Food allergy is a global public health problem that until recent years lacked any aetiological treatment supported by academy, industry and regulators. Food immunotherapy (AIT) is an evolving treatment option, supported by clinical practice and industry trial data. Recent AIT metaanalyses have highlighted the difficulty in pooling safety and efficacy data from AIT trials, due to secondary heterogeneity in the study. An EAACI task force (CO-FAITH) initiated by the Paediatric Section was created to focus on AIT efficacy outcomes for milk, egg and peanut allergy rather than in trial results. A systematic search and a narrative review of AIT controlled clinical trials and large case series was conducted. A total of 63 manuscripts met inclusion criteria, corresponding to 23, 21 and 22 studies of milk, egg and peanut AIT, respectively. The most common AIT efficacy outcome was desensitization, mostly defined as tolerating a maintenance phase dose, or reaching a particular dose upon successful exit oral food challenge (OFC). However, a large degree of heterogeneity was identified regarding the dose quantity defining this outcome. Sustained unresponsiveness and patientreported outcomes (e.g. quality of life) were explored less frequently, and to date have been most rigorously described for peanut AIT versus other allergens. Change in allergen threshold assessed by OFC remains the most common efficacy measure, but OFC methods suffer from heterogeneity and methodological disparity. This review has identified multiple heterogeneous outcomes related to measuring the efficacy of AIT. Efforts to better standardize and harmonize which outcomes, and how to measure them must be carried out to help in the clinical development of safe and efficacious food allergy treatments.

Because long-term effectiveness of pollen allergen immune therapy (AIT) for allergic rhinitis (AR) is not well-described, we studied effectiveness over 18 years in Denmark.

A register-based cohort study using data on filled prescriptions, 1995-2016, Denmark. In a cohort of 1.1 million intranasal corticosteroid inhaler users (proxy for AR), we matched users treated with grass, birch or mugwort AIT 1:2 with non-treated users on baseline year and 24 characteristics in the 3 years prior to baseline. The primary outcome was the odds ratio (OR) of using anti-allergic nasal inhaler during the pollen season in the treated versus non-treated group by years since baseline.

Among 7760 AR patients treated with pollen AIT, the OR of using nasal inhaler 0-5 years after baseline was reduced when compared with 15,520 non-treated AR individuals (0-2 years, OR 0.84 (0.81-0.88); 3-5 years, OR 0.88 (0.84-0.92)), but was close to unity or higher thereafter (6-9 years, OR 1.03 (0.97-1.08); 10-18 years, OR 1.18 (1.11 1.26)). In post hoc analyses, results were more consistent for those who already had 3 of 3 baseline years of use, and in patients using nasal inhaler in the latest pollen season (0-2 years, OR 0.76 (0.72-0.79); 3-5 years OR 0.86 (0.81-0.93); 6-9 years, OR 0.94 (0.87-1.02); 10-18 years, OR 0.94 (0.86 1.04)) as opposed to no such use.

Patients treated with pollen AIT in routine care to a higher degree stopped using anti-allergic nasal inhaler 0-5 years after starting the standard 3 years of therapy, and not beyond 5 years. Post hoc analyses suggested effectiveness was more consistent among patients with persistent AR.

Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment in allergic airway diseases. Underlying immunological mechanisms and candidate biomarkers, which may be translated into predictive/surrogate measures of clinical efficacy, remain an active area of research. The aim of this study was to evaluate Pollinex Quattro (PQ) Grass AIT induced immunomodulatory mechanisms, based on transcriptome profiling of peripheral blood mononuclear cells.

119 subjects with grass pollen induced seasonal allergic rhinitis (SAR) were randomized in a 2:2:1:1 ratio to receive a cumulative dose of PQ Grass as a conventional or extended pre-seasonal regimen, placebo, or placebo with MicroCrystalline Tyrosine. Gene expression analysis was an exploratory endpoint evaluated in a subgroup of 30 subjects randomly selected from the four treatment arms. Samples were collected at three time points: screening (baseline), before the start of the grass pollen season and at the end of the season. This study was funded by the manufacturer of PQ.

Transcriptome analysis demonstrated that the most significant changes in gene expression, for both treatment regimens, were at the end of the grass pollen season, with the main Th1 candidate molecules (IL-12A, IFNγ) upregulated and Th2 signature cytokines downregulated (IL-4, IL-13, IL-9) (p < .05). Canonical pathways analysis demonstrated Th1, Th2, Th17 and IL-17 as the most significantly enriched pathways based on absolute value of activation z-score (IzI score ≥ 2, p < .05). Upstream regulator analysis showed pronounced inhibition of pro-inflammatory allergic molecules IgE, IL-17A, IL-17F, IL-25 (IL-17E) (IzI score ≥ 2, FDR < 0.05) and activation of pro-tolerogenic molecules IL-12A, IL-27, IL-35 (EBI3) at the end of the grass pollen season.

Peripheral blood mononuclear cells transcriptome profile showed an inhibition of Th2, Th17 pro inflammatory allergic responses and immune deviation towards Th1 responses. PQ Grass extended regimen exhibited a superior mechanistic efficacy profile in comparison with PQ conventional regimen.

Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR.

Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s).

Treatment with dupilumab (normalized enrichment score [NES] = -1.73, p = .002) or SCIT + dupilumab (NES = -2.55, p < .001), but not SCIT alone (NES = +1.16, p = .107), significantly repressed the AR disease signature. Dupilumab (NES = -2.55, p < .001), SCIT (NES = -2.99, p < .001), and SCIT + dupilumab (NES = -3.15, p < .001) all repressed the NAC gene signature.

These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression.

House dust mite (HDM)-induced allergic rhinitis (AR) is a major cause of allergic respiratory disease. The efficacy and safety of the 300 IR HDM sublingual immunotherapy (SLIT) tablet in patients with moderate-to-severe HDM-AR was confirmed in a large, international, phase 3 randomized controlled trials (RCTs). Here, we analyzed the results in the European population.

Data from 91 European centers that participated in the international, double-blind, RCT (EudraCT 2014-004223- 46, NCT02443805) with the 300 IR HDM SLIT tablet versus placebo over 12 months were analyzed post hoc. The treatment effect in European adults and adolescents was notably assessed through the European Academy of Allergy and Clinical Immunology (EAACI)- recommended combined symptom and medication score (CSMS0-6 , pre-defined endpoint) and the total combined rhinitis score (TCRS0-24, post hoc endpoint, also balanced) during the primary evaluation period (4 weeks at the end of treatment period) using analysis of covariance (ANCOVA).

There were 818 patients who comprised the modified full analysis set in Europe. Over the primary period, the differences in CSMS0-6 and TCRS0-24 between the 300 IR and placebo groups were statistically significant (p < 0.0001): -0.32 (95%CI [-0.46; -0.17]) and - 1.28 (95%CI [-1.63; -0.94]), respectively, with relative differences of -20.9% and -21.2%. All post hoc and the rhinoconjunctivitis quality of life endpoints were significantly improved with 300 IR versus placebo. The 300 IR HDM tablet was generally well tolerated.

This RCT sub-analysis confirmed the 300 IR HDM SLIT tablet is an effective and safe treatment for European adults and adolescents with HDM-AR with clinically meaningful benefits from the patients' perspective. Trial registration: NCT02443805. Registered on April 29, 2015./EudraCT 2014-004223-46. Registered on September 16, 2015.

Allergic rhinitis with or without conjunctivitis (AR/C) can negatively impact many aspects of quality of life (QoL). The efficacy and safety of SQ sublingual immunotherapy (SLIT)-tablets have been confirmed across large clinical trials in adults with grass, tree, ragweed, and house dust mite (HDM) AR/C.

This pooled analysis investigates whether the reduction in symptom burden found across the clinical trials is supported by improvements in QoL.

11 phase II/III randomized placebo-controlled trials across the SQ grass, tree, ragweed and HDM SLIT tablets (Grass: N=3179; Ragweed: N=767; Tree: N=634; HDM: N=2221) were included. QoL was assessed using the standardized Rhinitis Quality of Life Questionnaire (RQLQ) with the exception of three grass trials that used the non-standardized version. The overall RQLQ scores were expressed as a mean of seven domains. In the pooled analysis, treatment was used as fixed effect; the trial, and the interaction between region/country with the trial as random effects.

The pooled analysis showed consistent and statistically significant improvements in overall RQLQ scores across all four SQ SLITtablets vs. placebo (Pooled estimate [95%CI], p value. Grass: -0.20 [-0.28, -0.12], P<0.001. Tree: -0.42 [-0.58, -0.26], P<0.001. Ragweed: - 0.36 [-0.55, -0.17], P<0.001. HDM: -0.28 [-0.39, -0.17], P<0.001). Furthermore, significant improvements vs. placebo for all four SQ SLITtablets were seen across the 7 individual domains.

The proven efficacy of SQ SLIT-tablets to reduce symptoms across four of the most common respiratory allergens, is supported by concurrent significant improvements in RQLQ scores - overall and for all 7 domains.

Pediatric allergic rhinitis (AR), including cedar pollinosis (CP), is increasing in Japan. We investigated the effects of sublingual immunotherapy (SLIT), which has limited studies of its effectiveness in real-world settings, on children with CP.

This retrospective cohort study used a claim database in 2018-2021. Children aged ≤15 years with CP records in 2019 were eligible and were followed up through 2021. We included 2962 CP children undergoing SLIT and 547 who were not. The medication score was used to evaluate SLIT effectiveness in the cedar pollen dispersal season each year. Adverse events and the occurrence of allergic diseases were also evaluated.

Medication score was higher in the SLIT group during the index period but lower in 2021 compared to the non-SLIT group (mean ± standard deviation: 5.17 ± 2.39 and 4.74 ± 2.38 in 2019, 3.13 ± 2.30 and 3.55 ± 2.48 in 2021, respectively). The adjusted mean difference between groups from 2019 to 2021 was -0.62 (95% confidence interval: -0.86 to -0.39, p < .0001), and the medication score was reduced in the SLIT group (risk ratio: 1.2: 1.1 to 1.3). The occurrence of adverse events involving abdominal disorders (adjusted odds ratio [aOR]: 0.64: 0.51 to 0.81), asthma exacerbation (aOR: 0.37: 0.24 to 0.57), and allergic diseases involving hay fever unrelated to CP (aOR: 0.60: 0.45 to 0.80) or asthma (aOR: 0.71: 0.58 to 0.86) was lower in the SLIT group.

In children with CP, SLIT is effective, well tolerated, and could decrease the occurrence of other allergic diseases.

Oral Allergy Syndrome (OAS), or Pollen Food Allergy Syndrome (PFAS) represents a common clinical conundrum when the reported trigger food is a tree nut (usually almond or hazelnut) or peanut. The PFAS may give rise to uncertainty about the potential severity of the future reactions, indications for prescribing epinephrine, and the extent of the necessary dietary avoidance. As a food allergy, secondary to cross-reactivity with airborne pollen, PFAS usually manifests towards the end of the first decade of life as contact urticaria of the oropharyngeal mucous membranes. Molecular allergology facilitates diagnosis and risk stratification by establishing the profile of sensitization. Exclusive sensitization to PR10 and profilins indicates signs and symptoms are due to PFAS, whereas sensitization to seed storage proteins with or without sensitization to PR10 and profilins may indicate a more severe primary nut allergy phenotype. Management relies on avoidance of the specific nut trigger, advice on the likelihood of more severe local or systemic symptoms, and treatment of reactions according to the severity. Future studies are needed to better delineate the risk of systemic reactions in individuals with nut PFAS, and to establish the role of food or pollen allergen immunotherapy for the prevention or moderation of this condition.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a Th2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, like the gut, may be crucial for lowering the risk and preventing atopic diseases particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in AD patients, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1 (TRPV1), and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and TCI, along with pioneering trials proposed to change their current use (PACI and SEAL). We provide an overview of the novel therapies that enhance the skin barrier, like probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and IL and JAK inhibitors. Lastly, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy (EPIT) and the experimental use of single-dose of adeno-associated virus (AAV) vector gene immunotherapy.

There still are few data on the long-term safety of sublingual immunotherapy (SLIT). The aim of this study was to assess the appearance of autoimmune diseases in patients before and after SLIT.

New cases of autoimmune diseases were monitored. Patients in the SLIT group (n = 816) were compared with controls (n = 1096).

The new incidences of autoimmune diseases in the SLIT group were lower compared with the control group: 18 (2.2%) versus 58 (5.3%); p < 0.05. Systemic lupus erythematosus, psoriasis and Hashimoto appeared much more often in the control group.

SLIT had no significant effect on the induction of autoimmune diseases.