Athina L. Van Gasse

IgE to Poppy Seed and Morphine Are Not Useful Tools to Diagnose Opiate Allergy

BACKGROUND Correct diagnosis of genuine IgE-mediated opiate allergy poses a significant challenge, mainly because of uncertainties associated with opiate skin testing and the unavailability of drug-specific IgE (sIgE) assays. Recently, it has been suggested that sIgE to poppy seed extract and morphine would be reliable in the diagnosis of opiate allergy. However, given the high prevalence of sIgE antibodies to these compounds in an allergic population, the predictive value of these tests leaves significant doubts. OBJECTIVE This study aims at verifying the predictive value of positive poppy seed and morphine sIgE assays results. METHODS A total of 22 individuals with a positive sIgE to poppy seed or morphine were selected. All had controlled drug challenges with increasing doses of morphine and/or codeine. Of these, 18 patients had an additional basophil activation test (BAT) with morphine and codeine. RESULTS None of the 22 patients demonstrated objective or subjective symptoms on provocation with morphine and/or codeine. Regarding BAT with morphine and codeine, expression of CD63 on basophils from 14 opiate tolerant individuals remained comparable to spontaneous expression by resting cells. The remaining 4 patients were classified as nonresponders. CONCLUSION Positive sIgE results to poppy seed and morphine are not per se predictive for genuine opiate allergy and should not be used in isolation to diagnose morphine or codeine allergy. To avoid overdiagnosis, for the time being, we propose to supplement serological diagnosis with an oral provocation test. Whether BAT might help to discriminate between clinical reactivity and sensitization remains to be confirmed in larger collaborative studies.

State of the Art and Perspectives in Food Allergy (Part I): Diagnosis

IgE-mediated food allergy is a major and increasing health issue with significant impairment of quality of life and significant morbidity and mortality. It affects children, as well as adolescents and adults. This review focuses on novelties in the diagnosis of food allergy. Correct diagnosis relies upon history supplemented by quantification of specific IgE (sIgE) antibodies and/or skin tests. Unfortunately, as these tests do not demonstrate absolute predictive values, controlled oral provocation tests are needed to confirm/exclude diagnosis. To a certain extent, novel in vitro diagnostics in the form of allergen component-based sIgE assays and flow-assisted quantification of in vitro activated basophils might help to discriminate between genuine allergy and merely sensitization. Furthermore they make it possible to establish individual risk profiles, to predict persistence of allergy, and facilitate therapeutic approach.

Cannabis Allergy: What do We Know Anno 2015

For about a decade, IgE-mediated cannabis (marihuana) allergy seems to be on the rise. Both active and passive exposure to cannabis allergens may lead to a cannabis sensitization and/or allergy. The clinical manifestations of a cannabis allergy can vary from mild to life-threatening reactions, often depending on the route of exposure. In addition, sensitization to cannabis allergens can trigger various secondary cross-allergies, mostly for plant-derived food. This clinical entity, which we have designated as the “cannabis-fruit/vegetable syndrome” might also imply cross-reactivity with tobacco, latex and plant-food derived alcoholic beverages. These secondary cross-allergies are mainly described in Europe and appear to result from cross-reactivity between non-specific lipid transfer proteins or thaumatin-like proteins present in Cannabis sativa and their homologues that are ubiquitously distributed throughout plant kingdom. At present, diagnosis of cannabis-related allergies rests upon a thorough history completed with skin testing using native extracts from buds and leaves. However, quantification of specific IgE antibodies and basophil activation tests can also be helpful to establish correct diagnosis. In the absence of a cure, treatment comprises absolute avoidance measures including a stop of any further cannabis (ab)use.

State of the Art and Perspectives in Food Allergy (Part II): Therapy

Currently management of food allergy is mainly based on absolute avoidance of the offending food(s) and the use of rescue medication. However, the risk of severe or life-threatening reactions due to inadvertent exposure, nutritional imbalance and social isolation raises the demand of disease-modifying treatments. The aim of the different treatments is to allow patients to safely ingest the offending food(s). However this unresponsiveness can be transient and requires continued treatment (desensitization) and has to be permanent and sustained also after stopping the treatment (tolerance). This review focuses on non-allergen specific (anti-IgE, Chinese herbal formula, etc..) and allergen specific treatments for food allergy. The anti-IgE treatment is at the moment the only non-allergen-specific therapy, for which some data on a temporarily clinical efficacy have been provided. Regarding allergen-specific treatments, different protocols (oral, sublingual, subcutaneous and epicutaneous) with natural, heat treated or recombinant food allergens have been investigated. Although promising, results of the different clinical trials are heterogeneous. In particular data on long-term effects are lacking. At the moment food specific immunotherapy can be considered an experimental interventional strategy, limited to research, and not yet ready for routine use.

Basophil Activation Tests: A Diagnostic Break-Through in Opiate Allergy

We have read the manuscript about codeine (3-methylmorphine) anaphylaxis by Hey-Soo Yoo et al.1 with great interest and would like to take the opportunity to raise some issues and communicate our experience. As recently reviewed, despite their frequent and ubiquitous use, genuine IgE-mediated allergy to opiates remains exceedingly rare. Also, correct diagnosis is not straightforward, mainly because of uncertainties associated with measurement of drug-specific IgE antibodies and skin testing.2 Actually, the key to correct diagnosis of opiate allergy lies in elucidating the clinical significance of positive specific IgE (sIgE) results and distinguishing skin test responsiveness resulting from direct histamine release from a true IgE-mediated activation of cutaneous mast cells. From investigations about morphine and pholcodine (3-[2-morpholinyl-ethyl] morphine)-reactive IgE antibodies it is clear that positive IgE results towards these compounds cannot be considered as a proof for opiate allergy. As a matter of fact, sIgE reactivity to opiates has been observed in up to 10% of the general population and over 80% of patients allergic to rocuronium.3,4,5 Mutatis mutandis, this observation applies to skin testing with these potent histamine releasers that, for years, have been used as a positive control in skin testing (for review2). In contrast, opiates seem not to trigger histamine release from human basophils,6,7,8 making these cells highly attractive as a complementary diagnostic instrument to discriminate non-immunologic hypersensitivity reactions from genuine allergy with an underlying IgE-mediated mechanism (for review2). In their manuscript the authors describe a patient who suffered from anaphylaxis due to oral intake of codeine and document their diagnosis with a drug provocation and histamine release tests. However, due to the unavailability of codeine-sIgE tests, they were unable to establish a potential IgE-mediated mechanism. However, several points might be addressed here. First, measurement of pholcodine and morphine sIgE antibodies, that are readily available from Phadia Thermo Fisher Scientific, might have proven to be useful. As a matter of fact, these three opiates are structurally almost identical, except the substituent in position 3. At this position codeine has a methoxy group, morphine a hydroxyl group, and pholcodine a 2-morpholinoethyl group. Second, mutatis mutandis, the recommendation also applies to histamine release and drug provocation tests. Recently, we have described three patients with immediate hypersensitivity reactions to pholcodine in who measurement of drug-specific IgE and basophil activation tests (Figure) lead to the diagnosis of an IgE-mediated pholcodine allergy.9 Because these patients demonstrated a positive sIgE to morphine but negative basophil activation and provocation tests with the closely related structures morphine and pholcodine, the conclusion seems inescapable that the currently available quantification of opiate-sIgE tests should not be used to diagnose or predict clinical outcomes. Moreover, these observations seem to indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, the position 3 substituent. Figure Representative plot CD63 appearance and histamine release in response to buffer, anti-IgE as a positive control, pholcodine 10 µg/mL (top), and the structurally almost similar opiates codeine 100 mg/mL and morphine 100 µg/mL (both bottom) ...

Cross-reactive aeroallergens: which need to cross our mind in food allergy diagnosis?

Secondary food allergies due to cross-reactivity between inhalant and food allergens are a significant and increasing global health issue. Cross-reactive food allergies predominantly involve plant-derived foods resulting from a prior sensitization to cross-reactive components present in pollen (grass, tree, weeds) and natural rubber latex. Also, primary sensitization to allergens present in fungi, insects, and both nonmammalian and mammalian meat might induce cross-reactive food allergic syndromes. Correct diagnosis of these associated food allergies is not always straightforward and can pose a difficult challenge. As a matter of fact, cross-reactive allergens might hamper food allergy diagnosis, as they can cause clinically irrelevant positive tests to cross-reacting foods that are safely consumed. This review summarizes the most relevant cross-reactivity syndromes between inhalant and food allergens. Particular focus is paid to the potential and limitations of confirmatory testing such as skin testing, specific IgE assays, molecular diagnosis, and basophil activation test.

Rocuronium hypersensitivity: Does off-target occupation of the MRGPRX2 receptor play a role?

BACKGROUND The neuromuscular blocking agent (NMBA) rocuronium is a relevant cause of perioperative hypersensitivity (POH) with a significant risk of diagnostic error. Recently, it has been suggested to reclassify hypersensitivity to NMBA as type A reactions resulting from off-target occupation of the nonimmune MRGPRX2 receptor. OBJECTIVE To investigate whether basophil activation experiments can benefit diagnosis and add to the insights in the pathomechanisms of rocuronium hypersensitivity. METHODS A total of 140 patients with a suspected POH to rocuronium in whom peak tryptase was available had complete diagnostic workup for all potential culprits including triple confirmatory testing with skin tests, basophil activation test (BAT), and quantification of specific IgE (sIgE) antibodies to rocuronium and morphine. To further analyze the clinical relevance of sIgE antibodies, quantitative basophil inhibition experiments were performed by coincubation of the cells with rocuronium and morphine, an opiate known to harbor a substituted ammonium structure. RESULTS Diagnosis of rocuronium hypersensitivity was established in 72 of 140 patients (51.4%), of whom 65 (90.3%) demonstrated mast cell activation. Of the 72 patients, 64 displayed a positive skin test, 8 (11.1%) had their diagnosis documented only by BAT. Coincubation of morphine and rocuronium induced a dose-dependent inhibition of BAT with rocuronium that was restricted to 4 of 6 patients with IgE reactivity to rocuronium and/or morphine. CONCLUSIONS BAT can benefit diagnosis of rocuronium hypersensitivity. As basophils barely express MRGPRX2 and BAT rocuronium can be inhibited by morphine, we believe that hypersensitivity to rocuronium still mainly results from IgE/high-affinity receptor for sIgE (FcεRI)-dependent effector cell activation. However, it cannot be excluded that in a few patients rocuronium hypersensitivity results from off-target occupation of the MRGPRX2 receptor.

Exploring the diagnosis and profile of cannabis allergy

BACKGROUND Cannabis allergy (CA) has mainly been attributed to Can s 3, the nonspecific lipid transfer protein (nsLTP) of Cannabis sativa. Nevertheless, standardized diagnostic tests are lacking and research on CA is scarce. OBJECTIVE To explore the performance of 5 cannabis diagnostic tests and the phenotypic profile of CA. METHODS A total of 120 patients with CA were included and stratified according to the nature of their cannabis-related symptoms; 62 healthy and 189 atopic controls were included. Specific IgE (sIgE) hemp, sIgE and basophil activation test (BAT) with a recombinant Can s 3 protein from Cannabis sativa (rCan s 3), BAT with a crude cannabis extract, and a skin prick test (SPT) with an nCan s 3-rich cannabis extract were performed. Clinical information was based on patient history and a standardized questionnaire. RESULTS First, up to 72% of CA reporting likely-anaphylaxis (CA-A) are Can s 3 sensitized. Actually, the Can s 3-based diagnostic tests show the best combination of positive and negative predictive values, 80% and 60%, respectively. sIgE hemp displays 82% sensitivity but only 32% specificity. Secondly, Can s 3+CA reported significantly more cofactor-mediated reactions and displayed significantly more sensitizations to other nsLTPs than Can s 3-CA. Finally, the highest prevalence of systemic reactions to plant-derived foods was seen in CA-A, namely 72%. CONCLUSIONS The most effective and practical tests to confirm CA are the SPT with an nCan s 3-rich extract and the sIgE rCan s 3. Can s 3 sensitization entails a risk of systemic reactions to plant-derived foods and cofactor-mediated reactions. However, as Can s 3 sensitization is not absolute, other cannabis allergens probably play a role.

Letter to the Authors Concerning the Published Manuscript by Rial and Sastre: Food Allergies Caused by Allergenic Lipid Transfer Proteins: What Is Behind the Geographic Restriction?

To the Editor, We read with great interest the manuscript by M. J. Rial and J. Sastre [1] about the geographical distribution of sensitization to non-specific lipid transfer proteins (ns-LTPs). In present day, this is an interesting topic, and therefore we would like to raise some issues and questions, especially concerning the prevalence of ns-LTP sensitization outside the Mediterranean area. The authors report that sensitization to ns-LTPs is infrequent in Central Europe and other non-Mediterranean regions; however, it appears that the authors have overlooked a large Belgian survey performed in 718 patients [2]. As a matter of fact, we demonstrated that the prevalence of sIgE reactivity towards nsLTP(s) is demonstrable in about one-quarter of Belgian patients presenting with symptoms of a pollen and/or plant food allergy. In this survey, all patients were systematically screened for nsLTP sensitization using a panel of six different ns-LTPs; four food ns-LTPs respectively rPru p 3 of peach (Prunus persica), rMal d 3 of apple (Malus domestica), rCor a 8 of hazelnut (Corylus avellana), and rAra h 9 of peanut (Arachis hypogaea) and two weed pollen ns-LTPs specifically nArt v 3 of mugwort (Artemisia vulgaris) and rPar j 2 of wall pellitory (Parietaria judaica). To the best of our knowledge, this study is the largest prevalence study focusing on ns-LTP sensitization in northwestern Europe. Moreover, this study also demonstrated that in a northwestern European country, patients with ns-LTP sensitization can exhibit distinct phenotypes that are not readily predictable by the sIgE results. Although, similar to initial observations in the Mediterranean basin [3–5], some of our patients demonstrated systemic reactions, the majority of patients with sIgE reactivity towards ns-LTPs did not report any clinical reaction to the respective plant food(s). A possible explanation for the absence of overt allergy could be the high prevalence of sensitization to the major allergen of birch pollen, Bet v 1 (Betula verrucosa) [6–8]. However, for the time being, this explanation is highly speculative, but relies on observations from the Mediterranean basin on sensitization to Bet v 1 (PR10 molecule) to protect for ns-LTP-related allergies. In other words, patients co-sensitized to Bet v 1 and Bet v 1 homologues report milder clinical symptoms compared to patients without co-sensitization to PR10 molecules. Clearly, more studies are needed to fully elucidate the protective effect of PR10 molecules. The exact reason(s) for the high prevalence of ns-LTP sensitization in our country remain(s) elusive. Although we cannot exclude our findings (in part) to reflect our methodology (usage of multiple sensitive single-plexed assays), we believe that in most patients, ns-LTP sensitization is genuine and might result from various sensitization routes that extend beyond pollen and plant-derived foods. Actually, we observed that Can s 3, the ns-LTP from Cannabis sativa, is a major allergen in cannabis allergy in our regions [9]. Moreover, it appears that sensitization to Can s 3 can result from both active and passive exposure to marijuana smoke [10] and that the Can s 3 cross-reactivity syndrome extends beyond fruits and vegetables but can also involve beverages and latex [11]. In conclusion, sensitization towards ns-LTP, although historically predominantly described in the Mediterranean basin, is not uncommon in north-western Europe and can result in clinically distinct phenotypes. Further collaborative studies are required to obtain insight into sensitization routes, clinical * Margaretha A. Faber margaretha.faber@uantwerpen.be

Update on Quinolone Allergy: A Complementary Note

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.