Real-World Study of Ragweed Sublingual Immunotherapy in Hungary.

BACKGROUND: Ragweed (Ambrosia elatior) has become invasive in Europe, causing significant respiratory issues. Subcutaneous allergen immunotherapy (SCIT) has long been used to manage pollen allergies, but sublingual immunotherapy (SLIT) has gained interest. OBJECTIVE: This study aimed to evaluate the clinical benefits of ragweed SLIT under real-world in a cohort of Hungarian patients allergic to ragweed pollen. METHODS: We retrospectively reviewed the clinical records of 57 patients during the 2015 and 2016 ragweed pollen seasons. Patients were divided into two groups: Group 1 (n = 29), who had not received immunotherapy, and Group 2 (n = 28), who had previously undergone immunotherapy with another sublingual preparation. All patients were treated with Oraltek® ragweed for 4-6 months, initiating 2-4 months before the pollen season and rest of the period was 2 months of the 2016 pollen season. Symptom score (SS), medication score (MS), and combined symptom and medication score (CSMS) were evaluated intra- and intergroup. RESULTS: Pollen counts were consistent between 2015 and 2016. All patients showed significant improvement in SS, MS, and CSMS, with a large effect size (>0.8). Group 2 had significantly lower SS and CSMS in 2015 because of prior immunotherapy. By 2016, both groups exhibited marked improvements, with Group 1 showing a 75% improvement in CSMS. No local or systemic reactions were recorded, indicating a high safety profile. CONCLUSIONS: Ragweed SLIT significantly improved symptoms and reduced use of medication in patients allergic to ragweed pollen. The treatment was effective even in patients with previous immunotherapy, with a high benefit-risk ratio demonstrated by the absence of adverse reactions. These findings support the use of Oraltek SLIT for managing ragweed pollen allergy.

Unraveling wasp sensitization in a patient with systemic mastocytosis by CAP-inhibition assay.

Systemic mastocytosis (SM) is a clonal mast cell disorder that can lead to potentially severe anaphylactic reactions. Hymenoptera sting is one of the most frequent triggers of anaphylaxis in these patients, and diagnosis of indolent SM (ISM) without skin involvement (ISMs) is not rare. In this subgroup of patients, venom immunotherapy (VIT) is an effective treatment decreasing subsequent systemic reactions, and lifelong administration is recommended. An individualized diagnosis is necessary to offer the most adequate VIT, and molecular diagnosis (MD) may be useful to discriminate between primary sensitization and cross-reactivity. Nevertheless, other techniques such as ImmunoCAP inhibition assays may be necessary to identify the genuine sensitization to offer the most suitable VIT. We present a male patient with an anaphylactic reaction following several wasp stings. The patient was diagnosed with ISM, and allergy to both Polistes dominula and Vespula sp venom was confirmed. In this scenario, MD did not discriminate between a genuine double sensitization and venom cross-reactivity between both vespids. Thus, CAP-inhibition assay was performed. This case indicated the importance of an accurate diagnosis of hymenoptera venom allergy (HVA). It also highlights the usefulness of CAP-inhibition assays when MD fails to distinguish between genuine double Polistes-Vespula sensitization and cross-reactivity.

Augmented type 2 inflammatory response in allergic rhinitis patients experiencing systemic reactions to house dust mite subcutaneous immunotherapy.

BACKGROUND: Subcutaneous immunotherapy (SCIT) can induce systemic reactions (SRs) in certain patients, but the underlying mechanisms remain to be fully elucidated. METHODS: AR patients who were undergoing standardized HDM SCIT (Alutard, ALK) between 2018 and 2022 were screened. Those who experienced two consecutive SRs were included in the study group. A control group was established, matched 1:1 by gender, age, and disease duration with the study group, who did not experience SRs during SCIT. Clinical and immunological parameters were recorded and analyzed both before SCIT and after 1 year of treatment. RESULTS: A total of 161 patients were included, with 79 (49.07%) in the study group. The study group had a higher proportion of AR combined asthma (26.8% vs. 51.8%, p < 0.001) and higher levels of sIgE to HDM and HDM components (all p < .001). Serum IL-4 and IL-13 levels in the study group were higher than those in the control group (p < .05). The study group received a lower maintenance dosage of HDM extracts injections than control group due to SRs (50000SQ vs. 100000SQ, p < .05). After 1 year of SCIT, the VAS score, the lung function parameters of asthmatic patients over 14 years old significantly improved in both groups (all p < .05). After a 7-day exposure to 20 µg/mL HDM extracts, the percentages of Th1, Th17, Tfh10, and Th17.1 in PBMCs decreased, while the Tfh13 cells significantly increased in the study group (p < .05). CONCLUSION: The type 2 inflammatory response is augmented in HDM-induced AR patients who experienced SRs during SCIT. Despite this, SCIT remains effective in these patients when administered with low-dosage allergen extracts.

Efficacy and safety of low-dose sesame oral immunotherapy in paediatric patients: a protocol for a single-centre, randomised controlled trial.

INTRODUCTION: Sesame allergy, though with low prevalence, can result in severe, potentially life-threatening reactions and poses challenges in allergen avoidance due to hidden sources. In the majority of patients, sesame allergy persists and there is currently no effective long-term treatment available. Therefore, oral immunotherapy (OIT) is a promising alternative approach to managing sesame allergy. In this study protocol, we present a randomised controlled trial evaluating the efficacy and safety of OIT with low-dose sesame protein in paediatric patients. The study's aim is to compare OIT with a 300 mg maintenance dose of sesame protein against controls. METHODS AND ANALYSIS: 39 participants aged 3-17 with IgE-mediated sesame allergy confirmed by oral food challenge will be enrolled into the study. The trial will be conducted at the Paediatric Hospital of the Medical University of Warsaw, Poland. The study comprises two arms-sesame OIT and control. In the sesame OIT group, interventions will be administered once daily for up to 18 months. During the first phase, the dose will be escalated every 2-4 weeks, and in the second phase, the maintenance dose of 300 mg sesame protein will continue for 3 months. Members of the control group will receive standard treatment, which includes an elimination diet and will remain under observation for 1 year. The primary outcome is the proportion of participants tolerating a single dose of 4000 mg of sesame protein during the final oral food challenge in the experimental group versus the control group. Secondary outcomes assess adverse events, changes in immunological parameters and the maximum tolerated doses of sesame protein in each group. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the Medical University of Warsaw (approval number: KB/269/2023). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: NCT06261554.

Impact of COVID-19 on adverse reactions to subcutaneous specific immunotherapy in children:a retrospective cohort study.

BACKGROUND: COVID-19 is a new infectious disease. To investigate whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the adverse reactions of subcutaneous specific immunotherapy (SCIT) in children. METHODS: This study was conducted by collecting relevant data from children who underwent house dust mite SCIT from April 3, 2021, to March 18, 2023, including information on the time of COVID-19 infection, symptoms, and adverse reactions after each allergen injection. A mixed effects model was used to analyze the changes in adverse reactions before and after the COVID-19 infection. RESULTS: Among the records of adverse reactions from 2658 injections in 123 children who underwent SCIT, the overall adverse reaction rate before COVID-19 infection was 39.8% and 30.0% after COVID-19 infection. Compared with pre-infection with COVID-19, the risks of overall adverse reactions, local adverse reactions, and systemic adverse reactions of immunotherapy after COVID-19 infection were reduced (odds ratio [OR] = 0.24, 0.31, and 0.28, all P < 0.05). Among the local adverse reactions, the incidence of the unvaccinated group was the highest (15.3% vs. 7.1%). The incidence of overall and local adverse reactions to SCIT decreased in 2-vaccinated COVID-19 recipients (OR = 0.29-0.31, P < 0.05). CONCLUSIONS: In children, SARS-CoV-2 infection does not increase the incidence of adverse reactions to SCIT. This finding can provide a basis for the implementation of allergen-specific immunotherapy (AIT) during the COVID-19 pandemic.

Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.

BACKGROUND: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs. METHODS: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens. FINDINGS: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5. INTERPRETATION: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure. FUNDING: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.

Intranasal administration of a synthetic TLR4 agonist INI-2004 significantly reduces allergy symptoms following therapeutic administration in a murine model of allergic sensitization.

Introduction: Atopic diseases have been steadily increasing over the past decades and effective disease-modifying treatment options are urgently needed. These studies introduce a novel synthetic Toll-like receptor 4 (TLR4) agonist, INI-2004, with remarkable efficacy as a therapeutic intranasal treatment for seasonal allergic rhinitis. Methods: Using a murine airway allergic sensitization model, the impact of INI-2004 on allergic responses was assessed. Results: One or two intranasal doses of INI-2004 significantly reduced airway resistance, eosinophil influx, and Th2 cytokine production - providing strong evidence of allergic desensitization. Further investigations revealed that a liposomal formulation of INI-2004 exhibited better safety and efficacy profiles compared to aqueous formulations. Importantly, the liposomal formulation demonstrated a 1000-fold increase in the maximum tolerated intravenous dose in pigs. Pre-clinical GLP toxicology studies in rats and pigs confirmed the safety of liposomal INI-2004, supporting its selection for human clinical trials. Discussion: These findings lay the groundwork for the ongoing clinical evaluation of INI-2004 in allergic rhinitis as a stand-alone therapy for individuals poly-sensitized to multiple seasonal allergens. The study underscores the significance of innovative immunotherapy approaches in reshaping the landscape of allergic rhinitis management.

A retrospective study of a novel 3-session rush venom immunotherapy protocol.

BACKGROUND: Venom immunotherapy (VIT) is an effective treatment for life-threatening stinging-insect hypersensitivity. Rush VIT protocols allow patients to reach maintenance dosing faster, thus conferring protection sooner. The published protocols vary in dosing regimens, monitoring parameters, and safety profiles. OBJECTIVE: To describe a novel 3-session outpatient rush VIT protocol with full therapeutic dosing achieved at the end of session 3. METHODS: We conducted a retrospective chart review of adult patients treated with rush VIT in an outpatient university allergy/immunology clinic. Demographic and clinical data, including the type of sting reaction, the number of venom allergens, and any systemic reactions (SRs) during VIT, were analyzed. RESULTS: Over a 14-year period, 55 patients (28 females and 27 males) with a median age of 47 years underwent our VIT protocol. A total of 46 patients (84%) tolerated the procedure without SR, and 53 (96%) attained full maintenance dosing. All reactions during rush were Brown anaphylaxis criteria grade 1 or 2. Although the most common venom allergy was yellow jacket, most patients had multiple venom allergies and received therapy with more than 1 venom. Furthermore, 10 patients were re-stung while on maintenance with only 1 patient having a mild SR. CONCLUSION: Our 3-session outpatient rush VIT protocol is effective and safe. Most patients had no SR and attained maintenance dosing. Compared with other 3-session rush protocols, our protocol requires non-invasive monitoring, and patients achieved monthly maintenance dosing immediately on completion.

Standardizing the skin tape stripping method for sensitization and using it to create a mouse model of peanut allergy.

BACKGROUND: Animal models for food allergies serve as crucial tools in understanding allergy mechanisms and assessing the efficacy of potential desensitization methods. The effectiveness of inducing allergies in mice through intragastric lavage sensitization varies. The intraperitoneal method can trigger systemic anaphylaxis, however it lacks anatomical relevance. Hence, a uniform and reliable allergy induction method in mice is required. Tape -stripping can mimic atopic dermatitis (AD), a precursor to lifelong peanut allergies in humans. Furthermore, skin damage triggers the upregulation of skin alarmins and the expansion of small-intestinal mast cells, both implicated in allergy development. METHODS: We standardized a skin-based sensitization method in a mouse model of peanut allergy using skin tape-stripping followed by allergen application. We compared this method with intragastric sensitization. RESULTS: Skin-based sensitization led to increased mast cells, goblet cells, and eosinophils in the small intestine, elevated systemic IgE levels, murine mast cell protease-1 (mMCP-1), histamine, and eosinophilic activity in peripheral blood. Moreover, it resulted in a significant hypothermic response, with nearly 30% mortality following an oral challenge one-month post-sensitization. CONCLUSION: Our research offers a standardized and readily reproducible method for inducing peanut allergy in mice, which could also be adapted for other food allergens.

Grass pollen allergoids conjugated with mannan for subcutaneous and sublingual immunotherapy: a dose-finding study.

Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen (Phleum pratense and Dactylis glomerata) administered via either the subcutaneous or sublingual route. Methods: A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Conclusion: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search (EudraCT), identifier 2014-005471-88; https://www.clinicaltrials.gov, identifier NCT02654223.

A retrospective comparison of IgE-mediated cow's milk protein allergy management strategies in pediatric cohorts.

BACKGROUND: Complete avoidance of milk is the usual management for IgE-mediated cow's milk protein allergy (CMPA). A baked milk ladder is a method of dietary advancement therapy in IgE-mediated CMPA in Ireland, while in Spain, avoidance of milk awaiting natural tolerance acquisition through an oral food challenge (OFC) is employed. The aim of this study was to evaluate the use of dietary advancement therapy using a milk ladder compared with complete avoidance of milk for managing IgE-mediated CMPA. METHODS: This is a retrospective chart review of 371 pediatric patients from the population who have been treated for IgE-mediated CMPA between 2011 and 2020, with the milk ladder (Ireland) or complete avoidance followed by an OFC (Spain). The main outcome was the introduction of cow's milk. RESULTS: Milk ladder patients were 3.67 times more likely to succeed in comparison with milk avoidance (p < .001). Anaphylaxis during the treatment period occurred in 34 patients in the milk avoidance groups, while three patients in the milk ladder group experienced anaphylaxis due to accidental exposure to milk (p < .001). Failure to complete treatment was associated with a higher skin prick test in the milk avoidance group and a raised specific IgE in the milk ladder group. CONCLUSION: This is the first study that compares outcomes of dietary advancement therapy to complete avoidance for CMPA management, demonstrating that cow's milk can be successfully and safely reintroduced using dietary advancement therapy using a milk ladder.

Efficacy and safety of hymenoptera venom immunotherapy.

Background: Being stung by Hymenoptera species can cause life-threatening anaphylaxis. Although venom immunotherapy (VIT) seems to be the most effective treatment, its long-term efficacy, and risk factors for adverse events remain unclear. Objective: The objective was to investigate the long-term efficacy of VIT and evaluate adverse events and risk factors related to this. Method: Patients who received VIT in a tertiary-care adult allergy clinic between January 2005 and July 2022 were included. Patients' data were compared with those of individuals who had been diagnosed with bee and/or wasp venom allergy during the same period but had not received VIT and experienced field re-stings. Results: The study included 105 patients with venom allergy, of whom 68 received VIT and 37 did not receive VIT. Twenty-three patients (34%) completed 5 years of VIT, and the overall mean ± standard deviation VIT duration was 46.9 ± 20.9 months. Re-stings occurred in 5 of 23 patients who completed 5 years of VIT, and none of them developed a systemic reaction. Eighteen patients (40%) experienced re-stings after prematurely discontinuing VIT, of whom eight (44%) developed a systemic reaction. In the control group of patients who did not receive VIT, 26 patients (70.3%) experienced re-stings, and all had systemic reactions (100%), with no change in their median Mueller scores. There was a significant difference in the median Mueller score change between the patients who received VIT and the controls who did not (p = 0.016). A total of 13 patients (19%) experienced adverse events while receiving VIT, which were systemic reactions in nine honeybee VIT. The use of ß-blockers was determined as the most important risk factor (odds ratio 15.9 [95% confidence interval, 1.2-208.8]; p = 0.035). Conclusion: It was confirmed that VIT was effective in both reducing the incidence and the severity of re-sting reactions. These effects were more pronounced in the patients who completed 5 years of VIT.

A real-life ImmunoCAT study: impact of molecular diagnosis through ImmunoCAPTM ISAC 112 on immunotherapy prescription in pollen-polysensitized patients in Catalonia, Spain.

BACKGROUND: Molecular diagnosis in allergology helps to identify multiple allergenic molecules simultaneously. The use of purified and/or recombinant allergens increases the accuracy of individual sensitization profiles in allergic patients. OBJECTIVE: To assess the impact of molecular diagnosis through the ImmunoCAPTM ISAC 112 microarray on etiological diagnosis and specific immunotherapy (SIT) prescription. This was compared to the use of conventional diagnoses in pediatric, adolescent, and young adult patients with rhinitis or rhinoconjunctivitis and/or allergic asthma, sensitized to three or more pollen allergens of different botanical species. METHODS: A multicenter, prospective, observational study was conducted in patients aged 3-25 years who received care at the Allergology service of 14 hospitals in Catalonia from 2017 to 2020. Allergology diagnosis was established based on the patient's clinical assessment and the results of the skin prick test and specific immunoglobulin E assays. Subsequently, molecular diagnosis was conducted using ImmunoCAPTM ISAC® 112 to recombinant and/or purified allergen components. RESULTS: A total of 109 patients were included; 35 (32.1%) were pediatric patients and 74 (67.9%) were adolescents or young adults (mean age: 18 years), with 58.0% being females. A change of 51.0% was observed in SIT prescription following molecular etiological diagnosis by means of a multi-parameter microarray. CONCLUSIONS: Molecular diagnosis by means of multi-parameter tests increases the accuracy of etiological diagnosis and helps to define an accurate composition of SIT.

Oral food immunotherapy in patients with atopic dermatitis.

Atopic dermatitis (AD) is one of the main risk factors for infants in the development of food allergy. Oral immunotherapy (OIT) in early childhood has been found to be highly effective and safe in preschoolers with and without AD, especially in young infants. Delays in initiation of OIT in infants and children due to uncontrolled AD risk expansion of the number of foods children develop allergy to through unnecessary avoidance of multiple foods. Parents and caregivers may attribute eczema flares to OIT doses, which physicians usually ascribe to non-food triggers such as weather changes, psychological stress, and infection. There is a lack of published literature confirming OIT as a trigger of AD flares, and the degree to which OIT may be associated with AD flares needs to be further studied. We describe 8 case scenarios with varying degrees of AD flare before and during OIT. We propose management algorithms for children with preexisting concurrent AD and food allergy who are being considered for starting OIT and children with AD flares during OIT. Optimizing AD control strategies and providing adequate AD care education before starting OIT can reduce confusion for both parents and allergists if rashes arise during OIT, thus improving adherence to OIT.