CORRESPONDENCE: LETTER TO THE EDITOR
Allergic Reactions Following Implantation of Drug-Eluting Stents: A Manifestation of Kounis Syndrome?
Nicholas G. Kounis, MD, FESC, FACC*,
George N. Kounis, MD,
Sophia N. Kouni, MSc,
George D. Soufras, MD,
Constantinos Niarchos, MD and
Andreas Mazarakis, MD
* Medical Sciences, Patras Highest Institute of Education and Technology, Queen Olgas Square, 7 Aratou Street, Patras 26221, Greece (Email: ngkounis{at}otenet.gr).
In the very interesting study (1) and editorial (2) published in the January 3, 2006 issue of the Journal, the investigators reported and commented on 17 patients who developed allergic reactions after implantation of drug-eluting stents (DES). These reactions included rash, hives, itching, dyspnea, and fever. However, four patients developed in-stent thrombosis and died at 4, 5, 18, and 18 months after implantation, respectively. Eosinophilia and elevated immunoglobulin E (IgE) titers accompanied the allergic reactions. One patient had implanted a TAXUS (Boston Scientific Corp., Natick, Massachusetts) stent impregnated with the antineoplastic agent paclitaxel, and the other three had CYPHER (Cordis Corp., Miami Lakes, Florida) stents impregnated with the anti-inflammatory agent rapamycin. The other components of the stents include the polymer coating and the metal stent itself. The investigators concluded that hypersensitivity to DES is a real entity that causes serious clinical sequelae, and they recommended continuous vigilance and surveillance for any allergic reactions in patients receiving DES.
The Kounis syndrome (3) was described 15 years ago as the concurrence of acute coronary events with allergic or hypersensitivity reactions as well as anaphylactic or anaphylactoid insults. Arachidonic acid metabolites such as leukotrienes and thromboxane; proteolytic enzymes such as chymase and tryptase; histamine and a variety of cytokines and chemokines released during the activation of various interrelated and interacting inflammatory cells such as macrophages, T-lymphocytes, and mast cells have all been incriminated to induce Kounis syndrome. Two variants of Kounis syndrome have been described recently (4). The type I variant, includes patients with normal coronary arteries and represents a manifestation of endothelial dysfunction; the type II variant, includes patients with culprit but quiescent preexisting atheromatus disease. Causes of Kounis syndrome (5) include various conditions, a variety of environmental exposures, and many drugs such as antibiotics, contrast media, intravenous anesthetics, analgesics, skin disinfectants, corticosteroids, thrombolytics, anti-inflammatories, and antineoplastics. Antineoplastics capable of inducing acute coronary syndrome (5) are the antimetabolite 5-fluorouracil (Adrucil, UpJohn Pharmaceuticals, Kalamazoo, Michigan), its prodrug capecitabine (Xeloda, Roche Laboratories, Nutley, New Jersey), the alkaloid cisplatin (Platinol, Bristol-Myers Squibb), the antimicrotubule paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, New Jersey), the interleukin-2 agent denileukin difitox (Ontak, Ligand Pharmaceuticals, San Diego, California), the vinca alkaloids, and interferons.
All three components of DES could be responsible for inducing allergic reactions and Kounis syndrome. Polymers, like those in latex and vinyl gloves, have been reported to induce allergic reactions and Kounis syndrome (6). Antineoplastics and anti-inflammatory drugs can also induce Kounis syndrome (6). Patients positive for allergic patch-test reactions to stent metal components nickel and molybdenum appear to have increased rates of in-stent thrombosis (7). The inflammatory cells found at autopsy to infiltrate the intima, the media, and the adventitia in one of the patients who died from in-stent thrombosis (8) were the same—namely lymphocytes, plasma cells, macrophages, and eosinophils—with those participating in the process of Kounis syndrome. Indeed, the proportion of 262 cases of allergic reactions in 2 million DES insertions is very low, but it seems likely that some cases might go unreported; thus, it is anticipated that many more cases will be encountered in the coming years.
Responding, therefore, to the appeal of the RADAR (Research on Adverse Drug events And Reports) project and until further studies characterizing the incidence and the course of the reactions and confirming or predicting the DES allergy are undertaken, we recommend, especially in atopic individuals, the following: 1) careful history of adverse drug reactions and allergies in patients receiving DES; 2) intradermal skin tests for every DES component and desensitization strategies; 3) antibody testing including enzyme-linked immunosorbent assay and radioallergosorbent test for every DES component; 4) monitoring the levels of tryptase, histamine, and arachidonic acid products immediately after the allergic reaction appears; and 5) considering the use of corticosteroids and mast-cell stabilizers when the allergic reaction appears. The latter have also abrogated late thrombotic events experimentally (9).
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References
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- Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stentsa review of available cases from the Research on Adverse Drug events And Reports (RADAR) project. J Am Coll Cardiol 2006;47:175-181.[Abstract/Free Full Text]
- Azarbal B, Currier JW. Allergic reactions after the implantation of drug-eluting stents J Am Coll Cardiol 2006;47:182-183.[Free Full Text]
- Kounis NG, Zavras GM. Histamine-induced coronary artery spasmthe concept of allergic angina. Br J Clin Pract 1991;45:121-128.[ISI][Medline]
- Nikolaidis LA, Kounis NG, Grandman AH. Allergic angina and allergic myocardial infarctiona new twist on an old syndrome. Can J Cardiol 2002;18:508-511.[ISI][Medline]
- Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction)a natural paradigm?. Int J Cardiol 2006;110:7-14.[CrossRef][ISI][Medline]
- Soufras GD, Ginopoulos PV, Papadaki PJ, et al. Penicillin allergy in cancer patients manifesting as Kounis syndrome Heart Vessels 2005;20:159-163.[CrossRef][ISI][Medline]
- Kawano H, Koide Y, Baba T, et al. Granulation tissue with eosinophil infiltration in the restenotic lesion after coronary stent implantation Circ J 2004;68:722-723.[CrossRef][ISI][Medline]
- Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stentShould we be cautious?. Circulation 2004;109:701-705.[Abstract/Free Full Text]
- Nemmar A, Hoet PHM, Vermylen J, et al. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters Circulation 2004;110:1670-1677.[Abstract/Free Full Text]
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