A biomarker that could identify individuals at high risk for severe honeybee sting allergic reaction and/or systemic adverse events (SAEs) during venom immunotherapy (VIT) would improve the management of patients with honeybee (HB) venom allergy.

To identify biomarkers for risk of severe sting reactions or SAEs during VIT.

 We recruited 332 patients undergoing HB VIT. We ascertained predictors of the severity of the field-sting reaction and the severity and threshold of SAEs during VIT. We assessed the use of cardiovascular medications; baseline serum tryptase (BST) levels; specific IgEs to HB venom, rApi m 1, and rApi m 10; and basophil activation test (BAT) response.

: Significant and independent predictors of a severe HB field-sting reaction were age (P = .008), an absence of skin symptoms (P = .001), BST (P = .014), and BAT response at an HB venom concentration of 0.1 μg/mL (P = .001). Predictors of severe SAEs during HB VIT were age (P = .025), BST (P = .006), and BAT response (P = .001). BAT response was also an individual and significant predictor of any SAEs and SAEs at a low cumulative allergen dose (median, 55 μg) during VIT build-up (P < .001). The use of β-blockers and angiotensin-converting-enzyme inhibitors and specific IgE levels were not associated with the severity of HB field-sting reactions or VIT SAEs.

 BST and basophil activation are independent risk factors for severe HB sting anaphylaxis and SAEs during HB VIT. BAT response was the best biomarker for any SAEs and a lower threshold of SAEs during HB VIT. These risk factors can help guide recommendations for VIT and overcome systemic reactions to HB VIT.

Medicinal products for allergen immunotherapy (AIT) of food allergies have gained enormous momentum in recent years. With this new class of products entering marketing authorization procedures, compliance to regulatory requirements becomes a critical element. Here, an overview is provided on specific requirements and aspects concerning the quality control and manufacturing of these products.

 Recent developments in the field of AIT for food allergies are divers, including products for oral, epicutaneous, and subcutaneous application, most notably targeting egg, milk, and peanut allergy. As the source materials for food AIT product are typically produced for food consumption and not for medicinal purposes, unique challenges arise in the manufacturing processes and controls of these medicinal products. Individual approaches are needed to assure acceptable quality, including control of relevant quantitative and qualitative characteristics. Major characteristics for quality verification include determination of protein content, total allergenic activity, and major allergen content. The applied manufacturing processes need to be established such that relevant process parameters are kept within justified limits and consistency of produced batches is assured. Allergen products for food AIT present specific challenges with respect to quality aspects that differentiate them from other commonly available AIT products. While established regulation is available and provides clear guidance for most aspects, other issues require consideration of new and individual settings relevant here. Consequently, as experience grows, respective amendments to currently available guidance may be needed.

Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts.

OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort.

The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase.

This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.

Allergic rhinitis (AR) is an IgE-mediated inflammatory condition that causes symptoms of sneezing, nasal congestion, rhinorrhea, and nasal itch. Although subcutaneous immunotherapy (SCIT) for the treatment of AR has been in use and well established as a treatment modality, sublingual immunotherapy (SLIT) is increasingly considered to be the safer and more convenient alternative. Thus, the objective of this review is to describe recent findings pertaining to the use of SLIT tablets (SLIT-T) for AR.

A total of 11 RCTs were selected for full-text review and included in the analysis. All studies investigated the use of SLIT on patients with seasonal allergic rhinitis (4 tree pollen studies, 1 grass pollen study, 1 Japanese Cedar) or perennial allergic rhinitis (3 house dust mite studies).

A database search (PubMed.gov) for articles published between January 1 st, 2017 to February 9 th, 2021 was conducted using the following key words: "allergic rhinitis", AND-ed "sublingual immunotherapy". Included were randomized placebocontrolled trials (RCTs). Other experimental designs studies were excluded.

Our review of 7 recently published randomized placebo-controlled trials with 2348 subjects receiving SLIT, reported increased efficacy, safety, supportive immunological parameters (IgE and IgG4 levels pre- and post-treatment levels) and improved quality of life. All studies excluded subjects with overlapping seasonal or perennial allergens, a history of moderate to severe, uncontrolled asthma or reduced lung function.

Our review highlights that SLIT is a safe and effective treatment that significantly reduces symptoms and medication requirements in allergic rhinitis, and improved quality of life.

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with type 1-mediated allergic diseases such as allergic rhinitis/rhinoconjunctivitis with/without allergic asthma. Although many innovations have been developed since the first clinical report of Noon et al in 1911, the improvement of clinical efficacy and tolerability of this treatment is still an important unmet need. Hence, much progress has been made in the characterization of the cell types, cytokines, and intracellular signaling events involved in the development, maintenance, and regulation of allergic reactions, and also in the understanding of the mechanisms of tolerance induction in AIT. This comprehensive review aims to summarize the current innovative approaches in AIT, but also gives an outlook on promising candidates of the future. On the basis of an extensive literature review, integrating a clinical point of view, this article focuses on recent and future innovations regarding biologicals, allergen-derived peptides, recombinant allergens, "Toll"-like receptor agonists and other adjuvants, and novel application routes being developed for future AIT.

In line with evidence for a role of pathogenic TH2A in seasonal allergies, we previously showed that individuals suffering from food allergy exhibited a decrease in circulating TH2A cells following multi-food immunotherapy. Herein, we aim to confirm the decline of TH2A cells in individuals undergoing house dust mite immunotherapy (HDM-AIT) and extend our observation to a new subset of CD38 expressing activated TH2A cells.

The frequencies of TH2A and CD38+ TH2A cells were analysed by flow cytometry in blood cells from 182 Japanese HDM-allergic individuals included in a 1-year clinical trial assessing the efficacy of HDM tablets. Interrelationship between these cellular responses and humoral mite-specific IgE and IgG4 levels was further explored.

 A decrease in TH2A cells was observed in both active and placebo groups. Interestingly, CD38+ TH2A cell frequencies significantly decreased only in active groups. In younger individuals (16-30 years), both TH2A and CD38+ TH2A cells were significantly reduced in active groups but not in the placebo group. Significant inverse correlations were observed in the course of HDM-AIT between changes in TH2A or CD38+ TH2A frequencies and IgG4 antibody levels.

 We confirm the value of monitoring TH2A cell frequencies in allergic individuals and extend this observation to perennial allergy to HDM. We highlight the interest of CD38 to better identify the subset of TH2A cell down-regulated by AIT. Finally, correlated cellular and humoral responses observed in immunoreactive individuals stress that coordinated pathways occur in the adaptive responses during AIT.

Allergen immunotherapy (AIT)-associated adverse events are a major concern for safety and efficacy of AIT. Presently, there is no consensus to whether antihistamine premedication could improve such conditions.

To identify the superiority of antihistamine pretreatment in AIT.

A comprehensive literature search for randomized controlled trials (RCTs) reporting the effects of antihistamine premedication on safety and efficacy of AIT was performed in MEDLINE, Embase and Cochrane Library databases. Safety was assessed according to the number of patients reporting systemic adverse reactions (SARs; the primary outcome), efficacy according to the number of patients achieving target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergen.

Eleven RCTs (including 609 patients) satisfied the inclusion criteria for the meta-analysis. All premedication protocols were temporary. Pooled analysis demonstrated that compared to control patients, significantly fewer antihistaminepretreated patients reported total and moderate-to-severe SARs (OR= 0.36; 95%CI, 0.23 to 0.56, P<0.05; and OR= 0.20; 95%CI, 0.06 to 0.74, P<0.05; respectively), as well as total and moderate-to-severe SAR episodes (OR= 0.42; 95%CI: 0.34 to 0.53, P<0.05; and OR= 0.09; 95%CI: 0.01 to 0.50, P<0.05; respectively). Similarly, antihistamine pretreatment significantly increased the number of patients achieving TMD (OR= 2.94; 95%CI: 1.72 to 5.03, P<0.05), but not SU (OR= 1.65; 95%CI: 0.77 to 3.54, P=0.2), compared with the control group. Subgroup analysis according to different allergens and dose escalating approaches also displayed superiority of antihistamine pretreatment over control.

Antihistamine premedication can significantly improve safety and efficacy of AIT by reducing frequency and severity of SAR and increasing TMD.

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions.

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase 3 registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) air flow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.

Allergic rhinitis (AR) is a very common disease. In most cases, therapy is based on symptomatic drugs, while allergen immunotherapy (AIT), which is the only one to act on the cause of the disease, is reserved for patients with a greater burden of disease. In particular, the possible evolution towards asthma substantiates the use of AIT, but requires the availability of diagnostic indices related to the risk of developing asthma. We analyzed the available literature on risk factors for onset of asthma in patients with AR, including bronchial hyperresponsiveness, uncovering by respiratory function tests of airway impairment, measurement of fractioned exhaled nitric oxide, given IgE sensitization pattern, and respiratory infections detected by nasal mucus samples or by particular microbiomes. Most of these risk predictors have been investigated too little or do not have consistent results, while various studies have confirmed that early bronchial impairment in AR patients, particularly concerning small airways, should be considered as prescriptive criteria for AIT.