From the Ramsey County Medical Examiner’s Office, St Paul, MN.
Manuscript received January 12, 2012; accepted December 5, 2012.
The authors report no conflicts of interest.
Reprints: Butch Huston, MD, Ramsey County Medical Examiner’s Office, 300 E. University Ave. St Paul, MN 55101. E-mail: email@example.com.
Abstract: We report a case of a 16-year-old boy who was treated for a suspected dental infection with a tooth extraction and amoxicillin therapy. The decedent developed a rash and presented to the emergency department with what was thought to be a possible allergic reaction to amoxicillin despite completion of the antibiotic course. The patient was given a course of prednisone. Several weeks later, while still completing the course of prednisone, the patient experienced shortness of breath and collapsed. Resuscitation efforts were unsuccessful. Postmortem examination revealed a necrotizing eosinophilic myocarditis. This case reveals that despite steroid therapy, a patient may still die of eosinophilic myocarditis.
While out of town on vacation, a 16-year-old boy developed a severe toothache and was found to have a large deep decay and infection of tooth number 19 with an exposed nerve. Tooth 19 was subsequently extracted, and the patient was given a prescription for the treatment of infection (amoxicillin, 250 mg) and pain (Lortab [Amneal Pharmaceuticals, Glasgow, KY], 5/500) by the dentist.
Approximately 12 days later, the patient presents to the emergency department with complaints of a cough and sore throat. The patient also states that he developed a new rash on his chest and arms. The patient denied any pain/discomfort or dyspnea. There were no reported changes in diet, laundry detergent, soaps, or exposures. The amoxicillin course had been completed. The physical examination revealed cervical adenopathy and generalized urticaria. A normal cardiac rhythm and heart sounds were noted. Laboratory studies included a negative rapid Strep test result and a white blood cell (WBC) count of 9.2 K/µL. A WBC differential was not performed. The patient was prescribed a Zithromax Z-Pak (Pfizer, New York, NY) and a course of prednisone. Prednisone was prescribed in a tapering dose with days 1 to 7, 40 mg; days 8 to 10, 35 mg; days 11 to 13, 30 mg; days 14 to 16, 25 mg; continuing this regimen by tapering 5 mg every 3 days.
While at home, approximately 4 weeks after the tooth extraction and while currently taking prednisone for 2 weeks, the decedent became short of breath, complained of not feeling well, and suddenly collapsed. A neighbor who is a nurse started cardiopulmonary resuscitation and initiated 911. The decedent was transported to the local hospital. On initial presentation, the decedent was noted to be cyanotic with a blood pressure of 85/34 and pulse of 174. The decedent became combative, and he was sedated and intubated to control his airway. After intubation, he suddenly became pulseless. Resuscitation was ultimately unsuccessful.
An external examination revealed a normally developed white boy measuring 6 ft in length and weighing 151 lb. A prominent rash on the upper extremities and chest was noted (Fig. 1). Internal examination revealed bilateral pulmonary edema and congestion, hepatomegaly (liver weight, 2280 g), splenomegaly (spleen weight, 425 g), and severe cardiomegaly. The heart weighed 460 g, and there was approximately 25 mL of straw-colored fluid within the pericardial sac. The epicardial surface and cross-sections of the myocardium showed a tan-yellow mottled appearance (Fig. 2). The left ventricle measured 1.2 cm concentrically, and the right ventricle measured 0.3 cm.
Myocardial culture revealed a Gram stain touch preparation with no polymorphonuclear leukocyte and no organisms seen. The myocardial tissue culture was positive for rare Stenotrophomonas maltophilia (Xanthomonas) and rare Micrococcus species. Postmortem lung cultures were negative.
Histologic analysis revealed diffuse, transmural, inflammatory infiltrate throughout the endocardium, interstitium, and epicardium (Figs. 3 and 4). The infiltrate was predominately composed of eosinophils but also contained mononuclear cells and scattered multinucleated giant cells. Examination of the other major organ systems was unremarkable for postmortem specimens. The liver and spleen showed vascular congestion but were otherwise unremarkable for postmortem specimens. No eosinophilic infiltrate were noted in any other organ system.
Myocarditis is an inflammatory response within the myocardium that is not due to an ischemic event or rejection in cases of heart transplantation. Four main categories of myocarditis include infection, postviral autoimmune, autoimmune disorders, and drug related. Most of the clinical cases are idiopathic and thought to be the result of postviral autoimmune related, even if a viral agent cannot be demonstrated. Drug-related myocarditis can be classified into 5 different patterns: hypersensitivity myocarditis, endocardial fibrosis (ergotamine tartrate, methysergide, phentermine), drug-induced cardiomyopathy (anthracycline, chloroquine), giant cell myocarditis, and toxic myocarditis.1,2 Toxic myocarditis results from drug-induced injury, which persists after cessation of the drug and is not mediated by hypersensitivity. Hypersensitivity myocarditis is the most common form of drug-related myocarditis. More than 2 dozen of drugs have been associated with hypersensitivity myocarditis, but most of the cases are caused by sulfonamides, methyldopa, and penicillin and its derivatives (Table 1).3,4 Although histiocytes and lymphocytes may be present, the predominate infiltrating cell type is the eosinophil.
The association between cardiac disorders and eosinophilia has been documented in the literature since Loffler5 described his 2 cases of endocarditis parietalis fibroplastica with blood eosinophilia in 1936. Infiltrates composed predominately of eosinophils may be found in parasitic infestations, allergic drug reactions, or hypereosinophilic syndrome.3,4,6–8
Myocyte necrosis is not a common component in the hypersensitivity form of eosinophilic myocarditis.3,4 A more severe form of hypersensitivity eosinophilic myocarditis is necrotizing eosinophilic myocarditis. It is characterized by a more severe, diffuse, eosinophilic infiltration with diffuse myocyte necrosis. Necrotizing eosinophilic myocarditis typically follows a more fulminant course.3 Necrotizing eosinophilic myocarditis is characterized by a sudden onset of severe heart failure and exhibits a high mortality rate. The high levels of eosinophils in the blood and tissues of affected patients indicate that eosinophils lead directly to myocardial necrosis and ultimately heart failure.6,9
Studies indicate that degenerating eosinophils or degranulation with the release of major basic protein, cationic protein, and peroxidase results in necrotic myocardial cells. Degenerating eosinophils and loss of the cytoplasmic membrane leading to extracellular release of eosinophil granules can contribute to myocyte cell death.8,10,11
The symptoms and signs accompanying eosinophilic myocarditis are nonspecific and include fever, skin rashes, sinus tachycardia, conduction delays, and ST-T wave abnormalities. Peripheral blood eosinophilia is not necessarily seen in all cases of eosinophilic myocarditis, and thus, the diagnosis is often not suspected clinically.12 Myocardial fibrosis can occur despite treatment and puts the patient at high risk for fatal arrhythmias.13
The decedent reported in this case exhibited necrotizing eosinophilic myocarditis after antibiotic therapy. There was no evidence of an infectious process because the Gram stain touch preparation result of the heart was negative and the culture results were considered postmortem contaminants. The typical prednisone dose for confirmed eosinophilic myocarditis is 1 mg/kg per day. Despite being slightly less than the recommended dose for steroid therapy, the decedent’s course continued to heart failure. Clinical laboratory testing was limited to a normal WBC count of 9.2 K/µL, and although a blood cell differential was not performed, histologic examination of the tissues and organ systems did not reveal any other significant eosinophilic infiltration.
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