The high prevalence of allergic diseases reached over the last years is attributed to the complex interplay of genetic factors, lifestyle changes, and environmental exposome. Allergen-specific immunotherapy (AIT) is the single therapeutic strategy for allergic diseases with the potential capacity to modify the course of the disease. Our knowledge of the mechanisms involved in allergy and successful AIT has significantly improved. Recent findings indicate that long-term allergen tolerance upon AIT discontinuation not only relies on the generation of proper adaptive immune responses by the generation of allergen-specific regulatory T and B cells enabling the induction of different isotypes of blocking antibodies but also relies on the restoration of proper innate immune responses. Trained immunity (TRIM) is the process by which innate immune cells acquire memory by mechanisms depending on metabolic and epigenetic reprogramming, thus conferring the host with increased broad protection against infection. This concept was initially explored for infectious diseases, as well as for vaccination against infections, but compelling experimental evidence suggests that TRIM might also play a role in allergy and AIT. Hyperinflammatory innate immune responses in early life, likely due to TRIM maladaptations, lead to aberrant type 2 inflammation-enhancing allergy. However, exposure to farming environments and specific microbes prevents recurrent infections and allergy development, likely due to mechanisms partially depending on TRIM. TRIM-based vaccines and next generation AIT vaccines inducing metabolic and epigenetic reprogramming in innate immune cells and their precursors have shown protective antiallergic effects. A better understanding of the factors involved in early-life TRIM mechanisms in the context of allergy and the identification and characterization of novel tolerance inducers might well enable the design of alternative TRIM-based allergen vaccines for allergic diseases.

Remission is the desired outcome following OIT as it allows individuals to discontinue treatment and eat the allergen freely. Early initiation of OIT in infants and toddlers has been embraced as an approach to increase the likelihood of remission. However, there is no high-quality evidence supporting younger age as an independent factor driving remission; available studies are limited by small samples of younger subjects and lack of adjustment for confounding covariates, particularly peanut-specific IgE (sIgE) levels which is closely correlated with age.

This study examined relationships between peanut sIgE and age at baseline and remission, in children aged 1-10 who completed 18 months of OIT in the PPOIT-003 RCT (n = 162). Remission was defined as absence of clinical reactivity to peanut after 8 weeks of allergen avoidance/treatment discontinuation. Age and sIgE were examined as continuous variables in univariate and multivariate regression models.

Higher peanut sIgE was consistently predictive of lower likelihood of remission, independent of age. In contrast, there was no independent association between age and remission after adjusting for baseline sIgE (OR 0.94 [0.79-1.12], p = 0.5).

Findings do not support age as an independent predictor of remission following OIT. Additional studies examining safety and efficacy of OIT in infants and younger children are urgently needed, ahead of widespread adoption of early intervention.

Peanut allergy is a common, life-threatening food allergy in children. We evaluated whether dupilumab, which blocks the activity of interleukin (IL)-4/IL-13, enhances the efficacy of oral immunotherapy (OIT) AR101 in pediatric patients with peanut allergy.

A Phase II, multicenter, randomized, double blind study was conducted in the USA (NCT03682770) in pediatric patients (6-≤ 17 years old) with confirmed peanut allergy. Patients were randomized 2:1 to receive dupilumab + OIT or placebo + OIT during a 28-40-week up-dosing period. Patients in the dupilumab + OIT group were re randomized 1:1 and received dupilumab + OIT or placebo + OIT during 24-week OIT maintenance, undergoing a 2044 mg (cumulative) of peanut protein double-blind, placebo-controlled food challenge (DBPCFC) following up-dosing, maintenance, and at 12-week post-treatment follow-up.

The study enrolled 148 patients, 123 of whom were included in the modified full analysis set, with a mean age of 11.1 years. Dupilumab + OIT treatment (n = 84) led to a 20.2% increase (p < 0.05) in the number of patients who passed a DBPCFC to 2044 mg (cumulative) of peanut protein following the up-dosing period versus placebo (OIT alone, n = 39). Following the OIT maintenance period, continuous dupilumab treatment improved the number of patients who passed a DBPCFC to 2044 mg (cumulative) of peanut protein versus patients continuously on OIT alone (16.6% difference [95% CI -9.7, 42.8], p = 0.2123). Safety was consistent with known dupilumab safety profile.

Dupilumab provided a modest increase efficacy of OIT in children and adolescents with peanut allergy, though it did not provide protection against OIT-related anaphylaxis.

Several major sensitization profiles have been described in children with asthma, but it remains unclear how these profiles relate to asthma phenotypes. The aim of this study was to determine allergenic sensitization profiles in a megacity cohort (SAMP).

This was a cross-sectional analysis performed from 2011 to 2015 including preschool and school-age children with severe and moderate asthma from the SAMP cohort. We performed ALEX multiplex array and carried out cluster analysis.

Data from 367 children were analyzed: 224 of preschool age and 143 of school age, respectively 84 (38%) and 114 (80%) presented at least one allergic sensitization. At preschool age, three clusters were identified: Cluster 1, Few sensitizations to inhaled allergen molecular families and nontype 2 (T2) inflammation (n = 61); Cluster 2, Predominant sensitization to HDM molecular families (n = 16); Cluster 3, Severe asthma with multiple sensitizations to inhaled and food allergen molecular families (n = 7). At school age, five clusters were identified: Cluster 1, Few sensitizations to inhaled allergen molecular families and non-T2 inflammation (n = 43); Cluster 2, Predominant sensitization to HDM molecular families (n = 31); Cluster 3, Predominant sensitization to PR-10 protein family (n = 25); Cluster 4, Severe asthma with predominant sensitization to tropomyosin family (n = 11); Cluster 5, Severe asthma with multiple sensitizations to inhaled and food allergen molecular families (n = 4).

These results underline the heterogeneity of sensitization profiles in severe allergic childhood asthma. The most severe asthma phenotypes were associated with multiple sensitizations to both inhaled and food allergen molecular families as expected, and to the tropomyosin molecular family, a novel finding.

Allergen-specific immunotherapy (AIT) is so far the only disease-modifying therapy for allergy, resulting in a long lasting tolerance. However, the existing safety concerns and the need for more efficacious alternatives that shorten the duration of treatment have stimulated research into the development of novel alternatives. Some of these novel alternatives involve modifying allergens with molecules that target innate immunomodulatory receptors to suppress the immune activity of immune cells.

Freshly prepared monocyte-derived dendritic cells (moDCs) from mite-allergic and non-atopic volunteers were treated with α2-3 sialic acidconjugated recombinant Der p 2 ((sia)-Der p 2) and unconjugated Der p 2 in culture and matured with Toll-like receptor (TLR) 1/2 (Pam3CSK4) (Pam3) and 2/4 (lipopolysaccharide) (LPS) agonists, followed by co-culture with autologous CD4+ T cells. Secretion of cytokines in supernatants were measured by ELISA and expression of cell surface and intracellular markers was measured by flow cytometry.

Sia-Der p 2 unlike Der p 2, modulated moDCs from mite-allergic volunteers by reducing expression of CD83 and CXCR5. We also observed that sia-Der p 2-treated moDCs in the presence of Pam3 and LPS significantly suppressed the proportion of CD25+, Ki67+, IL-13+ and IFN-y+ CD4+ T cells of mite-allergic volunteers while Der p 2-treated moDCs did not. Sia-Der p 2-treated moDC did not alter these CD4+ T cell populations in non-atopic volunteers.

Our data suggests that Der p 2 conjugated with α2-3 sialic acids modifies moDCs and promotes the differentiation of allergen specific CD4+ T cells towards a regulatory profile.

Allergen-specific immunotherapy (AIT) is a disease modifying therapy and is effective to reduce the symptoms of grass pollen-allergy. The airway epithelium of these patients releases inflammatory mediators including type-2 cytokines, which are associated with cellular processes involved in the symptomatic response of the affected tissue. Aim of the study was to identify epithelial biomarkers indicating AIT progress.

In an exploratory, observational allergy cohort, we longitudinally phenotyped 56 grass pollen-allergic patients undergoing AIT for over three years and 18 controls using nasal secretions at critical time windows during therapy to assess peak-season responses along the course of therapy. Type-2 cytokine protein levels were analyzed using the high-sensitivity multiplex electrochemiluminescence mesoscale technique.

The type-2 cytokines CCL26 and POSTN oscillated seasonally, in contrast to TSLP and IL-33. However, only POSTN was reduced over the three-year AIT progression. In addition to POSTN, IL-24 and IL-37 levels were continuously reduced during AIT, while IFN-g and CCL27 were increased. Compared to healthy individuals, AIT did not restore healthy secretion levels but rather induced a novel homeostasis.

Nasal secretions trace the epithelial response during different phases of AIT. We demonstrate that AIT only partially controls the epithelial type 2 cytokine CCL26, which also adapts to seasonal changes, while POSTN and IL-24 are potential indicators of therapy success. Therefore, nasal secretions represent a promising, non-invasive tool for monitoring seasonal progress of AIT.

The milk ladder (ML) approach, which is the gradual reintroduction of the milk allergen from the least allergenic forms to the most allergenic forms into the diet of the patients, has been utilized mostly in non IgE-mediated but in some countries also in IgE-mediated CMPA due to its possible benefits which include nutrition, quality of life and tolerance induction. Despite increasing interest, so far, there is no guideline on ML; thus, the use of this approach shows discrepancies among healthcare professionals as many factors such as dietary habits, patient history, test results, workload, and facilities of the hospitals, the anxiety of the parents/patients may affect the decision on how, when, where and whom to use ML. Here, we reviewed current data on implementing the ML, suggested a 4-step ML including receipts and amounts, and shared our experience on optimal patient selection, appropriate time and steps for initiating ML, and time intervals between the steps targeting the lowest risk of reaction. We also added the newly developed twice-baked biscotti cake to the ML. We presented the analyses of this product, showing its low allergenicity compared to conventional cake, which provides a safer introduction of milk into the diet.

Efficacy of allergen immunotherapy is dose dependent; however, high doses of allergen may imply a greater risk of adverse reactions.

To assess the safety and tolerability of subcutaneous immunotherapy (SCIT) with mixtures of mite allergen extracts, Dermatophagoides pteronyssinus/Blomia tropicalis (Dpt/Bt) and Dermatophagoides pteronyssinus/Lepidoglyphus destructor (Dpt/Ld) at maximum concentrations, in adult patients with allergic rhinitis or rhinoconjunctivitis, and controlled allergic asthma due to a clinically relevant sensitisation to these mites.

An open-label, noncontrolled, nonrandomised, phase IIb clinical trial was carried out in three hospitals in Spain between September 2014 and May 2018. Patients received SCIT of either Dpt/Bt (100/1000 DPP/mL) or Dpt/Ld (100/100 DPP/mL) in two phases: a rush build-up phase on the first day (0.2 mL and 0.3 mL with a 30-min interval) and a monthly maintenance phase administration (0.5 mL) up to 48 months.

Forty patients were recruited for the study, seven allocated to the Dpt/Bt group and 33 to the Dpt/Ld. None experienced immediate or delayed systemic Grade ≥ 2 reactions (EAACI classification) (systemic reactions were mostly Grade 1) nor died during the study. Local reactions were mostly mild (0‒10 cm). Thirty-nine patients (97.5%) experienced at least one adverse event (AE). Of the 283 reported AEs, eight (2.8%) were systemic reactions experienced by six (15%) subjects and 14 (4.9%) were local reactions sustained by ten (25%) subjects.

SCIT treatment of patients with allergic rhinitis or rhinoconjunctivitis and controlled asthma with mixtures of Dpt/Bt and Dpt/Ld allergen extracts at maximum concentrations showed a favourable safety profile.

From a taxonomic point of view, Hymenoptera are subclassified into families: Apidae, including honeybees (Apis mellifera) and bumblebees (Bombus), and Vespidae, which, in turn, are divided into the subfamilies of Vespinae (wasps, including hornets, vespules, dolichovespules) and Polistinae (paper wasp). Hypersensitivity to Hymenoptera venom can be linked to immunological (IgE-mediated or non-IgE mediated) and non-immunological mechanisms. Reactions are classified into local reactions, large local reactions, systemic reactions, toxic reactions, and unusual reactions. In general, children sensitize less frequently and have less severe reactions than adults, probably due to less exposure to repeated stings and fewer comorbidities. There are risk factors for systemic reactions that should be discussed with patients and their parents as appropriate. A correct diagnosis of Hymenoptera venom allergy relies on a careful clinical history and the appropriate use of skin and in vitro tests. The in vitro tests include serum specific IgE toward venom extracts and toward allergenic molecules. In complex diagnoses, CAP-inhibition and the Basophil Activation Test can also be used. In the presence of a systemic reaction, the basal serum tryptase measurement should be performed to rule out mastocytosis. In case of allergic reactions to Hymenoptera stings, in the acute phase, according to the current guidelines, the treatment of signs and symptoms mainly includes the use of adrenaline as first-line treatment in case of anaphylaxis and antihistamines and corticosteroids as subsequent lines of treatment. Given the impossibility of avoiding a new sting with certainty, the treatment of choice in subjects with hypersensitivity to Hymenoptera venom who have experienced systemic reactions is based on venom immunotherapy (VIT), with the venom of the responsible stinging insect identified after an adequate allergological work-up. VIT is performed in a suitable environment and has proved to be safe and effective with various administration protocols, both accelerated and conventional. The prevention of Hymenoptera venom anaphylaxis in patients who have already developed a previous episode is crucial and must be supported by environmental protection interventions and early therapy. Places where one is more likely to encounter insects and risky behaviors should be avoided.

Food allergy is a common disease which has substantial impacts on the quality of life of patients and their families, and all reactions have the potential for causing life-threatening anaphylaxis. Food allergic individuals currently have 2 FDA approved therapeutic options available to them aside from lifelong allergen avoidance: oral immunotherapy (OIT), and omalizumab. OIT for food allergy has been extensively studied in clinical trials and currently provides the greatest level of protection, however it also has a high burden of treatment. Studies suggest that more successful OIT outcomes may be attained with earlier intervention; however, early OIT presents its own challenges. Omalizumab, recently FDA approved, is a biologic targeting immunoglobulin E, a major driver of allergic reactions. In contrast to OIT, omalizumab monotherapy offers a low treatment burden therapeutic option that provides a safety net against reactions to accidental ingestion to multiple allergens. Additionally, omalizumab has also been investigated as an adjunct to OIT, improving the speed and safety of single or multi allergen OIT. Here we discuss the clinical use of these therapeutic options and provide a guide for shared decision-making between patients and physicians about what therapeutic option might be more appropriate.