Allergic rhinitis/rhinoconjunctivitis(AR/C) induced by house dust mites (HDM) often begins in childhood and negatively impacts a child's quality of life. The daily burden can be further compounded by comorbid asthma. Allergen immunotherapy is the only available treatment targeting the underlying cause of allergic disease. Efficacy and safety of the SQ HDM sublingual immunotherapy (SLIT)-tablet has been demonstrated in adults and adolescents with HDM AR/C with or without asthma, but data are lacking for younger children.

Phase III, randomised, double-blind, placebo-controlled trial in younger children (5-11 years) with HDM AR/C with or without asthma. Eligible subjects were randomised1:1 to SQ HDM SLIT-tablet or placebo for ∼1 year and had free access to AR/C symptom-relieving medications. The primary outcome was the total combined rhinitis score (TCRS) during the final 8 weeks of the treatment period (∼1 year). Secondary outcomes included the rhinitis daily symptom score (DSS) and medication score (DMS), the rhinoconjunctivitistotal combined score (TCS), and the PaediatricRhinoconjunctivitisQuality of Life Questionnaire (PRQLQ) score. Efficacy analyses were conducted on the full analysis set (observed cases). Asthma-related outcomes were also explored. The trial was registered on ClinicalTrials.gov:NCT04145219and EudraCT: 2019-000560-22.

A total of 1460 subjects were randomisedto SQ HDM SLIT-tablet (n = 729) or placebo (n = 731). The primary outcome, TCRS, was statistically significantly different for SQ HDM SLIT-tablet (n = 693) versus placebo (n = 706), with an absolute difference of 1.0 (95% CI: 0.5, 1.4; p < 0.0001) corresponding to a relative reduction of 22.0% (95% CI: 12.0, 31.1). Key secondary outcomes (DSS, DMS, TCS, PRQLQ) showed statistically significant reductions in symptoms and medication use, and improved disease-related quality of life for SQ HDM SLIT-tablet versus placebo. Improvements in asthma symptoms and reduced asthma medication use indicated an additional effect of SQ HDM-SLIT tablet versus placebo. The SQ HDM SLIT-tablet showed a higher event rate for treatment-related adverse events (AEs) than placebo. Most events were of mild or moderate severity and few subjects discontinued due to AEs (2.5%).

The trial confirmed the efficacy and safety of the SQ HDM SLIT-tablet for treating HDM AR/C in younger children (5-11 years) with or without asthma. The safety profile supports daily self-administration of the SQ HDM SLIT-tablet in children.

Peanut allergy (PA) is one of the most prevalent food allergies with a lack of favorable safety/efficacy treatment. A cucumber mosaic virus-like particle expressing peanut allergen component Ara h 2 (VLP Peanut) has been developed as a novel therapeutic approach for PA.

We assessed the tolerogenic properties and reactivity of VLP Peanut.

Whole blood and peripheral blood mononuclear cells were collected from 6 peanut-allergic children. Modulation of dendritic cells(DCs), T cells, and B cells, stimulated with VLP Peanut, Ara h 2, and whole peanut extract in vitro, were assessed by quantitative real-time PCR and flow cytometry, respectively. Basophil and skin reactivity in response to VLP Peanut was assessed by basophil activation test and skin prick test, respectively.

VLP Peanut showed beneficial biochemical properties, fit for use in clinical studies. VLP Peanut induced IFN-γ+TH1 (P < .05) while having reduced capacity to elicit proliferation of TH2, allergen-specific TH2, and IL-4+-T follicular helper cells. Moreover, VLP Peanut is associated with upregulation of DC1-associated genes (MX1) compared to Ara h 2 and whole peanut extract. VLP Peanut was the most prominent at inducing IL-10+regulatory B cells (P < .05). Unbiased clustering analyses identified metaclustersof T and B cells targeted by VLP Peanut. Finally, VLP Peanut had reduced capacity to elicit high-and low-affinity IgEreceptor-mediated responses compared to Ara h 2 or whole peanut extract (all P < .05). Finally, in an open-label first-in-humancohort of 6 peanut-allergic adults, administration of increasing concentration of VLP Peanut through skin prick test was tolerated and demonstrated no development of skin reactivity.

VLP Peanut displayed tolerogenic properties by modulating DCs, T cells, and B cells in vitro. Preliminary findings of skin reactivity using VLP Peanut in 6 peanut-allergic adults was safe and well tolerated in an open-label phase 1 study. Clinical trial identifier:PROTECT,NCT05476497.

Oral Mucosal Immunotherapy (OMIT) uses a specifically formulated toothpaste to deliver allergenic proteins to immunologicallyactive areas of the oral cavity. This represents a new delivery mechanism with several features designed to improve food allergy desensitization. OMIT presents advantages over other approaches to allergy immunotherapy due to its targeted delivery and simplified administration.

To determine the safety, tolerability, and adherence of OMIT with INT301 in peanut allergic adults.

This Oral Mucosal Escalation Goal Assessment (OMEGA) study enrolled 32 adults, age 18-55, with peanut allergy in a 3:1 ratio to receive either an escalating dose of INT301 or placebo. Entry criteria included a positive SPT with a wheal diameter ≥ 3mm greater than controland/or psIgE≥ 0.35 kU/L. Subjects were required to fail an oral food challenge ≤ 100 mg dose of peanut protein. Safety and tolerability were monitored during this 48-week trial.

100% of active subjects tolerated the pre-specified protocol highest dose. No moderate nor severe systemic reactions occurred inactive participants. Non-systemic adverse reactions were mostly local (oral and nasal cavity), mild and transient. Active subjects adhered to treatment 97% of days on study, with no withdrawals due to study medication.

In the OMEGA trial, INT301 met all primary and secondary endpoints of safety, tolerability, and adherence. OMIT appears to bea safe and convenient option for individuals with food allergies. These results support its further evaluation in the pediatric population

Allergic diseases are common clinical diseases. Although allergen-specific immunotherapy (AIT) and biologics have been widely recognized, the clinical efficacy, safety, advantages and disadvantages of the combined application have not yet been sufficiently recognized. We aimed to investigate the efficacy and safety of AIT combined with biologics in patients with allergic rhinitis and asthma.

PubMed, EMBASE, the Cochrane Library, and Web of Science were systematically searched to identify RCTs investigatingAIT combined with biologics for treating allergic rhinitis and asthma. The relevant outcome indicators, including incidences of emergency drugsuse, severe nasal symptoms, severe adverse effects (AEs), local reactions at the site of administration, headache, and general AEs, were collected and extracted. Routine and network meta-analyses were conducted using RevMan-5.4 and STATA-MP-14 to assess efficacy and safety.

Eight RCTs and a retrospective study involving 1494 patients aged 5 to 65 years with allergic rhinitis and asthma were included in this review. ①Routine meta-analysis revealed that AIT combined with biologics was significantly better than control treatment (placebo, AIT orbiologics) in terms of the incidence of emergency drugs use, severe nasal symptoms, and severe AEs (P=0.0002; P=0.01; P=0.02). However, the differences in the incidence of local reactions at the site of administration, headache and general AEs were not significant. ②In the network meta-analysis, compared with AIT or placebo alone, AIT combined with biologics observably reduced the incidence of emergency drugs use and severe nasal symptoms (OR=0.32, 95% CI 0.14-0.73; OR=0.41, 95% CI 0.26-0.63). Furthermore, AIT combined with biologics yielded an evidently lower incidence of serious adverse reactions than AIT alone (OR=0.42, 95% CI 0.23-0.74).

The combined application of AIT and biologics has promising prospects in the clinical treatment of allergic rhinitisand asthma due to the improvement of both clinical efficacy and safety. Trial registration: SYSTEMATIC REVIEW REGISTRATION (PROSPERO #CRD42024496277)

Allergic patients are characterized by complex and patient-specific IgEsensitization profiles to various allergens, which are accompanied by different phenotypes of allergic disease. Molecular allergy (MA) diagnosis establishes the patient's IgEreactivity profile at a molecular allergen level and has moved allergology into the "Precision Medicine" era. Molecular allergology started in the late 1980s with the isolation of the first allergen-encoding DNA sequences. Already in 2002, the first allergen microarrays were developed for the assessment of complex IgEsensitization patterns. Recombinant allergens are used for a precise definition of personal IgEreactivity profiles, identification of genuine IgEsensitization to allergen sources for refined prescription of allergen-specific immunotherapy and allergen avoidance diagnosis of co-versus cross-sensitization, epidemiological studies and prediction of symptoms, phenotypes, and development allergic disease. For example, molecular IgEsensitization patterns associated with more severe respiratory allergies, severe food allergy and allergy to honeybee or vespids are already established. The implementation of MA diagnosis into daily clinical practice requirescontinuous medical education, training of doctors in MA diagnosis and may be facilitated by clinical decision support systems such as diagnosticalgorithms which may take advantage of artificial intelligence (AI).

Data on oral immunotherapy (OIT) for hazelnut allergy is limited and its potential to cross-desensitize for other nuts is unknown.

To study the efficacy and safety of hazelnut OIT in desensitizing hazelnut and additional tree nuts.

A prospective observational study of 30 hazelnut allergic patients aged ≥4 years who underwent hazelnut OIT. Full desensitization (4000 mg protein) rates were compared to 14 observational controls, and immunological changes during OIT were measured. Cross-desensitization was determined in cases of walnut and cashew co-allergy (n=12). Inhibition of IgEbinding to walnut by hazelnut was evaluated in a separate set of walnut-hazelnut dual allergic patients, by ELISA.

The rate of full hazelnut desensitization following OIT was 96.7% (29/30) compared to 14.3% (2/14) in controls (OR=25.7, 95% CI 3.7-178.7, p<0.001). Five patients (16.7%) were treated with injectable epinephrine for home reactions. Hazelnut SPT and sIgEto hazelnut and its main components, Cora 9, 14 and 16, decreased while sIgG4 increased during OIT. A maintenance dose of 1200 mg hazelnut protein was sufficient to maintain full desensitization. No cross-desensitization was noted in dual hazelnut-cashew allergic patients (n=6). In dual hazelnut-walnut allergic patients, an increase in the walnut eliciting dose was observed in 2/6 (33.2%) patients (to 1200 and 4200 mg, respectively). Similarly, by cross-inhibition ELISA, hazelnut competed for IgE-binding to walnut in 5/25 (20%) hazelnut-walnut co-allergic patients.

Hazelnut OIT is highly effective, with a similar safety profile as OIT to other nuts. Cross-desensitization to walnut and cashewis unlikely. 6

There is ongoing debate about the safety and efficacy of epicutaneous immunotherapy (EPIT) in treating food allergies. The systematic review and meta-analysis aimed to evaluate the safety and efficacy of EPIT.

We systematically searched international trial registers (ClinicalTrials.gov), PubMed, Embase, the Cochrane Central of Controlled Trials (CENTRAL), and Web of Science from the inception of the database until June 25, 2023. Two authors independently screened potential studies based on the following criteria: food allergy, epidermal immunotherapy, and randomized controlled trials(RCTs). The risk-of-bias assessment was performed using the Cochrane risk-of-bias 2 (ROB 2) tool. The primary outcomes included desensitization, local adverse events, systemic adverse events, and quality of life. Secondary outcomes included epinephrine utilization, topical medication utilization, and severe adverse events. We assessed certainty of evidence by the GRADE approach.

Ten studies involving 1970 participants were included. Ten high-quality RCTs focusing on peanut allergy and cow's milk allergy were included in the analysis. The meta-analysis revealed that EPIT promoted desensitization in patients with food allergy (RR 2.11, 95% CI 1.72-2.58; I2= 0%, high certainty), particularly in aged ≤ 11 years (RR 3.84, 95% CI 2.39-6.26; I2= 34%). Additionally, treatment duration ≥ 52 weeks was found to increase immune tolerance (RR 3.37, 95% CI 2.39-4.75; I2= 13%). Patients who undergo EPIT treatment not only raised the local adverse reactions (RR 1.63, 95% CI 1.10-2.41; I2= 82%, low certainty) but also raised systemic adverse reactions (RR 1.52, 95% CI 1.01-2.28; I2= 0%, high certainty).

After EPIT treatment, patients with food allergy can effectively increase their immune tolerance to food. However, it also significantly increases mild-to-moderate anaphylaxis. There is limited data on the impact of EPIT on quality of life and other food allergic diseases, indicating a need for further research.

The role of memory B cells and their subgroups in allergic rhinitis (AR) and allergen immunotherapy (AIT) remains unclear. This study aimed to investigate the characteristics of memory B cells in the circulation of patients with AR and those undergoing AIT, as wellastheir clinical significance.

This study involved a cohort comprising 32 healthy control subjects, 39 individuals diagnosed with AR, and 31 AR patients whohad received AIT for over one year. Visual analog scale (VAS) scores were used for symptom assessment, and the serum concentrations of immunoglobulins and cytokines were quantified. This study evaluated alterations in the proportions of peripheral blood memory B cells and their subpopulations, plasma cells, and various T-cell subsets across the three participant groups.

The proportion of IgA+CD27-class-switched memory B cells in the AR group significantly decreased compared to the control group,but significantly increased following AIT (P < 0.05). In AR patients, circulating IgA+CD27-class-switched memory B cells were significantly positively correlated with Treg cells, IL-10, and IL-4 and significantly negatively correlated with IFN-γ, total IgE, sIgE, and VAS scores (P < 0.05). After AIT, the number of circulating IgA+CD27-class-switched memory B cells in AR patients was significantly positively correlated with the number of Treg cells and IL-10 and significantly negatively correlated with the VAS score (P < 0.05).

The IgA+CD27-class-switched memory cell subset in human peripheral blood may serve as a potential biomarker for evaluating AR symptoms and treatment efficacy. Its mechanism may be associated with interactions between T and B cells.

Oral immunotherapy (OIT) for food allergy has been largely studied in older children within the context of clinical trials, and its availability has historically been limited for younger patients with food allergy. Data have shown that the most impact may actually be seen with the use of OIT in younger infants and toddlers.

To evaluate the safety and feasibility of OIT in subjects 24 months and younger in a real-world setting using commercially available food products.

This was a retrospective study of subjects 24 months and younger initiated on OIT for peanut, tree nut, or sesame allergy withinthe Scripps Clinic allergy department. Medical records were reviewed for data regarding initial oral food challenges, OIT, and adverse outcomes.

Fifty-two subjects 24 months and younger were initiated on OIT. Most subjects (84.6%) were on single-food OIT, and some (15.4%) were on multifoodOIT. No increased adverse outcomes were observed on multifoodOIT. Of the 59 initial oral food challenges, objective reactions occurred during 42 challenges, most being low-grade reactions. During initial oral food challenges, 86.1% of peanut-allergic children tolerated 1/8 of 1 Bamba stick with no reaction. Most subjects (73.1%) updosedat home, and most (51.9%) had no reactions while updosing. Some had low-grade cutaneous reactions, none requiring epinephrine or emergency evaluation.

OIT in infants is safe and feasible to perform in a real-world setting using commercially available food products with at-home updosing, thus increasing the availability of OIT for patients.

Venom-allergic patients are frequently double-sensitized to honeybee venom (BV) and Vespula venom (VV). Genuine double allergy is uncommon.

To assess whether a quantitative comparison of BV-and VV-specific IgElevels permits an identification of the culprit venom in double-sensitized patients, and to evaluate whether independent sensitization to BV-and VV-specific components corresponds to an indication for double immunotherapy.

This single-center observational study evaluated 1,069 consecutive patients; 490 nonallergic controls were available for statistical comparison. The diagnosis (BV allergy, VV allergy, or double allergy) was based on a comprehensive allergologicalworkup including patient history, IgEserology, intradermal skin test, and, when required, basophil activation testing. Quantitative allergen-specific IgEto BV, VV, rApim 1, and rVesv 5 was retrospectively compared with the final diagnosis. The ratio of BV/VV-specific IgElevels was considered in double-sensitized venom-allergic patients.

Sensitization to whole-venom preparations and components was frequent in patients and asymptomatic controls, with higher specific IgElevels in the patient group. At least 5:1 dominance of the specific IgEto either BV or VV was documented in 239 of 459 double-sensitized venom-allergic patients (52.1%). Of these patients 232 (97.1%) received a diagnosis of monoallergyto only the venom to which they were dominantly sensitized.

Dominant specific IgEat a ratio of 5:1 indicates the culprit venom in double-sensitized allergic patients. Additional component-resolved diagnostic testing can be restricted to cases with double sensitization to whole venom at a ratio of less than 5:1. Double sensitization to rApim 1 and rVesv 5 per se does not justify double venom immunotherapy.