Current Allergen Immunotherapy (AIT) guidelines provide no definitive guidance on route selection, whether subcutaneous (SCIT) or sublingual (SLIT). The primary objective of this study was to characterize real-world AIT prescription patterns, with emphasis on route selection, using a factor analysis approach in a large international cohort.

The CHOICE study is a real-life, multicentre, international, observational, cross-sectional web-based survey conducted across 20 countries between November 2019 and April 2024. Participating doctors completed standardized questionnaires for each consecutive AIT prescription. Thirteen patient-related and product-related parameters were analyzed using exploratory and confirmatory factor analysis. Latent factors identified were subsequently incorporated into multivariate mixed logistic regression models with country and physician nested within country as random intercepts.

Data from 467 physicians and 11,550 patients were analyzed; 60.0% of prescriptions were SCIT and 40.0% were SLIT. Three latent factors were identified: (F1) Scientific and clinical evidence-Based; (F2) Resource and access optimisation; and (F3) Tailored for the patient and their lifestyle. When country was modeled as a random intercept, all three factors were significantly associated with SLIT prescription. After adjustment for both country and physician, F2 was associated with reduced probability of SLIT prescription (OR 0.42; 95% CI 0.31, 0.59), while F3 was strongly associated with an increased probability of SLIT prescription (OR 10.90; 95% CI 7.20, 16.57). Variability attributable to country (ICC 0.86) and physician (ICC 0.74) was high.

Patient-centred considerations increase the likelihood of SLIT use while considering the cost of the treatment increases the likelihood of SCIT use. Substantial variability in AIT route selection is attributable to country- and physician-level factors.

Intralymphatic immunotherapy (ILIT) has been investigated for two decades in small clinical trials, typically using native allergens adsorbed to aluminium hydroxide (alum). This randomised, double-blind, placebo-controlled study evaluated the safety and efficacy of ILIT with a grass pollen allergoid formulated with microcrystalline tyrosine (MCT).

Sixty adults with grass pollen-induced allergic rhinoconjunctivitis (ARC) were randomised to receive ILIT with grass allergoid (equivalent to 60 ng Phl p 5; n = 31) or placebo (n = 29). Three ultrasound-guided injections (100 μL) were administered into inguinal lymph nodes at 4-week intervals in early 2022. The primary endpoint was the combined symptom and medication score (cSMS), recorded daily during the 2022 and 2023 grass pollen seasons. Secondary endpoints included safety, Rhinitis Quality of Life Questionnaire (RQLQ), serology, spirometry, fractional exhaled nitric oxide (FeNO), and skin-prick testing (SPT). An open-label extension, in which the placebo participants received active ILIT, was conducted in 2024.

ILIT was well tolerated, with no severe adverse events (SAEs). Mild local reactions (wheal, erythema, swelling) occurred after 50 of 93 active injections (53.8%), and three moderate reactions (3.2%) were reported. In the placebo group, one mild and no moderate reactions occurred. No allergen-specific systemic reactions were observed. Compared with placebo, ILIT reduced cSMS by 33% in 2022 (p > 0.05) and 50% in 2023 (p 0.05), respectively.

ILIT with a grass pollen allergoid formulated with MCT was well tolerated and associated with clinically relevant reductions in symptom and medication use in grass pollen-induced ARC. In this small study cohort, ILIT proved to be efficient and safe, but further optimisation of dosing regimens should follow.

Oral immunotherapy (OIT) is an emerging treatment for peanut allergy. A variety of protocols have been investigated, and accumulating evidence suggests that younger children may benefit from greater immune plasticity. The aim of the Small Children Oral Immunotherapy (SMACHO) study was to investigate the efficacy and safety of 3 years of peanut OIT with slow up-dosing and a low maintenance dose followed by 4-6 weeks of peanut-free diet in peanut-allergic toddlers.

SMACHO is an open-labelled randomised controlled trial in Stockholm, Sweden (NCT04511494). After a positive peanut challenge to a cumulative dose of maximum 278 mg peanut protein, 75 allergic children, aged 1-3 years, were randomised 2:1 to peanut OIT, with slow up-dosing every 4-6 weeks and a low maintenance dose of 285 mg peanut protein, or to avoidance. Primary outcome was the proportion of children achieving sustained unresponsiveness, defined as tolerating a cumulative dose of ≥750 mg peanut protein in a challenge after 3 years of OIT followed by 4-6 weeks of a peanut-free diet.

After OIT, 82% (41 of 50) achieved sustained unresponsiveness to a cumulative dose of ≥750 mg peanut protein. Before the peanut-free period, 84% (42 of 50) tolerated ≥750 mg peanut protein, compared with 3 of 25 children (12%) without treatment: difference 72% (95% confidence interval (CI) 56-88), p < 0.0001. Median cumulative tolerated dose after treatment was 5000 mg peanut protein compared with 3 mg after 3 years of peanut avoidance: difference 4997 mg (95% CI 4867-5127), p < 0.0001. Adverse events occurred in 0.7% of administered peanut doses, and most were mild. Six children reported eight severe dose-related events, with affected breathing, affected general well-being, or anaphylaxis. Epinephrine was administered at home three times in two children for dose-related reactions, all during up-dosing.

Peanut OIT for young children, using slow up-dosing and a low maintenance dose, may be safer than protocols that escalate more rapidly or involve a higher maintenance dose. Our protocol can be implemented in clinical practice. When combined with early dietary introduction of peanut, this strategy has potential to contribute to a future decline in the prevalence of peanut allergy. Funding: This work was supported by a private non-commercial donation through Karolinska Institutet. Additionally by the Swedish Asthma and Allergy Association's Research Foundation; the Ellen, Walter and Lennart Hesselman Foundation for Scientific Research; Karolinska Institutet; Region Stockholm (ALF (FoUI-961605 and FoUI-973325) and clinical research appointments for Asarnoj, Nilsson, Konradsen and Klevebro); HRH Crown Princess Lovisa's association for child healthcare; the Samariten foundation for paediatric research; the Swedish Association for Allergology; the Freemasons of Sweden; the Swedish Society of Medicine; the Swedish Paediatric Society's Section for Allergy and Asthma, the Swedish Research Council (Dnr 2020-01839; 2023-02616); the Cancer and Allergy Foundation; the association Mjölkdroppen in Sweden; the Golden Jubilee Memorial Foundation; the Magnus Bergvall Foundation.

Food allergy is common, affecting up to 8% to 10% of children and adults. Treatment options include oral immunotherapy (OIT) and omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody.

To compare omalizumab with OIT for the treatment of patients with multifood allergy.

This was a double-blind, placebo-controlled, randomized clinical trial comparing omalizumab with omalizumab-facilitated multiallergen OIT (MOIT) in participants who completed stage 1 of the Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults With Food Allergy (OUTMATCH) trial, which led to the approval of omalizumab. The setting comprised 10 academic centers across the US. Included in this analysis were individuals aged 1 to 55 years with an allergy to peanuts and at least 2 other foods (milk, eggs, wheat, cashews, hazelnuts, walnuts). Eligibility was based on oral food challenge thresholds, requiring dose-limiting symptoms to cumulative doses of 144 mg or less of protein for peanuts and 444 mg or less for nonpeanut allergens. Data were analyzed from October 2024 to February 2026.

Participants were randomized to receive MOIT with placebo omalizumab or omalizumab with placebo MOIT. All received 16 weeks of open-label omalizumab; at week 8, active or placebo MOIT was initiated and escalated to goal doses of 1000 mg per food. At week 16, participants transitioned to blinded omalizumab or placebo injections for 44 weeks.

The primary end point was cumulative tolerated dose (CTD) of 4044 mg or greater for all 3 foods. Predefined secondary end points included CTDs of 1044, 2044, 4044, 6044, or 8044 mg for 1, 2, or all 3 foods.

A total of 117 participants (median [IQR] age, 7 [1-29] years; 64 male [55%]) were randomized to receive active MOIT (n = 58) or active omalizumab (n = 59). A total of 30 participants (51%) receiving active MOIT and 51 (88%) receiving active omalizumab completed the study. In the intention-to-treat (ITT) analysis, omalizumab was superior to MOIT (21 of 58 [36%] vs 11 of 59 [19%]; odds ratio, 2.6; 95% CI, 1.1-6.3; P = .03), with no differences in per-protocol analyses. Omalizumab superiority for CTDs of 4044 mg or greater was also demonstrated for 2 or more foods and for several individual foods. More participants taking active MOIT experienced adverse events (serious adverse events in 18 of 59 [31%] vs 0%; events leading to discontinuation in 13 of 59 [22%] vs 0%; events treated with epinephrine [22 of 59 (37%) vs 4 of 58 (7%)]).

Although the ITT analysis found a higher rate of treatment success in those receiving omalizumab compared with MOIT, results suggest that the difference was largely driven by the high rate of study discontinuation in the participants treated with MOIT, mostly related to adverse events.

The Combined Symptom and Medication Score (CSMS) has been recommended as the primary endpoint in allergen immunotherapy (AIT) trials, resting on the assumption that symptom scores (SS) and medication scores (MS) provide complementary and proportional information. However, the empirical relationship between SS and MS effect sizes across individual randomized controlled trials (RCTs) has never been systematically examined at the study level.

We extracted Hedges' g for SS and MS from 14 double-blind, placebo-controlled RCTs of ALK grass pollen AIT products (4 SCIT, 3 SLIT-Drops, 7 SLIT-Tablets; 4,850 patients). Bivariate scatter plot analysis with weighted least squares (WLS) meta-regression was performed overall and stratified by delivery route. A prespecified sensitivity analysis excluded two studies at high risk of bias (Dolz 1996, Feliziani 1995).

The SS-MS relationship varied markedly across delivery routes and was not universally proportional. SLIT-Tablets (k = 7) showed no consistent SS-MS correlation (Pearson r = 0.001, P = 0.999; WLS slope = 0.923), driven by Scadding 2017, which exhibited marked dissociation (gSS = -0.047, gMS = -0.429) attributable to its use of nasal allergen challenge rather than seasonal symptom scores. SCIT studies exhibited systematic dissociation: MS effect sizes consistently exceeded SS effect sizes (ratio 2.2:1 in Varney 1991; 4.6:1 in Walker 2001). The overall sensitivity analysis (k = 12) yielded r = 0.551 (P = 0.064). SLIT-Drops showed negligible SS effects (gSS ≈ 0) in the sensitivity analysis.

SS and MS are not universally interchangeable measures of AIT efficacy. The relationship is route-dependent and sensitive to endpoint methodology: systematic MS > SS dissociation for SCIT; near-zero SS effects for SLIT-Drops; and heterogeneous correspondence for SLIT-Tablets, where a single study using a non-seasonal symptom endpoint sufficed to collapse the overall correlation. These findings challenge the validity of the CSMS as a universal primary endpoint and reinforce the separate reporting of SS and MS in all AIT trials.

Sublingual immunotherapy with allergens requires high allergen doses to achieve the desired clinical efficacy. Given the current differences among products on the market, this study aims to compare seven therapeutic sublingual grass pollen extracts to quantify the Group 5 allergen concentrations, assess their biological activity and characterise allergenic profiles. The extracts were analysed by protein quantification (Bradford method), characterisation of the protein profile (SDS-PAGE) and determination of biological activity (ELISA inhibition and immunoblotting). Major allergens (Group 5) were also quantified using a sandwich ELISA. Differences were observed between the various allergenic extracts. Protein content ranged from 27 to 231 μg/mL, with Apioral Forte, SlitOne Ultra and Sublivac showing similar protein profiles. These extracts also displayed the highest biological activity, while the quantification of major Group 5 allergens was greatest in Apioral Forte, Sublivac and Tol Forte. The differences observed between extracts may have a relevant clinical impact. It is essential to have standardised, comparative analytical methods that allow specialists to select the most appropriate treatment.

Predicting the course of chronic rhinosinusitis (CRS) and assessing the clinical relevance of IgE-mediated sensitization to house dust mite (HDM) in preschool children remain challenging. We aimed to identify early clinical characteristics of HDM-induced allergic rhinitis (AR-HDM) in preschoolers and to determine predictors of CRS persistence.

We conducted a 5-year prospective follow-up of a well-defined multi-omics cohort of 133 children aged 4-8 years with CRS symptoms, with or without IgE-mediated sensitization to HDM. We developed a multivariate logistic regression model with clinical and multi-omics variables assessed at preschool age to predict CRS persistence and AR-HDM diagnosis at school age.

Among 117 children who completed the 5-year follow-up, CRS persisted in 35%. Higher baseline SN-5 (Sinus and Nasal Quality of Life Survey) scores (>3.6 points) significantly increased the risk of persistent CRS (OR = 3.41; 95% CI: 1.50-7.76; p = .003). ILC-2 cells were detected more frequently in nasal samples from preschool children with persistent CRS. Independent predictors of AR-HDM included a history of food allergy in infancy (OR = 3.87; 1.10-13.60; p = .034) and prominent allergic symptoms at baseline (allergy-related SN-5 domain ratio ≥21%) (OR = 3.96; 1.20-13.10; p = .025). The combined presence of these factors additionally improves the prediction of AR-HDM.

Higher SN-5 score and presence of ILC-2 in the nasal mucosa increase the risk of persistence of CRS. The co-occurrence of a relatively higher allergy domain of SN-5 score and a history of food allergy facilitates prediction of HDM allergy in preschoolers, enabling the timely initiation of allergen immunotherapy in allergic children.

Pollen from birch and other trees in the birch homologous group (e.g., oak) is a common trigger of allergic rhinitis and/or conjunctivitis (AR/C) in Canada. The efficacy and safety of the tree sublingual immunotherapy (SLIT)-tablet in children with AR/C was evaluated post hoc in the Canadian subpopulation of a phase III, double-blind trial (EudraCT 2020-004372-17).

Children and adolescents aged 5-17 years with moderate-to-severe tree AR/C were randomized to either daily tree SLIT-tablet or placebo for up to 52 weeks. Participants had free access to symptom-relieving medication. The primary endpoint was the average total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during birch pollen season (BPS). Average TCS during tree pollen season (TPS, consisting of birch, alder, hazel, and oak pollen seasons), oak pollen season (OPS), and pure OPS (excluding days from birch, alder, or hazel pollen seasons) were also analyzed.

In the Canadian subpopulation (n = 87), treatment with the tree SLIT-tablet reduced the average TCS by 26.8% versus placebo during BPS (absolute difference [95% CI] = 1.89 [-0.71, 4.49], p = 0.138), 32.0% during TPS (absolute difference = 2.14 [-0.03, 4.32], p = 0.042), 46.6% during OPS (absolute difference = 3.70 [0.98, 6.42], p = 0.004), and 50.6% during pure OPS (absolute difference = 4.20 [1.12, 7.27], p = 0.005). Reductions in DSS and DMS with tree SLIT-tablet versus placebo were also observed. In the total trial population (N = 952), tree SLIT-tablet treatment reduced the average TCS by 19.2% versus placebo during BPS (absolute difference = 1.13 [0.42, 1.84], p = 0.002), 16.8% during TPS (absolute difference = 0.76 [0.26, 1.26], p = 0.003), 23.4% during OPS (absolute difference = 1.32 [0.60, 2.05], p < 0.001), and 19.9% during pure OPS (absolute difference = 1.03 [0.27, 1.80], p = 0.009). The tree SLIT-tablet was well tolerated in the total trial and Canadian subgroup populations.

Oral immunotherapy (OIT) is a promising therapeutic strategy for desensitizing patients with immunoglobulin E (IgE)-mediated food allergies. Although effective, OIT is frequently associated with adverse events (AEs), and gastrointestinal (GI) manifestations are among the most common and challenging AEs, which are the leading cause of OIT discontinuation. These reactions range from immediate IgE-mediated signs and symptoms to delayed, non-IgE-mediated, eosinophil-associated disorders, including eosinophilic esophagitis (EoE). While systemic reactions, such as anaphylaxis, are well-known concerns, GI manifestations are frequently encountered, although they are often less severe than systemic reactions. A thorough understanding of GI signs and symptoms is therefore essential for patients and clinicians to navigate OIT effectively. This narrative review provides a comprehensive overview of GI AEs observed during OIT, detailing their clinical presentation, underlying pathophysiology, and evidence-based management approaches. A clear understanding of these manifestations and their management is essential for optimizing patient safety and treatment adherence in the era of OIT.

The nasal microbiome's role in predicting sublingual immunotherapy (SLIT) efficacy in children with allergic rhinitis (AR) remains unclear. Haemophilus, a Proteobacteria genus linked to respiratory inflammation, is a promising candidate biomarker.

To evaluate Haemophilus dynamics as a potential predictor of SLIT response in children with moderate-severe AR.

In this prospective cohort, 63 children with AR and 40 healthy controls (CG) were enrolled. AR patients were stratified by disease severity (mild [MAR] vs. moderate-severe [MSAR]), with MSAR patients receiving 1-year standardized house dust mite SLIT. Based on >20% reduction in Total Nasal Symptom Score (TNSS), patients were classified as responders (RG, n = 25) or non-responders (NRG, n = 15). Nasal microbiome was profiled via 16S rDNA sequencing.

Compared to CG, AR children showed increased alpha diversity (Chao1, p < .05; Shannon, p 4, p < .001). After SLIT, RG patients showed normalized microbial evenness (Pielou E index) to CG levels, driven by marked Haemophilus depletion (p < .001). In contrast, NRG patients maintained high Haemophilus abundance. Haemophilus and Moraxella showed strong positive correlation (r = .68, p < .001), with both decreasing in RG post-SLIT.

Elevated nasal Haemophilus is associated with AR severity, and its depletion correlates with SLIT efficacy. Haemophilus may serve as a clinically actionable microbial biomarker for monitoring SLIT response in pediatric AR, offering a novel precision medicine approach to allergen immunotherapy.