Allergen immunotherapy (AIT) is the only causal treatment for respiratory allergy. Long-term real-life effectiveness of AIT remains to be demonstrated beyond the evidence from randomised controlled trials (RCTs).

REACT (Real world effectiveness in allergy immunotherapy) is a retrospective cohort study using claims data between 2007 and 2017. Study eligibility was a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analysed as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up (ClinicalTrial.gov: NCT04125888).

46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort. AIT-treated subjects were 29¢5 (16¢3) years and 53% were male. Compared to pre index year, AIT was consistently associated with greater reductions compared to control subjects in AR and asthma prescriptions, including both asthma controller and reliever prescriptions. Additionally, the AIT group had significantly greater likelihood of stepping down asthma treatment (P <0¢0001). In addition to the reduction in asthma treatment in the AIT group, a greater reduction in severe asthma exacerbations was demonstrated (P<0¢05). Reductions in pneumonia with antibiotic prescriptions, hospitalisations, and duration of inpatients stays were all in favour of AIT.

The study extends the existing RCT evidence for AIT by demonstrating longer-term and sustained effectiveness of AIT in the real world. Additionally, in patients with concurrent asthma, AIT was associated with reduced likelihood of asthma exacerbations and pneumonia.

Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy.

PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1–10 years, weighing more than 7 kg, with peanut allergy confirmed by a double blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (≥3 mm) or peanut-specific IgE (≥0·35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 × 10¹⁰ colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Clinical Trials Registry, 12616000322437.

Between July 4, 2016, and Sept 21, 2020, 201 participants were enrolled and included in the intention-to-treat analysis. 36 (46%) of 79 children in the PPOIT group and 42 (51%) of 83 children in the OIT group achieved sustained unresponsiveness compared with two (5%) of 39 children in the placebo group (risk difference 40·44% [95% CI27·46 to 53·42] for PPOIT vs placebo, p<0·0001), with no difference between PPOIT and OIT (–5·03% [–20·40 to 10·34],p=0·52). Treatment-related adverse events were reported in 72 (91%) of 79 children in the PPOIT group, 73 (88%) of83 children in the OIT group, and 28 (72%) of 39 children in the placebo group. Exposure-adjusted incidence of adverse events was 10·58 in the PPOIT group, 11·36 in the OIT, and 2·09 in the placebo group (ratio 0·92 [95% CI 0·85 to 0·99]for PPOIT vs OIT, p=0·042; 4·98 [4·11–6·03] for PPOIT vs placebo, p<0·0001; 5·42 [4·48 6·56] for OIT vs placebo,p<0·0001), with differences seen primarily in gastrointestinal symptoms and in children aged 1–5 years. During the12-month post-treatment period, 60 (85%) of 71 participants in the PPOIT group, 60 (86%) of 70 participants in the OITgroup, and six (18%) of 34 participants in the placebo group were eating peanut; rescue epinephrine use was infrequent(two [3%] of 71 in the PPOIT group, four [6%] of 70 in the OIT group, and none in the placebo group).

Both PPOIT and OIT were effective at inducing sustained unresponsiveness. Addition of a probiotic did not improve efficacy of OIT, but might offer a safety benefit compared with OIT alone, particularly in preschool children.

Wasp allergy with a diagnostic profile of double sensitizations to vespid venom is a frequent clinical problem in areas where different genera of wasps are present. Identification of the insect responsible for serious reactions poses a diagnostic challenge as the only effective treatment to date is immunotherapy based on the specific venom. In southern Europe, the double sensitization to Vespula and Polistes venoms is highly frequent. It has been shown that the major allergenic proteins (Phospholipase A1 and Antigen 5) share sequences across the different genera and species, which would be the cause of cross-reactivity. Additionally, the minor allergens (Dipeptidyl-peptidases, Vitellogenins) have been found to share partial sequence identity. Furthermore, venom contains other homologous proteins whose allergenic nature still remains to be clarified. The traditional diagnostic tools available are insufficient to discriminate between allergy to Vespula and Polistes in a high number of cases. IgE inhibition is the technique that best identifies the cross-reactivity. When a double sensitization has indeed been shown to exist or great uncertainty surrounds the primary sensitization, therapy with two venoms is advisable to guarantee the safety of the patient. In this case, a strategy involving alternate administration that combines effectiveness with efficiency is possible.

The immune system interacts with many nominal ‘danger’ signals, endogenous danger associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)- associated molecular pattern molecules. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs, and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regards to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.

This Position Paper is a product of the EAACI Working Group for AllergoOncology, an expert panel of clinical immunologists, allergists, biochemists and epidemiologists. The topic of the manuscript was identified at the WG workshop in May 2020 and a streamline of relevant subtopics was extensively revised and designated to individual WG members. After following workshops and using a circulation process, the final manuscript was recirculated for review to the WG authors, compiled and again recirculated for complete consensus on text, tables and figures. The final manuscript was read and approved by all authors and represents an expert consensus position, with recommendations summarized in the “Highlights box”.

A precise diagnosis is key for the optimal management of allergic diseases and asthma. In vivo or in vitro diagnostic methods that use allergen extracts often fail to identify the molecules eliciting the allergic reactions.

Component-resolved diagnosis (CRD) has solved most of the limitations of extract based diagnostic procedures and is currently valuable tool for the precision diagnosis in the allergy clinic, for venom and food allergy, asthma, allergic rhinitis, and atopic dermatitis. Its implementation in daily practice facilitates: a) the distinction between genuine multiple sensitizations and cross-reactive sensitization in polysensitized patients; b) the prediction of a severe, systemic reaction in food or insect venom allergy; c) the optimal selection of allergen immunotherapy based on the patient sensitization profile. This paper describes its main advantages and disadvantages, cost-effectiveness and future perspectives.

The diagnostic strategy based on CRD is part of the new concept of precision immunology, which aims to improve the management of allergic diseases.

Allergen Immunotherapy (AIT) is a well-established, efficient, and safe way to treat respiratory and insect-venom allergies. After determining the diagnosis of the clinically relevant culprit allergen, AIT can be prescribed. However, not all patients are eligible for AIT, since some diseases/ conditions represent contraindications to AIT use, as described in several guidelines. Allergists are often preoccupied on whether an extensive workup should be ordered in apparently healthy AIT candidates in order to detect contra-indicated diseases and conditions. These preoccupations often arise from clinical, ethical and legal issues. The aim of this article is to suggest an approach to the workup and assessment of the presence of any underlying diseases/conditions in patients with no case history before the start of AIT. Notably, there is a lack of published studies on the appropriate evaluation of AIT candidates, with no globally accepted guidelines. It appears that Allergists are mostly deciding based on their AIT training, as well as their clinical experience. Guidance is based mainly on experts’ opinions; the suggested preliminary workup can be divided into mandatory and optional testing. The evaluation for possible underlying neoplastic, autoimmune, and cardiovascular diseases, primary and acquired immunodeficiencies and pregnancy, might be helpful but only in subjects for whom the history and clinical examination raise suspicion of these conditions. A workup without any reasonable correlation with potential contraindications is useless. In conclusion, the evaluation of each individual candidate for possible medical conditions should be determined on a case-by-case basis.

Although the rates of SRs have declined to an estimated rate of 1 per 1000 injections, FRs still occur. A risk stratification before the initiation of AIT may be of value to better select patients for such treatment. Risk versus benefit is a consideration for any treatment program, including SCIT. Risk factors for FRs include the following: uncontrolled asthma, a history of SR, and injections administered during a peak pollen season.Unmet needs include the safety of SLIT versus SCIT in highrisk populations and safety of modified recombinant allergens. In addition, the impact of COVID-19 on the use of SCIT and SLIT, as well as SRs, is still unclear.

House dust mite sublingual immunotherapy (HDM SLIT) effectively treats allergic rhinitis (AR). However, the evidence of HDM SLIT for allergic asthma remained limited.

To systematically review the efficacy and safety of HDM SLIT tablets in patients with allergic asthma.

We performed a systematic search through PubMed, Scopus, EMBASE, Web of Science, the Cochrane Center of Controlled Trials, and Google Scholar for randomized controlled trials (RCTs) that addressed the efficacy and safety of HDM SLIT tablets compared with placebo or no intervention in allergic asthma from their inception date until September 2021. The primary outcome was the reduction in inhaled corticosteroid (ICS) dose. Additional outcomeswere asthma control, exacerbation, lung function, quality-of-life, and adverse events (AEs).

There were seven RCTs, 5 studies in allergic asthma (4 in adults and one in children), and 2 in AR with or without asthma. The 6 SQ-HDM effectively reduced ICS dose in well- to partly-controlled mild-to-moderate asthma in 1 RCT. Two RCTs evaluated the efficacy of 6 SQ- and 12 SQ-HDM in reducing asthma exacerbation in partly-controlled moderate-to severe asthma, and their results were inconsistent. One study in children with mild-to moderate asthma found no benefit of HDM SLIT. Two RCTs in AR with or without mild-to moderate asthma showed improvement of asthma symptoms. AEs were primarily local, and anaphylaxis treated with epinephrine was reported in 3 patients.

HDM SLIT tablets tend to effectively reduce ICS use in adults and adolescents with well- to partly-controlled mild-to-moderate allergic asthma with a favorable safety profile.

This study investigated patients' preference for allergy immunotherapy (AIT) administered as either sublingual immunotherapy-tablets versus monthly or weekly subcutaneous immunotherapy (SCIT) from a Spanish patient perspective.

A discrete choice experiment (DCE) consisting of two blocks with eight choice sets in each was constructed to elicit the preferences for AIT. Three attributes were included in the DCE for the mode of administration, including the frequency of administration, the risk of systemic reactions and the co-payment. Adults and caregivers of children with moderate to severe allergic rhinitis (AR) were included if they were not currently receiving or had not previously received AIT.

In total, 587 adults and 613 caregivers started the survey. Of those, 579 adults and 611 caregivers completed the survey and were included in the study. Both adults and caregivers had a significant preference for tablets compared with both monthly and weekly injections (p ≤ 0.0001). Furthermore, the respondents showed a significant preference for reducing the risk of systemic reactions. Subgroup analyses showed that caregivers of polyallergic children and female caregivers were significantly less price sensitive when choosing their preferred treatment.

Our study demonstrated that both adults with AR and caregivers of children with AR prefer daily SLIT-tablets to SCIT with either a weekly or monthly dose schedule.

-The clinical history of an insect reaction is key to determining the diagnostic evaluation and therapeutic options that are needed. -Patients with Hymenoptera venom allergy should be assessed for factors that may place them at risk during the diagnostic evaluation and treatment of venom allergy. -Venom immunotherapy is the treatment of choice to decrease future risk in Hymenoptera venom allergy and should be considered for all patients with insect-triggered anaphylaxis. Patients deemed to be at high risk for relapse should be candidates for lifelong immunotherapy.