The efficacy and safety of preventive allergen immunotherapy (pAIT) in children are currently under investigation. Here, we provide an overview of pAIT with respiratory allergens concerning the prevention of new sensitizations, allergic disease onset and progression as well as further immunomodulatory effects. Three databases were searched for clinical pAIT studies in children. Selected publications were reviewed for preventive outcomes according to prevention level (primary, secondary, and tertiary), allergen type, administration route, dose, and treatment duration. The primary prevention approach appears safe but showed no allergen-specific effect on new sensitizations. Secondary prevention seems feasible and may induce regulatory T cell-mediated immunotolerance. The number of studies at these prevention levels is limited. Tertiary prevention with grass and/or tree pollen-based pAIT has shown efficacy in preventing disease progression from allergic rhinitis/conjunctivitis to asthma. Data on tertiary pAIT with house dust mites and other allergen types are inconclusive. Subcutaneous and sublingual routes appear similarly effective, but head-to-head comparative paediatric studies are scarce. Additionally, there are fewer placebo-controlled studies. Nevertheless, immunomodulatory outcomes of pAIT are encouraging. Currently, limited but favourably suggestive evidence is available for preventing respiratory allergic diseases in children by pAIT. Primary and secondary prevention have potential and warrant further investigation through well-designed studies.

Patients with Hymenoptera venom allergy (HVA), especially those with severe anaphylaxis, frequently have concomitant clonal mast cell disease (MCD) in the form of systemic mastocytosis or monoclonal mast cell activation syndrome. Detection of clonal MCD is important since it will have significant consequences for management of HVA. Therefore, we recommend patients with HVA be systematically screened for clonal MCD. The pre-test probability of clonal MCD can be assessed in a stepwise fashion starting with examination of the skin for typical monomorphic maculopapular cutaneous mastocytosis (MPCM) lesions; measurement of the baseline serum tryptase (BST) and tryptase genotyping for patients with BST>11 ng/mL; followed by the REMA score which is calculated by utilizing anaphylaxis clinical features, BST, and patient sex. A bone marrow biopsy should be performed in patients with monomorphic MPCM, a REMA score ≥2, or an elevated BST based upon tryptase genotype. Patients with HVA and a clonal MCD should be treated with immunotherapy directed against the Hymenoptera venom for which they are sensitized. For this high-risk subgroup of HVA patients, it is recommended to continue immunotherapy for more than 5 years or indefinitely and to carry at least three epinephrine autoinjectors. Future studies should determine whether KIT D816V-selective tyrosine kinase inhibitors are effective at preventing or reducing severity of Hymenoptera-venom triggered anaphylaxis in patients with clonal MCD.

Understanding the risk factors leading to severe systemic sting reactions (SSR) is crucial for initiating venom immunotherapy (VIT) and for educating affected individuals and their families. Some of these risk factors are well-established, some are no longer considered risk factors, and some remain controversial. Well-established risk factors for severe SSR include clonal mast cell disease, high baseline serum tryptase, and advanced age. The absence of skin symptoms and the rapid onset of symptoms are indicators of severe SSR. Recent publications indicate that antihypertensive treatment and stings in the head and neck area are not risk factors for severe SSR. VIT is the only available treatment that can potentially prevent further anaphylactic reactions. Although rare and generally manageable, individuals undergoing VIT may experience systemic adverse events (sAE). More sAE are expected in patients undergoing bee VIT compared to vespid VIT. The role of elevated baseline serum tryptase as a risk factor for sAE remains debated, but if it is a factor, the risk is increased by only about 1.5-fold. Rapid up-dosing protocols, depending on the specific regimen, can also be associated with more sAE. Severe initial SSR, antihypertensive medication, high skin test reactivity, and high specific IgE levels are not risk factors for sAE.

Registries can yield important insights on allergen immunotherapy (AIT) outcomes in daily clinical practice. However, systematic recordings of adverse events (AE) due to AIT in real-life are lacking.

The Allergen Immunotherapy Adverse Events Registry (ADER) is a prospective, multicenter registry on real life AIT safety. Data on adults (>18 years old) with respiratory allergies receiving AIT with mites, pollens, epithelia, and/or molds were retrieved and analyzed from ADER. The frequency, characteristics and risk factors of AE were investigated. The MedDRA terminology was used to record AE.

A total of 1545 individuals with a mean age of 33 ± 10 years receiving 1815 AIT courses (n = 1060 sublingual (SLIT); n = 755 subcutaneous (SCIT)) in centers from eight countries were included. Patients had allergic rhinitis (65%) or, asthma only (3.7%) or rhinitis with asthma (31.2%). Grass was the most frequent specific sensitizer (60.7%), followed by mites (45.5%), birch pollen (20.6%), epithelia (16.1%), and molds (8%). There were 296 AE recorded in 115 patients (7.4%). A higher frequency of AE occurred during up-dosing (59%) compared to maintenance. Severe reactions were rare (0.2%), all in the context of SCIT. After 6 weeks of maintenance only one moderate AE was recorded. The most frequently reported symptoms were from the respiratory system and the skin. Having asthma, doing SCIT, AIT with mugwort, cat, or birch were associated with higher risk for AE while the use of allergoids induced lower risk.

In real life clinical practice, AIT-associated AE occur in a minority of patients, while severe reactions are rare. The presence of asthma and use of SCIT are risk factors, while the use of modified allergens lowers the risk.

Randomized controlled trials have demonstrated responses to clinical parameters, but a significant proportion of allergy patients in reallife settings would have been excluded from such studies. Therefore, real world research is needed, and there is a growing body of information on allergen immunotherapy's long-term effectiveness and safety. Real-world evidence can be a valuable instrument to better understand the patient's journey and the effectiveness and safety of therapies. For this purpose, a registry will be used for the first time in Italy to evaluate the impact of allergen immunotherapy on several outcomes, including quality of life and disease related effects in the pediatric and adult allergic population with a socio economic assessment and respect to real-world health.

Subcutaneous immunotherapy (SCIT) can induce systemic reactions (SRs) in certain patients, but the underlying mechanisms remain to be fully elucidated.

AR patients who were undergoing standardized HDM SCIT (Alutard, ALK) between 2018 and 2022 were screened. Those who experienced two consecutive SRs were included in the study group. A control group was established, matched 1:1 by gender, age, and disease duration with the study group, who did not experience SRs during SCIT. Clinical and immunological parameters were recorded and analyzed both before SCIT and after 1 year of treatment.

A total of 161 patients were included, with 79 (49.07%) in the study group. The study group had a higher proportion of AR combined asthma (26.8% vs. 51.8%, p < 0.001) and higher levels of sIgE to HDM and HDM components (all p < .001). Serum IL-4 and IL-13 levels in the study group were higher than those in the control group (p < .05). The study group received a lower maintenance dosage of HDM extracts injections than control group due to SRs (50000SQ vs. 100000SQ, p < .05). After 1 year of SCIT, the VAS score, the lung function parameters of asthmatic patients over 14 years old significantly improved in both groups (all p < .05). After a 7-day exposure to 20 μg/mL HDM extracts, the percentages of Th1, Th17, Tfh10, and Th17.1 in PBMCs decreased, while the Tfh13 cells significantly increased in the study group (p < .05).

The type 2 inflammatory response is augmented in HDM-induced AR patients who experienced SRs during SCIT. Despite this, SCIT remains effective in these patients when administered with low-dosage allergen extracts.

Asthma is a common chronic condition in children globally. Allergen-specific immunotherapy, such as subcutaneous (SCIT) and sublingual (SLIT) therapies, are promising by increasing allergen tolerance. This meta-analysis compares the efficacy and safety of SLIT and SCIT in pediatric asthma.

We searched PubMed, Cochrane Library, and Embase for randomized controlled trials and case-control studies comparing SLIT and SCIT in asthmatic children. Meta-analysis was conducted using random-effects models with calculations via R software version 4.3.2 and RevMan version 5.4. Study quality and bias risk were assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool.

The literature search yielded a total of 1787 records, with 7 studies meeting the inclusion criteria after screening and assessments. There was no significant difference in the Total Asthma Symptoms Score between SLIT and SCIT (mean difference -0.05 [95% CI: -0.21; 0.10]). However, asthma improvement rates were higher in the SLIT group (risk ratio 0.77 [95% CI: 0.64; 0.93]). FEV1 improvement showed no significant difference (mean difference -1.60 [95% CI: -6.27; 3.08]). Adverse events were similar between the treatments (risk ratio 0.56 [95% CI: 0.11; 2.82]).

SLIT and SCIT were generally similarly effective and safe for treating pediatric asthma. SLIT may be preferred due to its noninvasive administration. More research is needed on long-term effects and tailored treatment approaches.

House dust mite (HDM) allergen immunotherapy (AIT) has an established role in the treatment of perennial allergic rhinitis (AR) and allergic asthma (AA) triggered by HDM sensitization. We aimed to identify all double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AR and AA in humans and to summarize the evidence for AIT products that are currently manufactured and available for clinical use. A total of 56 eligible double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AA and/or AR in humans fit the inclusion criteria and investigated a total of 14 commercial AIT products; together, the 56 studies enrolled a total of 14,619 patients. Of the 56 studies, 39 studies investigated the current manufacturer-recommended maintenance dose (MRMD) of the product, and 17 investigated other doses. We identified 39 studies (12,539 patients randomized) for 8 sublingual immunotherapy (SLIT) products and 17 studies (2,080 patients randomized) for subcutaneous immunotherapy products. For AR, 3 products, the ALK 12 standardized-quality (SQ-HDM) SLIT tablet, the ALK 6 SQ HDM tablet, and the SG 300 index of reactivity SLIT tablet, had both dose-finding studies (DFSs) and phase III definitive studies (DSs) to demonstrate efficacy of the MRMD of the product. For AA, 2 products, the ALK 12 SQ-HDM SLIT tablet and the ALK 6 SQ-HDM tablet, had both DFSs and DSs for the MRMD. No subcutaneous immunotherapy product had a paired DFS and DS supporting the MRMD. A total of 30 studies of products no longer commercially manufactured were excluded. This study will help to inform clinical care and product selection for the treatment of HDMinduced AR and AA.

This study evaluated uptake of infant and toddler, younger than 4 years, peanut oral immunotherapy (POIT), revealing that 67% of families with a peanut-allergic child chose to pursue therapy. The potential for the resolution of peanut allergy was the most cited reason to pursue POIT.

Precision dosing in sublingual immunotherapy (SLIT) has become a hotspot gradually, yet no standardized dose adjustment pattern for house dust mite (HDM)-SLIT. This study aims to investigate the clinical feasibility of the dynamic maintenance dose ascending regimen for individualized SLIT.

A total of 258 allergic rhinitis (AR) patients treated with HDM-SLIT were included in this retrospective study. Patients were divided into the regular dose (RD) group (n = 101) and the high dose (HD) group (n = 157) according to different maintenance dosages of SLIT. In the RD group, patients received the fixed dose recommended by the manufacturer. In the HD group, patients received a maximum tolerance dose determined by dynamic dose ascending. The clinical efficacy was evaluated by combined symptom and medication score (CSMS) and visual analogue scale score (VAS) at the baseline, 0.5-year, 1-year, and 2-year. The safety was evaluated by adverse events (AEs).

Significant reductions of CSMS and VAS at 0.5 year, 1-year, and 2-year were observed in both the RD group and the HD group compared to the baseline (P < 0.05). In addition, greater improvements in these clinical parameters from 0.5- to 2 year were found in the HD group compared to the RD group (P < 0.05). For subgroup analysis in the HD group, no significant differences in CSMS and VAS were observed among subgroups of patients 0.05). No serious AEs in the two groups and no significant differences were observed between the AE incidence rate of the RD group and HD group during the incremental and maintenance phases.

The 2-year HDM-SLIT with dynamic maintenance dose ascending regimen offers an "optimal" treatment for AR patients while maintaining safety. This study introduced a pattern for individualized dose adjustment in clinical practice, offering potential benefits for AR patients.