Allergic diseases are the most common chronic immune-mediated disorders, and can manifest with an enormous diversity in clinical severity and symptoms. Underlying mechanisms for the adverse immune response to allergens and its downregulation by treatment are still being revealed. As a result, there have been, and still are, major challenges in diagnosis, prediction of disease progression/evolution and treatment. Currently, the only corrective treatment available is allergen immunotherapy (AIT). AIT modifies the immune response through long-term repeated exposure to defined doses of allergen. However, as the treatment usually needs to be continued for several years to be effective, and can be accompanied by adverse reactions, many patients face difficulties completing their schedule. Long-term therapy also potentially incurs high costs. Therefore, there is a great need for objective markers to predict or to monitor individual patient’s beneficial changes in immune response during therapy so that efficacy can be identified as early as possible. In this review we specifically address recent technical developments that have generated new insights into allergic disease pathogenesis, and how these could potentially be translated into routine laboratory assays for disease monitoring during AIT that are relatively inexpensive, robust and scalable.

Only some patients with peanut allergy undergoing oral immunotherapy (OIT) achieve sustained clinical response. Basophil activation could provide a functional surrogate of efficacy.

We hypothesized that changes in basophil sensitivity and area under the curve (AUC) to the immunodominant allergen Ara h 2 correlate with clinical responses to OIT.

Children with peanut allergy aged 7 to 13 years were enrolled in a single-center, open-label peanut OIT trial. Levels of specific immunoglobulins were measured throughout OIT. Peripheral blood from multiple time points was stimulated in vitro with peanut allergens for flow cytometric assessment of the percentage of CD63hi activated basophils.

Twenty-two of 30 subjects were successfully treated with OIT; after avoidance, 9 achieved sustained unresponsiveness (SU), and 13 had transient desensitization (TD). Basophil sensitivity, measured by using the dose that induces 50% of the maximal basophil response, to Ara h 2 stimulation decreased from baseline in subjects with SU (after OIT, P = .0041; after avoidance, P = .0011). At 3 months of OIT, basophil sensitivity in subjects with SU decreased from baseline compared with that in subjects with TD (median, 18-fold vs 3-fold; P = .01), with a receiver operating characteristic of 0.84 and optimal fold change of 4.9. Basophil AUC to Ara h 2 was suppressed after OIT equally in subjects with SU and those with TD (P = .4). After avoidance, basophil AUC rebounded in subjects with TD but not those with SU (P < .001). Passively sensitized basophils suppressed with postavoidance SU plasma had a lower AUC than TD plasma (6.4% vs 38.9%, P = .03).

Early decreases in basophil sensitivity to Ara h 2 correlate with SU. Basophil AUC rebounds after avoidance in subjects with TD. Therefore, different aspects of basophil activation might be useful for monitoring of OIT efficacy.

Allergies to cats are the most common animal-origin allergy, and affect approximately 1 in 5 adults worldwide. The prevalence of allergy to furry animals has been increasing, and allergy to cats is a major risk factor for the development of asthma and rhinitis. The diagnosis of cat allergy is now well established. The exact significance of component-resolved diagnosis in the diagnosis of cat allergy remains to be fully understood. Allergen avoidance is effective but often has a psychologic impact. Allergen immunotherapy is not well demonstrated. There is a need for innovative approaches to better manage cat allergens. Next-generation care pathways for asthma and rhinitis will define the place of cat allergen avoidance.

This manuscript, based on content presented at the European Academy of Allergy and Clinical Immunology Congress 2019, provides information on the prevalence and impact of cat allergies and the molecular biology of Fel d 1, the major cat allergen.

The authors present the scientific basis of a novel care pathway that utilizes anti-Fel d 1 IgY antibodies to safely and effectively neutralize Fel d 1 after its production by the cat but before human exposure.

Efficacy of a feline diet with an egg product ingredient containing anti-Fel d 1 IgY antibodies was demonstrated in vitro, ex vivo, and in vivo, and further validated by a pilot exposure study involving cat-allergic human participants.

Specific immunotherapy is the only treatment acting on causes and not only on symptoms of respiratory allergy. It was first introduced as subcutaneous immunotherapy (SCIT) with the aim to induce immunological tolerance to the administered allergen(s). In the 1980s, sublingual immunotherapy (SLIT) was developed, mainly to improve the safety, which was a critical issue at that time.

This article reviews the available literature, including a large number of randomized controlled trials, meta-analyses, and real-life studies as well, on the outcomes of SCIT and SLIT concerning the treatment critical issues of the two routes, that are efficacy, safety, cost-effectiveness, and compliance to treatment.

SCIT and SLIT are similarly effective in treating patients with respiratory allergy, providing, based on the induction of typical changes in the immunologic response, an early control of symptoms that steadily increases during the treatment and, once reached the recommended duration of 3 years, continues to work after stopping. This outcome is the major factor influencing the economic advantage of SCIT and SLIT over drug treatment.

The usefulness of low-dose oral immunotherapy (OIT) for the treatment of egg allergy has been unclear.

To evaluate the efficacy and safety of OIT with low allergen cookies (LACs) containing a low dose of hen’s egg.

Thirty-three patients with severe hen’s egg allergy were randomly administered either OIT with LACs (n = 21) or placebo (n = 12). Two patients in the LACs group withdrew before completing OIT. The primary endpoint was the number of good responders (G-R), patients with negative results in the oral food challenge (OFC) with a final dose of 2 g hard-boiled egg whites after 4 months of OIT, in each group. Total OFC Aichi score for anaphylaxis/cumulative protein dose (TS/Pro) as the marker of severity of food allergy was also compared. Adverse events during OIT were evaluated using patients’ diaries.

The proportion of G-R in the LACs group was higher than in the placebo group (7/19 [37%] vs. 1/12 [8%], χ2 test; p = 0.077). The TS/Pro after OIT in the LACs group was lower than in the placebo group (median score, 44.2 vs. 104.1, p = 0.059; Mann-Whitney U test). The threshold and TS/Pro before and after OIT significantly improved in the LACs group (p = 0.015, p = 0.027, respectively; Wilcoxon signed-rank test). There were 99 recorded incidences of symptoms of 1,938 intake events in the LACs group during OIT. Of these, 90 were mild; no severe symptoms occurred.

OIT with LACs potentially increases the OFC threshold and decreases allergy severity and is a relatively safe treatment modality.

Allergen-specific immunotherapy (AIT) for aeroallergens consists of the administration of standardized allergen extracts to patients with respiratory IgE-mediated diseases to the same allergen in order to achieve immune tolerance to the allergen and prevent onset of symptoms. AIT is usually delivered by sublingual, subcutaneous route. Both sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) are given at increasing doses in the build-up phase and then at maintenance dose. The allergen dose is regularly administered throughout the year or pre/co-seasonally, depending on the causal allergen and the type of allergen extract. AIT with one or multiple allergens currently represents the only causal treatment able to change the natural history of allergic airways diseases (1). Significant progresses have been made in terms of AIT efficacy and safety since the first report of the treatment of hay-fever by SCIT using pollen extracts, described by Noon and Freeman in 1911 (2; 3). The first randomized study on SLIT dates back to 1986 (4). Several placebo-controlled studies on AIT in the subsequent years have allowed systematic reviews suggesting evidence for improvement of symptoms and reduction of medication use for both allergic rhinitis (AR) and asthma (5). However, AIT remains underused since interpretation of evidence remains challenging for heterogeneity among studied populations, selection of potential responders, outcomes, regimens and products for AIT. Moreover, the use of AIT is hampered by fluctuating availability of AIT products, different educational level of physicians and lack of consciousness of AIT in the general population (6).

Allergic asthma is the predominant phenotype in clinical practice. Allergen immunotherapy is the only curative and specific approach for the treatment of allergies with clinical benefits for several years after its discontinuation. Despite advances, the use of allergen immunotherapy in allergic asthma is still suboptimal and controversial.

The purpose of this article is to review the published data about the impact of allergen immunotherapy with the most commonly used allergen extracts on allergic asthma outcomes, including both clinical parameters and patients’ subjective experience (quality of life).

As data sources several databases were used, including PubMed, Scopus, Web of Science (2002-2019) and search in English and Spanish languages was performed using the following terms: “allergen immunotherapy” and “asthma” in combination with “house dust mite”, “birch pollen”, “grass pollen”, “olive tree pollen”, “molds”, “pets” and “asthma quality of life”. Randomised control trials and meta-analysis from reviewed publications were selected.

Emerging data relating to the positive impact on asthma outcomes of allergen immunotherapy allows the addition of this treatment as a therapeutic option in mild to moderate asthmatics sensitized to house dust mite and pollens. Limited data are available for patients sensitized to molds and pets, as well in severe allergic asthma population.

Allergen immunotherapy remains a potential therapeutic option for some patients with allergic asthma. Further research is needed to define the optimal period of treatment, the possible therapeutic role in the treatment of severe allergic asthma, and the cost-effectiveness of allergen immunotherapy in asthmatic patients.

The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features. Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development. Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit. More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that.

Nowadays, people pay more attention to biomarkers that can predict clinical efficacy of immunotherapy for allergic rhinitis. As the only recognized aetiological treatment, the efficacy of allergen immunotherapy (AIT) has been proved by many studies. However, treatment success depends on compliance and persistence greatly, which can be impaired by the lengthy duration of AIT and socioeconomic status of patients. Besides, ineffectiveness is another factor that accounts for non-adherence. If the clinical efficacy can be predicted in the early stage of immunotherapy, it can help patients choose appropriate treatment plans, increase patient compliance and optimize the allocation of medical resources. This paper mainly focuses on five candidate biomarkers, the sIgE/tIgE ratio before treatment, serum inhibitory activity for IgE, decreased basophil activation, upregulation of Tregs and tolerogenic DCs, reviews the time when potential biomarkers can predict or monitor the efficacy of AIT, discusses the reason why these indicators could serve as efficacy biomarkers and interactions among potential biomarkers.

Hymenoptera venom allergy (HVA) is the most frequent cause of anaphylaxis in Europe, accounting for most of the severe reactions occurring in adults, and being the second cause of anaphylaxis in children. Prevention of further episodes in patients who developed a systemic reaction (SR) is based on the correct management of the allergic emergency, the referral to an allergist for a correct diagnosis, prescription of adrenaline auto-injectors (AAI) and specific venom immunotherapy (VIT), if recommended. Diagnosis is based on the classification of the type of reaction, confirmation of an IgE-mediated pathogenesis and the identification of the offending insect. The use of component resolved diagnostics may be helpful in case of poly-sensitization or negative allergy tests with a proven history of previous SRs. When a severe SR occurs, baseline serum tryptase levels should always be assessed. The prescription of AAI is recommended or suggested for untreated patients, patients undergoing VIT and after discontinuation of treatment, according to multiple evidence. VIT is the most effective treatment available for HVA patients, as confirmed by recent European guidelines. VIT has an early, sustained and persistent protective effect and modifies the natural course of the disease. Moreover, VIT proved to be safe and well tolerated. According to a recent systematic review, no treatment-related fatalities were recorded to date. Compared to AAI, VIT significantly improves the quality of life of HVA patients by reducing the anxiety and limitations in daily activities caused by the fear of stinging insects. The memory of a life-threatening experience is the most likely reason why adherence to VIT is higher compared to immunotherapy with inhalant allergens. Several risk factors in HVA have been identified that can influence not only the severity of sting reactions in untreated patents, but also the occurrence of side effects, treatment effectiveness and the risk of relapse after discontinuation of VIT. Patient and treatment-related risk factors must be considered while selecting the best candidates for VIT, the type and duration of treatment. In this paper we address the most important issues related to HVA and VIT that may have an impact on daily clinical practice.