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Eosinophilic Myocarditis
Heart Failure Clin 1 (2005) 419 – 429
Eosinophilic Myocarditis Fredric Ginsberg, MDa,T, Joseph E. Parrillo, MDa,b a
Camden University of Medicine and Dentistry of New Jersey, Camden, NJ, USA b Cooper University Hospital, Camden, NJ, USA
Eosinophilic myocarditis is a rare form of myocarditis that is characterized pathologically by myocardial inflammation with eosinophils, often in association with elevated levels of circulating blood eosinophils. Eosinophilic myocarditis can be classified according to the presumed etiology (eg, hypersensitivity/allergic), associated clinical conditions, or abnormalities found on endomyocardial biopsy or at autopsy. There is overlap in the clinical features and pathologic findings among these different disorders, reflecting our incomplete understanding of the etiology and pathogenesis of the different forms of eosinophilic heart disease.
Hypersensitivity myocarditis French and Weller [1] are credited with the first report linking myocarditis characterized by eosinophilic infiltration to the use of a particular drug: sulfonamides in their report. In this retrospective study, 126 hearts with eosinophilic myocarditis were found at autopsy in patients treated with sulfonamides within the several weeks before death. These patients had no other illnesses associated with myocarditis, and the authors believed that an ‘‘idiosyncratic reaction’’ to sulfonamides was responsible. There was no correlation between the duration and the dose
T Corresponding author. Robert Wood Johnson Medical School, Camden University of Medicine and Dentistry of New Jersey, One Cooper Plaza, Suite D 378, Camden, NJ 08103. E-mail address: [email protected] (F. Ginsberg).
of medication and the severity of the myocarditis. These authors went on to administer intraperitoneal sulfonamides to laboratory rats and mice, with production of a similar eosinophilic myocarditis in these animal models. Since then, multiple other medications have been associated with eosinophilic myocarditis (Box 1) [2,3]. Most commonly implicated drugs are hydrochlorothiazide, methyldopa, penicillin, ampicillin, sulfadiazine, and sulfasoxisole [4]. The mechanism responsible is believed to be an allergic delayed hypersensitivity reaction, and not a toxic effect of the offending drug. Myocardial damage is not known to be a pharmacologic or direct toxic effect of these drugs. Hypersensitivity myocarditis occurs independent of the dose of the medication, and often occurs after the drug has been used initially without complication, stopped, and later reinitiated; both features are consistent with an allergic response. Patients may present with signs of a typical allergic reaction, including fever, rash, and blood eosinophilia [4,5]. Hypersensitivity myocarditis is diagnosed infrequently antemortem because patients often are not critically ill and the clinical signs of cardiac involvement are often nonspecific. ECG abnormalities may include sinus tachycardia, atrial fibrillation or atrial flutter, premature ventricular contractions, nonspecific ST segment abnormalities, ST segment elevation mimicking myocardial infarction, or conduction delays. ECG abnormalities may be transient or sustained. Echocardiographic findings are compatible with myocarditis, including left ventricular dilatation and regional or global left ventricular wall motion abnormalities. There is also a significant incidence of sudden cardiac death, however, presumably as a result of arrhythmias. Thus the
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Box 1. Drug causes of eosinophilic myocarditis Acetazolamide Amitriptyline Amphotericin B Ampicillin Carbamazepine Cefaclor Chloramphenicol Chlorthalidone Desipramine Hydrochlorothiazide Indomethacin Interleukin (IL)-4 Isoniazid Methyldopa Oxyphenylbutazone Para-aminosalicylic acid Penicillin Phenindione Phenobarbital Phenylbutazone Phenytoin Spironolactone Streptomycin Sulfadiazine Sulfisoxazole Sulfononylureas Tetanus toxoid Tetracycline From Zaacks, Klein L, Tan C, et al. Hypersensitivity myocarditis associated with ephedra use. Clinical Toxicology 1999; 37(4):489; with permission.
clinical scenario is that of patients who are being treated for noncardiac, nonsevere illness, who often had clinically recognizable but minor and nonspecific cardiac abnormalities before their unexpected deaths [6,7]. Pathologic findings were described in a series of 24 patients who died of hypersensitivity myocarditis [4]. Most common clinical presentations were stroke, back pain, nausea, headache, dyspnea, and other symptoms of heart failure. Presenting symptoms were recognized days to months after initiation of the offending drug. One third of patients were on more than one potentially offending medication. Blood testing showed mild elevation of cardiac enzymes. These patients also tended to die suddenly. At autopsy,
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myocarditis was marked by a patchy interstitial and perivascular infiltration with eosinophils, with a less prominent lymphocytic, histocytic, and plasma cell infiltration. Myocytolysis was seen, but frank myocyte necrosis and interstitial fibrosis were uncommon pathologic findings. Another series reported 69 cases of eosinophilic myocarditis diagnosed at autopsy [5]. This diagnosis was not suspected clinically antemortem. Histologic findings were similar to those described above, and the authors emphasized that within the heart, the inflammatory lesions were at a similar stage of development, suggesting the illness had an abrupt onset caused by a particular etiology. Right ventricular and left ventricular involvement was observed commonly, whereas the atria were less often affected. Importantly, 50% of patients had eosinophilic infiltrates detected in other organs (eg, lungs, liver) that were not affected as severely as the myocardium. The eosinophilic myocardial infiltrates ranged from mild to severe, but this histopathologic finding did not correlate with the severity of clinical symptoms or the incidence of sudden cardiac death. The diagnosis of hypersensitivity myocarditis thus requires a high clinical index of suspicion and should be considered in patients with signs and symptoms of a systemic allergic illness who are being administered a potentially offending agent. These patients generally but not universally have abnormalities detected on ECG, echocardiography [8], and by serum cardiac enzymes; they frequently have clinical signs and symptoms of chest pain or heart failure. Endomyocardial biopsy is necessary to make this diagnosis [9]. Effective treatment requires suspicion of the illness and immediate cessation of the offending drug. Pharmacologic therapy of left ventricular dysfunction and heart failure is indicated, using beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics as indicated. Temporary pacing and standard antiarrhythmic therapy may be necessary to treat heart block and supraventricular or ventricular arrhythmias. Although controlled trials are lacking, a course of corticosteroid therapy is indicated in patients with significant cardiac findings, in severe cases, or in patients who do not respond within days or weeks to cessation of the offending medication [2].
Acute necrotizing eosinophilic myocarditis A more severe form of eosinophil-mediated heart disease is termed acute necrotizing eosinophilic myo-
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carditis. Patients who have this illness present with the acute onset of severe chest pain, fever, rash, and acute heart failure symptoms [10]. They may have evidence of hepatitis, conjunctivitis [11], and pericardial effusions [12]. Some patients have been described with fulminant heart failure and cardiogenic shock, and this form of myocarditis may be rapidly fatal. The electrocardiogram in patients who have this condition often shows conduction abnormalities and diffuse ST segment elevation, mimicking acute myocardial infarction [9], similar to other etiologies of acute myopericarditis. Eosinophilia and elevated serum levels of the MB fraction of creatine phosphokinase (CPK-MB) and troponin are present, and elevated IgE levels have been reported [12]. Echocardiography will show dilatation of the left ventricle with significant systolic dysfunction, usually with prominent global wall motion abnormalities. Left ventricular wall thickness is increased, presumably as a result of interstitial myocardial edema. Right ventricular dilatation and dysfunction and pericardial effusions also may be seen. A case of biopsy-proven eosinophilic myocarditis was reported with abnormal findings on MRI, which showed a dilated left ventricle with global dysfunction, with an unusual patchy distribution to gadolinium enhancement. This imaging finding was used to guide diagnostic endomyocardial biopsies [13]. Pathologic findings of acute necrotizing eosinophilic myocarditis differ from hypersensitivity myocarditis. In addition to an intense and diffuse myocardial infiltration with eosinophils and lymphocytes, there is also a marked degree of myocardial necrosis. Some authors believe that this entity represents the most severe form in the spectrum of abnormalities caused by hypersensitivity myocarditis [14,15]. Medications incriminated as etiologic agents in case reports have included hydroxychloroquine and amitriptyline [16], ciprofloxacin [14], carbamazepine [11], and cysteinyl leukotriene antagonists (zafirlukast, montelukast, and pranlukast) given for treatment of asthma, often after a corticosteroid taper [17]. A case report of necrotizing eosinophilic myocarditis was described occurring in a patient taking ephedra in the form of the over-the-counter preparation Ma Huang (containing ephedrine and pseudoephedrine), although the patient also was taking furosemide and pravastatin [3]. A case report of acute necrotizing eosinophilic myocarditis caused by the sting from an ocean animal has been reported, and an allergic response to venom was hypothesized [18]. Cases of acute necrotizing eosinophilic myocarditis also have been reported that are not believed to
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be caused by drug hypersensitivity [9]. Generalized allergic diatheses [10] associated with viral infections, cancer, or connective tissue diseases (eg, systemic lupus erythematosis) have been described. Pathologic findings of acute necrotizing eosinophilic myocarditis also are reported with Churg-Strauss syndrome (see later discussion). The diagnosis of acute necrotizing eosinophilic myocarditis requires suspicion of this disorder and early endomyocardial biopsy. Without rapid recognition and treatment, this form of myocarditis is often rapidly fatal [11]. The first step of therapy is immediate cessation of all unnecessary medications. Treatment of severe or fulminant heart failure should include the pharmacologic agents used for heart failure caused by more common etiologies. Immunosuppressive drug regimens consisting of high-dose corticosteroids and azathioprine have been successful in uncontrolled series. Mechanical support with intraaortic balloon counterpulsation or left ventricular assist devices may be necessary until improvement in left ventricular function and hemodynamic status occurs. Case reports describe that the aggressive treatment strategies outlined above can improve left ventricular size and function rapidly. Significant improvement can be seen in echocardiographic signs of left ventricular dysfunction after weeks to months of therapy, and complete recovery of left ventricular function is observed frequently. With therapy, serial biopsies have shown resolution of the myocarditis, although fibrosis may be seen late. One case of severe acute necrotizing eosinophilic myocarditis resolved after pericardiocentesis only, without immunosuppressive drug treatment [12], with documented improvement in left ventricular function and resolution of eosinophilic myocarditis on repeat biopsy. This suggests that only transient exposure to the initiating agent had occurred.
Hypersensitivity myocarditis associated with specific agents Smallpox vaccine Smallpox, a highly contagious infectious disease caused by the variola virus, was declared eradicated worldwide by the World Health Organization in 1980. Routine vaccination of children in the United States was discontinued in 1972, and routine vaccination of United States military personnel was stopped in 1990 [19]. In response to a perceived
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threat of bioterrorism, 468,000 United States military recruits were administered smallpox vaccine using live attenuated virus between December 2002 and June 2003. A higher-than-expected incidence of cardiac complications of the vaccine was seen, estimated at 1 per 12,800 vaccinated persons [19,20] with an estimated increased incidence of 3.6 fold compared with nonvaccinated recruits [20]. Two confirmed biopsy-proven cases of eosinophilic myocarditis [21] and 50 ‘‘probable’’ cases of myopericarditis [19] occurred within 30 days of vaccination. The diagnosis of ‘‘probable myocarditis’’ was based on symptoms of chest pain, ECG abnormalities including ST segment elevation, elevation of cardiac enzymes, and abnormal left ventricular function or pericardial effusion on echocardiography [19]. Patients generally recovered and no deaths were reported. Review of the worldwide literature regarding cardiac complications after smallpox vaccine includes a 2% to 3% incidence of asymptomatic T-wave changes on ECG in Swedish military recruits. Five fatal cases of myocarditis occurred after vaccination of the general public in France in the 1950s, and 12 cases of myocarditis, one fatal, were reported in Australia [19]. A postvaccination incidence of myopericarditis of 1 per 10,000 military recruits was reported from Finland in 1983 [21]. One case of myocarditis associated with eosinophilia also was reported occurring 4 days after diphtheria-tetanus-pertussis vaccination [22]. The true incidence of myocarditis after smallpox vaccination is likely higher because milder, selflimited cases with complete resolution likely go unreported [20,21]. Treatment of this condition includes rest, nonsteroidal anti-inflammatory drugs, or highdose corticosteroids [19]. One biopsy-proven case of eosinophilic myocarditis was treated with prednisone with resolution of signs of heart failure and normalization of left ventricular function within 10 days. In the event that smallpox vaccination is recommended in the future for the general population, physicians should be knowledgeable concerning potential cardiac complications. Older persons with heart disease, including coronary artery disease and heart failure, probably should not undergo vaccination [19].
Dobutamine In several studies, eosinophilic myocarditis has been found in the explanted hearts of patients undergoing cardiac transplantation. Spear [23] studied the explanted hearts of all 31 patients un-
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dergoing cardiac transplantation in his institution over a 6-year period. Eosinophilic myocarditis was detected in 7 of 31 hearts, and all patients had received parenteral dobutamine for over 1 month (34 days to 5 months). Importantly, eosinophilic myocarditis had not been suspected before transplantation. Five of these seven patients had endomyocardial biopsies before transplant that did not show eosinophilic infiltration. Blood eosinophilia was noted 15 to 75 days after initiation of dobutamine, which suggests that eosinophilic myocardial infiltration occurred subsequent to the endomyocardial biopsy and before transplantation. After reviewing all of the medications administered to these patients and to the transplant patients who did not show evidence of eosinophilic myocarditis, only prolonged continuous administration of dobutamine could be linked temporally to the development of the eosinophilic myocarditis. In a study by Hawkins and colleagues [24], the incidence of eosinophilic myocarditis in explanted hearts during a 5-year period was 8 of 111 (7.2%). Pathology was consistent with a hypersensitivity eosinophilic myocarditis, although one heart showed extensive myocte necrosis. This incidence was remarkably similar to that reported by Takkenburg and colleagues [25], who identified eosinophilic myocarditis in 14 of 190 explanted hearts (7.4%). This incidence is much higher than the incidence of 0.04% to 0.5% of eosinophilic myocarditis in general hospital autopsy series [24,26]. Three of the 14 patients reported by Takkenburg had hypersensitivity symptoms, and two patients had peripheral eosinophilia that subsided after dobutamine had been tapered. Six of the 14 patients had eosinophilic myocarditis with myocyte necrosis. These authors believed that the myocarditis was consistent with a hypersensitivity reaction, and that dobutamine infusion was the likely etiology. Other individual case reports of eosinophilic myocarditis occurring in patients awaiting cardiac transplantation also have been published [7,27,28]. A case of pericarditis in association with marked hypereosinophilia was reported in a patient awaiting cardiac transplantation who was receiving dobutamine. Eosinophilia subsided 5 days after stopping dobutamine, and recurred 1 day after rechallenge with a low dose of the drug [29]. One case of self-limited eosinophilic infiltration in the transplanted heart of a patient who had pretransplant hypersensitivity myocarditis also is reported [30]. This patient was well 18 months after transplant. The presence of hypersensitivity myocarditis in the explanted hearts had no influence on the post-
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transplant course or survival in these series [24,25]. Eosinophilic myocarditis should be suspected in patients awaiting transplantation, who are receiving dobutamine, or who develop fever, eosinophilia, or abrupt deterioration in left ventricular function. Consideration then should be given to changing the inotropic agent, or supporting the patient with a left ventricular assist device.
Hypereosinophilic syndrome Hypereosinophilic syndrome (HES) is a lymphoproliferative disease of unknown etiology characterized by overproduction of eosinophils, with eosinophilia in blood and bone marrow [31]. This disorder is not considered a clonal or leukemic illness [32]. Tissue infiltration with eosinophils occurs in multiple organs, including skin, brain, liver, peripheral nerves, intestines, spleen, and lung [8], leading to widely variable clinical presentations and disease course. Cardiac involvement is most common, however, and is the major determinant of morbidity and mortality [33]. The diagnosis of HES requires sustained eosinophilia greater than 1500/mL for at least for 6 months in the absence of allergic diathesis or parasitic infection, and evidence for organ damage by eosinophils [31,32]. Approximately 90% of patients with HES are male, generally between 20 and 50 years of age. Extracardiac symptoms include fatigue, fever, myalgias, and skin rashes. Patients with cardiac involvement generally develop signs and symptoms of heart failure; 15% to 27% of patients will present with chest pain. Systemic embolization, including signs and symptoms of stroke, also can occur. The cardiac pathologic findings of HES are distinctive. Its three hallmarks are (1) endocardial fibrosis, (2) myocardial inflammation with eosinophils, and (3) mural thrombi in right ventricle and left ventricle (Fig. 1) [33]. Heart failure may occur as a result of the development of a restrictive cardiomyopathy. Patients also may develop heart failure as a result of severe mitral regurgitation because endocardial fibrosis may involve the papillary muscle and subleaflet structures, leading to valvular deformity and restricted leaflet motion. Mural thrombi can lead to systemic embolization, most often resulting in stroke. Autopsy will show evidence of emboli to cerebrum and retina more often than will be detected clinically [34]. The first stage of cardiac involvement is characterized by acute myocarditis with inflammation with
Fig. 1. Gross anatomic findings in a patient who died of cardiac complications of hypereosinophilic syndrome. Extensive left ventricular endocardial fibrosis, apical thrombus, and distortion of the normal position of mitral valve structures are evident.
lymphocytes and eosinophils, myoctye necrosis, and endomyocardial damage. The second stage is marked by thrombotic lesions overlying endocardial damage in right ventricle and left ventricle. Lastly, fibrosis and endocardial scarring are seen, producing obliteration of left ventricular or right ventricular apex, leading to a restrictive heart failure physiology. Mitral and tricuspid valvular regurgitation also is seen during this third stage of the disease [31,35]. ECG findings are nonspecific and include T-wave inversions, left atrial enlargement, and left ventricular hypertrophy. Up to 35% of patients may have a normal ECG, however [33]. Erythrocyte sedimentation rate and levels of IgE, CPK-MB, or troponin may be elevated. Three patients who had HES were described who had normal echocardiograms and had mean elevation of serum troponin-T up to five times the upper limit of normal [36]. These patients had abnormal endomyocardial biopsies showing infiltration with eosinophils. Therefore, serum troponin-T may be a sensitive marker for cardiac involvement in HES, but its sensitivity and specificity require additional studies. Echocardiographic findings include left ventricular wall thickening, apical thrombosis in left ventricle or right ventricle, restricted motion of posterior mitral valve leaflet, and pericardial effusion (Figs. 2 and 3) [15,37]. Left ventricular ejection fraction is generally normal. Doppler examination will show
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Fig. 2. Apical long-axis echocardiographic view revealing a large thrombus extending along the lateral wall of the left ventricle. (From Ascione L, DeMichele M, Accadia M, et al. Reversal of cardiac abnormalities in a young man with idiopathic hypereosinophilic syndrome using a tyrosine kinase inhibitor. Euro J Echo 2004;5:388; with permission.)
mitral regurgitation and evidence of restrictive left ventricular filling patterns. The prognosis of patients who have HES depends on the presence and severity of cardiac involvement at the time of diagnosis. Cardiac findings tend to worsen over time, although spontaneous remissions also have been described [33]. Patients with cardiac involvement have a higher incidence of heart failure, stroke and other manifestations of systemic emboli, and need for corrective cardiac surgery. Noncardiac manifestations such as pulmonary infiltrates, angioedema, encephalopathy, and gastrointestinal involvement also can cause morbidity and death [37]. Progression of cardiac disease is variable. Echocardiography may be normal at the time of diagnosis of HES, and may be abnormal and indicate cardiac involvement months or years later [37]. Serial echocardiograms at 6-month intervals are recommended follow-up following initial diagnosis. The development of eosinophilic myocarditis does not seem to be related to the extent or duration of eosinophilia [31]. Historical series have described a poor prognosis without treatment for HES patients with an average survival of 9 months and a 3-year overall survival rate of 12% [38]. Survival is worse in patients who have congestive heart failure, blood leukocytosis greater than 90,000/mL, or myeloblasts in peripheral blood. The prognosis has been improved substantially since the introduction of immunosuppressive therapy (Fig. 4) [39]. The treatment of HES is aimed at controlling organ damage; therefore immunosuppressive therapy is used only in the presence of significant organ damage [38]. In a series of 26 HES patients,
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five patients did not require therapy and had the disease for an average of 14.5 years. Drugs that can be used for the treatment of HES are listed in Box 2. Glucocorticoids are initiated for treatment of HES with significant end-organ damage. Overly aggressive cytotoxic therapy to eradicate eosinophilia is not indicated [31]. Prednisone is started at a dose of 1 mg/kg/d, and is typically administered for 1 week. If patients demonstrate a response, then this regimen is altered to 1 mg/kg on alternate days and is continued for 3 to 12 months. The dose then can be tapered slowly as long as manifestations of the disease are controlled, with frequent monitoring of eosinophil counts and evaluation of end-organ function every 3 months. Of 21 patients treated with this therapeutic strategy [38], 38% had a good response and 31% demonstrated a partial response, including five patients who had echocardiographically documented stabilization or reversal of cardiac abnormalities with therapy. In patients whose disease continues to progress despite corticosteroid therapy, hydroxyurea should be added at a dose of 0.5 to 2.0 g/d [38]. Of eight patients who had a partial or poor response to prednisone alone, six demonstrated a good response to hydroxyurea. Combination therapy was most effective among patients with significant leukocytosis. Vincristine also has been recommended as treatment for patients with a leukocytosis over 100,000/mL [38]. It has been suggested that glucocorticoids suppress the transcription of genes that code for inflam-
Fig. 3. Apical four-chamber echocardiographic view demonstrating thrombotic material (arrows) in right and left ventricular apices. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (From Ommen S, Seward J, Tajik A. Clinical and echocardiographic features of hypereosinophilic syndrome. Am J Cardiol 2000;86:111; with permission.)
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Fig. 4. Cumulative survivals of patients with hypereosinophilic syndrome. A comparison of historical controls (closed circles) with present National Institutes of Health series (open circles). Upper-left panel shows comparison of entire patient population (P < .0001). Upper-right panel shows comparison of subpopulation of patients who have congestive heart failure (P < .001). Lower-left panel shows comparison of subpopulation of patients with myeloblasts seen on at least one occasion in peripheral blood (P < .001). Lower-right panel shows comparison of subpopulation of patients with peripheral leukocyte counts greater than 90,000 cells/mm3 (P < .02). Numbers in parentheses represent number of patients in each group. Cumulative survivals were computed by life-table analysis. Statistical significance was calculated by using Student’s t test. WBC, total peripheral leukocyte count. (From Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Int Med 1978;89(2):169; with permission.)
matory mediators such as IL-3, IL-4, IL-5, and granulocyte-macrophage colony stimulating factor (GM-CSF) [40]. By inhibiting production of these key mediators, glucocorticoids and other immunosuppressives decrease eosinophil numbers and prevent end-organ damage. Cyclosporine therapy also has been suggested because this drug also blocks transcription of genes for eosinophil activating cytokines [40]. A patient with marked peripheral eosinophilia and severe cardiac involvement diagnosed as having HES was treated successfully with imatinib mesylate, a tyrosine kinase inhibitor often used in the treatment of some patients who have acute and chronic myelogenous leukemia. Blood eosinophilia was reduced significantly, and ECG and echo findings of eosinophilic myocarditis were improved greatly within 4 months of treatment [41]. Other medications that may be considered for HES cases that fail to respond to prednisone and hydroxyurea therapy can include interferon-alpha, cladribine, leukotriene antagonists, and etoposide [32,40].
Treatment of heart failure requires diuretics and possibly ACE-inhibitors and beta-blockers. Systemic anticoagulation is indicated if mural thrombi are detected on echocardiography or thromboembolic complications have occurred already. Therapeutic anticoagulation with warfarin, however, is not fully protective, and the addition of antiplatelet agents should be considered, especially among the subset of patients who experience emboli despite treatment with therapeutic doses of anticoagulation therapy. Cardiac surgery has been performed in patients who have severe heart failure caused by severe atrioventricular-valvular regurgitation. Mitral valve and tricuspid valve repair or replacement have been reported [42]. Because a high incidence of thrombosis on mechanical valve prostheses in these patients has been described, bioprosthetic valves are recommended [43]. More recently, good results have been reported with mitral valve repair, with excision of subvalvular thrombosis and patch repair of posterior mitral valve leaflet [44]. Endomyocardectomy or thrombectomy alone also have been performed
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Box 2. Drug therapy for hypereosinophilic syndrome Prednisone: first-line therapy for patients with significant end-organ involvement. Hydroxyurea: used in combination with prednisone for patients with initial poor or partial response. Vincristine: useful for acute reductions with high eosinophil counts (>50,000/ML) and can ameliorate thrombocytopenia. Cyclosporine, imatinib mesylate, interferon-B, cladibrine, etoposide: can be used in patients refractory to above therapies. ACE-inhibitors, diuretics, beta-blockers: use as indicated for manifestation of heart failure. Anticoagulation: use if intracardiac mural thrombi seen on echocardiography or if thromboembolic complications (eg, stroke) occur. Antiplatelet drugs: consider adding if thromboembolic complications occur while on adequate anticoagulation therapy. Adapted from Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:2768; with permission.
successfully. Endocardial fibrosis generally will not recur after successful surgical therapy [45], provided that eosinophilia is treated effectively.
Other causes of eosinophilic endomyocardial disease Loeffler’s endocarditis, a restrictive cardiomyopathy with endocardial fibrosis first described in 1936, probably belongs in the same spectrum of cardiac illness described in the HES but at a different, later stage of development [33,42]. Eosinophilic myocarditis also can occur in association with parasitic infections. Myocarditis is associated with infection with the protozoans Trypanosoma cruzi and Toxoplasma gondii, as well as with Trichinella spiralis, Entamoeba fragilis, Isospora belli, strongyloidiosis, Toxocara canis, echinococcus, and schistosomiosis [8,31]. It is believed that the heart becomes infiltrated with eosinophils in relation to the significant and sustained blood eosinophilia caused by the parasitic infection [8].
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Tropical endomyocardial fibrosis was described by Davies and colleagues in 1948 [46,47]. This illness occurs in persons living in subtropical Africa, India, and South America, within 15 of the equator [31,41]. As opposed to the endomyocardial fibrosis that occurs with HES, this illness occurs as frequently in females as in males, and is seen in children and young adults. Pathologically, cardiac involvement is indistinguishable from other forms of eosinophilic endomyocardial disease. Other organs are not involved, however, and there are no other signs of systemic disease. Patients tend to present in the late stages of disease with more severe cardiac fibrosis. It has been postulated that a marked hypersensitivity response to filariasis or repeated exposure to parasites in childhood may predispose to this disease. Eosinophilic myocarditis has been reported to occur to association with the vasculitis of ChurgStrauss syndrome [8,34]. This condition, first described in 1951, is a systemic vasculitis of unknown cause, marked pathologically by necrotizing vasculitis and granulomas. Clinically, these patients demonstrate a history of asthma, mononeuropathy or polyneuropathy, abnormalities of paranasal sinuses, and pulmonary infiltrates, in association with blood eosinophilia [42]. Cardiac involvement with eosinophilic myocarditis and endocardial fibrosis will worsen the prognosis of these patients [48]. In one series, 13 of 96 patients who had Churg-Strauss syndrome had myocardial involvement [48]. One case of eosinophilic coronary arteritis also has been described [49]. Successful therapy with corticosteroids has been reported. Eosinophilic myocarditis also has been described rarely in association with neoplastic disease, including T-cell lymphoma [34] and carcinomas of the lung and biliary tract [8].
Theories on pathogenesis Eosinophils play a role in immediate and delayed hypersensitivity reactions, and both mechanisms may play a role in hypersensitivity myocarditis. In sensitized subjects, allergen exposure leads to IgE-mediated degranulation of mast cells and basophils, which release prostaglandins, leukotrienes, and GM-CSF. These mediators are proinflammatory and lead to peripheral blood eosinophilia; they also act as eosinophil chemotactic factors. The late-phase response, which peaks in 8 hours, involves activation of type-2 helper T-lymphocytes that produce IL-5, a potent stimulator of eosinophil production and release from bone marrow [40]. Once in tissues, eo-
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sinophils generally undergo apoptosis and rapid clearance in 48 hours, but the presence of IL-3, IL-5, and GM-CSF can lead to activation of eosinophils and prolonged survival in tissue, with 12- to 14-day survivals noted in vitro. Standard blood staining techniques reveal characteristic red-orange granules in the cytoplasm of eosinophils. These granules contain cationic proteins, cytokines, and lipid mediators [32]. The cationic proteins—major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase—are potent mediators of damage to microbes, and they are cytotoxic to human tissue [8,32]. Laboratory studies have shown that eosinophils cause substantial cytotoxicity to antibody-coated red blood cells and human embryonic heart cells [50]. Eosinophilic proteins cause increased membrane permeability in target cells by creating membrane pores or channels that lead to effective target cell killing [51]. Patients who have eosinophilic myocarditis may have elevated levels of serum MBP and ECP [34,48]. Cardiac biopsy specimens from patients who have eosinophilic myocarditis show eosinophilic degranulation [9] with extracellular deposition of MBP and ECP adjacent to the thrombotic and necrotic lesions [9,15,52,53]. Extracellular staining with antibodies to MBP has been reported in two pediatric cases of fulminant necrotizing eosinophilic myocarditis, along with activated eosinophilic granules seen on electron microscopy [49]. The extent of cardiac damage in these patients seems to be related to the extent of eosinophilic cytoplasmic vacuolization and hypogranularity [31]. Corticosteroids inhibit the degranulation of eosinophils and the release of granulocyte proteins [34]. No consistent change in coagulation or fibrinolytic activity has been described, although MBP is a platelet stimulator and may promote clot formation [8,54]. Eosinophilic proteins also may induce apoptosis [35]. Why eosinophils particularly target the heart in eosinophilic myocarditis is understood poorly. Markedly elevated levels of IL-5 and IL-13, cytokines that cause hypereosinophilia, reportedly are present in the pericardial effusion in a patient who has acute necrotizing eosinophilic myocarditis. It was postulated that IL-5 was produced in the heart during acute myocarditis, which may stimulate eosinophil production, activation, and recruitment to myocardium [12]. Thus eosinophils are believed to be activated and directly toxic to myocardial cells, and are the mediators of myocardial injury in these forms of myocarditis. In some etiologies of eosinophilic myo-
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carditis (eg, parasitic infestation or allergic responses) the myocardial damage occurs as an ‘‘innocent bystander’’ in the setting of marked or chronic eosinophilia. Determining why eosinophils localize to myocardium in these conditions may be a productive line of investigation and may lead to therapies to prevent or ameliorate this illness [31].
Summary Eosinophilic myocarditis is an unusual but potentially fatal form of myocarditis. It may be caused by a delayed hypersensitivity response to a drug or vaccination, or it may occur in illnesses characterized by marked or chronic hypereosinophilia, such as HES or Churg-Strauss syndrome. Pathologically, a patchy interstitial myocardial eosinophilic and lymphocytic infiltrate may be present in the heart, or a more severe diffuse form of necrotizing myocarditis may be seen. Eosinophilic heart disease also may take the form of endocardial fibrosis, a restrictive cardiomyopathy, with mural thrombi and atrioventricular valve insufficiency. Diagnosis requires clinical suspicion of this illness with early endomyocardial biopsy. Treatment includes cessation of all potentially causative drugs, treatment of heart failure, immunosuppressive therapy, and consideration of cardiac surgery in selected cases.
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ginsberg from bench to bedside. Totowa (NJ)7 Humana Press; 2003. p. 437 – 53. Galiuto L, Enriquez-Sarano M, Reeder G, et al. Eosinophilic myocarditis manifesting as myocardial infarction: early diagnosis and successful treatment. Mayo Clin Proc 1997;72(7):603 – 10. Herzog C, Snover D, Staley N. Acute necrotising eosinophilic myocarditis. B Heart J 1984;52:343 – 8. Salzman M, Valderrama E, Sood S. Carbamazepine and fatal eosinophilic myocarditis. N Engl J Med 1997;336:878 – 9. Kazama R, Okura Y, Hoyano M, et al. Therapeutic role of pericardiocentesis for acute necrotizing eosinophilic myocarditis with cardiac tamponade. Mayo Clin Proc 2003;78:901 – 7. Chun W, Grist T, Kamp T, et al. Infiltrative eosinophilic myocarditis diagnosed and localized by cardiac magnetic resonance imaging. Circulation 2004;110:e19. Aggarwal A, Bergin P, Jessup P, et al. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transplant 2001;20:1241 – 4. Parrillo JE. Heart disease and the eosinophil. N Engl J Med 1990;323:1560 – 1. Getz M, Subramanian R, Logemann T, et al. Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis. Ann Intern Med 1991;115:201 – 2. Hayashai S, Furuya S, Imamura H. Fulminant eosinophilic endomyocarditis in an asthmatic patient treated with pranlukast after corticosteroid withdrawal. Heart 2001;86:e7 – 9. Adsett M, West M, Galbraith A, et al. Eosinophilic heart: marked left ventricular wall thickening and myocardial dysfunction improving with corticosteroid therapy. Echocardiography 2003;20:369 – 74. Cassimatis D, Atwood JE, Engler R, et al. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol 2004;43:1503 – 10. Halsell J, Riddle J, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA 2003;289:3283 – 9. Murphy J, Wright R, Bruce GK, et al. Eosinophilic lymphocytic myocarditis after smallpox vaccination. Lancet 2003;362:1378 – 80. Boccara F, Benhaiem-Sigaux N, Cohen A. Acute myopericarditis after diphtheria, tetanus, and polio vaccination. Chest 2001;120:671 – 2. Spear GS. Eosinophilic explant carditis with eosinophilia: hypersensitivity to dobutamine infusion. Jnl Hrt Lung Transplant 1995;14:755 – 60. Hawkins ET, Levine TB, Goss SJ, et al. Hypersensitivity myocarditis in the explanted heart of transplant recipients. Pathol Ann 1995;30(pt 1):287 – 304. Takkenberg JJ, Czer LS, Fishbein MC, et al. Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med 2004;32:714 – 21. Johnson MR. Eosinophilic myocarditis in the explanted hearts of cardiac transplant recipients: interesting pathologic finding or pathophysiologic entity of
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clinical significance? Crit Care Med 2004;32(3): 888 – 90. Bilinska ZT, Bilinska M, Grzybowski J, et al. Unexpected eosinophilic myocarditis in a young woman with rapidly progressive dilated cardiomyopathy. Int J Cardiol 2002;86:295 – 7. Butany J, Nair V, Ahluwalia MS, et al. Hypersensitivity myocarditis complicating hypertrophic cardiomyopathy heart. Can J Cardiol 2004;20(9):911 – 4. El-Sayed OM, Abdelfattah RR, Barcelona R, et al. Dobutamine-induced eosinophilia. Am J Cardiol 2004; 93:1078 – 9. di Gioia C, d’Amati G, Grillo P, et al. Eosinophilic infiltration immediately following transplantation: recurrent hypersensitivity reaction? Cardiovas Path 1999;8(5):297 – 9. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:2759 – 79. Tefferi A. Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment. Mayo Clin Proc 2005;80(1):75 – 83. Parrillo JE, Borer JS, Henry WL, et al. The cardiovascular manifestations of the hypereosinophilic syndrome. Am J Med 1979;67:572 – 82. Spry C, Take M, Tai P. Eosinophilic disorders affecting the myocardium and endocardium: a review. Heart Vessels Suppl 1985;1:240 – 2. Corradi D, Vaglio A, Maestri R, et al. Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death. Hum Pathol 2004;35:1160 – 3. Sato Y, Taniguchi R, Yamada T, et al. Measurement of serum concentrations of cardiac troponin T in patients with hypereosinophilic syndrome: a sensitive non-invasive marker of cardiac disorder. Int Med 2000; 39:350. Ommen S, Seward J, Tajik A. Clinical and echocardiographic features of hypereosinophilic syndrome. Am J Cardiol 2000;86:110 – 3. Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med 1978; 89(2):167 – 72. Fauci AS, Harley JB, Roberts WC, et al. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982;97:78 – 92. Rothenberg M. Eosinophilia. N Engl J Med 1998; 338(32):1592 – 600. Ascione L, DeMichele M, Accadia M, et al. Reversal of cardiac abnormalities in a young man with idiopathic hypereosinophilic syndrome using a tyrosine kinase inhibitor. Euro J Echo 2004;5:386 – 90. Blake DP, Palmer TE, Olinger GN. Mitral valve replacement in idiopathic hypereosinophilic syndrome. J Thorac Cardiovasc Surg 1985;89:630 – 8. Watanabe K, Olivier T, Lionel F, et al. Recurrent thrombosis of prosthetic mitral valve in idiopathic hypereosinophilic syndrome. J Heart Valve Dis 2002; 11:447 – 9.
eosinophilic myocarditis [44] Fuzellier JF, Chapoutot L, Torossian PF. Mitral valve repair in idiopathic hypereosinophilic syndrome. J Heart Valve Dis 2004;13:529 – 31. [45] Olsen E, Spry C. Relation between eosinophilia and endomyocardial disease. Prog Cardiovas Dis 1985;27: 241 – 54. [46] Davies JNP. Endomyocardial necrosis: a heart disease of obscure aetiology in Africans. MD thesis. University of Bristol; 1948. [47] Davies JNP. African endomyocardial fibrosis. In: Brest AN, Burch GE, editors. Cardiomyopathy, cardiovascular clinics, Vol. 4. Philadelphia: FA Davis; 1972. p. 345 – 59. [48] Ramakrishna G, Connolly H, Tazelaar H, et al. ChurgStrauss syndrome complicated by eosinophilic endomyocarditis. Mayo Clin Proc 2000;75:631 – 5. [49] Lie JT, Bayardo RJ. Isolated eosinophilic coronary arteritis and eosinophilic myocarditis. A limited forum of Churg-Strauss Syndrome. Arch Pathol Lab Med 1989;113:199 – 201.
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[50] Parrillo JE, Fauci AS. Human eosinophils. Purification and cytotoxic capability of eosinophils from patients with the hypereosinophilic syndrome. Blood 1978; 51(3):457 – 73. [51] Young JD, Peterson C, Venge P, et al. Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 1986;321:613 – 6. [52] Arima M, Kanoh T. Eosinophilic myocarditis associated with dense deposits of eosinophil cationic protein (ECP) in endomyocardium with high serum ECP. Heart 1999;81:669 – 75. [53] DeMello D, Liapis H, Jureidini S, et al. Cardiac localization of eosinophil granule major basic protein in acute necrotizing myocarditis. N Engl J Med 1990;323:1542 – 5. [54] Case Records of the Massachusetts General Hospital (Case 30 – 2000). A 25-year-old man with asthma, cardiac failure, diarrhea, and weakness of the right hand. N Engl J Med 2000;343:953 – 61 [erratum in N Engl J Med 2000;343(21):1584].
Eosinophilic Myocarditis Fredric Ginsberg, MDa,T, Joseph E. Parrillo, MDa,b a
Camden University of Medicine and Dentistry of New Jersey, Camden, NJ, USA b Cooper University Hospital, Camden, NJ, USA
Eosinophilic myocarditis is a rare form of myocarditis that is characterized pathologically by myocardial inflammation with eosinophils, often in association with elevated levels of circulating blood eosinophils. Eosinophilic myocarditis can be classified according to the presumed etiology (eg, hypersensitivity/allergic), associated clinical conditions, or abnormalities found on endomyocardial biopsy or at autopsy. There is overlap in the clinical features and pathologic findings among these different disorders, reflecting our incomplete understanding of the etiology and pathogenesis of the different forms of eosinophilic heart disease.
Hypersensitivity myocarditis French and Weller [1] are credited with the first report linking myocarditis characterized by eosinophilic infiltration to the use of a particular drug: sulfonamides in their report. In this retrospective study, 126 hearts with eosinophilic myocarditis were found at autopsy in patients treated with sulfonamides within the several weeks before death. These patients had no other illnesses associated with myocarditis, and the authors believed that an ‘‘idiosyncratic reaction’’ to sulfonamides was responsible. There was no correlation between the duration and the dose
T Corresponding author. Robert Wood Johnson Medical School, Camden University of Medicine and Dentistry of New Jersey, One Cooper Plaza, Suite D 378, Camden, NJ 08103. E-mail address: [email protected] (F. Ginsberg).
of medication and the severity of the myocarditis. These authors went on to administer intraperitoneal sulfonamides to laboratory rats and mice, with production of a similar eosinophilic myocarditis in these animal models. Since then, multiple other medications have been associated with eosinophilic myocarditis (Box 1) [2,3]. Most commonly implicated drugs are hydrochlorothiazide, methyldopa, penicillin, ampicillin, sulfadiazine, and sulfasoxisole [4]. The mechanism responsible is believed to be an allergic delayed hypersensitivity reaction, and not a toxic effect of the offending drug. Myocardial damage is not known to be a pharmacologic or direct toxic effect of these drugs. Hypersensitivity myocarditis occurs independent of the dose of the medication, and often occurs after the drug has been used initially without complication, stopped, and later reinitiated; both features are consistent with an allergic response. Patients may present with signs of a typical allergic reaction, including fever, rash, and blood eosinophilia [4,5]. Hypersensitivity myocarditis is diagnosed infrequently antemortem because patients often are not critically ill and the clinical signs of cardiac involvement are often nonspecific. ECG abnormalities may include sinus tachycardia, atrial fibrillation or atrial flutter, premature ventricular contractions, nonspecific ST segment abnormalities, ST segment elevation mimicking myocardial infarction, or conduction delays. ECG abnormalities may be transient or sustained. Echocardiographic findings are compatible with myocarditis, including left ventricular dilatation and regional or global left ventricular wall motion abnormalities. There is also a significant incidence of sudden cardiac death, however, presumably as a result of arrhythmias. Thus the
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Box 1. Drug causes of eosinophilic myocarditis Acetazolamide Amitriptyline Amphotericin B Ampicillin Carbamazepine Cefaclor Chloramphenicol Chlorthalidone Desipramine Hydrochlorothiazide Indomethacin Interleukin (IL)-4 Isoniazid Methyldopa Oxyphenylbutazone Para-aminosalicylic acid Penicillin Phenindione Phenobarbital Phenylbutazone Phenytoin Spironolactone Streptomycin Sulfadiazine Sulfisoxazole Sulfononylureas Tetanus toxoid Tetracycline From Zaacks, Klein L, Tan C, et al. Hypersensitivity myocarditis associated with ephedra use. Clinical Toxicology 1999; 37(4):489; with permission.
clinical scenario is that of patients who are being treated for noncardiac, nonsevere illness, who often had clinically recognizable but minor and nonspecific cardiac abnormalities before their unexpected deaths [6,7]. Pathologic findings were described in a series of 24 patients who died of hypersensitivity myocarditis [4]. Most common clinical presentations were stroke, back pain, nausea, headache, dyspnea, and other symptoms of heart failure. Presenting symptoms were recognized days to months after initiation of the offending drug. One third of patients were on more than one potentially offending medication. Blood testing showed mild elevation of cardiac enzymes. These patients also tended to die suddenly. At autopsy,
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myocarditis was marked by a patchy interstitial and perivascular infiltration with eosinophils, with a less prominent lymphocytic, histocytic, and plasma cell infiltration. Myocytolysis was seen, but frank myocyte necrosis and interstitial fibrosis were uncommon pathologic findings. Another series reported 69 cases of eosinophilic myocarditis diagnosed at autopsy [5]. This diagnosis was not suspected clinically antemortem. Histologic findings were similar to those described above, and the authors emphasized that within the heart, the inflammatory lesions were at a similar stage of development, suggesting the illness had an abrupt onset caused by a particular etiology. Right ventricular and left ventricular involvement was observed commonly, whereas the atria were less often affected. Importantly, 50% of patients had eosinophilic infiltrates detected in other organs (eg, lungs, liver) that were not affected as severely as the myocardium. The eosinophilic myocardial infiltrates ranged from mild to severe, but this histopathologic finding did not correlate with the severity of clinical symptoms or the incidence of sudden cardiac death. The diagnosis of hypersensitivity myocarditis thus requires a high clinical index of suspicion and should be considered in patients with signs and symptoms of a systemic allergic illness who are being administered a potentially offending agent. These patients generally but not universally have abnormalities detected on ECG, echocardiography [8], and by serum cardiac enzymes; they frequently have clinical signs and symptoms of chest pain or heart failure. Endomyocardial biopsy is necessary to make this diagnosis [9]. Effective treatment requires suspicion of the illness and immediate cessation of the offending drug. Pharmacologic therapy of left ventricular dysfunction and heart failure is indicated, using beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics as indicated. Temporary pacing and standard antiarrhythmic therapy may be necessary to treat heart block and supraventricular or ventricular arrhythmias. Although controlled trials are lacking, a course of corticosteroid therapy is indicated in patients with significant cardiac findings, in severe cases, or in patients who do not respond within days or weeks to cessation of the offending medication [2].
Acute necrotizing eosinophilic myocarditis A more severe form of eosinophil-mediated heart disease is termed acute necrotizing eosinophilic myo-
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carditis. Patients who have this illness present with the acute onset of severe chest pain, fever, rash, and acute heart failure symptoms [10]. They may have evidence of hepatitis, conjunctivitis [11], and pericardial effusions [12]. Some patients have been described with fulminant heart failure and cardiogenic shock, and this form of myocarditis may be rapidly fatal. The electrocardiogram in patients who have this condition often shows conduction abnormalities and diffuse ST segment elevation, mimicking acute myocardial infarction [9], similar to other etiologies of acute myopericarditis. Eosinophilia and elevated serum levels of the MB fraction of creatine phosphokinase (CPK-MB) and troponin are present, and elevated IgE levels have been reported [12]. Echocardiography will show dilatation of the left ventricle with significant systolic dysfunction, usually with prominent global wall motion abnormalities. Left ventricular wall thickness is increased, presumably as a result of interstitial myocardial edema. Right ventricular dilatation and dysfunction and pericardial effusions also may be seen. A case of biopsy-proven eosinophilic myocarditis was reported with abnormal findings on MRI, which showed a dilated left ventricle with global dysfunction, with an unusual patchy distribution to gadolinium enhancement. This imaging finding was used to guide diagnostic endomyocardial biopsies [13]. Pathologic findings of acute necrotizing eosinophilic myocarditis differ from hypersensitivity myocarditis. In addition to an intense and diffuse myocardial infiltration with eosinophils and lymphocytes, there is also a marked degree of myocardial necrosis. Some authors believe that this entity represents the most severe form in the spectrum of abnormalities caused by hypersensitivity myocarditis [14,15]. Medications incriminated as etiologic agents in case reports have included hydroxychloroquine and amitriptyline [16], ciprofloxacin [14], carbamazepine [11], and cysteinyl leukotriene antagonists (zafirlukast, montelukast, and pranlukast) given for treatment of asthma, often after a corticosteroid taper [17]. A case report of necrotizing eosinophilic myocarditis was described occurring in a patient taking ephedra in the form of the over-the-counter preparation Ma Huang (containing ephedrine and pseudoephedrine), although the patient also was taking furosemide and pravastatin [3]. A case report of acute necrotizing eosinophilic myocarditis caused by the sting from an ocean animal has been reported, and an allergic response to venom was hypothesized [18]. Cases of acute necrotizing eosinophilic myocarditis also have been reported that are not believed to
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be caused by drug hypersensitivity [9]. Generalized allergic diatheses [10] associated with viral infections, cancer, or connective tissue diseases (eg, systemic lupus erythematosis) have been described. Pathologic findings of acute necrotizing eosinophilic myocarditis also are reported with Churg-Strauss syndrome (see later discussion). The diagnosis of acute necrotizing eosinophilic myocarditis requires suspicion of this disorder and early endomyocardial biopsy. Without rapid recognition and treatment, this form of myocarditis is often rapidly fatal [11]. The first step of therapy is immediate cessation of all unnecessary medications. Treatment of severe or fulminant heart failure should include the pharmacologic agents used for heart failure caused by more common etiologies. Immunosuppressive drug regimens consisting of high-dose corticosteroids and azathioprine have been successful in uncontrolled series. Mechanical support with intraaortic balloon counterpulsation or left ventricular assist devices may be necessary until improvement in left ventricular function and hemodynamic status occurs. Case reports describe that the aggressive treatment strategies outlined above can improve left ventricular size and function rapidly. Significant improvement can be seen in echocardiographic signs of left ventricular dysfunction after weeks to months of therapy, and complete recovery of left ventricular function is observed frequently. With therapy, serial biopsies have shown resolution of the myocarditis, although fibrosis may be seen late. One case of severe acute necrotizing eosinophilic myocarditis resolved after pericardiocentesis only, without immunosuppressive drug treatment [12], with documented improvement in left ventricular function and resolution of eosinophilic myocarditis on repeat biopsy. This suggests that only transient exposure to the initiating agent had occurred.
Hypersensitivity myocarditis associated with specific agents Smallpox vaccine Smallpox, a highly contagious infectious disease caused by the variola virus, was declared eradicated worldwide by the World Health Organization in 1980. Routine vaccination of children in the United States was discontinued in 1972, and routine vaccination of United States military personnel was stopped in 1990 [19]. In response to a perceived
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threat of bioterrorism, 468,000 United States military recruits were administered smallpox vaccine using live attenuated virus between December 2002 and June 2003. A higher-than-expected incidence of cardiac complications of the vaccine was seen, estimated at 1 per 12,800 vaccinated persons [19,20] with an estimated increased incidence of 3.6 fold compared with nonvaccinated recruits [20]. Two confirmed biopsy-proven cases of eosinophilic myocarditis [21] and 50 ‘‘probable’’ cases of myopericarditis [19] occurred within 30 days of vaccination. The diagnosis of ‘‘probable myocarditis’’ was based on symptoms of chest pain, ECG abnormalities including ST segment elevation, elevation of cardiac enzymes, and abnormal left ventricular function or pericardial effusion on echocardiography [19]. Patients generally recovered and no deaths were reported. Review of the worldwide literature regarding cardiac complications after smallpox vaccine includes a 2% to 3% incidence of asymptomatic T-wave changes on ECG in Swedish military recruits. Five fatal cases of myocarditis occurred after vaccination of the general public in France in the 1950s, and 12 cases of myocarditis, one fatal, were reported in Australia [19]. A postvaccination incidence of myopericarditis of 1 per 10,000 military recruits was reported from Finland in 1983 [21]. One case of myocarditis associated with eosinophilia also was reported occurring 4 days after diphtheria-tetanus-pertussis vaccination [22]. The true incidence of myocarditis after smallpox vaccination is likely higher because milder, selflimited cases with complete resolution likely go unreported [20,21]. Treatment of this condition includes rest, nonsteroidal anti-inflammatory drugs, or highdose corticosteroids [19]. One biopsy-proven case of eosinophilic myocarditis was treated with prednisone with resolution of signs of heart failure and normalization of left ventricular function within 10 days. In the event that smallpox vaccination is recommended in the future for the general population, physicians should be knowledgeable concerning potential cardiac complications. Older persons with heart disease, including coronary artery disease and heart failure, probably should not undergo vaccination [19].
Dobutamine In several studies, eosinophilic myocarditis has been found in the explanted hearts of patients undergoing cardiac transplantation. Spear [23] studied the explanted hearts of all 31 patients un-
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dergoing cardiac transplantation in his institution over a 6-year period. Eosinophilic myocarditis was detected in 7 of 31 hearts, and all patients had received parenteral dobutamine for over 1 month (34 days to 5 months). Importantly, eosinophilic myocarditis had not been suspected before transplantation. Five of these seven patients had endomyocardial biopsies before transplant that did not show eosinophilic infiltration. Blood eosinophilia was noted 15 to 75 days after initiation of dobutamine, which suggests that eosinophilic myocardial infiltration occurred subsequent to the endomyocardial biopsy and before transplantation. After reviewing all of the medications administered to these patients and to the transplant patients who did not show evidence of eosinophilic myocarditis, only prolonged continuous administration of dobutamine could be linked temporally to the development of the eosinophilic myocarditis. In a study by Hawkins and colleagues [24], the incidence of eosinophilic myocarditis in explanted hearts during a 5-year period was 8 of 111 (7.2%). Pathology was consistent with a hypersensitivity eosinophilic myocarditis, although one heart showed extensive myocte necrosis. This incidence was remarkably similar to that reported by Takkenburg and colleagues [25], who identified eosinophilic myocarditis in 14 of 190 explanted hearts (7.4%). This incidence is much higher than the incidence of 0.04% to 0.5% of eosinophilic myocarditis in general hospital autopsy series [24,26]. Three of the 14 patients reported by Takkenburg had hypersensitivity symptoms, and two patients had peripheral eosinophilia that subsided after dobutamine had been tapered. Six of the 14 patients had eosinophilic myocarditis with myocyte necrosis. These authors believed that the myocarditis was consistent with a hypersensitivity reaction, and that dobutamine infusion was the likely etiology. Other individual case reports of eosinophilic myocarditis occurring in patients awaiting cardiac transplantation also have been published [7,27,28]. A case of pericarditis in association with marked hypereosinophilia was reported in a patient awaiting cardiac transplantation who was receiving dobutamine. Eosinophilia subsided 5 days after stopping dobutamine, and recurred 1 day after rechallenge with a low dose of the drug [29]. One case of self-limited eosinophilic infiltration in the transplanted heart of a patient who had pretransplant hypersensitivity myocarditis also is reported [30]. This patient was well 18 months after transplant. The presence of hypersensitivity myocarditis in the explanted hearts had no influence on the post-
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transplant course or survival in these series [24,25]. Eosinophilic myocarditis should be suspected in patients awaiting transplantation, who are receiving dobutamine, or who develop fever, eosinophilia, or abrupt deterioration in left ventricular function. Consideration then should be given to changing the inotropic agent, or supporting the patient with a left ventricular assist device.
Hypereosinophilic syndrome Hypereosinophilic syndrome (HES) is a lymphoproliferative disease of unknown etiology characterized by overproduction of eosinophils, with eosinophilia in blood and bone marrow [31]. This disorder is not considered a clonal or leukemic illness [32]. Tissue infiltration with eosinophils occurs in multiple organs, including skin, brain, liver, peripheral nerves, intestines, spleen, and lung [8], leading to widely variable clinical presentations and disease course. Cardiac involvement is most common, however, and is the major determinant of morbidity and mortality [33]. The diagnosis of HES requires sustained eosinophilia greater than 1500/mL for at least for 6 months in the absence of allergic diathesis or parasitic infection, and evidence for organ damage by eosinophils [31,32]. Approximately 90% of patients with HES are male, generally between 20 and 50 years of age. Extracardiac symptoms include fatigue, fever, myalgias, and skin rashes. Patients with cardiac involvement generally develop signs and symptoms of heart failure; 15% to 27% of patients will present with chest pain. Systemic embolization, including signs and symptoms of stroke, also can occur. The cardiac pathologic findings of HES are distinctive. Its three hallmarks are (1) endocardial fibrosis, (2) myocardial inflammation with eosinophils, and (3) mural thrombi in right ventricle and left ventricle (Fig. 1) [33]. Heart failure may occur as a result of the development of a restrictive cardiomyopathy. Patients also may develop heart failure as a result of severe mitral regurgitation because endocardial fibrosis may involve the papillary muscle and subleaflet structures, leading to valvular deformity and restricted leaflet motion. Mural thrombi can lead to systemic embolization, most often resulting in stroke. Autopsy will show evidence of emboli to cerebrum and retina more often than will be detected clinically [34]. The first stage of cardiac involvement is characterized by acute myocarditis with inflammation with
Fig. 1. Gross anatomic findings in a patient who died of cardiac complications of hypereosinophilic syndrome. Extensive left ventricular endocardial fibrosis, apical thrombus, and distortion of the normal position of mitral valve structures are evident.
lymphocytes and eosinophils, myoctye necrosis, and endomyocardial damage. The second stage is marked by thrombotic lesions overlying endocardial damage in right ventricle and left ventricle. Lastly, fibrosis and endocardial scarring are seen, producing obliteration of left ventricular or right ventricular apex, leading to a restrictive heart failure physiology. Mitral and tricuspid valvular regurgitation also is seen during this third stage of the disease [31,35]. ECG findings are nonspecific and include T-wave inversions, left atrial enlargement, and left ventricular hypertrophy. Up to 35% of patients may have a normal ECG, however [33]. Erythrocyte sedimentation rate and levels of IgE, CPK-MB, or troponin may be elevated. Three patients who had HES were described who had normal echocardiograms and had mean elevation of serum troponin-T up to five times the upper limit of normal [36]. These patients had abnormal endomyocardial biopsies showing infiltration with eosinophils. Therefore, serum troponin-T may be a sensitive marker for cardiac involvement in HES, but its sensitivity and specificity require additional studies. Echocardiographic findings include left ventricular wall thickening, apical thrombosis in left ventricle or right ventricle, restricted motion of posterior mitral valve leaflet, and pericardial effusion (Figs. 2 and 3) [15,37]. Left ventricular ejection fraction is generally normal. Doppler examination will show
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Fig. 2. Apical long-axis echocardiographic view revealing a large thrombus extending along the lateral wall of the left ventricle. (From Ascione L, DeMichele M, Accadia M, et al. Reversal of cardiac abnormalities in a young man with idiopathic hypereosinophilic syndrome using a tyrosine kinase inhibitor. Euro J Echo 2004;5:388; with permission.)
mitral regurgitation and evidence of restrictive left ventricular filling patterns. The prognosis of patients who have HES depends on the presence and severity of cardiac involvement at the time of diagnosis. Cardiac findings tend to worsen over time, although spontaneous remissions also have been described [33]. Patients with cardiac involvement have a higher incidence of heart failure, stroke and other manifestations of systemic emboli, and need for corrective cardiac surgery. Noncardiac manifestations such as pulmonary infiltrates, angioedema, encephalopathy, and gastrointestinal involvement also can cause morbidity and death [37]. Progression of cardiac disease is variable. Echocardiography may be normal at the time of diagnosis of HES, and may be abnormal and indicate cardiac involvement months or years later [37]. Serial echocardiograms at 6-month intervals are recommended follow-up following initial diagnosis. The development of eosinophilic myocarditis does not seem to be related to the extent or duration of eosinophilia [31]. Historical series have described a poor prognosis without treatment for HES patients with an average survival of 9 months and a 3-year overall survival rate of 12% [38]. Survival is worse in patients who have congestive heart failure, blood leukocytosis greater than 90,000/mL, or myeloblasts in peripheral blood. The prognosis has been improved substantially since the introduction of immunosuppressive therapy (Fig. 4) [39]. The treatment of HES is aimed at controlling organ damage; therefore immunosuppressive therapy is used only in the presence of significant organ damage [38]. In a series of 26 HES patients,
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five patients did not require therapy and had the disease for an average of 14.5 years. Drugs that can be used for the treatment of HES are listed in Box 2. Glucocorticoids are initiated for treatment of HES with significant end-organ damage. Overly aggressive cytotoxic therapy to eradicate eosinophilia is not indicated [31]. Prednisone is started at a dose of 1 mg/kg/d, and is typically administered for 1 week. If patients demonstrate a response, then this regimen is altered to 1 mg/kg on alternate days and is continued for 3 to 12 months. The dose then can be tapered slowly as long as manifestations of the disease are controlled, with frequent monitoring of eosinophil counts and evaluation of end-organ function every 3 months. Of 21 patients treated with this therapeutic strategy [38], 38% had a good response and 31% demonstrated a partial response, including five patients who had echocardiographically documented stabilization or reversal of cardiac abnormalities with therapy. In patients whose disease continues to progress despite corticosteroid therapy, hydroxyurea should be added at a dose of 0.5 to 2.0 g/d [38]. Of eight patients who had a partial or poor response to prednisone alone, six demonstrated a good response to hydroxyurea. Combination therapy was most effective among patients with significant leukocytosis. Vincristine also has been recommended as treatment for patients with a leukocytosis over 100,000/mL [38]. It has been suggested that glucocorticoids suppress the transcription of genes that code for inflam-
Fig. 3. Apical four-chamber echocardiographic view demonstrating thrombotic material (arrows) in right and left ventricular apices. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (From Ommen S, Seward J, Tajik A. Clinical and echocardiographic features of hypereosinophilic syndrome. Am J Cardiol 2000;86:111; with permission.)
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Fig. 4. Cumulative survivals of patients with hypereosinophilic syndrome. A comparison of historical controls (closed circles) with present National Institutes of Health series (open circles). Upper-left panel shows comparison of entire patient population (P < .0001). Upper-right panel shows comparison of subpopulation of patients who have congestive heart failure (P < .001). Lower-left panel shows comparison of subpopulation of patients with myeloblasts seen on at least one occasion in peripheral blood (P < .001). Lower-right panel shows comparison of subpopulation of patients with peripheral leukocyte counts greater than 90,000 cells/mm3 (P < .02). Numbers in parentheses represent number of patients in each group. Cumulative survivals were computed by life-table analysis. Statistical significance was calculated by using Student’s t test. WBC, total peripheral leukocyte count. (From Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Int Med 1978;89(2):169; with permission.)
matory mediators such as IL-3, IL-4, IL-5, and granulocyte-macrophage colony stimulating factor (GM-CSF) [40]. By inhibiting production of these key mediators, glucocorticoids and other immunosuppressives decrease eosinophil numbers and prevent end-organ damage. Cyclosporine therapy also has been suggested because this drug also blocks transcription of genes for eosinophil activating cytokines [40]. A patient with marked peripheral eosinophilia and severe cardiac involvement diagnosed as having HES was treated successfully with imatinib mesylate, a tyrosine kinase inhibitor often used in the treatment of some patients who have acute and chronic myelogenous leukemia. Blood eosinophilia was reduced significantly, and ECG and echo findings of eosinophilic myocarditis were improved greatly within 4 months of treatment [41]. Other medications that may be considered for HES cases that fail to respond to prednisone and hydroxyurea therapy can include interferon-alpha, cladribine, leukotriene antagonists, and etoposide [32,40].
Treatment of heart failure requires diuretics and possibly ACE-inhibitors and beta-blockers. Systemic anticoagulation is indicated if mural thrombi are detected on echocardiography or thromboembolic complications have occurred already. Therapeutic anticoagulation with warfarin, however, is not fully protective, and the addition of antiplatelet agents should be considered, especially among the subset of patients who experience emboli despite treatment with therapeutic doses of anticoagulation therapy. Cardiac surgery has been performed in patients who have severe heart failure caused by severe atrioventricular-valvular regurgitation. Mitral valve and tricuspid valve repair or replacement have been reported [42]. Because a high incidence of thrombosis on mechanical valve prostheses in these patients has been described, bioprosthetic valves are recommended [43]. More recently, good results have been reported with mitral valve repair, with excision of subvalvular thrombosis and patch repair of posterior mitral valve leaflet [44]. Endomyocardectomy or thrombectomy alone also have been performed
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Box 2. Drug therapy for hypereosinophilic syndrome Prednisone: first-line therapy for patients with significant end-organ involvement. Hydroxyurea: used in combination with prednisone for patients with initial poor or partial response. Vincristine: useful for acute reductions with high eosinophil counts (>50,000/ML) and can ameliorate thrombocytopenia. Cyclosporine, imatinib mesylate, interferon-B, cladibrine, etoposide: can be used in patients refractory to above therapies. ACE-inhibitors, diuretics, beta-blockers: use as indicated for manifestation of heart failure. Anticoagulation: use if intracardiac mural thrombi seen on echocardiography or if thromboembolic complications (eg, stroke) occur. Antiplatelet drugs: consider adding if thromboembolic complications occur while on adequate anticoagulation therapy. Adapted from Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:2768; with permission.
successfully. Endocardial fibrosis generally will not recur after successful surgical therapy [45], provided that eosinophilia is treated effectively.
Other causes of eosinophilic endomyocardial disease Loeffler’s endocarditis, a restrictive cardiomyopathy with endocardial fibrosis first described in 1936, probably belongs in the same spectrum of cardiac illness described in the HES but at a different, later stage of development [33,42]. Eosinophilic myocarditis also can occur in association with parasitic infections. Myocarditis is associated with infection with the protozoans Trypanosoma cruzi and Toxoplasma gondii, as well as with Trichinella spiralis, Entamoeba fragilis, Isospora belli, strongyloidiosis, Toxocara canis, echinococcus, and schistosomiosis [8,31]. It is believed that the heart becomes infiltrated with eosinophils in relation to the significant and sustained blood eosinophilia caused by the parasitic infection [8].
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Tropical endomyocardial fibrosis was described by Davies and colleagues in 1948 [46,47]. This illness occurs in persons living in subtropical Africa, India, and South America, within 15 of the equator [31,41]. As opposed to the endomyocardial fibrosis that occurs with HES, this illness occurs as frequently in females as in males, and is seen in children and young adults. Pathologically, cardiac involvement is indistinguishable from other forms of eosinophilic endomyocardial disease. Other organs are not involved, however, and there are no other signs of systemic disease. Patients tend to present in the late stages of disease with more severe cardiac fibrosis. It has been postulated that a marked hypersensitivity response to filariasis or repeated exposure to parasites in childhood may predispose to this disease. Eosinophilic myocarditis has been reported to occur to association with the vasculitis of ChurgStrauss syndrome [8,34]. This condition, first described in 1951, is a systemic vasculitis of unknown cause, marked pathologically by necrotizing vasculitis and granulomas. Clinically, these patients demonstrate a history of asthma, mononeuropathy or polyneuropathy, abnormalities of paranasal sinuses, and pulmonary infiltrates, in association with blood eosinophilia [42]. Cardiac involvement with eosinophilic myocarditis and endocardial fibrosis will worsen the prognosis of these patients [48]. In one series, 13 of 96 patients who had Churg-Strauss syndrome had myocardial involvement [48]. One case of eosinophilic coronary arteritis also has been described [49]. Successful therapy with corticosteroids has been reported. Eosinophilic myocarditis also has been described rarely in association with neoplastic disease, including T-cell lymphoma [34] and carcinomas of the lung and biliary tract [8].
Theories on pathogenesis Eosinophils play a role in immediate and delayed hypersensitivity reactions, and both mechanisms may play a role in hypersensitivity myocarditis. In sensitized subjects, allergen exposure leads to IgE-mediated degranulation of mast cells and basophils, which release prostaglandins, leukotrienes, and GM-CSF. These mediators are proinflammatory and lead to peripheral blood eosinophilia; they also act as eosinophil chemotactic factors. The late-phase response, which peaks in 8 hours, involves activation of type-2 helper T-lymphocytes that produce IL-5, a potent stimulator of eosinophil production and release from bone marrow [40]. Once in tissues, eo-
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sinophils generally undergo apoptosis and rapid clearance in 48 hours, but the presence of IL-3, IL-5, and GM-CSF can lead to activation of eosinophils and prolonged survival in tissue, with 12- to 14-day survivals noted in vitro. Standard blood staining techniques reveal characteristic red-orange granules in the cytoplasm of eosinophils. These granules contain cationic proteins, cytokines, and lipid mediators [32]. The cationic proteins—major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase—are potent mediators of damage to microbes, and they are cytotoxic to human tissue [8,32]. Laboratory studies have shown that eosinophils cause substantial cytotoxicity to antibody-coated red blood cells and human embryonic heart cells [50]. Eosinophilic proteins cause increased membrane permeability in target cells by creating membrane pores or channels that lead to effective target cell killing [51]. Patients who have eosinophilic myocarditis may have elevated levels of serum MBP and ECP [34,48]. Cardiac biopsy specimens from patients who have eosinophilic myocarditis show eosinophilic degranulation [9] with extracellular deposition of MBP and ECP adjacent to the thrombotic and necrotic lesions [9,15,52,53]. Extracellular staining with antibodies to MBP has been reported in two pediatric cases of fulminant necrotizing eosinophilic myocarditis, along with activated eosinophilic granules seen on electron microscopy [49]. The extent of cardiac damage in these patients seems to be related to the extent of eosinophilic cytoplasmic vacuolization and hypogranularity [31]. Corticosteroids inhibit the degranulation of eosinophils and the release of granulocyte proteins [34]. No consistent change in coagulation or fibrinolytic activity has been described, although MBP is a platelet stimulator and may promote clot formation [8,54]. Eosinophilic proteins also may induce apoptosis [35]. Why eosinophils particularly target the heart in eosinophilic myocarditis is understood poorly. Markedly elevated levels of IL-5 and IL-13, cytokines that cause hypereosinophilia, reportedly are present in the pericardial effusion in a patient who has acute necrotizing eosinophilic myocarditis. It was postulated that IL-5 was produced in the heart during acute myocarditis, which may stimulate eosinophil production, activation, and recruitment to myocardium [12]. Thus eosinophils are believed to be activated and directly toxic to myocardial cells, and are the mediators of myocardial injury in these forms of myocarditis. In some etiologies of eosinophilic myo-
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carditis (eg, parasitic infestation or allergic responses) the myocardial damage occurs as an ‘‘innocent bystander’’ in the setting of marked or chronic eosinophilia. Determining why eosinophils localize to myocardium in these conditions may be a productive line of investigation and may lead to therapies to prevent or ameliorate this illness [31].
Summary Eosinophilic myocarditis is an unusual but potentially fatal form of myocarditis. It may be caused by a delayed hypersensitivity response to a drug or vaccination, or it may occur in illnesses characterized by marked or chronic hypereosinophilia, such as HES or Churg-Strauss syndrome. Pathologically, a patchy interstitial myocardial eosinophilic and lymphocytic infiltrate may be present in the heart, or a more severe diffuse form of necrotizing myocarditis may be seen. Eosinophilic heart disease also may take the form of endocardial fibrosis, a restrictive cardiomyopathy, with mural thrombi and atrioventricular valve insufficiency. Diagnosis requires clinical suspicion of this illness with early endomyocardial biopsy. Treatment includes cessation of all potentially causative drugs, treatment of heart failure, immunosuppressive therapy, and consideration of cardiac surgery in selected cases.
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