Kounis Syndrome

A 25-year-old man develops sudden-onset chest pain, shortness of breath, and generalized urticaria shortly after receiving intravenous atropine for symptomatic bradycardia. He also reports palpitations, vomiting, and diaphoresis. On examination, he appears pale and diaphoretic, with diffuse wheezing and generalized urticaria. Oxygen saturation is reduced. Electrocardiography shows ST-segment elevation in the inferolateral leads with reciprocal changes. Cardiac troponin levels may be normal or elevated. Emergency coronary angiography reveals normal or nonobstructive coronary arteries. In the setting of transient ST-segment elevation and an acute hypersensitivity reaction, these findings strongly support transient allergic coronary vasomotor dysfunction. Echocardiography may be normal, particularly after resolution of the ischemic episode. Symptoms and ECG changes resolve after treatment of the anaphylactic reaction and myocardial ischemia. Diagnosis?

Diagnosis is Type I Kounis syndrome, likely triggered by atropine.

The simultaneous occurrence of an acute hypersensitivity reaction and acute myocardial ischemia, with normal coronary arteries and transient coronary vasomotor dysfunction, is characteristic of Type I Kounis syndrome.

1. Definition

Kounis syndrome is an allergy-associated acute coronary syndrome in which an allergic, hypersensitivity, or anaphylactic reaction produces acute myocardial ischemia through coronary vasomotor dysfunction, plaque disruption, coronary thrombosis, stent thrombosis, or, in expanded classifications, coronary bypass graft involvement.

2. Pathophysiology

1.      Exposure to a triggering antigen activates mast cells and other inflammatory pathways.

2.      Mast cell degranulation releases mediators including:

1.      Histamine

2.      Tryptase

3.      Leukotrienes

4.      Platelet-activating factor

5.      Thromboxane

6.      Cytokines

3.      These mediators may cause:

1.      Coronary vasomotor dysfunction, including epicardial and/or microvascular spasm

2.      Endothelial dysfunction

3.      Plaque erosion or rupture

4.      Platelet activation and thrombosis

5.      Stent thrombosis

6.      Coronary bypass graft thrombosis in the expanded Type IV phenotype

4.      The mechanism depends partly on the underlying coronary anatomy and determines the Kounis syndrome subtype.

3. Classification

1.      Type I

1.      Occurs in patients with normal or near-normal coronary arteries without significant underlying coronary atherosclerosis

2.      Allergic mediator release produces coronary vasomotor dysfunction, including epicardial and/or microvascular spasm

3.      Cardiac troponin may remain normal if ischemia is transient

4.      Troponin may increase if ischemia results in myocardial necrosis

2.      Type II

1.      Occurs in patients with pre-existing coronary atherosclerosis

2.      The hypersensitivity reaction may produce coronary vasospasm and may precipitate plaque erosion, plaque rupture, or coronary thrombosis

3.      This may result in acute myocardial infarction

3.      Type III

1.      Occurs in patients with a coronary stent

2.      The hypersensitivity reaction is associated with stent thrombosis

3.      Some expanded classifications also include hypersensitivity-associated in-stent restenosis

4.      Type IV

1.      An expanded or emerging phenotype described in recent literature

2.      Characterized primarily by hypersensitivity-associated coronary artery bypass graft thrombosis

3.      Graft vasospasm has also been described, but whether it should be classified as Type I or Type IV remains uncertain

4.      Type IV is not yet incorporated into all Kounis syndrome classification frameworks

4. Clinical Features

4.1 Cardiac Features

1.      Chest pain

2.      Dyspnea

3.      Palpitations

4.      Diaphoresis

5.      Nausea or vomiting

6.      Syncope

7.      Arrhythmias

8.      Hypotension or cardiogenic shock in severe cases

4.2 Allergic / Anaphylactic Features

1.      Urticaria

2.      Pruritus or flushing

3.      Angioedema

4.      Wheezing or bronchospasm

5.      Stridor or airway edema

6.      Gastrointestinal symptoms such as vomiting or abdominal cramping

7.      Hypotension or anaphylactic shock

The combination of generalized urticaria and acute respiratory involvement such as wheezing after exposure to a likely trigger is strongly consistent with anaphylaxis.

Cutaneous manifestations may occasionally be absent, so the absence of urticaria does not exclude Kounis syndrome.

5. Diagnosis

5.1 Clinical Diagnosis

Diagnosis requires a high index of suspicion when acute myocardial ischemia occurs during or shortly after an allergic or hypersensitivity reaction.

5.2 Electrocardiography

ECG abnormalities may include:

1.      ST-segment elevation

2.      ST-segment depression

3.      T-wave abnormalities

4.      Arrhythmias

5.      Conduction abnormalities

ECG abnormalities may be transient, particularly in Type I Kounis syndrome.

5.3 Cardiac Biomarkers

1.      Cardiac troponin may be normal when transient ischemia occurs without myocardial necrosis.

2.      Troponin may be elevated when myocardial injury or infarction occurs.

3.      Serial measurements are appropriate when acute coronary syndrome is suspected.

5.4 Coronary Angiography

1.      Type I may demonstrate:

1.      Normal or near-normal coronary arteries

2.      Epicardial coronary spasm if present during angiography

3.      Resolution of angiographic spasm spontaneously or after intracoronary vasodilator administration

2.      Normal coronary angiography alone does not prove epicardial coronary spasm.

3.      In the appropriate clinical setting, normal coronary arteries combined with transient ischemic ECG changes and rapid symptom resolution strongly support allergic coronary vasomotor dysfunction, which may involve epicardial or microvascular mechanisms.

4.      Type II may demonstrate underlying atherosclerotic coronary disease, culprit stenosis, or coronary thrombosis.

5.      Intravascular imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) may be required to directly identify plaque rupture or erosion.

6.      Type III may demonstrate stent thrombosis.

7.      Expanded Type IV disease may demonstrate coronary artery bypass graft thrombosis.

5.5 Echocardiography

1.      Echocardiography assesses ventricular function and regional wall motion.

2.      Findings may be normal in transient Type I disease.

3.      Regional wall motion abnormalities may occur during significant or prolonged ischemia.

5.6 Allergy Evaluation

1.      Acute serum tryptase should ideally be obtained as early as possible and within 2 hours of symptom onset when feasible.

2.      A later baseline serum tryptase should be obtained for comparison.

3.      A significant rise in acute tryptase relative to baseline supports mast cell activation.

4.      A normal acute tryptase does not exclude anaphylaxis or Kounis syndrome.

5.      Further allergy evaluation may include trigger-specific testing when clinically appropriate.

6.      Total serum IgE is nonspecific and is not diagnostic of Kounis syndrome.

6. Differential Diagnosis

1.      Acute atherosclerotic myocardial infarction

2.      Vasospastic angina

3.      Myocarditis

4.      Takotsubo syndrome

5.      Coronary embolism

6.      Spontaneous coronary artery dissection

7.      Pulmonary embolism

8.      Anaphylaxis-associated myocardial injury secondary to profound hypotension

9.      Other causes of myocardial infarction with nonobstructive coronary arteries

7. Management

Management requires simultaneous treatment of the anaphylactic or hypersensitivity reaction and myocardial ischemia, with therapy tailored to the Kounis syndrome subtype and the patient's hemodynamic status.

There are currently no dedicated high-level treatment guidelines specific to Kounis syndrome. Management is therefore based on the available Kounis literature combined with established principles of anaphylaxis and acute coronary syndrome care.

7.1 Immediate Measures

1.      Stop exposure to the suspected triggering agent.

2.      Assess and support airway, breathing, and circulation.

3.      Establish intravenous access and continuous cardiac monitoring.

4.      Give supplemental oxygen when hypoxemia is present.

5.      Administer intravenous crystalloid fluids when clinically indicated, particularly in anaphylactic hypotension, while monitoring for fluid overload.

7.2 Anaphylaxis

1.      Intramuscular epinephrine is first-line treatment for anaphylaxis.

2.      This patient has clinical anaphylaxis, so intramuscular epinephrine is indicated despite the coexistence of myocardial ischemia.

3.      Kounis syndrome is not a reason to withhold appropriately administered intramuscular epinephrine.

4.      Epinephrine should preferably be administered intramuscularly into the anterolateral thigh.

5.      Intravenous epinephrine carries a greater risk of coronary vasospasm and arrhythmia and should generally be reserved for refractory anaphylaxis or cardiovascular collapse in a closely monitored setting.

6.      Epinephrine may aggravate myocardial ischemia or coronary vasospasm, so close cardiac monitoring is required.

7.3 Adjunctive Allergy Therapy

1.      Antihistamines may be used for persistent cutaneous symptoms such as urticaria or pruritus after stabilization.

2.      Antihistamines do not treat the cardiovascular or respiratory manifestations of anaphylaxis and must not delay epinephrine.

3.      Corticosteroids are not first-line treatment for anaphylaxis and should not delay epinephrine.

4.      Routine corticosteroid use is not supported for prevention of biphasic anaphylaxis.

5.      Corticosteroids may be considered selectively when there is another indication, such as significant concomitant asthma or refractory bronchospasm.

7.4 Type I Kounis Syndrome

1.      Treat the underlying allergic or anaphylactic reaction.

2.      Nitrates may relieve coronary vasomotor dysfunction when blood pressure is adequate.

3.      Calcium channel blockers may also be used for persistent coronary vasospasm.

4.      Vasodilators should be used cautiously in hypotensive patients because they may worsen hemodynamic instability.

5.      Initial ACS-directed therapy may be necessary while the mechanism is being clarified.

6.      Once isolated Type I Kounis syndrome is established and plaque disruption or coronary thrombosis has been excluded, continued antithrombotic therapy may not be required unless another indication exists.

7.      Routine percutaneous coronary intervention is unnecessary when coronary arteries are normal and the ischemic episode resolves without evidence of thrombosis or fixed obstructive disease.

7.5 Type II Kounis Syndrome

1.      Treat the allergic or anaphylactic reaction.

2.      Manage the coronary event according to appropriate acute coronary syndrome protocols.

3.      Coronary angiography and percutaneous coronary intervention may be required when plaque rupture, coronary thrombosis, or obstructive coronary disease is present.

4.      OCT or IVUS may be useful when clarification of the underlying plaque mechanism is clinically important.

7.6 Type III Kounis Syndrome

1.      Treat the allergic or anaphylactic reaction.

2.      Manage as acute stent thrombosis with urgent cardiology intervention when stent thrombosis is present.

3.      Percutaneous coronary intervention and antithrombotic therapy are generally required for acute stent thrombosis.

7.7 Type IV Kounis Syndrome

1.      Type IV is an expanded or emerging phenotype and is not universally included in all classification systems.

2.      Treat the underlying allergic or anaphylactic reaction.

3.      Evaluate urgently for coronary artery bypass graft thrombosis.

4.      Graft vasospasm has been described, but its classification as Type I or Type IV remains uncertain.

5.      Management should be individualized according to the graft lesion, presence of thrombosis, hemodynamic status, and coronary anatomy.

6.      Urgent cardiology assessment and revascularization may be required when graft thrombosis causes significant myocardial ischemia.

7.8 Important Drug Considerations

1.      Epinephrine

1.      Remains first-line and potentially lifesaving in anaphylaxis

2.      Prefer the intramuscular route initially

3.      Monitor closely because it may worsen coronary vasospasm or provoke arrhythmias

2.      Beta blockers

1.      Generally avoided during acute Kounis syndrome

2.      May worsen coronary vasospasm through unopposed alpha-adrenergic activity

3.      May reduce the therapeutic response to epinephrine

4.      Glucagon may be considered in patients receiving beta blockers who have refractory anaphylaxis

3.      Morphine and other histamine-releasing opioids

1.      Should be avoided when possible or used cautiously because they may promote mast cell degranulation and worsen the hypersensitivity reaction

2.      If opioid analgesia is essential, an agent with less mast cell activation, such as fentanyl, may be preferable

4.      Aspirin

1.      Antiplatelet therapy is appropriate when conventional acute coronary thrombosis is present

2.      Aspirin should be used cautiously when it is the suspected allergen or when significant aspirin hypersensitivity exists

3.      Routine aspirin is not necessarily required for isolated Type I disease without plaque disruption or thrombosis

8. Monitoring and Follow-up

1.      Continuous ECG and hemodynamic monitoring during the acute episode

2.      Serial cardiac troponin measurements

3.      Repeat ECG after symptom resolution

4.      Echocardiography when clinically indicated

5.      Cardiology evaluation according to the severity of myocardial ischemia

6.      Allergy or immunology evaluation to identify the triggering agent

7.      Avoidance of the responsible drug or allergen when confirmed

8.      Education regarding future anaphylaxis management when appropriate

9. Prognosis

1.      Type I often resolves after control of the hypersensitivity reaction and coronary vasomotor dysfunction.

2.      Normal coronary anatomy does not make Type I Kounis syndrome completely benign.

3.      Severe cases may result in:

1.      Myocardial infarction

2.      Ventricular arrhythmias

3.      Cardiogenic shock

4.      Cardiac arrest

5.      Death

4.      Prognosis in Type II, Type III, and Type IV also depends on the severity of the underlying coronary or graft pathology and the extent of myocardial injury.

10. Key Clinical Insight

The combination of acute allergic or anaphylactic manifestations with chest pain and ischemic ECG changes should raise immediate suspicion for Kounis syndrome.

In this patient, the temporal relationship to intravenous atropine, generalized urticaria, wheezing, ST-segment elevation, and normal coronary arteries with transient ischemic changes strongly support Type I Kounis syndrome likely triggered by atropine, caused by transient allergic coronary vasomotor dysfunction.

References

1.      Granata LG, Andò G, Marchetta M, Giubilato S, Kounis NG, de Gregorio C. Kounis Syndrome in the Modern Era: A Comprehensive Review of Allergic Acute Coronary Syndromes. J Clin Med. 2026;15(16):6417. doi:10.3390/jcm15166417.

2.      Ganeshanandha R, Teoh ZH, Hii R, Chew DP, Leung M. Allergy-Associated Acute Coronary Syndromes: Therapeutic Framework for Kounis Syndrome. JACC Case Rep. 2026;31(21):107946. doi:10.1016/j.jaccas.2026.107946.

3.      Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: A 2023 Practice Parameter Update. Ann Allergy Asthma Immunol. 2024;132(2):124-176. doi:10.1016/j.anai.2023.09.015.