Evaluation of the Cytokine Response Induced by Specific Allergen Immunotherapy in Patients with Vespa velutina Anaphylaxis.

INTRODUCTION: Changes in the cytokine profile from type 2 to type 1 together with the induction of regulatory cells are expected during hymenoptera venom immunotherapy (VIT). The present study was aimed to investigate the changes in type 1, type 2, and regulatory cytokines induced by a Vespula spp. VIT in patients with anaphylaxis to Vespa velutina. METHODS: Twenty consecutive patients with anaphylaxis due to Vespa velutina were treated with Vespula spp. VIT. Serum cytokines (IL-4, IL-5, IL-10, IL-13, and IFN-É£) were measured at baseline, 6, and 12 months after starting VIT. RESULTS: A significant increase in serum IFN-y was detected after 6 and 12 months of VIT. An increase in serum IL-10 and a decrease in IL-5 were observed after 12 months. IL-4 was undetectable all along the study, and an unexpected increase of IL-13 was present at 12 months of treatment. CONCLUSION: Vespula spp. VIT seems to be able to induce a shift to type 1 cytokine production measured through IFN-y levels and IL-10 production after, at least, 6 and 12 months of VIT, respectively.

Unraveling wasp sensitization in a patient with systemic mastocytosis by CAP-inhibition assay.

Systemic mastocytosis (SM) is a clonal mast cell disorder that can lead to potentially severe anaphylactic reactions. Hymenoptera sting is one of the most frequent triggers of anaphylaxis in these patients, and diagnosis of indolent SM (ISM) without skin involvement (ISMs) is not rare. In this subgroup of patients, venom immunotherapy (VIT) is an effective treatment decreasing subsequent systemic reactions, and lifelong administration is recommended. An individualized diagnosis is necessary to offer the most adequate VIT, and molecular diagnosis (MD) may be useful to discriminate between primary sensitization and cross-reactivity. Nevertheless, other techniques such as ImmunoCAP inhibition assays may be necessary to identify the genuine sensitization to offer the most suitable VIT. We present a male patient with an anaphylactic reaction following several wasp stings. The patient was diagnosed with ISM, and allergy to both Polistes dominula and Vespula sp venom was confirmed. In this scenario, MD did not discriminate between a genuine double sensitization and venom cross-reactivity between both vespids. Thus, CAP-inhibition assay was performed. This case indicated the importance of an accurate diagnosis of hymenoptera venom allergy (HVA). It also highlights the usefulness of CAP-inhibition assays when MD fails to distinguish between genuine double Polistes-Vespula sensitization and cross-reactivity.

A parasitoid wasp of Drosophila employs preemptive and reactive strategies to deplete its host's blood cells.

The wasps Leptopilina heterotoma parasitize and ingest their Drosophila hosts. They produce extracellular vesicles (EVs) in the venom that are packed with proteins, some of which perform immune suppressive functions. EV interactions with blood cells of host larvae are linked to hematopoietic depletion, immune suppression, and parasite success. But how EVs disperse within the host, enter and kill hematopoietic cells is not well understood. Using an antibody marker for L. heterotoma EVs, we show that these parasite-derived structures are readily distributed within the hosts' hemolymphatic system. EVs converge around the tightly clustered cells of the posterior signaling center (PSC) of the larval lymph gland, a small hematopoietic organ in Drosophila. The PSC serves as a source of developmental signals in naïve animals. In wasp-infected animals, the PSC directs the differentiation of lymph gland progenitors into lamellocytes. These lamellocytes are needed to encapsulate the wasp egg and block parasite development. We found that L. heterotoma infection disassembles the PSC and PSC cells disperse into the disintegrating lymph gland lobes. Genetically manipulated PSC-less lymph glands remain non-responsive and largely intact in the face of L. heterotoma infection. We also show that the larval lymph gland progenitors use the endocytic machinery to internalize EVs. Once inside, L. heterotoma EVs damage the Rab7- and LAMP-positive late endocytic and phagolysosomal compartments. Rab5 maintains hematopoietic and immune quiescence as Rab5 knockdown results in hematopoietic over-proliferation and ectopic lamellocyte differentiation. Thus, both aspects of anti-parasite immunity, i.e., (a) phagocytosis of the wasp's immune-suppressive EVs, and (b) progenitor differentiation for wasp egg encapsulation reside in the lymph gland. These results help explain why the lymph gland is specifically and precisely targeted for destruction. The parasite's simultaneous and multipronged approach to block cellular immunity not only eliminates blood cells, but also tactically blocks the genetic programming needed for supplementary hematopoietic differentiation necessary for host success. In addition to its known functions in hematopoiesis, our results highlight a previously unrecognized phagocytic role of the lymph gland in cellular immunity. EV-mediated virulence strategies described for L. heterotoma are likely to be shared by other parasitoid wasps; their understanding can improve the design and development of novel therapeutics and biopesticides as well as help protect biodiversity.

Evolution of an insect immune barrier through horizontal gene transfer mediated by a parasitic wasp.

Genome sequencing data have recently demonstrated that eukaryote evolution has been remarkably influenced by the acquisition of a large number of genes by horizontal gene transfer (HGT) across different kingdoms. However, in depth-studies on the physiological traits conferred by these accidental DNA acquisitions are largely lacking. Here we elucidate the functional role of Sl gasmin, a gene of a symbiotic virus of a parasitic wasp that has been transferred to an ancestor of the moth species Spodoptera littoralis and domesticated. This gene is highly expressed in circulating immune cells (haemocytes) of larval stages, where its transcription is rapidly boosted by injection of microorganisms into the body cavity. RNAi silencing of Sl gasmin generates a phenotype characterized by a precocious suppression of phagocytic activity by haemocytes, which is rescued when these immune cells are incubated in plasma samples of control larvae, containing high levels of the encoded protein. Proteomic analysis demonstrates that the protein Sl gasmin is released by haemocytes into the haemolymph, where it opsonizes the invading bacteria to promote their phagocytosis, both in vitro and in vivo. Our results show that important physiological traits do not necessarily originate from evolution of pre-existing genes, but can be acquired by HGT events, through unique pathways of symbiotic evolution. These findings indicate that insects can paradoxically acquire selective advantages with the help of their natural enemies.

Independent effects on cellular and humoral immune responses underlie genotype-by-genotype interactions between Drosophila and parasitoids.

It is common to find abundant genetic variation in host resistance and parasite infectivity within populations, with the outcome of infection frequently depending on genotype-specific interactions. Underlying these effects are complex immune defenses that are under the control of both host and parasite genes. We have found extensive variation in Drosophila melanogaster's immune response against the parasitoid wasp Leptopilina boulardi. Some aspects of the immune response, such as phenoloxidase activity, are predominantly affected by the host genotype. Some, such as upregulation of the complement-like protein Tep1, are controlled by the parasite genotype. Others, like the differentiation of immune cells called lamellocytes, depend on the specific combination of host and parasite genotypes. These observations illustrate how the outcome of infection depends on independent genetic effects on different aspects of host immunity. As parasite-killing results from the concerted action of different components of the immune response, these observations provide a physiological mechanism to generate phenomena like epistasis and genotype-interactions that underlie models of coevolution.

Immune-inducible non-coding RNA molecule lincRNA-IBIN connects immunity and metabolism in Drosophila melanogaster.

Non-coding RNAs have important roles in regulating physiology, including immunity. Here, we performed transcriptome profiling of immune-responsive genes in Drosophila melanogaster during a Gram-positive bacterial infection, concentrating on long non-coding RNA (lncRNA) genes. The gene most highly induced by a Micrococcus luteus infection was CR44404, named Induced by Infection (lincRNA-IBIN). lincRNA-IBIN is induced by both Gram-positive and Gram-negative bacteria in Drosophila adults and parasitoid wasp Leptopilina boulardi in Drosophila larvae, as well as by the activation of the Toll or the Imd pathway in unchallenged flies. We show that upon infection, lincRNA-IBIN is expressed in the fat body, in hemocytes and in the gut, and its expression is regulated by NF-κB signaling and the chromatin modeling brahma complex. In the fat body, overexpression of lincRNA-IBIN affected the expression of Toll pathway -mediated genes. Notably, overexpression of lincRNA-IBIN in unchallenged flies elevated sugar levels in the hemolymph by enhancing the expression of genes important for glucose retrieval. These data show that lncRNA genes play a role in Drosophila immunity and indicate that lincRNA-IBIN acts as a link between innate immune responses and metabolism.

Functional insights from the GC-poor genomes of two aphid parasitoids, Aphidius ervi and Lysiphlebus fabarum.

BACKGROUND: Parasitoid wasps have fascinating life cycles and play an important role in trophic networks, yet little is known about their genome content and function. Parasitoids that infect aphids are an important group with the potential for biological control. Their success depends on adapting to develop inside aphids and overcoming both host aphid defenses and their protective endosymbionts. RESULTS: We present the de novo genome assemblies, detailed annotation, and comparative analysis of two closely related parasitoid wasps that target pest aphids: Aphidius ervi and Lysiphlebus fabarum (Hymenoptera: Braconidae: Aphidiinae). The genomes are small (139 and 141 Mbp) and the most AT-rich reported thus far for any arthropod (GC content: 25.8 and 23.8%). This nucleotide bias is accompanied by skewed codon usage and is stronger in genes with adult-biased expression. AT-richness may be the consequence of reduced genome size, a near absence of DNA methylation, and energy efficiency. We identify missing desaturase genes, whose absence may underlie mimicry in the cuticular hydrocarbon profile of L. fabarum. We highlight key gene groups including those underlying venom composition, chemosensory perception, and sex determination, as well as potential losses in immune pathway genes. CONCLUSIONS: These findings are of fundamental interest for insect evolution and biological control applications. They provide a strong foundation for further functional studies into coevolution between parasitoids and their hosts. Both genomes are available at https://bipaa.genouest.org.

COMMD8 changes expression during initial phase of wasp venom immunotherapy.

BACKGROUND: Hymenoptera venom allergy (HVA) is of great concern because of the possibility of anaphylaxis, which may be fatal. Venom immunotherapy (VIT) is the only disease-modifying treatment in HVA and, although efficient, its mechanism remains partially unknown. Gene expression analysis may be helpful for establishing a proper model of tolerance induction during the build-up phase of VIT. The present study aimed to analyze how the start of VIT changes the expression of 15 selected genes. METHODS: Forty-five patients starting VIT with a wasp venom allergy were enrolled. The diagnosis was established based on anaphylaxis history (third or fourth grade on the Mueller scale) and positive soluble immunoglobulin E and/or skin tests. Two blood collections were performed in the patient group: before and after 3 months of VIT. One sample was taken in the control group. Gene expression analysis was performed using a reverse transcriptase-polymerase chain reaction with microfluidic cards and normalized to the 18S housekeeping gene. RESULTS: Commd8 was the only gene that changed expression significantly after the start of VIT (p = 0.012). Its expression decreased towards the levels observed in the healthy controls. Twelve out of 15 genes (commd8, cldn1, cngb3, fads1, hes6, hla-drb5, htr3b, prlr, slc16a4, snx33, socs3 and twist2) revealed a significantly different expression compared to the healthy controls. CONCLUSIONS: The present study shows that commd8 changes significantly its expression during initial phase of VIT. This gene might be a candidate for VIT biomarker in future studies.

Parallel and costly changes to cellular immunity underlie the evolution of parasitoid resistance in three Drosophila species.

A priority for biomedical research is to understand the causes of variation in susceptibility to infection. To investigate genetic variation in a model system, we used flies collected from single populations of three different species of Drosophila and artificially selected them for resistance to the parasitoid wasp Leptopilina boulardi, and found that survival rates increased 3 to 30 fold within 6 generations. Resistance in all three species involves a large increase in the number of the circulating hemocytes that kill parasitoids. However, the different species achieve this in different ways, with D. melanogaster moving sessile hemocytes into circulation while the other species simply produce more cells. Therefore, the convergent evolution of the immune phenotype has different developmental bases. These changes are costly, as resistant populations of all three species had greatly reduced larval survival. In all three species resistance is only costly when food is in short supply, and resistance was rapidly lost from D. melanogaster populations when food is restricted. Furthermore, evolving resistance to L. boulardi resulted in cross-resistance against other parasitoids. Therefore, whether a population evolves resistance will depend on ecological conditions including food availability and the presence of different parasite species.

Changing microRNA Expression during Three-Month Wasp Venom Immunotherapy.

MicroRNAs are small non-coding molecules playing a significant regulatory role in several allergic diseases. However their role in tolerance induction remains unclear. The aim of this study was to determine the expression of selected microRNAs during the first three months of wasp venom immunotherapy (VIT). 5 adult patients with a history of severe systemic reactions after stinging by wasps and confirmed sensitization were included. Venous blood samples were collected before VIT, 24 hours after completing its initial phase and after 3 months of the maintenance therapy. A control group was comprised of 5 healthy individuals with no history of allergy. In the blood samples expression of 96 microRNAs was determined with the use of microfluidic cards. In a statistical analysis the expression was compared between the study groups as well as between the pre- and post-VIT samples. Significant differences were found between the patients with wasp venom allergy and the healthy controls in the expression of miR-601 and miR-1201 upregulated in allergic patients at every time point (p = 0.04; p = 0.015, respectively). During VIT profile of microRNA was changing with lower expression of 6 microRNAs (including miR-182, miR-342, miR-375) and higher of 11 microRNAs (including let-7d, miR-34b, miR-143). To conclude, VIT has led to some changes in the expression of microRNA associated with Th2-type inflammation and tolerance induction.

Plant Volatiles Modulate Immune Responses of Spodoptera litura.

Plants emit a specific blend of volatiles in response to herbivory and these volatiles, which often attract predators and parasitoids function as an indirect plant defense. The impact of plant volatiles in shaping herbivore defenses is unclear. Here, we report that specific plant volatiles induce immune responses in the polyphagous herbivore, Spodoptera litura. We characterized the hemocyte profile and established their functional significance with respect to ontogeny and exposure to specific plant volatiles. Fifth instar larvae showed the highest number and hemocytes diversity. We characterized seven different types of hemocytes, of which granulocytes performed phagocytosis, oenocytoids showed melanization activity, and plasmatocytes along with granulocytes and oenocytoids were found to be involved in encapsulation. Among the six volatiles tested, exposure to (E)-ß-ocimene caused the highest increase in total hemocytes number (THC) followed by linalool and (Z)-3-hexenyl acetate exposure. Although THC did not differ between these three volatile treatments, circulating hemocytes diversity varied significantly. (E)-ß-ocimene exposure showed higher number of plasmatocytes and phenol oxidase activity. The interaction of the parasitic wasp Bracon brevicornis with (E)-ß-ocimene exposed larvae was poor in terms of delayed paralysis and lower egg deposition. In choice assays, the wasp showed clear preference towards control larvae indicating (E)-ß-ocimene treatment renders the host unattractive. Hemocyte profiles post-parasitoid exposure and (E)-ß-ocimene treatment were similar indicating cue-based priming. When challenged with Bacillus thuringiensis, linalool exposure resulted in the highest survival as compared to other volatiles. Our results show that specific HIPVs can modulate cellular immunity of S. litura, revealing a new role for HIPVs in tri-trophic interactions.

Immune response and susceptibility to Cotesia flavipes parasitizing Diatraea saccharalis larvae exposed to and surviving an LC25 dosage of Bacillus thuringiensis.

Biological control using entomopathogens and natural enemies is an ecofriendly method for pest management in agriculture. Biological control agents often can be simultaneously employed and compatibility between agents may improve pest suppression. We investigated the influence of the entomopathogen Bacillus thuringiensis (Bt) on the immune system of the sugarcane borer Diatraea saccharalis (Fabricius, 1794) (Lepidoptera: Crambidae) to determine if such changes impact parasitization by Cotesia flavipes Cameron, 1891 (Hymenoptera: Braconidae). The immune response of surviving D. saccharalis larvae fed with an LC25 dosage of a Bt-based biopesticide (Dipel®) was analyzed (total hemocyte count, hemocyte adhesion, and activities of phenoloxidase and lysozyme). Furthermore, the suitability of surviving Bt-fed larvae as hosts for C. flavipes was assessed by measuring parasitoid attributes such as number and size of teratocytes, weight of pupae, length of adult female tibia and number of emerged adults. Total hemocyte count, but not hemocyte adhesion, total protein content and phenoloxidase activity increased in the hemolymph of non-parasitized Bt-fed larvae (Bt-NP) compared to control larvae (NBt-NP). Lysozyme activity increased only after parasitization without Bt exposure (NBt-P). After parasitization, the immunological parameters activated in Bt-NP larvae decreased to levels at or below those observed in control larvae, showing that C. flavipes can regulate the activated immune response of Bt-fed larvae. The development of C. flavipes was not impaired in Bt-fed larval hosts (Bt-P); no changes were observed for teratocyte size, weight of pupal mass, length of hind tibia and number of adults emerged.

Mechanical stress to Drosophila larvae stimulates a cellular immune response through the JAK/STAT signaling pathway.

Acute inflammation can cause serious tissue damage and disease in physiologically-challenged organisms. The precise mechanisms leading to these detrimental effects remain to be determined. In this study, we utilize a reproducible means to induce cellular immune activity in Drosophila larvae in response to mechanical stress. That is, forceps squeeze-administered stress induces lamellocytes, a defensive hemocyte type that normally appears in response to wasp infestation of larvae. The posterior signaling center (PSC) is a cellular microenvironment in the larval hematopoietic lymph gland that is vital for lamellocyte induction upon parasitoid attack. However, we found the PSC was not required for mechanical stress-induced lamellocyte production. In addition, we observed that mechanical injury caused a systemic expression of Unpaired3. This cytokine is both necessary and sufficient to activate the cellular immune response to the imposed stress. These findings provide new insights into the communication between injured tissues and immune system induction, using stress-challenged Drosophila larvae as a tractable model system.

Safety and Efficacy of a Progressively Prolonged Maintenance Interval of Venom Immunotherapy.

BACKGROUND: The long-term protection provided by venom immunotherapy (VIT) is related to the dose administered and to its long duration; the latter, however, becomes inconvenient for patients in countries like Greece, with many islanders or inhabitants of distant mountainous areas. Maintenance interval prolongation reduces the number of office visits - saving time and money - and as a consequence contributes to the patients' compliance. The aim of this prospective study was to evaluate the safety and efficacy of VIT on a progressively prolonged maintenance interval (PPMI). METHOD: 450 venom-allergic patients were reviewed for participation in our study; all of them were initially treated with a modified rush or an ultrarush protocol using freshly reconstituted, pure venoms. Upon reaching the maintenance dose, the VIT interval was scheduled to be gradually prolonged - by 1 week each time - aiming at a maximal interval of 26 weeks. RESULTS: 267/450 patients consented to participate in our VIT PPMI protocol: 98 were treated with vespid(s) venom, 142 with honeybee venom, and 27 with both. The mean duration of patient follow-up was 9.1 ± 4.2 years. The majority of systemic reactions due to VIT injections occurred up to the 8-weeks PPMI; few additional reactions were documented in a small fraction (2.9%) of our patient population beyond 9 weeks and up to 16 weeks; all were caused by honeybee VIT. No reactions were observed during VIT administration at the 26-week interval. Ninety-six patients reported 204 field sting occurrences by the culprit insect. Ten systemic reactions (8 mild and 2 moderate in severity) were registered between the 9- and 18-week PPMI; the honeybee was the culprit insect in all cases. 108 field stings by the offending insect were sustained beyond the 20- and up to the 26-week PPMI; there were no reactions at all. CONCLUSIONS: Progressively prolonging the VIT maintenance interval up to 26 weeks appears to be safe and efficacious.

CAP-Inhibition, Molecular Diagnostics, and Total IgE in the Evaluation of Polistes and Vespula Double Sensitization.

Cross-reactions between Polistes dominula and Vespula species are common in southern Europe. Currently, only CAP-inhibition demonstrates high accuracy in identifying genuine sensitizations, but this method is time-consuming and expensive, so a new approach is required. This study investigates skin tests, molecular diagnostics, total IgE (tIgE), and the Ves v 5/Pol d 5 (or vice versa) ratio. The ratio generated low-accuracy results and poor agreement with CAP-inhibition, and we did not find any agreement between CAP-inhibition test and double values of Ves v 5/Pol d 5. Nevertheless, a slight diagnostic improvement was obtained when Ves v 5/tIgE and Pol d 5/tIgE were measured.

Component-resolved diagnosis in selecting patients for yellowjacket venom immunotherapy.

BACKGROUND: Venom immunotherapy is effective in preventing systemic allergic reactions (SARs), but the diagnosis of venom allergy is problematic. OBJECTIVE: To compare the performance of component-resolved diagnosis and conventional tests in patients referred for venom immunotherapy. METHODS: We measured serum-specific immunoglobulin E to yellowjacket and honeybee venoms (Ves v 1 and Ves v 5 and Api m 1), cross-reactive carbohydrate determinants, serum basal tryptase (ImmunoCAP, ThermoFisher Scientific, Uppsala, Sweden), and skin prick test reactions in 84 patients referred to receive venom immunotherapy. History of SAR and its severity were evaluated. RESULTS: Of the 78 patients with suspected yellowjacket venom (YJV) allergy, a history of SAR was confirmed in 47 (60%) and 31 (40%) had a non-SAR reaction. The most accurate tests to confirm venom allergy after a SAR were serum-specific immunoglobulin E to yellowjacket whole-venom extract spiked with Ves v 5 (area under the curve 0.87, 95% confidence interval 0.77-0.97, P < .001) and Ves v 5 (area under the curve 0.86, 95% confidence interval 0.76-0.96, P < .001). Sensitization to Ves v 1 was infrequent and its area under the curve was low (0.62, 95% confidence interval 0.47-0.76, P = .106). Sensitivity of the YJV skin prick test was 86%, but its specificity was low at 54%. Double sensitization to yellowjacket and honeybee occurred frequently in skin prick tests. Of the patients without a SAR, 26% showed a positive reaction to YJV in any serum test and 46% showed a positive reaction in skin tests. CONCLUSION: Specific immunoglobulin E to the YJV spiked with Ves v 5 confirmed the allergy after a SAR. A history of SAR should be confirmed before testing, because venom sensitization is frequent in other types of reactions.

Edin Expression in the Fat Body Is Required in the Defense Against Parasitic Wasps in Drosophila melanogaster.

The cellular immune response against parasitoid wasps in Drosophila involves the activation, mobilization, proliferation and differentiation of different blood cell types. Here, we have assessed the role of Edin (elevated during infection) in the immune response against the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster larvae. The expression of edin was induced within hours after a wasp infection in larval fat bodies. Using tissue-specific RNAi, we show that Edin is an important determinant of the encapsulation response. Although edin expression in the fat body was required for the larvae to mount a normal encapsulation response, it was dispensable in hemocytes. Edin expression in the fat body was not required for lamellocyte differentiation, but it was needed for the increase in plasmatocyte numbers and for the release of sessile hemocytes into the hemolymph. We conclude that edin expression in the fat body affects the outcome of a wasp infection by regulating the increase of plasmatocyte numbers and the mobilization of sessile hemocytes in Drosophila larvae.

Skin Test Reactivity to Hymenoptera Venom after Venom Immunotherapy Correlates Inversely with the IgG/IgE Ratio.

BACKGROUND: Skin test reactivity to hymenoptera venom and venom-specific IgE are important for diagnosing venom allergy and deciding on the appropriate allergen for venom immunotherapy (VIT). Longitudinal data on skin test reactivity during VIT and their correlation with venom-specific immunoglobulin (Ig)E and IgG are scarce. METHODS: We retrospectively analyzed shifts in skin test reactivity and serum levels of venom-specific IgE and IgG in patients allergic to hymenoptera venom before the initiation of VIT with ultrarush therapy and after ≥3 years of VIT. RESULTS: Fifty-four patients received ultrarush desensitization and subsequent VIT with wasp venom, 26 with honeybee venom, and 8 with both wasp and honeybee venom. Hymenoptera-specific skin test reactivity decreased during VIT in most patients, and became negative in 8% of the wasp-allergic patients and in 25% of the honeybee-allergic patients. Serum levels of venom-specific IgE positively correlated to skin test reactivity before VIT, but did not change significantly during VIT. IgG serum levels and the IgG/IgE ratio increased during VIT in most patients. A high IgG/IgE ratio correlated with low skin test reactivity after ≥3 years of VIT. CONCLUSIONS: The correlation between a high venom-specific IgG/IgE ratio and low skin test reactivity after VIT may be interesting for future investigations that assess its role as a potential marker for VIT efficacy.

Safety and tolerability during build-up phase of a rush venom immunotherapy.

BACKGROUND: Safety and tolerability of venom immunotherapy (VIT) in patients with concomitant disease and comedications, especially ß-blockers (BBs) and angiotensin-converting enzyme inhibitors (ACEIs), are under discussion. OBJECTIVE: To identify risk factors for the occurrence of systemic reactions (SRs) during the build-up phase of a 3-day rush VIT with focus on comorbidities and related comedications. METHODS: Data of 175 three-day rush VIT courses (Vespula venom, n = 161; honeybee venom, n = 14) were analyzed. Starting with 0.02 µg of venom, the maintenance dose of 100 µg was reached in 15-dose increments within 3 days. Local reactions (LRs) and SRs were documented during the build-up phase. Comorbidities and related comedications were registered. Univariate, bivariate, and multivariate data analysis was performed. RESULTS: During the 3-day rush VIT, an LR was seen in 74 (42.3%) of 175, a large LR (>10-cm diameter) in 82 (46.9%) of 175, and SRs in 19 (10.9%) of 175 VIT courses. Multivariate logistic regression revealed that female sex (P = .01), immunotherapy with honeybee venom (P = .003), and accompanying ACEI medication (P = .03) were independent predictors of the development of SRs during the build-up phase of VIT. CONCLUSION: This study revealed that female sex, honeybee VIT, and ACEI use independent predictors for SRs.

Safety of Ultrarush Venom Immunotherapy: Comparison Between Children and Adults.

BACKGROUND: The ultrarush protocol is an attractive approach in the buildup phase of venom immunotherapy (VIT-UR). However, the degree of risk of VIT-UR in children remains unknown. The objective of this study was to compare the safety of VIT-UR in children and adults. METHODS: We performed a study based on prospectively gathered medical records of children and adults with hymenoptera venom allergy treated with VIT-UR in 3 allergy centers in Poland. RESULTS: The study population comprised 134 children (mean [SD] age, 12.6 [3.7] years; males, 70.1%) and 207 adults (mean age, 42.4 [14.0] years; males, 47.8%). The number of children in the subgroups of bee venom (BV) allergy and wasp venom (WV) allergy were comparable, although sensitization to WV was more predominant in the adult group (70.1%). Skin reactivity to both venoms was more common in children than in adults (P < .001); however, children had higher concentrations of total IgE and specific IgE to BV (both P < .001). Systemic allergic reactions (VIT-SARs) occurred in 6.2% of the patients (3.7% in children and 7.7% in adults; nonsignificant). In adults, SARs occurred more frequently in patients treated with BV than WV extracts (21.4% vs 2.6%; P < .001). The same pattern was observed in children (7.2% vs 0%; P = .058). However, VIT-SARs to BV were less frequent in children than in adults (P = .034). Similarly, no significant relationship was noted between children and adults receiving WV VIT (2.6% vs 0%; nonsignificant). The severity of VIT-SAR did not differ between children and adults. CONCLUSIONS: VIT-UR is safer in children. Age below 18 is not a risk factor for VIT-SARs.