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The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2015.02.044
Clinical Communications: Adults MYOCARDIAL INFARCTION IN THE SETTING OF ANAPHYLAXIS TO CELECOXIB: A CASE OF KOUNIS SYNDROME Anthony C. Regis, MD, Carl A. Germann, MD, and Jacob G. Crowell, MD Department of Emergency Medicine, Maine Medical Center, Portland, Maine Reprint Address: Anthony C. Regis, MD, Department of Emergency Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102
, Abstract—Background: Acute coronary syndromes in the setting of an allergic or hypersensitivity reaction are known as Kounis syndrome. The syndrome involves release of inflammatory mediators after an allergen exposure that leads to coronary artery vasospasm or platelet activation. A variety of foods, drugs, and environmental exposures have been implicated in this condition. Case Report: The case involves a 62-year-old woman with dyspnea, chest pain, and transient ST-segment elevation after ingesting celecoxib. Her symptoms resolved with treatment for a suspected allergic reaction. Although she did have mild elevation of serum cardiac biomarkers, subsequent cardiac catheterization demonstrated normal coronary arteries. Why Should an Emergency Physician Be Aware of This?: This is the first reported case of ST-segment elevation myocardial infarction after allergy to celecoxib. Knowledge of Kounis syndrome will better prepare physicians in both its identification and clinical management. Ó 2015 Elsevier Inc.
numerous case reports, Kounis syndrome remains a poorly recognized clinical entity. We report a case of Kounis syndrome in an adult female shortly after ingesting celecoxib. Awareness of this phenomenon and its proposed treatments will better prepare physicians in both identification of Kounis syndrome and its clinical management. CASE REPORT A 62-year-old female with a medical history of hypertension, hypothyroidism, osteoarthritis, and Samter’s syndrome (i.e., bronchial asthma, nasal polyposis, and aspirin sensitivity) sought medical attention after experiencing sudden shortness of breath 15 min after taking her prescribed celecoxib. There were no other recent ingestions or known exposures that may have precipitated an allergic response. The patient further noted persistent chest tightness, emesis, skin flushing, and pruritus. She had been taking celecoxib on an intermittent basis for arthritis over the previous 6 months. She denied any previous reaction to this medication. Her only known allergy was an anaphylactic response to aspirin 20 years earlier, which she noted was similar to her current symptoms. The patient was otherwise healthy, does not smoke, and has no significant family history of medical illnesses. She was a seasonal resident on an island off the coast of Maine. On initial assessment by island emergency medical services, the patient appeared to be in significant respiratory distress with flushed and diaphoretic skin, but no visible urticaria or angioedema. Initial vital signs included a heart
, Keywords—Kounis syndrome; celecoxib; ST-segment elevation; anaphylaxis; hypersensitivity reaction
INTRODUCTION Kounis syndrome is the occurrence of acute coronary syndrome secondary to an allergic or hypersensitivity reaction (1). The syndrome is caused by inflammatory mediators released during mast cell activation that induce coronary artery vasospasm and platelet activation (1). A variety of foods, drugs, and environmental exposures have been implicated in this condition (2). Despite
RECEIVED: 17 April 2013; FINAL SUBMISSION RECEIVED: 9 January 2015; ACCEPTED: 27 February 2015 1 FLA 5.2.0 DTD - JEM10339_proof - 16 May 2015 - 11:40 am - ce
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
2 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
A. C. Regis et al.
Figure 1. Prehospital 12-lead electrocardiogram showing >4 mm of ST-segment elevation in inferior (II, III, aVF) and anterolateral (V3, V4, V5, V6) leads and ST-segment depression in aVL.
rate of 170 beats/min, blood pressure 82/62 mm Hg, respiratory rate of 20 breaths/min, and oxygen saturation of 86% on ambient air. Cardiac and pulmonary auscultation were unremarkable. Transport time from the scene to the nearest hospital was prolonged due to the need for both rescue boat and ambulance transfers. En route to the hospital, the patient received supplemental oxygen, 1 liter of normal saline, 50mg of intravenous diphenhydramine, and a 2.5 mg albuterol sulfate nebulization. Her hemodynamics and oxygenation improved during transport. Upon arrival to the mainland, a prehospital 12-lead electrocardiogram (ECG) revealed sinus rhythm with 4-mm STsegment elevations in the inferior and anterolateral leads accompanied by premature ventricular contractions. Reciprocal changes were evident in aVL (Figure 1).
The patient arrived at a nearby tertiary care center 1 h and 15 min after the onset of her symptoms. At that time, her dyspnea and chest discomfort had markedly improved although ST-segment elevations and depression persisted on ECG (Figure 2). Chest x-rays and routine laboratory studies were without abnormalities. Cardiac biomarkers returned mildly elevated, with a troponin T of 0.41 ng/ mL, peak total creatinine kinase 218 U/L, and creatinine kinase MB equaling 10.5 ng/mL. While awaiting cardiac consultation, she was administered i.v. doses of methylprednisolone (125mg), unfractionated heparin (60U/kg bolus then 12U/kg/hr drip), and eptifibatide (180mcg/kg bolus followed by 2mcg/kg/min drip) as well as clopidogrel (600mg) taken orally. Aspirin was never given due to reported allergy. Serial ECGs revealed normalization of
Figure 2. Initial electrocardiogram obtained on arrival to the emergency department and over an hour after symptom onset reveals persistent ST-segment elevation in leads II, III, aVF as well as leads V3–V6. Reciprocal ST-segment depression in aVL continues.
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196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260
Kounis Syndrome 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325
3
Figure 3. Repeat electrocardiogram 2 h after hospitalization demonstrates marked regression of ST-segment elevation.
ST elevation within 2 h of hospital arrival (Figure 3). Cardiac consultation was obtained in the emergency department. Immediate cardiac catheterization was deferred, given the patient’s symptomatic improvement as well as resolution of ischemia on ECG. The patient was continued on i.v. heparin and eptifibatide. A transthoracic echocardiogram performed later that day revealed akinesis of the apical third of the left ventricle with a preserved ejection fraction. The next morning, cardiac catheterization and angiography demonstrated normal coronary arteries (Figure 4). The patient was discharged home in good condition on a steroid taper. DISCUSSION The occurrence of allergic reaction concomitant with myocardial infarction was first observed and published in 1950 during a protracted hypersensitivity response to
penicillin (3). Decades later, Kounis and Zavras coined the syndromes of allergic angina and allergic myocardial infarction to describe the coincidental occurrence of acute coronary events with allergic or hypersensitivity reactions (4,5). Today, such phenomena are referred to as Kounis syndrome (1). The pathophysiology of Kounis syndrome centers on the activation and degranulation of mast cells during an allergic insult. Once triggered via immunoglobulin E crosslinking, the complement system, or other mechanisms, mast cells release potent inflammatory substances both locally and in the peripheral circulation (1). These chemical mediators, which include histamine, thromboxane, leukotrienes, and neutral proteases can induce coronary artery spasm and platelet activation in susceptible individuals (6,7). Various medications, environmental exposures, and medical conditions can provoke Kounis syndrome (2). Although several nonsteroidal antiinflammatory drugs can precipitate this condition, this
Figure 4. Cardiac catheterization with coronary angiography performed the following day shows normal patency of left anterior descending and left circumflex arteries (left image), as well as a normal right coronary artery (right image).
FLA 5.2.0 DTD - JEM10339_proof - 16 May 2015 - 11:40 am - ce
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A. C. Regis et al.
case is the first known report connecting celecoxib with Kounis syndrome. Three subtypes of Kounis syndrome exist in the medical literature. The type I variant encompasses individuals who have normal coronary arteries and are free of atheromatous risk factors, and in whom the acute release of inflammatory mediators induces coronary artery spasm with or without elevation of serum cardiac biomarkers (1). Type II variant consists of subjects with pre-existing coronary artery disease in whom proinflammatory compounds induce either coronary vasospasm or atheromatous plaque erosion and rupture (1). More recently, a third subtype of Kounis syndrome involving coronary stent thrombosis owing to drug allergy has been proposed (8). Severity of symptoms involving Kounis syndrome can range from mild angina with hives and pruritus to lifethreatening anaphylaxis associated with left ventricular dysfunction and cardiogenic shock (9). Individuals with atopy are at increased risk of developing Kounis syndrome compared to normal individuals, and often experience worse symptoms due to an amplified inflammatory response (10,11). Prognosis depends on several elements, including magnitude of the initial response, patient sensitivity, comorbidity, site of antibody-antigen reaction, allergen concentration, and the route of allergen entrance (12). Although adults are more frequently affected, events in children have also been documented (13,14). Medical management of patients with Kounis syndrome is often challenging because the clinician must consider and treat both cardiac and allergic insults simultaneously. To date, no definitive guideline exists, and current strategies for treating Kounis syndrome derive from published case reports. Therapies aimed at suppressing the hypersensitivity response consist of histamine receptor blockers, corticosteroids, epinephrine, and intravascular volume replacement (15,16). Pharmacotherapeutic measures in acute coronary syndromes include anti-platelets, anti-coagulants, and when appropriate, agents that decrease myocardial oxygen consumption (nitrates, beta-blockers, calcium channel blockers) (15,16). Cardiac catheterization along with intracoronary vasodilator infusion has helped treat type I Kounis (16). Angioplasty and thrombus evacuation may have utility for type II variants. Administration of epinephrine for Kounis syndrome is a complex issue. Although a lifesaving medication in anaphylaxis, epinephrine’s a-adrenergic effects can exacerbate coronary vasospasm and worsen myocardial ischemia (17,18). Current anaphylaxis guidelines have no absolute contraindications against administration of epinephrine, and support its application in life-threatening situations (19). Long-term treatment and prevention of Kounis syndrome should be tailored to the specific subtype affecting the patient. In type I, allergen avoidance might be sufficient. For more complicated cases of Kounis syndrome,
the use of mast cell–stabilizing medications has been suggested. Inhibition of mast cell degranulation avoids the release of inflammatory mediators and helps prevent adverse sequelae, such as coronary vasospasm and plaque erosion (15). Mast cell stabilizers can also have value in managing unstable angina and myocardial infarction of nonallergic etiology (15). Several of the vasoactive substances known to cause Kounis syndrome are found at elevated concentrations in patients experiencing acute coronary syndromes–unrelated to hypersensitivity (2022). This approach has been shown to reduce the incidence of thrombotic events in laboratory animals after experimental mast cell activation (23). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? It is important to consider the diagnosis of Kounis syndrome in patients presenting with chest discomfort, ECG changes and accompanying allergic symptoms.While the severity of cases is variable, prompt recognition and medical intervention is essential for optimizing patient outcomes. Treatments should be directed at both suppression of the allergic reaction and relaxation of the coronary vasculature. The use of epinephrine in Kounis syndrome is a challenging decision and probably best reserved for life-threating situations. REFERENCES 1. Kounis N. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006;110:7–14. 2. Lopez PR, Peiris AN. Kounis syndrome. South Med J 2010;103: 1148–55. 3. Pfister CW, Plice SG. Acute myocardial infarction during prolonged allergic reaction to penicillin. Am Heart J 1950;40:945–7. 4. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991;45:121–8. 5. Kounis NG, Zavras GM. Allergic angina and allergic myocardial infarction. Circulation 1996;94:1789. 6. Steffel J, Akhmedov A, Greutert H, Lusher TF, Tanner FC. Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 2005;112:341–9. 7. Constantinides P. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1083. 8. Akyel A, Murat SN, Cay S, et al. Late drug eluding stent thrombosis due to acemetacine: type III Kounis syndrome: Kounis syndrome due to acematacine. Int J Cardiol 2012;155:461–2. 9. Tanboga IH, Karabay CY, Can MM, et al. Kounis syndrome presenting with cardiogenic shock. J Cardiovasc Med 2010;12:833–6. 10. Criqui MH, Lee ER, Hamburger RN, et al. IgE and cardiovascular disease. Results from a population based study. Am J Med 1987;82: 964–8. 11. Viana-Tejedor A, Espinosa MA, Cuesta J, et al. Kounis syndrome secondary to amoxicillin use in an asthmatic patient. Int J Cardiol 2011;150:113–5. 12. Mori E, Iceda H, Ueno T, et al. Vasospastic angina induced by nonsteroidal anti-inflammatory drugs. Clin Cardiol 1997;20:656–8. 13. Biteker M, Duran NE, Biteker FS, et al. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr 2010;169:27–9.
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Kounis Syndrome 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585
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14. Morel O, Jesel L, Morel N, et al. Transient left ventricular dysfunction syndrome during anaphylactic shock vasospasm, Kounis syndrome or epinephrine-induced stunned myocardium? Int J Cardiol 2010;145:501–3. 15. Cevik C, Nugent K, Goutam SP, et al. Treatment of Kounis syndrome. Int J Cardiol 2010;143:223–6. 16. Rosen P, Marx JA, Hockberger RS, Walls RM, Adams J et al., eds. Rosen’s emergency medicine: Concepts and clinical practice. Philadelphia, PA: Mosby/Elsevier, 2010. 17. Yurtdas M, Aydin MK. A case of coronary spasm with resultant acute myocardial infraction: likely the result of an allergic reaction. Intern Med 2012;51:2161–4. 18. Izgi C, Cevik C, Nugent K. Severe myocardial ischemia after concentrated epinephrine use for the treatment of anaphylaxis: Kounis syndrome or epinephrine effect? Heart Lung 2010;39:160–3.
19. Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the context of life threatening allergic reactions. Br Med J 2003;326: 589–90. 20. Simmons FER, Ardusso LRF, Bilo MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;2:13–36. 21. Clejan S, Japa S, Clemetson C, et al. Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis. J Cell Mol Med 2002;6:583–92. 22. Deliargris EN, Upadhya B, Sane DC, et al. Mast cell tryptase: a new biomarker in patients with stable coronary artery disease. Atherosclerosis 2005;178:381–6. 23. Nemmar A, Hoet PHM, Vermyien J, et al. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation 2004;110:1670–7.
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The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2015.02.044
Clinical Communications: Adults MYOCARDIAL INFARCTION IN THE SETTING OF ANAPHYLAXIS TO CELECOXIB: A CASE OF KOUNIS SYNDROME Anthony C. Regis, MD, Carl A. Germann, MD, and Jacob G. Crowell, MD Department of Emergency Medicine, Maine Medical Center, Portland, Maine Reprint Address: Anthony C. Regis, MD, Department of Emergency Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102
, Abstract—Background: Acute coronary syndromes in the setting of an allergic or hypersensitivity reaction are known as Kounis syndrome. The syndrome involves release of inflammatory mediators after an allergen exposure that leads to coronary artery vasospasm or platelet activation. A variety of foods, drugs, and environmental exposures have been implicated in this condition. Case Report: The case involves a 62-year-old woman with dyspnea, chest pain, and transient ST-segment elevation after ingesting celecoxib. Her symptoms resolved with treatment for a suspected allergic reaction. Although she did have mild elevation of serum cardiac biomarkers, subsequent cardiac catheterization demonstrated normal coronary arteries. Why Should an Emergency Physician Be Aware of This?: This is the first reported case of ST-segment elevation myocardial infarction after allergy to celecoxib. Knowledge of Kounis syndrome will better prepare physicians in both its identification and clinical management. Ó 2015 Elsevier Inc.
numerous case reports, Kounis syndrome remains a poorly recognized clinical entity. We report a case of Kounis syndrome in an adult female shortly after ingesting celecoxib. Awareness of this phenomenon and its proposed treatments will better prepare physicians in both identification of Kounis syndrome and its clinical management. CASE REPORT A 62-year-old female with a medical history of hypertension, hypothyroidism, osteoarthritis, and Samter’s syndrome (i.e., bronchial asthma, nasal polyposis, and aspirin sensitivity) sought medical attention after experiencing sudden shortness of breath 15 min after taking her prescribed celecoxib. There were no other recent ingestions or known exposures that may have precipitated an allergic response. The patient further noted persistent chest tightness, emesis, skin flushing, and pruritus. She had been taking celecoxib on an intermittent basis for arthritis over the previous 6 months. She denied any previous reaction to this medication. Her only known allergy was an anaphylactic response to aspirin 20 years earlier, which she noted was similar to her current symptoms. The patient was otherwise healthy, does not smoke, and has no significant family history of medical illnesses. She was a seasonal resident on an island off the coast of Maine. On initial assessment by island emergency medical services, the patient appeared to be in significant respiratory distress with flushed and diaphoretic skin, but no visible urticaria or angioedema. Initial vital signs included a heart
, Keywords—Kounis syndrome; celecoxib; ST-segment elevation; anaphylaxis; hypersensitivity reaction
INTRODUCTION Kounis syndrome is the occurrence of acute coronary syndrome secondary to an allergic or hypersensitivity reaction (1). The syndrome is caused by inflammatory mediators released during mast cell activation that induce coronary artery vasospasm and platelet activation (1). A variety of foods, drugs, and environmental exposures have been implicated in this condition (2). Despite
RECEIVED: 17 April 2013; FINAL SUBMISSION RECEIVED: 9 January 2015; ACCEPTED: 27 February 2015 1 FLA 5.2.0 DTD - JEM10339_proof - 16 May 2015 - 11:40 am - ce
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
2 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
A. C. Regis et al.
Figure 1. Prehospital 12-lead electrocardiogram showing >4 mm of ST-segment elevation in inferior (II, III, aVF) and anterolateral (V3, V4, V5, V6) leads and ST-segment depression in aVL.
rate of 170 beats/min, blood pressure 82/62 mm Hg, respiratory rate of 20 breaths/min, and oxygen saturation of 86% on ambient air. Cardiac and pulmonary auscultation were unremarkable. Transport time from the scene to the nearest hospital was prolonged due to the need for both rescue boat and ambulance transfers. En route to the hospital, the patient received supplemental oxygen, 1 liter of normal saline, 50mg of intravenous diphenhydramine, and a 2.5 mg albuterol sulfate nebulization. Her hemodynamics and oxygenation improved during transport. Upon arrival to the mainland, a prehospital 12-lead electrocardiogram (ECG) revealed sinus rhythm with 4-mm STsegment elevations in the inferior and anterolateral leads accompanied by premature ventricular contractions. Reciprocal changes were evident in aVL (Figure 1).
The patient arrived at a nearby tertiary care center 1 h and 15 min after the onset of her symptoms. At that time, her dyspnea and chest discomfort had markedly improved although ST-segment elevations and depression persisted on ECG (Figure 2). Chest x-rays and routine laboratory studies were without abnormalities. Cardiac biomarkers returned mildly elevated, with a troponin T of 0.41 ng/ mL, peak total creatinine kinase 218 U/L, and creatinine kinase MB equaling 10.5 ng/mL. While awaiting cardiac consultation, she was administered i.v. doses of methylprednisolone (125mg), unfractionated heparin (60U/kg bolus then 12U/kg/hr drip), and eptifibatide (180mcg/kg bolus followed by 2mcg/kg/min drip) as well as clopidogrel (600mg) taken orally. Aspirin was never given due to reported allergy. Serial ECGs revealed normalization of
Figure 2. Initial electrocardiogram obtained on arrival to the emergency department and over an hour after symptom onset reveals persistent ST-segment elevation in leads II, III, aVF as well as leads V3–V6. Reciprocal ST-segment depression in aVL continues.
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196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260
Kounis Syndrome 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325
3
Figure 3. Repeat electrocardiogram 2 h after hospitalization demonstrates marked regression of ST-segment elevation.
ST elevation within 2 h of hospital arrival (Figure 3). Cardiac consultation was obtained in the emergency department. Immediate cardiac catheterization was deferred, given the patient’s symptomatic improvement as well as resolution of ischemia on ECG. The patient was continued on i.v. heparin and eptifibatide. A transthoracic echocardiogram performed later that day revealed akinesis of the apical third of the left ventricle with a preserved ejection fraction. The next morning, cardiac catheterization and angiography demonstrated normal coronary arteries (Figure 4). The patient was discharged home in good condition on a steroid taper. DISCUSSION The occurrence of allergic reaction concomitant with myocardial infarction was first observed and published in 1950 during a protracted hypersensitivity response to
penicillin (3). Decades later, Kounis and Zavras coined the syndromes of allergic angina and allergic myocardial infarction to describe the coincidental occurrence of acute coronary events with allergic or hypersensitivity reactions (4,5). Today, such phenomena are referred to as Kounis syndrome (1). The pathophysiology of Kounis syndrome centers on the activation and degranulation of mast cells during an allergic insult. Once triggered via immunoglobulin E crosslinking, the complement system, or other mechanisms, mast cells release potent inflammatory substances both locally and in the peripheral circulation (1). These chemical mediators, which include histamine, thromboxane, leukotrienes, and neutral proteases can induce coronary artery spasm and platelet activation in susceptible individuals (6,7). Various medications, environmental exposures, and medical conditions can provoke Kounis syndrome (2). Although several nonsteroidal antiinflammatory drugs can precipitate this condition, this
Figure 4. Cardiac catheterization with coronary angiography performed the following day shows normal patency of left anterior descending and left circumflex arteries (left image), as well as a normal right coronary artery (right image).
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case is the first known report connecting celecoxib with Kounis syndrome. Three subtypes of Kounis syndrome exist in the medical literature. The type I variant encompasses individuals who have normal coronary arteries and are free of atheromatous risk factors, and in whom the acute release of inflammatory mediators induces coronary artery spasm with or without elevation of serum cardiac biomarkers (1). Type II variant consists of subjects with pre-existing coronary artery disease in whom proinflammatory compounds induce either coronary vasospasm or atheromatous plaque erosion and rupture (1). More recently, a third subtype of Kounis syndrome involving coronary stent thrombosis owing to drug allergy has been proposed (8). Severity of symptoms involving Kounis syndrome can range from mild angina with hives and pruritus to lifethreatening anaphylaxis associated with left ventricular dysfunction and cardiogenic shock (9). Individuals with atopy are at increased risk of developing Kounis syndrome compared to normal individuals, and often experience worse symptoms due to an amplified inflammatory response (10,11). Prognosis depends on several elements, including magnitude of the initial response, patient sensitivity, comorbidity, site of antibody-antigen reaction, allergen concentration, and the route of allergen entrance (12). Although adults are more frequently affected, events in children have also been documented (13,14). Medical management of patients with Kounis syndrome is often challenging because the clinician must consider and treat both cardiac and allergic insults simultaneously. To date, no definitive guideline exists, and current strategies for treating Kounis syndrome derive from published case reports. Therapies aimed at suppressing the hypersensitivity response consist of histamine receptor blockers, corticosteroids, epinephrine, and intravascular volume replacement (15,16). Pharmacotherapeutic measures in acute coronary syndromes include anti-platelets, anti-coagulants, and when appropriate, agents that decrease myocardial oxygen consumption (nitrates, beta-blockers, calcium channel blockers) (15,16). Cardiac catheterization along with intracoronary vasodilator infusion has helped treat type I Kounis (16). Angioplasty and thrombus evacuation may have utility for type II variants. Administration of epinephrine for Kounis syndrome is a complex issue. Although a lifesaving medication in anaphylaxis, epinephrine’s a-adrenergic effects can exacerbate coronary vasospasm and worsen myocardial ischemia (17,18). Current anaphylaxis guidelines have no absolute contraindications against administration of epinephrine, and support its application in life-threatening situations (19). Long-term treatment and prevention of Kounis syndrome should be tailored to the specific subtype affecting the patient. In type I, allergen avoidance might be sufficient. For more complicated cases of Kounis syndrome,
the use of mast cell–stabilizing medications has been suggested. Inhibition of mast cell degranulation avoids the release of inflammatory mediators and helps prevent adverse sequelae, such as coronary vasospasm and plaque erosion (15). Mast cell stabilizers can also have value in managing unstable angina and myocardial infarction of nonallergic etiology (15). Several of the vasoactive substances known to cause Kounis syndrome are found at elevated concentrations in patients experiencing acute coronary syndromes–unrelated to hypersensitivity (2022). This approach has been shown to reduce the incidence of thrombotic events in laboratory animals after experimental mast cell activation (23). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? It is important to consider the diagnosis of Kounis syndrome in patients presenting with chest discomfort, ECG changes and accompanying allergic symptoms.While the severity of cases is variable, prompt recognition and medical intervention is essential for optimizing patient outcomes. Treatments should be directed at both suppression of the allergic reaction and relaxation of the coronary vasculature. The use of epinephrine in Kounis syndrome is a challenging decision and probably best reserved for life-threating situations. REFERENCES 1. Kounis N. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006;110:7–14. 2. Lopez PR, Peiris AN. Kounis syndrome. South Med J 2010;103: 1148–55. 3. Pfister CW, Plice SG. Acute myocardial infarction during prolonged allergic reaction to penicillin. Am Heart J 1950;40:945–7. 4. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991;45:121–8. 5. Kounis NG, Zavras GM. Allergic angina and allergic myocardial infarction. Circulation 1996;94:1789. 6. Steffel J, Akhmedov A, Greutert H, Lusher TF, Tanner FC. Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 2005;112:341–9. 7. Constantinides P. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1083. 8. Akyel A, Murat SN, Cay S, et al. Late drug eluding stent thrombosis due to acemetacine: type III Kounis syndrome: Kounis syndrome due to acematacine. Int J Cardiol 2012;155:461–2. 9. Tanboga IH, Karabay CY, Can MM, et al. Kounis syndrome presenting with cardiogenic shock. J Cardiovasc Med 2010;12:833–6. 10. Criqui MH, Lee ER, Hamburger RN, et al. IgE and cardiovascular disease. Results from a population based study. Am J Med 1987;82: 964–8. 11. Viana-Tejedor A, Espinosa MA, Cuesta J, et al. Kounis syndrome secondary to amoxicillin use in an asthmatic patient. Int J Cardiol 2011;150:113–5. 12. Mori E, Iceda H, Ueno T, et al. Vasospastic angina induced by nonsteroidal anti-inflammatory drugs. Clin Cardiol 1997;20:656–8. 13. Biteker M, Duran NE, Biteker FS, et al. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr 2010;169:27–9.
FLA 5.2.0 DTD - JEM10339_proof - 16 May 2015 - 11:40 am - ce
456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520
Kounis Syndrome 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585
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14. Morel O, Jesel L, Morel N, et al. Transient left ventricular dysfunction syndrome during anaphylactic shock vasospasm, Kounis syndrome or epinephrine-induced stunned myocardium? Int J Cardiol 2010;145:501–3. 15. Cevik C, Nugent K, Goutam SP, et al. Treatment of Kounis syndrome. Int J Cardiol 2010;143:223–6. 16. Rosen P, Marx JA, Hockberger RS, Walls RM, Adams J et al., eds. Rosen’s emergency medicine: Concepts and clinical practice. Philadelphia, PA: Mosby/Elsevier, 2010. 17. Yurtdas M, Aydin MK. A case of coronary spasm with resultant acute myocardial infraction: likely the result of an allergic reaction. Intern Med 2012;51:2161–4. 18. Izgi C, Cevik C, Nugent K. Severe myocardial ischemia after concentrated epinephrine use for the treatment of anaphylaxis: Kounis syndrome or epinephrine effect? Heart Lung 2010;39:160–3.
19. Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the context of life threatening allergic reactions. Br Med J 2003;326: 589–90. 20. Simmons FER, Ardusso LRF, Bilo MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;2:13–36. 21. Clejan S, Japa S, Clemetson C, et al. Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis. J Cell Mol Med 2002;6:583–92. 22. Deliargris EN, Upadhya B, Sane DC, et al. Mast cell tryptase: a new biomarker in patients with stable coronary artery disease. Atherosclerosis 2005;178:381–6. 23. Nemmar A, Hoet PHM, Vermyien J, et al. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation 2004;110:1670–7.
FLA 5.2.0 DTD - JEM10339_proof - 16 May 2015 - 11:40 am - ce
586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650
