Respiratory allergies often begin in childhood and can progress over time, leading to increased disease burden. Allergen immunotherapy (AIT) is the only causal treatment for allergic respiratory diseases with disease-modifying potential. While randomised trials support its efficacy in controlling allergic rhinitis (AR) and asthma symptoms, long-term real-world data in children remain limited.

This paediatric study (n = 11,036) was conducted within the pre-defined framework of the REACT study, based on protocol-specified objectives. Children (< 18 years) with physician-diagnosed AR, with or without pre-existing asthma, were included. AIT-treated patients were matched 1:1 to non-AIT controls. Effectiveness was assessed over 9 years by comparing AR and asthma medication prescriptions, using a public database covering all reimbursable AIT products. Relative differences were calculated across the full observation period.

AIT-treated children (mean age 11.4 years; 62.1% male) exhibited greater reductions in AR medication use than controls (additional 9% reduction beyond 61% in controls). In children with asthma, AIT was associated with additional reductions in asthma medication use (-21% beyond -48% in controls), severe exacerbations (-21% beyond -36%), and new oral corticosteroid prescriptions (-33% beyond -41%). Age stratification revealed more pronounced AR medication reductions in younger children (0-11 years) than in adolescents (12-17 years).

This large-scale, real-world study supports the long-term effectiveness of AIT in children with AR, with or without asthma. The findings reflect improved disease control and suggest a disease-modifying effect of AIT. Early intervention, particularly in younger children, may help mitigate the progression of allergic disease.

A Sting Challenge Test (SCT) is the only reliable method to verify the effectiveness of venom immunotherapy (VIT) in patients allergic to Hymenoptera venom, a leading cause of anaphylaxis in adults. This European Academy of Allergy and Clinical Immunology (EAACI) position paper provides an in-depth analysis of the SCT's key applications, risks, and outcomes in clinical practice, focusing on its role in monitoring VIT efficacy, improving patient quality of life, and ensuring appropriate therapeutic interventions. The SCT is primarily used to assess VIT protection, adjust VIT dosage, and confirm patient safety but is not recommended for routine diagnosis due to the risk of provoking systemic allergic reactions. This position paper also offers practical considerations for performing the SCT, including insect handling, patient preparation, and risk management. While SCT is a valuable tool in personalized allergy treatment, it requires careful handling of live insects and patient preparation to ensure safety. This position paper reviews the literature and presents the expert experience of the Insect Venom Hypersensitivity Working Group of the European Academy of Allergy and Clinical Immunology.

In children, house dust mite (HDM) sensitisation is a contributing factor for developing allergic asthma. HDM allergen immunotherapy has demonstrated efficacy and safety in adults with allergic asthma; however, evidence for its use in children is limited. MT-11 evaluated the efficacy and safety of the SQ HDM sublingual immunotherapy (SLIT) tablet in children (5-17 years) with HDM allergic asthma.

This phase III, randomised, double-blind, placebo-controlled trial randomised 533 children with a recent history of asthma exacerbations, despite treatment with inhaled corticosteroids and/or long-acting beta-agonists, to daily treatment with SQ HDM SLIT-tablet or placebo for 24-30 months. The primary endpoint was the annualised rate of clinically relevant asthma exacerbations. Adverse events (AEs) were reported throughout the trial.

The rate ratio for the annualised rate of clinically relevant asthma exacerbations was 0.89 (95% CI: 0.60, 1.31), in favour of the SQ HDM-SLIT tablet; superiority over placebo was not established. Most treatment-related AEs (TRAEs) were of mild or moderate severity, and few subjects discontinued due to TRAEs (< 2%). The most common TRAEs were local application site reactions (oral pruritus, throat irritation, ear pruritus, and upper abdominal pain). There was no increased incidence of asthma-related events, and no anaphylaxis or adrenaline use in the SQ HDM SLIT-tablet group.

As a result of the coronavirus disease 2019 pandemic, asthma exacerbation rates were much lower than expected, contributing to the primary endpoint not being met. The SQ HDM SLIT-tablet was well tolerated in a paediatric population with inadequately controlled HDM allergic asthma.

Until now, no study has investigated the impact of allergen immunotherapy (AIT) on genome-wide DNA methylation in a longitudinal set-up. Herein, we investigated whether differences in DNA methylation occur in birch pollen allergic patients undergoing 6 months of birch pollen AIT, assessed alterations in methylation-based blood cell type composition, and correlated DNA methylation to serological AIT biomarkers.

We performed genome-wide DNA-methylation analysis on bisulfite-converted DNA derived from whole blood samples of 16 birch pollen-allergic patients (pre-/post-birch pollen AIT) and 15 placebo (pre-/post-placebo treatment).

Our analysis identified cg22187251, located within a regulatory region upstream of the glucosaminyl (N-acetyl) transferase 2 (GCNT2) gene, and cg22336863 upstream of the transcription start site of actin binding rho activating protein (ABRA), as hypermethylated. Functional assays revealed that these regions exhibit methylation-dependent promoter and enhancer activities. We identified differentially methylated positions within the HLA gene complex, and an AIT-specific increase of CD8+ T cell populations accompanied by a decrease in natural killer (NK) cell proportion. Strong to moderate correlations with clinical biomarkers (such as specific IgG4) were observed for 42% of the top 100 differentially methylated positions.

GCNT2 and ABRA are implicated in Rho-signaling, a pathway involved in Th2 differentiation. GCNT2 modulates the SMAD-dependent TGF-β pathway, indicating a role in mediating AIT-induced immunotolerance. This is the first longitudinal study investigating DNA methylation changes induced by birch pollen AIT.

Venom immunotherapy (VIT) is the only treatment for honey bee venom allergy; however, some patients develop severe allergic reactions (SAR) during therapy. Omalizumab, an anti-IgE antibody, may improve VIT tolerance, though data in honeybee VIT remain limited.

To evaluate the efficacy of adjuvant omalizumab in honeybee VIT, identify predictors of omalizumab requirement, and inform protocol selection.

A retrospective chart review was conducted of all adults undergoing honeybee VIT at Fiona Stanley Hospital, Perth, Western Australia, from 2015 to 2024. Baseline characteristics, biomarkers, protocols, and outcomes were analysed.

Among 354 VIT patients, 57 (16%) experienced SARs, with 36 (10%) receiving omalizumab. Predictors of omalizumab need included severe sting anaphylaxis, asthma, and elevated basal tryptase. One patient used omalizumab to escalate VIT dosing after already reaching maintenance. Of 35 patients using omalizumab during VIT up-titration, 22 (63%) achieved unsupported maintenance, 7 (20%) ceased due to SARs, and 5 (14%) remain on omalizumab. Excluding 5 patients who declined or lacked access to ongoing omalizumab, the success rate increases to 73%. The most common protocol involved a 12-week VIT up-titration to 100 μg with omalizumab 300 mg loading 2 weeks prior, followed by 150 mg fortnightly until maintenance VIT was reached. SARs most frequently occurred at omalizumab cessation. In 3 cases, these were overcome by resuming omalizumab with a higher VIT maintenance dose target.

Omalizumab could be considered in patients experiencing recurrent SARs to standard VIT. A semi-rush protocol with omalizumab loading 1 to 2 weeks prior was well tolerated.

The last decades have shown the number of subjects developing allergic rhinitis (AR), allergic asthma (AA), atopic dermatitis (AD), and food allergy rose continuously worldwide. To cure these allergic diseases, allergen-specific immunotherapy (AIT) represents the unique treatment capable of providing clinical outcomes through the induction of long-term immunological tolerance. Despite proven efficacy, the duration of treatment, AIT-associated side effects, and the difficulty in identifying potential responders by diagnosis lead to poor patient compliance. Clinical investigations evidenced the role of blocking IgG antibodies induced by AIT in long-term tolerance. These observations suggested that passive allergy immunotherapy (PAIT) with low doses of allergen-specific blocking IgG antibodies represents an elegant alternative to frequent administrations of allergen extracts. Tremendous technological progress in the discovery/production of fully human monoclonal antibodies (mAbs) with very low immunogenicity has been made in the last decades, and these therapeutic antibodies revolutionised the treatment of cancers or infectious diseases. The recent advances in the isolation of rare allergen-specific IgE+ B cells and the generation of human antibodies in transgenic mice made possible the production of human monoclonal blocking antibodies against any allergen, sharing the same affinity with the corresponding naturally occurring IgE. This comprehensive review will describe the first promising preclinical and clinical data obtained with antibody cocktails targeting several IgE epitopes to some key single allergens. PAIT is safe and effective for the downregulation of the allergic response. Compared with conventional extract-based AIT, the positive outcomes could require much less dosing.

The efficacy and safety of allergen immunotherapy (AIT) have been demonstrated in randomized controlled trials (RCTs). However, differences in study protocols, populations, and AIT products lead to variability in outcomes. The World Allergy Organization and the European Academy of Allergy and Clinical Immunology advise assessing individual AIT products rather than assuming a universal class effect. We conducted a meta-analysis on the efficacy and safety of 5-grass pollen liquid sublingual immunotherapy (SLIT) (5-grass SLIT liquid) in patients affected by allergic rhinoconjunctivitis (ARC) with and without asthma. We searched computerized databases (MEDLINE, ISI Web of Science, LILACS, the Cochrane Library, ClinicalTrial.gov) up to June 2023, supplemented our approach with manual literature searches, and included RCTs comparing 5-grass SLIT-liquid to placebo, irrespective of primary endpoints or treatment duration. Efficacy was assessed based on standardized mean differences (SMDs) in symptom score (SS) and medication score (MS). Subgroup analyses included age and sensitization status, while meta-regression was applied to evaluate asthma comorbidity, dose, and treatment duration. Bias and certainty of evidence were assessed using the Cochrane Risk of Bias 2 tool and the Grading of Recommendations Assessment, Development and Evaluation approach. Data from 8 RCTs for SS (621 patients) and 6 RCTs for MS (507 patients) showed a significant benefit for SLIT over placebo in SS (SMD, -0.34; 95% CI, -0.62 to -0.06; P < .05) and MS (SMD, -0.54; 95% CI, -0.97 to -0.10; P < .05). Subgroup analyses showed no differences based on age or sensitization status. Meta-regression revealed no significant impact of cumulative dose, treatment duration, or asthma on efficacy. No safety issues were observed. This meta-analysis confirms that 5-grass SLIT-liquid offers significant clinical benefits and is safe, providing an effective option for treating the cause of ARC in patients with and without asthma.

The lowest dose of peanut oral immunotherapy (P-OIT) has not been determined.

To evaluate if very low dose OIT (30 mg) may safely and effectively increase tolerated doses and induce immunological changes.

Peanut-allergic children reactive to ≤444 mg peanut protein (PP) in double-blind placebo-controlled food challenges (DBPCFC) were prospectively enrolled and randomly assigned to 3 groups: two groups were double-blinded P-OIT groups escalating to 30 mg (Group-30mg) or 300 mg (Group-300mg) PP maintenance doses. A third group followed open-label avoidance (Group-Avoid). Cumulative tolerated doses of ≥443 and ≥1043 mg PP were compared to Group-Avoid by DBPCFC planned at 1 yr. Safety and laboratory parameters (sIgE, sIgG4) were assessed.

We enrolled 51 children (26 [51%] male, median age 10 yrs [IQR 7-13]), with initial cumulative tolerated dose of 44 mg (IQR 14-144). In Group-30mg, 15/17 completed DBPCFC (2/17 withdrawn). In Group-300mg, 12/17 completed DBPCFC (5/17 withdrawn). In Group-Avoid, 12/17 completed DBPCFC (5/17 lost to follow-up). By intention to treat, Group-30mg, 13/17 (p <<0.001 vs. Group-Avoid) tolerated ≥443 and 7/17 (p = 0.007 vs. Group-Avoid) tolerated ≥1043 mg PP. In Group-300mg 10/17 (p <0.001 vs. Group-Avoid) tolerated ≥443 and 8/17 (p = 0.003 vs Group-Avoid) tolerated ≥1043 mg PP. No Group-Avoid (0/17) tolerated ≥443 or ≥1043 mg PP. Laboratory parameters (sIgE, sIgG4) were similar between Group-30mg and Group-300mg and significantly improved from Group-Avoid. Systemic adverse events were fewer in Group-30mg vs Group-300mg.

A 30 mg maintenance dose for P-OIT significantly increases threshold over strict avoidance, clinically similarly to 300 mg, and may allow for a simplified and safer OIT regimen and less treatment drop-outs. NCT03532360.

Allergic diseases with their epidemic prevalence on the rise have been one of the major global health problems of the 21st century. The association of increased prevalence with lifestyle changes including increased urbanization, and hygiene practices highlighted the importance of host-microbiome interactions for maintaining immune homeostasis. In support, numerous studies demonstrated altered gut microbiome composition in allergic patients, and suggested dysbiosis as a possible cause of allergic diseases. Nevertheless, despite being the second largest microbiota in the human body, oral microbiota has not yet received the attention it deserves in the literature. With this review article, we aim to highlight its significance by summarizing the data obtained from studies evaluating oral microbiome composition in patients with allergic respiratory diseases. Additionally, their importance will be further elaborated by discussing the findings presented by animal and human studies investigating the possible effect of oral probiotic uptake to the clinical efficacy of sublingual allergen immunotherapy.

This review highlights current limitations of allergen-specific immunotherapy (AIT) methods and introduces microneedles (MNs) as an innovative transdermal platform to enhance AIT safety, efficacy, and patient adherence.

Conventional approaches such as Subcutaneous immunotherapy (SCIT), Sublingual immunotherapy (SLIT), and Oral immunotherapy (OIT) have shown clinical effectiveness but face challenges including systemic adverse reactions, prolonged treatment durations, poor adherence. Meanwhile, Epidermal allergen-specific immunotherapy (EPIT) and other skin-targeted AIT approaches is constrained by the limited epidermal penetration of allergens. Recent preclinical studies demonstrate that MN-based transdermal immunotherapy (MN-TDIT) effectively delivers allergen directly into immune-rich dermal layers, significantly enhancing allergen-specific immune responses, inducing a regulatory T-cell response, modulating Th1/Th2 balance, and decreasing allergic inflammation in preclinical respiratory, skin, and food allergy models. MN-TDIT exhibits clear advantages over existing AIT strategies, including improved immunogenicity, fewer side effects, ease of administration, and potential for self-administration. Further research should focus on resolving formulation stability issues, optimizing controlled allergen release, and validating safety and efficacy in large-scale clinical trials, thus facilitating MNs as a transformative strategy for improving AIT outcomes.