Refractory Anaphylaxis: Data From the European Anaphylaxis Registry

Abstract

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 (11,596 cases in total) we identified refractory anaphylaxis cases (n = 42) and analyzed these in comparison to a control group of severe anaphylaxis cases (n = 4,820). 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.

Precision Medicine in Hymenoptera Venom Allergy: Diagnostics, Biomarkers, and Therapy of Different Endotypes and Phenotypes

“…Using the data from the European Anaphylaxis Registry (11,596 cases in total), 42 cases of refractory anaphylaxis of different origin were identified and compared to a control group of severe anaphylaxis cases (n = 4820). Cases elicited by insects were very few (n = 8) and often due to bee stings (76). Specific risk factors were not identified in Hymenoptera venom-allergic patients.…”

The association between neutrophil-to-lymphocyte ratio and anaphylaxis refractory to epinephrine treatment

“…The term 'refractory anaphylaxis' is not clearly defined. We used the definition from a previous study [6], which described refractory anaphylaxis as a condition that required more than two doses of 0.3 mg intramuscular epinephrine for complete symptom resolution. According to the definition, the enrolled patients were divided into two groups: refractory and non-refractory anaphylaxis.…”

“…A previous study by Korenblat et al reported that 17 out of 105 patients (16.2%) required three or more intramuscular epinephrine injections [28]. A more recent analysis of the European Anaphylaxis Registry by Francuzik et al reported that only less than 1% of severe anaphylaxis cases were refractory to epinephrine treatment [6]. The variation in disease prevalence may be because of epidemiologic factors.…”

“…However, some patients follow a more severe clinical course, where symptoms are refractory to intramuscular epinephrine injections [5]. According to a previous study, 0.37% of all anaphylaxis cases required more than two intramuscular epinephrine injections [6]. These patients, in whom anaphylaxis was triggered mostly by drugs, were at a higher risk of death and required admission to the intensive care unit and additional treatment measures.…”

Using National Registries to Identify Targeted Therapies for Refractory Urticaria

“…Well-maintained registries provide a temporal profile of how chronic conditions are being managed, e.g., the Finnish National Anaphylaxis Registry and the European Anaphylaxis Registry (refractory anaphylaxis data) [5, 6]. However, such data is only effective in leading to policy change if it remains highly accurate from the primary point of entry to the methodologies used to interpret and analyse it.…”