Kounis syndrome following COVID-19 vaccination: Clinical manifestations, mechanisms and management

ABSTRACT

Kounis syndrome is an acute coronary syndrome triggered by allergic mediators that induce coronary vasoconstriction and thrombosis, leading to further myocardial damage and anaphylactic shock. Kounis syndrome is also a rare but severe adverse reaction to the COVID-19 vaccine, a phenomenon that underscores the importance of collecting and analyzing similar cases to improve treatment and prognosis. Through comprehensive searches of the Web of Science, Embase, and PubMed databases, this study aimed to gather detailed patient data on patients who developed Kounis syndrome after receiving the COVID-19 vaccine and to further investigate the possible underlying mechanisms using currently available studies. A total of 15 patients (8 females, 7 males) were found. We analyzed comprehensive patient data, including demographics, vaccination details, time of onset of illness after vaccination, clinical manifestations, treatment and outcomes, duration of illness, and relevant examination results. Analysis of these data combined with known allergy-related mechanisms indicated that, regardless of the vaccine type, the first dose of the vaccine was more likely to cause Kounis syndrome than subsequent doses. Therefore, early diagnosis and clinical symptomatic treatment are particularly crucial for managing the severity of Kounis syndrome and preventing further cardiac complications. Additionally, when an unusual and severe allergic reaction occurs within a few hours after vaccination, it is important to closely monitor the development of cardiac-related symptoms and prepare clinically for the potential onset of Kounis syndrome.

KEYWORDS:

• COVID-19
• vaccines
• Kounis syndrome
• allergic reaction
• clinical manifestation

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged at the end of 2019, is a highly transmissible and pathogenic virus.¹ The virus caused a pandemic of an acute respiratory disease known as coronavirus disease 2019 (COVID-19),² posing a global threat to human well-being and public security.³

The development and global approval of more than two dozen COVID-19 vaccines more than a year after the virus’ emergence played a crucial role in curbing the transmission of COVID-19 and reducing the death toll due to COVID‐19.^4–6 These vaccines utilized a variety of platforms, such as adenovirus vectors, mRNA, subunits, and inactivated SARS-CoV-2 or DNA technology. To date, only eight of these vaccines have received emergency use authorization (EUA) from the World Health Organization (WHO). Notable examples include the BNT162b2 mRNA-based vaccine from BioNTech/Pfizer, which utilizes specifically modified sequences of the spike protein-encoding gene; the AZD1222/ChAdOx1 vaccine from Oxford/AstraZeneca and the ChAdOx1_nCoV19 vaccine, marketed as Covishield, which are nonreplicating adenovirus vector-based DNA vaccines; and CoronaVac from Sinovac Biotech, which is an inactivated virus vaccine. The ChAdOx1 nCoV-19 vaccine (AZD1222) is a vectored vaccine developed at Oxford University, and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the full-length structural surface glycoprotein (spike protein) of SARS-CoV-2. The receptor-binding domain (RBD) and the N-terminal domain (NTD) are the main targets of the antibody response induced by the vaccines and the mutations in the domains may cause the immune escape. While these vaccines offer significant benefits, it is crucial to remain vigilant about their potential adverse effects.^7,8

Kounis syndrome is a coronary artery disease associated with allergies, hypersensitivity, anaphylaxis and allergic-like reactions.^9,10 Kounis syndrome is classified into three types, vasospastic angina pectoris, anaphylactic myocardial infarction and stent thrombosis, in which eosinophils and/or mast cells infiltrate the occluded thrombus.^8,10 Its known manifestations and etiological agents are constantly expanding.¹¹ In addition to being induced by drugs and environmental exposures,¹² Kounis syndrome can also be induced by vaccines.¹³ Treatment of Kounis syndrome follows existing guideline recommendations based primarily on electrocardiographic criteria, as no specific recommendations are currently available. The different types of Kounis syndrome are treated based on the symptoms, and treatments can be classified as pharmacological (including antiallergic, anticoagulant and cardiac-related medications) or nonpharmacological (including aspiration thrombectomy and balloon angioplasty).^14,15

Although Kounis syndrome is an extremely uncommon clinical occurrence,^7,16 cases of Kounis syndrome after vaccination have gradually been reported since COVID-19 vaccines became widely available, which raises similar clinical concerns. This study analyzed pooled case reports of Kounis syndrome after COVID-19 vaccination to better evaluate its clinical manifestations and medical examination features and to improve the ability of clinicians to recognize this rare syndrome in the early stage.¹⁷

Methods

Search strategies

We searched the PubMed, Web of Science and Embase public databases up to January 15, 2024, for case reports of patients with Kounis syndrome associated with COVID-19 vaccination. Additionally, we reviewed all the references of the above case reports to ensure that no cases were missed. Our search formula in Web of Science was as follows: TS=(covid OR cov OR SARS-CoV-2 OR coronavirus) AND (vaccine OR vaccination OR vaccinium) AND (Kounis syndrome OR Anaphylactic myocardial infarction OR Allergic myocardial infarction). For the purpose of broad screening, we did not limit the field and identified the studies mentioned above.¹⁸

Data extraction

A total of 73 articles were retrieved (35 from Web of Science, 26 from PubMed, and 12 from Embase). After filtering out duplicate case reports (n = 50), reports unrelated to Kounis syndrome (n = 17), and studies that were not case reports (n = 31), 13 case reports comprising 15 patients were eventually included (Figure 1).

Figure 1. Flowchart of prisma used for study selection.

We extracted relevant patient information, including age, sex, region, past medical history, vaccine type, number of vaccine doses, time of onset after vaccination, clinical presentation, examination results (including ECG, coronary angiography, cardiac enzymology, and echocardiography), and treatment.

Results

Basic information

A total of 15 patients who developed Kounis syndrome after COVID-19 vaccination were included in the study. The details are summarized in Table 1. Most of the 15 patients were from Asia and Europe (four from India; two from Turkey; two from China; and one each from Portugal, Italy, Sri Lanka, Kuwait, and Poland), with two patients from the United States, with an average age of 59 years. Seven patients received the Oxford-AstraZeneca AZD1222 COVID-19 vaccine, 4 patients received the Pfizer-BioNTech mRNA vaccine, 3 patients received the Sinovac Life Sciences Beijing vaccine, and 1 patient received the Moderna COVID-19 vaccine. Twelve patients experienced symptoms after the first dose of the vaccine, 2 patients experienced symptoms after the second dose, and only one patient experienced symptoms after the third dose. Eleven patients had past medical histories of cardiac (including angina and heart disease), allergic, or chronic conditions (including hypertension and diabetes).

Table 1. Basic information of the 15 included patients.

Reference	Year/ Region	Age/ Gender	Past medical history	Vaccine type/times	Time of onset after vaccination	Clinical presentation	Treatment	Outcome	Course of disease
Özdemir İ H et al.^Citation16	2021/Turkey	41/F	None	Sinovac Life Sciences, Beijing, China/1^st	15 minutes	Flushing, palpitation, lip and tongue swelling, shortness of breath, and chest pain, erythematous appearance in face and edema in lips and uvula	Intravenous pheniramine maleate 4.5 mg, dexamethasone 8 mg, oxygen treatment, continuous salbutamol by nebulizer, and epinephrine 0.5 mg intramuscular in the ED. Then aspirin, oral antihistamines, diltiazem, and corticosteroid for 4 days.	Recovery	4–7 days
Allam C et al.^Citation37	2022/USA	64/M	None	Pfizer-BioNTech mRNA vaccine/1^st	15 minutes	Chills, chest pain, pallor, diaphoresis, hypotension, multiple episodes of pulseless ventricular tachycardia and ventricular fibrillation	Electrical defibrillation, aspiration thrombectomy, balloon angioplasty, intracoronary tirofiban injection and an implantable cardioverter-defibrillator.	Recovery	1 month
Fialho I et al.^Citation38	2022/Portugal	59/M	Rheumatoid arthritis, atrial fibrillation and a former smoker	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/1^st	20 minutes	Pale, sweaty, and had a discrete micropapular rash on chest	A balloon dilatation, an implantable drug-eluting stent, antiplatelet therapy, oral anticoagulation, clopidogrel 75 mg and rivaroxaban 20 mg.	Recovery	4 months
Minciullo PL et al.^Citation39	2021/Italy	54/F	Previous adverse reactions to iron therapy and acetylsalicylic acid	Pfizer-BioNTech mRNA vaccine/1^st	10 minutes: general discomfort, visual changes, and pharyngeal itching. 2 hours: dyspnea, confusion, tachycardia and hypotension.		Polygeline iv, hydrocortisone iv, chlorphenamine, methylprednisolone, oxygen therapy, and two consecutive administrations of adrenaline iv (0.5 mg × 1 mL).	Recovery	4 days
Farook AM et al.^Citation40	2021/Sri Lanka	54/F	Hypertension, ischemic heart disease stable angina, bronchial asthma on inhalers and allergies	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/1^st	15 minutes	Severe anaphylactic reaction: generalized urticaria, shortness of breath, nausea, severe vomiting, and in anaphylactic shock with diffuse rhonchi in the lungs bilaterally	Intramuscular 1:10,000 adrenaline, oxygen inhalation, antiallergy treatment (intramuscular promethazine hydrochloride 25 mg, intravenous hydrocortisone), fluid resuscitation, epinephrine infusion, and dobutamine hydrochloride (15 µg/kg/minute) via intravenous pump along with moderate rehydration therapy	Recovery	7 days
Deng Y et al.^Citation41	2022/China	43/F	4 pregnancies (1 live birth and 3 abortions), previous adverse reactions to beer and tetanus vaccination	Sinovac Life Sciences, Beijing, China/3^th	30 minutes: generalized itch, accompanied by shortness of breath, nausea, and severe vomiting. 40 minutes: suffocating and crushing pain associated with sweating and cold limbs. 60 minutes: chest tightness and pain in the precordial region		Anti-allergic, anti-shock, and management of acute myocardial ischemia, including methylprednisolone, aspirin, clopidogrel, atorvastatin, low molecular weight heparin calcium subcutaneous injection, pantoprazole, nitroglycerin infusion, and maintenance of water-electrolyte acid-base balance.	Recovery	17 days
Şancı E et al.^Citation42	2022/Turkey	22/F	Previous egg and tomato allergy	Pfizer-BioNTech mRNA vaccine/1^st	15 minutes	Palpitations, uneasiness of the chest, shortness of breath and chest pain	Asetil salisilic acid 300 mg, pheniramine maleate 45.5 mg, and dexametasone 8 mg	Recovery	5 minutes
Maadarani O et al.^Citation43	2021/Kuwait	62/F	Diabetes mellitus, hypertension and dyslipidaemia	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/1^st	1.5 hours	Central chest pain radiated to left shoulder and neck and associated with fascial numbness.	Dual antiplatelet, heparin, drug eluting stent, and thrombolysis In Myocardial Infarction III flow	Recovery	3 days
Chatterjee S et al.^Citation44	2021/India	63/M	None	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/1^st	42 hours	Chest pain, uneasiness, dizziness and excessive sweating	Thrombolysed with 1.5 million IU streptokinase, anti-platelets, and anti-anginal drugs	Recovery	>5 days
Boivin Z et al.^Citation45	2021/USA	96/F	Hypertension	Moderna COVID-19 vaccine/1^st	1 hour	Chest discomfort	Heparin drip	Recovery	3 days
Tajstra M et al.^Citation46	2021/Poland	86M	Prostate cancer, paroxysmal atrial fibrillation	Pfizer-BioNTech mRNA vaccine/1^st	30 minutes	Collapsed, unconscious, cardiogenic shock, and recurrent bradyarrhythmias	Primary percutaneous coronary intervention of the right coronary artery with manual aspiration thrombectomy, coronary balloon angioplasty and glycoprotein IIb/IIIa receptor inhibitor(eptifibatide) administration	Died	3 days
Ou W et al.^Citation47	2022/China	83/M	Subtotal gastrectomy and cholecystectomy	Sinovac Life Sciences, Beijing, China/1^st	10 minutes: cold sweat, dizziness, fatigue and transient loss of consciousness. 24 hours: chest tightness, diarrhea and a lowest blood pressure		Thrombus aspiration, two implantable drug-eluting stents accompanied by oral drugs(aspirin, ticagrelor, atorvastatin, metoprolol), an inplantable DES and a drug-coated balloon into the OM and d-LCX respectively	Recovery	7 days
Srinivasan KN et al.^Citation48	2021/India	46/M	Diabete, hypertension	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/2^nd	12 days	Difficulty in breathing and acute persistent cough	Adhoc percutaneous coronary intervention (PCI) to RCA and proximal LAD	Recovery	2 days
		48/M	Branch vessel coronary artery disease (CAD) treatment for 3 years	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/2^nd	6 days	Severe chest pain associating cough and sweat	Adhoc primary PCI to LAD	Recovery	2 days
		75/F	Unknown	Oxford-AstraZeneca AZD1222 COVID-19 vaccine/1^st	1 day	Central chest blocking sensation with profuse sweating	Anti-platelets, statins and anti-anginal drugs	Recovery	< 1 day

Abbreviations: DES, drug-eluting stents; d-LCX, distal Left circumflex artery; ED, emergency department; F, female; LAD, Left Anterior descending artery; M, male; USA United States of America of America; OM, obtuse marginal branch; RCA, right coronary artery.

Clinical characteristics

The clinical presentations and major characteristics of the 15 patients are summarized in Table 2. The time between vaccination and the onset of symptoms ranged from 15 minutes to 12 days, with a median of 40 minutes. Patient onset can be divided into systemic and localized types. Four patients had systematic onset, including discomfort and itch. The localized onsets are as follows: 11 patients presented with chest pain, tightness, and discomfort; 6 patients presented with sweating; 5 patients presented with respiratory symptoms, including shortness of breath, dyspnea and cough, accompanied by heart rate changes with uncertain direction of heart rate variability (4 patients) and blood pressure decreases (3 patients); 3 patients presented with shock; 2 patients presented with skin changes, with discrete micropapular rash on the chest and flushing in 1 patient each; and 2 patients presented with nausea and vomiting.

Table 2. Patients from respective case reports included in the research.

Reference	ECG	Coronary angiography	Cardiac Enzymology	echocardiography
Özdemir İ H et al.^Citation16	Poor R wave progression in precordial leads, V4–6 T wave inversion, and fragmented QRS in aVL	No sign of coronary atherosclerosis	Troponin-I estimated on arrival was 0.068 ng/mL (reference: < 0.023 ng/mL), creatine kinase-MB fraction was 5.01 ng/mL (reference: < 4.88 ng/mL)	Posterior and apicolateral wall hypokinesia with a left ventricular ejection fraction (LVEF) of 55%
Allam C et al.^Citation37	ST-segment elevation in the anteroseptal precordial leads	Stent thrombosis in the proximal segment of the LAD and TIMI grade 0 flow	None	Anterior and apical akinesis with an estimated left ventricular ejection fraction of 30%, which did not improve on follow-up.
Fialho I et al.^Citation38	Sinus rhythm, pathological q waves and t wave inversion in V2-V5 leads and ST segment elevation in II, III, and aVF leads	Right coronary stent thrombosis	A high-sensitivity troponin T of 60 ng/L (upper limit 14 ng/mL), a creatine kinase of 32 U/L (upper limit 308 U/L), N-terminal prohormone of B-type natriuretic peptide of 4,455 pg/mL (upper limit 210 pg/mL). After admission the peak high-sensitivity troponin T value was 7,795 ng/L and peak creatine kinase value was 1,271 ng/L 12 hours.	Severe left ventricular dysfunction
Minciullo PL et al.^Citation39	ST segment depression in V3–V4 leads	No evidence of coronary artery obstruction or plaque rupture	All normal	Lower and lateral akinesia
Farook AM et al.^Citation40	Sinus rhythm, ST-segment elevation in leads I, II, and aVL ST-segment depression and T-wave inversion in leads III and V1–V4	None, because of a history of severe anaphylaxis to contrast agents	Serum cardiac troponin I (cTnI) level was 17.61 ng/ml (<0.5), and IgE levels were elevated at 895.7/IU/ml	Left ventricular global systolic dysfunction with a left ventricular ejection fraction of 35%. And all motion abnormalities, namely a segmental hypokinesia in the lateral wall and inferior wall
Deng Y et al.^Citation41	Sinus rhythm, ST-segment elevation in leads I, II, and avL, and ST-segment depression and T-wave inversion in leads III and V1-V4	None, because of high risk of an allergic reaction to the contrast agent	Serum cardiac troponin I (cTnI) level was 0.12 ng/mL (normal range, 0–0.028 ng/mL) and creatine kinase-MB (CK-MB) was 16.37 ng/mL (normal range, 0–25 U/L)	Left atrial enlargement and left ventricular global systolic dysfunction with left ventricular ejection fraction (LVEF) of 29.1%.And wall motion abnormalities namely a segmental hypokinesia in the lateral wall of left ventricle in the apical four-chamber view, suggesting the presence of anterior descending diagonal branch lesion.
Şancı E et al.^Citation42	Sinus tachycardia, ST-segment elevations in the inferior and anterior derivations	Unknown	Troponin-I was 0.003 ng/mL (reference: <0.016 ng/mL)	No abnormalities
Maadarani O et al.^Citation43	ST elevation in inferior leads (II, III and AVF) and reciprocal ST segment depression in lead I and AVL	A critical stenosis of middle segment of right coronary artery	High-sensitivity cardiac troponin T test (hs-cTnT) : 40 ng/l (normal <15 ng/l), with a peak of 200 ng/L	Inferior wall motion abnormality and preserved systolic function of left ventricle.
Chatterjee S et al.^Citation44	ST elevation in leads II, III and aVF, suggestive of acute ST elevated inferior wall myocardial infarction (STEIWMI).	Unknown	Serum creatine kinase-MB (CK-MB) and cardiac troponin-I (cTnI) were > 150 IU/L (n, <9) and 49.28 ng/ml (n < 0.04) respectively	Inferior wall hypokinesia with left ventricular ejection fraction of 50%
Boivin Z et al.^Citation45	ST segment elevation in the inferior leads with reciprocal ST segment depression in the lateral leads	Patient refused to be examined	Initial troponin was 0.07 ng/mL, with a peak of 2.63 ng/mL	An ejection fraction of 35%, and an anterior and apical wall motion abnormality consistent with an anterior myocardial infarction (MI)
Tajstra M et al.^Citation46	Acute ST-segment elevation myocardial infarction of the inferior wall	Occlusions or distal embolization in the distal part of the left anterior descending coronary artery, in the first diagonal branch, and in the distal part of the dominant right coronary artery, with large thrombus	None	None
Ou W et al.^Citation47	ST segments elevation in leads II, III and avF, with reciprocal depression in leads I and avL	95% stenosis in the right coronary artery (RCA) with thrombotic shadow locally, 80% stenosis in the left anterior descending coronary artery, 70%–80% stenosis in the distal left circumflex coronary artery (d-LCX), and 80%–90% stenosis in the obtuse marginal branch (OM)	High sensitivity troponin-T level more than 2,000 (reference: 0–100) ng/L, myohemoglobin 291 (reference: 28–72) ng/ml, creatine kinase (CK) 2771.7 (reference: 50–310) U/L, CK-MB fraction 348.2 (reference: 0–19) U/L, D-dimer 1.09 (reference: 0–0.55) mg/L, and N-terminal pro-brain natriuretic peptide 1,770 (reference: 0–125) pg/ml	Hypokinesia on the inferior and posterior walls, with a left ventricular ejection fraction of 54%
Srinivasan KN et al.^Citation48	Sinus rhythm (SR), and evolved infero-posterior wall myocardial infarction (IPWMI)	(TVD) (severe disease of left anterior descending artery (LAD), distal left circumflex(dLCX) and 100% occlusion of distal right coronary artery (dRCA))	Troponin-T tested positive	Mild left ventricular hypertrophy (LVH), regional wall motion abnormality (RWMA) involving infero-posterolateral wall with left ventricular ejection fraction(LVEF)of 55%
	SR 142/min with ST elevation in V1eV2, avR with qR in lead I and avL	Double vessel disease (DVD): The culprit vessel LAD had thrombus containing 95% proximal stenosis and distal LCX had 70% lesion	None	RWMA involving mid anterior wall, mild to moderate LV dysfunction, LVEF-45%, mild mitral regurgi tation (MR)
	SR, 62/min, ST elevation with qR in lead II, III & avF (IWMI)	TVD with 100% occlusion of postero-lateral branch (PLB), moderate disease of LAD and severe disease of small 1st branch of obtuse marginal (OM1)	Troponin T: positive	RWMA involving basal inferior wall and inferior septum with mildly impaired LV function, LVEF-55%, 2þ MR

Imaging results

The imaging results are shown in the table. Coronary angiography revealed vascular disease in seven of the 15 patients (3 patients with both thrombus and stenosis, one patient with stenosis, and one patient with thrombus). Of the other 8 patients, 3 had unknown angiographic results, 2 did not undergo angiography examination because of allergies, 2 had normal results, and 1 had a stent. Echocardiography revealed cardiac dysfunction or ventricular wall motion abnormalities in 13 patients.

Nonimaging results

Nonimaging examinations included electrocardiography and cardiac enzymology. None of the 15 patients presented with nonsinus arrhythmias, and sinus tachycardia was observed in only 1 patient. In addition, 14 patients showed ST-segment changes, which varied from lead to lead. T-wave inversions with QRS waveform changes were observed in 4 patients. In the myocardial enzymology tests, we collected data on cardiac troponin-I and troponin-T levels and creatine kinase-MB fractions. All recorded results from these tests were positive, indicating significant myocardial involvement.

Treatment and recovery

Treatments included pharmacological and nonpharmacological treatments. Of the patients who received pharmacological treatment, antithrombotic drugs were used in 12 patients (antiplatelet drugs in 7 patients and anticoagulants in 5 patients); antiallergic drugs were used in 5 patients; hormones were used in 5 patients; and cardiac-related medications were used in 5 patients, including medications for angina pectoris in 3 patients and myocardial infarction in 2 patients. The remaining drugs can be categorized as lipid-lowering drugs, antihypertensive drugs or antipyretic and analgesic drugs. The mode of administration of the 15 patients included intramuscular, intravenous, drug-coated balloon and implantable drug-eluting stent administration.

Nine of the fifteen patients received nonpharmacological treatments, and some patients received several treatments at the same time. Of the 9 patients, 4 underwent balloon dilatation, 3 underwent aspiration thrombectomy, 3 received oxygen therapy, and 3 underwent percutaneous coronary intervention (PCI), with the remaining six patients not receiving nonpharmacological related treatments.

Of the 16 patients, 15 were successfully cured, and one died; the median course of disease was approximately 5 days.

Discussion

The release of allergic mediators induces coronary vasoconstriction and thrombosis, which can lead to further myocardial damage and acute coronary syndrome associated with anaphylaxis, known as Kounis syndrome,^19,20 which is classified into 3 types: type I Kounis syndrome is characterized by coronary artery spasm with normal coronary arteries but no contributing cause of coronary artery disease; type II Kounis syndrome is characterized by atheromatous plaque rupture or coronary spasm with a preexisting atheromatous disease; and type III Kounis syndrome is characterized by stent thrombosis^21,22 (Figure 2). Kounis syndrome following COVID-19 vaccination is rare. As of October 2023, 68158,988 global COVID-19 vaccination doses have been administered, and we identified only 15 cases that met the criteria, although there is a possibility of incomplete case reporting. This finding is sufficient to support the rarity of Kounis syndrome among such a large number of vaccination doses.

Figure 2. Schematic mechanism of kounis syndrome induced by COVID-19 vaccination.

To better discuss the Kounis syndrome-related cases, we summarized the basic case information and presenting symptoms. The majority of the patients were from Asia and Europe, and there was no significant correlation between the onset of Kounis syndrome and sex. According to the available cases, Kounis syndrome occurred after the first, second or booster doses of the COVID-19 vaccine but mainly developed after the first dose of the vaccine. Near half of the vaccines administered to the 15 patients were non‐replicating adenovirus vector‐based DNA vaccine. Most patients developed clinical manifestations associated with Kounis syndrome within 2 hours of vaccination and progressed rapidly.

As shown in Figure 2, Kounis syndrome patients present with clinical manifestations of intense allergic reactions, including generalized itching, dyspnea, sweating and general malaise.²³ Inflammatory mediators released during anaphylactic injury, postinflammatory cellular activation, and multidirectional stimulus interactions are the main causative factors of Kounis syndrome.²⁴ Inflammatory mediators include histamine, neutral proteases, platelet-activating factor, arachidonic acid products, and a variety of cytokines and chemokines released during allergic activation, and inflammatory cells include interconnections and interactions among mast cells, macrophages, and T lymphocytes.^25,26 Since 20% of the platelet subpopulation with high- and low-affinity IgE surface receptors are involved in this process, Kounis syndrome is not a single-organ disease but a multisystemic and multiorgan arterial clinical condition that may affect the skin, respiratory system and so on.²⁴ In addition to allergic symptoms, the patients presented with signs of acute coronary syndrome, including chest tightness, precordial pain, and restlessness. The heart, especially the coronary arteries, may be the main target of allergic inflammatory mediators;²⁵ the release of these mediators can lead to coronary artery spasm or induce further coronary artery damage, such as plaque rupture,²⁷ resulting in elevated cardiac troponin levels and causing the cardiac symptoms described above.²⁸ Notably, most patients had hypotension-related manifestations, which may have been caused by the combination of allergic reactions and myocardial injury factors²⁹ (Figure 2).

The examinations commonly used to diagnose Kounis syndrome are electrocardiogram (ECG), cardiac enzyme analysis, coronary angiography, and echocardiogram. The clinical ECG manifestations in patients with Kounis syndrome are ST-segment changes, and laboratory tests are positive for troponin. In addition, in most patients, echocardiographic findings suggest abnormal ventricular wall motion; the degree of reduced ejection function varies depending on disease progression. Most patients who underwent coronary angiography had thrombi or coronary stenosis. Coronary angiography results were missing in a total of five cases in this article: two patients did not undergo the test due to contrast allergy, one patient refused to undergo the test, and the reason for missing coronary angiography results in the remaining two cases was unknown. All of the above abnormalities may be associated with myocardial injury and myocardial infarction due to allergic reactions. In addition, ECG findings such as arrhythmias, elevated or depressed ST segments, any degree of cardiac block,²⁵ and a variety of electrocardiographic changes may be associated with the cardiac symptoms of Kounis syndrome.³⁰ In terms of laboratory findings, in addition to cardiac troponin, increases in serum tryptase, histamine, and cardiac biomarkers are particularly useful findings.^24,27

Both cardiac and allergy treatments are recommended for the treatment of Kounis syndrome; however, the drugs for cardiac manifestations can exacerbate allergies, while the drugs for allergic symptoms can exacerbate cardiac insufficiency.³¹ Treatment of acute coronary syndrome due to Kounis syndrome caused by COVID-19 vaccination should follow the existing guidelines based on ECG criteria, as no specific recommendations are currently available. For the different subtypes of Kounis syndrome, the appropriate treatment depends on the symptoms.³² In type I subtype, coronary vasospasm can be relieved by vasodilators such as calcium chloride channel inhibitors³³ (diltiazem was used in the present study) and nitrates. Other signs of hypersensitivity, such as asthma and skin rashes, can facilitate the recognition of an anaphylactic reaction at an early stage and lead to the judicious administration of corticosteroids³³ such as hydrocortisone and antihistamines such as diphenhydramine; both drug classes were widely used in the cases reported here. In type II Kounis syndrome, treatment consists of an acute coronary event regimen as well as corticosteroids and antihistamines; in patients with type III Kounis syndrome, treatment includes the current acute myocardial infarction regimen; urgent aspiration of in-stent thrombus; and the use of antihistamines, corticosteroids, and mast-cell stabilizers if necessary.^21,33

In summary, Kounis syndrome is a rare and serious adverse reaction that occurs after vaccination for COVID-19.³⁴ In this paper, a review of vaccination-related Kounis syndrome was conducted using the known cases. The specific etiology and pathway mechanisms of Kounis syndrome caused by the COVID-19 vaccine deserve further investigation. Considering the difficulty in confirming the diagnosis of Kounis syndrome in some patients,³⁵ as well as the small number of patients who were diagnosed but not reported, our study was not able to include all of the patients who developed Kounis syndrome after vaccination, so the statistical results have some limitations. In addition, the number of patients with Kounis syndrome is very small compared to the number of vaccinated patients, and a definitive association between vaccination and Kounis syndrome still needs to be confirmed by additional case‒control and direct experimental tests. However, given the symptoms of COVID-19, vaccination remains an encouraging option for susceptible populations despite the potential associated rare complications, such as Kounis syndrome.³⁶

Conclusion

In this article, we reviewed patients with Kounis syndrome that developed after COVID-19 vaccination and explored the possible underlying mechanisms involved. Early diagnosis and clinical symptomatic treatment are particularly crucial for managing the severity of Kounis syndrome and preventing further cardiac complications, and patients who develop abnormal and severe allergic reactions within hours of vaccination should be closely monitored for cardiac-related symptoms and clinically prepared for possible Kounis syndrome.

Author contribution

Chengjie Zhao and Ruoyan Lei contributed equally as the first authors. Mingyi Zhao contributed as a correspondence author. Siyang Liu contributed as an ordinary author. Mingyi Zhao, Chengjie Zhao, and Ruoyan Lei designed the study, Chengjie Zhao, Ruoyan Lei, and Siyang Liu carried out the manuscript searches and participated in data processing; Mingyi Zhao contributed to polishing articles, Chengjie Zhao, Ruoyan Lei, Siyang Liu and Mingyi Zhao revised the manuscript. All authors agree to be accountable for all aspects of the work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated in this article are included in the paper and supplementary materials.

Additional information

Funding

This study was funded by the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University [YX202212].