Hrev_master Abstract Acute coronary syndromes can develop with an unusual and challenging presentation. Kounis syndrome is a mostly overlooked Acute Coronary Syndrome (ACS) in the setting of anaphylactic or anaphylactoid reactions in response to an allergic insult that can lead to severe complications including cardiac arrest. A 52-year- old-man presented to the emergency department of our hospital because of acute transient loss of consciousness that developed some minutes after almonds ingestion. The complex diagnostic workup led to the diagnosis of vasospastic Kounis syndrome, an infrequent type of acute coronary syndrome, mostly overlooked, with challenging diagnostic and therapeutic features. Peculiarities on clinical presentation, the approach adopted by the emergency physician and the consultant cardiologist to achieve the correct diagnosis and our proposed management with a brief revision of the literature will be reported. Unusual clinical presentations of acute coronary syndromes represent part of the pitfalls that an emergency physician can face during the everyday practice. Prompt identification of these conditions is always struggling but of crucial importance to improve patient prognosis with a correct diagnostic work-up and therapeutic management. Introduction Acute coronary syndromes can develop with an unusual and challenging presentation. Kounis syndrome is a mostly overlooked Acute Coronary Syndrome (ACS) in the setting of anaphylactic or anaphylactoid reactions in response to an allergic insult. It is part of the pitfalls that an emergency physician or a cardiologist of emergency departments can face during the everyday practice. This case will underline how to promptly recognize and cor- rectly manage these situations even in the absence of specific guidelines. Case Report A 52-year-old man with no previous medical and cardiovascu- lar history and no cardiovascular risk factors presented to the emer- gency department of our institution because of acute transient loss of consciousness. The episode was preceded by acute onset of low thoracic/epigastric pain associated with nausea, vomiting, cold sweating and intense tremors. He referred to have eaten almonds about ten minutes before the onset of symptoms. At his arrival he appeared worried, confused and sweaty. Arterial blood gas analysis revealed mild compensated metabolic acidosis (pH 7,3, CO2 30mmHg, HCO3- 18mmol/L, COHb 0,4%), p02 78mmHg and abnormal lactate levels (7mmol/L). Neurological evaluation and brain CT ruled out ischemic or hemorrhagic stroke. ECG showed sinus tachycardia with mild ST elevation in V1-V2-V3, hyperacute T in precordial leads and reciprocal ST depression in inferior and lateral leads (Figure 1). Complete blood count underlined lympho- cytic leukocytosis without anemia and with normal eosinophil count (WBC 15 x 109/L, 65% Lymphocytes, reference value 4,8- 10,8 x 109/L), C-reactive protein 44mg/L (reference value <6mg/L) and high-sensitive Troponin-T was negative at first meas- urement and highly increased at 2 hours-check (7ng/L to 532ng/L, reference value 0-14ng/L). In the suspicion of anaphylaxis, intramuscular epinephrin and intravenous corticosteroids (CCS, Methylprednisolone 60mg) and antihistamine H1 (Chlorphenamine 10mg) therapy was adminis- tered by the emergency physician. A second ECG was recorded about 30 minutes later and showed complete normalization of the previous alterations and transthoracic echocardiography performed by the consultant cardiologist highlighted normal biventricular function without kinetic abnormalities. Toxicological screening for Emergency Care Journal 2021; volume 17:9806 Correspondence: Giorgio Fiore, Clinical Cardiology Department, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milano, Italy. Tel.: +393391449399 E-mail: gio.fio@hotmail.it Key words: Kounis syndrome; allergic angina; vasospastic angina; acute chest pain; acute coronary syndrome. Conflicts of interest: The authors declare no conflict of interest. Availability of data and materials: All data underlying the findings are fully available. Ethics approval and consent to participate: No ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human participants or ani- mals. Informed consent was obtained from the patient included in this study. Consent for publication: The patient gave his written consent to use his personal data for the publication of this case report and any accompany- ing images. Received for publication: 13 April 2021. Revision received: 17 June 2021. Accepted for publication: 21 June 2021. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2021 Licensee PAGEPress, Italy Emergency Care Journal 2021; 17:9806 doi:10.4081/ecj.2021.9806 [Emergency Care Journal 2021; 17:9806] [page 1] Kounis syndrome after almonds ingestion: From the diagnostic approach to new therapeutic options Giorgio Fiore, Carlo Gaspardone, Silvana Di Maio, Michele Oppizzi, Alberto Margonato Clinical Cardiology Unit, IRCCS San Raffaele University Hospital, Milan, Italy Non -co mmerc ial us e o nly common drugs (amphetamines, cocaine, barbiturates, benzodi- azepines, cannabinoids, opioids) resulted negative. Coronary Computed Tomography Angiography (CCTA) revealed no signifi- cant epicardial coronary stenosis with mild atherosclerosis of the left anterior descending artery (Figure 2). The patient was kept under observation for 48h. No arrhythmias were registered and he remained asymptomatic without new ECG alterations. After 10h, Troponin T was more than halved and serial assays presented a constant descending trend. A final diagnosis of coronary spasm secondary to allergic reaction was done (Kounis syndrome, type I). The patient was discharged about 60 hours after the ED access with a calcium channel antagonist (Diltiazem 60mg tid) therapy and indication to undergo a Cardiac MRI, a 24-hour Holter moni- toring and a complete immuno-allergologic evaluation. Discussion Clinical presentation and how to reach diagnosis Kounis syndrome is an Acute Coronary Syndrome (ACS) in the setting of anaphylactic or anaphylactoid reactions in response to an allergic insult, including food, insect bites or drugs (Table 1).1 Subsequent mast cell and platelet activation induces the release of inflammatory mediators such as histamine, arachidonic acid prod- ucts, platelet-activating factor, cytokines and chemokines.2 In this context, coronary artery spasm in predisposed subjects (type I), plaque rupture (type II) or stent thrombosis (type III) can occur.3 A variety of ECG alterations may be observed, including ST-segment elevation or depression, any degree of heart block and cardiac arrhythmias.2 Prompt identification of this overlooked syndrome and correct patient management is always struggling. In our case, the absence of cardiovascular risk factors and atypical chest pain features made the suspicion of ACS low. However, the ECG at the presentation was suggestive of ST-elevation myocardial infarction. In this setting, an urgent coronary angiography might have been performed to exclude coronary thrombosis. Nevertheless, the rapid reversal of symptoms and ECG alterations after infusion of intra- venous CCS and H1 antagonists along with normal echocardio- graphic findings guided the decision to a more conservative strat- egy. Because of the high elevation of Troponin T at two hours and the feasibility of urgent CCTA at our institution, this was the exam- ination of choice that excluded coronary thrombosis and athero- sclerotic disease, making the diagnosis of vasospastic (type 1) Kounis syndrome very likely. In addition, lymphocytic leukocyto- sis and increased lymphocyte-total leukocytes ratio has been linked to anaphylaxis4 and together with high C-reactive protein levels, temporal correlation with almond ingestion, gastrointestinal symptoms (but absence of other allergic manifestations) strengthen the diagnosis of anaphylaxis and subsequent coronary vasospasm as the cause of the clinical presentation. Serum triptase levels were not tested but could have been of great interest to rapidly confirm diagnosis. Case management and therapy There is no established treatment in this atypical ACS, as man- agement according to the most recent guidelines for ACS does not appear totally appropriate in this context.5 Our proposed approach is reported in Figure 3. It is not surprising that vasospastic Kounis syndrome may overlap with Prinzmetal angina, as they share sim- ilar pathophysiological mechanisms and the diagnosis and treat- ment should therefore be directed in the same way.6 A limitation of our approach was probably the choice of CCTA. An invasive study of the coronary flow reserve with provocation tests for epicardial Case Report Table 1. Some possible triggers of Kounis Syndrome according to reported cases. Drugs Food Clinical conditions and environment Analgesics (Aspirin, NSAIDs) Fresh and dried fruit Anisakis Anesthetics (isoflurane, midazolam, propofol, remifentanil, Nuts Anaphylaxis rocuronium bromide, succinylcholine, Mushrooms Bronchial asthma suxamethonium, trimethaphan) Sgombroid reaction Chronic Autoimmune Urticaria Antibiotics (beta-lactams, trimethoprim– Vegetables Churg Strauss syndrome sulfamethoxazole, sulperazon, vancomycin, amikacin) Intracoronary stenting Anticoagulants (heparin) Mastocitosis Contrast Media (iodinated contrast, ultrasound contrast) Serum sickness Corticosteroids Echinococcal cyst rupture Immunoglobulins and biologic drugs Hymenoptera and scorpion sting Thrombolytics Jellyfish sting Others (antineoplastics, amiodarone, clopidogrel, enalapril, esmolol) Snake venom Latex Millet and other respiratory allergies Figure 1. ECG at presentation. ST segment elevation in anterior precordial leads, hyperacute T waves and reciprocal ST segment depression in inferior and lateral leads. [page 2] [Emergency Care Journal 2021; 17:9806] Non -co mmerc ial us e o nly and microvascular vasospasm may better identify patients that could benefit from vasodilating drugs. Intravenous CCS and hista- mine H1 antagonists, reducing the acute inflammatory burden, may partially revert allergic and anginal symptoms and arterial vasospasm.7 On the contrary, epinephrine, administered to our patient in the suspicion of anaphylactic shock, can worsen coro- nary vasospasm. Glucagon infusion or Methoxamine may also be considered in patients who are receiving beta-blockers or are in shock refractory to epinephrine.8 In the case of severe anginal pain extreme caution should be reserved to the use of Morphine and opiates, which can induce massive mast cell degranulation and aggravate the allergic reaction. Fentanyl and its derivatives are pre- ferred drugs while intravenous paracetamol (acetaminophen) can cause severe hypotension.8 Due to the absence of significant coronary atherosclerosis, we decided to not administer a long-term antiplatelet therapy to our patient. Furthermore, Aspirin through inhibition of cyclooxyge- nase may shunt arachidonic acid degradation to the Leukotriene pathway producing mediators of anaphylaxis.9 Concerning long- term therapy, non-dihydropyridine calcium channel blocker (or nitrates) are the drug of choice to reduce the risk of new coronary spasms. Beta-blockers are instead generally contraindicated in this setting, as they can elicit unopposed coronary alpha-1 mediated vasospasm and offset the beneficial effect of epinephrine. Mast cell stabilizers (e.g. sodium cromoglycate) may be considered for future prevention in predisposed atopic subjects, but their efficacy in the acute setting is questionable. Monoclonal antibodies that avert mast cell degranulation by masking the IgE binding site10 are future promising therapies to avoid vasospasm and to stabilize inflamed vulnerable atherosclerotic plaques.11,12 Along with a non- urgent full cardiologic workup, cardiac MRI was counseled to spot subclinical myocardial damage or scar. The role of cardiac SPECT remain anecdotal and debatable; nowadays ICA or CCTA, com- pleted by MRI in residual doubtful cases, appear the best manage- ment to rule-in or rule-out ACS, as reported by ESC guidelines for N-STE ACS.5 Finally, full allergologic evaluation with serum tryptase, skin prick test and IgE screening is mandatory to strengthen diagnostic suspect, identify etiologic triggers and avoid new events. Conclusions We presented the case of a type I (vasospastic) Kounis syn- drome. This is an infrequent type of ACS, mostly overlooked, with challenging diagnostic and therapeutic workup. Drugs commonly used as first line therapy for ACS (Aspirin, betablockers) do not appear completely appropriate in this context. A personalized man- agement based on the clinical scenario is encouraged in the absence of specific guidelines. Coronary computed tomography angiography in the emergency setting to exclude major coronary stenosis or plaque instability and rupture permits to safely dis- charge patients after clinical stabilization and acute pharmacologi- cal management. Intravenous CCS and H1 antagonists together with vasodilators like calcium channel blockers or nitrates (if blood pressure is satisfactory) appears adequate drugs. Long term treatment after discharge should be discussed with a cardiologist and immunologist, if appropriate, and individualized based on patient characteristics, pathophysiological considerations, identi- fied causes, presence of atherosclerotic disease and residual car- diac function. References 1. Rodrigues MC, Coelho D, Granja C. Drugs that may provoke Kounis syndrome. Braz J Anesthesiol 2013;63:426–8. 2. Kounis NG. Coronary hypersensitivity disorder: the Kounis Case Report [Emergency Care Journal 2021; 17:9806] [page 3] Figure 2. Coronary computed tomography angiography. Absence of atherosclerotic obstructive disease of the epicardial coronary arteries. LAD: left anterior descending artery; CX: left circumflex artery; RI: ramus intermedius of the left coronary artery; RCA: right coronary artery; PDA: posterior descending artery. Figure 3. Proposed algorithm for the management of KOUNIS syndrome during the acute phase. ECG: electrocardiography; MI: myocardial infarction; CCS: corticosteroids; ICA: invasive coro- nary angiography; CCTA: coronary computed tomography angiography; CCB: calcium channel blocker; ACE-I: angiotensin converting enzyme inhibitors; ACS: acute coronary syndrome. Non -co mmerc ial us e o nly syndrome. Clin Ther 2013;35:563-71. 3. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991;45:121–8. 4. Yanagawa Y, Sakamoto T, Okada Y. Lymphocytosis without anemia in a patient presenting with anaphylactic shock. Am J Emerg Med 2005;23:763-6. 5. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients pre- senting without persistent ST-segment elevation. Eur Heart J 2020:ehaa575. 6. Rich MW. Is vasospastic angina an inflammatory disease? Am J Cardiol 2005;96:1612. 7. Numasawa Y, Motoda H, Yamazaki H, et al. Successful treat- ment using corticosteroids in a patient with refractory vasospastic angina and bronchial asthma. J Cardiol Cases 2014;10:132-5. 8. Kounis NG, Koniari I, Velissaris D, et al. Kounis syndrome- not a single-organ arterial disorder but a multisystem and mul- tidisciplinary disease. Balkan Med J 2019;36:212-21. 9. Berkes EA. Anaphylactic and anaphylactoid reactions to aspirin and other NSAIDs. Clin Rev Allergy Immunol 2003;24:137-48. 10. Leung DYM, Sampson HA, Ynginger JW, et al. Effect of anti- IgE therapy in patients with peanut allergy. N Engl J Med 2003;348:986-93. 11. Kaartinen M, Penttila A, Kovanen PT. Accumulation of acti- vated mast cells in the shoulder region of human coronary atheroma, the prediction site of atheromatous rupture. Circulation 1994;90:1669-78. 12. Kounis NG, Koniari I, Tsigkas G, Davlouros P. Humanized monoclonal antibodies against IgE antibodies as therapy for IgE-mediated coronary syndromes: are we there yet? Can J Cardiol 2020;36:816-9. Case Report [page 4] [Emergency Care Journal 2021; 17:9806] Non -co mmerc ial us e o nly