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Front. Immunol. | doi: 10.3389/fimmu.2019.02482

Refractory anaphylaxis: Data from the European Anaphylaxis Registry

 Wojciech Francuzik1, Sabine Dölle-Bierke1,  Macarena Knop2, Kathrin Scherer-Hofmeier3, Ewa Cichocka-Jarosz4, Blanca E. Garcia5, Roland Lang6, Ioana Maris7, 8, Jean-Marie Renaudin9 and Margitta Worm1*
  • 1Department of Dermatology, Venerology and Allergology, Charité Medical University of Berlin, Germany
  • 2Hospital of the University of Munich, Germany
  • 3University Hospital of Basel, Switzerland
  • 4Jagiellonian University Medical College, Poland
  • 5Complejo Hospitalario de Navarra, Spain
  • 6Paracelsus Medical University, Austria
  • 7Bon Secours Hospital Cork, Ireland
  • 8University College Cork, Ireland
  • 9Réseau d’Allergo-Vigilance (Allergy Vigilance Network), France

Refractory anaphylaxis (unresponsive to treatment with at least two doses of minimum 300 µg adrenaline) is a rare and often fatal hypersensitivity reaction. Comprehensive data on its definition, prevalence, and risk factors are missing. Using the data from the European Anaphylaxis Registry (11596 cases in total) we identified refractory anaphylaxis cases (n = 42) and analyzed these in comparison to a control group of severe anaphylaxis cases (n = 4820).
The data show that drugs more frequently elicited refractory anaphylaxis (50% of cases, p < 0.0001) compared to other severe anaphylaxis cases (19.7%). Cases elicited by insects (n = 8) were more often due to bees than wasps in refractory cases (62.5% vs 19.4%, p = 0.009). The refractory cases occurred mostly in a perioperative setting (45.2% vs. 9.05, p < 0.0001). Intramuscular adrenaline (as a first-line therapy) was administered in 16.7% of refractory cases, whereas in 83.3% of cases it was applied intravenously (significantly more often than in severe anaphylaxis cases: 12.3%, p < 0.0001). Second-line treatment options (e.g. vasopression with dopamine, methylene blue, glucagon) were not used at all for the treatment of refractory cases. The mortality rate in refractory anaphylaxis was significantly higher (26.2%) than in severe cases (0.353%, p < 0.0001).
Refractory anaphylaxis is associated with drug-induced anaphylaxis in particular if allergens are given intravenously. Although physicians frequently use adrenaline in cases of perioperative anaphylaxis, not all patients are responding to treatment. Whether a delay in recognition of anaphylaxis is responsible for the refractory case or whether these cases are due to an overflow with mast cell activating substances - requires further studies. Reasons for the low use of second-line medication (i.e., methylene blue or dopamine) in refractory cases are unknown, but their use might improve the outcome of severe refractory anaphylaxis cases.

Keywords: Anaphylaxis, adrenaline, Epinephrine, beta-blockers, Insect venom allergy, Drug allergic reactions, vasopression, Refractory

Received: 21 Nov 2018; Accepted: 04 Oct 2019.

Copyright: © 2019 Francuzik, Dölle-Bierke, Knop, Scherer-Hofmeier, Cichocka-Jarosz, Garcia, Lang, Maris, Renaudin and Worm. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Margitta Worm, Charité Medical University of Berlin, Department of Dermatology, Venerology and Allergology, Berlin, Germany,