Hymenoptera venom allergy among children in Italy: time for pediatricians to take action.

Hymenoptera venom allergy (HVA) is one of the most frequent causes of anaphylaxis following a bee, vespid or ant sting. Real-life data regarding the management of HVA in children are lacking. To address this unmet need, we carried out a survey defining the current management of HVA in children among pediatric allergists in Italy. Educational investments on the improvement of the management of pediatric patients with HVA are urgently needed, and our analysis represents a relevant instrument in targeting a roadmap with this aim. The time for pediatric allergists to take action has come, and a task force from the Rare Allergic Diseases Commission of the Italian Society of Pediatric Allergy and Immunology is working on the topic to improve pediatricians' knowledge and optimize the care of these patients.

Insect Venom Immunotherapy: Analysis of the Safety and Tolerance of 3 Buildup Protocols Frequently Used in Spain.

INTRODUCTION: Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk, as both local and systemic adverse reactions may occur, especially in the initial phases. We compared the tolerance to 3 VIT buildup protocols and analyzed risk factors associated with adverse reactions during this phase. MATERIALS AND METHODS: We enrolled 165 patients divided into 3 groups based on the buildup protocol used (3, 4, and 9 weeks). The severity of systemic reactions was evaluated according to the World Allergy Organization model. Results were analyzed using exploratory descriptive statistics, and variables were compared using analysis of variance. RESULTS: Adverse reactions were recorded in 53 patients (32%) (43 local and 10 systemic). Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). The severity of the local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the onset of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association between severity of the local reaction and female gender. As for the risk factors associated with systemic reactions during the buildup phase, we found no significant differences in values depending on the protocol used or the insect responsible. CONCLUSIONS: The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied, patients undergoing the 9-week schedule presented no systemic reactions. Therefore, this protocol can be considered the safest approach.

Hymenoptera venom immunotherapy while maintaining cardiovascular medication: safe and effective.

BACKGROUND: The hypothetical risks of cardiovascular medication during Hymenoptera venom immunotherapy (VIT) are still a matter of controversy. OBJECTIVE: To assess the potential influence of ß-blockers (BBs) and/or angiotensin-converting enzyme inhibitors (ACEIs) on the long-term safety and outcome of VIT. METHODS: Data on the course of VIT maintenance phase, Hymenoptera re-stings, and concurrent medication were retrospectively derived from standardized questionnaires in a cohort of patients with significant cardiovascular comorbidity. RESULTS: Of 225 patients, 125 (55.6%) were taking cardiovascular medication at the time of data collection: 71 (31.6%) took an ACEI, and 40 (17.8%) took a BB. A total of 3,397 months of maintenance VIT during intake of an ACEI and 1,418 months during BB therapy were evaluated. Cumulative VIT-related reaction rates, including subjective symptoms, were 9.1% per treatment cycle and 0.31% per injection, with objective reaction rates of 1.7% and 0.06%, respectively. The incidence of adverse events was significantly higher in patients with a previous history of systemic reactions at VIT buildup (P = .004). Surprisingly, reaction rates were lower in patients taking any kind of cardiovascular medication (P = .04) or an ACEI (P = .03). The overall reexposure rate to Hymenoptera stings was 42.7%, and the field sting-induced objective reaction rate was 7.3%. There was no evidence of an increase of field sting-related relapse or hospitalization rates by concurrent cardiovascular medication. CONCLUSION: Cardiovascular medication does not impair the safety and/or the efficacy of Hymenoptera VIT.

Mechanisms of acute kidney injury induced by experimental Lonomia obliqua envenomation.

Lonomia obliqua caterpillar envenomation causes acute kidney injury (AKI), which can be responsible for its deadly actions. This study evaluates the possible mechanisms involved in the pathogenesis of renal dysfunction. To characterize L. obliqua venom effects, we subcutaneously injected rats and examined renal functional, morphological and biochemical parameters at several time points. We also performed discovery-based proteomic analysis to measure protein expression to identify molecular pathways of renal disease. L. obliqua envenomation causes acute tubular necrosis, which is associated with renal inflammation; formation of hematic casts, resulting from intravascular hemolysis; increase in vascular permeability and fibrosis. The dilation of Bowman's space and glomerular tuft is related to fluid leakage and intra-glomerular fibrin deposition, respectively, since tissue factor procoagulant activity increases in the kidney. Systemic hypotension also contributes to these alterations and to the sudden loss of basic renal functions, including filtration and excretion capacities, urinary concentration and maintenance of fluid homeostasis. In addition, envenomed kidneys increase the expression of proteins involved in cell stress, inflammation, tissue injury, heme-induced oxidative stress, coagulation and complement system activation. Finally, the localization of the venom in renal tissue agrees with morphological and functional alterations, suggesting also a direct nephrotoxic activity. In conclusion, the mechanisms of L. obliqua-induced AKI are complex involving mainly glomerular and tubular functional impairment and vascular alterations. These results are important to understand the mechanisms of renal injury and may suggest more efficient ways to prevent or attenuate the pathology of Lonomia's envenomation.

Simultaneous intradermal testing with hymenoptera venoms is safe and more efficient than sequential testing.

BACKGROUND: According to current guidelines, skin testing for hymenoptera venom allergy should be performed in a stepwise manner, maintaining 15- to 20-min intervals between the injections of venom. Given the long-winded procedure of sequential skin testing, we retrospectively explored the safety of simultaneous intradermal testing. METHODS: Four hundred and seventy-eight consecutive patients with a convincing history of an anaphylactic reaction after a hymenoptera sting were tested. All venom concentrations (0.02 ml of 0.001, 0.01, 0.1, and 1.0 µg/ml of honey bee and wasp venom) were administered simultaneously to the skin. RESULTS: Four hundred and seventy-two (98.7%) patients tolerated the simultaneous intradermal test without any side-effects. Only three subjects (0.6%) had a presumed allergic reaction during the test; another three reactions were considered vasovagal. CONCLUSION: Our skin test protocol with four simultaneously injected concentrations of two hymenoptera venoms is safe and permits the investigator to draw rapid conclusions about the individual's sensitization pattern.

Ultrarush versus semirush initiation of insect venom immunotherapy: a randomized controlled trial.

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 IgG(4) 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.

Chapter 4: Stinging insect allergy and venom immunotherapy.

The Hymenoptera order is divided into three families: Apids, Vespidae, and Formicidae. Apids include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is found mostly in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald)-faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >5 in. and lasting >24 hours, the likelihood of anaphylaxis from a future sting is ∼5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin tests to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and carrying and knowing when to self-inject epinephrine, but immunotherapy (IT) with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. IT is highly effective in that by 4 years of injections, the incidence of subsequent sting-induced anaphylactic reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported >10% in follow-up.

Clinical immunology review series: an approach to desensitization.

Allergen immunotherapy describes the treatment of allergic disease through administration of gradually increasing doses of allergen. This form of immune tolerance induction is now safer, more reliably efficacious and better understood than when it was first formally described in 1911. In this paper the authors aim to summarize the current state of the art in immunotherapy in the treatment of inhalant, venom and drug allergies, with specific reference to its practice in the United Kingdom. A practical approach has been taken, with reference to current evidence and guidelines, including illustrative protocols and vaccine schedules. A number of novel approaches and techniques are likely to change considerably the way in which we select and treat allergy patients in the coming decade, and these advances are previewed.

Gene expression analysis in predicting the effectiveness of insect venom immunotherapy.

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.

Immunotherapy throughout the decades: from Noon to now.

OBJECTIVE: To review major milestones in the development of subcutaneous allergen immunotherapy in 20-year segments. DATA SOURCES: Review of the literature available in textbooks and journals. STUDY SELECTION: Articles and books addressing major achievements in the development of subcutaneous allergy immunotherapy were selected for inclusion in this review. RESULTS: Immunotherapy administration has improved the lives of possibly millions of patients with hay fever. Asthmatic symptoms have been relieved if not ablated in millions as well. Insect venom hypersensitivity became treatable and highly effective. In the beginning years of immunotherapy, it was clear that immunotherapy worked; in the later years, the mechanisms for this efficacy were discovered. In this case, the therapy preceded its validation. Methods, materials, and safety have vastly improved. Postulated mechanisms explain much but not everything. CONCLUSIONS: There is still research to be accomplished, improvements to be made, and, of course, patients to be made well.

The effect of hymenoptera venom immunotherapy on neutrophils, interleukin 8 (IL-8) and interleukin 17 (IL-17).

OBJECTIVES: Venom immunotherapy (VIT) is an effective treatment method and is addressed to patients with a history of an anaphylactic reaction to Hymenoptera stings. However, the immunological mechanisms of protection have not been explained yet. The objective of this study was to analyze neutrophils, interleukin 8 (IL-8) and interleukin 17 (IL-17) before and after the initial phase of the immunotherapy. MATERIAL AND METHODS: Overall, 40 individuals, including 20 wasp venom sensitized and 20 bee venom sensitized patients, were included in the study. The patients had had a history of severe allergic reactions type III and IV according to Mueller's classification. An ultra-rush VIT protocol was used in this study. The concentration of serum IL-8 and IL-17A was determined using the ELISA enzymatic method. RESULTS: The authors demonstrated a significant rise in the IL-8 level after the immunotherapy, compared to baseline (14.9 vs. 24.7, p < 0.05). The rise in the neutrophils level was also noticeable but proved to be barely out of the range of statistical significance (4.3 vs. 5.0, p = 0.06). The shift in IL-17A was negligent and not statistically significant in the paired samples t-test (1.6 vs. 1.5, p = 0.34). CONCLUSIONS: Venom immunotherapy induces neutrophils and IL-8 activity after 2 days. After the desensitization, the level of IL-17A did not change. Int J Occup Med Environ Health. 2020;33(6):811-7.

Effectiveness of Lonomia antivenom in recovery from the coagulopathy induced by Lonomia orientoandensis and Lonomia casanarensis caterpillars in rats.

In South America, accidental contact with Lepidoptera larvae can produce a diversity of reactions that vary from dermatological problems to severe hemorrhagic syndromes, such as those caused by contact with caterpillars of the genus Lonomia (Saturniidae). Lonomia venom can alter the hemostatic system and lead to renal failure, internal and brain bleeding, and in severe cases, death. The only specific treatment available for these envenomations is the Lonomia Antivenom (LAV) produced by the Butantan Institute, in Brazil, using an extract of Lonomia obliqua scoli as the antigen. LAV has been used to treat exposure to other Lonomia species across South America. However, no experimental studies have been performed to test the efficacy of LAV in neutralizing the venom of species other than L. obliqua found in Southern Brazil. In this study, we tested the effectiveness of LAV in reversing the hemostatic disturbances induced by injecting Lonomia casanarensis (Lca) and Lonomia orientoandensis (Lor) scolus extracts into rats and compared the effects to the case of L. obliqua (Lob) scolus extract-induced envenomation. Lca and Lor caterpillars were collected in Colombia, and some of them were reared to adults for identification. The Minimum Defibrinating Doses (MDD) of Lca and Lor were estimated. Rats were injected (i.d.) with a dose of 3 MDD per rat of each scolus extract and treated (i.v.) with 1.5 mL of LAV or 1.5 mL of saline. Twenty-four hours after the treatment, the fibrinogen levels and platelet counts had recovered to the hemostatic levels in the groups treated with LAV. The groups treated with the saline solution had fibrinogen levels and platelet counts at non-hemostatic levels. Thromboelastometric analyses confirmed these results. In conclusion, the results showed that LAV is effective at neutralizing the envenomation induced by Lca and Lor spine extracts in rats and restoring hemostasis.

Application of precision medicine to the treatment of anaphylaxis.

PURPOSE OF REVIEW: Recognize the presentation of anaphylaxis for prompt management and treatment and to provide tools for the diagnosis of the underlying cause(s) and set up a long-term treatment to prevent recurrence of anaphylaxis. RECENT FINDINGS: The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and biomarkers for broad clinical use. SUMMARY: Anaphylaxis is the most severe hypersensitivity reaction and can lead to death. Epinephrine is the first-line treatment of anaphylaxis and it is life-saving. Patients with first-line therapy-induced anaphylaxis are candidates for desensitization to increase their quality of life and life expectancy. Desensitization is a breakthrough novel treatment for patients with anaphylaxis in need of first-line therapy, including chemotherapy, mAbs, aspirin and others. Ultrarush with venom immunotherapy should be considered in patients who present with life-threatening anaphylaxis after Hymenoptera sting with evidence of IgE-mediated mechanisms. Food desensitization is currently being expanded to provide increased safety to adults and children with food-induced anaphylaxis.

Cardiovascular disease and anaphylaxis.

PURPOSE OF REVIEW: In severe anaphylaxis, the cardiovascular system is often heavily involved. Preexisting cardiovascular disease may therefore influence the course of anaphylaxis in a negative way. RECENT FINDINGS: Systemic mastocytosis and elevated baseline serum tryptase are associated with severe and fatal anaphylaxis to hymenoptera stings. This is due to an increased number of cardiac mast cells resulting in high concentrations of cardiotoxic mast cell mediators in cardiac tissue during anaphylaxis. Severe anaphylaxis in coronary heart disease, in particular, is explained by an increased load of cardiac mast cells together with coronary stenosis favouring myocardial hypoxia. Contraindications for the use of medications for cardiac disease in patients with anaphylaxis, especially beta-blockers, have been questioned by epidemiologic studies considering the positive effects of these drugs on much more prevalent cardiac diseases. SUMMARY: Preexisting cardiovascular disease, mastocytosis and elevated baseline serum tryptase are risk factors for fatal anaphylactic reactions or lasting morbidity due to myocardial or cerebrovascular infarction induced by anaphylaxis. Life-saving cardiac medications like beta-blockers may increase the severity of anaphylaxis. Since life-threatening cardiovascular diseases are much more frequent than anaphylaxis, the relative risk of either disease with and without these drugs must be analyzed carefully together with the cardiologist.

Basophil-activation tests in Hymenoptera allergy.

PURPOSE OF REVIEW: Despite recent advances in our understanding of basophil biology and discovery of new markers for basophil activation, tests measuring basophil activation are not widely utilized in Hymenoptera allergy. Studies of the basophil-activation test in Hymenoptera allergy were examined and the clinical utility of this test was assessed. RECENT FINDINGS: It has been demonstrated that the results of basophil-activation tests correlate quite well with those of serum IgE testing or skin-prick tests. Many studies compare test outcomes with history in patients and nonallergic controls, so that specificity in sensitized but clinically nonreactive individuals remains unknown. Although one study showed that the basophil-activation test might predict immunotherapy side effects, this could not be confirmed in a second study, and no role has been established for the basophil-activation test in the monitoring of venom immunotherapy. The basophil-activation test has no extra value in assessing sting challenges, although experience is limited. SUMMARY: The measurement of basophil-activation markers may be useful in detecting IgE-mediated sensitization but the relevance for application of the basophil-activation test in prediction of clinical reactivity in Hymenoptera allergy is very limited. For this reason, this test currently has no established role in the diagnosis and management of patients with insect sting allergy.

[Side effects of specific immunotherapy in patients with hymenoptera venom allergy]. / Objawy niepozadane podczas immunoterapii swoistej u chorych z alergia na jady owadów blonkoskrzydlych.

The aim of this study was to estimate safety of specific immunotherapy to insects' venom. The frequency of side effects was compared in two groups of patients: subjects with hypersensitivity to insects' venom only and patients with allergy to other allergens. In the examined group of 32 patients with Hymenoptera venoms allergy skin prick tests with common aeroallergens were performed in 30 subjects. In 18 patients (60%) at least one test was positive. In 23 patients (71.9%) immunotherapy with Hymenoptera venom was connected with side effects observed just after administration of vaccine. They were mainly local reactions (itching, redness and oedema). In 6 patients late reactions were observed. No correlation has been found between frequency of side effects of immunotherapy and positive results of skin prick tests. However systemic reactions were revealed only in the group of patients with at least one positive result of skin prick tests.

A distinct three-helix centipede toxin SSD609 inhibits I(ks) channels by interacting with the KCNE1 auxiliary subunit.

KCNE1 is a single-span transmembrane auxiliary protein that modulates the voltage-gated potassium channel KCNQ1. The KCNQ1/KCNE1 complex in cardiomyocytes exhibited slow activated potassium (I(ks)) currents. Recently, a novel 47-residue polypeptide toxin SSD609 was purified from Scolopendra subspinipes dehaani venom and showed I(ks) current inhibition. Here, chemically synthesized SSD609 was shown to exert I(ks) inhibition in extracted guinea pig cardiomyocytes and KCNQ1/KCNE1 current attenuation in CHO cells. The K(+) current attenuation of SSD609 showed decent selectivity among different auxiliary subunits. Solution nuclear magnetic resonance analysis of SSD609 revealed a distinctive three-helix conformation that was stabilized by a new disulfide bonding pattern as well as segregated surface charge distribution. Structure-activity studies demonstrated that negatively charged Glu19 in the amphipathic extracellular helix of KCNE1 was the key residue that interacted with SSD609. The distinctive three-helix centipede toxin SSD609 is known to be the first polypeptide toxin acting on channel auxiliary subunit KCNE1, which suggests a new type of pharmacological regulation for ion channels in cardiomyocytes.