Severe Anaphylactic Reactions Research Articles

Impaired HDL function and endothelial barrier stability in severe anaphylaxis

Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins (Apo) A1 and B in serum from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient serum, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Lastly, the effect of anaphylactic-derived HDL particles on the endothelial barrier was studied. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. Severe anaphylactic reactions show statistically significant low levels of HDL-C, LDL-C, ApoA1, and ApoB, which points to a possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human sera-cell assays, we observed an impaired capacity of ApoB-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

Recommendations for the management of children with influenza in a primary care setting – COMPAS INFLUENZA. Update for the 2023/2024 season

Five years after publishing the first Polish recommendations on the management of influenza, especially after the COVID-19 pandemic, there was a need to update the recommendations. Influenza is an acute infectious disease of the respiratory tract that occurs in all age groups. The course of the disease may vary in severity and clinical picture, from asymptomatic to severe with symptoms of respiratory failure. The possibility of pandemic infections and serious complications distinguish influenza from other viral respiratory diseases. Diagnosis is most often clinical, and in justified cases additional tests may be helpful. The disease is characterised by a sudden onset with general symptoms such as fever, feeling cold, chills, headache, muscle and joint pain, malaise, lack of appetite and severe weakness. General symptoms are accompanied by respiratory manifestations. Physical examination shows no characteristic features. In outpatient settings during the epidemic season (October – April), the diagnosis should be made based on clinical symptoms and physical examination. Oseltamivir is recommended for both treatment and chemoprophylaxis. Clinical benefits are greatest when treatment is started as early as possible, within 48 hours of symptom onset. Clinical trials indicate that early treatment with oseltamivir may reduce both the duration of the disease and the risk of complications. Annual vaccination is the most effective method of preventing influenza, with severe anaphylactic reaction after previous vaccination being the only absolute contraindication.

Milk-induced anaphylaxis among children presenting to Canadian emergency departments

BackgroundCow's milk is one of the most common and burdensome allergens in pediatrics, and it can induce severe anaphylactic reactions in children. However, data on cow's milk-induced anaphylaxis are sparse. ObjectiveTo describe the epidemiology of pediatric cow's milk-induced anaphylaxis and to determine risk factors for repeat emergency department (ED) epinephrine administration. MethodsBetween April 2011 and May 2023, data were collected on children with anaphylaxis presenting to 10 Canadian EDs. A standardized form documenting symptoms, triggers, treatment, and outcome was used. Multivariate logistic regression was used. ResultsOf 3118 anaphylactic reactions, 319 milk-induced anaphylaxis cases were identified (10%). In the prehospital setting, 54% of patients with milk-induced anaphylaxis received intramuscular epinephrine. In those with milk-induced anaphylaxis, receiving epinephrine before presenting to the ED was associated with a reduced risk of requiring 2 or more epinephrine doses in the ED (adjusted odds ratio, 0.95 [95% CI, 0.90-0.99]). Children younger than 5 years of age were more likely to experience a mild reaction compared with that in older children, who experienced a moderate reaction more often (P < .0001). Compared with other forms of food-induced anaphylaxis, children presenting with milk-induced anaphylaxis were younger; a greater proportion experienced wheezing and vomiting, and less experienced angioedema. ConclusionPrehospital epinephrine in pediatric milk-induced anaphylaxis is underused; however, it may decrease risk of requiring 2 ED epinephrine doses. Milk-induced anaphylaxis in children younger than 5 years of age may be less severe than in older children. Wheezing and vomiting are more prevalent in milk-induced anaphylaxis compared with that of other foods.

Multidisciplinary Approach to Deciphering Etoposide Infusion Reactions and Potential Role of Polyethersulfone Filter Membranes.

Etoposide, a topoisomerase II inhibitor used clinically to treat cancer, has been associated with severe anaphylactic infusion related adverse drug reactions (ADRs). In a previous study we identified a hydrophilic polyethersulfone filter as a possible cause of increased rates of pediatric etoposide infusion reactions. In this multidisciplinary follow-up analytical study, we aimed to assess the chemical structure of etoposide after passing through the same hydrophilic polyethersulfone filter. An etoposide 0.4 mg/mL infusion was prepared under aseptic conditions and then passed through a standard IV infusion set with an in-line filter in place. Samples were taken in triplicate using a needle-less access system to include sampling sites directly from the IV bag port and from the IV tubing both before and after the in-line filter. Samples were diluted into mobile phase, then an aliquot was injected into a high-performance liquid chromatography mass spectrometry HPLC-MS (Thermo TSQ Quantum Ultra) system coupled to a Diode Array Detector (DAD) (Thermo Dionex Ultimate 3000). Etoposide was monitored using a selected reaction monitoring scan (SRM) of 606.2/228.8 and wavelengths of 210, 220, 254, and 280 nm for 30 minutes. No detectable differences were observed upon comparing the three samples. Based on these results, a chemical change in etoposide resulting from an in-line filter is unlikely to be the primary cause of increased rates of infusion reactions. Pharmacists working in healthcare systems, observe many ADRs, but rarely have the resources necessary to investigate the potential etiology or causality. This report highlights importance of multi-disciplinary collaboration to investigate serious ADRs.

Clinical relevance of gibberellin-regulated protein

Since 2013, a total of nine allergenic sources of gibberellin-regulated protein (GRP) have been described in the literature. The first gibberellin-regulated protein considered to be an allergen was extracted from peach (Prunus persica) and was named Pru p 7. This article aims to provide an overview of the GRP’s characteristics, to emphasize their importance and relevance in clinical practice, and to bring to attention the methods of diagnosis and treatment proposed in the literature published to date. After certain fruit consumption in patients sensitized to GRP, it has been described the occurrence of allergic reactions of various degrees (oral allergy syndrome, up to severe anaphylactic reactions). This fact raises a series of questions regarding the clinical expression of this sensitization, but also confers a change of perspective in relation to fruit allergy. At this moment, it is not clear if the sensitization to food GRP is always a primary sensitization or if the sensitization to food GRP appears subsequent to sensitization to Cupresaceae pollen’s GRP. Pru p 7 is considered to be a potential marker of severity in case of sensitization to peach allergens. Furthermore, the presence of cofactors in GRP sensitized patients may induce systemic allergic reactions. The diagnosis of this type of allergy might be difficult, and the personalized treatment is not yet available.  

Food allergy - New risks through vegan diet? Overview of new allergen sources and current data on the potential risk of anaphylaxis.

A vegan diet is increasingly en vogue, i.e., a diet based on plants, in which animal products are completely avoided, often for health and environmental reasons. The menu is supplemented with pulses (e.g., soy, lentils, peas), nuts (e.g., cashew, macadamia, almond, pecan, para, walnut) and seeds (e.g., chia, flaxseed) or pseudo-grains (quinoa, buckwheat). Indeed, the product range is expanding to include vegan foods such as milk alternatives (e.g., oat, almond, soy drinks) and cheese or meat substitutes (e.g., soy-based). Food allergies are also on the rise, with an increasing prevalence worldwide. It is worthy of note that the main allergens of anaphylactic reactions to food in adults are predominantly of plant origin, mainly pulses and nuts - the very foods that form the main source of protein in the vegan diet. In this context, allergies to storage proteins (e.g., Gly m 5 and Gly m 6 from soya beans) can lead to severe anaphylactic reactions, while highly processed substitute products containing plant protein isolates (e.g., pea flour) in concentrated form continue to be of particular concern and may therefore be allergologically problematic. In this article, we aim to provide an overview of allergens and emerging allergen sources in vegan foods and highlight the anaphylaxis risk of the vegan diet.

[Skin Prick Test as a Provocation Test - Severe Anaphylactic Reaction to Skin Tests with Ceftriaxone in Two Occupationally Exposed Workers].

[Skin Prick Test as a Provocation Test - Severe Anaphylactic Reaction to Skin Tests with Ceftriaxone in Two Occupationally Exposed Workers].

Severe Anaphylactic Reactions to Home Doses of Oral Immunotherapy for Food Allergy.

Severe anaphylactic reactions to home-doses may occur during food allergy oral immunotherapy (OIT). To study the rate and risk factors for such reactions. All patients aged >3.5 years who completed OIT in a single center, between April-2010 and January-2020, were studied. All home epinephrine-treated reactions (HETRs) were identified. High-grade HETRs (HG-HETRs) were defined as HETR involving respiratory (SpO2 ≤94%), cardiovascular (low blood pressure), or CNS (loss of consciousness) impairment. The rate and risk factors for HG-HETRs were investigated. A total of 1637 OIT treatments were studied: milk, 880; peanut, 346; tree-nuts, 221; sesame, 115; and egg, 75. Of 390 identified HETRs, 30 HG-HETRs occurred during 27 treatments (1.65% of all treatments). Nearly all (26/30) were during milk OIT in patients with HDM-sensitization and asthma (26/30 each). Of the 30 HG-HETRs, 21 recovered with 1-2 epinephrine treatments, but 9 cases (0.55% of all treatments) did not respond to a second dose of epinephrine and were deemed refractory anaphylaxis. Three patients required ICU admission, and 3 received epinephrine drip but none required ventilatory support. Risk factors for HG-HETRs included milk-OIT (p=0.031), asthma (p=0.02) and house dust mite (HDM) sensitization (p=0.02). No specific triggers for HG-HETR were identified. Of patients with HG-HETRs, 25.9% were fully desensitized, including the 4 non-milk treated patients, 22.2% were partially desensitized and 51.9% failed. HG-HETRs and particularly refractory anaphylactic reactions to home OIT doses are uncommon. While milk OIT, asthma and HDM sensitization are the main risk factors for such reactions, identification of patients at risk is challenging.

Severe Anaphylactic Reaction to Ferric Carboxymaltose With Positive Skin and Basophil Activation Tests.

Severe Anaphylactic Reaction to Ferric Carboxymaltose With Positive Skin and Basophil Activation Tests.

Protocol Development of a Personalized Balanced Nutrition Concept for Preschool Children, Primarily Those with Food Allergies, Using an IT Platform.

Children with food allergies are at higher risk for severe anaphylactic reactions and for key nutrient deficiency. In order to address these concerns, enable early detection, and improve the monitoring of children with food allergies, an innovative IT platform will be developed by IT experts (IN2 Ltd. Zagreb, Croatia, part of Constellation Software Inc. (Toronto, ON, Canada)) and Srebrnjak Children's Hospital, Zagreb, Croatia (SCH) for the effective implementation of personalized balanced nutrition in preschool institutions in Croatia. Additionally, the data obtained through this research, including epidemiological data on allergic diseases, clinical data (diagnostic allergy tests and others), anthropometry, and physical activity status, will be used to create a national Allergy registry. Other than being a tool for personalized and balanced nutrition for children, especially those with special dietary requirements (including food allergy and intolerance), the IT platform developed in this study will enable the continuous monitoring of these children as a part of their clinical management plan and earlier detection of food allergies, intolerance, and other conditions, even outside of the healthcare system. This research also aims at optimizing current and developing novel personalized therapeutic regimes, detecting novel early biomarkers in children with food allergies and intolerances, and involving all key stakeholders (caregivers, preschool institutions, etc.) in the shared-care approach in the management of food allergies in children.

Immuno-embolization plus PD1 antibody in metastatic uveal melanoma.

e21592 Background: More than 90% of patients with metastatic uveal melanoma (MUM) have metastatic disease in the liver. MUM has a poor prognosis following development of liver metastasis. Control of disease progression in the liver correlates with improved survival in MUM. We present a single-institution experience of treating MUM patients with immuno-embolization (IE) of liver metastasis using GM-CSF in combination with an anti-PD1 antibody (Pembrolizumab). Methods: This retrospective study includes MUM patients who received liver-directed therapy (IE) in combination with IV Pembrolizumab at the University of Iowa. Patients selected for IE treatment had liver-predominant metastatic disease involving less than 50% of the total liver parenchyma, total bilirubin &lt; 2, serum albumin &gt; 3, and patient ECOG PS of 0-1. Alternating lobar IE was administered every 4 weeks using a combination of GM-CSF (2000 mcg) and Lipiodol. Pembrolizumab was administered IV at 200 mg every 3 weeks. Results: 11 MUM patients received a total of 58 IE treatments concurrently with IV Pembrolizumab. 4 patients achieved stable disease, and 2 patients achieved partial response as their best radiographic response during treatment. 6 patients received additional lines of therapy; of these, 4 were enrolled into clinical trials. 5 patients were alive at the time of analysis, and 2 patients were actively receiving IE plus Pembrolizumab therapy. The median overall survival (OS) from diagnosis was 25.6 months, and the median OS from the first IE treatment was 21.3 months. Complications related to IE treatments included bleeding (n = 1), severe post-procedural pain (n = 2), infection (n = 1), and anaphylactic reaction (n = 1). No unexpected immune-related side effects occurred with Pembrolizumab. Specifically, no immune-related hepatic toxicity was reported in any patient. Conclusions: Immuno-embolization of liver metastasis using GM-CSF in combination with systemic check-point inhibitor therapy is promising in the treatment of MUM patients, and had no reported immunologic hepatic toxicity in a single-institution patient cohort. The treatment combination is currently being evaluated in a prospective clinical trial (NCT03472586).

Milk Allergen Micro-Array (MAMA) for Refined Detection of Cow's-Milk-Specific IgE Sensitization.

Immunoglobulin-E(IgE)-mediated hypersensitivity to cow's milk allergens is a frequent cause of severe and life-threatening anaphylactic reactions. Besides case histories and controlled food challenges, the detection of the IgE antibodies specific to cow's milk allergens is important for the diagnosis of cow-milk-specific IgE sensitization. Cow´s milk allergen molecules provide useful information for the refined detection of cow-milk-specific IgE sensitization. A micro-array based on ImmunoCAP ISAC technology was developed and designated milk allergen micro-array (MAMA), containing a complete panel of purified natural and recombinant cow's milk allergens (caseins, α-lactalbumin, β-lactoglobulin, bovine serum albumin-BSA and lactoferrin), recombinant BSA fragments, and α-casein-, α-lactalbumin- and β-lactoglobulin-derived synthetic peptides. Sera from 80 children with confirmed symptoms related to cow's milk intake (without anaphylaxis: n = 39; anaphylaxis with a Sampson grade of 1-3: n = 21; and anaphylaxis with a Sampson grade of 4-5: n = 20) were studied. The alterations in the specific IgE levels were analyzed in a subgroup of eleven patients, i.e., five who did not and six who did acquire natural tolerance. The use of MAMA allowed a component-resolved diagnosis of IgE sensitization in each of the children suffering from cow's-milk-related anaphylaxis according to Sampson grades 1-5 requiring only 20-30 microliters of serum. IgE sensitization to caseins and casein-derived peptides was found in each of the children with Sampson grades of 4-5. Among the grade 1-3 patients, nine patients showed negative reactivity to caseins but showed IgE reactivity to alpha-lactalbumin (n = 7) or beta-lactoglobulin (n = 2). For certain children, an IgE sensitization to cryptic peptide epitopes without detectable allergen-specific IgE was found. Twenty-four children with cow-milk-specific anaphylaxis showed additional IgE sensitizations to BSA, but they were all sensitized to either caseins, alpha-lactalbumin, or beta-lactoglobulin. A total of 17 of the 39 children without anaphylaxis lacked specific IgE reactivity to any of the tested components. The children developing tolerance showed a reduction in allergen and/or peptide-specific IgE levels, whereas those remaining sensitive did not. The use of MAMA allows for the detection, using only a few microliters of serum, of IgE sensitization to multiple cow's milk allergens and allergen-derived peptides in cow-milk-allergic children with cow-milk-related anaphylaxis.

Platelet-activating factor as an endogenous cofactor of food anaphylaxis.

Anaphylaxis is a severe, acute, life-threatening generalized or systemic hypersensitivity reaction. The incidence of anaphylaxis is increasing worldwide, with medications and food contributing to most cases. Physical exercise, acute infections, drugs, alcohol, and menstruation are the external cofactors associated with more severe systemic reaction. The aim of this review is to show that platelet-activating factor contributes to the development of severe anaphylactic reaction, and even to anaphylactic shock.

Dedicator of cytokinesis 8 (DOCK8) is a negative regulator of skin mast cell function

Abstract Dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. In humans, homozygous or compound heterozygous deletions of DOCK8 cause a combined immunodeficiency characterized by allergic disorders. Based on this evidence, we hypothesized that DOCK8 may be a negative regulator of mast cell function. To address this hypothesis, we used mice with a loss-of-function mutation in Dock8 (primuris, Dock8 pri/primice) and conditional mice in which DOCK8 is ablated in connective tissue mast cells (Mcpt5-Cre +; Dock8 fl/flmice). Dock8 pri/primice exhibited increased plasma levels of mast cell protease-1 (MCPT1) in homeostatic conditions. Furthermore, Dock8 pri/primice and Mcpt5-Cre +; Dock8 fl/flmice experienced a more severe IgE-dependent passive cutaneous anaphylactic reaction (PCA) than control mice. This data suggests that DOCK8 deficiency is linked to increased mast cell activation in homeostatic conditions and upon stimulation by IgE-dependent mechanisms. Fetal skin derived cultured mast cells (FSMCs) generated from Dock8 pri/primice released increased amounts of β-hexosaminidase upon IgE-dependent activation. Consistent with this finding, naïve DOCK8-deficient FSMCs exhibited alterations in cytoskeletal dynamics that may facilitate mast cell degranulation. Finally, we observed an increased number of tryptase positive cells in skin biopsies obtained from three pediatric patients diagnosed with hyper IgE syndrome (HIES) due to DOCK8 mutations, suggesting that DOCK8 immunodeficiency may contribute to skin mast cell expansion in humans. Our findings provide strong evidence that DOCK8 can contribute to negative regulation of skin mast cell activation and expansion. R01 AI140626-05

Canada’s First Joint Oncology-Allergy Clinic: Successful Desensitization to Trastuzumab Following Severe Anaphylactic Reaction in Which Epinephrine Was Inappropriately Withheld

Recognition of anaphylaxis and differentiation from other infusion reactions in an oncology setting is imperative; epinephrine is the recommended treatment for anaphylaxis and should be administered immediately to patients in whom anaphylaxis is suspected. Trastuzumab has a potentially tremendous oncological benefit, and when hypersensitivity reactions occur, rechallenge with desensitization protocols has become more common. Oncology presents a unique situation in which repeat drug exposure after a serious adverse reaction is often warranted due to the mortality risk of untreated cancer-allergists can assist with both symptom assessment and risk mitigation. This case showcases successful desensitization in a 43-year-old female with locally advanced HER2-positive breast cancer following a severe anaphylactic reaction to trastuzumab, in which epinephrine was not administered. We report the establishment of the Medical Oncology and Allergy Clinic: Canada's first multidisciplinary clinic aimed at expediting the assessment and management of oncology patients with adverse drug reactions (including chemotherapy, contrast media, antimicrobials) and those with primary and acquired immunodeficiency. We propose this multidisciplinary clinic model as a treatment framework moving forward, with the goal of continuing first-line therapies in cancer patients who develop drug-hypersensitivity (i.e., through desensitization). This case highlights the unmet need for a multidisciplinary approach to the management of oncology patients who experience hypersensitivity reactions.

Impact of Outpatient Antihypertensive Medication Use on Epinephrine Resistance in Anaphylaxis.

There has been anincrease in allergy-related emergency department (ED) visits over the past several years. Underlying cardiovascular disease or respiratory disease and concurrent beta blocker or angiotensin-converting enzyme inhibitor use have been identified as potential risk factors for severe or refractory anaphylactic reactions. Conflicting evidence exists regarding the association between antihypertensive (AH) use and the incidence of refractory anaphylaxis. The purpose of this study was to determine the incidence of refractory anaphylaxis in patients presenting to the ED while prescribed select AH medications outpatient. This was a retrospective cohort study of all adult and pediatric patients presenting to the ED between February 16, 2021, and August 31, 2021, with a diagnosis of anaphylaxis. The primary objective was to compare the proportion of patients experiencing refractory anaphylaxis that were prescribed versus not prescribed AH medications in the outpatient setting. A total of 101 patients were treated for anaphylaxis in the ED during the study timeframe with 13 patients in the AH group and 88 patients in the no AH group. There was no difference in the incidence of refractory anaphylaxis between groups (0% vs 9%; p=0.48). Significantly fewer patients in the AH group required any epinephrine doses compared to the no AH group (38% vs 88%; p<0.001). Outpatient use of select AH medications was not associated with an increased incidence of refractory anaphylaxis in patients presenting to the ED.

Peach extract induces systemic and local immune responses in an experimental food allergy model

Peach allergy is among the most frequent food allergies in the Mediterranean area, often eliciting severe anaphylactic reactions in patients. Due to the risk of severe symptoms, studies in humans are limited, leading to a lack of therapeutic options. This study aimed to develop a peach allergy mouse model as a tool to better understand the pathomechanism and to allow preclinical investigations on the development of optimized strategies for immunotherapy. CBA/J mice were sensitized intraperitoneally with peach extract or PBS, using alum as adjuvant. Afterwards, extract was administered intragastrically to involve the intestinal tract. Allergen provocation was performed via intraperitoneal injection of extract, measuring drop of body temperature as main read out of anaphylaxis. The model induced allergy-related symptoms in mice, including decrease of body temperature. Antibody levels in serum and intestinal homogenates revealed a Th2 response with increased levels of mMCPT-1, peach- and Pru p 3-specific IgE, IgG1 and IgG2a as well as increased levels of IL-4 and IL-13. FACS analysis of small intestine lamina propria revealed increased amounts of T cells, neutrophils and DCs in peach allergic mice. These data suggest the successful establishment of a peach allergy mouse model, inducing systemic as well as local gastrointestinal reactions.

Effect of Remifentanil vs Neuromuscular Blockers During Rapid Sequence Intubation on Successful Intubation Without Major Complications Among Patients at Risk of Aspiration

It is uncertain whether a rapid-onset opioid is noninferior to a rapid-onset neuromuscular blocker during rapid sequence intubation when used in conjunction with a hypnotic agent. To determine whether remifentanil is noninferior to rapid-onset neuromuscular blockers for rapid sequence intubation. Multicenter, randomized, open-label, noninferiority trial among 1150 adults at risk of aspiration (fasting for <6 hours, bowel occlusion, recent trauma, or severe gastroesophageal reflux) who underwent tracheal intubation in the operating room at 15 hospitals in France from October 2019 to April 2021. Follow-up was completed on May 15, 2021. Patients were randomized to receive neuromuscular blockers (1 mg/kg of succinylcholine or rocuronium; n = 575) or remifentanil (3 to 4 μg/kg; n = 575) immediately after injection of a hypnotic. The primary outcome was assessed in all randomized patients (as-randomized population) and in all eligible patients who received assigned treatment (per-protocol population). The primary outcome was successful tracheal intubation on the first attempt without major complications, defined as lung aspiration of digestive content, oxygen desaturation, major hemodynamic instability, sustained arrhythmia, cardiac arrest, and severe anaphylactic reaction. The prespecified noninferiority margin was 7.0%. Among 1150 randomized patients (mean age, 50.7 [SD, 17.4] years; 573 [50%] women), 1130 (98.3%) completed the trial. In the as-randomized population, tracheal intubation on the first attempt without major complications occurred in 374 of 575 patients (66.1%) in the remifentanil group and 408 of 575 (71.6%) in the neuromuscular blocker group (between-group difference adjusted for randomization strata and center, -6.1%; 95% CI, -11.6% to -0.5%; P = .37 for noninferiority), demonstrating inferiority. In the per-protocol population, 374 of 565 patients (66.2%) in the remifentanil group and 403 of 565 (71.3%) in the neuromuscular blocker group had successful intubation without major complications (adjusted difference, -5.7%; 2-sided 95% CI, -11.3% to -0.1%; P = .32 for noninferiority). An adverse event of hemodynamic instability was recorded in 19 of 575 patients (3.3%) with remifentanil and 3 of 575 (0.5%) with neuromuscular blockers (adjusted difference, 2.8%; 95% CI, 1.2%-4.4%). Among adults at risk of aspiration during rapid sequence intubation in the operating room, remifentanil, compared with neuromuscular blockers, did not meet the criterion for noninferiority with regard to successful intubation on first attempt without major complications. Although remifentanil was statistically inferior to neuromuscular blockers, the wide confidence interval around the effect estimate remains compatible with noninferiority and limits conclusions about the clinical relevance of the difference. ClinicalTrials.gov Identifier: NCT03960801.

Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade >I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2weeks after the sting, the tests shall be repeated (at least 4-6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of β-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5-6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200µg to a maximum of 400µg in adults, maximum of 200µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3-5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.

Multimodal In Vivo Tracking of Chimeric Antigen Receptor T Cells in Preclinical Glioblastoma Models.

Iron oxide nanoparticles have been used to track the accumulation of chimeric antigen receptor (CAR) T cells with magnetic resonance imaging (MRI). However, the only nanoparticle available for clinical applications to date, ferumoxytol, has caused rare but severe anaphylactic reactions. MegaPro nanoparticles (MegaPro-NPs) provide an improved safety profile. We evaluated whether MegaPro-NPs can be applied for in vivo tracking of CAR T cells in a mouse model of glioblastoma multiforme. We labeled tumor-targeted CD70CAR (8R-70CAR) T cells and non-tumor-targeted controls with MegaPro-NPs, followed by inductively coupled plasma optical emission spectroscopy, Prussian blue staining, and cell viability assays. Next, we treated 42 NRG mice bearing U87-MG/eGFP-fLuc glioblastoma multiforme xenografts with MegaPro-NP-labeled/unlabeled CAR T cells or labeled untargeted T cells and performed serial MRI, magnetic particle imaging, and histology studies. The Kruskal-Wallis test was conducted to evaluate overall group differences, and the Mann-Whitney U test was applied to compare the pairs of groups. MegaPro-NP-labeled CAR T cells demonstrated significantly increased iron uptake compared with unlabeled controls ( P < 0.01). Cell viability, activation, and exhaustion markers were not significantly different between the 2 groups ( P > 0.05). In vivo, tumor T2* relaxation times were significantly lower after treatment with MegaPro-NP-labeled CAR T cells compared with untargeted T cells ( P < 0.01). There is no significant difference in tumor growth inhibition between mice injected with labeled and unlabeled CAR T cells. MegaPro-NPs can be used for in vivo tracking of CAR T cells. Because MegaPro-NPs recently completed phase II clinical trial investigation as an MRI contrast agent, MegaPro-NP is expected to be applied to track CAR T cells in cancer immunotherapy trials in the near future.