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• W3091180964 abstract "Editor—We read with great interest the paper by Suzuki and colleagues1Suzuki Y. Liu S. Kadoya F. Takasaki Y. Yorozuya T. Mogi M. Association between mutated Mas-related G protein-coupled receptor-X2 and rocuronium-induced intraoperative anaphylaxis.Br J Anaesth. 2020; 125: e446-e448Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar about the association between the Mas-related G protein-coupled receptor-X2 (MRGPRX2) and rocuronium-induced perioperative anaphylaxis. The authors describe a patient who experienced severe perioperative anaphylaxis. Based on a positive intradermal skin test (IDT) and a negative serum-specific IgE (sIgE) antibody result to rocuronium, the authors posit this reaction to have resulted from occupation of MRGPRX2 by the aminosteroid-derived neuromuscular blocking agent (NMBA) rocuronium. However, we would like to express some comments and concerns about their diagnosis and interpretation of the data. Perioperative anaphylaxis constitutes a significant condition with serious consequences of diagnostic mismanagement.2Harper N.J.N. Cook T.M. Garcez T. et al.Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6).Br J Anaesth. 2018; 121: 172-188Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar In this respect, firstly establishing the correct cause of the reaction and secondly resolving between IgE- and MRGPRX2-dependent reactions are critical for NMBA stewardship. In this case, the diagnosis of rocuronium hypersensitivity relied upon a positive IDT with undiluted rocuronium (10 mg ml−1) without details about injection volume, injection bleb, or final wheal and flare reaction. Most importantly, the test concentration is 200-fold the maximum non-irritative concentration of 0.05 mg ml−1 as recommended for IDT in the recent European Academy of Allergy and Clinical Immunology position paper on the investigation of perioperative immediate hypersensitivity reactions.3Garvey L.H. Ebo D.G. Mertes P.M. et al.An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions.Allergy. 2019; 74: 1872-1884Crossref PubMed Scopus (42) Google Scholar Therefore, a false-positive result of IDT cannot be excluded, as this concentration is likely to induce wheal and flare responses in healthy control individuals.4Mertes P.M. Moneret-Vautrin D.A. Leynadier F. Laxenaire M.C. Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers.Anesthesiology. 2007; 107: 245-252Crossref PubMed Scopus (64) Google Scholar Moreover, it seems that not all compounds that the patient was exposed to were tested (e.g. remifentanil); other important compounds (e.g. latex and chlorhexidine) were simply not investigated, and for lidocaine and cefazolin, investigations should have included a challenge test.5Garvey L.H. Ebo D.G. Krøigaard M. et al.The use of drug provocation testing in the investigation of suspected immediate perioperative allergic reactions: current status.Br J Anaesth. 2019; 123: e126-e134Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Furthermore, a negative rocuronium sIgE result does not rule out an IgE-mediated rocuronium allergy. We have shown the negative predictive value for sIgE rocuronium to be 72%, compared with 95% for skin testing and 75% for basophil activation testing (BAT).6Leysen J. Bridts C.H. De Clerck L.S. et al.Allergy to rocuronium: from clinical suspicion to correct diagnosis.Allergy. 2011; 66: 1014-1019Crossref PubMed Scopus (64) Google Scholar Therefore, the basis for confirming rocuronium as cause is inadequate, and the anaphylaxis in this patient may have resulted from another cause. We also respectfully disagree with the statement that the negative rocuronium sIgE result excludes cross-reactivity with vecuronium, another aminosteroid-derived NMBA that was used earlier in this patient. A morphine-based sIgE assay could have been a more sensitive method to detect an eventual sensitisation to substituted tertiary and quaternary ammonium structures, the major antigenic determinant of NMBAs.7Fisher M.M. Baldo B.A. Immunoassays in the diagnosis of anaphylaxis to neuromuscular blocking drugs: the value of morphine for the detection of IgE antibodies in allergic subjects.Anaesth Intensive Care. 2000; 28: 167-170Crossref PubMed Google Scholar,8Ebo D.G. Venemalm L. Bridts C.H. et al.Immunoglobulin E antibodies to rocuronium: a new diagnostic tool.Anesthesiology. 2007; 107: 253-259Crossref PubMed Scopus (90) Google Scholar Moreover, potential cross sensitisation could have been explored by skin testing or BAT, as the latter more closely mirrors the in vivo situation than traditional sIgE binding assays,6Leysen J. Bridts C.H. De Clerck L.S. et al.Allergy to rocuronium: from clinical suspicion to correct diagnosis.Allergy. 2011; 66: 1014-1019Crossref PubMed Scopus (64) Google Scholar,9Ebo D.G. Lechkar B. Schuerwegh A.J. Bridts C.H. De Clerck L.S. Stevens W.J. Validation of a two-color flow cytometric assay detecting in vitro basophil activation for the diagnosis of IgE-mediated natural rubber latex allergy.Allergy. 2002; 57: 706-712Crossref PubMed Scopus (87) Google Scholar, 10Uyttebroek A.P. Sabato V. Leysen J. Bridts C.H. De Clerck L.S. Ebo D.G. Flowcytometric diagnosis of atracurium-induced anaphylaxis.Allergy. 2014; 69: 1324-1332Crossref PubMed Scopus (44) Google Scholar, 11Uyttebroek A.P. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. Immunoglobulin E antibodies to atracurium: a new diagnostic tool?.Clin Exp Allergy. 2015; 45: 485-487Crossref PubMed Scopus (22) Google Scholar as described in a recent review on the value and limitations of BAT in perioperative hypersensitivity and anaphylaxis.12Takazawa T. Sabato V. Ebo D.G. In vitro diagnostic tests for perioperative hypersensitivity, a narrative review: potential, limitations, and perspectives.Br J Anaesth. 2019; 123: e117-e125Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar This case report does offer an opportunity to consider the molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis, as recently reviewed.13Ebo D.G. Clarke R.C. Mertes P.M. Platt P.R. Sabato V. Sadleir P.H. Molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis: a narrative review.Br J Anaesth. 2019; 123: e38-e49Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Mast cell degranulation via off-target occupation of the MRGPRX2 heralds a new domain in our knowledge of immediate drug hypersensitivity,14Porebski G. Kwiecien K. Pawica M. Kwitniewski M. Mas-related G protein-coupled receptor-X2 (MRGPRX2) in drug hypersensitivity reactions.Front Immunol. 2018; 9: 3027Crossref PubMed Scopus (54) Google Scholar and challenges the dogma that NMBAs mainly cause IgE-dependent anaphylaxis that can be documented by positive skin testing believed to be specific for an IgE-mediated mechanism.15Spoerl D. Nigolian H. Czarnetzki C. Harr T. Reclassifying anaphylaxis to neuromuscular blocking agents based on the presumed patho-mechanism: IgE-mediated, pharmacological adverse reaction or “innate hypersensitivity”?.Int J Mol Sci. 2017; 18: 1223Crossref PubMed Scopus (45) Google Scholar However, based on the limited evidence currently available in the literature, we think that it is incorrect and potentially dangerous to reclassify the majority of rocuronium-related anaphylaxis as MRGPRX2-dependent reactions, which have been speculated to be preventable by reducing the speed of administration or lowering the dose.15Spoerl D. Nigolian H. Czarnetzki C. Harr T. Reclassifying anaphylaxis to neuromuscular blocking agents based on the presumed patho-mechanism: IgE-mediated, pharmacological adverse reaction or “innate hypersensitivity”?.Int J Mol Sci. 2017; 18: 1223Crossref PubMed Scopus (45) Google Scholar In our experience, the majority of patients with skin-test-proved rocuronium anaphylaxis have their diagnosis further confirmed by sIgE serology and BAT.6Leysen J. Bridts C.H. De Clerck L.S. et al.Allergy to rocuronium: from clinical suspicion to correct diagnosis.Allergy. 2011; 66: 1014-1019Crossref PubMed Scopus (64) Google Scholar,16Van Gasse A.L. Elst J. Bridts C.H. et al.Rocuronium hypersensitivity: does off-target occupation of the MRGPRX2 receptor play a role?.J Allergy Clin Immunol Pract. 2019; 7: 998-1003Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Furthermore, there is currently no evidence for non-specific triggering by rocuronium of basophil or mast cell degranulation in humans via wild-type MRGPRX2.17Lansu K. Karpiak J. Liu J. et al.In silico design of novel probes for the atypical opioid receptor MRGPRX2.Nat Chem Biol. 2017; 13: 529-536Crossref PubMed Scopus (134) Google Scholar,18Navines-Ferrer A. Serrano-Candelas E. Lafuente A. Munoz-Cano R. Martin M. Gastaminza G. MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia.Sci Rep. 2018; 8: 11628Crossref PubMed Scopus (59) Google Scholar Clearly, such patients should be warned against this NMBA until thoroughly investigated, including testing with other NMBAs to identify safe alternatives for the future. Finally, it is of note that the authors emphasise the expression of MRGPRX2 by basophils, as claimed by Wedi and colleagues,19Wedi B. Gehring M. Kapp A. The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: expression and function.Allergy. 2020; https://doi.org/10.1111/all.14213Crossref Scopus (30) Google Scholar and the role these cells play in IgE-independent perioperative anaphylaxis in humans. However, we would like to point out that there is little, if any, irrefutable evidence for IgE-independent basophil degranulation in response to anaesthetics and related compounds, and that constitutive expression of MRGPRX2 by basophils is a subject of ongoing controversy. First, ex vivo basophil activation experiments for perioperative anaphylaxis have mainly been validated in the context of allergy to beta-lactam antibiotics (e.g. aminopenicillins and cefazolin), natural rubber latex (from Hevea brasiliensis), and chlorhexidine, all IgE-mediated conditions par excellence.12Takazawa T. Sabato V. Ebo D.G. In vitro diagnostic tests for perioperative hypersensitivity, a narrative review: potential, limitations, and perspectives.Br J Anaesth. 2019; 123: e117-e125Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar With respect to NMBAs, such as rocuronium, succinylcholine, and atracurium, in a large majority of our patients with positive BAT results, concomitant positive skin testing and sIgE results generally point to an IgE-dependent mechanism.6Leysen J. Bridts C.H. De Clerck L.S. et al.Allergy to rocuronium: from clinical suspicion to correct diagnosis.Allergy. 2011; 66: 1014-1019Crossref PubMed Scopus (64) Google Scholar,8Ebo D.G. Venemalm L. Bridts C.H. et al.Immunoglobulin E antibodies to rocuronium: a new diagnostic tool.Anesthesiology. 2007; 107: 253-259Crossref PubMed Scopus (90) Google Scholar,10Uyttebroek A.P. Sabato V. Leysen J. Bridts C.H. De Clerck L.S. Ebo D.G. Flowcytometric diagnosis of atracurium-induced anaphylaxis.Allergy. 2014; 69: 1324-1332Crossref PubMed Scopus (44) Google Scholar,11Uyttebroek A.P. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. Immunoglobulin E antibodies to atracurium: a new diagnostic tool?.Clin Exp Allergy. 2015; 45: 485-487Crossref PubMed Scopus (22) Google Scholar,16Van Gasse A.L. Elst J. Bridts C.H. et al.Rocuronium hypersensitivity: does off-target occupation of the MRGPRX2 receptor play a role?.J Allergy Clin Immunol Pract. 2019; 7: 998-1003Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Note that a specific IgE:total IgE ratio does not benefit diagnosis of rocuronium allergy.20Van Der Poorten M.M. Molina-Molina G. Van Gasse A.L. et al.Application of specific-to-total IgE ratio does not benefit diagnostic performance of serologic testing for rocuronium allergy.Br J Anaesth. 2020; https://doi.org/10.1016/j.bja.2020.05.032Abstract Full Text Full Text PDF Scopus (3) Google Scholar Second, the statement that basophils constitutively express MRGPRX2 is difficult to align with the negative results observed in control individuals enrolled in several studies on BAT with potent MRGPRX2 agonists, such as opiates, vancomycin, and fluoroquinolones that are well known to elicit non-specific histamine release by skin mast cells.21Leysen J. De Witte L. Sabato V. et al.IgE-mediated allergy to pholcodine and cross-reactivity to neuromuscular blocking agents: lessons from flow cytometry.Cytometry B Clin Cytom. 2013; 84: 65-70Crossref PubMed Scopus (44) Google Scholar, 22Van Gasse A.L. Hagendorens M.M. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. IgE to poppy seed and morphine are not useful tools to diagnose opiate allergy.J Allergy Clin Immunol Pract. 2015; 3: 396-399Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 23Van Gasse A.L. Sabato V. Uyttebroek A.P. et al.Immediate moxifloxacin hypersensitivity: is there more than currently meets the eye?.Allergy. 2017; 72: 2039-2043Crossref PubMed Scopus (28) Google Scholar, 24Aranda A. Mayorga C. Ariza A. et al.In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones.Allergy. 2011; 66: 247-254Crossref PubMed Scopus (126) Google Scholar, 25Fernandez T.D. Ariza A. Palomares F. et al.Hypersensitivity to fluoroquinolones: the expression of basophil activation markers depends on the clinical entity and the culprit fluoroquinolone.Medicine (Baltimore). 2016; 95: e3679Crossref PubMed Scopus (35) Google Scholar Mast cell degranulation via off-target occupation of the MRGPRX2 heralds a new domain in our knowledge of immediate drug hypersensitivity. However, in most patients who experience rocuronium anaphylaxis, a positive IDT to rocuronium, using non-irritative test concentrations, is likely to reflect IgE-dependent sensitisation that should be explored by quantification of sIgE and BAT with identification of safe alternatives for the future. In more rare cases, displaying negative sIgE and BAT results, genetic analyses to identify pathogenic MRGPRX2 polymorphisms/mutations could help to further elucidate the conundrum of MRGPRX2-related anaphylaxis and identify patients at risk to other agonists of the MRGPRX2. Before conclusions can be formulated about underlying mechanisms of perioperative anaphylaxis, diagnostic work-up should be carried out in a standardised way and according to the guidelines. DGE (Fonds Wetenschappelijk Onderzoek [FWO]: 1800614N) and VS (FWO: 1804518N) are senior clinical researchers of the Research Foundation—Flanders/FWO. The authors declare that they have no conflict of interest. Association between mutated Mas-related G protein-coupled receptor-X2 and rocuronium-induced intraoperative anaphylaxisBritish Journal of AnaesthesiaVol. 125Issue 6PreviewEditor—Unexpected perioperative anaphylaxis is one of the most challenging clinical scenarios for anaesthesiologists.1 The perioperative drugs most likely to cause anaphylaxis are antibiotics, neuromuscular blocking agents (NMBAs) and opioids. Recent studies have shown that NMBAs and opioids directly stimulate the Mas-related G protein-coupled receptor b2 (Mrgprb2), which is specifically expressed by mouse mast cells and which induces mast cell histamine release.2 This immunoglobulin E (IgE)-independent pathway is referred to as a non-IgE-mediated allergic reaction. Full-Text PDF Association between mutated Mas-related G-protein-coupled receptor-X2 and rocuronium-induced intraoperative anaphylaxis. Comment on Br J Anaesth 2020; 125: e448–50British Journal of AnaesthesiaVol. 127Issue 1PreviewEditor—Mas-related G-protein-coupled receptor member X2 (MRGPRX2) has attracted considerable attention because it could play an important role in allergic responses independent of specific immunoglobulin E (IgE) antibodies. Numerous reports suggest that neuromuscular blocking agents, such as rocuronium and opioids (such as morphine), can stimulate MRGPRX2 to release histamine,1–4 and anaesthesiologists are particularly interested in this receptor. Full-Text PDF" @default.
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