Emmanouil Chourdakis

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.

The euphoria, the warnings and the downfall of the current bioresorbale stents: could the journey be restarted?

Correspondence to Nicholas G. Kounis, M.D. Department of Cardiology, University of Patras Medical School, Queen Olgas Square, 7 Aratou St, Patras 26221, Greece Tel: +30-2610279579 Fax: +30-2610279579 E-mail: ngkounis@otenet.gr Bioresorbable scaffolds have been developed in an effort to avoid metals in the coronary arteries, to maintain vessel pulsatility and to diminish late and especially very late stent thrombosis. In the recent very interesting paper published in Korean Journal of Internal Medicine [1] concerning 105 consecutive patients with bioresorbable stent implantation neither stent thrombosis, nor deaths and urgent revascularizations occurred during hospitalization and the follow-up period. Whereas the mean follow-up was 105.4 ± 74.9 days, 43 patients had at least 6-month follow-up period and clinical follow-up at 6-month was available for all period-eligible patients. The patients received dual antiplatelet therapy with aspirin and an adenosine diphosphate receptor antagonist (clopidogrel, ticagrelor, or prasugrel) for at least 12 months and cilostazol had been added to the above therapy at the physician’s discretion. Could the latter have contributed to the above excellent results that making the journey to restart, for these devices, after the initial euphoria, warnings and final abandoning? THE INITIAL EUPHORIA: NIL STENT THROMBOSIS

Negative association between previous allergy and intradermal tests for rocuronium and cisatracurium: what about additional tests?

Anesthesiology [1] concerning the relationship between intradermal tests for neuromuscular blocking agents in patients with history of allergy to various anesthetic agents, no association between allergy history and positive skin test was found. This report raises the following important issues with respect to anaphylaxis during anesthesia, rocuronium-sugammadex complex, additive anaphylactic effect of anesthetic agents, and additional diagnostic tests in anesthesia: 1. Anaphylaxis during anesthesia constitutes a severe adverse event, rendering its identification and early treatment imperative. and partially explains its causality, pathophysiology, and mortality. The incidence of hypersensitivity reactions during anesthesia varies from 1 : 3,180 to 1 : 10,000 based on several prospective studies; however, this incidence might be underestimated [2]. Multiple causative factors have been implicated, including drugs, liquids, metal devices, materials, and procedures during anesthesia. The incidence of perioperative reactions in Spain was 1 : 381, involving mild skin reactions (48%) and cases of anaphylaxis (52%). On rare occasions, skin rash might be absent, as seen with drug reactions in eosinophilia and Kounis syndrome. 2. Sugammadex induces selective reversal of aminosteroidal non-depolarizing neuromuscular blockers acting as muscle relaxants, such as rocuronium and vecuronium. Sugammadex is a modified gamma cyclodextrin with eight carboxyl thio ether groups at the sixth carbon positions, creating a cavity that can encapsulate the rocuronium molecule and further produce the rocuronium-sugammadex complex. The rocuronium-sugammadex complex can induce anaphylactic reactions, and is also suggested to induce Kounis syndrome [3]. Notably, during anesthesia, patients may be exposed to various agents such as propofol, remifentanil, rocuronium, fentanyl, and sugammadex, all able to induce immunological changes. 3. In a recent report [4], a 46-year-old male patient developed tachycardia with ST elevation in the inferior leads and shock without cutaneous manifestations following propofol, remifentanil, rocuronium, fentanyl, and sugammadex administration during anesthesia for laparoscopic surgery. Two years later, a similar anaphylactic reaction occurred, this time accompanied by generalized erythema, following perioperative administration of rocuronium and sugammadex. Serum histamine and tryptase levels were increased, whereas skin prick tests were negative for rocuronium and sugammadex but positive for histamine and rocuronium-sugammadex complex. The authors wondered how rocuronium-sugammadex complex formation could induce imLetter to the Editor

Acute Myocardial Infarction Induced by Anaphylaxis in China: The Kounis Syndrome

In the very interesting report published in Chinese Medical Journal[1] concerning a 65‐year‐old hypertensive and hyperlipidemic male patient, with stent implantation 5 years previously, the patient developed anaphylactic shock accompanied by chest discomfort, palpitation, itchiness, nausea, vomiting, dyspnea, wheezing, abdominal pain, sweating, pale complexion, dizziness, and syncope following bread and milk consumption. The clinical symptomatology was associated with electrocardiographic and laboratory evidence of acute inferolateral myocardial infarction, and the patient recovered with epinephrine, antiallergic, and myocardial infarction protocol therapy including ticagrelor and Clexane. Coronary arteriography demonstrated lesions in the left trunk and the three coronary branches, but the stented areas were unobstructed. The allergen test revealed a Grade 2 (2.11 kUA/L) for wheat and Grade 0 for milk.

Significant Iatrogenic High Flow AV-Communication after MitraClip Treated with Endovascular Covered Stent

The percutaneous mitral valve repair therapy (MitraClip) constitutes an alternative for high peri- operative risk patients with severe symptomatic mitral regurgitation. Various complications, especially access -related have been described post mitraclip procedure as iatrogenic femoral arteriovenous fistulas with an incidence approximately of 0.1-1.5% following cardiac catheterization. We report a case of a 84-year-old male with a high flow AVcommunication at the puncture site after mitral clip procedure accompanied with decompensated heart failure symptoms and NTproBNP increase treated with endovascular covered stent.