Kounis syndrome/allergic coronary spasm

The Kounis syndrome, associated with the greek physician Nicholas Kounis, is defined as "the concurrence of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells, and including allergic or hypersensitivity and anaphylactic or anaphylactoid insults." "It is caused by inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet activating factor and a variety of cytokines and chemokines released during the activation process."{1,2}

Inflammatory mediators including histamine, neutral proteases, arachidonic acid products, platelet activating factor and a variety of cytokines and chemokines are increased in blood or urine in both allergic episodes and acute coronary syndromes. The release of mediators during allergic insults has been incriminated to induce coronary artery spasm and/or atheromatous plaque erosion or rupture. A common pathway between allergic and non-allergic coronary syndromes seems to exist. Today, there is evidence that mast cells not only enter the culprit region before plaque erosion or rupture but they release their contents before an actual coronary episode. Kounis syndrome is the concurrence of acute coronary syndromes with conditions associated with mast cell activation including allergic or hypersensitivity and anaphylactic or anaphylactoid insults. It is caused by inflammatory mediators released through mast cell activation. Kounis syndrome, as consequence, of the above pathophysiologic association is regarded as nature’s own experiment and magnificent natural paradigm showing novel way in an effort to prevent acute coronary syndromes.

It has been shown that the same mediators, released during acute allergic episodes, are increased in blood or urine of patients suffering from acute coronary syndromes of nonallergic etiology{3,4}. Consequently, the same substances from the same cells are present in both acute allergic episodes and acute coronary syndromes. Does, therefore, Kounis syndrome represent a magnificent natural paradigm and nature’s own experiment in a final trigger pathway implicated in cases of coronary artery spasm and plaque rupture? Drugs and natural molecules which stabilize mast cell membrane and monoclonal antibodies that protect mast cell surface could emerge as novel therapeutic modalities capable to prevent acute coronary and cerebrovascular events{5}.

1. Ridella M, Bagdure S, Nugent K, Cevik C. Kounis syndrome following beta-lactam antibiotic use: review of literature. Inflamm Allergy Drug Targets. 2009;8:11-6

2. Biteker M, Duran NE, Biteker FS, Civan HA, Kaya H, Gökdeniz T, Yildiz M, Ozkan M. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr. 2010;169: 27-9

3. Sakata V, Komamura K, Hirayama A, et al. Elevation of plasma histamine concentration in the coronary circulation in patients with variant angina. Am J Cardiol 1996;77:1121–6.

4. Cuculo A, Summaria F, Schiavino D, et al. Tryptase levels are elevated during spontaneous ischemic episodes in unstable angina but not after ergonovine test in variant angina. Cardiologia 1998; 43:189–93.

5. Kaartinen M, Penttila A, Kovanen PT. Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the prediction site of atheromatous rupture. Circulation 1994;90:1669–78.

Kounis syndrome variants

Type I variant: includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponins

Type II variant: includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction

Type III variant: includes patients with coronary artery thrombosis (including stent thrombosis) in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively

Causes of Kounis syndrome

CONDITIONS

• Angio-edema
• Bronchial asthma
• Exercise induced anaphylaxis
• Food allergy
• Idiopathic anaphylaxis
• Mastocytosis
• Serum sickness
• Urticaria
• Churg-Strauss syndrome

DRUGS

• Antibiotics
• Analgesics
• Antineoplastics
• Contrast Media
• Corticosteroids
• Intravenous anaesthetics
• Non steroidal
• Anti-inflammatory
• Drugs (NSAIDs)
• Skin disinfectants
• Thrombolytics
• Anticoagulants

ENVIRONMENTAL EXPOSURES

• Ant stings
• Bee stings
• Wasp stings
• Jellyfish sting
• Grass cutting
• Poison ivy
• Latex contact
• Limpet ingestion (The kiss of death)
• Millet allergy
• Shellfish eating (The kiss of death)
• Viper venom poisoning

DRUG-INDUCED KOUNIS SYNDROME

ANTIBIOTICS

• Ampicillin
• Ambicillin/sulfactam
• Amoxicillin
• Amikacin
• Cafazolin
• Cefoxitin
• Cerufoxime
• Cephradine
• Cinoxacin
• Lincomycin
• Penicillin
• Sulbactam/cefoperazone
• Sulperazon
• Vancomycin

CONTRAST MEDIA

• Iohexone
• Loxagate
• Meglumine diatrizoate
• Sodium indigotindisulfonate

CORTICOSTEROIDS

• Betamethasone
• Hydrocortisone

ANALGESICS

• Dipyrone

ANTINEOPLASTICS

• 5-fluoroucacil
• Capecitabine
• Carboplatin
• Denileukin
• Interferons
• Paclitaxel
• Vinca alkaloids

INTRAVENOUS ANESTHETICS

• Etomidate
• Rocuronium bromide
• Suxamethonium
• Trimethaphan
• NSAIDs
• Diclofenac
• Naproxen

THROMBOLYTICS AND ANTICOAGULANTS

• Heparin
• Lepirudin
• Streptokinase
• Urokinase

SKIN DISINFECTANTS

• Chlorhexidine
• Povidone-iodine

OTHERS

• Allopurinol
• Enalapril
• Esmolol
• Dextran 40
• Fructose
• Insulin
• Iodine
• Protamine
• Tetanus antitoxin
• Glaphenine

TREATMENT OF KOUNIS SYNDROME

1. Treatment of type I variant: Treatment of allergic event alone can abolish type I variant! a.Give corticosteroids and antiistamines b.Give vasodilators e. g. nitrates and Ca-blockers

2. Treatment of type II variant: a. Apply acute coronary event protocol + corticosteroids and antihistamines b. Give vasodilators e. g. nitrates and Ca-blockers when appropriate

One should bear in mind that:

• Epinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm. Sulfite free epinephrine is recommended I.M. 0.2-0.5 mg (1:1000) of aqueous solution is preferable.
• In patients on b-blockers epinephrine may be ineffective. It may also promote more vasospasm due to unopposed alpha adrenergic effect. Glucagon may be considered.
• Avoid opiates such as morphine, codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reaction.
• Fentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary

Literature

• 1950: Pfister CW, et al. Acute myocardial infarction during a prolonged allergic reaction to penicillin. Am Heart J 1950; 40: 945
• 1965: Zosin P, et al. Allergic myocardial infarction. Romanian Medical Review 1965;19: 26
• 1991: Kounis NG, et al. Histamine-induced coronary artery spasm: the syndrome of allergic angina. Br J Clin Pract 1991; 45: 121
• 1995: Constantinides P. “ Allergic reactions can promote plaque disruption” Circulation 1995; 92: 1083
• 1996: Kounis NG, et al. Allergic angina and allergic myocardial infarction. Circulation 1996; 94: 1789
• 1998: Braunwald E. “ Allergic reactions with mediators such as histamine or leukotrienes acting on coronary smooth muscle can induce vasospastic angina” Circulation 1998;98: 2219
• 2003: Zavras GM, et al. Kounis syndrome secondary to allergic reaction. Int J Clin Pract 2003; 57: 62
• 2006: Kounis NG. Kounis syndrome. Int J Cardiol 2006; 119: 7
• 2006: Kounis NG, et al. Hypersensitivity to DES: a manifestation of Kounis syndrome? J Am Coll Cardiol 2006; 48: 592
• 2007: Kounis NG, et al. Coronary stents , Hypersensitivity and the Kounis Syndrome. J Interv Cardiol 2007; 20: 314
• 2008:Tavil Y, et al. Kounis syndrome secondary to amoxicillin/clavulanic acid use. Int J Cardiol. 2008 20; 124: e4-7
• 2009: Chen JP, Hou D, Pendyala L, Goudevenos JA, Kounis NG. Drug-eluting stent thrombosis: the Kounis hypersensitivity-associated acute coronary syndrome revisited. JACC Cardiovasc Interv. 2009; 2: 583-93.