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Beekeepers represent a high-allergic risk population group due to their unavoidable seasonal or persistent exposure to the elicitors of Hymenoptera venom allergy, bees in particular. A systematic literature review and meta-analysis aimed to estimate the prevalence of self-reported systemic allergic reaction to Hymenoptera venom among beekeepers worldwide.

To make the treatment approach in patients suffering a European hornet sting allergy reaction more personalized, preparing them also for possible future risks.

To develop and validate a comprehensive questionnaire to be used as an instrument in cross-sectional studies among beekeepers.

The article in Clinical & Experimental Allergy explores the connection between lymphopenia, basopenia, and eosinopenia in chronic spontaneous urticaria (CSU) patients, particularly those with autoimmune CSU. The study involved 300 CSU patients and found that lymphopenia was associated with lower counts of basophils, eosinophils, monocytes, and platelets. The research suggests that lymphopenia may reflect the migration of lymphocytes from the bloodstream into skin lesions, similar to basophils and eosinophils. The study also identified associations between basopenia and high anti-C1q levels, supporting the hypothesis that these antibodies may be a marker of autoimmune CSU. [Extracted from the article]

Chronic spontaneous urticaria (CSU) is associated with skin mast cell activation, and its triggering mechanisms are not completely elucidated. Evidence suggests an autoimmune component of CSU. Our aim was to assess the usefulness of an autoimmune mast cell activation test (aiMAT) for diagnosing and differentiating CSU into different subtypes. We enrolled 43 patients with active, uncontrolled CSU before starting treatment with omalizumab and 15 controls. Patients were evaluated based on omalizumab response. aiMATs were performed using non-IgE-sensitized (NS) or myeloma IgE-sensitized (S) LAD2 cells, which were then stimulated with CSU/control sera (25 µL and 10 µL). The expression of CD63 was assessed with flow cytometry. CD63 response on NS-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera (p = 0.0007) and with 10 µL CSU/control sera (p = 0.0001). The ROC curve analysis demonstrated an area under the curve (AUC) of 0.82. The cutoff for autoimmune-non-IgE-sensitized-MAT was 40.3% CD63+ LAD2, which resulted in 73.3% sensitivity and 81.4% specificity. CD63 response on S-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera (p = 0.03). The ROC curve analysis demonstrated an AUC of 0.66. The cutoff for the autoimmune-myeloma IgE-sensitized-MAT was 58.4% CD63+ cells, which resulted in 62.8% sensitivity and 66.7% specificity. Overall, 36 out of 43 (84%) patients responded to omalizumab, and 7 (16%) were nonresponders. We found no differences between LAD2 CD63 response and response to omalizumab. In conclusion, aiMAT could represent a new diagnostic tool in CSU. Additional studies are needed to evaluate the potential benefits during omalizumab therapy. [ABSTRACT FROM AUTHOR]

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: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Upon first exposure to cetuximab, hypersensitivity reactions can occur. We aimed to assess the utility of the basophil activation test (BAT) to alpha-gal and cetuximab for predicting severe reactions. We prospectively recruited 38 patients and evaluated sIgE to alpha-gal in all patients before the first application of cetuximab. In all alpha-gal-sensitized patients, we evaluated skin tests to meat extracts, gelatine, and cetuximab and performed BAT with alpha-gal and cetuximab. In 24% (9/38) of patients, sIgE to alpha-gal was >0.10 kUA/L, and 8/9 reacted to the cetuximab. Basophil activation tests with alpha-gal were positive in all sensitized patients and were higher in those with severe reactions (18.3% in grade 4 [n = 4] vs. 1.8% in grade 2 [n = 3] or no reaction [n = 1] at 3.3 ng/mL of alpha-gal; p = 0.03). All patients with severe grade 4 reactions had a positive CD63 BAT response to cetuximab compared to patients with moderate or no reaction, who all had negative BAT (57.7% vs. 0.9% at 500 µg/mL, 63.2% vs. 4.1% at 100 µg/mL, 58.2% vs. 2.7% at 10 µg/mL, and 32.1% vs. 3.3% at 1 µg/mL of cetuximab, respectively; p ≤ 0.001). In summary, before initiating cetuximab treatment, sIgE to alpha-gal should be assessed in all patients. To predict the severity of the reaction and to assess the risk of cetuximab-induced anaphylaxis, we should perform BATs with alpha-gal or more discriminative BATs with cetuximab. [ABSTRACT FROM AUTHOR]

Allergen-specific venom immunotherapy (VIT) is a well-established therapy for Hymenoptera venom allergy (HVA). However, the precise mechanism underlying its clinical effect remains uncertain. Our study aimed to identify the molecular mechanisms associated with VIT efficiency. We prospectively included 19 patients with HVA undergoing VIT (sampled before the beginning of VIT, after reaching the maintenance dose, one year after finishing VIT, and after a sting challenge) and 9 healthy controls. RNA sequencing of whole blood was performed on an Illumina sequencing platform. Longitudinal transcriptomic profiling revealed the importance of the inhibition of the NFκB pathway and the downregulation of DUX4 transcripts for the early protection and induction of tolerance after finishing VIT. Furthermore, successful treatment was associated with inhibiting Th2, Th17, and macrophage alternative signalling pathways in synergy with the inhibition of the PPAR pathway and further silencing of the Th2 response. The immune system became activated when reaching the maintenance dose and was suppressed after finishing VIT. Finally, successful VIT restores the immune system's balance to a state similar to that of healthy individuals. Our results underline the important role of the inhibition of four pathways in the clinical effect of VIT: Th2, Th17, NFκB, and macrophage signalling. Two biomarkers specific for successful VIT, regardless of the time of sampling, were C4BPA and RPS10-NUDT3 and should be further tested as potential biomarkers. [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.