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Background: Indolent systemic mastocytosis (ISM) without skin lesions (ISMs(-)) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs(+)). Interestingly, in almost one-half of ISMs(-) patients, MC-mediator release episodes are triggered exclusively by insects., Objective: We aimed to determine the clinical and laboratory features of ISMs(-) associated with insect-induced anaphylaxis (insectISMs(-)) versus other patients with ISM., Methods: A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs(-), 72 ISMs(-) triggered by other factors (otherISMs(-)), 56 ISMs(+), and 64 nonclonal MC activation syndrome, were studied., Results: Compared with otherISMs(-) and ISMs(+) patients, insectISMs(-) cases showed marked male predominance (78% vs 53% and 46%; P < .001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 μg/L; P ≤ .009). Moreover, insectISMs(-) less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation., Conclusions: ISMs(-) patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs(-) and ISMs(+) patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined., Objective: Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting., Methods: In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models., Results: Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction., Conclusion: In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Background: The reported frequency of systemic reactions to challenge sting varies greatly., Objective: To evaluate the interaction of clinical and entomological factors that determine the outcome of a challenge sting., Methods: Patients allergic to yellow jacket were stung and monitored for systemic reaction. The frequency and severity of sting reactions were analyzed in relation to the species of insect used and patient characteristics., Results: Objective systemic reactions occurred in 21 of 69 patients (30%) stung with Vespula maculifrons and in 8 of 71 patients (11%) with Vespula germanica (P=.005). Systemic reactions were more frequent in patients with a severe history (9/30; 30%) than in those with a mild or moderate history (21/145; 14%; P=.04). In only 1 of 111 patients (0.9%) was the reaction to sting challenge more severe than previous reactions. The reaction rate was higher when venom skin tests were positive at <1.0 microg/mL (17/75=23%) than when sensitivity was milder (9/100=9%; P=.012). We compared sting outcome and venom-induced histamine release in relation to insects collected in July or in October, and found no difference., Conclusion: Allergic reactions to sting challenge are determined by the species of yellow jacket used, the severity of previous sting reactions, and the degree of skin test sensitivity, but not by the time of year. These factors are important to clinicians when they evaluate the chance of reaction to a future sting and to researchers when they design and report sting challenge studies.

Background: Venom immunotherapy (VIT) is effective in preventing anaphylactic reactions after insect stings. The effect of VIT on health-related quality of life (HRQL) was studied to evaluate whether this treatment is of importance to patients., Objective: We compared HRQL outcomes measured with a disease-specific instrument (Vespid Allergy Quality-of-Life Questionnaire [VQLQ]) in patients allergic to yellow jacket venom treated with VIT or with an adrenalin self-administration device (EpiPen) in an open-label, randomized, controlled trial., Methods: Consenting patients were block randomized to either VIT or EpiPen. Patients received uniform, standardized information, which specified the risk of their condition and the risks and benefits of both treatment options. HRQL measures took place before and after 1 year of treatment with VIT or EpiPen., Results: Seventy-four patients agreed to be randomized, of whom 36 received VIT and 38 an EpiPen. The mean change in VQLQ score in the group randomized to VIT was 1.07 (95% CI, 0.68-1.46), and this improvement was statistically significant (P <.0001) compared with that seen in the group randomized to the EpiPen, in which this change was -0.43 (95% CI, -0.71 to -0.16). These differences were seen in both men and women, persons with more or less general anxiety, and those stung recently and those stung more than a year before their outpatient department visit. The overall proportion of patients receiving benefit from VIT is 0.72, generating a number needed to treat of 1.4., Conclusions: VIT results in a clinically important improvement in HRQL in patients allergic to yellow jacket venom in all subgroups studied. Of every 3 patients treated with VIT, 2 patients experience an important improvement in their quality of life.

Background: The effects of an anaphylactic reaction after a yellow jacket sting on health-related quality of life (HRQL) have not been studied and are thus unknown., Objective: Development of a disease-specific instrument to measure HRQL in patients with yellow jacket allergy and validation of this instrument both cross-sectionally and longitudinally., Methods: Quality-of-life items were generated from patient interviews. Items with the highest impact were considered and correlated cross-sectionally with an independent measure (consisting of 2 questions in which patients were asked what they expected would happen if they were stung again, "Expectation of Outcome" questionnaire). Cross-sectional and longitudinal validation was achieved by administering this instrument to 69 Dutch patients. The questionnaire was also administered to 50 patients with yellow jacket allergy in Baltimore, Maryland, to establish cross-sectional validity of the English version., Results: The survey showed that patients experienced impairment in quality of life especially because of emotional distress. The resultant questionnaire has 14 items. The cross-sectional validation yielded a correlation coefficient of 0.69 for the Dutch version and 0.56 for the English version. The longitudinal validation yielded a correlation coefficient of 0.71. The responsiveness of this instrument was demonstrated by the questionnaire's ability to detect changes over time. It may be completed in approximately 10 minutes by patients without assistance., Conclusion: Patients with yellow jacket allergy experience impairment in quality of life especially because of emotional distress. It has been possible to develop and validate a questionnaire (the Vespid Allergy Quality of Life Questionnaire) by which the HRQL of these patients can be measured. The instrument may be administered rapidly and is easy to use.

Three known allergens of yellow jacket (Vespula vulgaris) venom are antigen 5, hyaluronidase, and phospholipase. Yellow jacket antigen 5 has been previously cloned and expressed in bacteria; it contains 204 amino acid residues, and it has 69% and 60% sequence identities with the homologous proteins of white-faced hornet (Dolichovespula maculata) and wasp (Polistes annularis), respectively. These studies are now extended to yellow jacket hyaluronidase and phospholipase; they contain 331 and 300 amino acid residues, respectively, and they show 92% and 67% sequence identity with their homologs of white-faced hornet. Tests with the natural and the recombinant vespid allergens in mice indicate partial antigenic cross-reactivity of their homologous proteins at both B- and T-cell levels. There is greater cross-reactivity among hornet and yellow jacket allergens than that among hornet or yellow jacket and wasp allergens. The order of cross-reaction of the three vespid allergens is hyaluronidase > antigen 5 > phospholipase. The continuous (linear) B-cell epitopes of vespid allergens show greater cross-reactivity than their discontinuous epitopes do. The discontinuous B-cell epitopes are immunodominant for all vespid allergens. The low degree of cross-reactivity of the immunodominant discontinuous B-cell epitopes of vespid allergens should be taken into consideration in selection of venoms for immunotherapy of patients with sensitivity to multiple vespids.

Background: Patients with a history of a serious anaphylactic reaction after a Hymenoptera sting are usually given venom immunotherapy. Because the natural history of Hymenoptera sting anaphylaxis is often of a declining severity, there is a chance of overtreatment., Objective: Identification of patients at risk for a future anaphylactic reaction may reduce the number of patients who need venom immunotherapy., Methods: We investigated the relation between the grade of hypersensitivity to an in-hospital sting challenge and the reaction to a subsequent accidental field sting. From 1982 through 1992, 348 patients with mild or no symptoms after a sting challenge were not given venom immunotherapy. All patients were asked by letter whether they had experienced a subsequent field sting. In case of a sting, the severity of the reaction was further evaluated., Results: Information could be obtained from 327 patients: 129 had been re-stung, and 110 of them had only had a local reaction. Thirteen patients had experienced mild systemic symptoms, and six patients had experienced serious manifestations. In two of the latter group hypotension was observed., Conclusion: In 95% of patients with a previous anaphylactic reaction, the result of the in-hospital sting challenge provided a good prediction of tolerance to a subsequent Hymenoptera field sting.

To investigate the reproducibility of a single negative response to sting challenge with a living insect, we rechallenged a group of 61 patients who showed no clinical response to a first sting challenge. All patients had previously had symptoms suggestive of anaphylaxis after a yellow jacket field sting. Thirteen patients (21%) had anaphylactic responses after the second sting challenge, and six of these patients had severe reactions including symptomatic hypotension requiring administration of Adrenalin. This rate was significantly lower than the response rate of the original patient group to a first sting challenge (39%). Thus although fewer positive responses were observed in patients who had had a previous negative challenge response, the number of anaphylactic reactions was considerable and included patients with potentially life-threatening symptoms. Consequently, a single sting challenge may not be used to select patients for venom immunotherapy.

Venoms of three vespid species, yellow jacket, bald-faced hornet, and yellow hornet, obtained by either electrostimulation of venom sac extraction were compared with regard to their enzymatic activity, antigenicity, and allergenicity. Phospholipase a, phospholipase B, and hyaluronidase enzymatic activities were present in all six preparations. The activity of venom sac extracts lay in the range found in different batches of venoms obtained by electrostimulation for each species. Analysis of sera from vespid-sensitive patients in the radioallergosorbent test (RAST) with discs coupled with either venom sac extracts or venoms obtained by electrostimulation showed a good correlation of the results within all three species (r = 0.95). In RAST inhibition the potency of venom sac extracts and venom obtained by electrostimulation was similar for each species. Analysis of rabbit antisera to the six preparations revealed similar patterns in immunoelectrophoresis and identity reactions between the major antigens within each species. Tissue protein contamination was detected in all venom sac extracts but not in venoms obtained by electrostimulation.

Patients referred from the Houston, Texas, metropolitan area were evaluated for allergic reactions to insect stings. Forty-eight persons reported at least one systemic reaction caused by a Polistes paper-nest wasp sting. Honey bees, imported fire ants, and other types of Hymenoptera were identified in that order by 19 other subjects with systemic allergic reactions. Life-threatening airway obstruction and/or hypotension were noted by most of our patients. Wasp venom skin testing was positive in 65% of subjects reporting sensitivity to this insect. Skin testing was correlated quantitatively with basophil histamine release, and qualitatively with RAST assays using Polistes wasp venom. Venoms from common species of Polistes were highly cross-reactive as shown by RAST and basophil histamine release. Patients having a positive history and laboratory response (by skin testing, histamine release, or RAST) to Polistes wasp venom also were positive to bee venom about 20% of the time and to another vespid (hornet or yellow jacket) over 50% of the time.

Specific IgE antibodies and total antibodies reacting with bee venom and yellow jacket venom were measured in sequential serum samples of insect-sensitive individuals. Venom-specific IgE decreased as a function of time and was not significantly affected by treatment with whole body extracts. There was no stimulation of total antibodies reacting with bee venom phospholipase A2 (PLA) following treatment with whole bee body extracts. These studies suggest that as measured by these parameters, whole body insect extracts used in the usual recommended doses are immunologically ineffective antigens.

Polistes wasps cause a majority of Hymenoptera-induced anaphylactic reactions in Texas. Using the in vitro release of histamine from basophils of patients allergic to Polistes stings, we have studied the cross-reactivity of venoms from three species of Polistes wasps as well as the cross-reactivity among Polistes, honeybee, and Vespula maculifrons (yellow jacket) venoms. Venom collected by an extrusion technique from Pollistes exclamans, Pollistes apachus, and Pollistes carolina caused release of histamine in seven Polistes-sensitive individuals. The dose-response curves from all three Polistes species were quite similar, suggesting extensive cross-reactivity among these species. None of these patients showed significant release of histamine from leukocytes exposed to yellow jacket or honeybee venom. We conclude that a source of Polistes venom is available for further study and possibly for therapy. It appears that any of three local common species of Polistes wasps could be used. Our studies confirmed earlier reports that Hymenoptera sensitivity if often genus-specific.

Phospholipases (PLs) isolated from the venoms of three species of yellow jackets, white-faced hornets, European hornets, and paper wasps were studied by peptide mapping after limited enzyme hydrolyses and cyanogen bromide cleavage. Significant differences in the primary structures were observed. Cross-reactivities of vespid PLs were studied by precipitation reactions in gel with rabbit antibodies, immunoblots of sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels with rabbit antisera, and RAST inhibition with individual sera from vespid-reactive patients. The cross-reactivities of both human IgE antibodies and rabbit IgG antibodies were variable and not reciprocal between antigen and antibody, suggesting that there are multiple antigenic determinants on the PL molecules and that individuals respond to different determinants. No general patterns of cross-reactivity could be observed.