Eosinophilia associated with dobutamine allergy causes eosinophilic endomyocarditis confirmed by serial endomyocardial biopsies

Open ArchivePublished:September 20, 2012DOI:https://doi.org/10.1016/j.jccase.2012.08.004

      Abstract

      We report a case of eosinophilic endomyocarditis caused by eosinophilia due to dobutamine allergy and successfully treated by a short-term and medium-dose steroid administration. Serial endomyocardial biopsies were useful for early diagnosis and evaluation of the effect of the treatment. Eosinophilic endomyocarditis due to dobutamine allergy is a rare entity; however, because of the high utilization rate of dobutamine in patients with low output heart failure, it is important to recognize that additional deterioration of cardiac function caused by eosinophilic endomyocarditis makes prognosis poor and early intervention is necessary.
      <Learning objective: Eosinophilic endomyocarditis due to dobutamine allergy is a rare entity; however, because of the high utilization rate of dobutamine in patients with low output heart failure, it is important to recognize that additional deterioration of cardiac function caused by eosinophilic endomyocarditis makes their prognosis poor and early intervention is necessary. Serial endomyocardial biopsies were useful for early diagnosis and evaluation of the effect of the treatment.>

      Keywords

      Introduction

      Dobutamine is widely used to stabilize patients compromised with low output congestive heart failure. Eosinophilic endomyocarditis, an infrequent but potentially lethal complication of dobutamine use, has been reported in studies of either endomyocardial biopsy or autopsy [
      • Takkenberg J.J.
      • Czer L.S.
      • Fishbein M.C.
      • Luthringer D.J.
      • Quartel A.W.
      • Mirocha J.
      • Queral C.A.
      • Blanche C.
      • Trento A.
      Eosinophilic myocarditis in patients awaiting heart transplantation.
      ,
      • Corradi D.
      • Vaglio A.
      • Maestri R.
      • Legname V.
      • Leonardi G.
      • Bartoloni G.
      • Buzio C.
      Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death.
      ,
      • Ginsberg F.
      • Parrillo J.E.
      Eosinophilic myocarditis.
      ]. We here report a case of eosinophilic endomyocarditis caused by eosinophilia due to dobutamine allergy, confirmed by drug-induced lymphocyte stimulation test (DLST) and serial endomyocardial biopsies, which was successfully treated by short-term and medium-dose steroid administration.

      Case report

      A 37-year-old woman with a 2-year history of chronic heart failure was referred to our hospital because of the worsening of her symptoms. On admission, the echocardiogram revealed left ventricular dilatation, left ventricular end-diastolic dimension (LVDd) and end-systolic dimension (LVDs) were 61 and 46 mm, respectively, severely reduced systolic function, ejection fraction (EF) was 21% and mild tricuspid insufficiency with a maximum 30 mmHg gradient. The electrocardiogram showed tachycardia, atrial fibrillation, mild intraventricular conduction defect, and nonspecific ST segment elevation in precordial lead (Fig. 1). A chest X-ray showed moderate cardiomegaly, pulmonary congestion, and a small pleural effusion (Fig. 2). The laboratory data on admission are shown in Table 1. Serum brain natriuretic peptide (BNP) level was 737 pg/mL. The patient was initially treated with diuretics, followed by a continuous infusion of dobutamine on day 11 in the hospital. Eight days after the onset of dobutamine infusion, erythema, pruritus, and phlebitis appeared around the route of the dobutamine infusion. The laboratory data showed a steady increase in eosinophils in the blood during the treatment with dobutamine (Fig. 3). Eosinophil count in the peripheral blood was elevated to 911/μL, 19.4% of total white blood cell count. Serum eosinophil cationic protein (ECP) was elevated to 37.4 μg/L where over 14.9 μg/L is regarded as positive. Since dobutamine was firstly considered a candidate cause of eosinophilia, the dobutamine infusion was gradually tapered and finally discontinued on day 25. An anti-histamine drug was started simultaneously; however eosinophilia continued. On day 28, the patient was stabilized except for eosinophilia. Because of her tattoo, cardiac magnetic resonance imaging was not performed. Cardiac catheterization demonstrated a pulmonary artery pressure of 25/8 (14) mmHg, cardiac index of 2.18 L/min/m2, pulmonary capillary wedge pressure of 7 mmHg, and left ventricular pressure of 97/edp12 mmHg. There was left ventricular enlargement and global systolic dysfunction at an EF of 33% and nonobstructive coronary artery. An endomyocardial biopsy from the septum of the right ventricle was performed to diagnose the etiology of left ventricular dysfunction and revealed mild interstitial fibrosis, hypertrophy, and disarrangement of residual myocytes compatible with dilated cardiomyopathy (DCM) and, furthermore, the presence of eosinophilic endomyocarditis by chance. Extensive eosinophilic infiltrate was recognized mainly in the subendocardial interstitium and to a lesser extent in the myocardial tissue. Major basic protein (MBP) was positive in the eosinophils and the area of extracellular edema as was demonstrated by immunohistochemistry (Fig. 4a and b). DLST for dobutamine expressed as a stimulatory index where over 180% is considered positive, yielded values of 758%. These findings suggested that eosinophilia due to hypersensitivity to dobutamine may cause eosinophilic endomyocarditis. On day 42, in spite of eosinophilic endomyocarditis, follow-up echocardiogram revealed slightly improved left ventricular dimensions (LVDd/LVDs = 58/43 mm), systolic function (EF = 39%), and immeasurable tricuspid insufficiency. Oral administration of 20 mg per day prednisolone was initiated on day 45 for both eosinophilia and eosinophilic endomyocarditis, and prednisolone was gradually tapered and stopped within 12 days. Eosinophil count in the blood had returned to normal values by day 56. The second endomyocardial biopsy on day 60 revealed very few scattered eosinophils and no extracellular deposition of MBP (Fig. 4c and d). Fortunately, our patient did not show additional deterioration of cardiac function on echocardiogram during eosinophilia and eosinophilic endomyocarditis. There was no remarkable change on electrocardiogram, cardiomegaly and pulmonary congestion on chest X-ray were improved and serum BNP level promptly decreased and showed no significant increase during eosinophilia and eosinophilic endomyocarditis (Fig. 1, Fig. 2, Fig. 3). She was discharged with administration of a beta blocker and an angiotensin-converting enzyme inhibitor on day 67 and has since been doing well. Follow-up echocardiogram after two months of leaving hospital revealed further improvement, LVDd/LVDs was 58/40 mm and EF was 43%.
      Figure thumbnail gr1
      Fig. 1Time course of the electrocardiograms.
      Figure thumbnail gr2
      Fig. 2Time course of the chest X-rays.
      Table 1Laboratory data on admission.
      WBC8800/μLTP6.4 g/dL
      Neut73.3%Alb4.0 g/dL
      Lymp19.1%T-Bil0.8 mg/dL
      Eos1.7%AST22 IU/L
      Mono5.4%ALT27 IU/L
      Baso0.5%γ-GTP25 IU/L
      RBC452 × 103/μLLDH169 IU/L
      Hb14.3 g/dLALP211 IU/L
      PLT23.8 × 104/μLAmy34 IU/L
      PT-INR2.08CK46 IU/L
      APTT36 sBUN18 mg/dL
      AT III99%Cr0.79 mg/dL
      Fibrinogen292 mg/dLUA7.9 mg/dL
      FDP2 μg/mLNa138 mEq/L
      D-dimer<0.5 μg/mLK4.3 mEq/L
      FT41.5 ng/dLCl100 mEq/L
      TSH1.96 μIU/mLCa9.1 mg/dL
      HbA1c5.7%CRP0.09 mg/dL
      Figure thumbnail gr3
      Fig. 3Time courses of peripheral blood eosinophilic cell count (blue squares and line), eosinophilic cationic protein (red triangles), and brain natriuretic peptide (green circle) relative to drug administration. Normal eosinophil count is <500/μL. Normal eosinophilic cationic protein value is <14.9 μg/L. Normal brain natriuretic peptide level is <18.4 pg/mL. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
      Figure thumbnail gr4
      Fig. 4Photomicrographs of serial endomyocardial biopsies. (a) The first biopsy on day 28 showed intensive eosinophilic infiltrate in subendocardial interstitium (hemataoxylin and eosin). (b) Immunohistochemistry of major basic protein (MBP) is positive mainly in endocardium. (c) The second biopsy on day 60; regression of eosinopilic endomyocarditis with few eosinophils is shown (hemataoxylin and eosin). (d) No deposition of MBP confirmed by immunohistochemistry. The bar in a, b, c, and d is 50 μm.

      Discussion

      Our patient was diagnosed as having idiopathic DCM on the basis of a number of investigations, including biopsy. Neither the eosinophilia nor the eosinophilic endomyocarditis was considered to be a cause of left ventricular dysfunction in our patient because left ventricular dilatation and severely reduced ejection fraction were found prior to the appearance of eosinophilia; in addition the period from appearance of eosinophilia to first biopsy was too short for eosinophilia to be a cause of left ventricular dysfunction.
      Eosinophilia in our patient was considered to be an allergic reaction to dobutamine because DLST for dobutamine was positive, eosinophil count remains in the normal range after cessation of dobutamine regardless of the continuation of other drugs and DLST for amiodarone and carvedilol were negative (Fig. 3). Allergic reaction to dobutamine is reported to be not dose related [
      • Takkenberg J.J.
      • Czer L.S.
      • Fishbein M.C.
      • Luthringer D.J.
      • Quartel A.W.
      • Mirocha J.
      • Queral C.A.
      • Blanche C.
      • Trento A.
      Eosinophilic myocarditis in patients awaiting heart transplantation.
      ]. This may explain why the eosinophil count in our patient increased while dobutamine was being tapered. Generally eosinophilia was observed only during dobutamine infusion, although eosinophilia in our patient continued after cessation of dobutamine infusion. Spear reported a case of eosinophilia that was noted after cessation of short-term dobutamine infusion [
      • Spear G.S.
      Eosinophilic explant carditis with eosinophilia? Hypersensitivity to dobutamine infusion.
      ]. Therefore, the association between dobutamine allergy and the duration of eosinophilia has not been understood clearly to date.
      Eosinophilia due to dobutamine allergy is often associated with long-term infusions, such as those employed over a period of a month as pharmacologic bridges to heart transplantation [
      • Spear G.S.
      Eosinophilic explant carditis with eosinophilia? Hypersensitivity to dobutamine infusion.
      ]. On the other hand, short-term dobutamine infusion has been reported to be associated with a local reaction at the site of dobutamine infusion accompanied by eosinophilia. Such dermal lesions have been considered to represent hypersensitivity to dobutamine [
      • Spear G.S.
      Eosinophilic explant carditis with eosinophilia? Hypersensitivity to dobutamine infusion.
      ,
      • Wu C.C.
      • Chen W.J.
      • Cheng J.J.
      • Hsieh Y.Y.
      • Lien W.P.
      Local dermal hypersensitivity from dobutamine hydrochloride (Dobutrex solution) injection.
      ,
      • El-Sayed O.M.
      • Abdelfattah R.R.
      • Barcelona R.
      • Leier C.V.
      Dobutamine-induced eosinophilia.
      ]. Therefore, eosinophils play a role in immediate and delayed hypersensitivity reactions, and both mechanisms may participate in eosinophilic endomyocarditis due to dobutamine allergy [
      • Ginsberg F.
      • Parrillo J.E.
      Eosinophilic myocarditis.
      ]. Endomyocardial injury may be provoked by eosinophil degranulation and deposition of eosinophilic granules such as MBP and ECP, suggesting that serum ECP, a marker of activated eosinophil granulocytes, may be helpful in diagnosing eosinophilic endomyocarditis [
      • Takkenberg J.J.
      • Czer L.S.
      • Fishbein M.C.
      • Luthringer D.J.
      • Quartel A.W.
      • Mirocha J.
      • Queral C.A.
      • Blanche C.
      • Trento A.
      Eosinophilic myocarditis in patients awaiting heart transplantation.
      ,
      • Corradi D.
      • Vaglio A.
      • Maestri R.
      • Legname V.
      • Leonardi G.
      • Bartoloni G.
      • Buzio C.
      Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death.
      ,
      • Tai P.C.
      • Ackerman S.J.
      • Spry C.J.
      • Dunnette S.
      • Olsen E.G.
      • Gleich G.J.
      Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease.
      ,
      • Kishimoto C.
      • Spry C.J.F.
      • Tai P.C.
      • Tomioka N.
      • Kawai C.
      In vivo cardiotoxicity of eosinophilic cationic protein in an animal preparation.
      ]. Eosinophilic endomyocarditis should be suspected when peripheral blood eosinophilia is present, or the eosinophil count is increased by at least two-fold [
      • Takkenberg J.J.
      • Czer L.S.
      • Fishbein M.C.
      • Luthringer D.J.
      • Quartel A.W.
      • Mirocha J.
      • Queral C.A.
      • Blanche C.
      • Trento A.
      Eosinophilic myocarditis in patients awaiting heart transplantation.
      ]. Endomyocardial biopsy is necessary to make a firm diagnosis and is warranted when a patient with eosinophilia shows signs of heart failure [
      • Ginsberg F.
      • Parrillo J.E.
      Eosinophilic myocarditis.
      ]; and examination of biopsy samples using both electron microscopy and immunohistochemistry with specific antibodies, are recommended to detect eosinophil granule components [
      • Janin A.
      Eosinophilic myocarditis fibrosis.
      ]. DLST, a measure of proliferation of T cells in response to a drug in vitro, is the most generally used in vitro test for the detection of the causative drug in drug-induced allergies. However there has been no report of DLST in dobutamine-associated eosinophilia, and further studies are necessary to evaluate the efficacy of DLST in relation to the side effects of dobutamine. Eosinophil counts and concomitant symptoms of drug allergy such as erythema and pruritus must be closely monitored. Furthermore, patients with clinically suspected dobutamine-related eosinophilia should be considered for treatment with alternative inotropic drugs. When patients do not respond to cessation of dobutamine or switching to another inotropic drug in a few days, steroid therapy should be considered. Although previous studies have documented dramatic responses to steroid therapy in some patients with eosinophilic endomyocarditis, the appropriate dose of steroid for eosinophilic endomyocarditis induced by drug allergy has not been determined to date. A medium dose of steroid may be effective in the early stage of drug allergy as in our patient, although steroid pulse therapy is generally recommended for hypereosinophilic syndrome [
      • Corradi D.
      • Vaglio A.
      • Maestri R.
      • Legname V.
      • Leonardi G.
      • Bartoloni G.
      • Buzio C.
      Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death.
      ].
      We have reported a case of eosinophilic endomyocarditis caused by eosinophilia due to dobutamine allergy and its successful treatment with a short-term and medium-dose steroid administration. Since we usually use dobutamine in patients with acute or chronic decompensated heart failure, it is important to recognize the possibility of eosinophilic endomyocarditis due to dobutamine allergy despite its rare occurrence. Because additional worsening of cardiac function caused by endomyocarditis results in poor clinical outcomes, serial eosinophil count examinations should be considered and a decision on early steroid intervention is necessary. DLST may be useful for early diagnosis of dobutamine allergy. Serial endomyocardial biopsy and serum ECP measurement are also useful for diagnosis and evaluation of the effect of the treatment.

      Conflict of interest

      None.

      Acknowledgment

      The present study was supported by Intramural Research Fund (22-5-6) for Cardiovascular Disease of National Cerebral and Cardiovascular Center.

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