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Kounis syndrome, cardiac arrest, allergy, anaphylaxis, coronary disease.
Kounis syndrome (KS) is a coronary syndrome in the setting of allergic/anaphylactic reactions and can be classified in three variants: vasospastic allergic angina (type I), allergic myocardial infarction (type II) and stent thrombosis (type III). The early diagnosis is of paramount importance for the correct management and the prognosis, being KS a life-threatening emergency condition. KS is not uncommon, but it is frequently unrecognized or undiagnosed in virtue of its broad clinical manifestations. The diagnosis should be based on the combination of cardiovascular and allergic/anaphylactic clinical symptoms and signs, as well as on laboratory, electrocardiographic, echocardiographic, and angiographic evidence. ECG monitoring, cardiac enzymes and troponin are mandatory to confirm or exclude KS in a patient with subclinical or clinical, acute or chronic allergic reactions. Nevertheless, the treatment is a real challenge for the emergency clinicians because guidelines have not been established yet, and the therapy is based on the variant type. We herein report the case of type I KS in a woman with no prior history of allergy, admitted to our emergency department for abdominal pain, nausea and hematochezia. Starting from this case we conducted a systematic search of the following databases: PubMed, Google Scholar, Science Direct, Medline, using the keywords of “Kounis syndrome”, “coronary spams”, “cardiac arrest”, “sudden death”, “allergy”, and “anaphylaxis”. The main purpose of this review is to remind emergency clinicians to keep a high index of suspicion regarding KS when dealing with patients with allergic reactions or anaphylaxis to promptly identify and correctly manage KS.
2. Nikolaidis LA, Kounis NG, Grandman AH - Allergic angina and allergic myocardial infarction: a new twist on an old syndrome. Can J Cardiol 2002;18:508-11.
3. Hangouche AJE, Lamliki O, Oukerraj L, et al. Kounis syndrome induced by oral intake of aspirin: case report and literature review. Pan Afr Med J 2018;30:301.
4. Viana-Tejedor A, Espinosa MÁ, Cuesta J, Núñez A, Bueno H, Fernández-Avilés F. Kounis syndrome secondary to amoxicillin use in an asthmatic patient. Int J Cardiol 2011;150(3):e113-5.
5. Leibee C, Getachew B, Ehmann MR. Vancomycin-induced Kounis Syndrome. Am J Emerg Med 2019;37:1806.
6. Kounis NG, Koniari I. Ampicillin/sulbactam-induced Kounis syndrome with cardiogenic shock. Anatol J Cardiol 2017;17:154-155.
7. Tambe V, Tambe A, Goodman A, Shepherd Z. Carboplatin-Induced Kounis Syndrome. Am J Ther 2020;27(6):e647-e652.
8. Vlahos NP, Vavilis GK, Giannelou AG, Georgopoulou CN, et al. Hypersensitivity to proton pump inhibitors: lansoprazole-induced Kounis syndrome. Int J Cardiol 2009;134(3):e94-6.
9. Canpolat U, Şahiner L, Aytemir K, Oto A. Allergic reaction to proton pump ınhibitor: pantoprazole induced Kounis syndrome. Int J Cardiol 2012;159(2):e27-8.
10. Kounis NG, Koniari I, Tsigkas G, et al. Gadolinium-induced Kounis syndrome including electrocardiographic considerations. Proc (Bayl Univ Med Cent). 2020;33:474-476.
11. van Ginkel AG, Sorgdrager BJ, de Graaf MA, Karalis I, Ajmone Marsan N. ST-segment elevation associated with allergic reaction to echocardiographic contrast agent administration. Neth Heart J 2013; 15:725-726.
12. Kounis NG, Koniari I, Tsigkas G, Davlouros P. Rectosigmoid ischemia and cerebral coma following gadolinium-induced anaphylaxis: A new manifestation of Kounis syndrome presented as devastating complication. Ann Ital Chir 2020;91:442-444.
13. Kounis NG, Koniari I, Soufras GD, Chourdakis E. Anaphylactic shock with methylprednisolone, Kounis syndrome and hypersensitivity to corticosteroids: a clinical paradox. Ital J Pediatr 2018;44(1):143.
14. Porcaro F, Paglietti MG, Diamanti A, et al. Authors' reply - anaphylactic shock with methylprednisolone, Kounis syndrome and Hypersitivity to corticosteroids: a clinical paradox. Ital J Pediatr 2019;45(1):5.
15. Okumura W, Nakajima M, Tateno R, Fukuda N, Kurabayashi M. Three cases of vasospastic angina that developed following the initiation of corticosteroid therapy. Intern Med 2014;53: 221-225.
16. Josefsson J, Fröbert O. Losartan-induced coronary artery spasm. BMJ Case Rep: pii: bcr2012006252, 2012.
17. Herrera-Lasso V, Dordal MT, Alonso G, Camprubí I, Lleonart R. Kounis Syndrome Due to Urapidil. J Investig Allergol Clin Immunol 2020 Sep 28:0.
18. Palacios-Zabalza I, Camino-Rodríguez E, Aguirre C. Kounis syndrome induced by ranitidine. Med Clin (Barc). 2018 Nov 9;151(9):e51-e53.
19. Rodrigues MC, Coelho D, Granja C. Drugs that may provoke Kounis syndrome. Braz J Anesthesiol 2013;63:426-8.
20. Kounis NG, Giannopoulos S, Soufras GD, Kounis GN, Goudevenos J. Foods, Drugs and Environmental Factors: Novel Kounis Syndrome Offenders. Intern Med 2015;54:1577-82.
21. Puttegowda B, Chikkabasavaiah N, Basavappa R, Khateeb ST. Acute myocardial infarction following honeybee sting. BMJ Case Rep 2014;2014:bcr2014203832.
22. Karadeniz M, Akyel A, Celik IE, Cankurt T, Barış VÖ, Murat SN. An unusual etiology of Kounis syndrome; warble fly. Indian Heart J 2013;65:358-9.
23. Cross B, Choudhury TR, Hindle M, Galasko G. Wasp sting induced STEMI with complete coronary artery occlusion: a case of Kounis syndrome. BMJ Case Rep 2017;bcr2017221256.
24. Ioannidis TI, Mazarakis A, Notaras SP, et al. Hymenoptera sting-induced Kounis syndrome: effects of aspirin and beta-blocker administration. Int J Cardiol;121:105-8.
25. Ng BH, Tan HX, Vijayasingham S. Kounis syndrome following solenopsis (fire ant) bite. Med J Malaysia 2019;74:344-346.
26. Katsanou K, Tsiafoutis I, Kounis NG. Timeo apis mellifera and dona ferens: bee sting-induced Kounis syndrome. Clin Chem Lab Med 2018;56:e197-e200.
27. Ralapanawa DM, Kularatne SA. A case of Kounis syndrome after a hornet sting and literature review. BMC Res Notes 2014;7:867.
28. Dogan V, Çelik O, Özlek B, et al. Allergic myocardial infarction: Type I Kounis syndrome following blue crab consumption. Acta Clin Belg 2019;74:375-377.
29. Vaina S, Chrysohoou C, Bonfanti L, et al. Anaphylactic cardiovascular collapse manifesting as myocardial infarction following salad consumption. A case of Kounis variant type I syndrome. Acta Biomed 2020;91:134-138.
30. Tzanis G, Bonou M, Mikos N, et al. Early stent thrombosis secondary to food allergic reaction: Kounis syndrome following rice pudding ingestion. World J Cardiol 2017;9:283-288.
31. Ridolo E, Martignago I, Senna G, Ricci G. Scombroid syndrome: it seems to be fish allergy but... it isn't. Curr Opin Allergy Clin Immunol 2016;16:516-21.
32. Mejía-Rentería HD, Viana-Tejedor A, Sánchez-Enrique C, et al. Kounis syndrome after ingestion of undercooked fish: new role of intracoronary imaging techniques. Int J Cardiol 2014;177:e58-60.
33. Guler Y, Kalkan S, Esen AM. An extremely rare trigger of Kounis syndrome: Actinidia chinensis. Int J Cardiol 2014;172:e324-5.
34. Chen JP, Hou D, Pendyala L, Goudevenos JA, Kounis NG. Drug-eluting stent thrombosis: the Kounis hypersensitivity-associated acute coronary syndrome revisited. JACC Cardiovasc Interv 2009;2:583-93.
35. Kounis NG, Koniari I, Roumeliotis A, et al. Thrombotic responses to coronary stents, bioresorbable scaffolds and the Kounis hypersensitivity-associated acute thrombotic syndrome. J Thorac Dis 2017;9:1155-1164.
36. Velasco E, Díaz E, Avanzas P, Rubín JM. Acute stent thrombosis due to Kounis syndrome. Int J Cardiol 2014;177:698-700.
37. Kounis NG, Soufras GD, Mazarakis A. Coronary stents attract like magnet inflammatory cells and induce stent thrombosis and Kounis syndrome. Turk Kardiyol Dern Ars 2013;41:180-1.
38. Raschi E, Fertonani Affini L, Antonazzo IC, Diemberger I, Poluzzi E, De Ponti F. Drug-induced Kounis syndrome: A matter of pharmacovigilance. Int J Cardiol 2019;274:381.
39. 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. Int J Cardiol 2017;232:1-4.
40. Biteker M, Duran NE, Biteker FS, et al. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr 2010;169:27–9.
41. Giovannini M, Alletto A, Koniari I, et al. Kounis Syndrome: a pediatric perspective. Minerva Pediatr 2020;72:383-392.
42. Biteker M, Duran NE, Biteker FS, et al. Kounis syndrome secondary to amoxicillin/clavulanic acid use in a child. Int J Cardiol 2009;136:e3-5.
43. Biteker M, Duran NE, Biteker FS, et al. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr 2010;169:27-9.
44. Tripathi S, Kulikowska A, Patel PM, Hassan NE. Acute Myocardial Ischemia Following Bee Sting in an Adolescent Male: A Case Report. Am J Case Rep 2020;21:e922120.
45. Terlemez S, Eryılmaz U, Tokgöz Y, Uysal P, Coşan A, Bulut Y. Kounis syndrome caused by metronidazole--a case of 14 year-old boy. Int J Cardiol 2015;179:222-4.
46. Ilhan E, Akbulut T, Gürsürer M. An underdiagnosed syndrome; Kounis syndrome secondary to amoxicillin/clavulanic acid use in a 16 year-old child. Int J Cardiol 2013;167:e90-1.
47. Ishikura M, Endo A, Sakamoto T, Tanabe J, et al. Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. Intern Med 2021;60:281-285.
48. Helbling A, Hurni T, Mueller UR, Pichler WJ. Incidence of anaphylaxis with circulatory symptoms: a study over a 3-year period comprising 940,000 inhabitants of the Swiss Canton Bern. Clin Exp Allergy 2004;34:285–90.
49. Renda F, Landoni G, Trotta F, et al. Kounis Syndrome: an analysis of spontaneous reports from international pharmacovigilance database. Int J Cardiol 2016;203:217–20.
50. Biteker M. Current understanding of Kounis syndrome. Exp Rev Clin Immunol 2010;6:777–88.
51. Pfister CW, Plice SG. Acute myocardial infarction during a prolonged allergic reaction to penicillin. Am Heart J 1950;40: 945–7.
52. Clark E. Serum carditis: morphologic cardiac alterations in man associated with serum disease. J Am Med Assoc 1938;110: 1098–100. Wadsworth GM, Brown CH. Serum reaction complicated by acute carditis. J Pediat 1940;17:801–5.
53. Rich AR, Gregory JE. Experimental evidence that lesions with basic characteristics of rheumatic carditis can result from anaphylactic hypersensitivity. Bull Johns Hopkins Hosp 1943;73:239–64.
54. Czickeli H. Contribution to the problem of the allergic etiology of angina pectoris and myocardial infarct. Klin Med Osterr Z Wiss Prakt Med 1950;5:364–7. 6. Schultheiss E. Clinical aspects of allergic heart diseases. Dtsch Med J 1964;15:15–8.
55. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991;45:121–8.
56. Constantinides P. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1083.
57. Brawnwald E. Unstable angina. An etiologic approach to management. Circulation 1998;98:2219–22.
58. Lippi G, Buonocore R, Schirosa F, Cervellin G. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. Int J Cardiol 2015;194:68–9.
59. Cha YS, Kim H, Bang MH, et al. Evaluation of myocardial injury through serum troponin I and echocardiography in anaphylaxis. Am J Emerg Med 2015.
60. Kounis NG. Coronary hypersensitivity disorder: the Kounis syndrome. Clin Ther 2013;35:563–71.
61. Galli SJ, Nakae S, Tsai M - Mast cells in the development of adaptive immune responses. Nat Immunol 2005;6:135-142. 7.
62. Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005;23:749-786.
63. Sedgwick JD, Holt PG, Tunner KJ. Production of a histamine releasing lymphokine by antigen - or mitogen-stimulated human peripheral T cells. Clin Exp Immunol 1981;45:409-418.
64. Miyazaki D, Nakamura T, Toda M, Cheung-Chau KW, Richardson RM, Ono SJ. Macrophage inflammatory protein-1a as a costimulatory signal for mast cell mediated immediate hypersensitivity reactions. J Clin Invest 2005;115:434–42.
65. Ishizaka T, Ishizaka K. Activation of mast cells for mediator release through IgE receptors. Prog Allergy 1984;34:188-235.
66. Liu MC, Proud D, Lichtenstein LM, et al. Human lung macrophage-derived histamine-releasing activity is due to lgE-depended factors. J Immunol 1986;136:2588-2595.
67. Genovese A, Spadaro G. Highlights in cardiovascular effects of histamine and H1-receptor antagonists. Allergy 1997;52(suppl 34):67-78.
68. Carl-McGrath S, Gräntzdörffer I, Lendeckel U, Ebert MP, Röcken C. Angiotensin II-generating enzymes, angiotensin converting enzyme (ACE) and mast cell chymase (CMA1), in gastric inflammation may be regulated by H. pylori and associated cytokines. Pathology 2009;41:419–27.
69. Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 1998;18:1707–15.
70. Kounis NG, Tsigkas G, Almpanis G, Kouni SN, Kounis GN, Mazarakis A. Anaphylaxis-induced hyperfibrinogenolysis and the risk of Kounis syndrome: the dual action of tryptase. Am J Emerg Med 2011;29:1229–30.
71. Kounis NG, Giannopoulos S, Tsigkas GG, Goudevenos J. Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome. Int J Cardiol 2012; 156: 125-132.
72. Saylan B, Cevik A, Firat C. Kounis syndrome, a cause of chest pain to keep in mind, may be associated with E148Q mutation. Hong Kong J Emerg Med 2012;19:278–82.
73. Kounis NG, Koniari I, Velissaris D, Tzanis G, Hahalis G. Kounis Syndrome — not a Single-organ Arterial Disorder but a Multisystem and Multidisciplinary Disease. Balkan Med J 2019;36:212-221.
74. González-de-Olano D, Alvarez-Twose I, Matito A, Sánchez-Muñoz L, Kounis NG, Escribano L. Mast cell activation disorders presenting with cerebral vasospasm-related symptoms: a “Kounis-like” syndrome? Int J Cardiol 2011; 150:210-211.
75. Goto M, Matsuzaki M, Fuchinoue A, et al. Chronic atherosclerotic mesenteric ischemia that started to develop symptoms just after anaphylaxis. Case Rep Gastroenterol 2012; 6:300-308.
76. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. Journal of Cerebral Blood Flow and Metabolism 2010; 30:689–702.
77. Davidson J, Zheng F, Tajima K, et al. Anaphylactic shock decreases cerebral blood flow more than what would be expected from severe arterial hypotension. Shock 2012; 38:429–35.
78. Peláez-Pérez JM, Sánchez Casado M, Álvarez-Twose I, Kounis NG. Amoxicillin-clavulanic acid-induced type II Kounis syndrome during general anaesthesia complicated with hypoxic-ischaemic encephalopathy. Rev Esp Anestesiol Reanim 2021;68:161-164.
79. Anastogiannis H, Litsardopoulos P, Anastopoulou GG, et al. Irreversible diffuse hypoxic-ischemic encephalopathy, secondary to type I Kounis syndrome. Int J Neurosci 2020;130:746-748.
80. Erxun K, Wei L, Shuying Q. Kounis syndrome caused by chronic autoimmune urticaria: A Case Report. J Emerg Med 2016;50:37-40.
81. Adachi H, Ihara M, Nojima Y, Kurimoto T, Nanto S. Kounis syndrome caused by anaphylaxis without skin manifestations after cefazolin administration. J Allergy Clin Immunol Pract 2019;7:317-9.
82. Kounis NG, Cervellin G, Koniari I, et al. Anaphylactic cardiovascular collapse and Kounis syndrome: systemic vasodilation or coronary vasoconstriction? Ann Transl Med 2018;6:332.
83. Biteker M. A new classification of Kounis syndrome. Int J Cardiol 2010;145:553.
84. Kogias JS, Papadakis EX, Tsatiris CG, et al. Kounis syndrome: a manifestation of drug-eluting stent thrombosis associated with allergic reaction to contrast material. Int J Cardiol 2010;139:206-9.
85. Vetander M, Helander D, Lindquist C, et al. Classification of anaphylaxis and utility of the EAACI Task force position paper on anaphylaxis in children. Pediatric Allergy and Immunology 2011;22:369–73.
86. Soufras GD, Kounis GN, Kounis NG. Brain injury due to anaphylactic shock: broadening manifestations of Kounis syndrome. Int Endod J 2014;47(4):309-13.
87. Khan S. Mast cell tryptase level should be checked in all patients with suspected Kounis syndrome. Eur Heart J 2020;41:3018.
88. Kounis NG. Serum tryptase levels and Kounis syndrome. Int J Cardiol 2007;114:407- 8.
89. Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016;54:1545-59.
90. Lopez PR, Peiris AN. Kounis syndrome. South Med J 2010;103:1148-55.
91. Goto K, Kasama S, Sato M, Kurabayashi M. Myocardial scintigraphic evidence of Kounis syndrome: what is the aetiology of acute coronary syndrome? Eur Heart J 2016;37:1157.
92. Okur A, Kantarci M, Karaca L, et al. The utility of cardiac magnetic resonance imaging in Kounis syndrome. Postepy Kardiol Interwencyjnej 2015;11:218-23.
93. Cervellin G, Lippi G, Kounis NG. Allergic Inflammation Is Associated With Coronary Instability and a Worse Clinical Outcome After Acute Myocardial Infarction. Circ Cardiovasc Interv 2015;8:e003166.
94. Fassio F, Losappio L, Antolin-Amerigo D, et al. Kounis syndrome: A concise review with focus on management. Eur J Intern Med 2016;30:7-10.
95. Cevik C, Nugent K, Shome GP, Kounis NG. Treatment of Kounis syndrome. Int J Cardiol 2010;143:223-6.
96. Akgullu C, Eryilmaz U, Gungor H, et al. Myocardial infarction secondary to morphine-induced Kounis syndrome. Herz 2014;39:874-6.
97. Chiam E, Bellomo R, Churilov L, Weinberg L. The hemodynamic effects of intravenous paracetamol (acetaminophen) vs normal saline in cardiac surgery patients: A single center placebo controlled randomized study. PLoS One 2018;13:e0195931.
98. Liu Y, Lu C, Guo Q. Recurrent Type III Kounis Syndrome: Will Anti-Immunoglobulin E Drug Be Another Option? Can J Cardiol 2020;36:e5-966.