Brief Report
Acute Necrotizing Eosinophilic Myocarditis as a Manifestation of Severe Hypersensitivity Myocarditis Antemortem Diagnosis and Successful Treatment Mark A. Getz, MD; Ramiah Subramanian, MD; Tim Logemann, MD; and Ford Ballantyne, MD Annals of Internal Medicine. 1991;115:201-202.
Acute necrotizing eosinophilic myocarditis is characterized by acute and fulminant congestive heart failure that has previously been uniformly fatal (1, 2). Predisposing factors include an initial viral infection and an underlying allergic diathesis. This disease's pathologic characteristics include eosinophilic and lymphocytic infiltration with extensive myocardial cell necrosis and no notable extracardiac pathologic findings. Hypersensitivity myocarditis is characterized by rash, fever, sinus tachycardia, and eosinophilia related to a drug allergy. This entity is also characterized by eosinophilic and lymphocytic infiltration of the myocardium, but necrosis is uncommon (3). Patients with hypersensitivity myocarditis usually are not critically ill, and they respond to withdrawal of the medication and, possibly, to corticosteroid therapy. To our knowledge, this is the first report of a case of acute necrotizing eosinophilic myocarditis that was diagnosed antemortem and treated successfully. We discuss the possible relation between acute necrotizing eosinophilic myocarditis and hypersensitivity myocarditis. Case Report A 41-year-old white woman with hypertension and a 16-year history of systemic lupus erythematosus was hospitalized with a 2-day history of progressive dyspnea and substernal chest pressure. One week before admission, a rheumatologist assessed the patient's lupus as quiescent and prescribed hydroxychloroquine to prevent flares of arthritis and amitriptyline to treat insomnia. At admission, the patient was also receiving prednisone, 5 mg/d; hydrochlorothiazide; aspirin; and ferrous sulfate. Her systolic blood pressure was 90 mm Hg (by Doppler), her pulse was 110 beats/min, and she was afebrile. The lungs were clear. A cardiovascular examinaFrom the University of Wisconsin Medical School and the William S. Middleton Memorial Veterans Affairs Hospital, Madison, Wisconsin. For current author addresses, see end of text.
tion showed marked jugular venous distension, a summation gallop, a right ventricular heave, and a new grade II-IV systolic murmur at the lower left sternal border. The leukocyte count was 9.4 x 109/L with 0.01 eosinophils. The creatine kinase level was 4.68 /xkat/L with a 0.16 MB fraction. A chest roentgenogram showed bilateral effusions and a marked increase in the cardiac silhouette. Electrocardiography revealed new findings of incomplete right bundle branch block, low voltage in the limb leads, right axis deviation, and anterior and inferior ST elevations. Echocardiography showed a thickened left ventricle with moderate reduction in systolic function and mild mitral regurgitation. The right ventricle was thickened, extremely dilated, and severely hypocontractile, with marked tricuspid insufficiency. Two days later, echocardiography showed nearly normal left ventricular function but persistent right ventricular dysfunction. Cardiac catheterization showed normal coronary arteries and confirmed the other echocardiographic findings. An endomyocardial biopsy showed extensive myocardial cell necrosis and infiltration of eosinophils and lymphocytes (Figure 1, A and B). Electron microscopy confirmed these findings and showed no immune complex deposition. Admission medications were withdrawn, and highdose corticosteroids were administered (methylprednisolone, 1 g intravenously for 3 days followed by 60 mg/d orally). The patient's condition improved markedly and rapidly. Serial echocardiograms indicated that right ventricular function had nearly normalized and that tricuspid insufficiency had decreased greatly. An endomyocardial biopsy specimen obtained 60 days after the initial biopsy showed resolution of the eosinophilic myocarditis, with replacement fibrosis and otherwise normal myocardium (Figure 1, C). Systemic lupus erythematosus is associated with a mild myocarditis, but the pathologic picture is that of lymphomononuclear rather than eosinophilic infiltration (4). Our patient had no other evidence of active lupus. She did not have peripheral eosinophilia, asthma, or vasculitis, nor did she have evidence of parasitic disease. Although this clinicopathologic picture is consistent with previous reports of acute necrotizing eosinophilic myocarditis, certain features suggest a hypersensitivity drug reaction. One is the temporal relation of the initiation of drug therapies (with hydroxychloroquine and amitriptyline) and the onset of illness. In addition, amitriptyline has been reported to cause hypersensitivity myocarditis. Nevertheless, the finding of extensive necrosis on biopsy would be inconsistent with present diagnostic criteria for hypersensitivity myocarditis (5). Earlier autopsy studies of hypersensitivity myocarditis describe cellular necrosis as "extremely uncommon"
1 August 1991 • Annals of Internal Medicine • Volume 115 • Number 3
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Figure 1. Endomyocardial biopsy specimens. Panels A and B. Extensive myocardial cell necrosis associated with lymphomononuclear and eosinophilic infiltration (arrows in B) was evident and necrotizing vasculitis was not evident in the initial biopsy specimen. The boxed area in panel A is shown at a higher magnification in panel B. M indicates the myocardium. Panel C. A repeat biopsy specimen obtained 60 days later shows focal scar formation (5), indicating previous necrosis. (Hematoxylin and eosin; original magnifications, A, x 24; B, x 100; C, x 10.)
(3, 6). However, in three subsequent case reports of deaths attributed to hypersensitivity myocarditis, myocardial cell necrosis was noted at autopsy (7, 8). All reported cases of acute necrotizing eosinophilic myocarditis have been in patients who had begun taking new medications shortly before the onset of severe disease. Despite this temporal association, the investigators were dissuaded from implicating a drug-induced hypersensitivity mechanism mainly by the presence of myocardial cell necrosis. Our case report supports Parrillo's theory (9) that acute necrotizing eosinophilic myocarditis may be a severe form of hypersensitivity myocarditis. We believe that a preexisting immune alteration (for example, viral antigenic stimulation or an autoimmune disease) alters the myocardial microenvironment to favor eosinophil localization and degranulation. A drug hypersensitivity reaction then could increase the number of available eosinophils enough to cause extensive necrosis and ventricular failure. The importance of early diagnosis by endomyocardial biopsy should be stressed; our patient's case suggests that acute necrotizing eosinophilic myocarditis may be successfully treated by withdrawal of the drug and administration of high-dose corticosteroids.
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1 August 1991 • Annals
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Medicine
Grant Support: In part by the Medical Research Service, U.S. Department of Veterans Affairs. Requests for Reprints: Ramiah Subramanian, MD, Section of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000. Current Author Addresses: Drs. Getz, Logemann, and Ballantyne: University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792. Dr. Subramanian: Section of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000. References 1. Herzog CA, Snover DC, Staley NA. Acute necrotizing eosinophilic myocarditis. Br Heart J. 1984;52:343-8. 2. deMello DE, Liapis H, Jureidini S, Nouri S, Kephart GM, Gleich GJ. Cardiac localization of eosinophil-granule major basic protein in acute necrotizing myocarditis. N Engl J Med. 1990;323:1542-5. 3. Fenoglio JJ Jr, McAllister HA Jr, Mullick FG. Drug related myocarditis. Hum Pathol. 1981;12:900-7. 4. Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J. 1984;110:1257-65. 5. Billingham ME. Pharmacotoxic myocardial disease: an endomyocardial study. Heart Vessels (Suppl). 1985;1:278-82. 6. French AJ, Weller CV. Interstitial myocarditis following the clinical and experimental use of sulfonamide drugs. Am J Pathol. 1942; 18: 109-21. 7. Morrow PL, Hardin NJ, Bonadies J. Hypersensitivity myocarditis and hepatitis associated with imipramine and its metabolite, desipramine. J Forensic Sci. 1989;34:1016-20. 8. Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo Clin Proc. 1985;60:463-8. 9. Parrillo JE. Heart disease and the eosinophil [Editorial]. N Engl J Med. 1990;323:1560-1.
• Volume 115 • Number 3
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Acute Necrotizing Eosinophilic Myocarditis as a Manifestation of Severe Hypersensitivity Myocarditis Antemortem Diagnosis and Successful Treatment Mark A. Getz, MD; Ramiah Subramanian, MD; Tim Logemann, MD; and Ford Ballantyne, MD Annals of Internal Medicine. 1991;115:201-202.
Acute necrotizing eosinophilic myocarditis is characterized by acute and fulminant congestive heart failure that has previously been uniformly fatal (1, 2). Predisposing factors include an initial viral infection and an underlying allergic diathesis. This disease's pathologic characteristics include eosinophilic and lymphocytic infiltration with extensive myocardial cell necrosis and no notable extracardiac pathologic findings. Hypersensitivity myocarditis is characterized by rash, fever, sinus tachycardia, and eosinophilia related to a drug allergy. This entity is also characterized by eosinophilic and lymphocytic infiltration of the myocardium, but necrosis is uncommon (3). Patients with hypersensitivity myocarditis usually are not critically ill, and they respond to withdrawal of the medication and, possibly, to corticosteroid therapy. To our knowledge, this is the first report of a case of acute necrotizing eosinophilic myocarditis that was diagnosed antemortem and treated successfully. We discuss the possible relation between acute necrotizing eosinophilic myocarditis and hypersensitivity myocarditis. Case Report A 41-year-old white woman with hypertension and a 16-year history of systemic lupus erythematosus was hospitalized with a 2-day history of progressive dyspnea and substernal chest pressure. One week before admission, a rheumatologist assessed the patient's lupus as quiescent and prescribed hydroxychloroquine to prevent flares of arthritis and amitriptyline to treat insomnia. At admission, the patient was also receiving prednisone, 5 mg/d; hydrochlorothiazide; aspirin; and ferrous sulfate. Her systolic blood pressure was 90 mm Hg (by Doppler), her pulse was 110 beats/min, and she was afebrile. The lungs were clear. A cardiovascular examinaFrom the University of Wisconsin Medical School and the William S. Middleton Memorial Veterans Affairs Hospital, Madison, Wisconsin. For current author addresses, see end of text.
tion showed marked jugular venous distension, a summation gallop, a right ventricular heave, and a new grade II-IV systolic murmur at the lower left sternal border. The leukocyte count was 9.4 x 109/L with 0.01 eosinophils. The creatine kinase level was 4.68 /xkat/L with a 0.16 MB fraction. A chest roentgenogram showed bilateral effusions and a marked increase in the cardiac silhouette. Electrocardiography revealed new findings of incomplete right bundle branch block, low voltage in the limb leads, right axis deviation, and anterior and inferior ST elevations. Echocardiography showed a thickened left ventricle with moderate reduction in systolic function and mild mitral regurgitation. The right ventricle was thickened, extremely dilated, and severely hypocontractile, with marked tricuspid insufficiency. Two days later, echocardiography showed nearly normal left ventricular function but persistent right ventricular dysfunction. Cardiac catheterization showed normal coronary arteries and confirmed the other echocardiographic findings. An endomyocardial biopsy showed extensive myocardial cell necrosis and infiltration of eosinophils and lymphocytes (Figure 1, A and B). Electron microscopy confirmed these findings and showed no immune complex deposition. Admission medications were withdrawn, and highdose corticosteroids were administered (methylprednisolone, 1 g intravenously for 3 days followed by 60 mg/d orally). The patient's condition improved markedly and rapidly. Serial echocardiograms indicated that right ventricular function had nearly normalized and that tricuspid insufficiency had decreased greatly. An endomyocardial biopsy specimen obtained 60 days after the initial biopsy showed resolution of the eosinophilic myocarditis, with replacement fibrosis and otherwise normal myocardium (Figure 1, C). Systemic lupus erythematosus is associated with a mild myocarditis, but the pathologic picture is that of lymphomononuclear rather than eosinophilic infiltration (4). Our patient had no other evidence of active lupus. She did not have peripheral eosinophilia, asthma, or vasculitis, nor did she have evidence of parasitic disease. Although this clinicopathologic picture is consistent with previous reports of acute necrotizing eosinophilic myocarditis, certain features suggest a hypersensitivity drug reaction. One is the temporal relation of the initiation of drug therapies (with hydroxychloroquine and amitriptyline) and the onset of illness. In addition, amitriptyline has been reported to cause hypersensitivity myocarditis. Nevertheless, the finding of extensive necrosis on biopsy would be inconsistent with present diagnostic criteria for hypersensitivity myocarditis (5). Earlier autopsy studies of hypersensitivity myocarditis describe cellular necrosis as "extremely uncommon"
1 August 1991 • Annals of Internal Medicine • Volume 115 • Number 3
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19731/ by a University of California San Diego User on 05/03/2017
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Figure 1. Endomyocardial biopsy specimens. Panels A and B. Extensive myocardial cell necrosis associated with lymphomononuclear and eosinophilic infiltration (arrows in B) was evident and necrotizing vasculitis was not evident in the initial biopsy specimen. The boxed area in panel A is shown at a higher magnification in panel B. M indicates the myocardium. Panel C. A repeat biopsy specimen obtained 60 days later shows focal scar formation (5), indicating previous necrosis. (Hematoxylin and eosin; original magnifications, A, x 24; B, x 100; C, x 10.)
(3, 6). However, in three subsequent case reports of deaths attributed to hypersensitivity myocarditis, myocardial cell necrosis was noted at autopsy (7, 8). All reported cases of acute necrotizing eosinophilic myocarditis have been in patients who had begun taking new medications shortly before the onset of severe disease. Despite this temporal association, the investigators were dissuaded from implicating a drug-induced hypersensitivity mechanism mainly by the presence of myocardial cell necrosis. Our case report supports Parrillo's theory (9) that acute necrotizing eosinophilic myocarditis may be a severe form of hypersensitivity myocarditis. We believe that a preexisting immune alteration (for example, viral antigenic stimulation or an autoimmune disease) alters the myocardial microenvironment to favor eosinophil localization and degranulation. A drug hypersensitivity reaction then could increase the number of available eosinophils enough to cause extensive necrosis and ventricular failure. The importance of early diagnosis by endomyocardial biopsy should be stressed; our patient's case suggests that acute necrotizing eosinophilic myocarditis may be successfully treated by withdrawal of the drug and administration of high-dose corticosteroids.
202
1 August 1991 • Annals
of Internal
Medicine
Grant Support: In part by the Medical Research Service, U.S. Department of Veterans Affairs. Requests for Reprints: Ramiah Subramanian, MD, Section of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000. Current Author Addresses: Drs. Getz, Logemann, and Ballantyne: University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792. Dr. Subramanian: Section of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000. References 1. Herzog CA, Snover DC, Staley NA. Acute necrotizing eosinophilic myocarditis. Br Heart J. 1984;52:343-8. 2. deMello DE, Liapis H, Jureidini S, Nouri S, Kephart GM, Gleich GJ. Cardiac localization of eosinophil-granule major basic protein in acute necrotizing myocarditis. N Engl J Med. 1990;323:1542-5. 3. Fenoglio JJ Jr, McAllister HA Jr, Mullick FG. Drug related myocarditis. Hum Pathol. 1981;12:900-7. 4. Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J. 1984;110:1257-65. 5. Billingham ME. Pharmacotoxic myocardial disease: an endomyocardial study. Heart Vessels (Suppl). 1985;1:278-82. 6. French AJ, Weller CV. Interstitial myocarditis following the clinical and experimental use of sulfonamide drugs. Am J Pathol. 1942; 18: 109-21. 7. Morrow PL, Hardin NJ, Bonadies J. Hypersensitivity myocarditis and hepatitis associated with imipramine and its metabolite, desipramine. J Forensic Sci. 1989;34:1016-20. 8. Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo Clin Proc. 1985;60:463-8. 9. Parrillo JE. Heart disease and the eosinophil [Editorial]. N Engl J Med. 1990;323:1560-1.
• Volume 115 • Number 3
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19731/ by a University of California San Diego User on 05/03/2017
