The prevalence of allergic disorders drastically increased over the last 50 years that today they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy targeting the underlying cause of allergic disorders, and its superior evidence is based on accumulated data from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unsolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and also the establishment of international reference standards for many allergens. This article discusses the issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products by different manufacturers are appropriate as basis to choose among the different AIT products. Allergen standardization in immunotherapy products is critical to ensure quality and thereby safety and efficacy. However, lack of harmonization in manufacturing process, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products solely based on major allergen amounts is not rationale and, in fact, impossible. Moreover, further inherent characteristics of products and their clinical use such as their state of extract modification, addition of adjuvant or adjuvant-system, route of administration (sublingual/subcutaneous) and cumulative dose as per posology (including the volume per administration) need to be taken into account, when rating the information given for a specific product. Finally, only convincing clinical data can serve as the product-specific evaluation, or the basis for cross-product comparability, for individual products.

Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL).

In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers.

No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups.

PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

The immunological changes underpinning acquisition of remission (also called sustained unresponsiveness) following food immunotherapy remain poorly defined. Limited access to effective therapies and biosamples from treatment responders has prevented progress. Probiotic peanut oral immunotherapy is highly effective at inducing remission, providing an opportunity to investigate immune changes.

Using a systems biology approach, we examined gene co-expression network patterns in peanut-specific CD4+ T cell responses before and after probiotic and peanut oral immunotherapy in subjects enrolled in the PPOIT-001 randomized trial: Responders who attained remission (n = 16), placebo-treated who remained allergic (n = 16).

Acquisition of remission was associated with rewiring of gene network patterns, which was characterized by integration of T helper 2 and interferon signalling modules, markedly reduced T helper 2 gene connectivity, and shutdown in co-expression activity between T helper 2 effectors and cell cycle regulators.

The immunological changes underlying remission following peanut oral immunotherapy are mediated by reprogramming of T helper 2-associated gene networks in the CD4+ T cell compartment. Findings provide insight into immune mechanisms driving the acquisition of remission following oral immunotherapy, paving the way for the development of improved approaches to induce remission/sustained unresponsiveness in patients with food allergy.

Local nasal immunotherapy (LNIT), an alternative noninjection immunotherapy method, is theoretically an efficient method for inducing immunotolerance directly in the affected organ. LNIT is more convenient and less invasive than injection immunotherapy, with fewer systemic reactions. The development of adjuvants to overcome LNIT's limitations raises the possibility of it being an alternative allergen immunotherapy.

To evaluate the clinical and immunological efficacy and safety of LNIT for patients with allergic rhinitis.

A systematic search for randomized controlled trials comparing LNIT and placebo was performed using OVID Medline and Embase. Outcomes were total nasal symptom score (TNSS), symptom-medication score (SMS), medication score, immunological assessment, and nasal provocation threshold. Data were pooled for meta-analysis.

A total of 20 studies with 698 participants were included. The LNIT group had greater posttreatment improvement in TNSS, SMS, and medication score than control (TNSS: standardized mean difference [SMD], -1.37 [95% confidence interval [CI], -2.04 to -0.69]; SMS: SMD, -1.55 [95% CI, -2.83 to -0.28]; and medication score: SMD, -1.09 [95% CI, -1.35 to -0.83]). Immunological assessments showed no significant differences in serum-specific IgE (mean difference [MD], 6.35; 95% CI, -4.62 to 17.31), nasal IgE (MD, -0.59; 95% CI, -1.99 to 0.81), or nasal eosinophil cationic protein (MD, 7.63; 95% CI, -18.65 to 33.91). Only serum IgG significantly increased with LNIT (MD, 0.45; 95% CI, 0.20, 0.70). Posttreatment, nasal provocation threshold was higher with LNIT (MD, 27.30; 95% CI, 10.13-44.46). No significant adverse events were reported.

LNIT is a safe alternative allergen immunotherapy route without significant adverse events. It improves clinical symptoms, reduces medication usage, and increases the nasal provocation threshold.

Dendritic cells are important mediators in the early presentation of antigen and regulation of the differentiation of T cells. Peanut oral immunotherapy (POIT) results in desensitization in most peanut allergic individuals (responders), but not in others due to allergic reactions (non-responders). Delineation of early immunologic changes contributing to desensitization would help clarify the POIT mechanism of action. We analyzed dendritic cells in 15 pediatric subjects (5-12 years) undergoing a phase 1 single-center POIT study. We examined dendritic cells at baseline, 6-, 12-, 18- and 24-weeks after initiation of POIT and responders of therapy were compared to non-responders and healthy controls. The distribution frequency of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) from peripheral blood samples were measured in vitro. A general linear mixed model was used, and included fixed effects for cohort (responder, non-responder, or healthy control), time (0-, 6-, 12-, 18-, and 24-weeks), and the cohort-time interaction term. P-values were adjusted for multiple hypothesis testing using Tukey's method. We observed that POIT responders had reduced TNFa producing myeloid dendritic cells (mDCs) compared to non-responders. Additionally, non-responders had increased OX40L expressing mDCs at 18-weeks compared to responders. In conclusion, our findings suggest that a reduced pro-inflammatory phenotype in DCs could potentially serve as a predictor of early outcome and success of POIT desensitization.

C-X-C motif ligand 13 (CXCL13) and B cell-activating factor (BAFF) are proven to be involved in inflammatory diseases, but their role in allergic rhinitis (AR) remains unclear. The aim of this study was to investigate the role of serum CXCL13 and BAFF in AR and their clinical values as objective biomarkers to predict the efficacy of subcutaneous immunotherapy (SCIT).

We prospectively recruited 90 children with AR treated with SCIT and collected their serum specimens before SCIT. One-year follow-up was conducted for all patients, and they were categorized into effective and ineffective groups based on efficacy. The serum concentrations of CXCL13 and BAFF were detected and compared between the two groups. A validation cohort of 52 responders and 26 non-responders were further assessed for both cytokines and serum CXCL13 and BAFF levels were assayed by enzyme-linked immunosorbent assay (ELISA).

Eighty children completed the follow-up schedule, and 56 children were categorized into the effective group and 24 children into the ineffective group. The serum levels of CXCL13 in the effective group were clearly higher than those in the ineffective group (P < 0.05). Receiver operating characteristic (ROC) curves revealed the potential values of CXCL13 as a biomarker in predicting the response of SCIT. Further, in the validation cohort, ELISA results demonstrated that serum CXCL13 levels were increased in responders than non-responders (P < 0.05). ROC curves showed good accuracy of serum CXCL13 in predicting the efficacy of SCIT.

Our discovery-validation study demonstrated that circulating CXCL13 might serve as a novel biomarker to predict the outcome of SCIT in childhood AR. The findings indicated that CXCL13 was involved in the pathological mechanisms of AR and made help to the fundamental therapeutic mechanism of SCIT.

Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. Aim: To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT).

This is a prospective register-based nationwide study of 18-44-year-olds treated with AIT during1995-2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analyzed before starting AIT (baseline) and three years after completing AIT (follow-up).

We identified 2688 patients with asthma treated with AIT, among whom, 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations, 23.8%, respectively, 16.5% p=<0.001 but there were no differences in LRTI. During the three-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. We also observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively.

AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal- and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than is seasonal allergy.

A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible patients. A total of 110 patients diagnosed with allergic rhinitis with or without concomitant asthma were enrolled in this study. Before beginning sublingual immunotherapy (SLIT), patients were evaluated by analyzing clinical and laboratory parameters. A specific rating was assigned to each parameter to be combined in a total score named PRIS. At baseline (T0) and follow-up [after 12 (T12) and 24 months (T24) of SLIT], a Visual Analogue Scale (VAS) was used to calculate a mean symptom score (MSS). Finally, the percentage variation between the MSS at T0 and at T12 [ΔMSS-12(%)] and T24 [ΔMSS-24 (%)] was measured. We observed a significant improvement of symptoms at T12 and T24 compared to T0 in all groups undergoing SLIT. PRIS was effective in predicting ΔMSS-24 (%) in patients treated with single-allergen SLIT. In addition, PRIS was effective in predicting ΔMSS-24 (%) in both patients with only rhinitis and with concomitant asthma. PRIS assessment can represent a useful tool to individuate potential responders before SLIT prescription.

Oral immunotherapy (OIT) is a promising approach to cow's milk and egg allergies, but reactions are frequent and some patients cannot be desensitized.

To evaluate long-term OIT outcomes with omalizumab (OMZ) in paediatric patients with severe egg and/or milk allergies. Methods: This retrospective real-life study analysed findings in children with Immunoglobulin E-mediated allergy to cow's milk and/or hen eggs refractory to conventional OIT, who underwent OIT with OMZ in our department between 1 January 2010 and 31 December 2015.

In all, 41 patients were included (median age: 7 years; interquartile range [IQR]: 5.5-9.5); 26/41 (63.4%) underwent OIT for milk, 8/41 (19.5%) for egg and 7/41 (17.1%) for both. The median time between initiation of OMZ and OIT was 27 weeks (IQR: 22-33). Forty (97.56%) patients reached the maintenance phase (200 mL of cow's milk and 30 mL of raw egg or 1 cooked egg) in a median time of 27 weeks (IQR: 18-37). The median total time with OMZ was 117 weeks (IQR: 88-144). During the OMZ period, 2.44% (1/41) of patients presented anaphylaxis. After discontinuation of OMZ, 29.3% (12/41) presented anaphylaxis, 50% of them had a poor adherence to daily ingestion. One patient (2.44%) was diagnosed with eosinophilic esophagitis after 2 years of discontinuation of OMZ. Currently, after a median time of 9 years (IQR: 7-10) since the initiation of OMZ, 75.6% (31/41) are desensitized (27/31 without OMZ).

Omalizumab allows desensitisation of children with severe allergies to cow's milk and/or egg without developing severe reactions while receiving this treatment. However, discontinuation of OMZ leads to severe allergic reactions, and hence must be monitored carefully.

This study aims to evaluate safety issues of house dust mite subcutaneous immunotherapy (SCIT) among allergic rhinitis (AR) children. A retrospective cohort study was done between 2015 and 2020 to investigate the side effects of SCIT among AR children caused by a house dust mite allergy. Among 1098 patients who received house dust mite subcutaneous immunotherapy injections, 284 patients (25.87%) had side effects (SE). SE were found to be 699 times higher or in 2.27% of the 30,744 subcutaneous immunotherapy injections. A total of 17.9% of the patients had local SE during SCIT administration. Systemic side effects occurred in 8.38% of children receiving SCIT and in 0.53% of the total population who received SCIT injections. Only 2/92 (2.18%) of patients suffered an allergic reaction within 30 minutes of injection and these patients responded well to antiallergic medication. Severe anaphylaxis occurred in 0.091% of the 1098 patients in the SCIT group and in 0.0033% of the 30,774 SCIT injections. Systemic SE after SCIT occurred in 8.38% of patients receiving SCIT or 0.53% of the total number of SCIT injections. Anaphylactic episodes occurred in 16 patients (1.46%) and 15 patients (1.37%) who had first and second episodes. One severe attack was found and it was resolved with adrenaline. This study demonstrates that in pediatric patients with AR who received HDM SCIT for 18 months with high adherence, some experienced significant local SE and systemic SE caused by SCIT, but this did not interfere with the course of AR treatment or the effectiveness of SCIT.