To the Editor: 

Neuromuscular blocking drugs (NMBDs) are the major cause of episodes of immediate hypersensitivity during the perioperative period.1The detection of liberated mast cell tryptase2is used to confirm an anaphylactic event; skin prick testing with all currently used unconjugated NMBDs, followed by intradermal tests if necessary, is central to identifying the culprit, as well as cross-reacting drugs. Identification of the implicated NMBD(s) is important for providing safe anesthesia for the patient in the future. Although skin tests remain the diagnostic tool of choice, their sensitivity and specificity have at times been questioned. Serum immunoglobulin E (IgE) antibody assays are often used in cases involving skin test-negative or equivocal reactors or when skin tests are unreliable or unavailable, making these tests useful adjuncts to skin and tryptase tests. They are also valuable when applied to sera taken at the time of the reaction, to preoperative serum samples, and serum taken before or after death.3The IgE assay in inhibition form can sometimes help in identifying and providing immunochemical insights into cross-reacting drugs.3,4After extensive testing over many years on hundreds of serum samples, a morphine-solid phase was shown to be superior to NMBD-solid phases and other selected solid phases for the detection of NMBD-reactive IgE antibodies, and its use, along with the tryptase and skin tests, was strongly advocated as the best diagnostic combination of examinations to confirm a true IgE-mediated reaction to a NMBD.3,5 

The value of the morphine immunoassay as a test for the detection of NMBD-reactive IgE antibodies is the subject of a recent study by Laroche et al.  6An initial response to the work could be statement of the precept “better late than never.” To expand on this, one needs to draw attention to a historic perspective that the paper does not provide. Although the study is entitled “Evaluation of a new  routine diagnostic test …” (my emphasis) the test is not new in the sense that it originates from a morphine immunoassay applied to detect NMBD allergic sensitivity over 20 yr ago7and stems directly from a large study over a decade ago in which the assay was used to examine sera from 347 patients who experienced an adverse reaction during anesthesia.5Describing the assay as new gives a wrong impression; describing the assay as “a new commercial  routine diagnostic test” or an “improved” test (if that is what it turns out to be) might perhaps be more correct.

A false claim in the paper, and one that has been repeated in the French NMBD-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. Choline chloride was used in one of the studies8and p -aminophenylphosphorylcholine in the other.9The presence of a charged phosphate group and a hydrophobic aromatic ring in the choline derivative p -aminophenylphosphorylcholine introduces unnecessary structures and potentially opens the door to unwanted interactions with antibodies with specificities unrelated to substituted ammonium ions. The reasons for using choline to detect IgE antibodies instead of succinylcholine and other NMBDs containing quaternary ammonium ions, together with a method of preparation, were provided in detail in two previous articles.10,11The two later studies8,9introduced no conceptual advancement.

A common error of loose terminology is perpetuated in the study by Laroche et al.  6In discussing the complementary structures recognized by NMBD-reactive IgE antibodies, the quaternary ammonium ion is often referred to in the literature as the IgE-binding determinant despite our ignorance in most cases of the origin and precise ammonium group specificity of the antibodies.3In the initial antibody combining site studies on sera from NMBD-allergic patients, cross-reactive tertiary as well as quaternary ammonium ions on a range of different drugs and chemicals were identified as IgE-binding (allergenic) determinants.4,12These determinants were therefore collectively described as substituted ammonium ions12rather than simply quaternary ammonium ions and that terminology should continue to be used. The commercial morphine immunoassay is called the quaternary ammonium morphine (QAM) test although morphine contains a monomethyl tertiary ring nitrogen, some NMBDs contain tertiary as well as quaternary ammonium groups, and the assay detects IgE-reactive tertiary as well as quaternary ammonium structures.

Despite these criticisms, the study by Laroche et al.  6is an overdue but welcome reminder of a specific, sensitive, and labor-saving procedure with a predictive value that is quite good. The test should be particularly appropriate as a backup for routine skin tests and in cases where clinical data indicate NMBD-induced anaphylaxis but skin tests prove negative, unreliable, or cannot be carried out. Widespread application of the morphine immunoassay together with carefully compiled case histories, serum tryptase determinations, and skin tests currently offers the best combination of examinations needed for successful diagnosis, and the IgE assay promises to identify some previously undetected NMBD-induced allergic reactions.5,6Until further significant advances are made in our understanding of the origin of NMBD sensitization and the consequent IgE antibody-combining site specificities,3or an improvement in the form of a new and/or novel diagnostic test is pioneered, routine application of these four diagnostic approaches currently offers the clinician the best chance of achieving a correct diagnosis.

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Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T: Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 1987; 316:1622–6
Baldo BA, Fisher MM, Pham NH: On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: An immunochemical perspective. Clin Exp Allergy 2009; 39:325–44
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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
Laroche D, Chollet-Martin S, Léturgie P, Malzac L, Vergnaud MC, Neukirch C, Venemalm L, Guéant JL, Roland PN: Evaluation of a new routine diagnostic test for immunoglobulin E sensitization to neuromuscular blocking agents. ANESTHESIOLOGY 2011; 114:91–7
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
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
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
Harle DG, Baldo BA, Fisher MM: Detection of IgE antibodies to suxamethonium after anaphylactoid reactions during anaesthesia. Lancet 1984; 1:930–2
Harle DG, Baldo BA, Fisher MM: Assays for, and cross-reactivities of, IgE antibodies to the muscle relaxants gallamine, decamethonium and succinylcholine (suxamethonium). J Immunol Methods 1985; 78:293–305
Baldo BA, Fisher MM: Substituted ammonium ions as allergenic determinants in drug allergy. Nature 1983; 306:262–4