The optimal oral immunotherapy (OIT) protocol following low-dose desensitization remains unclear.

To compare the efficacy and safety of fixed low-dose versus escalation to medium dose for severe cow's milk allergy.

This study included children who had a positive oral food challenge (OFC) to 3 mL of milk before initiating OIT, had continued low-dose OIT targeting 3 mL for a minimum of 1 year, and subsequently failed OFC with 25 mL. They were randomized (32 children each) into "fixed-dose group; 3-mL target (99-mg protein)" or "dose-escalation group; 25-mL target (825-mg protein)." Short-term unresponsiveness to 25 mL was assessed using the OFC at 1 and 2 years after the 2-week avoidance.

The fixed-dose group versus the dose-escalation group had the following characteristics, respectively: median age (9.2 vs 9.1 years), history of anaphylaxis (94% vs 100%), milk-specific IgE level (19.9 vs 27.0 kUA/L), and period from OIT initiation (2.0 vs 1.8 years). The rates of achieving 25 mL short-term unresponsiveness were 31% and 28% at 1 year and 47% and 44% at 2 years, respectively (P > .99). The total symptom frequency per OIT dose was 0.9% versus 3.8% in the first year, and 0.8% versus 2.0% in the second year (P < .001), and anaphylaxis was 0.01% versus 0.06% in the first year. Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

The fixed low-dose OIT protocol following low-dose desensitization provides comparable efficacy and improved safety compared with dose escalation.

Exposomic determinants substantially influence the variability of molecular IgE-mediated sensitization in allergic rhinitis and conjunctivitis across bioclimatic regions, underscoring their relevance in precision allergology. This study aimed to characterize molecular sensitization profiles in Spanish patients with respiratory allergy from distinct geographic and climatic areas.

A cross-sectional, multicenter study was performed in 12 Spanish cities. The study population comprised 291 patients diagnosed with allergic rhinitis and/or conjunctivitis according to the modified ARIA/DECA criteria. Participants underwent skin prick testing with standardized allergen extracts and multiplex molecular IgE analysis. Clinical, demographic, and regional bioclimatic variables were integrated to define exposomic sensitization patterns. Patients previously treated with allergen immunotherapy or biologics were excluded. Regional pooled sera were analyzed by ELISA and IgE immunoblotting to validate molecular data and identify IgE binding to nonrecombinant or poorly characterized allergenic components.

Distinct regional sensitization profiles were identified. Grass pollen allergens predominated in oceanic and continental climates, while olive and cypress pollens were more frequent in Mediterranean areas. Sensitization to house dust mite, particularly Dermatophagoides pteronyssinus and Blomia tropicalis, was highly prevalent in subtropical and humid zones. Molecular assays confirmed skin test findings and identified major allergenic molecules, including Phl p 1, Ole e 1, Der p 1, and Der p 2, along with region-specific components such as Der p 23, Cup a 1, Alt a 1, and Pla a 2.

This multicenter exposomic study demonstrated that climatic diversity modulates allergen sensitization in Spain, supporting region-tailored precision diagnostic and therapeutic strategies in respiratory allergy.

House dust mites (HDM) are a primary trigger of allergic rhinoconjunctivitis (ARC), a common condition associated with substantial symptom burden and impaired quality of life. Although sublingual immunotherapy (SLIT) of HDM extracts has shown therapeutic potential, its overall efficacy and safety profile in adults and adolescents with ARC remains incompletely defined. We aimed to assess the efficacy and safety of HDM SLIT in adults and adolescents with ARC.

We conducted a systematic search of PubMed, Scopus, Web of Science (WOS), and Cochrane CENTRAL databases up to May 2025. We included studies comparing HDM SLIT to placebo or pharmacotherapy. The main efficacy outcomes were the combined symptom and medication score (CSMS), rhinitis symptom score (RSS), rhinitis medication score (RMS), and rhinoconjunctivitis quality of life questionnaire (RQLQ). Safety was assessed by analyzing treatment-related adverse events (AEs), serious, severe, and local AEs. A random-effects model was used to pool standardized mean differences (SMD) and risk ratios (RR).

A total of 45 studies involving 30,288 participants were included in the systematic review, with 28 providing data for the meta-analysis. SLIT significantly improved multiple efficacy outcomes, including RSS and RMS, with a pooled SMD and 95% CI (-0.98, [-1.65, -0.31], p < 0.001) and (-1.00, [-1.80, -0.20], p = 0.01), respectively. SLIT was associated with a higher risk of treatment-related AEs with a pooled RR and 95% CI (1.16, [1.02, 1.33], p = 0.02), which were predominantly mild, local, and transient.

This study confirms that standardized HDM SLIT is an effective and safe disease-modifying therapy for adults and adolescents with ARC. It provides clinically meaningful reductions of symptoms and medication use and improves quality of life. The favorable safety profile supports its use as a foundational treatment in the management of HDM-induced ARC.

Allergen immunotherapy (AIT) is the only intervention capable of modifying the natural history of allergic diseases. The evidence supporting its effectiveness comes from two distinct but complementary methodological approaches: randomized controlled trials (RCTs), traditionally considered the gold standard for establishing causality, and real-world evidence (RWE), which reflects everyday clinical practice. The tension between these two paradigms is methodological, ethical, and political.

Critically examine the epistemological foundations, limitations, and strengths of RCTs and RWE in evaluating AIT, exploring the ethical implications and influence of the pharmaceutical industry in the construction of clinical evidence.

Narrative and reflective review of methodological and bioethical literature on RCTs and RWE, with a focus on AIT studies. The analysis considers internal and external validity, generalizability, data governance, conflicts of interest, and regulatory implications.

RCTs offer internally valid estimates of effectiveness, but these are difficult to generalize; RWE captures the complexity of clinical practice but is vulnerable to confounding and bias. The ethical dimensions differ: RCTs raise issues of equivalence and informed consent, while RWE raises issues of privacy and secondary use of data. The industry utilizes considerable influence on both paradigms, contributing to systematic distortions of the evidence.

Neither RCTs nor RWE, taken in isolation, provide a sufficient picture of the efficacy and safety of AIT. Only an integrated approach, combining methodological rigor and pragmatic relevance, accompanied by independent monitoring of conflicts of interest and greater transparency, can support truly evidence-based decision making in allergen immunotherapy.

Allergen immunotherapy is the only disease-modifying treatment for IgE-mediated diseases for patients 5 years and over. The question is often asked why children receive the same doses as adults. There is not a single dose-finding study including children and/or adolescents. Moreover, randomized controlled trials that include all age groups but report effects separately are rare.

This randomized trial investigated the safety and tolerability of an accelerated dose escalation schedule (One-Strength group) compared to the standard regimen (Standard group) when using a birch pollen SCIT allergoid in patients aged 5-65 years.

Overall, 201 patients were randomized to the two regimens: 87 adults, 52 adolescents, 62 children. Three hundred eighty-two treatment-related adverse drug reactions (ADRs) occurred in 81 patients (40.5%). A higher proportion of patients in the One-Strength group (48.5%) experienced at least one ADR compared to those in the Standard group (32.0%). The majority of ADRs were local (93.3%), and the majority were of mild intensity (95.8%). 3 patients in the One-Strength and 1 patient in the Standard group developed a total of 9 systemic ADRs, which all were classified as WAO grade 1 or 2 and most of mild intensity. No event of WAO grade 3 or higher was reported. No serious ADR occurred. Overall, tolerability was assessed as "very good" or "good" by more than 96% of investigators and patients. Safety and tolerability were comparable in the three age groups.

Birch pollen SCIT was safe and well-tolerated when administered using a One-Strength dose-escalation regimen in patients aged 5-65 years.

The airway epithelium not only acts as a physical barrier between the environment and the host, but also functions as an active immunological interface, facilitating crosstalk between the epithelial cells, immune cells and the microbiome aimed at protecting the host. Therefore, maintaining airway epithelial barrier integrity and its functions is crucial for prevention of chronic inflammatory airway diseases, such as allergy, asthma and chronic obstructive pulmonary disease. The potential to restore the epithelial barrier by therapeutic interventions has increasingly gained interest over recent years. As part of their disease-modifying properties, various treatment modalities including small molecule drugs, biologics, bronchial thermoplasty and allergen immunotherapy, showed beneficial effects on epithelial barrier integrity in select patient populations. In this review, we summarize current knowledge, discuss recent evidence of therapeutic interventions on restoring epithelial barrier function and highlight unmet needs and future research directions.

For young children with fish allergy, dietary avoidance is the current standard of care. We aimed to assess whether codfish oral immunotherapy (OIT) can induce desensitization or sustained unresponsiveness (SU) in this population.

We conducted a randomized, double-blind, placebo-controlled study in Hong Kong. Children aged 2-10 years reactive to codfish protein during DBPCFC were randomly assigned 1:1 to codfish OIT or placebo for 52 weeks (1000 mg daily maintenance) followed by 8 weeks avoidance. Primary outcome was desensitization at week 52; sustained unresponsiveness (SU) at week 60 was a key secondary outcome.

Between November 2022-September 2023, 70 children (median age 5.6 years) were randomized to codfish OIT (n = 35) or placebo (n = 35). At the week 52 end-of-treatment challenges, 15 (43%) OIT participants versus 4 (11%) placebo achieved desensitization (risk difference 32%, 95% CI 9%-51%; p = 0.003), with significantly greater increases in cumulative tolerated protein [median 4330 mg vs. 0 mg, p < 0.001]. At week 60, SU rates were 8 (23%) versus 3 (9%) (risk difference 14%, 95% CI -5% to 33%; p = 0.332). Codfish OIT significantly decreased codfish-specific IgE, rGad c1-specific IgE, and skin reactivity while increasing codfish-specific IgG4. The treatment demonstrated acceptable safety with minimal moderate-to-severe adverse events and epinephrine use (3% both groups), and immunological evidence of reduced cross-reactivity to salmon and catfish allergens.

In children with fish allergy, codfish OIT significantly increased desensitization rates compared to avoidance, though SU remained limited. The treatment demonstrated acceptable safety with predominantly mild reactions and reduced IgE cross-reactivity to other fish allergens.

House dust mites (HDMs) are the most important respiratory allergen sources. In temperate regions, the genus Dermatophagoides predominates, whereas in sub-tropical and tropical regions, the genus Blomia is also of high importance. There is only limited IgE cross-reactivity between Dermatophagoides and Blomia.

To produce a chip containing purified microarrayed Blomia tropicalis (Blo t) and Dermatophagoides pteronyssinus allergens (Der p) capable of identifying patients with a genuine Blo t or Der p IgE sensitisation, co-sensitisation and/or cross-sensitisation.

Chips containing seven purified Blo t and thirteen Der p allergens were generated by microarray technology and tested for IgE and IgG reactivity in HDM-sensitised patients from Blo t-endemic (group 1: n = 115) and Blo t-non-endemic (group 2: n = 33) regions. IgE cross-reactivity was analysed by IgE inhibition studies.

IgE levels to Blo t 2, Blo t 5, Blo t 10, Blo t 12 and Blo t 21 were significantly higher in HDM-sensitised patients from Blo t-endemic as compared to patients from Blo t-non-endemic regions, whereas the opposite was observed for IgE to Der p 2 and Der p 21 in patients from Blo t-non-endemic regions. An algorithm based on IgE reactivity profiles and allergen-specific IgE levels capable of discriminating genuine sensitisation to Blo t and Der p or co-sensitisation was established. In HDM-sensitised patients from Blo t-endemic regions, each of the aforementioned sensitisation profiles was observed, whereas in HDM-sensitised patients from Blo t-non-endemic regions, only genuine sensitisations to Der p and co-sensitisations to Blo t and Der p were observed.

The algorithm based on microarrayed Blo t and Der p allergens for discrimination of Blo t and Der p sensitisation may support prescription of allergen-specific immunotherapy. At minimum, it will be helpful in understanding disease aetiology and for fine resolution mapping of allergic reactivities in HDM sensitisation.

In China, therapeutic options are limited by the narrow availability of allergen preparations, with house dust mite (HDM) allergen immunotherapy (AIT) as the main choice for most patients. However, polysensitization is highly prevalent, and the benefit of HDM AIT in such patients remains uncertain. The study aims to evaluate the effectiveness of single-allergen HDM AIT on both perennial and coexisting allergen-specific symptoms in polysensitised allergic rhinitis (AR) patients and to explore predictors of treatment response.

We performed a multicenter retrospective cohort study including 81 patients with AR who were polysensitised to HDM and at least one other inhalant allergen (e.g., pollens, mould or animal dander). All participants received HDM subcutaneous immunotherapy (SCIT) for 12 to 36 months. Baseline characteristics, including serum allergen-specific IgE (sIgE) levels and comorbidities, were collected. Symptom severity was assessed using the Visual Analog Scale (VAS), and treatment response was defined as a ≥ 30% reduction in VAS scores from baseline. Statistical comparisons between responders and non-responders were conducted using Fisher's exact test for categorical variables and Mann-Whitney U tests for continuous data. Firth logistic regression was used to identify predictors of treatment response.

The overall response rate for perennial symptoms was 68.8%, and varied in patients with co-existing allergies: 72.7% for moulds, 70.0% for animal dander, 65.5% for tree pollen, 70.2% for weed pollens. Allergen-specific symptom response rates varied across allergens: 68.2% for moulds, 30.0% for animal dander, 56.7% for tree pollens, 74.5% for weed pollens. Higher sIgE levels to HDM and mould were significantly associated with lower response rates in patients co-sensitised to both. A predictive model incorporating both sIgEs showed good specificity.

Single-allergen HDM AIT is effective in many polysensitised AR patients; however, its efficacy varies by coexisting allergen type and sIgE level. Patients co-sensitised to mould with high HDM and mould sIgE appeared to have poorer outcomes. These preliminary findings require confirmation in larger prospective studies to guide tailored AIT strategies.

In a process termed trained immunity activated dendritic cells (DCs) and macrophages undergo distinct metabolic changes that contribute to their effector function: While certain activated DC subsets and M1 macrophages undergo a switch towards higher rates of glycolysis and a "disrupted Krebs cycle" to produce important immune effector molecules, alternatively activated (M2) macrophages, plasmacytoid DCs (pDCs), and conventional DCs type 1 (cDC1s) can rely on oxidative phosphorylation for their effector function. DCs and macrophages are also important cells in allergic reactions. While the induction of trained immune responses by microbial stimuli and vaccines is meanwhile well characterized, the contribution of trained immunity to either the establishment, elicitation, or treatment of allergic responses is largely unknown. In this context, recent results suggest distinct trained immunity responses to be established in allergic children. Here it seems that infections early in life predispose to the latter development of allergies, and trained immunity to also contribute to the immune modulation occurring in allergic patients during allergen-specific immunotherapy. Therefore, better understanding of trained immunity in these antigen-presenting cell (APC) subsets may allow to establish new biomarkers and enable a more targeted and efficient treatment of allergic diseases. This article summarizes the specific immune metabolic alterations observed in activated DCs and macrophages explaining their connection to DC and macrophage effector function. It then discusses our current knowledge on the contribution of trained immune responses in the establishment and treatment of allergic diseases.