Abstract
Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.
Highlights
The term “anaphylaxis” was previously used for IgE-mediated reactions only, whereas the term pseudo-allergic was used for similar clinical reactions, which occur via a non-IgE-dependent mechanism [1,2]
As it is not possible to distinguish anaphylactic from pseudo-allergic reactions clinically or by standard allergological investigations, a new definition has been suggested by the European Academy for Allergology and Clinical Immunology (EAACI)
As discussed in the previous chapters, these studies have several limitations and possible biases, and there are several facts that argue in favor of a pseudo-allergic mechanism: (1) most reactions occur upon first exposure, (2) there is a high rate of cross-sensitization to several Neuromuscular blocking agents (NMBA), (3) specific IgE is present in non-allergic individuals without a clear causal link to the anaphylactic reaction, and (4) there is an increased risk of a second anaphylactic reactions to NMBA in skin test-negative patients with previous reaction to another NMBA compared to patients without previous reaction [42]
Summary
The term “anaphylaxis” was previously used for IgE-mediated reactions only, whereas the term pseudo-allergic (or anaphylactoid) was used for similar clinical reactions, which occur via a non-IgE-dependent mechanism [1,2]. Both reactions may clinically present with hypotension, bronchospasm, and skin manifestations, typically urticaria [3,4]. The same symptoms might be seen in cases of non-immune mediated pharmacological adverse drug reactions [5]. Thereby, all immediate-type adverse drug reactions are named anaphylaxis with a further subclassification into allergic or non-allergic [6]. It has been shown that the anesthetist was able to correctly identify the culprit drug in only one third of all peri-operative reactions [9]
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