From Allergy to Infarction: A Rare Case of Kounis Syndrome Presenting as ST-elevation Myocardial Infarction

Abstract

Kounis syndrome refers to the simultaneous occurrence of acute coronary syndrome triggered by mast cell and platelet activation during hypersensitivity, allergic, or anaphylactic reactions. Although several medications and environmental factors have been identified as potential triggers, the complete spectrum of causative agents and the underlying mechanisms remains unclear. Kounis syndrome is frequently underdiagnosed, as distinguishing acute coronary events during episodes of anaphylaxis is challenging due to overlapping clinical features. Therefore, maintaining a strong clinical suspicion is crucial in identifying affected patients. Careful treatment of each entity is necessary, as the pharmacological agent in the treatment of one may adversely affect the other. Effective care of Kounis syndrome requires urgent treatment of ischemia in addition to identifying and managing both the allergic response and the inciting anaphylactic factor to prevent relapse. Here, we describe a Type II Kounis syndrome case: a previously healthy individual presenting with ST-elevation inferior posterior wall myocardial infarction and complete heart block after sustaining multiple bee stings.

Introduction

Anaphylaxis represents a life-threatening medical emergency, characterized by a rapidly progressing systemic hypersensitivity reaction involving multiple organ systems. The cardiovascular system plays a dual role in this condition, acting as both a primary target and a major source of inflammatory mediators released during the reaction. ¹ When acute coronary syndrome (ACS) occurs simultaneously with anaphylaxis, the outcome can be catastrophic for the patient.

In 1991, Kounis and Zavras first reported ACS associated with mast cell activation due to allergic, hypersensitivity, or anaphylactoid reactions, coining the terms “allergic angina” and “allergic myocardial infarction.”^{2, 3} The underlying pathophysiology of Kounis syndrome (KS) is attributed to coronary artery vasospasm and/or disruption of atherosclerotic plaques, triggered by inflammatory cytokine release from activated mast cells. Predisposing factors include a history of allergic disorders, hypertension, diabetes mellitus, smoking, and dyslipidemia. Among the reported precipitating agents, antibiotics (27.4%) and insect stings (23.4%) are the most frequent, although the spectrum of recognized triggers continues to expand. ⁴

Kounis syndrome is classified into three clinical variants: Type I occurs in individuals with angiographically normal coronary arteries, where acute exposure to inflammatory mediators during an anaphylactic reaction precipitates coronary vasospasm. In Type II, patients with pre-existing atherosclerosis experience an allergic insult that triggers coronary vasospasm or plaque disruption, culminating in ACS. Type III refers to stent thrombosis caused by mast cell and eosinophil infiltration within coronary stents.^{5, 6}

Currently, clinical signs are used to diagnose KS. It is challenging to ascertain the true incidence or prevalence of KS since many patients may go undiagnosed or underdiagnosed because doctors are unaware of the condition. Helbling et al. reported that the annual incidence of anaphylaxis accompanied by circulatory symptoms ranges between 7.9 and 9.6 cases per 100,000 population, with an associated case-fatality rate of just 0.0001%. ⁷ Several epidemiological studies have shown a progressive rise in both the prevalence of allergies and the occurrence of anaphylaxis, with the estimated lifetime risk ranging from 0.02% to 2.0%. ⁸ Consequently, the number of KS cases documented in the literature has been steadily increasing. We report a case of Type II KS triggered by multiple bee stings, which resulted in an anaphylactic reaction.

Case Report

A 74-year-old female with hypertension for 10 years presented with syncope a few minutes after multiple bee stings. She had no previous cardiac diseases. She went to a primary care center and was treated with injection pheniramine and injection hydrocortisone 100 mg IV, followed by 0.5 mL, adrenaline intramuscular (IM). She was then shifted to our hospital for further management. On arrival, she was drowsy, agitated, and tachypneic with blood pressure (BP)-80/50 mmHg, heart rate 40 bpm, and peripheral capillary oxygen saturation (SpO₂) of 94% in room air. On auscultation, bilateral crepitations were present. Electrocardiogram (ECG) showed ST-elevation in inferoposterior leads, left bundle branch block (LBBB), and complete heart block (Figure 1). Echocardiography showed hypokinetic inferior and posterolateral wall, moderate mitral regurgitation, moderate left ventricle (LV) dysfunction (ejection fraction (EF)-35%), right ventricle (RV) dysfunction, and inferior vena cava (IVC) of 2 cm. Cardiology consultation was taken, and emergency primary percutaneous coronary intervention (PCI) was planned. Emergency intubation was done in view of altered mentation, agitation, and the chance of worsening of pulmonary edema, and the patient was shifted to the cath lab. Temporary pacemaker implantation was done via the right femoral vein and proceeded with angiography. Coronary angiography showed severe eccentric 75% proximal vessel disease with acute thrombotic distal vessel occlusion in the right coronary artery (RCA), severe eccentric 90% proximal vessel disease in the left circumflex artery (LCx), and mild 50% proximal vessel disease in the left anterior descending (LAD) artery (Figure 2A). Primary PCI was done to the RCA with placement of 1 drug-eluting stent with a plan of staged percutaneous transluminal coronary angioplasty (PTCA) to the LCx after a few weeks. Good Thrombolysis in Myocardial Infarction (TIMI) 3 flow was obtained post-procedure (Figure 2B), the temporary pacemaker was removed, and the patient was shifted to the intensive care unit (ICU). Electrocardiogram post-PTCA showed resolving ST-elevations and good heart rate (Figure 3).

Figure 1.

Electrocardiogram (ECG) of the Patient Showing ST-elevation Inferoposterior Wall Myocardial Infarction (MI), Left Bundle Branch Block (LBBB), and Complete Heart Block.

Figure 2.

(A) Proximal Vessel Disease with Distal Occlusion in Right Coronary Artery (RCA). (B) RCA After Percutaneous Transluminal Coronary Angioplasty (PTCA) Showing Thrombolysis in Myocardial Infarction (TIMI) 3 Flow.

Figure 3.

Electrocardiogram (ECG) Post Percutaneous Transluminal Coronary Angioplasty (PTCA) Showing Resolving ST-elevations and No Evidence of Heart Block.

Discussion

Anaphylaxis is mediated through an immunoglobulin E (IgE)-dependent mechanism, in which prior allergen exposure leads to B-cell sensitization and subsequent formation of specific IgE antibodies. ⁸ Upon re-exposure, antigens trigger tissue mast cell activation, initiating the cascade responsible for the anaphylactic response. Mast cells are distributed throughout human tissues, especially in the skin and respiratory tract, but are found in high concentrations within the heart, particularly in patients with ischemic heart disease or dilated cardiomyopathy. Distinct from mast cells in other sites, cardiac mast cells can also be activated by complement components C3 and C4, as well as radiocontrast agents. ¹ When the anaphylactic reaction leads to coronary vasospasm, which in turn leads to an ACS, it is termed KS.

Bee and wasp stings, such as in our patient, introduce venom that contains bioactive proteins, peptides, and amines. These compounds may exert direct toxic effects on the heart, but at the same time, they can act as allergens, initiating mast cell activation. ⁹ When the body encounters allergens—including certain foods, insect venoms, contrast dyes, or specific medications—mast cells undergo degranulation. This process releases a wide range of mediators such as histamine, leukotrienes, and serotonin, along with proteolytic enzymes like tryptase and chymase, into the systemic circulation. ¹⁰ Histamine and leukotrienes act as strong coronary vasoconstrictors, while tryptase and chymase stimulate matrix metalloproteinases, leading to collagen breakdown and disruption of atherosclerotic plaques, ultimately precipitating coronary events. In addition, stented coronary vessels appear to exert an attractant effect on mast cells and platelets; in the presence of cytokine release, this interaction may culminate in coronary spasm, plaque rupture, or stent thrombosis. ¹¹

Cardiac histamine acts upon four types of receptors, each of which can contribute to the severity of allergic myocardial damage. The H₁ receptors mediate coronary vasoconstriction, while the H₂ receptors, to a lesser degree, intervene in coronary relaxation. Interaction between the two receptor pathways results in lowered diastolic pressure accompanied by an elevated pulse pressure. Histamine H₃ receptors function by suppressing the release of noradrenaline, whereas H₄ receptors play a role in regulating mast cell, eosinophil, and lymphocyte chemotaxis. This activity induces morphological changes in eosinophils and enhances molecular adhesion. ¹² Collectively, these mechanisms contribute to coronary vasospasm, plaque rupture, and thrombosis, leading to reduced coronary perfusion and the development of ACS.

Many drugs have been implicated in anaphylaxis and have the potential to cause KS. In Indian literature, there have been reports of KS due to nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac ¹³ and nimesulide ¹⁴ and antibiotics like ceftriaxone, a third-generation cephalosporin, ¹⁵ and even oral amoxicillin clavulanate. ¹⁶

Most of the time, KS is diagnosed clinically based on the existence of symptoms that point to a concomitant acute allergy and cardiac event. There are three known forms of KS. Type I KS is observed in patients without underlying risk factors for coronary artery disease (CAD). In such cases, the allergic insult may provoke either myocardial infarction with elevated cardiac biomarkers or coronary vasospasm with normal biomarker levels. These manifestations are thought to result from endothelial dysfunction or microvascular angina. ¹⁷ Patients with known or unknown culprit but dormant underlying atheromatous disease are included in the type II variety. In these patients, abrupt mediator release may cause atheroma plaque erosion or rupture, which could lead to an acute myocardial infarction. ⁵ Patients with drug-eluting stents who experience coronary artery stent thrombosis as a result of an allergic reaction are included in the type III variant. ⁶

In our patient, we believe she had vasospastic angina in the setting of pre-existing undiagnosed atheromatous CAD, which led to plaque rupture and thrombosis, favoring Type 2 KS. She had severe RCA occlusion, which led to RV dysfunction, complete heart block, and moderate LV dysfunction. The hypotension during presentation could be due to RV dysfunction or anaphylactic shock. The fact that heart block and hypotension persisted even after adrenaline injection and resolved only with PTCA favors the cardiac cause.

At present, there are no specific guidelines for the management of KS. Treating the allergic reaction is reportedly sufficient to resolve the ACS in Type 1 KS, whereas treating both allergic reaction and ACS is required in Type 2 and Type 3 KS, given the pre-existing CAD. If required, vasospasm can be managed with agents such as nitrates and calcium channel blockers. ¹⁸ Morphine, although commonly used for acute chest pain, should be administered cautiously in KS since it may provoke extensive mast cell degranulation and worsen the allergic response. Similarly, beta-blockers are not preferred during an acute episode of KS, as they can intensify coronary vasospasm through unopposed alpha-adrenergic stimulation. ¹⁹ In patients with pre-existing CAD, adrenaline should only be reserved for severe anaphylaxis as its adrenergic effects, causing coronary vasoconstriction and tachycardia, may be detrimental. ²⁰

In the management of ACS, antiplatelet therapy should be administered according to established guidelines. Aspirin is recommended for use in KS patients unless there is a known allergy to aspirin or NSAIDs. Both aspirin and NSAIDs inhibit the cyclooxygenase pathway, thereby decreasing the production of prostaglandin D2 (PGD2), a mediator that promotes coronary vasoconstriction. However, these agents may exacerbate anaphylaxis by increasing leukotriene synthesis due to unopposed lipoxygenase activity.^{21, 22}

Conclusion

Kounis syndrome is a rarely recognized and much underdiagnosed condition with potentially life-threatening consequences. Hence, a high degree of suspicion is needed in cases of ACS in the context of an allergic reaction. Given its overlapping mechanism, treatment is directed at both the allergic reaction and myocardial damage. Pharmacological management of both ACS and anaphylaxis should be weighed cautiously, as individual treatment may have severe and life-threatening consequences on the other entity. Prompt management of the acute ischemic event alongside cardiac protection, coupled with identification and treatment of the underlying allergic sensitization and anaphylaxis trigger, is crucial to prevent recurrence.