There have been few studies conducted on the efficacy and safety of specific immunotherapy with allergen extracts of fungi compared to other allergen extracts and there are no data on major allergen Alt a 1 of the fungus Alternaria alternata.

To evaluate the efficacy and safety of subcutaneous immunotherapy with two different doses of Alt a 1 in patients with rhinoconjunctivitis due to sensitisation to Alternaria alternata.

Multicentre, randomised, double-blind, placebo-controlled trial with Alt a 1 administered subcutaneously in patients with allergic rhinoconjunctivitis, with or without controlled asthma, aged 12-65 years. Three groups were included: placebo, and 0.2 μg, and 0.37 μg Alt a 1/doses. The main endpoint was the combined symptom and medication score. Secondary endpoints were cutaneous reactivity and serum IgE and IgG4 to Alt a 1. Recorded adverse reactions were graded according to WAO criteria.

There were significant reductions in the combined symptom and medication score for the dose of Alt a 1 0.37 μg compared with placebo at 12 months of treatment. Reduced cutaneous reactivity and IgE levels, together with increased IgG4 levels, were demonstrated for the two active groups versus placebo. A similar safety profile was found for both active groups compared with placebo. No serious ADR were reported.

Immunotherapy with Alt a 1 was efficacious and safe, reducing the symptoms and medication associated with rhinoconjunctivitis after only one year of treatment. The clinical benefits were associated with reduced skin reactivity and specific IgE, and increased IgG4

The safety and efficacy of oral immunotherapy for tree nut allergy has not been demonstrated to date, and its effectiveness is complicated by the high prevalence of coallergies to several nuts. This study aimed to investigate the use of walnut oral immunotherapy in the desensitisation of walnut and additional tree nuts in patients who are co-allergic to several nuts.

In a single-centre, prospective cohort study (the Nut Co-Reactivity ACquiring Knowledge for Elimination Recommendations study) at the Institute of Allergy, Immunology, and Paediatric Pulmonology at the Yitzhak Shamir Medical Centre, we recruited patients aged 4 years or older who were allergic to walnut, with or without co-allergy to pecan, hazelnut, and cashew. The diagnosis of each food allergy was based on a positive skin prick test or specific serum IgE (≥0·35 kUA/L) to the corresponding nut together with a positive oral food challenge, unless an immediate (within 2 h of exposure) reaction in the past year had been documented. Patients with uncontrolled asthma or a medical contraindication to receive adrenaline were excluded. Patients were assigned to walnut oral immunotherapy or the control group (observation and strict dietary exclusion) on the basis of the order of presentation to the clinic. Oral immunotherapy began with a 4-day dose-escalation phase to establish the single highest tolerated dose, which was consumed daily at home for 24 days; subsequent monthly dose escalations were repeated until 4000 mg walnut protein was achieved. Patients who were desensitised to walnut continued to consume 1200 mg walnut protein daily for 6 months as maintenance. The primary outcome was walnut desensitisation (passing an oral food challenge with 4000 mg of walnut protein) at the end of the study, analysed by intention to treat. In patients who were co-allergic to pecan, hazelnut, and cashew, the proportion who achieved cross-desensitisation to these nuts in addition to walnut desensitisation was examined.

73 patients with a walnut allergy were enrolled between May 15, 2016, and Jan 14, 2018. 49 (89%) of 55 patients in the oral immunotherapy group were desensitised to walnut compared with none of 18 patients in the control group (odds ratio 9·2, 95% CI 4·3-19·5; p < 0·0001). Following walnut desensitisation, all patients who were coallergic to pecan (n=46) were also desensitised to pecan. Additionally, 18 (60%) of 30 patients who were co-allergic to hazelnut or cashew, and 14 (93%) of 15 patients who were co-allergic to hazelnut alone, were either fully desensitised or responded to treatment. 47 (85%) of 55 patients had an adverse reaction (mostly grade 1 or 2) during up-dosing in the clinic; eight patients required intramuscular epinephrine in response to a dose at home. Of 45 patients who had follow-up data for the maintenance phase, all maintained walnut desensitisation and one patient required epinephrine during this period.

Immunotherapy with Alt a 1 was efficacious and safe, reducing the symptoms and medication associated with rhinoconjunctivitis after only one year of treatment. The clinical benefits were associated with reduced skin reactivity and specific IgE, and increased IgG4.

Allergen immunotherapy (AIT) is thought to be clinically effective and safe in treating allergic rhinitis, asthma, and stinging insect allergy in Europe and North America. However, there are intercontinental differences in AIT therapeutic products in terms of their application and regulation. In North America unmodified standardized and nonstandardized aqueous aeroallergen extracts are approved and used almost exclusively for subcutaneous immunotherapy, whereas more product options are available in Europe, including adsorbed allergens, chemically modified allergens, or both. Both liquid extracts and tablets are approved for sublingual immunotherapy in Europe. Nevertheless, within the European Union, there are major differences in AIT products approved and used in individual countries. There are major differences in the clinical approach to subcutaneous immunotherapy in polysensitized patients; in the United States mixed extracts containing multiple aeroallergens are used, whereas European allergists preferably administer separate injections of single allergen sources or homologous groups deemed to be clinically relevant.Moreover, the regulatory approach differs between the European Union and the United States. In contrast to the United States, where common allergen standards exist based on biologic activity, no common standards exist in Europe. In terms of development of new investigational products, the United States has followed the European example for phase II and III studies; no formal US Food and Drug Administration guidance has-been issued.

The extensive use of allergen molecules in birth cohort studies revealed that atopic sensitization is a sequential IgE response to distinct non-crossreacting molecules from the same allergenic source (ie, molecular spreading), starting with an initiator molecule. This phenomenon reaches different degrees of progression (monomolecular, oligomolecular, and polymolecular) according to the individual atopic propensity and allergen exposure, thus producing an extreme heterogeneity of IgE sensitization profiles in patient populations. In patients with allergic rhinitis, the broader the IgE molecular sensitization profile, the greater is the risk of asthma and other allergic comorbidities, such as oral allergy syndrome. Hence it has been proposed to anticipate immunologic intervention at disease onset (early allergen immunotherapy) or even earlier during the preclinical sensitization stage (allergen immunoprophylaxis). Diagnostic algorithms based on singleplex or multiplex molecular IgE tests allow the discrimination of genuine from crossreacting sensitization and the selection of the right extracts for allergen immunotherapy composition. Patients with extreme molecular poly-sensitization and greater risk of asthma or other IgE-mediated comorbidities, can be easily identified by means of allergen microarray or macroarray procedures and might benefit from anti-IgE treatment. IgE molecular tests have opened the era of precision allergology, and their routine use should aim at cost effectiveness, according to the principles of the Choosing Wisely initiative.

Three-week, short-course of adjuvant-free hydrolysates of Lolium perenne peptide (LPP) immunotherapy for rhinoconjunctivitis with/without asthma over 4 physician visits is safe, well-tolerated and effective.

To investigate immunologic mechanisms of LPP immunotherapy in a subset of patients who participated in a Phase III, multicenter, randomized, double blind, placebo-controlled trial (clinical.gov NCT02560948).

Participants were randomized to receive LPP (n=21) or placebo (PL; n=11) for 3 weeks over 4 visits. Grass pollen-induced basophil, T and B cell responses were evaluated before (V2), end of treatment (V6) and after the pollen season (V8).

Combined symptom and rescue medication scores (CSMS) were lower during the peak (-35.1%, P=.03) and throughout pollen season (-53.7%, P=.03) in LPP- compared to PL-treated group. CD63+ and CD203cbrightCRTH2+basophils were decreased following LPP treatment at V6 (all, P<.0001) and V8 (all, P<.001), compared to V2. No change in PL-treated group was observed. Blunting of seasonal increases of grass pollen-specific IgE was observed in LPP but not PL-treated group. LPP immunotherapy but not PL was associated with a reduction of IL-4+ Th2 (V6, P=.02), IL-4+ (V6, P=.001;V8, P=.0095) and IL21+ (V6, P=.0002) T follicular helper cells. Induction of FoxP3+, follicular regulatory T and IL-10+ Breg cells were observed at V6 (all, P<.05) and V8 (all, P<.05) in LPP-treated group. Induction of regulatory B cells was associated with allergen neutralizing IgG4 blocking antibodies.

For the first time, we demonstrate that the immunological mechanisms of LPP immunotherapy are underscored by immune modulation in the T and B cell compartments which is necessary for its effect.

Food allergen immunotherapy may benefit from adjunct therapies to enhance safety and efficacy. We review preclinical studies investigating the effects of probiotics and other microbial-based interventions on oral tolerance, describe the human clinical trial evidence thus far for microbial adjuncts, and discuss steps for translating research findings in this area to clinical therapy.

Murine studies support that microbial-based interventions confer protection against sensitization and may augment treatment efficacy for food allergy.Microbial adjunct therapies can promote regulatory T cells and modulate Th1 vs. Th2 responses. There is a wide array of novel modalities utilizing microbial components. Ongoing efforts are focused on translating preclinical data into potential treatments. Probiotics, prebiotics, and microbial components have all been examined as microbial adjunct therapies in murine models of food allergy. The effects of probiotics appear to be strain specific. Prebiotics and bacterial components are innovative modalities to modulate oral tolerance. Better characterization of dysbiosis inhuman cohorts with food allergy, deeper mechanistic understanding of microbial adjunct therapies, safety evaluation, and careful clinical trial design will be crucial for the development of microbial adjuncts for food allergen immunotherapy. Microbial adjunct therapies have the potential to enhance the efficacy, safety, and durability of food allergen immunotherapy.

The treatment and management of ocular allergy (OA) remains a major concern for different specialties, including allergists, ophthalmologists, primary care physicians, rhinologists, pediatricians, dermatologists, clinical immunologists and pharmacists. We performed a systematic review of all relevant publications in Medline, SCOPUS and WebScience including systematic reviews and meta-analysis. Publications were considered relevant if they addressed treatments, or management strategies of OA. A further wider systematic literature search was performed if no evidence or good quality evidence was found. There are effective drugs for the treatment of OA, however there is a lack an optimal treatment for the perennial and severe forms.Topical antihistamines, mast cell stabilizers or double action drugs are the first choice of treatment. All of them are effective in reducing signs and symptoms of OA. The safety and optimal dosing regimen of the most effective topical anti-inflammatory drugs, corticosteroids, is still a major concern.Topical calcineurine inhibitors may be used in steroid-dependent/resistant cases of severe allergic keratoconjunctivitis. Allergen specific immunotherapy may be considered in cases of failure of first line treatments or to modify the natural course of OA disease. Based on the current wealth of publications and on the collective experience, recommendations on management of OA have been proposed.

Aim of this review is the description of the medical conditions in which the support of molecular allergy diagnostics (MAD) has an impact on the clinical outcomes, such as laboratory diagnostics, prognosis, and therapy of allergic diseases.

The review of the literature of the last 2 years generated a wide number of results on this topic. As expected, not all were obtained by the use of MAD, but, in general, a clear trend is evident.

Within the large number of works available, laboratory allergy diagnostics seems to be the most frequently discussed topic, in particular considering the complexity of the biological environment where these assays are used. Some interesting news arrive from the prognostic potential of MAD, whereas for allergen immunotherapy, waiting for a well-conducted prospective randomized clinical study, data from retrospective studies still confirms the added values of MAD in the management of the allergic patients.

Food allergy prevalence has increased in recent decades, which has mobilized efforts to develop treatment alternatives.Epicutaneous immunotherapy (EPIT) is a novel method that involves transdermal administration of peanut allergen with the objective to induce tolerance. Recent clinical trials have shown its efficacy at increasing the eliciting dose in children with a favorable safety profile. Areas covered: This review covers the proposed mechanism of action of EPIT in murine models and humans, efficacy and safety data from clinical trials with peanut EPIT, and a discussion on its potential role in the future management of peanut allergy. Expert opinion: With the recent completion of pivotal trials for peanut EPIT and upcoming marketing, the main question for clinicians and food allergic patients is how to define its role in the management of peanut allergy and how it compares to oral immunotherapy (OIT). Like OIT, EPIT seems to promote immunological tolerance over time. However, EPIT could lack the rapid mast-cell desensitization induced by the progressive intake of food in OIT, which explains differences in short-term outcomes and safety profiles. Head-to-head and long-term comparison of real-life efficacy with regards to sustained unresponsiveness will help define its place in the food allergy arsenal.

The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endo types are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergenspecific immunotherapy and biologic therapies that target key molecules driving the Th2 response are already used in the clinic, and a wave of novel drug candidates are under development. In-depth analysis of the cells and tissues of patients treated with such targeted interventions provides a wealth of information on the mechanisms that drive allergies and tolerance to allergens. Here, we aim to deliver an overview of the current state of specific inhibitors used in the treatment of allergy, with a particular focus on asthma and atopic dermatitis and provide insight into the roles of these molecules in immunological mechanisms of allergic disease.