LAUSR

Dear Editor-in-Chief, We read the recent update on quinolone allergy by Doña I et al. [1] with great interest. Although this review is elegantly written and contains valuable information for the reader of the Journal, we would like to raise some points and comments, particularly about the immediate hypersensitivity reactions. In their epidemiology section, the authors state that these immediate reactions are genuine immune-mediated reactions that result from mast cell and/or basophil degranulation triggered by cross-linking of IgE/FcεRI. However, the authors seem to ignore that the quinolone scene has its own particularities, viz. many patients are drug-naïve [2, 3] and frequently do not show drug-specific IgE responses [4, 5]. Consequently, it is unlikely these hypersensitivity reactions mainly to result from an adaptive Th2-polarized immune response with IgE/FcεRImediated degranulation of effector cells. Actually, since the first description in 2015 by McNeil et al. [6], an increasing number of studies [7–11] have demonstrated and/or speculated upon the ability of various drugs (including quinolones) to trigger mast cell activation and degranulation via occupation of the promiscuous human Mas-related G-protein receptor X2 (MRGPRX2). This non-immune alternative mechanism of mast cell activation not only explains why many patients are drug-naïve and frequently do not show drug-specific IgE responses, it also explains the skin test uncertainties associated with these potent non-specific histamine-liberating antibiotics [12–14] and the poor sensitivity of basophil activation tests, especially assays using the anaphylactic degranulation marker CD63 as a readout [11, 15, 16]. As a matter of facts, unlike cutaneous mast cells, circulating basophils only barely express MRGPRX2 [17] and will therefore not respond in steady-state conditions of traditional basophil activation test. Whether basophils can be conditioned to express MRGPRX2 and subsequently applied to explore the ability of drugs and related compounds to activate, this receptor remains to be established. For the time being, comparative analysis between MRGPRX2 mast cells and MRGPRX2 basophils might add to unveil the mechanism beyond immediate quinolone hypersensitivity. Moreover, basophil activation experiments might not only help to resolve between IgE/FcεRI-dependent and off-target MRGPRX2 quinolone hypersensitivity [11] but also to explore the causes of cross-reactivity between structurally closely related nonspecific histamine releasers [18]. In essence, we appreciated the comprehensive review on quinolone allergy by Doña et al. [1]. Nevertheless, we felt appropriate to update the manuscript with the growing data on the recently described MRGPRX2 receptor as an alternative explanation for mast cell activation. Knowledge of this receptor might help to explain some clinical and diagnostic peculiarities of the quinolone scene. This comment refers to the article available at https://doi.org/10.1007/ s11882-017-0725-y.