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Angina and Arrhythmia Symptoms Following Multiple Bee Stings: Kounis Syndrome

Published:September 12, 2022DOI:https://doi.org/10.1016/j.wem.2022.06.003
      Kounis syndrome (KS) is an acute coronary syndrome including coronary spasm, acute myocardial infarction, and stent thrombosis preceded by an anaphylactic, anaphylactoid, allergic, or hypersensitivity injury. In this case presentation, we discussed Type I and Type II KS. Case 1 was a 72-y-old man who presented to the emergency department with allergic symptoms and chest pain that developed after multiple bee stings. Electrocardiography showed ST depression in the lateral leads. Case 2 was a 42-y-old woman who presented to the emergency department with complaints of chest pain, dizziness, and presyncope that developed after multiple bee stings. Mobitz Type II Block with right bundle branch block was observed in 42 beats·min-1 in the electrocardiography. Both patients were first treated for allergic reaction. Although early percutaneous coronary intervention was performed for graft thrombosis in Case 1, a permanent pacemaker was inserted in Case 2. The patients were discharged without any complications. Increasing physician awareness towards the existence of KS can prevent fatal outcomes with early diagnosis and treatment.

      Keywords

      Introduction

      Defined as the emergence of acute coronary syndrome in an allergic hypersensitivity or anaphylactic state, Kounis syndrome (KS) is a life-threatening medical emergency. It is thought that platelet activation, which leads to the degranulation of mast cells and releasing of multiple inflammatory mediators, makes arterial circulation susceptible to acute cardiac events. Vasospastic allergic angina (Type I), allergic myocardial infarction (Type II), and stent thrombosis forming an obstructive thrombus caused by eosinophils and/or mast cells (Type III) are the 3 variants of this syndrome that have been reported so far.
      • Kounis N.G.
      Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management.
      Various causes have been found to trigger KS, and their number is increasing rapidly. Various types of food, drugs, environmental exposures, and insect bites are the most frequently reported causes.
      • Kounis N.G.
      Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management.
      Bee venom is also one of the triggers. Although cardiovascular events after bee sting are mostly described as related to anaphylactic shock, some reports highlight that bee venom causes myocardial infarction with a direct effect on the heart and coronary circulation.
      • Puvanalingam A.
      • Karpagam P.
      • Sundar C.
      • Venkatesan S.
      • Ragunanthanan
      Myocardial infarction following bee sting.
      • Scherbak D.
      • Lazkani M.
      • Sparacino N.
      • Loli A.
      Kounis syndrome: a stinging case of ST-elevation myocardial infarction.
      • Puttegowda B.
      • Chikkabasavaiah N.
      • Basavappa R.
      • Khateeb S.T.A.
      Acute myocardial infarction following honeybee sting.
      In this study, we present patients with Type I and Type II KS with electrocardiography (ECG) changes and heart block after multiple bee stings.

      Case Presentation

      CASE 1

      A 72-y-old man was admitted to the emergency service of another hospital with allergic symptoms after multiple bee stings. He had a history of coronary artery bypass grafting in 2016 and surveillance angiography in 2019, which found the circumflex artery was 95% occluded. A bare metal stent was applied to the circumflex artery in the same session. Since the stent insertion in 2019, the patient had been using daily ramipril (5 mg), acetylsalicylic acid (100 mg), metoprolol (50 mg), clopidogrel (75 mg), and atorvastatin (40 mg), and his coronary artery disease had been stable for the last 2 y. The patient had no known allergic disease.
      After the patient’s admission following the multiple bee stings, intravenous prednisolone, diphenhydramine, and ranitidine were administered to the patient in the emergency service for widespread urticarial rash and itching that developed from multiple bee stings.
      After the allergic treatment, rashes and itching improved. Chest pain radiating to the left arm started approximately 1 h after the bee sting. Thereupon, the patient was transferred by ambulance to our emergency department for further examination and treatment. Vital signs at the time of arrival to our emergency department were as follows: temperature 36.2°C, blood pressure 145/80 mm Hg, heart rate 85 beats·min-1, respiratory rate 21 breaths·min-1, and SaO2 98% (in room air). In physical examination, there was diffuse hyperemia in the body. There was no urticarial rash or uvular edema, and lung sounds were normal. An ECG showed ST segment depression in the lateral leads. The burning sensation in his chest persisted. The high sensitivity troponin I value taken approximately 2 h after the bee sting was 1544 ng·L−1 (normal range 0–16 ng·L−1) and CKMB value was 27.5 μg·L−1 (normal range 0.6–6.3 μg·L−1). Other laboratory parameters (metabolic panel and blood counts) were normal.
      The patient was hospitalized in the coronary intensive care unit and coronary angiography was performed. Coronary angiography revealed thrombosis in the bypass graft (aorta–saphenous vein graft–obtrusive marginal arteries). Percutaneous coronary intervention was successfully performed in the same session as coronary angiography. The patient was diagnosed with Type II KS. The patient was followed in the hospital for 4 d and was discharged without any complications.

      CASE 2

      A 42-y-old woman with no known disease other than asthma and hypertension was brought to our emergency department by ambulance with complaints of chest pain in her left arm, dizziness, and presyncope that developed within 1 h after multiple bee stings. The patient had no known allergic disease. The patient had no symptoms until the bee sting and was performing normal activities. Her vital signs at the time of admission to the emergency service were as follows: temperature 36.4°C, blood pressure 120/80 mm Hg, heart rate 42 beats·min-1, respiratory rate 21 breaths·min-1, and SaO2 98% (in room air). In physical examination, there was widespread hyperemia in the body. Urticarial plaques and uvula edema were absent, and lung sounds were normal. Intravenous prednisolone and diphenhydramine were administered to the patient in the emergency service for the allergic reaction. Mobitz Type II Block with right bundle branch block was observed in 42 beats·min-1 in the ECG. The high sensitivity troponin I value taken approximately 90 min after the bee sting was 941 ng·L−1 (normal range 0–16 ng·L−1) and CKMB value was 6.9 μg·L−1 (normal range 0.6–6.3 μg·L−1). Other laboratory parameters (metabolic panel and blood counts) were normal. The patient was evaluated as non-ST elevation myocardial infarction. The patient, to whom a transcutaneous pacemaker was implanted in the first intervention in the emergency service for symptomatic bradycardia, was transferred to the coronary intensive care unit. During the coronary intensive care follow-ups, the patient continued to have symptomatic bradycardia. A permanent pacemaker was implanted approximately 24 h later, and coronary angiography was performed in the same session. The patient, whose angiography was reported as normal coronary and in whom Type I KS was considered, was discharged without any complications after 5 d of follow-up and treatment.

      Discussion

      KS is the concurrence of hypersensitivity disease with acute coronary syndrome after exposure to drugs, foods, environmental factors, and other triggers.
      • Abdelghany M.
      • Subedi R.
      • Shah S.
      • Kozman H.
      Kounis syndrome: a review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome.
      The prevalence of KS, which was defined as “allergic angina syndrome” in 1991,
      • Kounis N.G.
      • Zavras G.M.
      Histamine-induced coronary artery spasm: the concept of allergic angina.
      is estimated to be 1% among patients hospitalized for allergic reactions in the United States.
      • Desai R.
      • Parekh T.
      • Patel U.
      • Fong H.K.
      • Samani S.
      • Patel C.
      • et al.
      Epidemiology of acute coronary syndrome co-existent with allergic/hypersensitivity/anaphylactic reactions (Kounis syndrome) in the United States: a nationwide inpatient analysis.
      It is thought that the release of vasoactive inflammatory mediators such as histamine, serotonin, proteases, and various cytokines following an allergic reaction, along with vasospasm, and platelet activation play a role in the pathogenesis of KS-related anginal symptoms.
      • Kounis N.G.
      • Zavras G.M.
      Histamine-induced coronary artery spasm: the concept of allergic angina.
      ,
      • Kounis N.G.
      Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm?.
      During the degranulation of mast cells, the release of histamine and arachidonic acid products such as leukotrienes, thromboxane, prostaglandins, tryptase, and chymase might lead to vasoconstriction of coronary arteries, plaque eruption, and platelet aggregation.
      • Kounis N.G.
      Coronary hypersensitivity disorder: the Kounis syndrome.
      With these mechanisms, 3 types of KS occur in patients.
      Type I KS is defined as coronary artery vasospasm that develops with acute release of inflammatory mediators because of the underlying anaphylactic reaction in patients with no obstructive coronary artery disease or predisposing factors for coronary artery disease. Coronary artery vasospasm may develop with or without progression to acute myocardial infarction and cardiac enzyme elevation.
      • Kounis N.G.
      Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management.
      Vasospasm causes temporary and excessive lumen narrowing of the epicardial coronary arteries and ultimately leads to the limitation—or even complete cessation—of coronary blood flow, leading to ischemia.
      • Armstrong P.W.
      Prinzmetal’s variant angina.
      Various complications can occur with coronary vasospasm including myocardial necrosis, syncope, arrhythmias (eg, ventricular tachycardia and complete AV block) and cardiac arrest.
      • Yasue H.
      • Mızuno Y.
      • Harada E.
      Coronary artery spasm-clinical features, pathogenesis and treatment.
      Because the right coronary artery supplies the AV nodal artery, its occlusion and/or vasospasm may lead to abnormalities of the AV conduction system.
      • Thakkar A.B.
      • Goldschlager N.
      Right coronary artery vasospasm presenting as complete atrioventricular block.
      Therefore, the most likely explanation for bradycardia in Type I KS may be vasospasm stemming from allergic causes in the right coronary artery due to the degranulation of mast cells. Coronary vasospasm or stenosis may be demonstrated by cardiac catheterization. However, spontaneous spasm during coronary arteriography is observed only incidentally in patients with findings suggestive of vasospastic angina. Therefore, provocative tests (intravenous or intracoronary ergonovine, intracoronary acetylcholine, etc.) can be applied to show the presence and type of coronary spasm.
      • Deligonul U.
      • Armbruster R.
      • Hailu A.
      Provocation of coronary spasm by dobutamine stress echocardiography in a patient with angiographically minimal coronary artery disease.
      Nevertheless, these tests are known to have a potential risk of arrhythmic complications, including ventricular tachycardia, ventricular fibrillation, and brady-arrhythmias.
      • Bertrand M.E.
      • LaBlanche J.M.
      • Tilmant P.Y.
      • Thieuleux F.A.
      • Delforge M.R.
      • Carre A.G.
      • et al.
      Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography.
      • Sueda S.
      • Ochi N.
      • Kawada H.
      • Matsuda S.
      • Hayashi Y.
      • Tsuruoka T.
      • et al.
      Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.
      • Otani T.
      • Mineoi K.
      • Kondou T.
      • Yano K.
      • Ochi T.
      • Ochi N.
      • et al.
      Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.
      Considering the associated risks, provocative testing is not performed on every patient. In Type I KS, the reversal of the inflammatory response is often sufficient to control coronary vasospasm. The patient in Case 2, who had no cardiac history, required permanent pacing for symptomatic bradycardia after bee sting. Possible Type I KS was considered in the patient whose coronary angiography was normal. Considering the associated arrhythmic risks during angiography, a provocative test was not applied to the patient to diagnose vasospasm. It is likely no signs of vasospasm were observed because the patient received treatment for an allergic reaction in the emergency service and coronary angiography was performed 24 h after the symptoms were relieved.
      Type 2 KS is the type in which mediators released after an allergic reaction induce coronary artery spasm and plaque erosion or rupture manifesting themselves as acute myocardial infarction in patients with underlying asymptomatic coronary artery disease. Echocardiography changes and elevated cardiac enzymes can be seen in patients with KS. The reported ECG changes include ST elevations
      • Puvanalingam A.
      • Karpagam P.
      • Sundar C.
      • Venkatesan S.
      • Ragunanthanan
      Myocardial infarction following bee sting.
      or depressions, heart block,
      • Gangadharan V.
      • Bhatheja S.
      • Al Balbissi K.
      Kounis syndrome - an atopic monster for the heart.
      and various cardiac arrhythmias.
      • Kounis N.G.
      Coronary hypersensitivity disorder: the Kounis syndrome.
      In Case 1, the patient—who had a history of coronary artery disease—developed ischemic chest pain, high cardiac troponin level, and ischemic ECG changes after multiple bee stings. Percutaneous coronary intervention was applied successfully to the patient who had thrombosis in the bypass graft in his coronary angiography. Acute myocardial infarction due to allergic reaction, which is Type II KS, was considered in the case.
      Type 3 KS is a subtype that includes patients with coronary artery stent thrombosis caused by an allergic reaction.
      • Kounis N.G.
      Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management.
      Stent components include the metal strut made from stainless steel containing nickel, chromium, manganese, titanium, and molybdenum, the polymer coating and the eluted drugs.
      • Kounis N.G.
      • Mazarakis A.
      • Tsigkas G.
      • Giannopoulos S.
      • Goudevenos J.
      Kounis syndrome: a new twist on an old disease.
      At the same time, post-stent patients must also use known allergens clopidogrel and aspirin.
      • Kounis N.G.
      • Mazarakis A.
      • Tsigkas G.
      • Giannopoulos S.
      • Goudevenos J.
      Kounis syndrome: a new twist on an old disease.
      Together, with these drugs, stent components (6 elements) act as antigens after environmental exposure, such as any drug or insect sting, and cause hypersensitivity inflammation. The stents attract inflammatory cells like a magnet and lead to KS and stent thrombosis inducing possible intracoronary mast cell degranulation.
      • Kounis N.G.
      • Mazarakis A.
      • Tsigkas G.
      • Giannopoulos S.
      • Goudevenos J.
      Kounis syndrome: a new twist on an old disease.
      The most common triggers of KS are antibiotics and insect bites, with 80% of cases occurring within the first hour after exposure to the trigger.
      • Abdelghany M.
      • Subedi R.
      • Shah S.
      • Kozman H.
      Kounis syndrome: a review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome.
      Bee venom is one of the most important triggers. Bee venom can generally cause local reactions (erythema, edema, itching, pain), local and systemic allergic reactions triggered by immunoglobulin E (urticaria, angioedema, bronchoconstriction, and anaphylactic shock), and severe systemic toxic reactions.
      • Prasad S.K.
      • Mehta S.K.
      • Satyanarayan B.
      • Panda S.K.
      Multi-organ dysfunction following honeybee bite-A rare entity.
      A single bee sting usually releases the pheromone isoamyl acetate, which attracts other bees and causes multiple stings.
      • Deshpande P.R.
      • Farooq A.K.
      • Bairy M.
      • Prabhu R.A.
      Acute renal failure and/or rhabdomyolysis due to multiple bee stings: a retrospective study.
      ,
      • Przybilla B.
      • Ruëff F.
      Insect stings: clinical features and management.
      Each sting releases approximately 140 μg of venom into the circulation.
      • Przybilla B.
      • Ruëff F.
      Insect stings: clinical features and management.
      The severity of serious systemic toxic reactions will generally depend on the amount of venom injected, which is correlated with the number of stings. Reported systemic toxic reactions from multiple bee stings are acute kidney injury,
      • Silva Junior G.B.
      • Vasconcelos Junior A.G.
      • Rocha A.M.
      • Vasconcelos V.R.
      • Barros Neto J.D.
      • Fujishima J.S.
      • et al.
      Acute kidney injury complicating bee stings – a review.
      acute myocardial infarction (KS),
      • Sunder A.
      • Mohanty B.
      • Singh A.
      Kounis syndrome: a rare case.
      cerebrovascular disease,
      • Elavarasi A.
      • Haq T.M.
      • Thahira T.
      • Bineesh C.
      • Kancharla L.B.
      Acute Ischemic Stroke Due to Multiple Bee Stings-A Delayed Complication.
      and death.
      In the pathogenesis of KS, apart from the allergic reaction, bee venom also plays an active role in cardiac side effects. Apitoxin (from Latin apis [bee] and Greek toxikon [poison]) can be dangerous because of its neurotoxic, allergic, cardiovascular, and renal effects.
      • Katsanou K.
      • Tsiafoutis I.
      • Kounis N.G.
      Timeo apis mellifera and dona ferens: bee sting-induced Kounis syndrome.
      Apitoxin (bee venom) consists of vasoconstrictors like adrenaline and noradrenaline, and vasodilators such as histamine. Histamine modulates inflammatory cells, activates platelets, and can lead to coronary vasoconstriction.
      • Kounis N.G.
      Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm?.
      In a study, intravenous injection of bee venom to mice caused cardiac noradrenaline elevation and acute myocardial infarction.
      • Guimaraes J.V.
      • Costa R.S.
      • Machado B.H.
      • dos Reis M.A.
      Cardiovascular profile after an intravenous injection of Africanized bee venom in awake rats.
      After the injection, transient reductions in heart rate and mean arterial pressure, and ECG changes similar to Bezold-Jarisch reflex, have been reported. Melittin, which consists of a complex mixture of proteins, 26 amino acids, phospholipids, sugars, and biogenic amines, etc.,
      • Raghuraman H.
      • Chattopadhyay A.
      Melittin: a membrane-active peptide with diverse functions.
      is the main active and most toxic component that makes up 50 to 60%
      • Katsanou K.
      • Tsiafoutis I.
      • Kounis N.G.
      Timeo apis mellifera and dona ferens: bee sting-induced Kounis syndrome.
      of bee venom (apitoxin). Melittin is the main pain-producing agent of bee venom, and its use has been associated with cardiac toxicity and cardiac hypersensitivity.
      • Okamoto T.
      • Isoda H.
      • Kubota N.
      • Takahata K.
      • Takahashi T.
      • Kishi T.
      • et al.
      Melittin cardiotoxicity in cultured mouse cardiac myocytes and its correlation with calcium overload.
      It is responsible for the release of catecholamines. Metalloproteinases mediate hypersensitivity reactions and are responsible for serious cardiac effects, including coronary vasospasm and plaque destabilization.
      • Greif M.
      • Pohl T.
      • Oversohl N.
      • Reithmann C.
      • Steinbeck G.
      • Becker A.
      Acute stent thrombosis in a sirolimus eluting stent after wasp sting causing acute myocardial infarction: a case report.
      Apamin is a polypeptide bee venom also responsible for cardiac side effects and has been associated with the blockade of calcium-dependent potassium channels. Binding tightly to slow calcium channels, it blocks the slow action potential of the heart muscle.
      • Bkaily G.
      • Sperelakis N.
      • Renaud J.F.
      • Payet M.D.
      Apamin, a highly specific Ca2+ blocking agent in heart muscle.
      In a study showing the effects of bee venom on the heart muscle of frogs, the poison has been shown to cause severe bradycardia and an increase in the P-R interval and R-wave amplitude.
      • Hussein A.
      • Nabil Z.
      • Zalat S.
      • Rakha M.
      Effect of the bumble bee ‘Bombus morrisoni’ venom on cardiac, skeletal and smooth muscle activity.
      In a study conducted on 152 honeybee bite patients, bradycardia was reported in <0.7% of patients.
      • Otani T.
      • Mineoi K.
      • Kondou T.
      • Yano K.
      • Ochi T.
      • Ochi N.
      • et al.
      Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.
      Bee stings usually cause temporary electrocardiographic changes, considering the local vasoactive, cardiotoxic, or anaphylactic effects found in their venom.
      • Puvanalingam A.
      • Karpagam P.
      • Sundar C.
      • Venkatesan S.
      • Ragunanthanan
      Myocardial infarction following bee sting.
      A permanent pacemaker has been required in some patients after a bee sting.
      • Gupta P.N.
      • Kumar B.K.
      • Velappan P.
      • Sudheer M.D.
      Possible complication of bee stings and a review of the cardiac effects of bee stings.
      Our Case 2 patient was exposed to high doses of apitoxin (bee venom) because of multiple bee stings. The bradycardia and heart block observed in the case may have developed as a result of coronary vasospam effect of bee venom melittin and the blocking effect of apamin on myocardial Ca+2 mediated potassium channels.
      The first step in KS management is to remove the victim from the trigger. Management in emergency service requires a multidisciplinary approach. The patient’s allergic symptoms may progress from local to severe systemic reactions. Although patients are being treated with intravenous fluids, steroids, and antihistamines, severe systemic reactions may require adrenaline or even cardiac resuscitation. In this case, the diagnosis of KS becomes difficult because of the treatment management focusing on the severity of acute allergic reactions. However, it should not be forgotten that the treatment differs. Although early percutaneous coronary intervention was performed for graft thrombosis in Case 1, a permanent pacemaker was inserted in Case 2 in the cardiac laboratory.

      Conclusion

      Bee venoms can be potentially fatal for humans due to allergic reactions and the cardiotoxic effects. Regardless of the severity of allergic reactions, additional complaints such as chest pain, syncope, and dizziness should be investigated by physicians. While treating the allergic reactions, it should not be forgotten that in KS, early cardiac intervention may be required.
      Author Contributions: Study concept and design (SA, MG, SS, CY, MSS); acquisition of data (SA, SS, CY); drafting the manuscript (SA, MG, SS, CY, MSS); critical revision of manuscript (SA); approval of final manuscript (SA, MG, SS, CY, MSS).
      Financial/Material Support: None.
      Disclosures: None.

      Supplementary data

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