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International audience; BackgroundNeuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis.MethodsALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (

Background Investigation of immediate hypersensitivity reactions in the perioperative setting involves skin testing and measurement of specific IgE (sIgE) as standard practice. In the case of the neuromuscular blocking agents (NMBAs), the main allergenic epitopes have been shown to be substituted ammonium groups. Commercial assays are available for detection of sIgE to these epitopes using morphine and pholcodine substrates but questions have been raised about the effectiveness of these assays in the diagnosis of benzylisoquinoline anaphylaxis. This study was therefore undertaken to assess the effectiveness of these assays in the diagnosis of hypersensitivity reactions to this group of NMBAs. Methods Analysis was carried out on all available results for patients assessed at the Royal North Shore Hospital Anaesthetic Allergy Clinic during the period June 2009 to June 2016. Standardised intradermal skin tests were performed with a panel of NMBAs. Measurement of sIgE to morphine and pholcodine was performed via the Phadia ImmunoCAP® system. Results For all patients with positive skin test results to NMBAs which included a benzylisoquinoline NMBA (n = 24), 75% exhibited negative sIgE to both morphine and pholcodine. Where patients were reactive to benzylisoquinoline NMBAs alone (n = 12), 100% exhibited negative sIgE results, indicating 0% sensitivity of the assays relative to skin testing, in this subgroup. Conclusion Use of sIgE testing to morphine and pholcodine in the assessment of NMBA immediate hypersensitivity is a valuable tool particularly in the case of reactions to the aminosteroid NMBAs. However, these assays are unreliable in detecting sensitisation to benzylisoquinoline NMBAs.

Background As a strong inducer of IgE-antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). Three years after withdrawal of PHO in Norway, a significant reduction in IgE-sensitization and anaphylaxis reporting was seen. Objective Six year follow-up study on the effects of PHO withdrawal on IgE-sensitization and anaphylaxis reporting. Methods From 650 acute consecutive reports (2005-2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE-antibodies (≥0.35 kUA/L) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE-sensitization to PHO and SUX among “allergics” were monitored. Results From baseline period P0 (PHO on the market) through the first (P1) and second (P2) three year periods after withdrawal, significant falls in total reports (p

BACKGROUND Anaphylaxis is a serious life-threatening generalized or systemic hypersensitivity reaction. The aim of this paper is to provide knowledge on how to diagnose, treat and follow up patients with suspected anaphylaxis during general and local anaesthesia. MATERIAL AND METHODS The article is based on literature identified through a non-systematic search in PubMed, the Scandinavian Guidelines on anaphylaxis during anaesthesia and on own research. RESULTS Anaphylactic symptoms during anaesthesia vary with respect to severity. Manifestations from skin and the cardiovascular and respiratory systems are present simultaneously in approximately 70 % of patients. Early treatment with adrenaline, fluid and extra oxygen may be vital for survival without sequelae. The following patients should be assessed before anaesthesia: those with moderate or serious reactions or with reactions that raise suspicion of allergy which may cause problems in connection with future treatment. Neuromuscular blocking agents are the main cause of IgE-mediated anaphylaxis during anaesthesia in Norway. New research has shown that allergy towards neuromuscular blocking agents can develop after ingestion of cough syrup containing pholcodine (stimulates asymptomatic production of antibodies). These antibodies cause cross-sensibilisation with neuromuscular blocking agents. The cough syrup Tuxi was withdrawn from the Norwegian market during spring 2007. INTERPRETATION Allergic reactions during anaesthesia are rare and potentially life-threatening; patients should be followed up and treated in a standardized way.

Following the demonstration 25 years ago that substituted ammonium groups on neuromuscular blocking drugs (NMBDs) are the main allergenic structures recognized by IgE antibodies in the sera of some patients who experience anaphylaxis during anaesthesia, immunoassays for these drugs were quickly applied to supplement skin tests in the diagnostic assessment of suspected adverse reactions to anaesthetic agents. Many subjects who react to an NMBD do so on first exposure and this led to the speculation that the origin of allergic sensitization is an environmental agent(s) or another drug containing an ammonium ion. Direct antibody binding and hapten inhibition studies revealed that morphine, which contains a tertiary amino group, was strongly recognized by IgE in sera from anaphylactic patients and a morphine-solid phase immunoassay was found to be superior to NMBD-based assays for the detection of NMBD-reactive IgE antibodies. Extensive inhibition experiments indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, ammonium ions. Further quantitative investigations are needed to identify these neighbouring groups on different NMBDs. Recent work has implicated the morphine analogue pholcodine as the sensitizing agent in Norway where, unlike Sweden, anaphylactic reactions to NMBDs are not uncommon and the medicament is available over-the-counter. This has led to the suggestion that allergenic sensitization to the ammonium group of pholcodine may account for the different incidences of anaphylaxis during anaesthesia in the two countries. This work is subjected to critical review and some alternative speculations on the nature and origin of the sensitizing agent(s) are presented.

Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3,000 to 1 in 110,000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted.

PURPOSE OF REVIEW: The purpose of this review is to summarize new interesting findings in both research and clinical practice of nonhymenoptera anaphylaxis with particular emphasis on food and drug allergy. RECENT FINDINGS: Recent findings include some aspects of crossreactivity among betalactams, nonsteroidal anti-inflammatory drugs with special attention to an immunogenic metabolite of diclofenac and the mode of diclofenac-induced basophil degranulation. Also, new insights into the sometimes atypical anaphylaxis-like reactions after administration of monoclonal antibodies and the immunologic response to these molecules will be discussed, as well as the role of low-dose pholcodine exposure on the development of sensitization to neuromuscular blocking agents. In food-related anaphylaxis, a significant increase of incidents has been observed over the last few years, especially among children of less than 5 years of age. Unfortunately, the severity of subsequent reactions cannot be predicted from the reaction history. Tree nuts and peanuts are the most important elicitors of fatal food-induced anaphylaxis. SUMMARY: In food-related anaphylaxis, prospectively evaluated marker allergens that are indicative of a potential anaphylactic reaction are still lacking. The drug groups covered in this review are of special interest either due to their prominent role as allergens or due to new findings.

Radioimmunoassays (RIAs) for IgE antibodies to specific neuromuscular blocking drugs (NMBDs) are an important tool in the diagnosis of anaphylaxis during anaesthesia although they are performed in only a few laboratories throughout the world. NMBDs bind to antibodies by their substituted ammonium ions. We measured serum IgE antibodies to morphine and specific NMBDs in 347 patients with suspected anaphylaxis using blood specimens sent for mast cell tryptase assays. Morphine, which has a single substituted ammonium group, avidly binds in vitro to antibodies that react with NMBDs. The morphine RIA proved to be both a more sensitive and efficient test for the detection of IgE antibodies to NMBDs than the specific NMBD RIAs. We have adopted the morphine RIA in our laboratory in preference to the specific RIAs and predict that use of this single assay will become widespread for the in vitro diagnosis of allergic sensitivities to NMBDs.

Uyttebroek et al. [1] raise some pertinent questions regarding the utility of various testing modalities in the assessment of neuromuscular blocking agent (NMBA) hypersensitivity. In our cases, clinical history was the major assessment tool for identifying pholcodine as the inciting agent of anaphylaxis [2]. In both patients, the temporal association between pholcodine exposure and clinical reaction was in keeping with drug-induced anaphylaxis and no alternative causes were identified. The positive allergen-specific IgE levels to pholcodine (ImmunoCAP Phadia, Uppsala, Sweden) were used to substantiate the high index of clinical suspicion. As mentioned in the article, skin testing to pholcodine has limited utility because it causes wheal and flare reactions in normal control subjects. While drug provocation challenges are sometimes used to confirm allergy in situations where history and skin/allergen-specific IgE testing are ambiguous, in this circumstance this was not felt appropriate, owing to the severity of systemic reaction in both patients' index events. In one of our cases, a tramadol challenge was performed to give additional options if opiate analgesics were required, and the avoidance of codeine and its active metabolite morphine was recommended. Subsequent evaluation in both our patients was targeted toward the potential for NMBA hypersensitivity given previous studies [3–6], presented in the review, suggesting an association between pholcodine exposure and NMBA anaphylaxis. The recommendations regarding NMBA use in both patients were based on the outcome of skin testing and allergen-specific IgE testing. As Uyttebroek et al. [1] allude to, sensitization to a drug does not always equate with clinically meaningful allergy. However, provocation challenges with various NMBAs, as a means of demonstrating patient tolerance or allergy, are not feasible. Thus, the recommendations were made on the available testing at the time of assessment. The development of basophil activation tests as an adjunct to skin testing and specific IgE testing will no doubt help in the assessment of cases of suspected drug allergy. However, these tests are currently not validated or routinely available in most centres, and sensitivity may be lacking even when cases are carefully phenotyped and selected. The cases presented demonstrate the potential for sensitization to NMBA to occur in the context of pholcodine hypersensitivity. These case studies are reflective, at an individual patient level, of the population-based evidence cited previously [3,5,6]. We agree that consideration of whether the patients are able to tolerate opiates following true pholcodine immediate (IgE) hypersensitivity reactions is an important practical concern, and the specific haptenated products mediating such reactions are unknown. Indeed, codeine is metabolized by the genetically polymorphic isoform CYP2D6 to the active metabolite morphine, adding additional potential variability to potential cross-reactivity and patient tolerance. However, the focus of our article [2] was on the potential association of pholcodine exposure and NMBA allergy, and thus, the presentation of the case studies reflects this. Immunoglobulin E-mediated hypersensitivity reactions to pholcodine and morphine are rare, and this does indeed raise important questions regarding the pathogenesis of pholcodine sensitization and NMBA anaphylaxis. At present, the mechanisms underlying why exposure and sensitization to a substituted ammonium ion in pholcodine can prime NMBA anaphylaxis but not result in allergy to all compounds containing similar substituted ammonium ions remain unresolved.

We read with interest the manuscript by Brusch et al. [1] about the putative role of pholcodine in the sensitization to curarizing myorelaxants [2,3]. We would like to raise some issues and questions, especially concernig the recommendations put forward for the individual cases. In both cases, due to uncertainties associated with skin tests and the unavailability of basophil activation tests, the diagnosis of pholcodine allergy appears to rest upon history and measurement of pholcodine-specific IgE (sIgE) antibodies. Therefore, the authors presumably applied the technique available from Thermo Fisher Scientific, which is not a radioallergosorbent test as indicated. Because pholcodine is known to boost IgE production, results of total IgE and atracurium ImmunoCAP would be welcome, as this could shed light on the relevance of sIgE findings. In both patients, cross-sensitization was studied with skin testing. In the first patient, according to these results, combined with the sIgE results, future use of atracurium and rocuronium was discouraged. Suxamethonium and vecuronium were proposed as alternatives. Several issues should be considered here, as these recommendations might not be fully correct. First, the recommendation not to use atracurium relies upon a positive skin test with undiluted formulation, which is a 10-fold greater concentration than advocated [4]. Second, the patient is dissuaded further use of rocuronium, solely on the basis of a positive sIgE result. However, we recently demonstrated sIgE to exhibit low predictive value and we recommended additional basophil activation tests to elucidate on the clinical relevance of an solated IgE positivity [5]. Third, the authors did not make any recommendation about further use of the structurally related opiates, viz. morphine and codeine. In other words, why is the sIgE rocuronium considered relevant and the sIgE morphine not? Finally, taking into account the extensive cross-reactivity between rocuronium, vecuronium [6] and suxamethonium [7], it seems odd to propose vecuronium and suxamethonium as safe alternatives, particularly as basophil activation tests and measurement of IgE to suxamethonium were not performed. Would the authors recommend further use of suxamethonium with a positive sIgE result for this compound, or, like rocuronium, would they than alter their proposal? The same comments apply to the second case. However, in this patient the advice is limited to the suxamethonium that tested positive in the intradermal test. Could this be the reflection of an incomplete diagnostic approach in this patient (e.g. no measurement of sIgE to morphine and rocuronium)? The authors conclude their case reports to endorse the hypothesis that intake of pholcodine is associated with sensitivity to myorelaxants (without any precision). To us, this conclusion seems premature and controversial. In the absence of any provocation tests or longitudinal follow-up data, we would suggest prudence upon interpretation of a positive sIgE result to curarizing myorelaxants in patients with negative skin tests or basophil activation tests [5]. Pioneering studies have already made clear that the application of tests for curarizing myorelaxants and morphine should not be used to predict clinical outcomes [3]. It seems odd that sIgE results to curarizing myorelaxants in patients allergic to pholcodine should be interpreted differently from sIgE results to structurally almost similar opiates, such as morphine. As a matter of fact, we have recently reported that patients allergic to pholcodine were able to tolerate a graded codeine provocation test [8].

International audience; BackgroundAllergic IgE-mediated reactions to neuromuscular blocking agents (NMBAs) are the main cause of immediate hypersensitivity reactions in anaesthesia; their predominant occurrence in the absence of previous exposure to NMBAs suggests a risk related to environmental exposure.ObjectiveTo investigate the prevalence of specific IgE to quaternary ammonium ions in two populations professionally exposed to quaternary ammonium compounds, in the north-eastern France.MethodsThe study had a retrospective follow-up design whereby apprentices were assessed after their 2-year training period as apprentices. The professionally exposed hairdresser populations (n = 128) were compared with baker/pastry makers (n = 108) and ‘non-exposed’ matched control subjects (n = 379).ResultsWe observed a 4.6-fold higher frequency of positive IgE against quaternary ammonium ions in hairdressers (HD), compared with baker/pastry makers (BP) and control (C) groups. The competitive inhibition of quaternary ammonium Sepharose radioimmunoassay (QAS-IgE RIA) with succinylcholine was significantly higher in HD, compared with BP and C groups, with inhibition percentage of 66.2 ± 7.4, 39.7 ± 6.0 and 43.8 ± 9.9, respectively (P < 0.001). The specific IgE against quaternary ammonium ions recognized also two compounds widely used by hairdressers, benzalkonium chloride and polyquaternium-10, in competitive inhibition of IgE RIA. When considering the whole study population, hairdresser professional exposure and total IgE > 100 kU/L were the two significant predictors of IgE-sensitization against quaternary ammonium ions in the multivariate analysis of a model that included age, sex, professional exposure, increased concentration of total IgE (IgE > 100 kU/L) and positive IgE against prevalent allergens (Phadiatop®; P = 0.019 and P = 0.001, respectively).Conclusion and Clinical RelevanceThe exposure to hairdressing professional occupational factors increases IgE-sensitization to NMBAs and quaternary ammonium ion compounds used in hairdressing. Besides the pholcodine hypothesis, our study suggests that repetitive exposure to quaternary ammonium compounds used in hairdressing is a risk factor for NMBAs sensitization.

Velik broj osoba u kojih je došlo do anailaktčike reakcije na neuromuskularne blokatore nije bio s njima u prethodnom kontaktu. Ispitivanje mogu ih senzibiliziraju ih molekula dovelo je norveške i švedske znanstvenike do folkodina, antitusika koji se nalazi u širokoj upotrebi u Europi i svijetu. Folkodin sadrži amonijev ion, epitop koji je zajednički tom lijeku i neuromuskularnim blokatorima te koji je temelj njihove križne reaktivnosti. Nakon objavljenih rezultata istraživanja koja su dovela u vezu perioperativnu anailaktičku reakciju i upotrebu folkodina došlo je do povlačenja folkodina sa tržišta u Norveškoj i u kasnijem istraživanju dokazanog smanjenja broja anailaktičkih reakcija u toj zemlji. Europska agencija za lijekove u svom posljednjem izvještaju nije donijela odluku o povlačenju pripravaka folkodina s tržišta, ali je zatražila daljnja istraživanja koja bi trebala dodatno razjasniti ovu križnu reaktivnost između folkodina i neuromuskularnih blokatora., A large number of individuals experiencing anaphylactic reaction to neuromuscular blocking agents have not previously been in contact with them. The search for a substance inducing sensitization to muscle relaxants has led Norwegian and Swedish scientists to pholcodine, a cough suppressant, which is widely used in Europe and worldwide. Ammonium ion is an epitope common to pholcodine and neuromuscular blocking agents and it is the basis of their cross-reactivity. Based on the results of published studies that pointed to a connection of the use of pholcodine and perioperative anaphylactic reaction, pholcodine was withdrawn from the Norwegian market and subsequent research revealed a reduction of anaphylactic reactions in that country. In its latest report, the European Medicines Agency made a decision not to withdraw pholcodine mixtures from the market but it urged further research with the aim to clarify the cross-reactivity between pholcodine and neuromuscular blocking agents.

Anaphylactic reactions to neuromuscular blocking agents during general anesthesia constitute a major cause of concern and a great source of debate among anesthesiologists. The authors' recent investigations, taking the striking differences of incidence between Norway and Sweden as the point of departure, have provided valuable insights into the pathogenetic mechanisms and the highly uneven geographical distribution of these rare, but dramatic and notoriously unpredictable, events. Eventually, a cough syrup containing pholcodine emerged as the most likely suspect. This new knowledge led to the withdrawal of the drug from the Norwegian market and to the examination of the role of pholcodine-containing drugs in other countries. The present article is a brief summary of the research behind this development.

Background: Anaphylactic reactions to a neuromuscular blocking agent (NMBA) is more than six times as common in Norway as in Sweden, probably due to differences in preoperative sensitization. The prevalence of IgE-sensitization to morphine (MOR) and suxamethonium (SUX) in comparable populations in Bergen, Norway, and Stockholm, Sweden, was studied and related to possible sensitizing agents. Methods: Three hundred sera of ‘allergics’ and 500 blood donors in Bergen and Stockholm were tested for IgE antibodies to MOR and SUX using Pharmacia Diagnostics ImmunoCAP 1 (Uppsala, Sweden) assay and the results compared to those of 65 patients from Bergen with documented anaphylaxis to NMBA. In addition, 84 different household chemicals were tested, by IgE antibody inhibition, for SUX and MOR. Results: In Norway 0.4% of blood donors, 3.7% of allergics and 38.5% of anaphylactics were IgE-sensitized to SUX, and 5.0, 10.0 and 66.7%, respectively, to MOR. No serum from Sweden was positive. The majority of those sensitized (69%) were women. Several household chemicals contained SUX and/or MOR activity, but the only difference between Norway and Sweden was cough mixtures containing pholcodine (PHO). IgE antibodies to PHO were present in 6.0% of blood donors from Norway and in no serum from Sweden. Of the anaphylactics, 65—68% were sensitized to MOR or PHO but only 39% to SUX. Conclusions: IgE-sensitization to SUX, MOR and PHO was detected in Norway but not in Sweden. One possible explanation is the unrestricted use of cough mixtures containing MOR derivatives in Norway.