Kounis syndrome is defined as acute coronary syndrome (symptoms such as chest pain relating to reduced blood flow to the heart) caused by an allergic reaction or a strong immune reaction to a drug or other substance. It is a rare syndrome with authentic cases reported in 130 males and 45 females, as reviewed in 2017; however, the disorder is suspected of being commonly overlooked and therefore much more prevalent. Mast cell activation and release of inflammatory cytokines as well as other inflammatory agents from the reaction leads to spasm of the arteries leading to the heart muscle or a plaque breaking free and blocking one or more of those arteries. The Kounis syndrome is distinguished from two other causes of coronary artery spasms and symptoms viz., the far more common, non-allergic syndrome, Prinzmetal's angina and eosinophilic coronary periarteritis, an extremely rare disorder caused by extensive eosinophilic infiltration of the adventitia and periadventitia, i.e. the soft tissues, surrounding the coronary arteries.
Epidemiology Through various case observations, Kounis syndrome was noted in many different races and geographical areas. However, most cases have been found in southern Europe including Turkey, Greece, Italy, and Spain. A wide age range is observed from pediatric patients to the elderly including the ages from 2 to 90. Commonly seen comorbidities include hyperlipidemia, diabetes, smoking, hypertension, and prior allergic reactions to a precipitating factor. The exact prevalence is difficult to determine given that this diagnosis is missed or under-diagnosed. There is a possibility for gene-environment interactions as a study reported all patients admitted following emergency department evaluation had a heterozygous E148Q mutation.
Etiology Many causes have been discovered to precipitate this syndrome including drugs, various health conditions, food, and environmental exposures. Any of these precipitating factors that cause IgE antibody production can contribute to this syndrome. Drugs that have been found previously include analgesics such as aspirin and dipyrone (the so-called "Mexican aspirin"), anesthetics, multiple antibiotics, anticoagulants such as heparin and lepirudin, thrombolytics such as TPA, anti-platelet therapy including clopidogrel, antineoplastics, glucocorticoids, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and skin disinfectants. Additionally, sympathomimetics, volume expanders, antifungals, antivirals, and oral contraceptives can also trigger this syndrome. Other specific common medications include allopurinol, enalapril, losartan, insulin, and many more. Conditions that incriminate Kounis syndrome include bronchial asthma, eosinophilic granulomatosis with polyangiitis, serum sickness, scombroid syndrome, angioedema, hay fever, anaphylaxis (exercise induced or idiopathic), and anisakiasis. Coronary stenting, a common procedure used in coronary artery disease patients has also been found to be a cause. Environmental exposure to poison ivy, grass, latex, and nicotine are contributory. Bites from creatures that can precipitate Kounis syndrome include spiders, snakes, scorpions, fire ants, and jellyfish. Miscellaneous triggers include contrast media. Reactions to various foods that cause an allergic and inflammatory response can lead to acute coronary syndrome.
Signs and symptoms Allergic ACS is a syndrome involving two components. One component is immune-mediated resulting in hypersensitivity, allergy, and an anaphylactic or anaphylactoid reaction. The second component involves cardiac signs and symptoms seen with acute coronary syndrome (ACS). Cardiac symptoms vary depending on the type of variant the patient presents with. Acute coronary syndrome is usually associated with a constrictive pain in the chest, characteristically with radiation to the neck or the left arm and often associated with pallor, sweatiness, nausea, and breathlessness. Cardiac signs on exam also include cold extremities, bradycardia, tachycardia, hypotension, possible cardiorespiratory arrest, or sudden death. Just as an allergic reaction can vary from a mild and localized reaction to something widespread and life-threatening, the allergic component of allergic ACS presents the same way. In allergic ACS there may also be specific symptoms relating to the underlying allergic reaction, such as swelling of the face and tongue, wheeze, hives and potentially very low blood pressure (anaphylactic shock). Additional findings can include stridor, drowsiness, syncope, abdominal pain, diarrhea, vomiting, and acute pulmonary edema if severe. Myocardial infarction, acute cardiac failure, and sudden cardiac death may also be seen. As high as 13% of adult-onset sudden cardiac deaths are coupled with mast cell degranulation concluding that Kounis syndrome can involve a silent allergic reaction.
Pathophysiology In allergy, mast cells release inflammatory substances such as histamine, neutral proteases, arachidonic acid derivatives, platelet activating factor and a variety of cytokines and chemokines. These mediators can precipitate coronary artery spasm and accelerate the rupture of atheromatous plaques of the coronary arteries. This interferes with the blood flow to the heart muscle and causes symptoms otherwise indistinguishable from unstable angina. It is possible that even in people without direct evidence of allergy, the allergic response may be playing a role in acute coronary syndrome: markers of mast cell activation are found in people with ACS. The main marker of mast cell activation is inducible macrophage protein 1a (MIP-1α), which binds to mast cells when they are near each other. After allergen exposure, MIP-1α transcription and expression are induced by resident mononuclear cells in the substantia propria, which consist of CD68+ macrophages and monocytes.
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