George D. Soufras

Penicillin allergy in cancer patients manifesting as Kounis syndrome.

Two cases of allergic angina and allergic myocardial infarction (Kounis syndrome) following penicillin administration are described. The patients suffered from lung and mandible neoplasms and had previously received several courses of antineoplastic therapy without any sequelae. One patient had normal coronary arteries (type I variant of the syndrome) and the other had coronary artery disease with previous myocardial infarction (type II variant of the syndrome). The allergic reaction following penicillin administration seemed to have triggered the development of an acute coronary artery spasm in the first patient and an acute myocardial infarction in the second. This report shows that susceptible individuals expressing a magnified mast cell degranulation effect may be more vulnerable to coronary artery spasm and plaque erosion or rupture.

White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease.

Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil–lymphocyte ratio and eosinophil–leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil–leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods.

Anaphylactic Shock: Kounis Hypersensitivity-Associated Syndrome Seems to be the Primary Cause

Experiments have shown that anaphylaxis decreases cardiac output; increases left ventricular end diastolic pressure; induces severe early acute increase in respiratory resistance with pulmonary interstitial edema; and decreases splanchnic, cerebral, and myocardial blood flow more than what would be expected from severe arterial dilation and hypotension. This is attributed to the constrictive action of inflammatory mediators released during anaphylactic shock. Inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet-activating factor (PAF), and a variety of cytokines and chemokines constitute the pathophysiologic basis of Kounis hypersensitivity-associated acute coronary syndrome. Although the mechanisms of anaphylactic shock still remain to be elucidated, myocardial involvement due to vasospasm-induced coronary blood flow reduction manifesting as Kounis syndrome should be always considered. Searching current experimental and clinical literature on anaphylactic shock pathophysiology, causality, clinical appearance, and treatment via PubMed showed that differentiating global hypoperfusion from primary tissue suppression due to mast cell mediator constrictive action on systemic arterial vasculature is a challenging procedure. Combined tissue suppression from arterial involvement and peripheral vasodilatation, perhaps, occur simultaneously. In cases of anaphylactic shock treatment targeting the primary cause of anaphylaxis together with protection of coronary vasculature and subsequently the cardiac tissue seems to be of paramount importance.

Systolic and diastolic septal and posterior wall echocardiographic measurements in normal subjects.

M-mode echocardiographic measurement of septal and left ventricular ex cursions and velocities was attempted in 109 subjects. Seventy subjects had ade quate echocardiograms enabling detailed measurement. Two groups of subjects were studied: a group of normal adults aged nineteen to seventy-eight years and a group of normal juveniles aged nine to eighteen years. The posterior wall excursion (PWE), systolic septal excursion (SSE), diastolic septal excursion (DSE), and diastolic septal velocity (DSV) did not differ in these groups. There were significant differences in the posterior wall excursion during isovolumetric contraction (B-Ce, p < 0.002), mean posterior wall velocity (PWV mean, p < 0.002), and systolic septal velocity (SSV, p=0.05) between the two groups. The measurements were obtained by using the recently published method of the specific points for labeling and description of the wall motion.

Combined etiology of anaphylactic cardiogenic shock: amiodarone, epinephrine, cardioverter defibrillator, left ventricular assist devices and the Kounis syndrome.

Anaphylactic shock is a life-threatening condition which needs detailed and mediculous clinical assessment and thoughtful treatment. Several causes can join forces in order to degranulate mast cells. Amiodarone which is an iodine-containing highly lipophilic benzofuran can induce allergic reactions and anaphylactic shock in sensitized patients. Epinephrine is a life saving drug, but in sulfite allergic patients it should be given with caution due its metabisulfite preservative. Metals covering cardiac defibrillators and pacemakers can act as antigens attached to serum proteins and induce allergic reactions. In anaphylactic shock, myocardial involvement due to vasospasm-induced coronary blood flow reduction manifesting as Kounis syndrome should be always considered. Clinically, combined treatment targeting the primary cause of anaphylaxis together with protection of cardiac tissue seems to be of paramount importance.

Foods, Drugs and Environmental Factors: Novel Kounis Syndrome Offenders

Kounis syndrome is hypersensitivity coronary disorder induced by various types of environmental exposures, drugs, conditions and stents. Allergic, hypersensitivity, anaphylactic and anaphylactoid reactions are associated with this syndrome. The disorder manifests as coronary spasms, acute myocardial infarction and stent thrombosis and affects the cerebral and mesenteric as well as coronary arteries. Importantly, its manifestations are broad and its etiology is continuously increasing. Recently, a variety of unusual etiologies have been reported including Anisakis simplex, scombroid syndrome, the use of Gelofusin or ultrasound contrast agents, kiwifruit, fly bites, and bee stings. Furthermore, losartan and the paradox of corticosteroid allergy have been implicated as possible causes. Although not rare, Kounis syndrome is infrequently diagnosed. Therefore, awareness of its etiology, manifestations and pathophysiology is important for providing the proper diagnosis and treatment and determining prognosis.

Thrombotic responses to coronary stents, bioresorbable scaffolds and the Kounis hypersensitivity-associated acute thrombotic syndrome

Percutaneous transluminal coronary angioplasty with coronary stent implantation is a life-saving medical procedure that has become, nowadays, the most frequent performed therapeutic procedure in medicine. Plain balloon angioplasty, bare metal stents, first and second generation drug-eluting stents, bioresorbable and bioabsorbable scaffolds have offered diachronically a great advance against coronary artery disease and have enriched our medical armamentarium. Stented areas constitute vulnerable sites for endothelial damage, endothelial dysfunction, flow turbulence, hemorheologic changes, platelet dysfunction, coagulation changes and fibrinolytic disturbances. Implant surface attracts several proteins such as albumin, fibronectin, fibrinogen, and complement that lead to complement system activation. Macrophages recognize the implant as foreign substance due to protein adsorption and its continuous presence results in macrophage differentiation and fusion into foreign body giant cells. Polymer coating, stent metallic platforms and the released drugs can act as strong antigenic complex that apply continuous, repetitive, persistent and chronic hypersensitivity irritation to the coronary intima. The concomitant administration of oral antiplatelet drugs and environmental exposures can induce hypersensitivity inflammation. A class of platelets, activated via high-affinity and low-affinity IgE hypersensitivity receptors FCγRI, FCγRII, FCεRI and FCεRII, can induce Kounis hypersensitivity-associated thrombotic syndrome inside the stented coronaries. Type III variant of this syndrome is diagnosed when coronary artery stent thrombosis is associated with thrombus infiltrated by eosinophils or mast cells and/or when coronary intima, media and adventitia adjacent to stent, is infiltrated by eosinophils or mast cells. Careful history of hypersensitivity reactions to all implanted materials and concomitant drugs with monitoring of inflammatory mediators as well as lymphocyte transformation studies to detect hypersensitivity must be undertaken in order to avoid disastrous consequences. Food and Drug Administration recommendations for coronary stent implantation should be applied also to bioresorbable scaffolds. Further studies with inert and non-allergenic implants are necessary.

Coronary stent thrombosis: beware of an allergic reaction and of Kounis syndrome.

During their everyday practice, physicians are encountering some unexpected, peculiar, bizarre, strange, surprising, extraordinary and astonishing events that need quick explanation and emergency treatment. According to these events, patients with coronary stent implantation who accidentally developed an allergic reaction elsewhere in the human body from various causes developed, contemporarily, the much feared intrastent thrombosis. For example, acute myocardial infarction, in the stented area, has coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography.1 Stent thrombosis has been associated with allergic symptoms such as glottis edema, cold sweat, and tongue enlargement following a flavonate-propyphenazone administration a week after stent implantation.2 Intrastent thromboses have also been reported following insect and larvae sting-induced allergic reactions.3 Late drug eluting stent thrombosis defined as type III variant of Kounis syndrome4 has occurred following an allergic reaction to non steroidal anti-inflammatory agent acemetacine.5 The astonishing event is that even an allergic reaction to clopidogrel,6 the drug that is given to prevent stent thrombosis, itself has induced stent thrombosis! An additional report published in Indian Heart Journal7 was referred to a 60-year-old male patient with stent implantation for critical left anterior descending coronary artery stenosis who developed stent thrombosis following a snake bite. This patient was thrombolysed and his coronary angiogram, 5 days later, revealed patent stent with TIMI III flow and no evidence of thrombus. All above reports were concerning patients who were receiving multiple medications, known to induce allergic reactions, following stent implantation. Therefore, one can assume that stents, like magnet, attract inflammatory cells and constitute the area of possible mast cell and platelet activation.

Accumulation of eosinophils, mast cells, and basophils in the spleen and the coronary arteries in anaphylactic deaths: is the Kounis hypersensitivity associated syndrome present?

In a very interesting study published in Forensic Science,Medicine, and Pathology [1] it was found that measure-ment of eosinophils and mast cells in the spleen combinedwith serum tryptase measurement could diagnose anaphy-laxis and anaphylactic death with a high degree of cer-tainty. The authors stated that anaphylactic death cannot bediagnosed by autopsy alone or by counting mast cells in thelung and airways because these methods have failed to giveconsistent results. The search for other tissues infiltrated byallergic inflammatory cells could prove of paramountimportance in diagnosing anaphylactic sudden death. Theyrecommended that splenic tissue should be sampled forimmunohistochemical examination in all cases of unwit-nessed sudden death.Eosinophils, mast cells, and basophils are importanteffector cells in the allergic response and they have beenimplicated in the pathogenesis of anaphylaxis. Whilediagnosing the cause of sudden death is a challenging taskfor both physicians and forensic pathologists, anaphylacticetiology is rarely suspected. Frequently, sudden death casesare attributed to myocardial involvement, but unrecognizedanaphylaxis may accompany up to 13 % of sudden unex-pected deaths in adults [2]. There is experimental andclinical evidence that anaphylaxis is frequently associatedwith myocardial involvement due to coronary artery spasmand thrombosis manifesting as Kounis type I and Kounistype II variant [3]. Some experiments have shown thatanaphylactic cardiac damage is not due to peripheralvasodilation but is the result of the action of anaphylacticmediators on the coronary vasculature [4]. Clinically, thereare patients with anaphylactic cardiac shock who do notrespond to fluid replacement but need anti-allergic andcurrent myocardial infarction protocol treatment, thusdenoting that the heart and especially the coronary arteriesare primarily affected [5, 6]. However, differentiatingglobal myocardial hypoperfusion from a primary cardiacmyocardial suppression due to mast cell mediator action isclearly challenging and combined myocardial suppressionand peripheral vasodilatation might occur simultaneously.There are reports of sudden death due to coronary arteryspasm in which the coronary arteries are involved. In apatient with repeated episodes of coronary spasm, who diedsuddenly following cessation of his treatment, the numberof adventitial mast cells was found to be increased [7]. Inthis patient, histologic sections in all three major coronaryarteries, including the area of spasm, were stained withtoluidine blue and showed increased mast cells. In the samereport, two additional subjects with sudden cardiac deathalso had increased mast cells in their coronary arteries withthe highest counts in atherosclerotic and hemorrhagic pla-ques. Furthermore, coronary arteries of cardiac patients arehyper-reactive and contain stores of amines deriving frominflammatory cells that are the main culprits in inducingcoronary spasm [8]. Type I and type II variants of theKounis syndrome have led to coronary artery spasm andsudden death in two patients with drug-eluting stents. It is

Thrombus Formation Patterns in HeartMate II Continuous-Flow Left Ventricular Assist Devices: A Multifactorial Phenomenon Involving Kounis Syndrome?

Metallic devices are increasingly used in contemporary cardiological practice. They include coronary stents, artificial cardiac valves, bioprostheses for transcatheter aortic valve replacement, closure devices for patent foramen ovale and atrial septal defects, pacemakers, defibrillators, and left ventricular assist devices. Metals constitute the main components of these devices. Metal anions eluted from the components attached to circulating proteins can act as sensitizers able to induce hypersensitivity inflammation and thrombosis. Allergy to nickel occurs in up to one fourth of the population in several areas of the world and is the most frequent cause of allergic contact dermatitis. The HeartMate II device is made from titanium with ruby bearing. Titanium metal ions from HeartMate II are eluted through the action of blood, saline, proteins, and mechanical stress that can induce hypersensitivity and immune dysfunctions rendering titanium no longer biologically inert. An unexpected high rate of thrombosis with substantial morbidity and mortality has been observed with the use of this device, making the search of causality of thrombosis mandatory to predict and prevent this daunting complication. Although the cause of thrombosis seems to be multifactorial, careful history-taking regarding hypersensitivities, monitoring of inflammatory mediators, and lymphocyte transformation studies should be always performed in sensitive patients.