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Dobutamine-Induced Fever and Isolated Eosinophilic Myocarditis in a 66-Year-Old Male Awaiting Heart Transplantation: A Case Report
Dobutamine-Induced Fever and Isolated Eosinophilic Myocarditis in a 66-Year-Old Male Awaiting Heart Transplantation: A Case Report C.C. Leea,*, D.J. Luthringerb,c, and L.S.C. Czerc a Cedars-Sinai Medical Center, Department of Internal Medicine, Los Angeles, California, USA; bCedars-Sinai Medical Center, Department of Pathology, Los Angeles, California, USA; cCedars-Sinai Medical Center, Heart Institute, Los Angeles, California, USA
ABSTRACT A 66-year-old male with non-ischemic dilated cardiomyopathy who presented for decompensated heart failure and heart transplant evaluation had to be temporarily delisted from the transplant list due to fever. No infectious source was identified and drug fever was suspected. Dobutamine was discontinued and his fever subsequently defervesced. He eventually received an orthotopic heart transplantation without complication. Explanted heart showed eosinophilic myocarditis with pathologic features consistent with a druginduced pattern of myocarditis. Throughout the hospital course, he did not develop peripheral blood eosinophilia to suggest eosinophilic myocarditis. The importance of this report is to have a greater awareness of dobutamine-induced fever and eosinophilic myocarditis even in patients without peripheral eosinophilia. In febrile patients receiving prolonged dobutamine infusion with no other evidence of infection, consideration should be given to discontinuing dobutamine or switching to an alternative inotrope such as milrinone.
E
OSINOPHILIC MYOCARDITIS is a common finding in heart transplant patients and has been reported in up to 7% of cases [1e3] with the majority (86e100%) developing peripheral blood eosinophilia [1,4]. Signs and symptoms of eosinophilic myocarditis can be nonspecific and mimic infectious causes. Diagnosis can be difficult given that endomyocardial examination has low sensitivity and most cases are diagnosed during biopsy of the explanted heart. We present a rare case of dobutamine-induced eosinophilic myocarditis without peripheral eosinophilia. THE CASE REPORT A 66-year-old male with a 7-year history of dilated cardiomyopathy was admitted for heart transplant evaluation. His initial chest X-ray showed moderate cardiomegaly and pulmonary vascular congestion. His prior left heart catheterization revealed mild diagonal branch disease. Echocardiogram showed left ventricular ejection fraction of 17% and moderate mitral regurgitation. Cardiac catheterization done at outside hospital showed the following pressures (mm Hg): right atrial 21, pulmonary artery 36/25, pulmonary wedge 32, and reduced cardiac index 1.4 Liter/minute/ meter2 (cardiac output 3.1 Liter/min). Home lisinopril and spironolactone were continued and furosemide was switched to bumetanide. He was started on dobutamine and dopamine for inotropic support on day 1. Eventually cardiac index improved to 2.86 Liter/minute/meter2 (cardiac output 6.46 Liter/minute). By
day 6 of admission he developed leukocytosis (WBC range 11.2e13.3 x 1000/UL) predominantly neutrophilia without peripheral blood eosinophilia. By day 14, patient began to have fevers reaching 39.1 celsius. Infectious source was evaluated extensively with repeated blood and urine cultures; the only possible source identified was the Swan-Ganz catheter blood culture with 1 of 2 bottles positive for coagulase negative staphylococcus aureus. He was started on cefepime and vancomycin which later expanded to piperacillin/tazobactam, vancomycin, and doxycycline. The Swan-Ganz catheter was exchanged with negative culture of the catheter tip. Despite empiric antibiotic coverage and replacement of the Swan-Ganz catheter, he continued to have fever. Followup CT scan of the chest, abdomen, and pelvis, and nuclear whole-body gallium scan were unremarkable. Rheumatological workup was also negative (negative ANA, ANCA, PR3, MPO). By day 21, patient continued to have persistent fevers. Given that patient had negative infectious and rheumatological workup, it was considered that the fever may be drug induced. Dobutamine was discontinued on day 22 and started on milrinone. Then patient defervesced after 1 day and remained afebrile for the remaining hospital course. He received a heart transplant on day 25. The explanted heart was enlarged and weighed 716 gram with a globular architecture and dilated ventricles. Microscopic evaluation *Address correspondence to Chin C. Lee, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 5512, Los Angeles, CA 90048, USA.
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.06.064
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2464
Transplantation Proceedings, 46, 2464e2466 (2014)
DOBUTAMINE-INDUCED FEVER AND ISOLATED EOSINOPHILIC MYOCARDITIS of sections derived from both ventricular walls revealed abundant mixed mononuclear infiltrates composed of lymphocytes, histiocytes, plasma cells and eosinophils, as seen in Fig 1, which are consistent with eosinophilic myocarditis. Infiltrates were interstitial and perivascular. Myocardial cells showed significant degrees of variation in fiber and nuclear size and shape (also noted in photomicrograph), with increased intracytoplasmic lipofuscin deposits. Interstitial fibrosis was increased throughout ventricular walls. Giant cells, granulomas and vasculitis were not identified. These findings were compatible with a drug-induced pattern of myocarditis. There was no pre-transplant endomyocardial biopsy available for comparison. His followup post-transplant endomyocardial biopsies showed no recurrence of eosinophilic myocarditis or evidence of cellular or antibody mediated rejection, and had an uneventful recovery.
DISCUSSION
Eosinophilic myocarditis is rarely recognized clinically due to nonspecific symptoms and signs including fever, rash, pruritis, bronchospasm, sinus tachycardia, conduction delay and ST-T wave abnormalities [1,5]. In fact, it is often only recognized when patient developed persistent peripheral blood eosinophilia. Transplant candidates are often delisted from the transplant list when they develop fever and are often subjected to extensive infectious disease and/or rheumatological workup. When those workups are negative, other etiologies, such as drug-induced fever have to be evaluated. There are many drugs known to cause eosinophilic myocarditis that are listed in Table 1 [6]. As in our case, dobutamine was considered. The mechanism of fever induced by dobutamine infusion has remained unclear. It has been suggested that the fever may be secondary to the dobutamine additive sodium bisulfite which is a known allergen [7]. Dobutamine infusion has been associated with eosinophilic myocarditis in about 2e7% of heart transplantations [1e3] and most eosinophilic myocarditis have peripheral eosinophilia (86e100%) [1,4]. It was also suggested that eosinophilic myocarditis was associated with
2465
Table 1. Drugs Known to Cause Eosinophilic Myocarditis [6] ACE Inhibitor Captopril Enalapril Diuretic Acetazolamide Chlorthalidone Hydrochlorothiazide Spironolactone Other Amitriptyline Dobutamine Digoxin Indomethacin Methyldopa Sulfonylurea Tetanus toxoid
Antibiotic Ampicillin Amphotericin B Cephalosporin Chloramphenicol Isoniazid Para-aminosalicylic acid Penicillin Streptomycin Tetracycline Anticonvulsant Carbamazepine Phenindione Phenytoin Sulfonamide Sulfadiazine Sulfisoxazole
*Adapted from “Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22:1233e7”.
>30 days of dobutamine infusion [4]. In our patient, he received 22 days of dobutamine infusion with high fever developed by day 14 and has evidence of isolated eosinophilic myocarditis on explanted heart without peripheral blood eosinophilia. His infectious workup has remained negative and did not respond to broad spectrum antibiotics. He also did not develop rashes or pruritis. It was unclear when the eosinophilic myocarditis may have developed given that no pre-transplant biopsy was available. There were two similar case reports [7,8] and patient series [1,4] that documented dobutamine-induced fever. In the majority of cases, eosinophilic myocarditis was diagnosed on autopsy while a few reports were based on endomyocardial biopsy. However, endomyocardial biopsy is not a sensitive test (less than 50% sensitivity [9]) for diagnosing eosinophilic myocarditis given that infiltrates are often focal. Therefore, if there is a high suspicion, a repeat biopsy should be performed. In our patient given his end-stage heart failure status and prior clinic experience, endomyocardial biopsy was not attempted. The importance of this report is to have greater awareness of prolonged dobutamine infusion (often >30 days) inducing fever and eosinophilic myocarditis even in patients without peripheral eosinophilia. In febrile patients receiving dobutamine with no other evidence of infection, consideration should be given to discontinuing dobutamine or switching to an alternative inotrope such as milrinone. Delay in recognition of dobutamine-induced fever may subsequently lead to delay in their cardiac transplantation.
REFERENCES Fig 1. 400 magnification. Bar is 100 mm. Abundant mixed mononuclear infiltrates of lymphocytes, histiocytes, plasma cells, eosinophils (arrows), and increased interstitial fibrosis (*) were identified in sections from both ventricular walls consistent with drug-induced eosinophilic myocarditis.
[1] Takkenberg JJM, Czer LSC, Fishbein MC, Luthringer DJ, Quartel AW, Mirocha J, et al. Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med 2004;32:714e21. [2] Gravanis MB, Hertzler GL, Franch RH, Stacy LD, Ansari AA, Kanter KR, et al. Hypersensitivity myocarditis in heart
2466 transplant candidates. J Heart Lung Transplant Off Publ Int Soc Heart Transplant 1991;10:688e97. [3] Lewin D, d’ Amati G, Lewis W. Hypersensitivity myocarditis: Findings in native and transplanted hearts. Cardiovasc Pathol 1992;1:225e9. [4] Spear GS. Eosinophilic explant carditis with eosinophilia: Hypersensitivity to dobutamine infusion. J Heart Lung Transplant Off Publ Int Soc Heart Transplant 1995;14:755e60. [5] Taliercio CP, Olney BA, Lie JT. Myocarditis Related to Drug Hypersensitivity. Mayo Clin Proc 1985;60:463e8.
LEE, LUTHRINGER, AND CZER [6] Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22:1233e7. [7] Chapman SA, Stephan T, Lake KD, Sonnesyn SW, Emery RW. Fever induced by dobutamine infusion. Am J Cardiol 1994;74:517. [8] Robison-Strane SR, Bubik JS. Dobutamine-induced fever. Ann Pharmacother 1992;26:1523e4. [9] Burke AP, Saenger J, Mullick F, Virmani R. Hypersensitivity myocarditis. Arch Pathol Lab Med 1991;115:764e9.
ABSTRACT A 66-year-old male with non-ischemic dilated cardiomyopathy who presented for decompensated heart failure and heart transplant evaluation had to be temporarily delisted from the transplant list due to fever. No infectious source was identified and drug fever was suspected. Dobutamine was discontinued and his fever subsequently defervesced. He eventually received an orthotopic heart transplantation without complication. Explanted heart showed eosinophilic myocarditis with pathologic features consistent with a druginduced pattern of myocarditis. Throughout the hospital course, he did not develop peripheral blood eosinophilia to suggest eosinophilic myocarditis. The importance of this report is to have a greater awareness of dobutamine-induced fever and eosinophilic myocarditis even in patients without peripheral eosinophilia. In febrile patients receiving prolonged dobutamine infusion with no other evidence of infection, consideration should be given to discontinuing dobutamine or switching to an alternative inotrope such as milrinone.
E
OSINOPHILIC MYOCARDITIS is a common finding in heart transplant patients and has been reported in up to 7% of cases [1e3] with the majority (86e100%) developing peripheral blood eosinophilia [1,4]. Signs and symptoms of eosinophilic myocarditis can be nonspecific and mimic infectious causes. Diagnosis can be difficult given that endomyocardial examination has low sensitivity and most cases are diagnosed during biopsy of the explanted heart. We present a rare case of dobutamine-induced eosinophilic myocarditis without peripheral eosinophilia. THE CASE REPORT A 66-year-old male with a 7-year history of dilated cardiomyopathy was admitted for heart transplant evaluation. His initial chest X-ray showed moderate cardiomegaly and pulmonary vascular congestion. His prior left heart catheterization revealed mild diagonal branch disease. Echocardiogram showed left ventricular ejection fraction of 17% and moderate mitral regurgitation. Cardiac catheterization done at outside hospital showed the following pressures (mm Hg): right atrial 21, pulmonary artery 36/25, pulmonary wedge 32, and reduced cardiac index 1.4 Liter/minute/ meter2 (cardiac output 3.1 Liter/min). Home lisinopril and spironolactone were continued and furosemide was switched to bumetanide. He was started on dobutamine and dopamine for inotropic support on day 1. Eventually cardiac index improved to 2.86 Liter/minute/meter2 (cardiac output 6.46 Liter/minute). By
day 6 of admission he developed leukocytosis (WBC range 11.2e13.3 x 1000/UL) predominantly neutrophilia without peripheral blood eosinophilia. By day 14, patient began to have fevers reaching 39.1 celsius. Infectious source was evaluated extensively with repeated blood and urine cultures; the only possible source identified was the Swan-Ganz catheter blood culture with 1 of 2 bottles positive for coagulase negative staphylococcus aureus. He was started on cefepime and vancomycin which later expanded to piperacillin/tazobactam, vancomycin, and doxycycline. The Swan-Ganz catheter was exchanged with negative culture of the catheter tip. Despite empiric antibiotic coverage and replacement of the Swan-Ganz catheter, he continued to have fever. Followup CT scan of the chest, abdomen, and pelvis, and nuclear whole-body gallium scan were unremarkable. Rheumatological workup was also negative (negative ANA, ANCA, PR3, MPO). By day 21, patient continued to have persistent fevers. Given that patient had negative infectious and rheumatological workup, it was considered that the fever may be drug induced. Dobutamine was discontinued on day 22 and started on milrinone. Then patient defervesced after 1 day and remained afebrile for the remaining hospital course. He received a heart transplant on day 25. The explanted heart was enlarged and weighed 716 gram with a globular architecture and dilated ventricles. Microscopic evaluation *Address correspondence to Chin C. Lee, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 5512, Los Angeles, CA 90048, USA.
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.06.064
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2464
Transplantation Proceedings, 46, 2464e2466 (2014)
DOBUTAMINE-INDUCED FEVER AND ISOLATED EOSINOPHILIC MYOCARDITIS of sections derived from both ventricular walls revealed abundant mixed mononuclear infiltrates composed of lymphocytes, histiocytes, plasma cells and eosinophils, as seen in Fig 1, which are consistent with eosinophilic myocarditis. Infiltrates were interstitial and perivascular. Myocardial cells showed significant degrees of variation in fiber and nuclear size and shape (also noted in photomicrograph), with increased intracytoplasmic lipofuscin deposits. Interstitial fibrosis was increased throughout ventricular walls. Giant cells, granulomas and vasculitis were not identified. These findings were compatible with a drug-induced pattern of myocarditis. There was no pre-transplant endomyocardial biopsy available for comparison. His followup post-transplant endomyocardial biopsies showed no recurrence of eosinophilic myocarditis or evidence of cellular or antibody mediated rejection, and had an uneventful recovery.
DISCUSSION
Eosinophilic myocarditis is rarely recognized clinically due to nonspecific symptoms and signs including fever, rash, pruritis, bronchospasm, sinus tachycardia, conduction delay and ST-T wave abnormalities [1,5]. In fact, it is often only recognized when patient developed persistent peripheral blood eosinophilia. Transplant candidates are often delisted from the transplant list when they develop fever and are often subjected to extensive infectious disease and/or rheumatological workup. When those workups are negative, other etiologies, such as drug-induced fever have to be evaluated. There are many drugs known to cause eosinophilic myocarditis that are listed in Table 1 [6]. As in our case, dobutamine was considered. The mechanism of fever induced by dobutamine infusion has remained unclear. It has been suggested that the fever may be secondary to the dobutamine additive sodium bisulfite which is a known allergen [7]. Dobutamine infusion has been associated with eosinophilic myocarditis in about 2e7% of heart transplantations [1e3] and most eosinophilic myocarditis have peripheral eosinophilia (86e100%) [1,4]. It was also suggested that eosinophilic myocarditis was associated with
2465
Table 1. Drugs Known to Cause Eosinophilic Myocarditis [6] ACE Inhibitor Captopril Enalapril Diuretic Acetazolamide Chlorthalidone Hydrochlorothiazide Spironolactone Other Amitriptyline Dobutamine Digoxin Indomethacin Methyldopa Sulfonylurea Tetanus toxoid
Antibiotic Ampicillin Amphotericin B Cephalosporin Chloramphenicol Isoniazid Para-aminosalicylic acid Penicillin Streptomycin Tetracycline Anticonvulsant Carbamazepine Phenindione Phenytoin Sulfonamide Sulfadiazine Sulfisoxazole
*Adapted from “Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22:1233e7”.
>30 days of dobutamine infusion [4]. In our patient, he received 22 days of dobutamine infusion with high fever developed by day 14 and has evidence of isolated eosinophilic myocarditis on explanted heart without peripheral blood eosinophilia. His infectious workup has remained negative and did not respond to broad spectrum antibiotics. He also did not develop rashes or pruritis. It was unclear when the eosinophilic myocarditis may have developed given that no pre-transplant biopsy was available. There were two similar case reports [7,8] and patient series [1,4] that documented dobutamine-induced fever. In the majority of cases, eosinophilic myocarditis was diagnosed on autopsy while a few reports were based on endomyocardial biopsy. However, endomyocardial biopsy is not a sensitive test (less than 50% sensitivity [9]) for diagnosing eosinophilic myocarditis given that infiltrates are often focal. Therefore, if there is a high suspicion, a repeat biopsy should be performed. In our patient given his end-stage heart failure status and prior clinic experience, endomyocardial biopsy was not attempted. The importance of this report is to have greater awareness of prolonged dobutamine infusion (often >30 days) inducing fever and eosinophilic myocarditis even in patients without peripheral eosinophilia. In febrile patients receiving dobutamine with no other evidence of infection, consideration should be given to discontinuing dobutamine or switching to an alternative inotrope such as milrinone. Delay in recognition of dobutamine-induced fever may subsequently lead to delay in their cardiac transplantation.
REFERENCES Fig 1. 400 magnification. Bar is 100 mm. Abundant mixed mononuclear infiltrates of lymphocytes, histiocytes, plasma cells, eosinophils (arrows), and increased interstitial fibrosis (*) were identified in sections from both ventricular walls consistent with drug-induced eosinophilic myocarditis.
[1] Takkenberg JJM, Czer LSC, Fishbein MC, Luthringer DJ, Quartel AW, Mirocha J, et al. Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med 2004;32:714e21. [2] Gravanis MB, Hertzler GL, Franch RH, Stacy LD, Ansari AA, Kanter KR, et al. Hypersensitivity myocarditis in heart
2466 transplant candidates. J Heart Lung Transplant Off Publ Int Soc Heart Transplant 1991;10:688e97. [3] Lewin D, d’ Amati G, Lewis W. Hypersensitivity myocarditis: Findings in native and transplanted hearts. Cardiovasc Pathol 1992;1:225e9. [4] Spear GS. Eosinophilic explant carditis with eosinophilia: Hypersensitivity to dobutamine infusion. J Heart Lung Transplant Off Publ Int Soc Heart Transplant 1995;14:755e60. [5] Taliercio CP, Olney BA, Lie JT. Myocarditis Related to Drug Hypersensitivity. Mayo Clin Proc 1985;60:463e8.
LEE, LUTHRINGER, AND CZER [6] Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22:1233e7. [7] Chapman SA, Stephan T, Lake KD, Sonnesyn SW, Emery RW. Fever induced by dobutamine infusion. Am J Cardiol 1994;74:517. [8] Robison-Strane SR, Bubik JS. Dobutamine-induced fever. Ann Pharmacother 1992;26:1523e4. [9] Burke AP, Saenger J, Mullick F, Virmani R. Hypersensitivity myocarditis. Arch Pathol Lab Med 1991;115:764e9.