Clinical Features, Course and Prognosis of Kounis Syndrome

Introduction

After the first report of allergic myocardial infarction in 1950, the occurrence of acute coronary syndrome following an allergic insult has been called Kounis Syndrome (KS).¹ This unique disease is also named “allergic angina” or “allergic angina syndrome”, and is characterized by transient left ventricular dysfunction with a variety of wall-motion abnormalities.^2,3 Although patients with KS usually do not have obstructive coronary lesions, electrocardiographic findings, signs, and symptoms are often similar to those of acute coronary syndromes.⁴ The most common symptoms of KS are related to allergic reactions such as pruritus, and acute coronary syndrome and/or acute heart failure such as chest pain, dyspnea, and palpitation.^4,5 Patients with KS typically are admitted to emergency departments after an allergic insult such as drugs, foods, or insect bites.^5,6 Three variants of KS have been described; type1: coronary artery spasm; type 2: coronary atherothrombosis or vasospasm in patients with preexisting atheromatous disease; and type 3: patients with coronary stent thrombosis (3A) or stent restenosis (3B) due to allergic reaction^7,8 Figure 1.

Figure 1 The pathophysiology of Kounis Syndrome.

Although it has been frequently reported in recent years, there is no consensus regarding the diagnostic criteria or management of KS. The pathophysiology, prevalence, and epidemiology of KS are also not clear. The prevalence of KS was estimated to be 0.002% in the catheterization laboratory of a tertiary hospital in Turkey.⁹ In another Turkish study, the annual incidence of KS in the emergency department among all the admissions and patients with allergy was 0.019%, and 3.4%, respectively.¹⁰ However, among the patients hospitalized for allergic reactions, the prevalence of KS was found to be 1.1% in the US.¹¹ The epidemiological characteristics and prevalence of KS have never been investigated worldwide, but the results of the above-mentioned studies suggest geographical variations. Furthermore, most of the case reports have been reported from the same parts of the world, including Turkey, Greece, Italy, and Spain.³ Increased awareness among physicians about KS, environmental conditions, exposures to hymenoptera, insects, or snakes, and overconsumption of medicines may contribute to this variation. Our study aimed to investigate demographic characteristics, clinical features, prognosis, and outcomes of patients with KS in real-life clinical practice.

Methods

From January 2018 to December 2024, all patients diagnosed with KS were retrospectively enrolled at the Mugla Education and Research Hospital. This study was approved by the Ethics Committee of study protocol was approved by Mugla Sitki Kocman University Medical Sciences Ethics Committee on 13.02.2025 (decision number 2025/22) and the trial conformed to the principles outlined in the Declaration of Helsinki, and informed consent was obtained from all patients.

Definition of Kounis Syndrome

In the absence of infectious myocarditis, the presence of acute-onset allergic reactions and cardiovascular symptoms associated with transient wall motion abnormality in the left ventricle, new ECG abnormalities, or elevation in cardiac biomarkers after exposure to an allergic insult was defined as KS (Supplementary box 1). Three types of KS have been identified: type 1- coronary spasm; type 2- coronary thrombosis; and type 3- coronary stent thrombosis (3A) or restenosis (3B) secondary to allergic insult.

Allergic reactions were primarily assessed based on a comprehensive clinical history, with particular attention to recent exposure to known allergens and the presence of characteristic symptoms such as rash, urticaria, angioedema, wheezing, or other signs of hypersensitivity. Emphasis was placed on the temporal association between exposure and the rapid onset of symptoms, typically occurring annually. In addition to routine specific IgE testing for a broad panel of allergens, total serum IgE levels were measured in all patients, with elevated values documented. Serum tryptase levels were assessed in a selected subset of patients during the acute phase to further support the diagnosis of an allergic episode. To rule out infectious myocarditis, a standardized evaluation protocol was employed. This included a focused clinical history to identify any recent viral illnesses or symptoms suggestive of myocarditis, assessment for the presence of fever or other systemic inflammatory signs, and comprehensive serological testing for common cardiotropic viruses. Only patients with negative viral serologies and no clinical features consistent with infectious myocarditis were included in the final analysis.

Measurements

Data for demographic information, comorbidities, and laboratory variables were collected. The presence of atopic diathesis, defined as personal or family history of asthma, allergic rhinitis and/or conjunctivitis, and atopic dermatitis was noted. Complete blood count, D-dimer, high-sensitivity cardiac troponin T, total IgE, creatine kinase-MB, serum cholesterol levels, and serologic tests for viral etiology were examined in all patients. Serum tryptase levels were measured in 18 (64.3%) of the study patients. All patients underwent transthoracic echocardiography using the Philips System (Philips Epiq 7G, Andover, MA), and left ventricular ejection fraction was measured by the modified Simpson’s method. Coronary angiography or 256-slice computed cardiac tomography was performed in all patients to exclude coronary artery disease and to diagnose subtypes of KS. Follow-up data were collected by telephone interviews and from the hospital database. Persistent left ventricular wall motion abnormality was defined according to the latest echocardiographic examination. Data were analyzed using SPSS for Windows (version 24; SPSS Inc, Chicago, IL), and p <0.05 was considered statistically significant.

Results

A total of 28 patients with KS (mean age 47.7±14.3 years), with a male predominance (64.3%), were included in the study.

Patient Characteristics at Presentation

Demographic characteristics, comorbidities, clinical, laboratory, ECG, and echocardiographic findings of the patients on admission are shown in Table 1. Allergic signs and symptoms such as pruritus, skin rashes, itching, hives, shortness of breath, trouble breathing, wheezing, and swelling of the lips, tongue, or throat were found in 92.8% of the patients. Cardiac symptoms such as chest pain, palpitation, and dyspnea were the other common presenting symptoms. The majority of the patients had no comorbid diseases, and the most common comorbidity was hypertension, with a prevalence of 21.4%. Of the study population, 14.3% had atopic diathesis. The most common ECG abnormalities at presentation were ST-segment elevation, ST-segment depression, and non-specific ST-T changes. Only one patient had atrial fibrillation, which spontaneously returned to normal sinus rhythm. The mean left ventricular ejection fraction was 58%, and 78.6% of the patients had left ventricular wall motion abnormality at presentation. The high-sensitivity cardiac troponin T and total IgE levels were increased in all patients. The serum tryptase levels were also increased in all of the 18 patients in whom tryptase levels could be measured. Artificial intelligence-assisted technologies (such as Large Language Models, chatbots, or image creators) were not used in the production of the submitted work in this study.

Table 1 Clinical Features of the Study Population

Types of Kounis Syndrome

Of the study group, 16 patients underwent invasive coronary angiography, and 12 patients underwent coronary tomographic angiography. There was no coronary artery lesion in 25 (89.3%) of the patients, and they were classified as Type 1-KS. Two patients (7.1%) had type 2-KS, and one patient (3.6%) had type 3A-KS.

Allergic Insult

Causes of KS in our study cohort are presented in Figure 2. The triggering factors were drugs in 71.4% of the patients, insect, bee, or hymenoptera stings in 14.3%, foods in 10.7%, and coronary stent in 3.6% of the study population. Nonsteroidal anti-inflammatory drugs and antibiotics were the most frequently involved drugs in our study cohort.

Figure 2 Distribution of allergic agents in Kounis Syndrome.

Management

All of our patients were treated with oral antihistamines (eg, intravenous diphenhydramine 25–50 mg) and corticosteroids (eg, intravenous methylprednisolone 80–125 mg or oral prednisone 0.5–1 mg/kg). Of the study population, 32.1% received antiplatelet and/or anticoagulant drugs, 14.3% received loop diuretic therapy, 14.3% received angiotensin-converting enzyme inhibitors, and 21.4% received beta-blockers. Antiplatelet agents were primarily administered to patients with Type 2 and Type 3 KS, in whom coronary atherothrombosis or stent thrombosis/restenosis was present or suspected. Three patients with type 2 and type 3-KS were also treated with coronary angioplasty, aligning with standard acute coronary syndrome guidelines. Vasodilators, including calcium channel blockers and nitrates, can effectively relieve persistent vasospasm. Intravenous or sublingual nitroglycerin has been used as a safe and reasonable treatment option in hemodynamically stable patients with KS. Only two patients needed short-term inotropic therapy. Inotropic therapy was reserved for patients who developed significant hemodynamic instability, severe left ventricular dysfunction, or cardiogenic shock refractory to initial fluid resuscitation and vasopressor support. The decision was made on a case-by-case basis by the treating cardiologist based on clinical assessment, echocardiographic findings, and hemodynamic parameters.

Outcomes

All of our patients had an uneventful in-hospital course. The median length of hospital stay was four days, and the mean duration of follow-up was 6.2 months. The electrocardiographic and echocardiographic abnormalities improved in 92.9% of the patients. The left ventricular wall motion abnormality was not completely recovered in 2 (7.1%) patients at the end of follow-up. None of the patients died in the hospital or during follow-up.

Discussion

To our knowledge, this is the largest real-world case series in the literature examining patients with KS. We found that: (1) there is a male predominance in KS; (2) allergic symptoms and chest pain were the most common symptoms at presentation; (3) drugs were the most common triggering factors; (4) in-hospital and long-term prognosis were better than those with atherosclerotic acute coronary syndromes.

There are a limited number of KS case reports, and only a few systematic reviews evaluating previously published KS case reports. Of note, these reports demonstrated that differential diagnosis of KS from acute myocardial infarction and myocarditis may be challenging as the symptoms and ECG, echocardiography, and laboratory signs may be similar. Moreover, invasive and non-invasive imaging modalities reveal normal coronary arteries in myocarditis and KS type 1. However, patients with myocarditis usually present with a history of infectious disease, and they are characterized by higher levels of cardiac biomarkers, and acute phase reactants. Due to the lack of adequate studies, there are no generally accepted recommendations addressing the prevalence, diagnosis, or management of KS. In a nationwide study, Desai and colleagues enrolled patients hospitalized for allergic reactions using the National Inpatient Sample.¹¹ Of the study population, 1.1% were defined as having KS.¹¹ The findings of the study by Desai et al were significantly different from our study; their patients were older, had a higher burden of comorbid diseases (76% hypertension, 25% heart failure, 36% diabetes, etc)., and had higher (7%) in-hospital mortality than our patients.¹¹ In an international pharmacovigilance database study, 51 patients with drug-induced KS were analyzed.¹² The results of this study were remarkably similar to our study, with a male ratio of 65%, a mean age of 46 years, and non-steroidal anti-inflammatory drugs as the most frequent trigger drugs.¹² Abdelghany et al searched MEDLINE and identified 175 KS cases.¹³ The results of this literature review were also comparable with our study findings, with a male ratio of 74%, and with a low prevalence of comorbid diseases (18% hypertension, 12% diabetes, etc). Similar to our study, Abdelghany and colleagues also demonstrated that the most common triggers of KS were drugs and insect bites, the type 1 variant was the most common (73%) subtype of KS, ST elevation was the most common ECG finding at presentation, and echocardiography showed regional wall motion abnormalities in 58% of the patients.¹³ They showed that 25% of the patients had a history of allergy, which was higher than our study ratio of 14%.

The definition and diagnostic criteria are controversial in KS. Serum histamine, tryptase, total IgE, and specific IgE antibody levels can help in the identification of KS.¹⁴ Histamine is short living and circulates for only 8 minutes after an allergic event; therefore, we could not obtain histamine levels in any of the patients. Serum tryptase levels should be measured within the first 30 minutes of initial symptoms, and we able to measure tryptase levels in 18 patients. In certain cases, a non-immunological mechanism is implicated, characterized by direct degranulation of mast cells and basophils. The resulting release of inflammatory mediators contributes to coronary vasospasm, platelet activation and aggregation, as well as proliferation of arterial smooth muscle cells. Histamine plays a key role in inducing coronary vasoconstriction and promoting platelet activation, whereas tryptase facilitates activation of the coagulation cascade, thereby contributing to both thrombus formation and fibrinolysis. Furthermore, matrix metalloproteinases, activated by tryptase and chymase, may destabilize pre-existing atherosclerotic plaques, leading to plaque erosion or rupture. The use of IgE levels in the diagnosis of KS remains unclear, and the absence of IgE antibodies does not exclude the diagnosis.¹³ Non-IgE-mediated reactions (anaphylactoid) based on IgG and IgM immune complex activation also contribute. However, we demonstrated that all the patients, who had tryptase and IgE measurements, had higher levels for these biomarkers.¹⁵

Evidence from the literature indicates that KS may develop across a wide age range and among various ethnic populations. This widespread distribution underscores the significant role of environmental factors, while also suggesting a potential contribution of host genetic factors in determining disease susceptibility, severity, and phenotypic expression. Elucidating the genetic basis of KS—through identification of relevant polymorphisms or molecular markers—remains a critical area for future research. Such insights may enhance risk stratification, guide personalized therapeutic strategies, and deepen our understanding of the pathophysiological diversity observed in KS. KS has been documented across a wide range of geographical regions and ethnic populations, supporting its ubiquitous nature. Nonetheless, reported prevalence appears to be higher in Southern European countries, notably Turkey, Greece, Italy, and Spain. This apparent regional clustering does not necessarily reflect a genuinely increased incidence but may instead be influenced by several confounding factors. First, heightened clinical awareness and diagnostic vigilance among physicians in these regions may contribute to more frequent recognition and reporting of KS cases. Second, specific climatic and environmental exposures—such as increased pollen cross-reactivity or a higher prevalence of hymenoptera stings—may elevate the incidence of allergic events that precipitate KS. Third, regional prescribing patterns, including the potential overuse or misuse of certain pharmacologic agents, could increase the likelihood of drug-induced KS. Finally, discrepancies in preventive healthcare strategies and allergen avoidance measures may further shape the observed epidemiological distribution.

Despite these regional disparities, KS is more accurately described as an underrecognized clinical syndrome rather than a truly rare disorder. Its diagnostic challenge lies in its shared inflammatory pathways with non-allergic acute coronary syndromes, underscoring the need for increased awareness and diagnostic precision to ensure appropriate clinical management.

The prognosis of patients with KS was very good, with the left ventricular function normalizing over three days to several weeks in our study. No consensus exists regarding appropriate therapy for KS, but it has two aspects that need to be treated: acute coronary syndrome and allergic reaction.¹⁶ Therefore, we treated patients with the type 1variant only with fluid replacement, antihistamines, and corticosteroids, and we treated patients with type 2 and type 3 variants following the most recent acute coronary syndrome guidelines.^17,18

Limitations

This study has several limitations. First, given the retrospective nature of this research, the management of the patients was at the discretion of the managing service and was based on clinical judgment. Our hospital is a single referral hospital to which patients are referred from peripheral hospitals, which may affect our results. Therefore, caution should be taken in extrapolating these results to other populations. Third, cardiac magnetic resonance imaging and endomyocardial biopsy were not performed in our study. Despite representing the largest case series to date, the relatively small sample size of 28 patients and the absence of a control group (eg, patients with non-allergic acute coronary syndrome) inherently limit the generalizability of the findings.

Conclusions

Rare diseases are defined as those affecting a very low number of patients, but which can be associated with inappropriate management, and adverse health outcomes. The true prevalence of rare diseases is unclear since the correct diagnosis is often missed. KS is an unusual and an “orphan” disease that is rare but probably under-reported. Our study showed that physicians, especially cardiologists and emergency-department physicians, should be aware of this unique disease and consider the diagnosis of KS in patients with acute-onset cardiac symptoms that start after a potentially allergic insult.