Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including health professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as on the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow up of patients.

Oral immunotherapy is an emerging experimental treatment for peanut allergy, but its benefits and harms are unclear. We systematically reviewed the efficacy and safety of oral immunotherapy versus allergen avoidance or placebo (no oral immunotherapy) for peanut allergy.

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, we searched MEDLINE, EMBASE, Cochrane Controlled Register of Trials, Latin American & Caribbean Health Sciences Literature, China National Knowledge Infrastructure, WHO’s Clinical Trials Registry Platform, US Food and Drug Administration, and European Medicines Agency databases from inception to Dec 6, 2018, for randomised controlled trials comparing oral immunotherapy versus no oral immunotherapy for peanut allergy, without language restrictions. We screened studies, extracted data, and assessed risk of bias independently in duplicate. Main outcomes included anaphylaxis, allergic or adverse reactions, epinephrine use, and quality of life, meta-analysed by random effects. We assessed certainty (quality) of evidence by the GRADE approach. This study is registered with PROSPERO, number CRD42019117930.

12 trials (n=1041; median age across trials 8·7 years [IQR 5·9-11·2]) showed that oral immunotherapy versus no oral immunotherapy increased anaphylaxis risk (risk ratio [RR] 3.12 [95% CI 1.76-5.55], I2=0%, risk difference [RD] 15·1%, high-certainty), anaphylaxis frequency (incidence rate ratio [IRR] 2.72 [1.57-4.72], I2=0%, RD 12.2%, high-certainty), and epinephrine use (RR 2.21 [1.27-3.83], I2=0%, RD 4.5%, high-certainty) similarly during build-up and maintenance (pinteraction=0.92). Oral immunotherapy increased serious adverse events (RR 1.92 [1.00-3.66], I2=0%, RD 5.7%, moderate-certainty), and non-anaphylactic reactions (vomiting: RR 1.79 [95%CI 1.35-2.38], I2=0%, high-certainty; angioedema: 2.25 [1.13-4.47], I2=0%, high-certainty; upper tract respiratory reactions: 1.36 [1.02-1.81], I2=0%, moderate-certainty; lower tract respiratory reactions: 1.55 [0.96-2.50], I2=28%, moderate-certainty). Passing a supervised challenge, a surrogate for preventing out-of-clinic reactions, was more likely with oral immunotherapy (RR 12.42 [95% CI 6.82-22.61], I2=0%, RD 36.5%, high-certainty). Quality of life was not different between groups (combined parents and self report RR 1.21 [0.87-1.69], I2=0%, RD 0.03%, low-certainty). Findings were robust to IRR, trial sequential, subgroup, and sensitivity analyses.

In patients with peanut allergy, high-certainty evidence shows that available peanut oral immunotherapy regimens considerably increase allergic and anaphylactic reactions over avoidance or placebo, despite effectively inducing desensitisation. Safer peanut allergy treatment approaches and rigorous randomised controlled trials that evaluate patient-important outcomes are needed.

Placebo control in allergen immunotherapy (AIT) trials presents ethical and blinding concerns. We tested a trial design with an “active allergen placebo”, as proposed by ARIA-GA2 LEN, to investigate in a double-blind trial the efficacy and safety of AIT in dual-allergic patients (grass and birch pollen) using active untargeted treatments as controls.

We randomized 95 patients to receive either grass (N=47) or birch AIT (N=48). Patients were exposed to both allergens in an allergen challenge chamber (ACC) before and after 9 months of AIT. Targeted (ACC-allergen = AIT-allergen) and untargeted (ACC-allergen ≠ AIT-allergen) treatment effects were assessed.

Immunotherapy reduced significantly the mean (95% confidence interval) area under the curve of total nasal symptom score (targeted effects) by -13.55 (-17.56, -9.54; p < .001) after grass and -9.81 (-14.13, -5.50; p < .001) after birch AIT. Differences in targeted vs untargeted effects between AIT groups (utility of control group) were statistically significant for both grass (p = .02) and birch (p = .02) allergens. Targeted vs untargeted differences within treatment groups (specificity of ACC measurement) were significant for grass AIT (p < .001) but not significant for birch AIT group (p = .24). Specific immunoglobulin G4 to both allergens increased significantly (p < .001) after targeted treatment, while remained unchanged for untargeted treatments. Both treatments were well tolerated.

Immunotherapies for both grass and birch allergens were efficacious and safe. The study confirms the specificity of AIT. Untargeted treatment groups could serve as controls in future AIT trials.

Improved quality of life (QoL) after oral immunotherapy (OIT) in peanut allergic children is often reported by their parents, while the child’s perspective is less clear.

We aimed to explore if two years of OIT improved QoL in children with peanut allergy and to identify factors influencing change in QoL.

In the open labelled TAKE-AWAY peanut OIT trial including children with anaphylaxis to peanuts, 57 were randomized to OIT and 20 to observation. The Pediatric Quality of Life Inventory Version 4.0 was completed by parents and children at enrolment (Y0 ), after one year (end of up-dosing) (Y1 ) and after two years (Y2 ) of OIT. Minimally clinically important difference (MCID) is ≥5.3. Perceived treatment burden was recorded by visual analogue scales, including adverse events (AEs). An open food challenge (OFC) was performed at Y2 .

At Y2 , 18 children had discontinued OIT, 2/39 OIT-children refused OFC, while 35/37 were desensitized to 7500 mg peanut protein. From Y0 to Y2, the mean change (95% confidence intervals) in QoL was 4.4 (0.5, 8.3) among child self-reports and twice as large among parental proxy-reports (9.3 (4.3, 14.3)) (both p<0.0001), without significant improvement among the controls. The change in QoL was significantly different from the controls for the parental proxy-reports only (p=0.002). Neither treatment burden nor AEs significantly predicted changes in QoL.

Two years of OIT improved child-QoL as reported by parents, but not by the children, suggesting that parents may over-estimate improvement in child-QoL by OIT.

The present patent relates to the use of bioadhesive, biodegradable poly-lacto-glycolic (PLGA) microparticles for allergen immunotherapy. Surface modification of allergen-loaded microspheres with Aleuria aurantia lectin causes selective enrichment, prolongation of the dwell time and uptake via mucosal M cells overlying the lymph nodes e.g. in tonsils, nasal mucosa and intestinal Peyer’s patches. The particulate microspheres permit that the entrapped antigens and/or DNA of antigens are released continuously and slowly over time at the mucosal uptake site. The entrapment of the antigens also prevents immediate type local and systemic adverse effects. The claims are based on 1) preclinical in vitro data showing that allergens, e.g. from pollen are efficiently entrapped, protected from gastric digestion, and released over the course of weeks; 2) in vivo prophylactic as well as therapeutic mouse studies, where oral microparticles only when functionalized with Aleuria aurantia lectin preferentially targeted M-cells overlying the Peyer’s patches and modulated an ongoing Th2 -response towards Th1 in vivo. The invention therefore provides a means to safely deliver also protease-sensitive antigens to the mucosal immune cells, where they are released over time and are able to modulate an ongoing immune response. This invention preferentially enhances the efficacy and safety of allergen immunotherapy, SLIT and OIT.

Skin is replete with immune-competent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underutilized with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, two key classes include dendritic cells (DCs) and regulatory T cells (Tregs). Immature DCs are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Tregs. Skin-homing Tregs also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of five such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes.

Oral immunotherapy (OIT) is a promising therapeutic approach to treat food allergic patients. However, concerns with regards to safety and long-term efficacy of OIT remain. There is a need to identify biomarkers that predict, monitor and/or evaluate the effects of OIT. Here we present a method to select candidate biomarkers for efficacy and safety assessment of OIT using the computational approaches Bayesian networks (BN) and Topological Data Analysis (TDA).

Data were used from fructo-oligosaccharide diet-supported OIT experiments performed in 3 independent cow’s milk allergy (CMA) and 2 independent peanut allergy (PNA) experiments in mice. Bioinformatical approaches were used to understand the data structure. The BN predicted the efficacy of OIT in the CMA with 86% and indicated a clear effect of scFOS/lcFOS on allergy parameters. For the PNA model, this BN (trained on CMA data) predicted an efficacy of OIT with 76% accuracy and shows similar effects of the allergen, treatment and diet as compared to the CMA model. The TDA identified clusters of biomarkers closely linked to biologically relevant clinical symptoms and also unrelated and redundant parameters within the network.

Here we provide a promising application of computational approaches to a) compare mechanistic features of two different food allergies during OIT b) determine the biological relevance of candidate biomarkers c) generate new hypotheses to explain why CMA has a different disease pattern than PNA and d) select relevant biomarkers for future studies.

4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+CD25+CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels.

Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8+CD25+ T cells and suppressive function of CD8+CD25+CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8+CD25+CD137+ T cells was analyzed by western blotting.

Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+CD25+CD137+ population in PBMCs. Pam3CSK4-stimulated CD8+CD25+CD137+ Tregs induced IL-10 and TGF-β and suppressed CD4+CD25- T cell proliferation mainly by cell contact inhibition. CD8+CD25+CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8+CD25+ T cells decreased Pam3CSK4-activated Foxp3 expression.

Der p IT expanded CD8+CD25+CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.

Cow’s milk allergy (CMA) is the most frequent food allergy in the first years of life, with prevalence rates estimated in the range of 2-3%. With the aim of reducing the risk of allergic reactions for accidental exposures to cow’s milk (CM) proteins and of favouring the regain of clinical tolerance, strategies of controlled oral exposure to CM have been developed as immunotherapy for the treatment of children with established food allergy. However, available data on the use of oral immunotherapy in infants with food allergy are very limited.

We reviewed the existing evidence base to desensitisation for food allergy, applying the Grading of Recommendations, Assessment, Development and Evaluation approach to discuss whether desensitisation is likely to become part of routine treatment for patients with food allergy.

Desensitisation for food allergy to peanut, egg and cow’s milk is efficacious, but whether such interventions are cost-effective is less clear, due to the issues over a sustained desensitisation effect and the increase in allergic reactions occurring in patients on treatment. Few studies have assessed the change in health-related quality of life associated with treatment, and most have not considered discordance between parent-reported changes in health-related quality of life (HRQL) outcomes compared to those of the patients themselves; none to date have controlled for the improvement in HRQL occurring after initial challenge which will confound outcomes. The lack of longer-term safety and cost-effectiveness data, as well as an absence of current consensus in the reporting of patient-relevant outcomes, must be addressed in order to be able to recommend the introduction of desensitisation as a routine treatment in healthcare systems.