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Introduction: While a consensus seems to have been reached with regard to the definition of anaphylaxis, there is no universal instrument for scoring allergic reaction severity despite more than 30 having been proposed by the time of writing. This severely hampers comparison of data between studies. While scales have been compared with regard to their utility in grading food-related reactions, no such comparisons have been made for Hymenoptera venom-associated reactions., Methods: The study conducted a retrospective analysis to compare the severity of Hymenoptera venom allergy reactions in 104 participants with suspected Hymenoptera venom allergy. The study applied six grading instruments to each reaction, also evaluating them against the NIAID/FAAN anaphylaxis criteria. Sensitivity, specificity, and receiver operating characteristic area under the curve (AUC) for identifying anaphylaxis were calculated. Severity scales were simplified into "mild," "moderate," and "severe" categories. The most common severity grade across the five scales was determined using a custom function to establish a consensus severity grade., Results: The most common culprit insects were honeybees (49.0%). Among the 88 participants with generalized reactions, the highest proportion had involvement of four organ systems. The scales showed high specificity for detecting anaphylaxis, especially when using higher grades of the Mueller, WAO, and Dribin scales. The diagnostic yields (AUC) varied, with the WAO scale having the highest AUC (0.94) for grades 3, 4, and 5. Spearman correlation analysis showed the strongest correlations seen between the Brown and Dribin, Ring and Messmer and Dribin, and Ring and Messmer and Reisman scales. The lowest correlations were observed with the Mueller scale when paired with the WAO, Reisman, and Dribin scales. An inter-rater reliability analysis showed substantial agreement between scales with the same number of grading levels. The agreement was highest for the Brown and Dribin scales, indicating a strong consistency in reaction severity classification across different instruments., Conclusion: While all instruments were effective in stratifying reactions, they showed limitations in differentiating milder phenotypes. The Brown and Dribin scales stood out for their high agreement with the consensus score and sensitivity in identifying anaphylaxis. Our findings suggest that adopting either of these scales could significantly unify the reporting of allergic reactions. We believe the format of an instrument should be tailored to its intended purpose, with clinical decision aids being simpler and research tools being more detailed., (© 2024 S. Karger AG, Basel.)

Introduction: In 15-35 percent of patients with anaphylaxis, the triggering allergen cannot be found; therefore, a diagnosis of idiopathic anaphylaxis (IA) is made. We report on the outcomes in patients with IA treated with omalizumab., Methods: We included consequent omalizumab-treated IA adult patients treated with omalizumab 300 mg every 4 weeks., Results: Out of 7 patients, 6 were female, median age 40 years with the frequency of anaphylaxis episodes from 3 in 2 years to 5 in 4 months. Baseline tryptase ranged from 1.71 to 12.0 μg/L. An increase in tryptase during anaphylaxis was documented in 6 patients. Activating KIT p.D816V variant was detected in 2 patients. One patient also had hereditary alpha-tryptasemia (HαT). The duration of omalizumab treatment was 0.5-7.5 years. None of the patients have experienced an anaphylactic reaction since the start of treatment. Mild systemic reactions were reported in 6 patients (86%). The presence of underlying cMCD had no impact on the treatment outcome., Conclusion: All patients in our study had complete responses to omalizumab. The presence of KIT p.D816V and HαT did not influence the response to omalizumab treatment., (© 2024 S. Karger AG, Basel.)

Hymenoptera venom-triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim's first manifestation of HVA. Mastocytosis represents one of the most important risk factors for severe HVA. We analyzed patients with documented fatal HVA for the presence of underlying clonal mast cell disorder (cMCD). Here, we report three cases of fatal HVA, with undiagnosed underlying cMCD identified by the presence of the peripheral blood and/or bone marrow KIT p.D816V missense variant postmortem. In the first case, anaphylaxis was the initial episode and was fatal. In the other two cases, both patients were treated with specific venom immunotherapy (VIT), nevertheless, one died of HVA after VIT discontinuation, and the other during VIT; both patients had cardiovascular comorbidities and were taking beta-blockers and/or ACE inhibitors. Our results point to the importance of screening all high-risk individuals for underlying cMCD using highly sensitive molecular methods for peripheral blood KIT p.D816V variant detection, including severe HVA and possibly beekeepers, for proper management and the need for lifelong VIT to prevent unnecessary deaths. Patients at the highest risk of fatal HVA, with concomitant cardiovascular and cMCD comorbidities, might not be protected from field stings even during regular VIT. Therefore, two adrenaline autoinjectors and lifelong VIT, and possibly cotreatment with omalizumab, should be considered for high-risk patients to prevent fatal HVA episodes.

Background: Anaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed., Objective: We sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis., Methods: Bulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to Hymenoptera venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken., Results: 1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling., Conclusion: Our study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rijavec, Maver, Turner, Hočevar, Košnik, Yamani, Hogan, Custovic, Peterlin and Korošec.)

Background: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized., Method: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed., Results: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable., Conclusions: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: A biomarker that could identify individuals at high risk for severe honeybee sting allergic reaction and/or systemic adverse events (SAEs) during venom immunotherapy (VIT) would improve the management of patients with honeybee (HB) venom allergy., Objective: To identify biomarkers for risk of severe sting reactions or SAEs during VIT., Methods: We recruited 332 patients undergoing HB VIT. We ascertained predictors of the severity of the field-sting reaction and the severity and threshold of SAEs during VIT. We assessed the use of cardiovascular medications; baseline serum tryptase (BST) levels; specific IgEs to HB venom, rApi m 1, and rApi m 10; and basophil activation test (BAT) response., Results: Significant and independent predictors of a severe HB field-sting reaction were age (P = .008), an absence of skin symptoms (P = .001), BST (P = .014), and BAT response at an HB venom concentration of 0.1 μg/mL (P = .001). Predictors of severe SAEs during HB VIT were age (P = .025), BST (P = .006), and BAT response (P = .001). BAT response was also an individual and significant predictor of any SAEs and SAEs at a low cumulative allergen dose (median, 55 μg) during VIT build-up (P < .001). The use of β-blockers and angiotensin-converting-enzyme inhibitors and specific IgE levels were not associated with the severity of HB field-sting reactions or VIT SAEs., Conclusions: BST and basophil activation are independent risk factors for severe HB sting anaphylaxis and SAEs during HB VIT. BAT response was the best biomarker for any SAEs and a lower threshold of SAEs during HB VIT. These risk factors can help guide recommendations for VIT and overcome systemic reactions to HB VIT., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Clonal mast cell disorders and elevated basal serum tryptase (BST) levels with unknown cause(s) are associated with severe Hymenoptera venom-triggered anaphylaxis (HVA). However, some individuals with clonal disease have a normal BST level (<11.4 ng/mL)., Objective: Our aim was to evaluate whether screening for KIT p.D816V in the blood is a useful clinical tool to risk-stratify patients with venom allergy., Methods: We prospectively recruited 374 patients with Hymenoptera allergy and no overt signs of mastocytosis who were referred to our center during the years 2018 and 2019. KIT p.D816V was determined in their peripheral blood by quantitative PCR, and tryptase genotyping was performed by droplet digital PCR., Results: In all, 351 patients (93.9%) had normal levels of BST, and KIT p.D816V was detected in 8% of patients (28 of 351), predominantly in patients with the most severe Mueller grade IV anaphylaxis (18.2% [24 of 132] vs 1.8% in patients with lower grades [4 of 88 with grade III and 0 of 131 with other grades]; P < .001). In grade IV patients with a normal BST level, KIT p.D816V was associated with more severe symptoms, including a significantly higher frequency of loss of consciousness (58.3% [14 of 24] vs 34.3% [37 of 108]; P = .03) and absence of skin symptoms (41.7% [10 of 24] vs 15.7% [17 of 108]; P = .004). Among patients with a normal BST level, KIT p.D816V (OR = 10.25 [95% CI = 3.75-36.14]; P < .0001) was the major risk factor associated with severe HVA. Hereditary α-tryptasemia (HαT) due to increased germline copies of TPSAB1 encoding α-tryptase was the most common cause (65.2% [15 of 23]) of elevated BST level in patients with HVA, and together with KIT p.D816V, it accounted for 90% of BST level elevations (20 of 23) in patients with HVA., Conclusion: These results indicate that routine KIT p.D816V screening identifies clonal disease in high-risk patients with HVA who are regularly missed when BST level is used alone., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: There is controversy whether taking β-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT)., Methods: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment., Results: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β-blockers, 11.9% ACEI, 5.0% β-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of β-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β-blockers, none an ACEI., Conclusions: This trial provides robust evidence that taking β-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629)., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Epinephrine autoinjector (EAI) is prescribed to prevent a fatal outcome in the case of a repeated anaphylactic reactions. We wanted to determine how adult patients who received their first prescription as part of an urgent treatment of an anaphylactic reaction or at their family physician were instructed on the use of EAI., Methods: Nurses assessing patients' knowledge asked the patient to demonstrate how to use the EAI training device. Patients who performed the critical steps correctly in 1 min were labelled as competent., Results: Forty-one patients (24% women, 46 ± 5 years) came for the allergy examination 116 ± 145 days after receiving a prescription for EAI. When prescribing, the doctor or nurse explained the instructions for the use of EAI to 63.4% patients, and 31.7 patients practiced the use of EAI using a training device. At the pharmacy, 22% received explanation and 7% also practiced using a training device. Fifty-four percent of patients were able to effectively administer EAI adrenaline within 1 min. Higher education level was associated with sufficient knowledge about the use of EAI (p = 0.026). At the time of the visit to the allergy specialist clinic, 61% of patients had EAI with them. The shelf life of EAI was known to 63% of patients., Conclusions: The activities to increase the prescription rate of EAI immediately after treatment of anaphylactic episode are not sufficient to prevent severe outcome after the repeated episodes of anaphylaxis as nearly a half of patients are not able to use EAI correctly., (© 2021 S. Karger AG, Basel.)

Background: We sought to determine whether basophil-allergen sensitivity could be transferred to donor basophils by passive IgE sensitisation in allergic rhinitis and anaphylactic Hymenoptera venom hypersensitivity., Methods: We studied 15 wasp venom-, 19 grass pollen- and 2 house dust mite-allergic patients, 2 healthy donors, and 8 wasp venom-allergic donors. In all subjects, we first evaluated the initial basophil response to wasp venom, grass pollen, or house dust mite allergen. Donor basophils were then stripped, sensitised with the different patients' serum IgE, and challenged with the corresponding allergen. The CD63 response of donor basophils was then compared with initial basophil responses., Results: In wasp venom-allergic subjects, the IgE transfer did not reflect the initial basophil-allergen sensitivity, because the venom IgE of subjects with high or low basophil sensitivity induced comparable responsiveness in healthy donor basophils. Furthermore, vice versa, when we sensitised the donor basophils of wasp venom-allergic individuals with different wasp venom or house dust mite IgE, we demonstrated that their response was predictable by their initial basophil allergen sensitivity. In the rhinitis allergy model, the IgE transfer correlated with the patients' initial basophil responsiveness because the grass pollen IgE of the subjects with high basophil allergen sensitivity induced significantly higher responsiveness of donor basophils than the IgE of subjects with initially low basophil allergen sensitivity., Conclusions: Our results suggest that basophil allergen sensitivity evaluated by flow-cytometric CD63 analysis depends on two distinct contribution factors. In anaphylactic Hymenoptera allergy, the major factor was intrinsic cellular sensitivity, whereas in pollen allergy, the major factor was allergen-specific IgE on the cell surface., (© 2016 S. Karger AG, Basel.)

Background: Previous reports suggest the usefulness of basophil activation testing (BAT) in Hymenoptera-allergic patients with negative venom-specific IgE antibodies. We sought to evaluate the diagnostic utility of this testing in a routine clinical laboratory setting., Materials and Methods: Twenty-one patients with anaphylactic reactions to Hymenoptera sting (median grade III) and negative venom-specific IgE were routinely and prospectively tested with BAT., Results: We were able to diagnose 81% (17 of 21) of patients with BAT and 57% (12 of 21) with intradermal skin testing. Three wasp venom-allergic patients showed IgE positivity to rVes v 5. Four patients (19%) were negative for all tests. In the case of double-positive BAT, the culprit insect correlated with the venom that induced a significantly higher basophil response., Conclusions: BAT allows the identification of severe Hymenoptera-allergic patients with negative specific IgE and skin tests. The routine use of this cellular test should facilitate prescription of venom immunotherapy in complex cases with inconclusive diagnostic results., (Copyright © 2013 S. Karger AG, Basel.)

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long‐term effectiveness of VIT. Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring‐Messmer grade 3–4 vs. 11% [n = 78 of 709] with Grade 1–2; p <.0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3–4 vs. 0.001% [n = 78] in Grade 1–2; p <.0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V‐positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p <.01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p <.01). Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT. [ABSTRACT FROM AUTHOR]

Introduction/Objective. Allergic reactions to insect stings are medical emergencies that could be prevented by venom immunotherapy (VIT). The main purpose of VIT is to prevent fatal or life-threatening reactions. We aimed to show the rapidity with which patients experience the benefits of VIT and estimate the number of emergency treatments that are prevented. Methods. We reviewed the medical files of patients who started VIT between 2010 and 2014. We calculated the costs of treatment of the sting reactions, the costs of immunotherapy, and estimated the costs of prevented allergic reactions. Results. In a cohort of 514 patients (40.9% female, age 47.2 ± 14.4 years), the cost of treatment of the index sting reaction was 180.4 ± 166.8 euros. During VIT, 195 patients experienced 446 field stings. In 86.3% of patients, stings were well tolerated, and only one patient experienced a severe reaction (grade III, according to Mueller). A total of 20.4% of VIT treated patients were stung during the first year of VIT and 57% during five years of VIT. The expenditure for five years of VIT was 2,886 euros per patient, which corresponded to an average of 16 emergency treatments for systemic reactions. Conclusion. Emergency situations are prevented in a substantial number of venom-allergic patients and a beneficial effect was already observed during the first year of VIT.

To cite this article:Žitnik SEK, Vesel T, Avčin T, Šilar M, Košnik M, Korošec P. Monitoring honeybee venom immunotherapy in children with the basophil activation test. Pediatr Allergy Immunol 2011 Doi: 10.1111/j.1399-3038.2011.01233.x Abstract Background: New in vitro methods are essential for developing better follow-up criteria for venom immunotherapy (VIT). Methods: Thirty-one children with a history of honeybee venom-induced systemic anaphylaxis were included in this prospective, single-blinded study. The basophil CD63 activation test (BAT) was assessed before starting VIT, at the end of the build-up phase (day 5), 6 months later, and after 2-4 yr of VIT. Results: Basophil CD63 activation test allowed identification of the culprit insect in 74% of honeybee venom-allergic children. In comparison, IgE reactivity was single positive in only 52% of children. Five days after starting VIT, BAT was highly comparable to before VIT. However, after 6 months and further after 2-4 yr of VIT, a significant and approximately fourfold decrease was demonstrated in CD63 response at sub-maximal 0.1 μg/ml allergen concentration, which mainly represents cellular sensitivity. No such differences were found at a higher 1 μg/ml of allergen concentration. Person-to-person analyses showed that after 2-4 yr of VIT, a marked CD63 decrease was evident in 85% of children. In addition, elevated basophil sensitivity measured before VIT was associated with the appearance of side effects observed during the build-up phase of VIT. Conclusion: Basophil CD63 allergen-specific sensitivity seems to be a promising tool for monitoring protective immune response in honeybee VIT. [ABSTRACT FROM AUTHOR]

Cat allergy is one of the most prevalent allergies worldwide and can lead to the development of rhinitis and asthma. Thus far, only allergen extracts from natural sources have been used for allergen-specific immunotherapy. However, extracts and whole allergens in immunotherapy present an anaphylaxis risk. Identification of allergen epitopes or mimotopes has an important role in development of safe and effective allergen-specific immunotherapy. Moreover, with a suitable immunogenic carrier, the absence of sufficient immune response elicited by short peptides could be surmounted. In this study, we identified five structural mimotopes of the major cat allergen Fel d 1 by immunoscreening with random peptide phage libraries. The mimotopes were computationally mapped to the allergen surface, and their IgE reactivity was confirmed using sera from cat-allergic patients. Importantly, the mimotopes showed no basophil activation of the corresponding cat-allergic patients, which makes them good candidates for the development of hypoallergenic vaccine. As bacteriophage particles are becoming increasingly recognized as immunogenic carriers, we constructed bacteriophage particles displaying multiple copies of each selected mimotope on major phage coat protein. These constructed phages elicited T cell-mediated immune response, which was predominated by the type 1 T cell response. Mimotopes alone contributed to the type 1 T cell response by promoting IL-2 production. Fel d 1 mimotopes, as well as their filamentous phage immunogenic carriers, represent promising candidates in the development of hypoallergenic vaccine against cat allergy. [ABSTRACT FROM AUTHOR]