Pharmacotherapy and immunotherapy of allergic rhinitis induced by house dust mite, grass, and birch pollen allergens: a meta-analysis of randomized clinical trials.

BACKGROUND: The aim of this study was to assess the efficacy and safety of oral antihistamines (AHs), intranasal antihistamines (INAH) intranasal glucocorticosteroids (INCS), subcutaneous immunotherapy (SCIT), and sublingual immunotherapy (SLIT) in the management of allergic rhinitis (AR). The authors focused on the division into selected AR's triggers: house dust mites (HDMs), grass pollen, and birch pollen. METHODS: For each drug and allergen class, a meta-analysis of the efficacy and adverse events (AEs) was performed. The obtained results were presented as a therapeutic index (TIX-Score). RESULTS: Twenty-seven randomized clinical trials (RCTs) were included. The best total efficacy was observed for: HDMs for INCS and grass pollen for combination of INCS with INAH in a single device and for INAH. Considering the data that was obtained for birch pollen, SLIT showed statistically significant total efficacy. Summation scores for efficacy and AEs showed highest TIX-Score for combination of INCS and INAH in a single device in grass pollen. CONCLUSIONS: Treatment methods selected for this review may serve as an effective and safe treatment in reducing perennial and seasonal AR's symptoms. However, due to high heterogeneity probably associated with potential confounders existence in control in some cases, results should be interpreted with caution.

Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.

Efficacy and safety of sublingual immunotherapy for allergic rhinitis: A network meta-analysis.

Background: To systematically evaluate the clinical efficacy and safety of sublingual immunotherapy for allergic rhinitis (AR) and provide evidence for clinical treatment. Methods: A literature search was performed on the China National Knowledge Infrastructure (CNKI), Wanfang database, PubMed, Web of Science, Cochrane Library, and Embase database. Data from randomized controlled trials (RCTs) of sublingual immunotherapy for AR were screened and extracted from the establishment of those databases to November 2022. Subsequently, a network meta-analysis was performed using a statistical software R 4.2. Results: Totally 22 RCTs that met the inclusion and exclusion criteria and screened from 1,164 literature were included. A total of 4,941 AR patients were involved in the 22 trials, as well as five interventions including placebo, pharmacotherapy, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_dust mite, and sublingual immunotherapy_ grass mix plus pollen extract. The results of network meta-analysis showed that, based on symptom scores after different interventions for AR, the most effective treatments for AR were in order as follows: sublingual immunotherapy_dust mite, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_ grass mix plus pollen extract, placebo, and pharmacotherapy. Importantly, sublingual immunotherapy had fewer adverse reactions and higher safety. Conclusion: Sublingual immunotherapy_dust mite for AR has the best efficacy, whereas traditional medicine has the worst. More high-quality studies with a large sample and multiple centers are needed to verify this conclusion in the future, so as to further provide more reliable evidence-based medical evidence for the clinical treatment options of AR patients.

Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy.

Allergen-specific sublingual immunotherapy (SLIT), a safe and efficient route for treating type I hypersensitivity disorders, requires high doses of allergens. SLIT is generally performed without adjuvants and delivery systems. Therefore, allergen formulation with appropriate presentation platforms results in improved allergen availability, targeting the immune cells, inducing regulatory immune responses, and enhancing immunotherapy's efficacy while decreasing the dose of the allergen. In this review, we discuss the adjuvants and delivery systems that have been applied as allergen-presentation platforms for SLIT. These adjuvants include TLRs ligands, 1α, 25-dihydroxy vitamin D3, galectin-9, probiotic and bacterial components that provoke allergen-specific helper type-1 T lymphocytes (TH1), and regulatory T cells (Tregs). Another approach is encapsulation or adsorption of the allergens into a particulate vector system to facilitate allergen capture by tolerogenic dendritic cells. Also, we proposed strategies to increasing the efficacy of SLIT via new immunopotentiators and carrier systems in the future.

Patient needs and benefits of sublingual immunotherapy for grass pollen-induced allergic rhinitis: an observational study.

Aim: Clinical efficacy of sublingual immunotherapy for grass pollen-induced allergic rhinitis (AR) needs to translate into patient benefit. Patients & methods: Patients received Oralair (Stallergenes, Antony, France) in real-life medical practice. Patient-relevant treatment benefits were measured with the AR-specific Patient Benefit Index. Subgroups were analyzed regarding distinct patient characteristics. Results: Data of 883 patients (children, adolescents, and adults) were analyzed. The highest-ranked patient needs referred to having less AR symptoms, being able to go outdoors, and being free in the choice of leisure activities. Most patients (89.2-94.6%) attained at least minimally relevant benefit. All subgroups reported relevant benefits, with significantly higher scores in some subgroups. Conclusion: Treatment with Oralair was associated with considerable patient-relevant benefit in all age groups.

Recent development on the use of sublingual immunotherapy tablets for allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is an immunoglobulin (Ig) E-mediated inflammatory condition that causes sneezing, nasal congestion, rhinorrhea, and nasal itch. Although subcutaneous immunotherapy for the treatment of AR has been in use and well established as a treatment modality, sublingual immunotherapy (SLIT) is increasingly considered to be the safer and more convenient alternative. Thus, the objective of this review is to describe recent findings pertaining to the use of SLIT tablets (SLIT-T) for AR. DATA SOURCES: A database search (PubMed.gov) for articles published between January 1, 2017, and February 9, 2021, was conducted using the following key words: "allergic rhinitis," AND-ed "sublingual immunotherapy." Included were randomized placebo-controlled trials. Other experimental design studies were excluded. STUDY SELECTIONS: A total of 11 randomized placebo-controlled trials were selected for full-text review and included in the analysis. All studies investigated the use of SLIT on patients with seasonal AR (4 tree pollen, 1 grass pollen, and 1 Japanese cedar) or perennial AR (3 house dust mite). RESULTS: Our review of 7 recently published randomized placebo-controlled trials with 2348 subjects receiving SLIT reported increased efficacy, safety, supportive immunologic parameters (IgE and IgG4 pre- and posttreatment levels), and improved quality of life. All studies excluded subjects with overlapping seasonal or perennial allergens, a history of moderate-to-severe uncontrolled asthma, or reduced lung function. CONCLUSION: Our review highlights that SLIT is a safe and effective treatment that considerably reduces symptoms and medication requirements in AR and improves quality of life.

Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response.

The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1- ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.

Long-term treatment of Japanese cedar pollinosis with Japanese cedar pollen SLIT drops and persistence of treatment effect: A post-marketing clinical trial.

BACKGROUND: There have been no reports of treatment effect persistence after long-term sublingual immunotherapy (SLIT) in patients with Japanese cedar (JC) pollinosis. Therefore, we conducted a post-marketing clinical trial to investigate the efficacy, safety, and effect persistence of JC pollen SLIT drops after approximately 3 years of treatment. METHODS: This was an open-label trial of 233 patients with JC pollinosis who were treated with JC pollen SLIT drops for approximately 3 years (2015-2017) and followed-up for an additional 2 years (2018-2019). Efficacy and effect persistence were evaluated using nasal and ocular symptom scores, daily use of rescue medication, and Japanese Rhinoconjunctivitis Quality of Life Questionnaire scores recorded during the JC pollen dispersal season of each year. Safety was evaluated by monitoring adverse events and adverse drug reactions. RESULTS: The mean combined total nasal symptom and medication score (range 0-18) during the peak symptom periods of 2015 through 2019 were 5.47 ± 3.38, 4.52 ± 3.13, 3.58 ± 2.63, 5.28 ± 4.01, and 6.83 ± 4.65, respectively. The percentage of patients who used no rescue medications during the same periods was 64.8%, 75.2%, 80.3%, 63.7%, and 50.3%, respectively. A total of 138 adverse drug reaction incidents were recorded in 73 of the 233 patients (31.3%), of which 134 incidents (97.1%) were mild in severity. CONCLUSIONS: JC pollen SLIT drops demonstrated treatment duration-dependent efficacy with effects that persisted for 2 years after cessation of treatment. The drug had a favorable safety profile over the 5-year study period.

Methods for Experimental Allergen Immunotherapy: Subcutaneous and Sublingual Desensitization in Mouse Models of Allergic Asthma.

Allergic asthma is characterized by airway hyperresponsiveness, remodeling, and reversible airway obstruction. This is associated with an eosinophilic inflammation of the airways, caused by inhaled allergens such as house dust mite or grass pollen. The inhaled allergens trigger a type-2 inflammatory response with the involvement of innate lymphoid cells (ILC2) and Th2 cells, resulting in high immunoglobulin E (IgE) antibody production by B cells and mucus production by airway epithelial cells. As a consequence of the IgE production, subsequent allergen reexposure results in a classic allergic response with distinct early and late phases, both resulting in bronchoconstriction and shortness of breath. Allergen-specific immunotherapy (AIT) is the only treatment that is capable of modifying the immunological process underlying allergic responses including allergic asthma. Both subcutaneous AIT (SCIT) as well as sublingual AIT (SLIT) have shown clinical efficacy in long-term suppression of the allergic response. Although AIT treatments are very successful for rhinitis, application in asthma is hampered by variable efficacy, long duration of treatment, and risk of severe side effects. A more profound understanding of the mechanisms by which AIT induces tolerance to allergens in sensitized individuals is needed to be able to improve its efficacy. Mouse models have been very valuable in preclinical research for characterizing the mechanisms of desensitization in AIT and evaluating novel approaches to improve its efficacy. Here, we present a rapid and reproducible mouse model for allergen-specific immunotherapy. In this model, mice are sensitized with two injections of allergen adsorbed to aluminum hydroxide, followed by subcutaneous injections (SCIT) or sublingual administrations (SLIT) of allergen extracts as an immunotherapy treatment. Finally, mice are challenged by intranasal allergen administrations. We will also describe the protocols as well as the most important readout parameters for the measurements of invasive lung function, serum immunoglobulin levels, isolation of bronchoalveolar lavage fluid (BALF), and preparation of cytospin slides. Moreover, we describe how to perform ex vivo restimulation of lung single-cell suspensions with allergens, flow cytometry for identification of relevant immune cell populations, and ELISAs and Luminex assays for assessment of the cytokine concentrations in BALF and lung tissue.

Sublingual immunotherapy for asthma.

BACKGROUND: Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. Fifty-two studies were identified and synthesised in the original Cochrane Review in 2015, but questions remained about the safety and efficacy of sublingual immunotherapy for people with asthma. OBJECTIVES: To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. SEARCH METHODS: The original searches for trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, WHO ICTRP, and reference lists of all primary studies and review articles found trials up to 25 March 2015. The most recent search for trials for the current update was conducted on 29 October 2019. SELECTION CRITERIA: We included parallel randomised controlled trials, irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. We selected outcomes to reflect recommended outcomes for asthma clinical trials and those most important to people with asthma. Primary outcomes were asthma exacerbations requiring a visit to the emergency department (ED) or admission to hospital, validated measures of quality of life, and all-cause serious adverse events (SAEs). Secondary outcomes were asthma symptom scores, exacerbations requiring systemic corticosteroids, response to provocation tests, and dose of inhaled corticosteroids (ICS). DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results for included trials, extracted numerical data, and assessed risk of bias, all of which were cross-checked for accuracy. Any disagreements were resolved by discussion. We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We considered the strength of evidence for all primary and secondary outcomes using the GRADE approach. MAIN RESULTS: Sixty-six studies met the inclusion criteria for this update, including 52 studies from the original review. Most studies were double-blind and placebo-controlled, varied in duration from one day to three years, and recruited participants with mild or intermittent asthma, often with comorbid allergic rhinitis. Twenty-three studies recruited adults and teenagers; 31 recruited only children; three recruited both; and nine did not specify. The pattern of reporting and results remained largely unchanged from the original review despite 14 further studies and a 50% increase in participants studied (5077 to 7944). Reporting of primary efficacy outcomes to measure the impact of SLIT on asthma exacerbations and quality of life was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence; 16 studies did not contribute any data, and a further six studies could only be included in a post hoc analysis of all adverse events. Allocation procedures were generally not well described; about a quarter of the studies were at high risk of performance or detection bias (or both); and participant attrition was high or unknown in around half of the studies. The primary outcome in most studies did not align with those of interest to the review (mostly asthma or rhinitis symptoms), and only two small studies reported our primary outcome of exacerbations requiring an ED or hospital visit; the pooled estimate from these studies suggests SLIT may reduce exacerbations compared with placebo or usual care, but the evidence is very uncertain (OR 0.35, 95% confidence interval (CI) 0.10 to 1.20; n = 108; very low-certainty evidence). Nine studies reporting quality of life could not be combined in a meta-analysis and, whilst the direction of effect mostly favoured SLIT, the effects were often uncertain and small. SLIT likely does not increase SAEs compared with placebo or usual care, and analysis by risk difference suggests no more than 1 in 100 people taking SLIT will have a serious adverse event (RD -0.0004, 95% CI -0.0072 to 0.0064; participants = 4810; studies = 29; moderate-certainty evidence). Regarding secondary outcomes, asthma symptom and medication scores were mostly measured with non-validated scales, which precluded meaningful meta-analysis or interpretation, but there was a general trend of SLIT benefit over placebo. Changes in ICS use (MD -17.13 µg/d, 95% CI -61.19 to 26.93; low-certainty evidence), exacerbations requiring oral steroids (studies = 2; no events), and bronchial provocation (SMD 0.99, 95% CI 0.17 to 1.82; low-certainty evidence) were not often reported. Results were imprecise and included the possibility of important benefit or little effect and, in some cases, potential harm from SLIT. More people taking SLIT had adverse events of any kind compared with control (OR 1.99, 95% CI 1.49 to 2.67; high-certainty evidence; participants = 4251; studies = 27), but events were usually reported to be transient and mild. Lack of data prevented most of the planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS: Despite continued study in the field, the evidence for important outcomes such as exacerbations and quality of life remains too limited to draw clinically useful conclusions about the efficacy of SLIT for people with asthma. Trials mostly recruited mixed populations with mild and intermittent asthma and/or rhinitis and focused on non-validated symptom and medication scores. The review findings suggest that SLIT may be a safe option for people with well-controlled mild-to-moderate asthma and rhinitis who are likely to be at low risk of serious harm, but the role of SLIT for people with uncontrolled asthma requires further evaluation.

Nasal reactivity evaluation in children with allergic rhinitis receiving grass pollen sublingual immunotherapy.

Background: The European Academy of Allergy and Clinical Immunology guidelines, strongly recommended allergen immunotherapy (AIT) as an effective treatment to achieve long-term clinical benefits and to modify the natural history of allergic diseases. Sublingual immunotherapy (SLIT) offers the possibility of home administration, which improves patient comfort and compliance. Objective: The primary outcome of this study was to assess the change in nasal reactivity after grass-pollen AIT treatment. Methods: This was a monocentric, prospective, observational study conducted in Rome from September 2016 to June 2018, in the Pediatric Department of Policlinico Umberto I. We enrolled children, ages between 6 and 12 years, with persistent allergic rhinitis (AR), sensitized to grass pollen. At the first visit (V0, September 2016), one group received the first dose of oral immunotherapy for grass-pollen spray buccal and the other group continued only standard therapy. All the patients had nasal specific immunoglobulin I (IgE) assay (Phl p1, Phl p5), active anterior rhinomanometry with a nasal provocation test (NPT), and spirometry. The patients attended two follow-up visits, in May 2017 (V1) and May 2018 (V2), with the same examinations as at V0. Results: During the treatment, we observed, in the treated group, a significant increase in the mean nasal flow compared with untreated children (p < 0.001). In the AIT group, we found an improvement of nasal function and only 21.05% of all the children in the active group with a positive NPT result at V2. In the control group, we found, at V2, a worsening of nasal function, with 89.47% of the children with a positive NPT result. Furthermore, we found a significant reduction of nasal specific IgE levels at the end of the observation period in the treated group. Conclusion: Analysis of our data provided evidence for a clinical effect of SLIT in inducing clinical changes and allergen tolerance in children with AR.

Allergen Stability and Immunological Reactivity during Co-dissolution and Incubation of House Dust Mite and Japanese Cedar Pollen SLIT-Tablets.

Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells.

Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor ß1 (TGF-ß1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-ß1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

Relevant Patient Benefit of Sublingual Immunotherapy with Birch Pollen Allergen Extract in Allergic Rhinitis: An Open, Prospective, Non-Interventional Study.

INTRODUCTION: Sublingual immunotherapy (SLIT) with birch pollen extract has been shown to be an efficacious treatment of allergic rhinitis (AR). An as-yet unanswered question is whether and how clinical benefit translates into patient benefit, i.e. what benefit patients derive from this treatment. METHODS: This 1-year, open, prospective, multicenter, non-interventional study conducted in 75 German centers measured patient-relevant benefit of birch pollen SLIT (Staloral® Birch) using the questionnaire "Patient Benefit Index for Allergic Rhinitis (PBI-AR)". At treatment onset, patients rated the importance of 25 treatment needs; after the first birch pollen season on treatment, goal achievement was evaluated. A preference-weighted benefit index was calculated and its association with gender, asthma, allergy status, and severity of AR symptoms was determined. RESULTS: Mean age of the 291 adult patients was 38.8 years; 58.4% were female. The most important treatment goals were to "be able to stay outdoors without symptoms" (87.3% quite or very important), "no longer have a runny or stuffed-up nose" (86.9%), and "be able to breathe through your nose more freely" (86.9%). The treatment goals with the highest benefit ratings (referring to those patients to whom the respective goal applied) were to "have confidence in the therapy" (60.5% has helped "quite" or "very much"), "have an easily applicable treatment" (55.6%), and "be able to breathe through my nose more freely" (51.7%). The average PBI-AR global score was 2.19 (SD 1.04) (0-4; with 4 indicating maximum benefit). No significant differences in PBI-AR global score or subscales were found between men and women, poly- and monoallergic patients, or patients with severe versus mild rhinoconjunctivitis. Patients with asthma reported relevant but lower benefit than patients without asthma. CONCLUSION: After 1 year of birch pollen SLIT treatment, patients reported considerable benefit, mainly due to a reduction of physical symptoms and treatment burden.

Impact of Tree Pollen Distribution on Allergic Diseases in Serbia: Evidence of Implementation of Allergen Immunotherapy to Betula verrucosa.

Background and objectives: The relationship between air pollen quantity and the sensitization of allergic patients is crucial for both the diagnosis and treatment of allergic diseases. Weather conditions influence the distribution of allergenic pollen and increases in pollen concentration may negatively affect the health of allergic patients. The aim of this study was to analyze the implementation of allergen immunotherapy with regard to air pollen concentration. Material and Methods: Here we examined the relationship between Betula air pollen concentration and the usage of Betula verrucosa allergen immunotherapy in Serbia. Examination covered the period from 2015 to 2018. Measurement of airborne pollen concentration was performed with Lanzoni volumetric pollen traps. The evidence of the usage of sublingual allergen immunotherapy (SLIT) was gathered from patients with documented sensitization to specific pollen. Results: During this period tree pollens were represented with 58% ± 21% of all measured air pollen species, while Betula pollen represented 15% ± 8% of all tree pollens. Betula pollination peaked in April. Allergen immunotherapy to Betula verrucosa in Serbia is entirely conducted as sublingual immunotherapy and represents 47.1% ± 1.4% of issued tree pollen SLIT. The use of pollen SLIT increased by 68% from 2015 to 2018, with an even greater increase in usage recorded for Betula SLIT-80%. Conclusions: This analysis shows a clear causative relationship between pollination and the type/prevalence of applied allergen immunotherapy. Information about the flowering seasons of allergenic plants is very important for people who suffer from allergy, for clinical allergologists, as well as for governing authorities. The presented data is of practical importance to the proper timing of immunotherapy initiation and of importance for urban landscaping. The obtained data can be the starting point for the instatement of a thorough epidemiological study and the inclusion of Serbia on the pollen map of Europe.

Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

A quality-of-life mapping function developed from a grass pollen sublingual immunotherapy trial to a tree pollen sublingual immunotherapy trial.

Aims: Allergic rhinitis is caused by sensitivity to environmental allergens that can significantly impact quality-of-life. The objective of this analysis was to estimate health state utilities and quality-adjusted life days (QALDs) for a tree allergy immunotherapy trial, TT-04 (EudraCT No.2015-004821-15). Health-state utilities are a measure of patient preference for health states and are necessary to derive QALDs for cost-utility analysis. Preference-based utilities were not collected in the TT-04 trial, so a mapping algorithm was developed based on a similar grass allergy immunotherapy trial, GT-08 (EudraCT No. 2004-000083-27), to estimate utilities.Methods: A two-part model was developed to predict utilities for the GT-08 trial and applied to the TT-04 trial to estimate the difference in mean utility and QALDs between SQ tree sublingual immunotherapy (SLIT)-tablet and placebo.Results: Mean utility difference between SQ tree SLIT-tablet and placebo was 0.030 [95% CI = 0.015-0.046] during the birch pollen season (BPS), 0.019 [95% CI = 0.007-0.030] during the tree pollen season (TPS) and 0.018 [95% CI = 0.007-0.030] during the full trial. The treatment showed a QALD benefit of 1.26 [95% CI = 0.619-1.917] during the BPS, 1.90 [95% CI = 0.692-3.047] during the TPS, and 2.47 [95% CI = 0.930-4.101] during the full trial.Limitations: The generalizability of this algorithm is limited to allergy trials containing the same covariates as those present in the model. The analysis also assumes that grass and tree pollen allergy have the same relationship with EQ5D utilities, which is supported by the fact that both grass and tree pollen induce similar symptoms.Conclusions: Application of the mapping function enabled the calculation of QALDs associated with the treatment, with the caveat that data were extrapolated from grass seasonal allergy to tree seasonal allergy. The results showed a significant QALD benefit of the treatment over placebo in treatment of tree pollen-induced rhinoconjunctivitis.

Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.

Real-life safety of 5-grass pollen tablet in 5-to-9-year-old children with allergic rhinoconjunctivitis.

BACKGROUND: Although 5-grass pollen sublingual immunotherapy has a good safety profile in controlled clinical trials, additional safety information among pediatric patients in a real-world setting would be useful. OBJECTIVE: To further document the safety of 5-grass tablet among children aged 5 to 9 years with allergic rhinoconjunctivitis (ARC). METHODS: This multicenter, observational study included allergy immunotherapy-naïve 5- to 9-year-old children with grass pollen-induced ARC prescribed with 5-grass tablet daily (3-day dose escalation to 300 index of reactivity [IR]). Patients were followed up daily for safety and tolerability over the first 30 treatment days. Adverse events (AEs) and adverse drug reactions (ADRs) were analyzed descriptively. RESULTS: Three hundred seven children (mean age, 7.1 years) were enrolled. Fifty-eight percent were confirmed as polysensitized, and 36% had mild-to-moderate asthma. Of 307 patients, 233 (76%) reported AEs, and 173/307 (56%) reported ADRs, most frequently mild application-site reactions (throat irritation, oral pruritus, oral paresthesia). Sixteen of 307 (5.2%) patients withdrew because of ADRs. In 143 of 173 (83%) patients, ADRs first occurred within 1 week of starting treatment. More than half of the ADRs lasted less than 2 days, and ADRs resolved spontaneously in 161 of 173 (93%) patients. Recurrences of ADRs were reported in 45 of 173 (26%) patients and were also mainly application-site reactions. No notable differences were found in ADRs related to whether patients had asthma at inclusion. Neither epinephrine use nor admission to intensive care unit was reported. CONCLUSION: The safety profile of 5-grass tablet in pediatric ARC patients aged 5 to 9 years was consistent with safety findings in older patients, most ADRs being at the application site and mild to moderate. ClinicalTrials.gov identifier: NCT02295969; EUPAS registration number: 8104.