Kounis syndrome: A concise review with focus on management

Highlights

• Kounis syndrome pathogenesis and epidemiology have been described.

• Treatment of Kounis syndrome has been discussed.

• A treatment flow-chart has been proposed.

• This narrative review has been conducted analyzing the scientific literature.

• More recent scientific evidence have been highlighted into this review.

Abstract

Kounis syndrome is defined as the co-incidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergenic event and was first described by Kounis and Zavras in 1991 as an allergic angina syndrome.

Multiple causes have been described and most of the data in the literature are derived from the description of clinical cases – mostly in adult patients – and the pathophysiology remains only partly explained.

Three different variants of Kounis syndrome have been defined: type I (without coronary disease) is defined as chest pain during an acute allergic reaction in patients without risk factors or coronary lesions in which the allergic event induces coronary spasm that electrocardiographic changes secondary to ischemia; type II (with coronary disease) includes patients with pre-existing atheromatous disease, either previously quiescent or symptomatic, in whom acute hypersensitive reactions cause plaque erosion or rupture, culminating in acute myocardial infarction; more recently a type-III variant of Kounis syndrome has been defined in patients with preexisting coronary disease and drug eluting coronary stent thrombosis.

The pathogenesis of the syndrome is discussed, and a therapeutic algorithm is proposed.

Introduction

Kounis syndrome (KS) is defined as the co-incidental occurrence of an acute coronary syndrome (ACS) with hypersensitivity reactions following an allergenic event. It was first described by Kounis and Zavras in 1991 as an allergic angina syndrome [1].

Multiple causes for KS have been described so far, including drugs, insect stings, foods, environmental exposures, medical conditions and following the performance of skin prick test to amoxicillin [2], [3], [4].

Most of the data in the literature are derived from the description of isolated clinical cases (almost 300) corresponding principally to adults, so the exact pathophysiological mechanisms remain elusive.

An interesting case series of children presenting with KS has also been published [5]. Two of them developed an allergic reaction to amoxicillin/clavulanic acid, and the other two after a hymenoptera sting. All four children developed chest pain associated with ST segment elevation and positive cardiac enzymes, while serum tryptase level was elevated only in one of them.

Hitherto, three different variants of KS have been defined [6], [7], [8]:

• Type I (without coronary disease): chest pain during an acute allergic reaction in patients without risk factors or coronary lesions in which the allergic event induces coronary spasm that electrocardiographic changes secondary to ischemia. The cardiac enzymes and troponins may be either normal or reflect progression toward acute myocardial infarction. The explanation for this type would be endothelial dysfunction and/or microvascular angina have been posit as probable pathophysiological mechanisms.

• Type II (with coronary disease): includes patients with pre-existing atheromatous disease, either previously quiescent or symptomatic, in which acute hypersensitive reactions cause plaque erosion or rupture, culminating in acute myocardial infarction.

• More recently a type-III variant of KS has been defined in patients with pre-existing coronary disease and drug eluting coronary stent thrombosis [9]. In these patients, Giemsa and hematoxylin–eosin staining reveals the presence of mast cells and eosinophils, respectively [10]. Virmani [11] first described in 2004 a case of hypersensitivity vasculitis in a patient with very late drug-eluting stent thrombosis. More recently, the hallmarks of hypersensitivity reactions have been demonstrated in autopsy specimens of patients with very late drug-eluting stent thrombosis, while using intravascular ultrasound in the same patients a high incidence of incomplete stent apposition and vessel remodeling has been demonstrated [12]. Very late stent thrombosis could be another manifestation to be recognized as part of the Kounis syndrome.

This review article is based on scientific publications on Kounis syndrome and the selection of articles has been made searching on PubMed these terms: Kounis syndrome; allergic angina; and acute allergic coronary syndrome. The search was not limited for a time period. As the great majority of literature data come from single case-reports or small case-series, all the published data have been taken into consideration and summarized into this review article.