Molecular antibody reactivity profiles have not yet been studied in depth in patients treated by sublingual house dust mite (HDM) tablet immunotherapy. Humoral immune responses to a large panel of HDM mite allergens were studied using allergen microarray technology in a subset of clinically defined high and low responder patients from a double-blind placebo-controlled allergen-specific immunotherapy (AIT) trial using sublingual 300 IR HDM tablets.

Serum levels of IgE, IgG and IgG4 to 13 Dermatophagoides pteronyssinus molecules were measured at baseline and after 1-year AIT, using allergen microarrays in 100 subjects exhibiting high or low clinical benefit.

Der p 1, Der p 2 and Der p 23 were the most frequently recognized allergens in the study population. Patients with HDM-related asthma had significantly higher allergen-specific IgE levels to Der p and Der p 23. No significant difference in the distribution of allergensensitization pattern was observed between high and low responders. An increase in serum allergen-specific IgG and IgG4 occurred upon AIT, in particular to allergens Der p 1, Der p 2 and Der p 23 (p < 0.0001).

We confirm for our study population that Der p 1-and Der p 23-specific IgE levels are associated with asthma. IgE reactivity profiles were not predicitive of sublingual AIT outcomes, with 300 IR tablets as efficacious in pauci- and multi-sensitized subjects. Our study is the first to demonstrate the induction of IgG and IgG4 specific for the HDM allergens Der p 1, Der p 2 and Der p 23 by sublingual AIT.

Cow's milk protein allergy (CMPA) is one of the most common food allergies in infancy. Most infants with CMPA tolerate baked milk from diagnosis and gradually acquire increased tolerance. Nevertheless, parents often display significant anxiety about this condition and a corresponding reluctance to progress with home introduction of dairy due to concerns about possible allergic reactions.

To evaluate the impact on gradual home introduction of foods containing cows' milk after a supervised, single low-dose exposure to whole milk at time of diagnosis.

Infants less than 12 months old referred with suspected IgE mediated cow's milk allergy were recruited to an open-label randomized, controlled trial of intervention-a single dose of fresh cow's milk, using the validated dose of milk that would elicit reactions in 5% of CMPA subjects-the ED05 - vs routine care. Both groups implemented graded exposure to CM (using the 12 step MAP Milk Tolerance Induction Ladder), at home. Parents completed food allergy quality of life questionnaires and State and Trait Anxiety Inventories (STAI). Main outcome measures were milk ladder position at 6 months and 12 months post-randomization.

Sixty patients were recruited, 57 (95%) were followed to 6 months. By 6 months, 27/37 (73%) intervention subjects had reached step 6 or above on the milk ladder compared to 10/20 (50%) control subjects (p = .048). By 6 months, 11/37 (30%) intervention subjects had reached step 12 (i.e. drinking unheated cow's milk) compared to 2/20 (10%) of the controls (p = .049). Twelve months postrandomization, 31/36(86%) of the intervention group and 15/19(79%) of the control group were on step 6 or above. However, 24/37 (65%) of the intervention group were at step 12 compared to 7/20 (35%) of the control group (p = .03). Maternal STAIs were significantly associated with their infants' progress on the milk ladder and with changes in skin prick test and spIgE levels at 6 and 12 months.

This study demonstrates the safety and effectiveness of introduction of baked milk implemented immediately after diagnosis of cows' milk allergy in a very young cohort. A supervised single dose of milk at the ED05 significantly accelerates this further, probably by giving parents the confidence to proceed. Maternal anxiety generally reflects infants' progress towards completion of the milk ladder, but pre-existing high levels of maternal anxiety are associated with poorer progress.

Owing to insufficient data, current guidelines recommend against initiating allergen-specific immunotherapy (AIT) during pregnancy but suggest that well-tolerated ongoing immunotherapy may be continued.

To evaluate the safety of AIT in pregnancy, especially the risk for congenital malformations.

This nationwide Swedish cohort study identified pregnancies exposed to AIT, both subcutaneous and sublingual, through the Swedish Medical Birth register and the Prescribed Drug Register between 2005 and 2014. Information on congenital malformations in offspring was retrieved from the National Patient Register. Using the personal identity number, we linked data between registers. Using logistic regression, we calculated odds ratios (ORs) with 95% CIs for congenital malformations and other adverse pregnancy outcomes after adjusting for potential confounders.

From 2005 to 2014, we identified 924,790 singleton pregnancies. Among these, 743 pregnancies had been exposed to AIT 3 months before conception up until gestational week 22. Allergen-specific immunotherapy in pregnancy was not linked to congenital malformations (OR = 0.90; 95% CI, 0.63-1.27) or other adverse pregnancy outcomes (preterm birth: OR = 0.98; 95% CI, 0.71-1.35; stillbirth: OR = 0.79; 95% CI, 0.26-2.47; or cesarean delivery: OR = 0.91; 95% CI, 0.76-1.09). Stratification by route of immunotherapy, subcutaneous or sublingual, resulted in similar ORs. Restricting the pregnancy cohort to women with asthma or pulmonary disease, nulliparous women, births in 2012 to 2014, or Swedish-born women yielded similar results.

This nationwide study found no evidence of congenital malformations or other adverse pregnancy outcomes in women treated with AIT in pregnancy.

Probiotic and Peanut Oral Immunotherapy (PPOIT) is effective at inducing sustained unresponsiveness (SU) at end-of-treatment and this effect persists up to four years post-treatment, referred to as persistent SU. We sought to evaluate (i) how PPOIT altered peanutspecific humoral immune indices, and (ii) how such longitudinal indices relate to persistent SU.

Longitudinal serum/plasma levels of whole peanut- and peanut component- (Ara-h1, -h2, -h3, -h8, -h9) specific-IgE (sIgE) and specific-IgG4 (sIgG4) antibodies were measured by ImmunoCAP and salivary peanut-specific-IgA (sIgA) by ELISA in children (n=62) enrolled in the PPOIT-001 randomised trial from baseline (T0) to 4-years post treatment (T5). Multivariate regression analyses of log-transformed values were used for point-in-time between group comparisons. Generalised estimating equations (GEE) were used for longitudinal comparisons between groups.

PPOIT was associated with changes in sIgE and sIgG4 over time. sIgE levels were significantly reduced post-treatment [T5, PPOIT v.s. Placebo ratio of geometric mean (GM): Ara-h1 0.07, p=0.008; Ara-h2 0.08, p=0.007; Ara-h3 0.15, p=0.021]. sIgG4 levels were significantly increased by end-of-treatment (T1, PPOIT v.s. Placebo ratio of GM: Ara h1 3.77, p=0.011; Ara-h2 17.97, p<0.001; Ara-h3 10.42, p<0.001) but levels in PPOIT group decreased once treatment was stopped and returned to levels comparable with Placebo group by T5. Similarly, salivary peanut sIgA increased during treatment, as early as 4 months of treatment (PPOIT v.s. Placebo, ratio of GM: 2.04, p=0.014), then reduced post-treatment.

PPOIT was associated with broad reduction in peanut specific humoral responses which may mediate the clinical effects of SU that persists to 4-years post-treatment.

Cost-effectiveness studies evaluating allergen immunotherapy (AIT) in children are limited but needed to drive clinical and policy-making decisions such as reimbursement of new interventions. In this study, we compared the cost-effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) tablets to the standard of care (SOC) treatment in children with house dust mite-driven (HDM) allergic asthma.

We developed a hypothetical Markov model based on the Global Initiative for Asthma (GINA) severity steps to compare the three strategies over a 10-year horizon divided by cycles of six months. SOC was used as a reference to calculate the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were used to assess models' uncertainty. Other scenarios were evaluated to strengthen the presentation of results.

The ICER for SCIT and SLIT tablets was 1281€ and 7717€, respectively. The cost-effectiveness threshold for Portugal was 18482,80€; both treatment approaches were below this limit. The major contributors to these results were the AIT effects on reducing moderate and severe exacerbations and asthma controller medication. In the sensitivity analysis, SCIT revealed a higher probability of cost-effectiveness than SLIT. When including allergic rhinitis as comorbidity, ICER values reduced markedly, especially for SCIT intervention.

AIT was cost-effective in children with HDM-driven allergic asthma, especially when given by the subcutaneous route. The high probability of cost-effectiveness, especially for SCIT, may drive future policy decisions and AIT prescribing habits. AIT adherence greatly influenced the results highlighting the value of implementing strategies to promote adherence rates.

The determinants of tolerance to food allergens are not fully understood. We aimed to elucidate the longitudinal association between oropharyngeal symptoms without systemic reactions (OSw/oS) and tolerance to food allergens.

We included all patients diagnosed with single food allergy to egg (n = 121), milk (n = 55), and wheat (n = 41) using the oral food challenge test (OFC) from 2014 to 2017. These patients received oral immunotherapy at home and/or in the hospital after diagnosis by OFC. We compared the incidence proportion of tolerance within 2 years by OSw/oS and other variables for 217 patients with food allergy. We defined OSw/oS as isolated symptoms of oropharyngeal discomfort that occurred after ingestion of a safe dose of the allergenic food determined by the OFC in the first 6 months.

Of the 217 patients (median age 37.5 months, male 64.5%), 53 developed OSw/oS (24.4%), and 151 (egg, 85 milk, 36 and wheat, 30) attained tolerance in 2 years. Patients without OSw/oS showed a significantly higher incidence of tolerance than those with the symptoms (crude hazard ratio [HR] 5.62, 95% confidence interval [CI] 3.58-8.82, p < 0.001). The association was consistently significant in the multivariable model (adjusted HR 9.50, 95% CI 5.25-17.20, p < 0.001) independent of other risk factors for intolerance, such as concomitant bronchial asthma (adjusted HR 3.33), history of anaphylaxis (adjusted HR 2.16), milk allergy (adjusted HR 2.02), and allergic symptoms with low dose OFC (adjusted HR 1.52).

Our results suggest that OSw/oS may be a risk factor for intolerance to food allergens. To reveal a high risk of food allergen intolerance may help patients and their families as well as healthcare professionals prepare for the challenge of continuing oral immunotherapy.

Oral immunotherapy (OIT) is a promising therapeutic approach for children with persistent IgE-mediated cow's milk allergy (CMA) but data are still limited.

To analyze the prevalence of life-threatening anaphylaxis in children with persistent CMA undergoing OIT and to evaluate potential risk factors.

This is a retrospective cohort study among children with persistent CMA undergoing OIT over a 20-year period, following a specific Oral Tolerance Induction protocol. Adverse reactions during the whole period and data on long-term outcome were registered. Descriptive and nondescriptive statistics were used to describe data.

Three hundred forty-two children were evaluated. During OIT, 12 children (3.5%) presented severe anaphylactic reactions that needed an adrenaline injection. None required intubation, intensive care unit (ICU) admission, or showed a fatal outcome. Five of them abandoned OIT, five reached unrestricted diet and the others are still undergoing OIT. As far as outcome is concerned, 51.2% reached an unrestricted diet; 13.5% are at the build-up stage; and 28.0% (97 patients) stopped the OIT. Among these 96 children, 6.3% experienced a severe reaction induced by accidental ingestion of milk with two fatal outcomes.

The risk of life-threatening reactions was nearly two times lower (3.5% vs. 6.3%) among patients assuming milk during OIT than in those who stopped the protocol. A trend in favor of more severe reactions, requiring ICU admission, or fatal, was shown in patients who stopped OIT.

Allergen immunotherapy (AIT) is considered the only disease modifying treatment available at present for allergic disorders. Its main benefits include improvement of symptoms, decreased need for pharmacotherapy, prevention of new sensitizations and sustained effect after AIT completion. The key pillars of AIT-induced tolerance include a shift from Th2 to Th1 response, an increase of regulatory T and B cells, pro-inflammatory effector cell downregulation and IgE suppression, in addition to IgG4, IgA and IgD induction. AIT may also induce trained immunity, characterized by a durable decrease in group 2 of innate lymphoid cells (ILCs) and increased ILC1 and ILC3s. Understanding the immune mechanisms of AIT is essential for validating biomarkers for the prediction of AIT response and for achieving AIT success.

To evaluate the efficacy of subcutaneous immunotherapy (SCIT) for the treatment of allergy to house dust mites (HDM) in adults with moderate/severe allergic rhinitis (AR). Methods: Patients sensitized to HDM were randomized to SCIT plus rescue medication (Group A, n = 38) or rescue medication alone (Group B, n = 18), and assessed at baseline and 2, 6 and 12 months.

At month 12, Group A presented significant improvement with respect to baseline as evaluated by a visual analogue scale at three concentrations of antigen (0.1, 1 and 10 IR/ml; p < 0.0001). Group A presented significant decreases in symptom scores after 2 months of treatment, which were maintained after 1 year. After 12 months of treatment, Group A showed rescue medication consumption reductions (p< 0.001) and quality of life improvements (p < 0.0001). SCIT elicited a strong immunological response and was well tolerated.

SCIT is efficacious for HDM allergy in patients with AR, generating a strong immunological response. Trial Registration Number: EUCTR2009-018155-16-ES (Cochrane Central Register of Controlled Trials).

It aims to detect basophil activation ratio (%CD63+ ) in peripheral blood of children with allergic asthma and rhinitis by using flow cytometry (FCM), so as to analyse the application values and clinical relevance of the basophil activation test (BAT) in diagnosis of Dermatophagoides farinae (Derf) sensitization and monitoring therapeutic efficacy of subcutaneous immunotherapy (SCIT). It was a prospective study. From the newly diagnosed children with asthma and rhinitis in our paediatric clinic, 39 patients diagnosed Derf sensitization and 15 patients not allergic to Derf were enrolled; another 4 healthy children were taken as control group. Using Derf extracts in concentration of 1, 10 μg/mL and 100μg/mL as the stimulus, BAT results were expressed as %CD63+ in diagnosis of Derf sensitization and its correlation with skin prick tests (SPT), serum total IgE (tIgE), specific IgE (sIgE), sIgE/tIgE, specific IgG4 (sIgG4), FEV1%pred in pulmonary ventilation function, exhaled nitric oxide (FeNO), children asthma control test (C-ACT) and visual analogue scale (VAS) were observed. In sensitization group, %CD63+ , sIgG4 and clinical indicators were detected again from patients who had received SCIT to analyse their internal connections. The average levels of %CD63+ in 3 concentrations showed an increasing concentration-dependent trend overall. %CD63+ in sensitization group was significantly higher than that in the other 2 groups. The analysis of ROC for Derf sensitization showed the area under the curve (AUC) for BAT in 3 concentrations was higher than that for sIgE whose AUC is 0.893. %CD63+ was positively correlated with SPT grade, sIgE, sIgE/tIgE and VAS, and negatively correlated with C-ACT. In patients receiving SCIT, %CD63+ became lower and sIgG4 level became higher than pretreatment. There was no obvious change in sIgG4 in those who had not received SCIT. BAT is a reliable and non invasive tool for diagnosis of Derf sensitization in children with asthma and rhinitis. CD63-based BAT has clinical value to monitor outcome of SCIT, and the change in basophil activation is inherently related to induction of sIgG4.