Intralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally.

We aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT.

One hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics.

The results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections.

Based on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT.

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated. However, these apps have a high potential for improving person-centred care (PCC), especially in allergen immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and late stopping rules and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment course. Future perspectives have been formulated in the first report of a joint task force (TF)-Allergic Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology (EAACI)-on digital biomarkers. The TF on AIT now aims to (i) outline the potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make proposals regarding further developments for both clinical practice and scientific purpose and (iv) suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT.

A previous study reported that house dust mite (HDM) sublingual immunotherapy (SLIT) for 48 weeks was effective as add-on treatment for allergic asthma; however, data regarding its long-term efficacy are scarce.

We sought to evaluate the effect of HDM SLIT on asthma control, pulmonary function, and airway inflammation and remodeling throughout the 5-year treatment period.

A total of 140 patients with asthma and allergic rhinitis sensitized to HDM were randomized to receive either drugs alone or drugs plus SLIT for 5 years. The 5-item Asthma Control Questionnaire (ACQ-5), Asthma Quality of Life Questionnaire (AQLQ), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), spirometry, quantitative computed tomography, and type 2 biomarkers were assessed.

An improvement in the ACQ-5, AQLQ, and RQLQ scores was observed in the SLIT group compared with the control group. HDM SLIT increased lung function and reduced the percentage of airway wall area. The levels of fractional exhaled nitric oxide (Feno), blood eosinophil, serum specific IgE for HDM, and total IgE decreased and were sustained during the 5 years. The change in type 2 biomarkers correlated with change in the AQLQ score. On the basis of receiver-operating characteristic analysis for predicting responders, the area under the receiver-operating characteristic curve in FEV1% predicted, airway wall area, Feno, and specific IgE was high. Multivariate regression analysis showed that the strongest predictor of responders was Feno.

HDM SLIT continued to provide sustained efficacy, improve lung function, and prevent progression of airway inflammation and remodeling in asthma throughout the 5-year treatment period.

Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS.

We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity.

For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS).

Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD = -0.56; 95% CI, - 0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12 month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively.

This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

Oral immunotherapy (OIT) is an increasingly acceptable therapeutic option for peanut-allergic (PA) children, despite significant side effects. Major peanut allergenic proteins are heat-resistant and are not rendered hypoallergenic after baking or cooking. Lyophilized peanut proteinMH (LPP-MH) is a novel composition from developing peanuts, enabling cooking-induced reduction in allergenicity. We aimed to explore the safety and efficacy of OIT, with extensively heated and baked (EHEB) LPP-MH in PA children.

In a single-arm, single-center, pilot study, PA children with a single highest tolerated dose of <100 mg peanut protein were placed on a 40-week OIT protocol with 300 mg daily of heat-treated LPP-MH. A repeat open peanut food challenge was performed after 40 weeks of treatment and at a 6-12 months of follow-up visit.

Thirty-three children with PA were enrolled, with a mean cumulative tolerated dose (MCTD) of 71.2 mg PP (95% CI 45-100 mg). After 40 weeks, 32/33 patients were able to consume more than 300 mg of natural PP, with MCTD of 1709 mg (CI 365 3675 mg). There were no severe allergic reactions requiring epinephrine, during any of the observed LPP-MH challenges or any treatment related doses at home. After 6-12 months on daily maintenance, the MCTD was 8821 mg (95% CI 1930 13,500 mg). This enabled most children age-appropriate dietary inclusion of peanuts.

An OIT protocol with heat-treated LPP-MH, a novel composition from developing peanuts, seems a potentially safe and efficacious OIT modality for PA children, enabling the introduction of dietary levels of peanut proteins in highly allergic PA children. Validation in randomized controlled studies is mandated.

Food allergy (FA) is a potentially life-threatening chronic condition that is becoming an increasing public health problem worldwide. This systematic review (SR) was carried out to inform the development of clinical recommendations on the treatment of IgE mediated FA with biologics and/or IT for the update of the EAACI guidelines. A SR of randomized controlled trials or quasi-controlled trials was carried out. Studies were identified via comprehensive search strategies in Medline, Embase, and Cochrane Library, up to April 2022.

Population: Human adults, children, and adolescents with IgE-mediated FA. Intervention: IT and/or biologics.

Placebo or standard-of-care (allergen avoidance).

Efficacy (desensitization, sustained unresponsiveness (SU), remission), quality of life, and safety (systemic and local adverse reactions (AR)). The Cochrane RoB tool was used to assess the risk of bias. It was reported according to PRISMA and registered in PROSPERO CRD4202229828. After screening, 121 studies were included (111 for IT and 10 for biologics). Most studies had a high risk of bias and showed high heterogeneity in design and results. Metanalysis showed a positive effect of biologics and IT in terms of relative risk (RR) for achieving tolerance to the culprit food compared to avoidance or placebo. Omalizumab for any FA showed a RR of 2.17 [95% confidence interval: 1.22, 3.85]. For peanut allergy, oral IT (OIT) had a RRof 11.94 [1.76, 80.84] versus avoidance or placebo, sublingual IT (SLIT) had a RR of 3.00 [1.04, 8.66], and epicutaneous IT (EPIT) of 2.16 [1.56, 3.00]. OIT had a RR of 5.88 [2.27, 15.18] for cow's milk allergy, and of 3.43 [2.24, 5.27] for egg allergy. There was insufficient data on SLIT or EPIT for the treatment of egg and milk allergies. Most ARs reported were mild. For OIT the most common AR involved the gastrointestinal system and for EPIT, AR's most commonly affected the skin. There was limited data on severe or life-threatening ARs. There was limited evidence for long term efficacy and quality of life. In conclusion, biologics and IT, alone or in combination, are effective in achieving desensitization while on active treatment but more evidence is needed on long-term tolerance as current evidence is not of high quality. Adverse events while on therapy are generally mild to moderate but a long-term comprehensive safety profile is missing. There is a critical need to optimize and standardize desensitization protocols and outcome measures to facilitate our understanding of the efficacy and safety as well as to allow for comparison between interventions.

Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR.

Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded updosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0- 12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10 min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 nonallergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses.

Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500 AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500 AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500 AU/mL of HDM extract produced no symptoms in SB allergics nor 1500 AU/mL SB extract in HDM allergics.

For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500 AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

Allergen immunotherapy remains a widely recognized and widely used method for the treatment of selected allergic diseases. Currently, according to the European Academy Of Allergy and Clinical Immunology (EAACI) guidelines, venom immunotherapy (VIT) may be considered for patients over 60. Nevertheless, no separate studies have confirmed the efficacy and safety of this therapy. This study aimed to evaluate the short-term effectiveness of VIT against wasp allergens in an ultra-rush protocol for older patients compared to young patients.

Among the 113 patients included in this study, 51 were older than 60 years (Group A), and 62 formed the control "young group" (age range: 18-35 years). All patients were desensitized to wasp venom using the ultra-rush protocol according to Muller and aqueous solutions of vaccines containing wasp venom. A basophil activation test (Basotest, Orpegen Pharma, Germany) and intracutaneous tests with dilutions of wasp allergen and specific IgE to extract wasp venom were performed at the start and after six months of VIT. The safety of VIT was assessed on the basis of the international Mueller scale.

One hundred and eleven patients with confirmed wasp allergies completed six months of VIT: 51 participants over 60 years of age (Group A) and 60 young people (Group B). No systemic adverse reactions were observed during the VIT induction phase. However, large local reactions were noted in 17% of older patients and 20% of young patients at a similar level (p > 0.05). During maintenance VIT, two mild grade I systemic reactions were confirmed in young patients. These symptoms resolved spontaneously. There were no such reactions in older patients. The effectiveness of VIT was tested using BAT. There was a statistically significant reduction in CD63 reactivity in 86% of patients in Group A, and a comparable and substantial decrease in 84% of young patients in Group B. According to the BAT test, the mean reductions in the area under the curve (AUC) after six months of VIT were significant (p < 0.05) and comparable between Groups A and B: -6.52 vs. 7.21.

VIT against wasp venom is safe and effective in short-term observation, and is comparable to that used for young patients.

Oral immunotherapy (OIT) is a promising allergen-specific approach in the management of food allergy; however, studies on OIT for allergic rhinitis (AR) have rarely been reported. The purpose of this study is to evaluate the efficacy and safety of OIT using enteric-coated capsules for AR induced by house dust mites.

A total of 49 patients with AR were enrolled, including 25 who received subcutaneous immunotherapy (SCIT) and 24 who received OIT. The clinical efficacy and safety in both groups were evaluated.

After 1 year of treatment, both SCIT and OIT demonstrated significant therapeutic effects. OIT was found to be more effective than SCIT in reducing the total AR symptom score and improving the results of nasal provocation tests. Local and systemic adverse reactions were observed in the SCIT group, while none were reported in the OIT group.

OIT is an effective and safe treatment for mite induced AR.

Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.

To determine if nasal allergen challenge (NAC) responses to cockroach allergen would improve following one year of SCIT.

Urban children with asthma, that were cockroach-sensitized and reactive on NAC, participated in a yearlong randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean total nasal symptoms scores (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test (SPT) wheal size, serum allergen-specific antibody production and T-cell responses to cockroach allergen were assessed.

Changes in mean NAC TNSS did not differ between SCIT-assigned (n=28) versus placebo-assigned (n=29) participants (p=0.63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum specific IgE (sIgE) decreased to a similar extent in both groups, while decreased cockroach SPT wheal size was greater among SCIT participants (p=0.04). A 200-fold increase in cockroach sIgG4 was observed among subjects receiving SCIT (p<0.001) but was unchanged in the placebo group. T-cell interleukin-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (p=0.002), while no effect was observed for interleukin-10 or interferon-gamma.

A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum sIgG4 production and down-modulation of allergen stimulated T cell responses.