PEDIATRICS Vol. 110 No. 5 November 2002, pp. 1014-1018
EXPERIENCE AND REASON |
Loffler's Endocarditis Presenting in 2 Children as Fever With Eosinophilia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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Hypereosinophilic syndromes are defined by the presence of peripheral and bone marrow eosinophilia and by the infiltration of multiple organs by mature eosinophilic cells. Loffler's endocarditis is a condition in which mature eosinophils infiltrate and damage the endocardium and myocardium. Male adults who live in the tropics are the population predominantly affected by this condition. Typical clinical features include weight loss, fever, cough, rash, and congestive heart failure. In this article, we report the typical presentation of an unusual illness that occurred in 2 pediatric patients in different geographic locations. In addition, we believe that these are the youngest patients with Loffler's endocarditis reported.
Key Words: Davies' endomyocardial fibrosis • hypereosinophilic syndromes • Loffler's endocarditis
Abbreviations: HES, hypereosinophilic syndromes • WBC, white blood cell count
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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Loffler's endocarditis refers to the cardiac component of the hypereosinophilic syndromes, which determines patient morbidity and mortality.1 In Loffler's endocarditis, mature eosinophils infiltrate the endocardium and subsequently the myocardium. Mature eosinophils promote free radical damage and thrombus formation, which can lead to a restrictive cardiomyopathy.2 Although patients with early cardiac involvement may be asymptomatic, overt cardiac dysfunction occurs in more than half of the patients. Death occurs from congestive heart failure, and affected patients often have associated renal, hepatic, or respiratory dysfunction.3 In the unusual case of presentation in childhood, this disease is associated with leukemia approximately 50% of the time.1 Treatment with steroids is directed at diminishing the number of eosinophils and inhibiting their localization, activation, and degranulation.4 If this strategy fails, then antineoplastic agents such as vincristine can be used to prevent mitosis of the eosinophil through inhibition of microtubule formation in the mitotic spindle. An alternative therapy to steroids is hydroxyurea, an inhibitor of cellular DNA synthesis.1
In this article, we report on 2 children who presented with cough, fever, and eosinophilic infiltration of multiple organs, including the bone marrow. These patients demonstrated respiratory distress in the presence of hypereosinophilia of unknown cause, and in both cases, the echocardiogram revealed marked endocardial changes and thickening, consistent with Loffler's endocarditis.
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CASE REPORTS |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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Patient 1
A 6-year-old girl was admitted to the Children's Hospital of Michigan because of tachypnea and fever of 38.9°C. She was healthy until 3 months before this admission, when she developed recurrent emesis, fever up to 39°C, and diarrhea accompanied by malaise and weight loss. Her history revealed that she lived with her parents and 2 young siblings on a farm and that she was in contact with multiple animals, including pigs, cows, turkeys, chickens, geese, dogs, and cats. There was no history of traveling outside Michigan. In addition, there was no previous parasitic infection.
Physical examination revealed a febrile (37.6°C axillary), pale white female breathing at 50 to 60 breaths/min with a nonproductive cough. The heart rate ranged from 148 to 156 beats/min, and the transcutaneous oxygen saturation was 91% in room air. Her skin was free of petechiae or ecchymoses, and there was no lymphadenopathy. The lungs were clear to auscultation. There was a soft systolic ejection murmur at the apex and an S4 gallop rhythm. No rubs or thrills were appreciated. Abdominal examination showed hepatomegaly at 6 cm below the right costal margin and splenomegaly at 4 cm below the left costal margin. There was no ascites or edema. Extremities were warm and well perfused with full pulses. The neurologic examination was unremarkable.
A chest radiograph showed diffuse densities with an area of consolidation in the middle portion of the left lingular area, no pleural effusions, and no cardiomegaly. Laboratory studies showed a white blood cell count (WBC) of 178 800 cells/mm3 with 1800 neutrophils/mm3, 16 100 lymphocytes/mm3, 160 900 eosinophils/mm3, and no blasts. A peripheral blood smear showed no immature forms. The hemoglobin was 7.4 g/100 mL, the hematocrit was 21%, and the reticulocyte count was 2.5%. The platelet count was adequate at 161 000/mm3. Liver function tests yielded an elevated lactic dehydrogenase of 557 U/L, although the rest of the parameters were normal.
Serum immunoglobulin G and immunoglobulin M for Toxocara, Strongyloides, Trichinella, and Bartonella henselae and microbiology for parasitic infestation were negative. Concentrated and trichrome smears of stool samples for ova and parasites were also negative.
Echocardiography revealed an abnormally thickened endocardium, mostly in the septal and posterior walls near the base of the heart. The apex was spared (Fig 1). Both papillary muscles appeared infiltrated, which resulted in papillary muscle dysfunction, moderate mitral valve insufficiency, and left atrial enlargement. Noninvasive interrogation of mild tricuspid regurgitation suggested a moderately elevated right ventricular pressure.
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Bone marrow aspiration showed a markedly hypercellular bone marrow as a result of mature eosinophilic myelopoiesis without a significant increase in blasts.
Chromosomal analysis uncovered a balanced translocation t(5,9)(q11.2-q34) of the Ablesom oncogene, which is a component of the Philadelphia chromosome. This was found to be a constitutional type of translocation because it was also present in the patient's father and in 1 of her brothers, although neither had eosinophilia.
Enalapril and furosemide were started, which resulted in a significant improvement in her respiratory symptoms. The patient was started on prednisolone at 1 mg/kg/d with little subsequent change in her hematologic profile. It was only after a single dose of vincristine (1.5 mg/m2) that the eosinophilia decreased significantly to 4100 cells/mm3, with an additional decrease to 900 cells/mm3 before discharge. Chest radiograph normalized with clear lungs and pleural margins. She was discharged from the hospital 2 months later with no tachypnea and no oxygen requirement. Serial follow-up echocardiograms showed improvement in diastolic relaxation, but severe mitral valve regurgitation persisted.
Patient 2
A previously healthy 5-year-old girl was admitted to the Children's Hospital of Winnipeg after a 3-day history of lethargy, fever, diarrhea, and a petechial rash. The patient owned a dog that had been treated recently for worms, although the dog had recently tested negative. There was no history of travel outside Manitoba, although she had been in contact with her uncle's pet snake a couple of weeks before the onset of the illness. The physical examination revealed an alert, mildly febrile (38.5°C axillary) child with a heart rate of 140 beats/min, a respiratory rate of 20/min, and a peripheral oxygen saturation of 99% (in room air). There was nonspecific cervical lymphadenopathy present. Lungs were clear to auscultation. On cardiac evaluation, she was hemodynamically stable with a soft, vibratory systolic ejection murmur and an S4 audible at the apex. The abdominal examination revealed splenomegaly at 2 cm below the left costal margin but no hepatomegaly. There was a nonconfluent petechial rash over the abdomen and thighs, extending down into her feet, but there was no evidence of any vasculitic or embolic lesions. The neurologic examination was unremarkable.
A chest radiograph revealed borderline cardiomegaly and some perihilar interstitial markings, but there were no effusions or parenchymal infiltrates present. Computed tomography of the thorax revealed a left ventricular mass and a right (1 cm) paratracheal lymph node, but there were no pulmonary nodules evident and no mediastinal enlargement present.
Her hematologic evaluation revealed a WBC count of 88 400 cells/mm3 with 1.2% neutrophils, 4.3% lymphocytes, and an absolute eosinophil count of 81 900 cells/mm3. The hemoglobin was 11 g/100 mL, and the platelets were 96 000/mm3. The serum lactic dehydrogenase was elevated to 1576 U/L, but the remainder of the liver function tests, the coagulation profile, serum electrolytes, renal function parameters, and urinalysis all were normal. Blood cultures obtained at a peripheral hospital grew 
-hemolytic streptococcus and Gram-negative bacilli, which were later thought to be contaminants as serial repeat blood cultures were negative.
Stool samples for ova and parasites, as well as serology for cytomegalovirus, Epstein-Barr virus, herpes simplex virus, varicella-zoster virus, Toxoplasma, Schistosoma, Strongyloides, Toxocara, Trichinella, Echinococcus, cysticercosis, and filarial parasites, were negative. Serum immunoglobulins and complement levels were within the normal range.
The electrocardiogram showed sinus tachycardia at a rate of 130 beats/min with biventricular hypertrophy and an intraventricular conduction delay (Fig 2). The echocardiogram revealed a homogeneous mass contiguous with the endocardium that occupied 50% to 65% of the left ventricular cavity and extended along the posterior wall from the mitral valve annulus and posterior mitral valve leaflet to approximately two thirds of the way to the apex. Although the systolic function of the left ventricle was preserved, diastolic dysfunction was present and moderate mitral valve regurgitation was evident.
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Bone marrow aspirate showed massive eosinophilic proliferation with normal cellular morphology. Cytogenetic chromosomal analysis revealed a normal female (46,XX) karyotype.
The patient was started on diuretic therapy to help control the tachypnea that developed shortly after hospital admission. Anticoagulation was begun with heparin and was later changed to warfarin to prevent thromboembolic phenomena. Steroids were administered to lower the eosinophil count. The steroid regimen consisted of high-dose intravenous Solu-Medrol (Pharmacia and Upjohn, Kalamazoo, MI; 1 mg/kg every 6 hours) and later oral prednisone (4 mg/kg every 8 hours). After 1 week of treatment, the eosinophil count decreased to 9000 cells/mm3 but thereafter began to increase and was constant at 16 500 cells/mm3. Because of the refractive nature of the hypereosinophilia, intravenous vincristine (1.5 mg/m2 once a week) and oral hydroxyurea (starting at 10 mg/kg and gradually increased to 40 mg/kg once a day over 4 weeks) were added to the treatment regimen. In addition to the anticoagulation therapy, she was continued on furosemide (0.5 mg/kg once a day), the above antineoplastic agents, prednisone (tapered to 2.5 mg/kg/d), and Pneumocystis prophylaxis with sulfamethoxazole/trimethoprim and monthly inhaled pentamidine.
She is currently asymptomatic (5 months after diagnosis), and the last eosinophil count was 600 cells/mm3 (total WBC count was 5200 cells/mm3). The most recent electrocardiogram shows no tachycardia or signs of ventricular hypertrophy (Fig 3). The echocardiogram revealed that the left ventricular mid-cavitary mass was somewhat smaller with persistent involvement of the lateral papillary muscle, causing immobilization of the posterior mitral valve leaflet and resulting in mild mitral valve regurgitation. Mild left ventricular inflow obstruction persists producing a peak mitral transvalvular gradient of 16 mm Hg. The systolic left ventricular function is normal, and there is no left ventricular outflow tract obstruction.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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The hypereosinophilic syndromes (HES) encompass a number of entities, including Loffler's endocarditis, Davies' disease, eosinophilic leukemia, and disseminated eosinophilic collagen disease. These diseases, which occur mostly in middle-aged men, are characterized by a striking peripheral blood eosinophilia and multiorgan eosinophilic infiltration.5 The heart is affected in 54% to 82% of the patients1 and is the main determinant of morbidity and mortality.4 There are few reports of HES in patients younger than 15 years, in whom there also is an overwhelming male preponderance of 91% to 92%.6,7 What makes our cases unusual is not only their very young age but also their gender.
Some form of leukemia is found in 50% of these patients,8 thus the need for bone marrow biopsy. In patient 1, chromosomal analysis uncovered a balanced translocation t(5,9)(q11.2-q34) of the Ablesom oncogene, a component of the Philadelphia chromosome. The significance of this finding warrants additional investigation, although it might be related to the high incidence of leukemia among pediatric patients with hypereosinophilic syndrome. In both patients, Loffler's endocarditis resulted from hypereosinophilia. They had recent exposure to animals, suggesting the possibility of parasitic infections triggering this phenomenon. In one of our patients, the bone marrow findings suggested a genetic predisposition for leukemoid reactions.
Loffler's endocarditis was first described as a nosologic entity by Dr W. Loffler in 1936, when he described the "syndrome of eosinophilia and chronic heart failure due to constrictive pericarditis with endocardial fibrosis."9 In 1948, Davies described "endomyocardial fibrosis" in Ugandan men with hypereosinophilia and parasitic infestation.10 Currently, Loffler's endocarditis and Davies' endomyocardial fibrosis are considered by many authors as the early and the late manifestations of the same myocardial process that occurs secondary to eosinophil-induced cardiotoxicity.11 Microscopically, Loffler's endocarditis is characterized by a diffuse eosinophilic infiltration of the endocardium and myocardium with focal lysis of myofibrils and myofilaments, cytoplasmic vacuolization, interstitial space fibrosis, and massive infiltration by eosinophils.12 Davies' endomyocardial fibrosis is the end-stage organization of the myocardial lesions and thrombus into a thick layer of granulation tissue, which replaces normal endocardium and thereafter becomes a fibrotic scar that also involves myocardium.13 The mechanism of damage to the endocardium and later to the myocardium is mediated by the eosinophils' specific granule proteins, such as cationic major basic protein and peroxidase, which accumulate on the endocardial surface. As a result, the development of thrombosis is promoted through the binding of cationic major basic protein to the anionic endothelial protein thrombomodulin, impairing its anticoagulant activity.3,8 Cellular damage to the myocyte is mediated by reactive oxygen species such as hydrogen peroxide released by peroxidase.14
Clinical manifestations are those of congestive heart failure and pulmonary vascular congestion secondary to left ventricular diastolic dysfunction.4 Electrocardiographic abnormalities comprise intraventricular conduction disturbances15 and ST-T changes12 with evidence of right or left ventricular hypertrophy.8 Progression of the hypereosinophilic heart disease may be slow and often subclinical and may be discovered only by echocardiography. The papillary muscles are classically affected by this infiltrative process, resulting in mitral and/or tricuspid valve insufficiency. The mitral valve regurgitation is further increased by the accumulation of thrombus and fibrosis and by attachment of the posterior mitral valve leaflet to the left ventricular free wall.8 Although intracardiac thrombus formation at the apex of the right and/or left ventricles is characteristic of Loffler's endocarditis, clinical manifestations of systemic embolization are not common.4 The combination of thrombus formation and fibrosis results in a restrictive cardiomyopathy with the typical echocardiographic findings of increased left ventricular wall thickness, increased left ventricular wall mass, and an enlarged left atrium.12 Diastolic dysfunction, evidenced echocardiographically by an increase in "A wave" velocity and equalization in the E/A ratio, may be present (as seen in our second patient). Pericardial effusion may also be present.8
When steroids and/or antineoplastic agents are used in these patients before the chronic fibrosis ensues, clinical and echocardiographic manifestations of disease may be arrested and sometimes reversed.4 It is postulated that the role of steroids is to reduce the number and activity of the eosinophils by inhibiting their localization, activation, and degranulation.4 Vincristine inhibits microtubule formation in the mitotic spindle, resulting in arrest of dividing cells at the metaphase stage, and hydroxyurea inhibits DNA synthesis. This combination results in diminished inflammation with a decrease in the number of eosinophils. Many authors advocate adjuvant thrombolytic therapy, unless no apical thrombi are seen on 2-dimensional echocardiography.1
Although Loffler's endocarditis is extremely unusual in children, a high index of suspicion in the presence of the findings of hypereosinophilia and respiratory distress should prompt an echocardiographic study, which will assist in the diagnosis.6 At the time this article was written, neither of our 2 patients, who did show mitral valve regurgitation, required mitral valve replacement. However, in many cases, mitral valve regurgitation will persist as a result of the eosinophilic infiltration of the papillary muscles and formation of fibrotic tissue within the posterior mitral valve leaflet.12 This process may ultimately necessitate surgical replacement of the native mitral valve to alleviate symptoms of dyspnea and congestive heart failure.2 It is hoped that early diagnosis and the prompt institution of medical treatment will result in less damage to the endocardium and the heart valves.
Division of Cardiology, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, Detroit, MI 48201-2196
Division of Cardiology, Department of Pediatrics, Children's Hospital of Winnipeg, University of Manitoba, Winnipeg, Manitoba, Canada
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FOOTNOTES |
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Received for publication Feb 19, 2002; Accepted May 13, 2002.
Reprint requests to (R.H.) Division of Cardiology, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201-2196. E-mail: rhumes{at}dmc.org
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCASE REPORTSDISCUSSIONREFERENCES |
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- Maron BJ. Hypereosinophylic syndrome. In: Emmanouilides GC, Riemenschneider TA, Allen HD, eds. Moss and Adams' Heart Disease in Infants, Children and Adolescents Including the Fetus and the Young Adult. 5th ed. Baltimore, MD: Williams & Wilkins; 1995:1360–1361
- Slungaard A, Vercellotti G, Tran T, et al. Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic syndrome. J Clin Invest.1993; 91 :1721 –1730
- Wynne J, Braunwald E. The myocardiopathies and myocarditides. In: Braunwald J, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders; 2001:1751–1782
- Parrillo J, Borer J, Henry W, et al. The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature. Am J Med.1979; 67 :572 –581[CrossRef][Web of Science][Medline]
- Curtis L, Schuyler M. Immunologically mediated lung diseases. In: Baum GL, Celli BR, Crapo JD, Karlinsky JB, eds. Textbook of Pulmonary Diseases. 6th ed. Philadelphia, PA: Lippincott-Raven; 1998:381–405
- Aoki Y, Nata M, Hashiyada H, et al. Sudden unexpected death in childhood due to eosinophilic myocarditis. Int J Legal Med.1996; 108 :572 –581
- Eber B, Schider P, Tiran A, et al. Differential diagnostic considerations in eosinophilia with reference to a 19-year-old patient with Loffler endocarditis. Acta Med Austriaca.1992; 19 :35 –39[Medline]
- Olson T, Virmani R, Ansinelli R, et al. Cardiomyopathy in a child with hypereosinophilic syndrome. Pediatr Cardiol.1982; 3 :161 –169[CrossRef][Web of Science][Medline]
- Loffler W. Endocarditis parietalis fibroplastica mit Bluteosinophilie, ein eigenartiges Krankheitsbild. Schweiz Med Wochenschr.1936; 17 :817
- Williams AW, Ball JD, Davies JNP. Endomyocardial fibrosis in Africa: its diagnosis, distribution and nature. Trans R Soc Trop Med Hyg.1954; 48 :290[Medline]
- Touze J, Fourcade L, Heno P, et al. The heart and the eosinophil. Med Trop (Mars).1998; 58 :459 –464
- Gonzalez Torrecilla E, Rey Perez M, Maravi Petri C, Alvarez Lacruz L, Cordoba Polo M. [Diagnostic usefulness of 2-dimensional echocardiography in eosinophilic endomyocardial disease (Loeffler disease)]. Rev Esp Cardiol.1989; 42 :126 –130[Medline]
- Brockington I, Olsen E. Loffler's endocarditis and Davie's endomyocardial fibrosis. Am Heart J.1973; 85 :308 –332[CrossRef]
- Davies J, Gibson D, Foale R. Echocardiographic features of eosinophilic endomyocardial disease. Br Heart J.1982; 48 :182 –187
- Hyogo M, Kamitani T, Oguni A, et al. Acute necrotizing eosinophilic myocarditis with giant cell infiltration after remission of idiopathic thrombocytopenic purpura. Int Med.1997; 36 :894 –897
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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