KOUNIS SYNDROME SECONDARY TO CEFUROXIME‐AXETIL USE IN AN OCTOGENARIAN

To the Editor: The concurrence of acute coronary syndromes with allergic or hypersensitivity, as well as with anaphylactic or anaphylactoid reactions, is increasingly encountered in clinical practice, and there are several reports associating mast cell activation with acute cardiovascular events in adults. Kounis first described this as "allergic angina syndrome" progressing to "allergic myocardial infarction."1 The main mechanism proposed is the vasospasm of coronary arteries. We present a 90-year-old man, referred to our hospital with thoracic pain, 10 minutes after intramuscular injection of 750 mg of cefuroxime-axetil. Kounis and Zavras1 described the "syndrome of allergic angina" as the coincidental occurrence of chest pain and allergic reactions accompanied by clinical and laboratory findings of classical angina pectoris caused by inflammatory mediators released during the allergic insult. Allergic angina can progress to acute myocardial infarction, which was named "allergic myocardial infarction."2,3 Causes of Kounis syndrome4 include medications (antibiotics, analgesics, antineoplastics, contrast media, corticosteroids, intravenous anesthetics, nonsteroidal antiinflammatory drugs, skin disinfectants, thrombolytics, anticoagulants), various conditions (angio-edema, bronchial asthma, urticaria, food allergy, exercise-induced allergy, mastocytosis, serum sickness), and environmental exposure (ant, bee, wasp, jellyfish stings; grass cutting, millet allergy; poison ivy; latex contact; shellfish eating; viper venom poisoning). A 90-year-old man who had been hospitalized for urinary tract infection developed chest pain and pruritic skin rashes. His complaints had started approximately 10 minutes after intramuscular injection of 750 mg of cefuroxime-axetil. His physical examination was normal upon admission, and his electrocardiogram showed ST segment elevations in leads II, III, aVF, V4, V5, and V6 (Figure 1). He had no history of coronary artery disease, diabetes mellitus, hypertension, or hyperlipidemia. Transthoracic echocardiography, performed in the coronary intensive care unit, revealed inferior wall hypokinesia. Complete blood count and liver and kidney function tests were normal except for mild leukocytosis. Coronary angiography performed to exclude coronary artery disease revealed noncritical coronary plaques in the left anterior descending and circumflex artery. Electrocardiogram at presentation showing ST elevation on II, III, aVF, V4, V5, and V6. Troponin-I estimated 4 hours after admission was 4 ng/mL (reference: 0–0.1 ng/mL) and rose to 22 ng/mL. Creatine kinase-MB fraction estimated 4 hours after admission was 42 U/L (reference: 0–25 U/L) and rose to 85 U/L on the second day. Total immunoglobulin E estimated on arrival was 54 IU/mL (reference: 0–100), and serum tryptase was 43.5 μg/L (reference: 5.6–13.5 μg/L). Subsequent daily estimations of serum tryptase were within normal limits. The patient was diagnosed to have Kounis syndrome type I variant, secondary to cefuroxime-axetil. He was treated with oral antihistamines and 8 mg of prednisolone every 6 hours for 5 days. Cefuroxime-axetil was stopped, and he was treated with levofloxacin for urinary tract infection. Five days later, the repeated cardiac markers were within normal limits, with resolution of electrocardiographic abnormalities and inferior wall motion echocardiographic changes. The man was discharged from hospital in excellent condition and was doing well at a 3-week follow-up visit. The concurrence of acute coronary syndrome with mast cell activation induced by inflammatory mediators released during allergic reaction characterizes Kounis syndrome.1–4 Two variants of Kounis syndrome have been described.4,5 The first exists in patients with normal coronary arteries in whom the allergic episode induces coronary spasm progressing to acute myocardial infarction. In the second type, coronary spasm occurs concurrent with a preexisting atheromatous disease in which allergic stimulation can cause plaque erosion or rupture manifesting as an acute coronary syndrome. Mast cells are found in most parts of the human body, including the heart and vessels, and are involved in allergic and anaphylactic reactions through activation–degranulation.6 After mast cell degranulation, several vasoconstricting and collagen-degrading compounds are released locally and in the peripheral circulation. These compounds include preformed mediators such as histamine, neutral proteases (tryptase, chymase), and platelet-activating factor and newly synthesized mediators such us an array of cytokines and chemokines and others by the metabolism of arachidonic acid through activation of a phospholipase.5,6 Tryptase levels were high, but histamine was undetected in this patient. Histamine is short lived and circulates for only 8 minutes after the allergic insult, but tryptase has a half-life of 90 minutes. The high levels of tryptase suggest an acute allergic reaction in which tryptase has been implicated in inducing coronary artery spasm and plaque erosion or rupture.5–7 Negative levels of histamine do not exclude the diagnosis of Kounis syndrome due to short half-life of histamine. Based on the above findings, the diagnosis of type I variant of Kounis syndrome induced by cefuroxime-axetil was made.8 To the best of our knowledge, the described patient is the oldest in the literature. This case highlights the fact that physicians should be aware of allergic myocardial infarction. The diagnosis of this unique disease should be entertained when allergic symptoms, electrocardiographic changes, and high cardiac enzymes accompany acute-onset chest pain. All patients admitted to the emergency department with chest pain and ST elevation on electrocardiography should be asked about allergic insults. We would like to acknowledge Prof. Dr. Nicholas G. Kounis for his great help in preparing this letter. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this letter. Author Contributions: All the authors contributed to the composition of this letter. Sponsor's Role: None.