History Of Severe Systemic Reactions Research Articles

Hymenoptera venom immunotherapy: Safety and efficacy of an accelerated induction regimen with depot aluminum adsorbed extracts.

Introduction: Hymenoptera venom immunotherapy (VIT) is the only therapy that protects patients with Hymenoptera venom allergy by preventing systemic reactions after a new sting. Various extracts for VIT are available and used. VIT administration consists of an induction phase and a maintenance phase. Depot preparations of Hymenoptera VIT extracts are typically used for cluster and conventional protocols, and the maintenance phase. Many patients with Hymenoptera allergy need to achieve tolerance quickly because of the high risk of re-sting and possible anaphylaxis. Objective: Our study aimed to show the safety and efficacy of an accelerated regimen with depot preparations on aluminum hydroxide by using relatively high starting doses in a heterogeneous group of patients. Methods: The research focused on a group of patients with a history of severe systemic reactions to Hymenoptera stings, with the necessity of swift immunization due to high occupational risks. Aluminum hydroxide depot extracts either of Vepula species or Apis mellifera extracts were used. Results: The induction protocol was started with the highest concentration of depot venom extract of 100,000 standard quality unit and was well tolerated by 19 of 20 patients. Onne patient presented with a mild systemic reaction during the accelerated induction schedule, which was promptly treated with intravenous steroids and intramuscular H1 antihistamine; when switched to a conventional induction protocol, he had a similar reaction but finally reached maintenance with an H1-antagonist premedication. Conclusion: If validated, the accelerated induction protocol by using depot aluminum adsorbed extracts with the highest concentration of venom from the beginning could offer a streamlined and accessible treatment modality for patients diagnosed with anaphylaxis from bee and wasp venoms in need of rapid desensitization.

Pru p 3 Sublingual Immunotherapy in Patients with Lipid Transfer Protein Syndrome: Is It Worth?

Background: Lipid transfer proteins (LTPs) syndrome is an important cause of multiple plant food allergy in the Mediterranean area. The effectiveness of sublingual immunotherapy (SLIT) with the LTP Pru p 3 extract has been little investigated in the real-world setting. This study aimed to investigate the outcome of Pru p 3 SLIT in real-life patients with LTP syndrome with/without concurrent reactions to peanut and/or nuts. Methods: This was a prospective real-life study including all patients diagnosed with LTP allergy and treated with Pru p 3 SLIT between 2011 and 2018 in a tertiary hospital in Spain. Patients underwent open oral food challenge (OFC) tests for unpeeled peach and nuts/peanuts 1 year after the treatment started to assess food tolerance. A control group of patients diagnosed with LTP allergy who refused treatment with immunotherapy were included. Severity of symptoms and diet avoidance was recorded in both groups. Results: Twenty-nine patients with a median age of 24.7 years (range 5.5–43.1) were included: 100% were allergic to fruit; 72%, to peanut and/or nuts; 19 had a history of severe systemic reactions. Seven patients discontinued therapy; 3 (10%), due to adverse events. One year after SLIT start, 16 (73%) patients had negative OFC to peach; 95%, after 2 years; 69% had negative OFC to nuts/peanuts. The control group included 13 patients: 53.8% experienced reactions with new foods; severity of symptoms increased significantly (p < 0.001), and diet restrictions were maintained in this group. Conclusions: SLIT with Pru p 3 shows a good safety profile, and avoid dietary restrictions in patients with LTP syndrome treated in the real-life setting.

Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma

Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Novel disease biomarkers and curative treatment options are strongly needed. We sought to apply untargeted metabolomic profiling to identify pathogenic mechanisms and candidate disease biomarkers in patients with FA. Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone, or both FA and asthma, as well as healthy pediatric control subjects. In this pilot study patients with FA exhibited a disease-specific metabolomic signature compared with both control subjects and asthmatic patients. In particular, FA was uniquely associated with a marked decrease in sphingolipid levels, as well as levels of a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T cells. Specific comparison of patients with FA and asthmatic patients revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, the history of severe systemic reactions and the presence of multiple FAs were associated with changes in levels of tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids. Children with FA have a disease-specific metabolomic profile that is informative of disease mechanisms and severity and that dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in children with FA might reflect the interplay between an altered microbiota and immune cell subsets in the gut.

Changing microRNA Expression during Three-Month Wasp Venom Immunotherapy

ABSTRACTMicroRNAs 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.

Changes in the Expression of MicroRNA in the Buildup Phase of Wasp Venom Immunotherapy: A Pilot Study

Background: Allergen-specific immunotherapy is the most effective method of treatment in allergy to wasp venom. However, its mechanism of action is still not fully understood. The aim of this study is to describe changes in microRNA (miRNA) expression in patients undergoing the buildup phase of venom immunotherapy. Methods: The study group comprised 7 adult patients with a history of severe systemic reactions after stinging by a wasp. In all patients, sensitization to wasp venom had been confirmed by skin tests and serum IgE. The buildup phase of wasp venom immunotherapy (VIT) was conducted according to an ultrarush protocol. In blood samples collected before and 24 h after completing the VIT buildup phase, 740 miRNAs were assessed. Results: Of the 740 miRNAs, 440 were detected in the study group, and in 5 expression was significantly changed after the buildup phase of VIT: miR-370, miR-539, miR-502-3p, miR-299, and miR-29c. Another 62 miRNAs changed 2-fold in some patients (nonsignificant), including increases in miR-143 (stimulating FOXp3 expression) and let-7d (reducing expression of IL-13, IL-6, and TLR4), and decreases in proinflammatory miR-301, miR-146b, miR-106, and miR-485. Conclusions: Several changes in miRNA expression have been found as a result of the buildup phase of wasp VIT, with lower expression of some miRNAs involved in allergic inflammation and higher expression of those possibly involved in tolerance induction. However, the role of the most significant changes is uncertain.

466 Bee venom Immunotherapy with Standardized Extract, Two Case Comunication and Clinical Progress

BackgroundBee venom immunotherapy is a safe and effective treatment, indicated in patients with previous history of severe systemic reactions to bee venom, demonstrating succesful desensitization in more than 90% of cases with standardized extract. Currently in Mexico there is no standardized extract commercially available for treatment, despite of having high activity of beekeeping and occupational exposure with at least 17,478 registered stings per year and an annually honey production of nearly 70 tons.MethodsWe present the clinical progress of 2 patients with history of severe systemic reactions to bee venom and occupational exposure, both with demonstrated sensitization by specific IgE and who underwent specific immunotherapy with standardized extract (Alk-US) reaching a maintenance weekly dose of 100 mcg (PLA2) for the last 4 years.ResultsBoth patients sufered of accidental stings after reached the maintenance dose presenting mild local reactions to stings. Both patients had very different clinical course presenting a wide variety of adverse reactions during desensitization protocol; from mild local to generalized reactions all generally well tolerated allowed to reach the maintenance dose with succesful desensitization proved by accidental exposure without severe systemic reactions.ConclusionsBee venom specific immunotherapy with standardized extract is a well tolerated and efective treatment preventing the development of life threathening reactions in sensitized patients. It is important to promote the use and availability of standardized extract in developing countries with poor safety measures and high occupational exposure.

Ultrarush venom desensitization after systemic reactions during conventional venom immunotherapy

Rush and ultrarush venom immunotherapy (VIT) protocols are safe and effective in patients with Hymenoptera hypersensitivity. However, these protocols have typically been used instead of conventional VIT and not in patients who have experienced adverse reactions during conventional VIT. To date, there are no reports of using an ultrarush VIT protocol to desensitize patients with a history of severe systemic reactions during conventional VIT. To determine whether ultrarush VIT can be safely administered to a high-risk patient with a history of severe systemic reactions to conventional VIT. Premedication with 40 mg of prednisone, 180 mg of fexofenadine, and 150 mg of ranitidine orally twice daily was initiated. The patient received VIT to mixed vespid and wasp in a medical intensive care unit via a 13-step buildup on day 1 followed by a 2-step buildup on day 2. Immunotherapy was begun with a dose of 0.005 microg of mixed vespid and 0.002 microg of wasp venom and achieved a total dose of 300 microg of mixed vespid and 100 microg of wasp venom. The patient tolerated the procedure with minimal adverse effects. She subsequently received maintenance dosing in the outpatient clinic weekly for 4 weeks and bimonthly for 8 weeks, and she continues monthly maintenance VIT. We report the first successful use of ultrarush VIT in a high-risk patient with a history of severe systemic reactions during conventional VIT. This protocol should be considered in patients with a history of allergy to vespids or wasps who require VIT but cannot reach a maintenance dose with conventional VIT owing to systemic reactions.

Lipid transfer protein and vicilin are important walnut allergens in patients not allergic to pollen

Walnut is the most common cause of allergic reactions to tree nuts, as reported by large population studies. Two major allergens of walnut have been identified up until now: a 2S albumin and a vicilin-like protein. This study was designed to identify the walnut major allergens in the Italian population and to compare the walnut IgE-binding profile in patients with or without pollen allergy. We selected 46 patients either with oral allergy syndrome confirmed by open oral challenge or with systemic symptoms after ingestion of walnut. These patients' sera were used for the immunoblotting of walnut extract; the identified allergens were purified by HPLC and sequenced. A peach-walnut cross-inhibition study was then performed. The only major allergen recognized by our study population was a 9-kd lipid transfer protein (LTP), recognized by 37 patients. Two other minor allergens of approximately 9-kd molecular weight, both belonging to the vicilin family, were recognized by 10 patients. IgE binding to walnut LTP was completely inhibited by peach LTP. In Italian patients with walnut allergy confirmed by documented history of severe systemic reactions or by open oral food challenge, the major allergen is an LTP. The sensitization to this protein seems to be secondary to the sensitization to peach LTP, which acts as the primary sensitizer. LTP and vicilins were able to sensitize patients not allergic to pollen.

Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils

Rapid clinical tolerance can be induced over several hours by very fast bee venom immunotherapy (VIT) protocols. To investigate the mechanisms underlying VIT we examined the changes of blood basophil responsiveness during VIT. Seven bee venom allergic patients with a history of severe systemic reactions after a bee sting were investigated. A cumulative dose of 111.1 micrograms bee venom (BV) was administered sc over 3.5 h under intensive care conditions according to an ultra-rush protocol. The release of histamine and the formation of leukotrienes in response to BV, major BV allergen Phospholipase A2 (PLA), IgE receptor cross-linking with the use of monoclonal antibodies against IgE and IgE receptor, as well as IgE independent activation in response to C5a were determined in vitro before and after ultra-rush VIT. We demonstrated a decrease of total histamine in peripheral blood leucocytes just after VIT. Histamine release in response to all the stimuli used is not affected by ultra-rush VIT, if expressed as per cent release of total histamine. However, the absolute amount product released in response to stimulation was decreased, particularly with allergen (BV, PLA). We also found a significant reduction of LTC4 formation after VIT in samples stimulated with specific allergen (BV, PLA). Blood basophils are a target for VIT, which induces impaired release of both preformed and newly generated mediators. However, we believe the basic mechanisms of rapid clinical tolerance induced by ultra-rush VIT remain to be investigated.

Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions

Carboplatin is the drug of choice for the treatment of nonresectable astrocytomas in children, but patients who are intolerant may require cranial irradiation which is associated with significant morbidity. Hypersensitivity reactions, including urticaria, bronchospasm, and hypotension, have been reported in 1% to 30% of patients treated with carboplatin. Although a few patients have attempted to continue therapy following pretreatment with antihistamines and corticosteroids, most have had recurrent severe reactions and have discontinued therapy. Two children with a history of severe systemic reactions to carboplatin were pretreated with 1 to 2 mg/kg of oral prednisolone the night before and the morning of their infusion. The initial desensitization was carried out in the intensive care unit (ICU) using doses of 1, 2.5, 5, 10, 25, and 50 mg of carboplatin infused at 1 mg/min every 15 minutes. This was well-tolerated and the remainder of the dose was infused at the standard rate of 200 mg/hr. One patient continued to receive infusions in the clinic without any difficulty. The other patient tolerated a second infusion, but during his third he experienced a systemic reaction that required discontinuation of the infusion and treatment with diphenhydramine. Desensitization was repeated in the ICU with pretreatment with prednisolone, diphenhydramine, and ranitidine, starting with 0.1 mg of carboplatin, and increasing more slowly than in the first protocol. This was well-tolerated, and subsequent infusions have been administered beginning with 1 mg doses without adverse effects. Both boys continued therapy with carboplatin; their astrocytomas are stable and they are clinically well. The use of the desensitization protocol enabled them to avoid cranial irradiation and improved their chances for normal neurologic development.

Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures.

The mechanisms of bee venom immunotherapy (VIT) are largely unknown. The aim of this study was to follow the changes of T cell cytokine secretion during the course of VIT. Ten bee venom-allergic patients with a history of severe systemic reactions, positive skin tests, and bee venom (BV)-specific serum IgE Abs were treated as follows: on the first day, a cumulative dose of 111 micrograms, starting with 0.1 microgram, was administered s.c. under intensive care conditions. Further injections of 100 micrograms BV were given on day 7, day 21, and thereafter at intervals of 4 wk. Blood samples were obtained just before the initiation of VIT, after the last injection on the same day, and before the subsequent BV injections on days 7, 21, and 50 of VIT. Peripheral blood mononuclear cells (PBMC) were stimulated with phospholipase A (PLA), the major BV allergen, or with a control Ag tetanus toxoid (TT). Cytokine secretion was measured 24 h after restimulation of the cultures with solid-phase bound OKT3 F(ab')2 mAbs after 7 days of culture. In PLA-stimulated cultures, VIT resulted in decreased IL-4 and IL-5 and increased IFN-gamma secretion. In TT-stimulated cultures, we observed similar levels of cytokines before and during VIT. We conclude that ultra-rush VIT changes allergen-specific T cell reactivity.

Honeybee venom allergy: Results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients

In 86 patients with a history of severe systemic reactions (SRs) to honeybee stings confirmed by a positive skin test and/or RAST to honeybee venom (HBV), immunotherapy (IT) with HBV was stopped after 3 to 10 years. All patients had tolerated well a honeybee sting during IT and were resubmitted to a sting 1 year after VIT was stopped. At the latter time, 15 patients (17%) developed an SR and 71 did not. There was no difference between the two groups regarding age, sex, IT duration, severity of the SR before treatment, as well as diagnostic tests with HBV (skin tests, RAST, and specific IgG) before the challenge. Patients with a relapse of their allergy had, however, developed allergic SRs to IT injections more frequently than patients with lasting protection ( p < 0.001). SRs to the sting challenge (CH) after IT was stopped occurred more frequently in those patients in whom efficacy of IT had previously been confirmed by lacking responses to a field sting than in patients who had tolerated an intentional CH during the injection period ( p < 0.025). Indeed, the incidence of relapse after venom IT was stopped was only 9.6% in patients who had previously tolerated an intentional CH. It is concluded that well-tolerated HBV IT may be stopped after at least 3 years, provided its efficacy has been documented by a CH without SR.

Predictive value of venom‐specific IgE, IgG and IgG subclass antibodies in patients on immunotherapy with honey bee venom

Sixty-seven patients with a history of severe systemic reactions following honey bee stings were treated by immunotherapy (IT) with honey bee venom. During maintenance therapy all were submitted to a sting challenge under clinical conditions. 15 developed mostly minor symptoms of a systemic reaction while 52 showed only a local swelling at the sting site. Phospholipase A2-specific IgE, IgG and IgG subclass serum antibodies were estimated in samples obtained before IT and immediately before the challenge. Specific IgE decreased in reactors and in non-reactors. There was no difference between the two groups at any time. Specific total IgG, IgG1 and IgG4 increased in both reactors and non-reactors during IT. An early increase of specific IgG1, was observed while specific IgG4 remained elevated throughout the treatment. Specific total IgG was higher in reactors than non-reactors before the challenge, specific IgG1 higher in reactors before treatment and specific IgG4 higher in reactors than non-reactors both before treatment and before challenge. In the individual patient, no single antibody estimation or combination of various antibodies was predictive of the outcome of a sting challenge.