Kounis Syndrome

Kounis syndrome is acute coronary syndrome occurring with mast cell and platelet activation in an allergic, hypersensitivity, anaphylactic or anaphylactoid reaction. It is also called allergic angina or allergic myocardial infarction.

Three variants are recognised. Type I is coronary spasm without atherosclerosis (normal coronary arteries). Type II is coronary spasm or plaque erosion or rupture on pre-existing atherosclerosis. Type III is stent thrombosis with mast cells and eosinophils in the thrombus, including from allergy to stent components.

Triggers are drugs (beta lactam antibiotics, NSAIDs, aspirin, contrast media, neuromuscular blockers, chemotherapy), insect stings (Hymenoptera), snake bites, foods (shellfish), latex, metals, and environmental allergens. Incidence is unknown. It is under recognised and mostly reported in men aged 40 to 70 years, with a rising frequency in adults with atopy.

Pathophysiology.

Allergen exposure activates mast cells, releasing histamine, tryptase, chymase, leukotrienes, platelet activating factor and cytokines. These cause coronary vasoconstriction, endothelial dysfunction, plaque erosion or rupture, platelet activation and thrombosis.

Histamine acts on H1 receptors (vasoconstriction) and H2 receptors (vasodilatation). Chymase converts angiotensin I to angiotensin II. Adrenaline given for anaphylaxis can itself worsen spasm.

Chest pain (angina or infarct pain) accompanied by allergic features within minutes to hours of exposure: urticaria, flushing, pruritus, angioedema, wheeze, hypotension, vomiting and diarrhoea. The cardiac event may be the only manifestation. Arrhythmia, heart block, cardiogenic shock and cardiac arrest occur.

• ECG: ST elevation or depression, T-wave change, atrioventricular block or arrhythmia.
• Troponin (rising and falling), echocardiography (regional wall motion abnormality, sometimes Takotsubo like).
• Allergy markers: serum tryptase taken 1 to 2 hours after onset, with a baseline value at 24 hours or later (an acute value over 1.2 times baseline plus 2 microgram/L supports mast cell activation), total and specific IgE, blood eosinophil count, histamine and complement where available.
• Coronary angiography when the ECG shows ST elevation or troponin is rising, ideally with a normal or non-obstructed vessel (type I), plaque (type II), or stent thrombosis (type III). Do not give provocation tests during allergy.
• Intracoronary imaging and thrombus aspirate histology (eosinophils and mast cells stained with tryptase or CD117) in suspected type III.
• Drug and exposure history, then allergy referral for skin and drug testing after recovery.

Differential diagnosis.

• Atherothrombotic acute coronary syndrome without allergy.
• Takotsubo syndrome (including adrenaline induced).
• Spontaneous coronary artery dissection and coronary spasm of other cause.
• Anaphylaxis with demand ischaemia and myocarditis.

Stop the trigger at once (including aspirin or other drugs if a suspected cause).

Anaphylaxis with airway, breathing or circulation compromise.

• Adrenaline 0.5 mg (0.5 mL of 1 mg/mL) intramuscularly into the anterolateral thigh in adults, repeated after 5 minutes if there is no improvement. It must not be withheld in life threatening anaphylaxis despite the risk of spasm. In refractory shock, intravenous adrenaline infusion 0.05 to 0.1 microgram/kg/min in a monitored setting, titrated to blood pressure.
• Oxygen, intravenous crystalloid 500 to 1000 mL, nebulised salbutamol 5 mg for bronchospasm.
• Chlorphenamine 10 mg intravenously slowly (adjunct), and hydrocortisone 200 mg intravenously (adjunct, not first line).
• Patients taking beta blockers with resistant shock: glucagon 1 to 5 mg intravenously over 5 minutes, then 5 to 15 microgram/min infusion.

Coronary treatment.

• Type I (spasm): glyceryl trinitrate 400 to 800 microgram sublingually or 10 to 200 microgram/min intravenously (adjusted to blood pressure), and a calcium channel blocker: diltiazem 60 mg orally four times daily (maximum 360 mg daily) or amlodipine 5 to 10 mg daily (maximum 10 mg). Avoid hypotension while allergic shock persists.
• Type II and type III: antithrombotic therapy and primary percutaneous coronary intervention by usual ST-elevation or non-ST-elevation practice: aspirin 150 to 300 mg loading dose (use clopidogrel 600 mg when aspirin is the culprit), ticagrelor 180 mg loading dose and 90 mg twice daily, heparin 70 to 100 units/kg during intervention. Thrombus aspiration is selective, and the aspirate is sent for histology.
• Avoid beta blockers in the acute phase (unopposed alpha stimulation worsens spasm and blunts the response to adrenaline), and avoid morphine and other histamine releasing opioids (fentanyl 25 to 50 microgram intravenously is preferred for pain).
• Corticosteroids and antihistamines are adjuncts, and evidence for benefit in preventing cardiac injury is limited.

Recurrence and prevention.

• Allergy referral for trigger identification and avoidance (drug, food, insect, contrast, metal allergy). Medic alert advice.
• Adrenaline auto injector 0.3 mg intramuscularly for adults weighing 30 kg or more, with training for use.
• In type III, allergy testing for stent materials (nickel, cobalt, chromium, polymers, antiproliferative drugs), and intensified antiplatelet therapy with allergy specialist input.
• Long term secondary prevention for atherosclerotic disease: atorvastatin 40 to 80 mg daily, antiplatelet therapy, blood pressure control.

Monitoring. Continuous ECG for 24 to 48 hours, serial troponin, tryptase at 1 to 2 hours and at 24 hours, echocardiography within 48 hours and at 3 months, follow up in allergy and cardiology clinics.

Referral and escalation. Immediate resuscitation team and cardiology for anaphylaxis with chest pain, ST elevation, shock or arrhythmia. Refer to allergy after any episode.

Special groups.

• Pregnancy: adrenaline remains first line in anaphylaxis; avoid beta blockers; deliver in a specialist unit.
• Children: adrenaline 0.01 mg/kg intramuscularly (maximum 0.5 mg).
• Kidney impairment and contrast reactions: premedication cannot be relied on; use alternatives to the offending contrast agent.
• Older adults: reduce vasodilator doses and monitor blood pressure closely.