Nicholas Patsouras

Kounis syndrome: Aspects on pathophysiology and management

We read with the great interest the excellent and concise review of Filippo Fassio et al. [1] focused on Kounis syndrome and its treatment. Since the description of this syndrome has paved the possibility for prevention of the progression of coronary plaques to unstable lesions with inhibition of mast cell activation, that has been already achieved experimentally [2], we believe that the following observations and additions on its pathophysiology and management would be of value.

After Administration of Intravenous Epinephrine for bee Sting-induced Anaphylaxis: Kounis Syndrome or Epinephrine Effect?

To the Editor: In the very important report published in Chinese Medical Journal,[1] a 50-year-old male patient, stented with a bare metal stent followed by 3 overlapping drug-eluting stents, developed anaphylactic reaction following a bee sting that was treated with intravenous 0.1 mg epinephrine at a 1:100,000 together with intravenous methylprednisolone, chlorpheniramine maleate, and ranitidine. He developed, immediately after, an anterior wall myocardial infarction, and subsequent coronary arteriography revealed total occlusion in the proximal left anterior descending stent and 90% stenosis with tissue growth in the mid-stent. The authors concluded that the acute myocardial infarction occurred due to acute stent thrombosis caused by exogenous epinephrine administration. This report, however, raises important questions related to the cause and pathophysiology of these events. First, could bee sting anaphylaxis be aggravated by concurrent anti-allergic therapy in atopic diathesis individuals? The described patient was given intravenously, apart from epinephrine, methylprednisolone, chlorpheniramine maleate, and ranitidine. These 4 drugs that are given to treat anaphylaxis have been incriminated, paradoxically, as inducing mild or severe allergic reactions! Indeed, most epinephrine preparations contain sulfite as a preservative and antioxidant, which itself may trigger anaphylaxis in atopic individuals.[2,3] We must always bring in mind that allergens have additive effects and the more allergens an atopic patient is exposed to, the easier and quicker anaphylactic shock and Kounis syndrome appear.[3] Second, the administration of epinephrine was the cause of stent thrombosis or the anaphylactic reaction? The described patient was stented with a bare metal stent followed by 3 overlapping drug-eluting stents. Bare metal and drug-eluting stents have components namely stainless steel that is a combination of nickel, chromium, titanium, manganese, molybdenum, polymer coating, and eluted antiproliferative drugs such as paclitaxel, zotarolimus, and accompanying antiplatelet therapy that constitute an allergenic complex. This allergenic complex embedded in the coronary intima is applying continuous, persistent, and chronic hypersensitivity inflammation able to induce stent thrombosis manifesting as the Kounis hypersensitivity coronary syndrome.[4] Several reports have shown that stents attract, such as magnet eosinophils and mast cells that release inflammatory mediators locally and in the systemic circulation able to induce coronary spasm and stent thrombosis. For example, acute myocardial infarction, in the stented area, manifesting as Kounis syndrome has coincided with allergic reactions from contrast material, insect and larvae stings, nonsteroidal anti-inflammatory agents, and even with allergy to clopidogrel the drug that is given to prevent stent thrombosis![5,6] Third, can we always give epinephrine intravenously? Epinephrine is the cornerstone of treatment for anaphylaxis but it can aggravate the ischemia, prolong QTc interval, promote platelet aggregation, and induce coronary vasospasm and arrhythmias. According to the current guidelines, there is no absolute contraindication to epinephrine use in anaphylaxis. However, the use of intravenous epinephrine is still controversial in severe allergic reactions. It should be considered in patients with severe hypotension or cardiac arrest who do not respond to aggressive fluid resuscitation. Intramuscular use of epinephrine is the safer and preferred route of administration unless the patient has severe anaphylaxis.[7] All above support the view that the described patients acute myocardial infarction due to stent thrombosis following the intravenous epinephrine for bee sting-induced anaphylaxis was due to Kounis syndrome rather than to intravenous epinephrine administration. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Medication contaminants as a potential cause of anaphylaxis to vincristine: What about drug-specific antigens?

To the Editor: We have read with interest the report published in Pediatric Blood Cancer1 concerning five male and three female patients, with an average age of 5 years, who developed symptoms including respiratory problem, vomiting, flushing without hives, hypotension, mouth itch, headache, or cardiac arrest during or immediately after intravenous vincristine infusion. Mass spectrometry identified three molecules, two of which were likely related to the vinca alkaloids but the third was not related to them. Vincristine itself is a vinca alkaloid that can be obtained from theMadagascar periwinkle,Catharanthus roseus, that has been associated with allergic reactions including acute myocardial infarction of Kounis type.2–4 The authors admitted that neither the cause nor the mechanism of these reactions could be identified with certainty. Therefore, this report raises important issues concerning premedication, vincristine administration, and the value of further research in identifying the cause of such reactions. Antihistamines and corticosteroids are routinely administered as premedication in anesthesia, hematology, oncology, and in several other disciplines. However, H2–antihistamines, such as cimetidine,5 famotidine,6 and ranitidine,7 and H1–antihistamines, such as cetirizine,8 hydroxyzin,9 and pheniramine,7 can themselves induce severe anaphylactic reactions and shock, although rare. Furthermore, corticosteroids, drugs used to treat allergy, paradoxically can also induce anaphylactic reactions.10 Indeed, in the report of Hill et al.1 four of their patients had received premedications (antihistamines± steroids) prior to subsequent infusions. It is known that mast cells degranulate and release their mediators when approximately 1,000 bridges between IgE antibodies and the corresponding receptors inmast cell surface are achieved. IgE antibodies with different specificities can have additive effects and small, even subthreshold numbers of them can join forces and trigger the cells to release their mediators. This can happen when the patient is simultaneously exposed to the corresponding antigens. Indeed, clinical studies indicate that allergic patients simultaneously exposed to several allergens have more symptoms than monosensitized individuals.11 These data suggest that a possible sensitization should not be clinically evaluated as a consequence of exposure to a single drug but rather viewed in the context of potential sensitization to multiple drugs. Indeed, the reported four patients apart of vincristine were under the influence of antihistamines, steroids, and possible medication contaminants. The following tests would be of additional value in an effort to elucidate drug-induced allergic reactions12: serum-specific IgE measurements for the suspected drug—such tests include radioallergosorbent testing, enzyme linked immunosorbent assay, or fluoroenzyme immunoassay; drug provocation test, which is a controlled challenge with the drug suspected of causing the hypersensitivity reaction; and basophil activation test, which is a cytometry method of measuring drug-induced activation of basophil markers CD63 or CD203c. In pediatric patients who are taking chemotherapy and presenting unusual reactions, the detailed and careful previous history of diseases; adverse drug reactions and hypersensitivities together with measuring serum histamine, serum tryptase, eosinophils, and total IgEs; and ordering intradermal skin tests, where and when are appropriate and possible, would be of additional value for prevention and treatment of such reactions.

Bioresorbable stent thrombosis, lactic acid release and Kounis syndrome

In the very interestingmeta-analysis of 6 randomized trialswith 5588 patients [1], it was found that the Absorb bioresorbable vascular scaffolds compared with cobalt-chromium durable polymer everolimus-eluting stents had increased myocardial infarction and definite-or-probable stent thrombosis rates, at one year, namely 4.3% vs. 2.3% and 1.3% vs. 0.6% respectively. Theseworrisome resultswere attributed to procedural, structural and technical factors. The higher rate of thrombosis, with bioresorbable scaffolds, is partly understood and needs further clarification. The currently used bioresorbable scaffolds are composed of poly L-lactide (PLLA) skeleton covered by poly D,L-lactide (PDLLA) that elutes everolimus. These substances can induce inflammatory responses leading to thrombosis, systemic reactions and Kounis syndrome [2]. During scaffold degradation, acidic products accumulate and decrease the pH, fact that could trigger inflammatory and foreign body reactions in vivo. PLLA and PDLLA are degraded into lactic acid and finally into carbon dioxide and water via the Krebs cycle. Furthermore, lactic acid stimulates sensory neurons innervating the heart and induces similar pain with that encountered in angina and acute myocardial infarction!

Hypertrophic obstructive cardiomyopathy, yamaguchi syndrome and kounis syndrome: Clinical challenges

485 The Editor, In the interesting report concerning the case of an apical variant of hypertrophic cardiomyopathy also called as Yamaguchi syndrome published in Annals of Cardiac Anesthesia,[1] the authors stated that anesthetic management of these patients is similar to case of hypertrophic obstructive cardiomyopathy. Therefore, alleviating sympathetic stimulation such as avoiding tachycardia, maintaining normal sinus rhythm and euvolemia, and avoiding any increase in cardiac contractility is helpful. However, serious challenges concerning anaphylaxis, labor, anesthesia, and surgery should be always considered in anesthesia and surgery.

The ATAK complex (Adrenaline, Takotsubo, Anaphylaxis, and Kounis hypersensitivity -associated coronary syndrome) in neurological conditions

Sir, Takotsubo syndrome, transient left ventricular apical ballooning, takotsubo cardiomyopathy, apical ballooning syndrome, atypical apical ballooning, ampulla cardiomyopathy, broken heart syndrome, transient left ventricular dysfunction syndrome, and stress cardiomyopathy were named after a round-bottomed and narrow-necked fishing pot - takotsubo in Japanese - for trapping octopus because of its resemblance to left ventriculogram. In the interesting report published in Indian Journal of Critical Care Medicine,[1] a 48-year-old man with progressive loss of vision, hypotension, tachycardia, and acidosis was found to have takotsubo syndrome while the coronary arteries were normal. Computerized tomography revealed dense sellar-suprasellar mass lesion extending into the hypothalamus resembling pituitary adenoma with hypocortisolism suggesting hypopituitarism. With dobutamine, atenolol, and noradrenaline, his condition improved. This case raises some issues concerning neurological conditions, mental stress adrenaline, anaphylaxis, and Kounis syndrome. Mental stress commences with impulses from high brain cortical centers that are relayed through the limbic system to hypothalamus resulting in the release of corticotropin-releasing hormone (main coordinator of the mental stress response) and norepinephrine, serotonin, acetylcholine, proopiomelanocortin, adrenocorticotropic hormone, glucagon, growth hormone, and homocysteine that stimulate sympathetic nervous system. These substances can induce heightened cardiovascular activity, endothelial injury, induction of adhesion molecules on the endothelial cells, to which recruited inflammatory cells adhere and translocate to the arterial wall and finally myocardial damage. An acute phase response is engendered, resulting in production of cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, acute phase proteins, macrophage, mast cell, and platelet activation that eventually culminate in the development of Kounis syndrome.[2] Stress-induced cytokine production has been incriminated for multivessel coronary artery spasm at epicardial or microvascular levels that induce takotsubo cardiomyopathy. Inflammatory mediators released during anaphylaxis can induce coronary spasm and takotsubo syndrome and adrenaline given for anaphylaxis might contribute to coronary spasm and transient takotsubo syndrome. Adrenaline and noradrenaline released by the renin-angiotensin-aldosterone system together with histamine stimulate the release of more catecholamines by direct action on the adrenal medullary cells. Administration of catecholamines for hemodynamic support of anaphylactic shock would also increase the plasma catecholamines. Catecholamine increase in patients with angina, renders blood platelets more sensitive and more prone to aggregation and thrombosis. Therefore, measurement of anaphylactic inflammatory mediators including histamine, chymase, leukotrienes, thromboxane, and platelet activating factor or the use of corticosteroids or mast cell stabilizers for prevention and treatment may shed light on etiology and pathophysiology of takotsubo cardiomyopathy. The concurrence of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells constitute the Kounis syndrome.[3] Inflammatory cells, such as mast cells, T-cells, and macrophages, activate each other via multidirectional stimuli and release mediators capable to induce coronary events. Experimental findings suggest that cardiac mast cell activation by acute stress may contribute to myocardial ischemia through the release of histamine or proinflammatory mediators.[4] Therefore, takotsubo cardiomyopathy should be always considered in neurological conditions with prolonged addisonian crisis. Furthermore, Adrenaline, takotsubo, Anaphylaxis, and Kounis syndrome (ATAK) seem to constitute a challenging contemporary complex that needs inexorable “attack” to elucidate its etiology, pathophysiology, and treatment.[5] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest

Scorpion bite, a sting to the heart and to coronaries resulting in Kounis syndrome.

Sir, In the very interesting paper published in IJCCM,[1] the authors reported on a 14-year-old-boy who was bitten by scorpion and developed chest pain, vomiting, loose stools, cold sweating, raised jugular venous pressure, tachycardia and hypotension. Laboratory findings showed increased troponin T, proBNP and CPKMB, bilateral lung fluffy shadows, reduced ejection fraction, and ST segment elevation in II, III, aVF, V3, V4, V5, and V6, and T-wave inversion in I, aVL, V1 and V2 leads compatible with acute myocardial injury and pulmonary oedema. This case raises the following important questions on pathophysiology, treatment, and differential diagnosis of scorpion envenomation: Centruroides and parabuthus scorpions are associated primarily with neuromuscular toxicity, whereas androctonus, buthus, and mesobuthus scorpion envenomation is associated with cardiovascular involvement, resulting from hyperstimulation of autonomic centers release of catecholamines and vasoactive peptides. Since venom specific immunoglobulin E (IgEs) have been identified by using skin tests and IgE immunoblots and mast cell degranulation and histamine release are also involved in scorpion venom-induced-inflammatory pain, hypersensitivity cardiovascular involvement is also present[2] Myocardial infarction has been reported following scorpion envenomation on some occasions.[3,4] Scorpion envenomation may result in immediate late and delayed hypersensitivity reactions in susceptible individuals. Cardiovascular toxicity implies venom amount-dependent action with progressing effects, while hypersensitivity means inflammation causing either Kounis hypersenstivity-associated acute coronary syndrome or hypersensitivity myocarditis, which are not venom amount dependent and may arise at any time during or soon after envenomation. It seems likely that the described patient developed coronary vasospasm manifesting as Type I variant of Kounis syndrome progressing to myocardial injury.[5] Hypersensitivity or toxic myocarditis could not be confirmed because neither coronary angiography nor magnetic resonance imaging was available. Coronary angiography is normal in myocarditis while in Kounis syndrome may reveal the coronary spasm. Magnetic resonance imaging shows subendocardial concentration of gadolinium in Kounis syndrome while in myocarditis the gadoliniun is concentrated in subepicardial areas[5] Several studies have shown no significant difference in patients on steroids and in steroid-free patients in terms of mortality and intensive care unit length of stay. The hydrocortisone hemisuccinate regimen has limited effect in critically ill envenomated children and, therefore, it should not be recommended.[6] Antivenom combined with prazosin and dobutamine is indicated for cardiovascular effects and benzodiazepines for neuromuscular involvement. Adrenaline and fluid resuscitation – not glucocorticoids, antihistamines, or mast-cell stabilizers – are the mainstays of treatment for scorpion venom-induced anaphylaxis. However, administration of antihistamines and mast cell stabilizers, but not hydrocortisone, could be used as a supplementary treatment of life-threatening scorpion envenomation. The described patient developed a pulmonary edema and received corticosteroids but not prazosin. Alpha receptor stimulation plays an important role in the pathogenesis of pulmonary edema. The use of prazosin, a postsynaptic alpha blocker, is recommended for significant sympathetic symptoms. Cardiogenic pulmonary edema with arterial hypertension responds favorably to prazosin. Oral prazosin is fast acting, easily available, and highly effective. Corticosteroids are beneficial in interstitial noncardiogenic pulmonary edema. Scorpion envenomation is a complex condition, which requires rigorous action, meticulous treatment and careful follow-up.