Correspondence  |   September 2011
In Reply
Author Affiliations & Notes
  • Dominique Laroche, M.D., Ph.D.
  • *Service de Biophysique, Centre Hospitalier Universitaire, Caen, France.
Article Information
Correspondence   |   September 2011
In Reply
Anesthesiology 9 2011, Vol.115, 659-660. doi:10.1097/ALN.0b013e3182268153
Anesthesiology 9 2011, Vol.115, 659-660. doi:10.1097/ALN.0b013e3182268153
We thank Dr. Baldo for his interest in reading our article “Evaluation of a New Routine Diagnostic Test for Immunoglobulin E (IgE) Sensitization to Neuromuscular Blocking Agents.”1 Dr. Baldo is a pioneer in the study of immunologic mechanisms of the sensitization to neuromuscular blocking agents. His group has been the first in demonstrating the presence of IgE reacting against drugs containing quaternary and tertiary ammonium in patients sensitized against muscle relaxants, using quaternary and tertiary chemical compounds coupled to epoxy-Sepharose.2,3 We confirmed these results 3 yr after their previous observation, using the same procedure.4,5 We disagree with Dr. Baldo's comment “the French NMBD [neuromuscular blocking drug]-anaphylaxis literature for many years attributes the introduction of a choline solid phase support for the detection of NMBD-reactive IgE antibodies to research results published in the early 1990s,” and we did cite eight of Dr. Baldo's publications. We invite him to read our recent review on this topic, which clearly chronicles his contribution in the field.6 
In our experience, the use of the epoxy-Sepharose solid phase was problematic for diagnostic use, and this led us to subsequently improve a quaternary ammonium Sepharose-radioimmunoassay, which shared superiority in several aspects7 : the epoxy-Sepharose procedure provided a much lower coupling efficiency of the chemical compound than the quaternary ammonium Sepharose reactive phase, with consequences in the sensitivity of the assay; and the epoxy-Sepharose procedure introduced an aliphatic hydrophobic chain between the Sepharose gel and the coupled drug, which could produce a nonspecific binding of hydrophobic IgE.8 In contrast, the choline is directly coupled to Sepharose by an ether bond, with a high coupling efficiency and no addition of any aliphatic chain, in the quaternary ammonium Sepharose assay. These differences may explain that the quaternary ammonium Sepharose-radioimmunoassay produces higher sensitivity and specificity than the epoxy-Sepharose method, in our experience.7 We would also like to point out that the radioimmunoassay with aminophenylphosphorylcholine was as efficient as the quaternary ammonium Sepharose-radioimmunoassay, in our hands.9 Finally, the diagnostic value of the choline solid phases used in France7,9 has been carefully evaluated and used in many clinical studies; these studies explain that they have been recommended by the European Network of Drug Allergy and the French Society for Anaesthesia and Intensive Care.10 
The concept of using a morphine solid phase to bind neuromuscular blocking agent (NMBA)-specific IgE is not new11 and was used in Dr. Baldo's laboratory for years.12 However, this homemade assay was not available outside Australia. In contrast, the assay that we evaluated is the first commercial test using morphine as a sensitive marker to detect NMBA-specific IgE and is available to any specialized laboratory worldwide. This is why the word “new” was associated with “routine” in the title of our article. The morphine-based assay may have some limitations for its predictive value.1 For example, Florvaag et al.  demonstrated a high prevalence of IgE antibodies against morphine in Norwegians, probably in relation to the high consumption of pholcodine-containing syrups in this country.13 
Dr. Baldo found questionable the name used to designate the assay we tested (quaternary ammonium, morphine), according to the nature of the ammonium ions responsible for NMBA allergy. The topic of our article was the clinical evaluation of a diagnostic test measuring sensitization to NMBA, and we have not discussed in any great detail the allergenic epitopes involved in NMBA allergy. We agree with Dr. Baldo that quaternary as well as tertiary ammonium ions are recognized by IgE from NMBA-allergic patients. This implicates that the positive charge on the nitrogen is essential for IgE antibody recognition, not primarily whether the nitrogen is quaternary or tertiary. The terminologic use of quaternary ammonium ions in NMBA allergy probably has its origin from the fact that all NMBAs contain at least one quaternary ammonium ion. We agree that the current terminology was not stringent. However, the proposed use of “substituted ammonium ions” as a generic term is less specific, because it also includes secondary and primary ammonium ions. The most prudent use of terminology when referring to NMBA epitopes should be “quaternary and tertiary ammonium ions.” Finally, the commercial test for IgE antibodies against NMBA described in our article is actually not marketed as a quaternary ammonium test but as “c260 morphine,” thus reflecting the actual antigen on the solid phase.
We appreciate that ultimately Dr. Baldo does agree with our conclusion that this commercial test for NMBA sensitization is a useful diagnostic tool.
Laroche D, Chollet-Martin S, Léturgie P, Malzac L, Vergnaud MC, Neukirch C, Venemalm L, Guéant JL, Nicaise Roland P: Evaluation of a new routine diagnostic test for immunoglobulin E sensitization to neuromuscular blocking agents. ANESTHESIOLOGY 2011; 114:91–7
Baldo BA, Fisher MM: Substituted ammonium ions as allergenic determinants in drug allergy. Nature 1983; 306:262–4
Baldo BA, Fisher MM: Anaphylaxis to muscle relaxant drugs: Cross-reactivity and molecular basis of binding of IgE antibodies detected by radioimmunoassay. Mol Immunol 1983; 20:1393–400
Guéant JL, Kamel L, Moneret-Vautrin DA, Widmer S, Laxenaire MC, Nicolas JP: Radioimmunoassay method for the detection of IgE antibodies specific to alcuronium. Ann Fr Anesth Reanim 1986; 5:570–3
Moneret-Vautrin DA, Guéant JL, Kamel L, Laxenaire MC, el Kholty S, Nicolas JP: Anaphylaxis to muscle relaxants: Cross-sensitivity studied by radioimmunoassays compared to intradermal tests in 34 cases. J Allergy Clin Immunol 1988; 82:745–52
Mertes PM, Aimone-Gastin I, Guéant-Rodriguez RM, Mouton-Faivre C, Audibert G, O'Brien J, Frendt D, Brezeanu M, Bouaziz H, Guéant JL: Hypersensitivity reactions to neuromuscular blocking agents. Curr Pharm Des 2008; 14:2809–25
Gueant JL, Mata E, Monin B, Moneret-Vautrin DA, Kamel L, Nicolas JP, Laxenaire MC: Evaluation of a new reactive solid phase for radioimmunoassay of serum specific IgE against muscle relaxant drugs. Allergy 1991; 46:452–8
Guéant JL, Mata E, Masson C, Gérard P, Moneret-Vautrin DA, Mouton-Faivre C, Laxenaire MC: Non-specific cross-reactivity of hydrophobic serum IgE to hydrophobic drugs. Mol Immunol 1995; 32:259–66
Guilloux L, Ricard-Blum S, Ville G, Motin J: A new radioimmunoassay using a commercially available solid support for the detection of IgE antibodies against muscle relaxants. J Allergy Clin Immunol 1992; 90:153–9
Mertes PM, Laxenaire MC, Lienhart A, the working group for the SFAR, Aberer W, Ring J, Pichler WJ, Demoly P, for ENDA and the EAACI interest group on drug hypersensitivity: Reducing the risk of anaphylaxis during anaesthesia: Guidelines for clinical practice. J Invest Allergol Clin Immunol 2005; 15:91–101
Harle DG, Baldo BA, Fisher MM: Immunoassays employing substituted ammonium compounds other than neuromuscular blocking drugs to increase the detection of IgE antibodies to these drugs. Mol Immunol 1990; 27:1039–45
Fisher MM, Baldo BA: 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; 28:167–70
Florvaag E, Johansson SG, Oman H, Venemalm L, Degerbeck F, Dybendal T, Lundberg M: Prevalence of IgE antibodies to morphine: Relation to the high and low incidences of NMBA anaphylaxis in Norway and Sweden, respectively. Acta Anaesthesiol Scand 2005; 49:437–44