Allergic reactions to stings of Hymenoptera species may be severe and are potentially fatal deviations of the immunological response observed in healthy individuals. However, venom-specific immunotherapy (VIT) is an immunomodulatory approach able to cure venom allergy in the majority of affected patients. An appropriate therapeutic intervention and the efficacy of VIT not only depend on a conclusive diagnosis, but might also be influenced by the patient-specific manifestation of the disease. As with other diseases, it should be borne in mind that there are different endotypes and phenotypes of venom allergy, each of which require a patient-tailored disease management and treatment scheme. Reviewed here are different endotypes of sting reactions such as IgE-mediated allergy, asymptomatic sensitization or a simultaneous presence of venom allergy and mast cell disorders including particular considerations for diagnosis and therapy. Additionally, phenotypical manifestations of venom allergy, as e.g. differences in age of onset and disease severity, multiple sensitization or patients unsusceptible to therapy, are described. Moreover, biomarkers and diagnostic strategies that might reflect the immunological status of the patient and their value for therapeutic guidance are discussed. Taken together, the increasing knowledge of different disease manifestations in venom hypersensitivity and the growing availability of diagnostic tools open new options for the classification of venom allergy and, hence, for personalized medical approaches and precision medicine in Hymenoptera venom allergy.

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (TFH ) cells, rather than type 2 T-helper (TH 2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (TFR ) cells, a specialized subset of regulatory T (TREG ) cells resident in B-cell follicles, restricts TFH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5+ TFH cells, not CXCR5– conventional TH 2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5+ TFR cell deletion. Upregulation of TFH cell activities, including a skewing toward type 2 TFH (TFH 2) and IL-13 producing TFH (TFH 13) phenotypes, and defects in TFR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between TFH and TFR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of TFH and TFR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.

The rising global burden of allergic diseases, particularly in the pediatric population, is of serious concern. Ocular allergy is one of the most common ocular pathologies met in clinical practice. A large proportion of children and adolescents suffer from allergic eye diseases (AEDs), which affect their quality of life. The available treatments and surgical modalities have their limitations and side effects. Therefore, the development of novel and alternate strategies is the need of the hour and requires a timely review of currently available knowledge.

The current review covers the incidence and prevalence of AEDs, factors influencing occurrence and severity of AED (age, sex, socioeconomic status etc.), underlying mechanisms, role of allergy testing and immunotherapy in children, development of diagnostic markers and novel therapies including cells and molecules.

Understanding the demographics, clinical patterns and risk factors of AED can help formulate appropriate preventive and therapeutic strategies for the effective management of this common cause of ocular morbidity. The future therapeutics for AED seems to rely primarily on cells (mesenchymal stem cells, Tregs, mast cells), cell products, molecules with immunosuppressive potential and immunotherapy.

Allergen-specific immunotherapy is currently the only treatment with the potential to modify and prevent progression of allergic asthma in children. In clinical practice, it is available in two forms: subcutaneous immunotherapy and sublingual immunotherapy. Trials and meta-analyses showed both the safety and the short- and long-term benefits of allergen-specific immunotherapy in asthmatic children. However, its use and role in asthma remains controversial, since studies are largely heterogeneous. This is mainly due to the lack of consensus on the optimal primary outcome to be considered for clinical trials evaluating the efficacy of allergen-specific immunotherapy in asthma. Therefore, well-conducted researchis needed using standardized and validated tools to evaluate key outcomes in asthmatic children.

The recent approval of Palforzia for treatment of peanut allergy by the US Food and Drug Administration (USFDA) predicts that additional products for oral immunotherapy (OIT) are on the horizon. In this article, the authors review the legal framework by which the USFDA regulates products for OIT of food allergy and the clinical data that demonstrated that the safety and effectiveness profile of Palforzia supported approval and conclude with a discussion of oral food challenge (OFC) as a clinical endpoint to demonstrate safety and effectiveness of OIT products.

There is no effective therapy for milk allergy. The role of lactic acid bacteria (LAB) and probiotics in protection against allergy-related outcomes is still under investigation. The aim of the study was to evaluate the immunomodulative and therapeutic potential of yogurt drinks in cow’s milk allergy (CMA) management. We compared immunoreactivity of α-casein (α-CN), β-casein (β-CN), κ-casein (κ-CN), α-lactalbumin (α-LA), and β-lactoglobulin (β-LG) in 27 yogurt drinks fermented with different basic yogurt cultures, or yogurt cultures enriched with Lactobacillus plantarum and/or Bifidobacterium lactis strains, by competitive ELISA assay. Drinks with the lowest antigenic potential were used as allergoids for CMA therapy. BALB/c mice were sensitized via intraperitoneal injection of α-CN + β-LG mixture with aluminum adjuvant, and gavaged with increasing doses of selected low-immunogenic drinks (YM—basic, or YM-LB—enriched with L. plantarum and B. lactis) to induce tolerance. Milk- or phosphate-buffered saline (PBS)-dosed mice served as controls. Compared to milk, the immunoreactivity of proteins in drinks increased or decreased, depending on the bacterial sets applied for fermentation. Only a few sets acted synergistically in reducing immunoreactivity. The selected low-immunogenic drinks stimulated allergic mice for profiling Th2 to Th1 response and acquire tolerance, and the effect was greater with YM-LB drink, which during long-lasting interventional feeding strongly increased the secretion of regulatory cytokines, i.e., IL-10 and TGF-β, and IgA and decreased IL-4, IgE, and anti-(α-CN + β-LG) IgG1. The studies revealed variations in the potency of yogurt bacteria to change allergenicity of milk proteins and the need for their strict selection to obtain a safe product for allergy sufferers. The YM-LB drink with reduced antigenic potential may be a source of allergoids used in the immunotherapy of IgE mediated CMA, but further clinical or volunteer studies are required.

IgE-mediated food allergies are caused by adverse immunologic responses to food proteins. Allergic reactions may present locally in different tissues such as skin, gastrointestinal and respiratory tract and may result is systemic life-threatening reactions. During the last decades, the prevalence of food allergies has significantly increased throughout the world, and considerable efforts have been made to develop curative therapies. Food allergen immunotherapy is a promising therapeutic approach for food allergies that is based on the administration of increasing doses of culprit food extracts, or purified, and sometime modified food allergens. Different routes of administration for food allergen immunotherapy including oral, sublingual, epicutaneous and subcutaneous regimens are being evaluated. Although a wealth of data from clinical food allergen immunotherapy trials has been obtained, a lack of consistency in assessed clinical and immunological outcome measures presents a major hurdle for evaluating these new treatments. Coordinated efforts are needed to establish standardized outcome measures to be applied in food allergy immunotherapy studies, allowing for better harmonization of data and setting the standards for the future research. Several immunological parameters have been measured in food allergen immunotherapy, including allergen-specific immunoglobulin levels, basophil activation, cytokines, and other soluble biomarkers, T cell and B cell responses and skin prick tests. In this review we discuss different immunological parameters and assess their applicability as potential outcome measures for food allergen immunotherapy that may be included in such a standardized set of outcome measures.

Allergen-specific immunotherapy (AIT) has the potential to provide long-term protection against allergic diseases. However, efficacy of AIT is suboptimal, while application of high doses allergen has safety concerns. The use of adjuvants, like 1,25(OH)2VitD3 (VitD3), can improve efficacy of AIT. We have previously shown that low dose VitD3 can enhance suppression of airway inflammation, but not airway hyperresponsiveness in a grass pollen (GP)-subcutaneous immunotherapy (SCIT) mouse model of allergic asthma. We here aim to determine the optimal dose and formulation of VitD3 for the GP SCIT. GP-sensitized BALBc/ByJ mice received three SCIT injections of VitD3-GP (30, 100, and 300 ng or placebo). Separately, synthetic lipids, SAINT, was added to the VitD3-GP-SCIT formulation (300 nmol) and control groups. Subsequently, mice were challenged with intranasal GP, and airway hyperresponsiveness, GP-specific IgE, -IgG1, and -IgG2a, ear-swelling responses (ESR), eosinophils in broncho-alveolar lavage fluid and lung were measured. VitD3 supplementation of GP-SCIT dose-dependently induced significantly enhanced suppression of spIgE, inflammation and hyperresponsiveness, while neutralizing capacity was improved and ESR were reduced. Addition of VitD3 further decreased Th2 cytokine responses and innate cytokines to allergens in lung tissue by GP-SCIT. However, addition of synthetic lipids to the allergen/VitD3 mixes had no additional effect on VitD3-GP-SCIT. We find a clear, dose dependent effect of VitD3 on GP-SCIT-mediated suppression of allergic inflammation and airway hyperresponsiveness. In contrast, addition of synthetic lipids to the allergen/VitD3 mix had no therapeutic effect. These studies underscore the relevance of VitD3 as an adjuvant to improve clinical efficacy of SCIT treatment regimens.

Subcutaneous immunotherapy (SCIT) is the standard approach for treating patients with sensitizations to aeroallergens. However, immunotherapy can trigger severe systemic reactions if delivered inappropriately or to high risk patients. We sought to characterize and quantify SCIT systemic reactions requiring epinephrine administration during a 6-year period in a Canadian setting following the recommendations for components and dosages published in the 2010 Canadian Society of Allergy and Clinical Immunology (CSACI) Immunotherapy Manual.

A single centre retrospective chart review was performed for all patients with systemic reactions to subcutaneous immunotherapy requiring intramuscular epinephrine injection between January 2011 and October 2017. Each systemic reaction requiring epinephrine was reviewed for baseline patient characteristics, details of the reaction, and reaction severity. Research ethics approval was obtained through McMaster University.

28 of 380 patients experienced a systemic reaction requiring epinephrine administration, with an incidence rate of 1 per 1,047 injection visits (0.095%). 26 of the 28 reactions occurred within the mandatory 30-minute observation period post allergen immunotherapy. Of the 28 patients that experienced a systemic reaction to SCIT, 11 patients had asthma and 5 patients had a history of possible food allergy. All of the systemic reactions occurred during injections from vial number 4, and five patients reacted to their first shot of a re-ordered extract. 10 of the 28 patients required more than one intramuscular injection of epinephrine, and 20 of 28 patients were transferred to the hospital by ambulance.

This is the first Canadian study to review patients with systemic reactions to subcutaneous immunotherapy. Several best practice methods were employed throughout the study to optimize subcutaneous delivery of immunotherapy extract, and our recorded per injection incidence rate for systemic reactions was comparable or below the rate published in similar studies. The recommendations in the CSACI Immunotherapy Manual provide an approach to standardizing prescriptions for SCIT to maximize immunotherapy efficacy and reduce the risk of systemic reactions, though similar studies in larger multicenter settings are needed to confirm these observations. These observations provide important objective information to clinicians about the potential risks for systemic reactions in patients considering SCIT.

House dust mites (HDMs) are the allergenic sources most frequently involved in airway allergy. Nevertheless, not every sensitized patient develops respiratory symptoms upon exposure to HDM, and there is a clinical need to differentiate allergic asthmatics (AAs) from atopic non-allergic asthmatics with HDM sensitization. This differentiation sometimes requires in vivo provocations like the bronchial allergen challenge (BAC). Interestingly, recent data demonstrate that non-atopic patients with asthma can also develop positive BAC results. This novel phenotype has been termed local allergic asthma (LAA). The interest in identifying the allergic triggers of asthma resides in the possibility of administering allergen immunotherapy (AIT). AIT is a disease-modifying intervention, the clinical benefit of which persists after therapy discontinuation. Recently, new modalities of sublingual tablets of HDM immunotherapy registered as pharmaceutical products (HDM-SLIT tablets) have become commercially available. HDM-SLIT tablets have demonstrated a robust effect over critical asthma parameters (dose of inhaled corticosteroids, exacerbations, and safety), thus being recommended by international guidelines for patients with HDM-driven AA. In this review, we will summarize the current knowledge on the phenotype and endotype of HDM-driven AA, and LAA, address the difficulties for BAC implementation in the clinic, and discuss the effects of AIT in AA and LAA.