

Loeffler endocarditis and endomyocardial fibrosis are restrictive cardiomyopathies, defined as diseases of the heart muscle that result in impaired ventricular filling with normal or decreased diastolic volume of either or both ventricles. Systolic function and wall thickness may remain normal, especially early in the disease, as reported by Richardson and associates.[1, 2] Both conditions are associated with eosinophilia.

The associations among eosinophilia, active carditis, and multiorgan involvement were first described by Loeffler in 1936.[3] Pathologic specimens in Loeffler endocarditis show eosinophilic myocarditis, a tendency toward endomyocardial fibrosis and clinical manifestations of thromboembolism, and acute heart failure.

Eosinophilic states that may occur in association with Loeffler endocarditis include hypereosinophilic syndrome, eosinophilic leukemia, carcinoma, lymphoma, drug reactions or parasites, as reported in multiple case series.

Although eosinophilic endocardial disease has been well described, myocardial and vascular damage due to eosinophilic infiltration and degranulation is rarely diagnosed during life, as reported by Oakley et al and others.[4] Herzog et al and Tonnesen et al have proposed that the reason for this situation may be the rapidly fatal evolution of most cases of eosinophilic arteritis and myocarditis.[5, 6] These conditions are usually diagnosed based on postmortem examination and nonspecificity of clinical manifestations, as reported by Kim et al, Isaka et al, and Seshadri et al.[7, 8, 9]

Pathophysiologically, the fibrotic stage of Loeffler endocarditis is very similar to the disease entity described as endomyocardial fibrosis, which is indolent in comparison to Loeffler endocarditis. The tropical form of endomyocardial fibrosis is associated with eosinophilia, a common finding in Loeffler endocarditis.

Endomyocardial damage in Loeffler endocarditis is well known and described in a study by Solley and associates.[10] Myocardial involvement is less well known and has been considered a manifestation of an acute necrotic stage of eosinophilic endomyocardial disease, as reported by Olsen and colleagues.[11] More recently, cases of isolated eosinophilic myocarditis have been reported without signs of endomyocardial involvement, with or without vasculitis.

Additionally, idiopathic eosinophilic endomyocarditis, in the absence of peripheral eosinophilia, has been reported by Priglinger et al.[12]

Morphologic abnormalities of eosinophils have been noted in patients with Loeffler endocarditis, suggesting that these eosinophils were mature or stimulated. The intracytoplasmic granular content of activated eosinophils is thought to be responsible for the toxic damage to the heart, as reported by Tai and associates.[13] Spry et al reported eosinophilic degranulation of basic proteins causing myocardial damage in tissue cultures in vitro.[14] Gliech et al reported a dose-dependent cytotoxic effect of the eosinophilic granular proteins, inhibiting multiple enzyme systems.[15]

The cationic eosinophilic proteins bind to the anionic endothelial protein, thrombomodulin. This complex impairs anticoagulant activities, leading to enhanced endocardial thrombus formation, as reported by Slungaard and colleagues.[16]

Toxins released by the eosinophils include eosinophil-derived neurotoxin, cationic protein, major basic protein, reactive oxygen species, and arachidonic acid derivatives. As described by Cunningham et al, these toxins may cause endothelial and myocyte damage, resulting in thrombosis, fibrosis, and infarction.[17]

The intensity and timing of the active carditis is related closely to the severity of the circulating eosinophilia. Some have suggested that, particularly in the tropics, patients who present with later fibrotic stages of endomyocardial disease may have had either transient earlier bouts of moderate eosinophilia with spontaneous resolution, or only moderate levels of eosinophilia leading to a low-grade endomyocarditis with gradual progressive fibrosis, as reported by Olsen et al.[11]

Molecular pathophysiology

Cools et al reported a landmark finding by treating patients with hypereosinophilic syndrome (HES) with imatinib, a tyrosine kinase inhibitor.[18] Among the findings were the following:

• The gene defect is localized to an interstitial chromosomal deletion on chromosome band 4q12, resulting in fusion of the Fip1-like1 (FIP1L1) gene to the platelet-derived growth factor gene alpha (PDGFRA). The protein product of this gene is a tyrosine kinase enzyme that transforms the hematopoietic stem cells. This FIP1L1-PDGFRA fusion gene defect was identified in 9 of 16 patients treated with imatinib.

• This study also highlights the importance of reclassifying HES as a myeloproliferative disorder of a possible single clone based on genotyping, as the FIP1L1-PDGFRA gene rearrangement is a clonal abnormality.

• Treatment with imatinib caused rapid regression of eosinophilic proliferation and endomyocardiopathy in subsequent cases reported by Vandenberghe et al and Rotoli et al.[19, 20]

The following list summarizes the initial clinical presentations of eosinophilic endomyocardial disease in relation to the predominant pathologic stage of the disease as reported by Alderman et al in the Textbook of Cardiovascular Medicine.[21] Death is usually related to multiorgan dysfunction in the presence of congestive heart failure.

The initial clinical presentation and stages of eosinophilic endomyocardial disease are described below.[21]

Necrotic stage (early stage)

Hypereosinophilia with systemic illness (20-30%) is associated with the following signs/symptoms:

• Fever

• Sweating

• Chest pain (as described by Bestetti et al[22] )

• Lymphadenopathy

• Splenomegaly

Acute carditis (20-50%) is associated with the following signs/symptoms:

• Anorexia

• Weight loss

• Cough

• Pulmonary infiltrates

• Skin and retinal lesion

• Atrioventricular valve (AV) valve regurgitation

• Biventricular failure

• Polymorphic ventricular tachycardia[23]

Thrombotic stage

Thrombotic emboli (10-20%) are associated with the following signs/symptoms:

• Cerebral, splenic, renal, and coronary infarction

• Splinter hemorrhages

Fibrotic stage (late stage)

Restrictive myopathy (10%) are associated with the following signs/symptoms:

• AV valvular regurgitation

• Right and left heart failure

The image shows dense fibrosis of ventricle in a postmortem dissected heart.

Loeffler endocarditis is primarily confined to the rain forest (tropical and temperate) belts of Africa, Asia, and South America[24] . The condition is rare in the United States and is seen mostly in immigrants from Africa, Asia, and South America.

Race-, sex-, and age-related demographics

The condition has a predilection for African and African American populations, notably the Rwanda tribe in Uganda, and for people of low socioeconomic status. Whether this is due to genetic factors or the epidemiology of underlying environmental factors is not known.

Loeffler endocarditis has a predilection for males. However, endomyocardial fibrosis, which has similar clinical manifestations, is found equally frequently in both sexes.

The reported age range is 4-70 years; in most cases the patient is 20-50 years old.[24] Loeffler endocarditis particularly affects young males, as does its close counterpart, endomyocardial fibrosis, which is more common in children and young adults.

The overall prognosis of patients with Loeffler endocarditis is poor and depends on the location of involvement in the heart. The disease is usually slow in onset, with progression to increasing degrees of right and left heart failure. Sudden death and syncope are not as common as in other causes of restrictive cardiomyopathy

Morbidity/mortality

The literature reports a 35-50% 2-year mortality rate in patients with advanced myocardial fibrosis. Substantially better survival rates may be seen in less symptomatic patients who have milder forms of the disease. As noted, this rate may reflect underdiagnosis of clinically inapparent disease, as for other types of cardiomyopathy.

Patients with Loeffler endocarditis may present with weight loss, fever, cough, rash, and symptoms related to congestive heart failure. Initial cardiac involvement has been reported in about 20-50% of cases; however, cardiac involvement rarely presents with chest pain, as reported by Bestetti et al.[22]

Signs of biventricular failure (eg, pedal edema, elevated jugulovenous pressure, pulmonary edema, third heart sound [S3] gallop) are commonly seen once congestive heart failure develops. Other signs include the following:

• Cardiomegaly may be present without overt signs of congestive heart failure.

• Murmur of mitral regurgitation may be present, as reported by multiple authors, including Weller et al.[25]

• Systemic embolism is frequent and may lead to neurologic and renal dysfunction.

• The Kussmaul sign may be present.

• S3 gallop may be present, but rarely fourth heart sound (S4).

• Restrictive cardiomyopathy, such as Loeffler endocarditis, is sometimes difficult to differentiate from constrictive pericarditis. Physical signs in constrictive pericarditis that may help differentiate the two conditions include a nonpalpable apex (usually), presence of pericardial knock, and usually absent regurgitation murmurs.

• Published case reports highlight presentations with unusual ECG changes mimicking posterior myocardial infarction as described by Maruyoshi et al,[26] acute myocardial infarction as described by Mor et al,[27] and aortic valve regurgitation secondary to valve fibrosis and fibrotic vegetations on the aortic valve as described by Gudmundsson et al.[28]

• Recently, a presentation with inflow and outflow tract obstruction of the left ventricle with a large organized thrombus on the mitral valve apparatus was described.[29]

• Occlusion and obstruction of the aortic bifurcation has been reported (Leriche syndrome).[30]

Echocardiography, Doppler studies using echocardiogram, cardiac catheterization, computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the chest, electrocardiography (ECG), and endomyocardial biopsy may all be useful in diagnosis, as for cardiomyopathy of any cause.[31]

Complete blood cell (CBC) counts should be performed to look for the presence of eosinophils. Peripheral eosinophilia should not be considered mandatory for the diagnosis of Loeffler endocarditis, as described by Priglinger et al.[12]

Cytogenetics, fluorescent in situ hybridization (FISH), and molecular analysis show the presence of the FIP1L1-PDGFRA fusion gene as demonstrated by Cools et al and Rotoli et al.[18, 20]

The echocardiographic hallmark of Loeffler endocarditis includes a restrictive pattern of filling with relatively preserved left ventricular systolic function, as reported by Parillo et al.[32, 33]

Localized thickening of the basal posterior wall of the left ventricular free wall and restricted motion of the posterior leaflet of the mitral valve are seen, as reported by Spyrou et al and Child et al.[34, 35]

Apical thrombus in the left ventricle also has been reported. Also, presentation with restriction of the mitral apparatus with a large thrombus has been reported.[29]

Regurgitant AV valve lesions are often present.

Recurrent thrombosis of the prosthetic mitral valve in the setting of rising eosinophilia has been reported.[36, 37]

Three echocardiographic features of amyloidosis, another cause of restrictive cardiomyopathy, include thickened interatrial septum; thickening of the cardiac valves; and granular, sparkling texture of the myocardium. All may be present in amyloidosis but not in Loeffler endocarditis.

Echocardiographic Doppler findings are of restrictive cardiomyopathy, including decreased right ventricular and left ventricular velocities with inspiration and inspiratory augmentation of hepatic-vein diastolic flow reversal.

Cardiac catheterization reveals markedly elevated ventricular filling pressures and the presence of mitral or tricuspid regurgitation.

On left ventriculography, a characteristic feature is preserved left ventricular systolic function with obliteration of the left ventricular apex, as reported by Weller and associates.[25]

The hemodynamic picture on cardiac pressure tracings reveals a restrictive picture due to dense endocardial scarring and a reduction in left ventricular cavity caused by an organized thrombus, as reported by Weller et al and Parillo et al.[25, 32] The hemodynamic picture may include elevation of left ventricular end diastolic pressure, often greater than 5 mm Hg over right ventricular end diastolic pressure; however the pressures may be identical at times.

Cardiac MRI findings of endomyocardial fibrosis include right ventricular diastolic dysfunction, mild systolic dysfunction, and extensive subendocardial delayed contrast enhancement.[38]

Hybrid positron emission tomography/MRI (PET-MRI) has the potential to be useful in confirming the diagnosis of Loeffler endocarditis and the progression of inflammatory activity in affected patients.[39]

ECG shows nonspecific ST-segment and T-wave abnormalities as reported by Spyrou et al and Arnold et al.[34, 40]

Arrhythmia, especially atrial fibrillation, and conduction system defects, particularly right-bundle branch block, may be present, as reported by Fawzy et al.[41]

Nonspecific findings may include pseudo infarction patterns of left-axis deviation.

Percutaneous endomyocardial biopsy often confirms diagnosis. As endomyocardial involvement may be patchy, a false-negative biopsy result also is possible, as reported by Felice and colleagues.[42]

Histologic specimens of the myocardial biopsy reveal thick and deep layers of loosely arranged collagen tissue, which, although localized primarily to the endocardium, may have strands extending into the underlying myocardium. Although peripheral eosinophilia is characteristic of Loeffler endocarditis, eosinophilic infiltration of the tissues and arteries is less common, possibly because of the infrequency of biopsy.

Perform serial CBC counts.

Symptomatic relief is achieved by routine cardiac therapy, including diuretics, digitalis, afterload reduction, and anticoagulation, as indicated by Weller et al and Parillo et al.[25, 32]

Treatment with low-dose imatinib causing rapid regression of both eosinophilic proliferation and endomyocardiopathy is described by Cools et al, Vandenberghe et al, and Rotoli et al.[18, 19, 20]

Early phases of the disease have been treated with immune suppressant and cytotoxic medications with varying degrees of success.

Corticosteroids appear to be beneficial in acute myocarditis, as reported by Uetsuka et al, among others.[43] Together with cytotoxic drugs, including hydroxyurea, corticosteroids may prolong survival substantially, as reported by Weller et al and others.[25, 32, 40, 44, 45, 46]

Interferon therapy also has been reported by Butterfield et al as having some success.[47]

Outpatient follow-up includes close follow-up observation for recurrence of symptoms of heart failure. Serial echocardiograms to evaluate ejection fraction are also helpful for titration of medications.

Once fibrosis ensues, surgical therapy may have a positive impact on palliation of symptoms.

Dubost et al performed the first endocardiectomy in endomyocardial fibrosis, which consists of decorticating the fibrosed endocardium in a manner similar to resection of constricting densely fibrotic pericardium.

In 150 published cases of surgical therapy of endomyocardial fibrosis and eosinophilic myocarditis, an operative mortality rate of 15-29% is reported, with AV block requiring a permanent pacemaker as a common complication.

Endocardiectomy is directed toward the predominant location of the restrictive process.

The mitral and tricuspid valves may be subject to replacement or repair, depending on the involvement of the subchordal apparatus.

Early surgery is assisted by the fact that fibrous septa may not have extended into the adjacent myocardium.

When the restrictive process is advanced, in individuals with congestive heart failure refractory to medical therapy, the only potential approach is endocardiectomy.

The extent to which fibrosis recurs postoperatively is not known.

In 2006, Tanaka et al reported endomyocardial resection as well as mitral valve replacement in a patient with severe restrictive myocardial disease and mitral leaflets involvement; however, the patient died 3 months later of cerebral infarction.[48] Jategaonkar et al reported a similar patient with a 4-year survival until last follow up.[49]

Symptomatic relief is achieved by routine cardiac therapy including diuretics, digitalis, afterload reduction, and anticoagulation.

Early phases of the disease have been treated, with varying degrees of success, with immune suppressants, including steroids and interferon therapy, and cytotoxic medications, particularly hydroxyurea.

Corticosteroids appear to be beneficial in acute myocarditis, together with cytotoxic drugs, including hydroxyurea, and may prolong survival substantially. Interferon therapy has also been reported as having some success.

Class Summary

These agents inhibit tyrosine kinase, which, in turn, inhibit activation of intracellular pathways that can promote deregulated cell proliferation.

Imatinib (Gleevec)

Small molecule that selectively inhibits the tyrosine kinase activity of c-kit, bcr-abl, and PDGFR.

Class Summary

These agents inhibit cell growth and proliferation.

Hydroxyurea (Hydrea)/Hydroxycarbamide

Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan, or chlorambucil.

Myelosuppressive effects last a few days to a week and are easier to control than those of alkylating agents. Hydroxyurea can be given as a single daily dose or divided bid or tid at higher dose ranges.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Methylprednisolone (Adlone, Solu-Medrol, Depo-Medrol, Medrol)

Immune-modifying agents that can be used, with varying degrees of success, in early stage of Loeffler endocarditis. Monitoring of liver function tests and eosinophil count may help to observe long-term response.

Class Summary

These agents provide relief of congestive heart failure symptoms.

Bumetanide (Bumex)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle. Does not appear to act in distal renal tubule.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after previous dose, until desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until satisfactory effect achieved.

Class Summary

These agents are used for treatment of systolic dysfunction in congestive heart failure.

Digoxin (Lanoxin)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Class Summary

These agents are used to treat congestive heart failure and reduce afterload.

Enalapril (Vasotec)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Class Summary

These agents inhibit the production, activation, and maturation of eosinophils.[50]

Mepolizumab

Received orphan drug status for first-line treatment in patients with hypereosinophilic syndrome in the US and the EU in 2004. Interleukin-5 stimulates the production, activation, and maturation of eosinophils. Since mepolizumab inhibits interleukin-5 and has a long terminal half-life, treatment with mepolizumab causes a sustained reduction in the numbers of circulating eosinophils. Thus, mepolizumab may be a useful therapeutic agent for the treatment of conditions characterized by increased levels of eosinophils.

A phase III, compassionate use trial of mepolizumab (NCT00244686) in patients with hypereosinophilic syndrome was ongoing in October 2007 in the US. Patients who have significant clinical disease but are unresponsive to traditional treatment and those who have demonstrated clinical benefit from previous anti-IL-5 treatment are eligible to take part in the trial.

Mepolizumab is also in phase I/II clinical development for the treatment of eosinophilic esophagitis.

A phase I/II trial (NCT00358449) began in August 2006 in the US, Australia, the UK, and Canada, and will enroll approximately 72 pediatric patients with eosinophilic esophagitis. The randomized, parallel-group clinical trial will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous mepolizumab for 12 weeks. In September 2006, GSK completed enrollment in a phase I/II study of mepolizumab for the treatment of eosinophilic esophagitis in 10 adult patients in Switzerland (NCT00274703). The randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of IV mepolizumab.

A phase I/II trial of mepolizumab in 4 patients with eosinophilic esophagitis conducted by Cincinnati Children's Hospital found the monoclonal antibody was safe and effective. Brigham and Women's Hospital, in association with GSK, is conducting a phase I/II trial of mepolizumab, in the US, in patients with Churg-Strauss Syndrome (CSS). The trial, which started in September 2007, will evaluate the potential of mepolizumab to reduce the need for corticosteroid therapy in patients with CSS (NCT00527566). CSS, otherwise known as allergic granulomatosis, is defined by patients with asthma, eosinophilia, and vasculitis.

Class Summary

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.

Interferon alfa-2b (Intron A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Butterfield et al reported use of interferon alpha in treatment of HES with some success.

Interferon alfa 2a (Roferon A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Butterfield et al reported use of interferon alpha in treatment of HES with some success.