Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the centre of the health system and is likely to optimise the practice of allergy. ARIA (Allergic Rhinitis and its Impact on Asthma) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomised controlled trials, observational real-life studies and allergen challenges. Using the MASK air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, were embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.

The application of allergen immunotherapy (AIT) in combination with biological agents has been found to increase both the safety and efficacy of the desensitisation procedure in patients with food and insect venom allergy. The aim of our study was to compare the effectiveness of AIT in patients with house dust mite (HDM)-driven asthma treated with and without omalizumab.

The study was a placebo-controlled, three-armed, randomised, parallel group, multicentre trial that included 52 patients with HDMdriven asthma. Only patients with monosensitisation to HDM were included. The study compared three patterns of therapy: omalizumab alone, HDM subcutaneous immunotherapy (SCIT-HDM)+ omalizumab, and SCIT alone. The main outcomes were evaluate the Asthma Control Questionnaire (ACQ) score, number of asthma exacerbations and reduction in the daily dose of inhaled steroids during 12 months of observation.

All variants of therapy led to significantly improved ACQ scores and reduction of asthma exacerbations in all study groups after 12 months of treatment. A statistically significant reduction in the daily doses of inhaled corticosteroids in the group with omalizumab alone (650±150 µg versus 500±50 µg for p=0.003) or SCIT-HDM+omalizumab (550±250 µg versus 375±75 µg for p=0.001) was observed, favouring the latter group.

The efficacy of AIT for HDM-driven asthma is significantly increased by the combination of allergen vaccine with omalizumab.

While both the incidence and general awareness of food allergies is increasing, the variety and clinical availability of therapeutics remain limited. Therefore, investigations into the potential factors contributing to the development of food allergy and the mechanisms of natural tolerance or induced desensitization are required. In addition, a detailed understanding of the pathophysiology of food allergies is needed to generate compelling, enduring, and safe treatment options. New findings regarding the contribution of barrier function, the effect of emollient interventions, mechanisms of allergen recognition, and the contributions of specific immune cell subsets through rodent models and human clinical studies provide novel insights. With the first approved treatment for peanut allergy, the clinical management of food allergy is evolving towards less intensive, alternative approaches involving fixed doses, lower maintenance dose targets, coadministration of biologicals, adjuvants, and tolerance-inducing formulations. The ultimate goal is to improve immunotherapy and develop precision-based medicine via risk phenotyping allowing optimal treatment for each food-allergic patient.

Intralymphatic immunotherapy (ILIT) is an emerging type of allergen immunotherapy with fewer injections and shorter course for allergic rhinoconjunctivitis (ARC). The efficacy and safety have not been confirmed by informative and powerful evidence yet.

A systematic review and meta-analysis were conducted through electronic searching with PubMed, Web of Science, Embase, Scopus, and China National Knowledge Infrastructure (CNKI). The safety (incidence of adverse events [AEs]), compliance (percent of patients completing treatment), and clinical efficacy of ILIT were evaluated. Clinical efficacy could be assessed by improvement of subjective symptom and rescue medication use or the nasal tolerance to specific allergen. This study is registered with PROSPERO (CRD42022353562)

12 randomized controlled trials (RCTs) comparing ILIT with placebo and 3 trials (2 RCTs and one case-control study) comparing ILIT and SCIT were included in this review. Totally, 582 patients diagnosed as AR or ARC were enrolled. Almost all the AEs were mild-to-moderate reactions except 2 patients developed anaphylactic reactions at the intralymphatic injection dose 5,000 SQ-U in one study. ILIT got higher incidence of local AEs than placebo, but their incidence of systemic AEs was similar. ILIT was safer than SCIT (p < 0.05). Almost all the patients could complete ILIT treatment, and the most common reason for discontinuation of ILIT was AEs. The compliance of patients receiving ILIT seemed higher than patients receiving SCIT. ILIT could significantly ameliorate subjective allergic symptoms, especially for seasonal ARC, and increase nasal tolerance, similar to SCIT.

ILIT was a safe and effective treatment for ARC and could achieve comparable clinical improvement with SCIT with shorter duration and higher compliance. Moreover, ILIT was safer than SCIT.

Atopic dermatitis (AD), a chronic inflammatory disorder, is often accompanied by allergic rhinoconjunctivitis (ARC) as a co morbidity. The use of a monoclonal anti-IL-4Rα antibody has been effective in controlling moderate to severe AD symptoms. Allergen-specific immunotherapy (AIT) is widely used for the treatment of ARC and asthma. The effects of AIT on basophil reactivity/effector functions have already been examined and used as indicators of the treatment efficacy. However, it is unclear, how an anti-IL-4Rα antibody can influence allergen-specific immune responses of basophils and T cells of AD patients with comorbid ARC.

To investigate the effect of a monoclonal anti-IL-4Rα antibody on the in vitro allergic responses of basophils and T cells deriving from AD patients with comorbid ARC.

Blood samples of 32 AD patients were obtained before, after 4 and 16 weeks of an anti-IL-4Rα antibody therapy (300 mg subcutaneously/2 weeks; n = 21) or AIT (daily sublingual application; n = 11). Patients treated with an anti-IL-4Rα antibody were grouped according to their serum specific immunoglobulin E levels and ARC symptoms, while patients receiving an AIT were additionally grouped according to the allergen specificity of their AIT. Basophil activation test and T cell proliferation assays were undertaken after an in vitro allergen stimulation.

A significant reduction of the immunoglobulin E levels and the allergen specific T cell proliferation was observed in AD patients treated with an anti-IL4Rα -antibody, while the allergen-specific basophil activation/sensitivity were found to be significantly increased. In patients receiving an AIT, the in vitro allergenspecific basophil activation and the T cell proliferation were found to be significantly decreased in response to seasonal allergens.

An IL-4Rα blockade induced by a monoclonal anti-IL-4Rα antibody leads to an increased activity/sensitivity of early effector cells (such as basophils), in contrast to a decreasing reactivity observed under an AIT. The late-phase T cell reaction to allergens did not differ between the herein assessed treatments.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta-analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], -1.77; 95% CI, -2.30, -1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT-RCTs reporting a moderate-to-high difference between SCIT and controls (SMD for SS, -0.81; 95% CI, - 1.12, -0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT-RCTs reporting a small benefit (SMD for SS, -0.28; 95% CI, -0.37, - 0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

There is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis.

Thirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALKAbelló) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA.

There were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-γ levels increased only in the actively treated group.

In this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

Diagnostic testing of patients who present for evaluation of insect venom allergy can involve many levels of investigation. A detailed initial history is critical for diagnosis and prognosis. The severity of previous sting reactions and the presence or absence of urticaria or hypotension predict severe future sting reactions and underlying mast cell disorders. Venom skin tests and specific IgE measurement can confirm the diagnosis but have limited positive predictive value for the frequency and severity of future sting reactions. Testing for serum IgE to recombinant venom component allergens can distinguish true allergy from crossreactivity to honey bee and yellowjacket venoms. Basophil activation tests can improve detection of venom allergy, and predict severity of reactions and the efficacy of venom immunotherapy, but are limited in availability. Elevated basal serum tryptase level is an important marker for severe sting anaphylaxis and underlying mast cell disorders (eg, hereditary alpha-tryptasemia and clonal mast cell disease). When there is high suspicion (eg, using the REMA score), bone marrow biopsy is the definitive tool to characterize the mast cell disorders that are associated with the most severe outcomes in patients with insect sting allergy.

Low-dose oral immunotherapy (OIT) is a safe treatment for hen's egg allergy; however, comparison of its therapeutic effects with those of highdose OIT has not been reported.

To compare the efficacy of low- and high-dose boiled egg-white (EW) OIT for hen's egg allergy.

Patients with hen's egg allergy were randomly assigned to two groups: OIT using hard-boiled EW with a maximum maintenance dose of 2 and 20 g in the low-dose (L-D) and high-dose (H-D) groups, respectively. The intake dose was ingested twice a week, increased by approximately 20% per week until reaching the target maintenance dose (2 or 20 g hard-boiled EW), and maintained thereafter according to the schedule. The threshold was confirmed via oral food challenge (OFC) after 6 months, and the difference in the proportion of subjects passing the exit OFC between groups was evaluated.

Fifty-two patients (L-D, n = 23; H-D, n = 29) were enrolled. Thirty-three patients (L-D, n = 17; H-D, n = 16) completed the 6-month OIT and underwent an exit OFC. In total, three (L-D, 3/17; H-D, 3/16) patients in each group tested negative for an exit OFC with a 20-g reactive dose (p = 1.000). EW-specific IgE levels in both groups decreased significantly after OIT (L-D, p < 0.001; H-D, p = 0.002).

A threshold-elevating effect was observed in the L-D group, not inferior to that in the H-D group. Low-dose OIT may be appropriate to treat hen's egg allergy for the first 6 months.

Oral immunotherapy (OIT) is limited by adverse events, and most patients require continued treatment to maintain their increased threshold. Adjunctive treatments have been explored to increase the safety and efficacy of OIT.

This study aimed to determine the safety and efficacy of E-B-FAHF-2 for inducing remission in subjects undergoing omalizumab-facilitated multiallergen OIT.

In this double-blind, placebo-controlled clinical trial, subjects were randomized 1:1 to receive either E-B-FAHF-2 or placebo, starting 2 months before OIT and continuing throughout OIT. All subjects received a 4-month course of omalizumab, starting 2 months before OIT through the 2-month OIT build-up phase. Following 24 months of multi-OIT (maintenance dose of 1000 mg of each allergen), desensitization and remission were assessed. The primary objective was to determine if subjects in the E-B-FAHF-2 group (EOIT) were more likely than the placebo group (OIT) to develop remission to all 3 allergens treated with multi-OIT, as defined by the absence of dose-limiting symptoms to a cumulative dose of 4,444 mg protein after discontinuing treatment for 3 months.

Thirty-three subjects were randomized. 63.6% were desensitized to 4444mg protein for each allergen at 26 months, and 24.2% met the primary outcome of remission at 29 months, with no difference between treatment groups. There was good adherence (>85%) with study medications, with no difference between treatment groups. There was no difference in reported overall adverse events between treatment groups.

Omalizumab facilitated multi-food OIT was safe and effective, and emission was achieved in about a quarter of subjects. However, utcomes were not improved by addition of E-B-FAHF-2.