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Mastocytosis is a risk factor for Hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in patients with HVA and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derive from European single-center studies, and the prevalence of HVA with and without mastocytosis in the United States is unknown. We sought to determine the prevalence of HVA and mastocytosis in the United States using an insurance claims database and evaluate the impact of mastocytosis on VIT in patients with HVA in a US cohort. The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Furthermore, a retrospective study of 161 patients undergoing VIT between 2015 and 2018 at the University of Michigan was conducted. In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among patients with HVA versus the general population. In the U-M cohort, 2.6% of patients with VIT had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US patients with HVA, though at lower rates than previously reported. In patients with VIT there was no correlation between tryptase level and reaction severity. [ABSTRACT FROM AUTHOR]

Oxidative stress occurs in many allergic and immunologic disorders as a result of the imbalance between the endogenous production of free reactive oxygen species (ROS) and/or the reduction of antioxidant defense mechanisms. Advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), and nitrosylated proteins (NPs) can be used as markers of oxidative stress and inflammation. Our objective was to examine the serum levels of AGEs, AOPPs, and NPs in patients with allergic reactions to hymenoptera venom before and after ultrarush venom immunotherapy (VIT). The study included two groups of patients: 30 patients allergic to yellow jacket or honey bee venom and treated by aqueous preparation of Vespula spp (26 patients) or Apis mellifera (four patients) VIT, and 30 healthy donors as controls. Blood samples were collected to measure serum levels of AGEs, AOPPs, and NPs at baseline (T1), at the end of the incremental phase of the VIT protocol (T2), and after 15 days (T3). Serum AOPP levels at T1 were significantly higher in comparison with controls (p = 0.001), whereas serum levels of NPs at T1 were significantly lower than those in controls (p < 0.0001). No significant difference in circulating levels of AOPPs, AGEs, and NPs was found during immunotherapy. These findings suggest that, although hymenoptera venom allergy (HVA) is characterized by isolated episodes of reactions to stinging insect venom and is not included among chronic inflammatory diseases, an oxidative stress status occurs in patients suffering from this kind of allergy. Furthermore, VIT does not modify serum levels of these oxidative stress biomarkers. [ABSTRACT FROM AUTHOR]

Quality of life is affected by history of bee sting allergy. In addition, worry about being stung and also the need to use self-injection of medicine can create or increase anxiety, which can further compromise a patient's ability to enjoy the outdoors and participate in activities. We sought to determine the depression and anxiety in three groups of individuals. We assessed patients with bee sting allergy without epinephrine, bee sting allergy with epinephrine, and bee sting allergy receiving immunotherapy (venom immunotherapy [VIT]). We use two standardized surveys after having Intuitional Review Board approval to determine depression and anxiety in the three cohorts noted previously. We compared the three groups using Wilcoxon rank sum test and statistical significance was considered present for a value of p = 0.05. Overall, the epinephrine group had higher mean anxiety and depression scores compared with the other treatment groups. The VIT group had the lowest mean and median scores for both anxiety and depression. It appears that VIT not only decreases the risk of anaphylaxis and death, but also improves quality of life by reduction of anxiety and depression, especially in female subjects. We found that VIT patients, when compared with nontreated and treated only with epinephrine, had lower anxiety and depression scores. [ABSTRACT FROM AUTHOR]

Insect venom hypersensitivity can pose a threat to personnel deployed to a combat zone but the exposure risk in Afghanistan is currently unknown. This study was designed to assess the threat of Hymenoptera stings and associated allergic reactions in Afghanistan. Hymenoptera species were collected during a deployment to southern Afghanistan from June 2010 through January 2011. The literature was also reviewed to determine species of medically important Hymenoptera recorded in the region. The U.S. Army theater electronic medical data system was mined for ICD-9 codes associated with insect stings to determine the number of theater medical clinic encounters addressing insect sting reactions. Three species of flying hymenoptera were commonly encountered during the study period: Vespa orientalis L., Polistes wattii Cameron, and Vespula germanica (F.). A literature review also confirms the presence of honeybees (Apidae), numerous velvet ant (Mutillidae) species, and various ant (Formicidae) species all capable of stinging. No evidence was identified to suggest that fire ants (Solenopsis ssp.) are a threat in the region. Based on electronic medical records from the U.S. Central Command area of operations over a 2-year period, roughly 1 in 500 clinic visits involved a patient with a diagnosis of insect bite or sting. Cross-reactive members of all five flying Hymenoptera species commonly assessed for in Hymenoptera allergy evaluations are present in Afghanistan. The review of in-theater medical records confirms that insect stings pose an environmental threat to deployed service members. [ABSTRACT FROM AUTHOR]

Background: Venom immunotherapy can be initiated by different schedules, but randomized comparisons have not been performed. Objective: We aimed to compare the safety of 2 initiation schedules. Methods: Patients of any age with prior immediate generalized reactions to jack jumper ant (Myrmecia pilosula) stings were randomized to venom immunotherapy initiation by a semirush schedule over 10 visits (9 weeks) or an ultrarush schedule over 3 visits (2 weeks). In a concurrent treatment efficacy study, the target maintenance dose was randomized to either 50 μg or 100 μg. The primary outcome was the occurrence of 1 or more objective systemic reactions during venom immunotherapy initiation. Analyses were by intention to treat. We also assessed outcomes in patients who declined randomization. Results: Of 213 eligible patients, 93 were randomized to semirush (44 patients) or ultrarush (49 patients) initiation. Objective systemic reactions were more likely during ultrarush initiation (65% vs 29%; P < .001), as were severe reactions (12% vs 0%; P = .029). Times to maximal increases in venom-specific IgG4 were no different between treatments, whereas the maximal increase in venom-specific IgE occurred earlier with ultrarush treatment. Similar differences between methods were observed in patients who declined randomization. One hundred seventy-eight patients were randomized to maintenance doses of either 50 μg (90 patients) or 100 μg (88 patients). The target maintenance dose had no effect on the primary outcome, but multiple-failure-per-subject analysis found that the 50 μg dose reduced the likelihood of reactions. Conclusion: Ultrarush initiation increases the risk of systemic reactions. A lower maintenance dose reduces the risk of repeated reactions, but the effect on treatment efficacy is unknown. [ABSTRACT FROM AUTHOR]

In 2011, one hundred years of allergen immunotherapy was celebrated. Several landmark studies date from the first decades of experience with this treatment and are still cited today, often without analysis of the original articles. Original articles of the oldest landmark studies on subcutaneous immunotherapy (SCIT) and sublingual immunotherapy were sought and reviewed in detail, together with some publications on their authors' historical background. Details that might be of importance to the present allergists are highlighted in this article. Study design, preparation of allergen extracts used for immunotherapy and clinical findings of the following studies are discussed. For the European school, Noon 1911 was the first report of successful application of grass pollen extract; Frankland 1954 was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT. For the European school: Noon published the first report of successful application of grass pollen extract (1911); Frankland was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT (1954). For the American line: Clowes published the first successful trial of ragweed SCIT (1913); Cooke used skin prick testing as diagnostic method (1915); Loveless used venom immunotherapy with purified venom (not whole body extract) (1956); in 1961/1968 Johnstone showed in a DBPC-RCT dose-effect of an allergen mix and highly significant asthma reduction after up to 14 yrs of treatment of asthmatic children; Lowell and Franklin did the first DB-RCT demonstrating ragweed pollen efficacy as part of a multi-allergen mix and 1967 ragweed pollen extract dose response. We discuss the first studies for SLIT in 1927 from Black (oral-IT versus SCIT) and 1986 from Scadding, DBPC-RCT with house dust mite extract. We conclude that an in-depth review of investigators' observations, methods, and thoughts, however, can also be enriching for investigators in the field today. [ABSTRACT FROM AUTHOR]

Background: Venom immunotherapy (VIT) enables longtime prevention of insect venom allergy in the majority of patients. However, in some, the risk of a resystemic reaction increases after completion of treatment. No reliable factors predicting individual lack of efficacy of VIT are currently available. Objective: To determine the use of gene expression profiles to predict the long-term effect of VIT. Methods: Whole genome gene expression analysis was performed on RNA samples from 46 patients treated with VIT divided into 3 groups: (1) patients who achieved and maintained long-term protection after VIT, (2) patients in whom insect venom allergy relapsed, and (3) patients still in the maintenance phase of VIT. Results: Among the 48.071 transcripts analyzed, 1401 showed a >2 fold difference in gene expression (P < .05); 658 genes (47%) were upregulated and 743 (53%) downregulated. Forty-three transcripts still show significant differences in expression after correction for multiple testing; 12 of 43 genes (28%) were upregulated and 31 of 43 genes (72%) downregulated. A naive Bayes prediction model demonstrated a gene expression pattern characteristic of effective VIT that was present in all patients with successful VIT but absent in all subjects with failure of VIT. The same gene expression profile was present in 88% of patients in the maintenance phase of VIT. Conclusion: Gene expression profiling might be a useful tool to assess the long-term effectiveness of VIT. The analysis of differently expressed genes confirms the involvement of immunologic pathways described previously but also indicates novel factors that might be relevant for allergen tolerance. [Copyright &y& Elsevier]

Background: Large local reactions to insect stings cause significant morbidity and impair quality of life. Venom immunotherapy is not recommended because of a low risk for future systemic reaction and unproven efficacy in preventing large local reactions. Objective: To determine the feasibility of performing a controlled trial to examine the efficacy of venom immunotherapy in reducing the size and duration of large local reactions. Methods: Sting challenge in 41 patients with previous large local reactions and positive venom skin tests caused large local reactions 16 cm or larger in 34 patients, and 29 consented to treatment. Venom immunotherapy was initiated in 19, and 10 were untreated controls. Sting challenge was repeated after 7 to 11 weeks (control patients then began venom immunotherapy), and annually for as long as 4 years. Results: After 7 to 11 weeks of treatment, the size and duration of large local reactions decreased 42% and 53%, respectively, in treated patients and 18% in controls (P < .01 for both). The response was similar after 1 year, and improved after 2 to 4 years to 60% and 70%, respectively. Conclusions: Venom immunotherapy significantly reduced the size and duration of the large local reactions, and the efficacy improved over a period of 2 to 4 years of treatment. Further studies are needed to establish the safety and efficacy of venom immunotherapy for large local reactions, the optimal duration of treatment, and the mechanism for the differences in degree and rate of clinical response compared with venom immunotherapy in systemic reactors. [Copyright &y& Elsevier]

Background: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. Objective: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). Method: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. Results: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A2-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-γ and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. Conclusions: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells. [Copyright &y& Elsevier]

Background: Venom immunotherapy (VIT) is a treatment with established efficacy for the prevention of repeated anaphylactic reactions in patients with Hymenoptera allergy, which also allows patients to discontinue carrying an EpiPen. Despite their merits, both treatments can have negative aspects potentially important to patients. Objective: We examined possible negative aspects of the EpiPen in comparison with VIT as perceived by patients. Methods: Positive and negative aspects of both treatments were measured by using a burden of treatment questionnaire together with statements about the EpiPen. Results: One hundred ninety-three patients were included, of whom 94 consented to randomization: 47 received VIT, and 47 received the EpiPen. Of the remaining 99, 75 chose VIT, and 26 chose the EpiPen. Of the patients receiving VIT, 91.5% were (extremely) positive about their treatment, and 85% would choose VIT again. Of the patients receiving the EpiPen, only 48% were positive about their treatment, and even of these patients, 68% preferred to be treated with VIT after 1 year of carrying the EpiPen. Although most patients indicated that it is reassuring to carry an EpiPen and makes them feel safe, many patients also indicated that it is inconvenient and troublesome. Especially patients who were negative about the EpiPen indicated that they would not dare use the EpiPen if necessary and were afraid at possible side effects. Conclusion: In contrast to VIT, the EpiPen is perceived as burdensome by most patients with venom allergy. For most patients, an EpiPen is an unsuitable definitive treatment. Clinical implications: As VIT enables patients with venom allergy to get rid of the EpiPen, patients should be offered VIT. [Copyright &y& Elsevier]

Background: Venom allergen immunotherapy (VIT) is proven to be highly effective for insect allergy, but the mechanisms and the biomarkers associated with clinical efficacy remain elusive. Objective: The aim of this study was to identify candidate biomarkers associated with successful VIT. Methods: Gene chip array and clustering analyses of PBMCs from subjects with or without VIT were performed. Results: From gene chip array and clustering analyses, an increased expression of osteopontin was found in patients who completed 5 to 6 years of VIT and discontinued therapy for 3 to 6 years (completed treatment group) compared with the untreated group. A significantly higher level of serum osteopontin was found in the completed treatment group compared with the untreated group (n=16 in each group; P < .001). Conclusion: The upregulation of osteopontin after VIT suggests a role of osteopontin as a candidate biomarker for VIT. [Copyright &y& Elsevier]

Whole-body extracts of Hymenoptera were used for diagnosis and treatment until controlled clinical trials proved them no better than placebo, whereas venom is 85% to 98% effective. Studies of natural history reveal why whole-body extracts were thought to work. The chance of future systemic reactions is low in large local reactors and in most children and varies between 20% and 70% in adults. Venom skin tests are most accurate, but RAST is an important complementary test. The degree of sensitivity on skin tests or RASTs does not reliably predict the severity of a sting reaction. Venom immunotherapy is recommended for patients at high risk for sting reactions. Rapid regimens are as safe as slower regimens. The recommended dose is 100 μg, but some patients require higher doses for full protection. Venom immunotherapy is continued every 4 to 8 weeks for at least 5 years in most cases. Skin test results become negative in only 25% after 5 years of therapy but in 60% to 70% after 7 to 10 years. When treatment is stopped after 5 years or more, there is a 10% chance of systemic reaction to each future sting, but most reactions are mild. Some patients have a higher risk of relapse and should continue treatment for an extended period. [ABSTRACT FROM AUTHOR]

Background: Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. Objective: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. Methods: In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. Results: Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. Conclusion: Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT. [Copyright &y& Elsevier]