Tolerability of sublingual versus vestibular allergy immunotherapy tablet administration: A randomized pilot study.

BACKGROUND: Local application site reactions are common with sublingual allergy immunotherapy (AIT)-tablets for the treatment of allergic rhinitis/conjunctivitis (AR/C) and occasionally lead to treatment discontinuation. Because of the lower mast cell density in the vestibular mucosa than the sublingual area, vestibular AIT-tablet administration may result in fewer adverse events (AEs). This pilot study evaluated the tolerability of the vestibular administration route of AIT-tablets compared with the sublingual route in adult subjects with AR/C. METHODS: Adults (n = 164) aged 18-65 years with AR/C treated with daily birch pollen, grass pollen, ragweed pollen or house dust mite AIT in tablet form were randomized 1:1 to vestibular or sublingual administration for 28 days, followed by 28 days of sublingual administration only. The primary endpoint was the severity (mild, moderate, severe) of local treatment-related adverse events (TRAEs) during the first 28 days of treatment. RESULTS: During the first 28 days, the percentage of subjects in the vestibular and sublingual groups reporting mild TRAEs were 55.6% versus 50.6%, respectively; moderate TRAEs were 27.2% versus 30.1%; and severe TRAEs were 12.3% versus 6.0% (p = .16). In the vestibular group, 95.1% of the subjects experienced at least one TRAE during the first period versus 81.9% in the sublingual group (p = .01) and discontinuation rates due to AEs were higher (12.3% vs. 3.6%). CONCLUSION: The frequencies of subjects experiencing severe TRAEs, at least one TRAE, and discontinuations due to AEs at the initiation of AIT-tablets were numerically higher with vestibular administration than sublingual administration. Sublingual administration should remain the standard of care for subjects treated with AIT-tablets for AR/C.

Rhinoconjunctivitis severity induced by cat exposure influences early and late asthmatic responses: Evidence from an environmental exposure chamber.

BACKGROUND: The impact of allergic rhinoconjunctivitis on the early (EAR) and late asthmatic response (LAR) has yet to be assessed during optimal allergen exposure conditions. OBJECTIVE: We aimed to assess predictive factors of the EAR and LAR and to evaluate the relation between rhinitis, conjunctivitis and asthma induced by cat allergen exposure in an environmental exposure chamber (EEC). METHODS: Data from two cohort studies involving asthmatic patients with cat allergy who performed a cat allergen exposure challenge in ALYATEC EEC were analysed. Spirometry, visual analogue scale (VAS) for asthma, VAS for rhinitis, Total Nasal Symptoms Score, Total Ocular Symptoms Score (TOSS), Rhinoconjunctivitis Total Symptoms Score and Abelson score were used to assess asthma, rhinitis and conjunctivitis during and after exposure. RESULTS: An EAR occurred in 65.1% of patients, 32.1% of whom had a LAR. The diameter of the prick test to cat allergens and non-specific bronchial hypersensitivity level were independent risk factors for EAR (p < .05). No independent risk factors for LAR were identified. Rhinoconjunctivitis severity during exposure correlated with the asthma VAS during EAR and LAR (p < .05). Allergen exposure time needed to trigger an EAR correlated with the Abelson score during exposure (p < .05). The asthma VAS and TOSS during exposure correlated with faster LAR occurrence (p < .05). CONCLUSION: Prick test size and non-specific bronchial hypersensitivity level were confirmed as independent predictive factors of EAR during allergen exposure in an EEC. This study demonstrated the relation between the severity of rhinitis, conjunctivitis and asthma induced by allergen exposure for both EAR and LAR.

Phosphorylated p38 MAP kinase expression by leucocytes is increased in allergic humans and associated with IgE responses.

Mitogen-activated protein kinases (MAPK) activate cascades that regulate cell proliferation, differentiation and death. Phosphorylated (phos-)p38 MAPK is a cell-signalling pathway associated with Th2 cytokine responses, which is required for immunoglobulin (Ig)E production. It is unknown whether MAPK are associated with IgE production. We examine the evidence linking p38 MAPK to inflammatory responses. Phos-p38, extracellular signal-related kinase (ERK) and c-JUN-n terminal (JNK) MAPK expression by blood leucocyte subsets and levels of serum Igs were measured in blood from adults with asthma and/or rhinoconjunctivitis (N = 28) and non-asthma (N = 10) (flow cytometry, microfluorenzymeimmunoassay). Peripheral blood mononuclear cells (PBMC) from allergic subjects were cultured for 10 days ± anti-CD40/recombinant IL-4 ± inhibitor of phos-P38. Culture supernatants were assayed for IgE (ELISA). Phos-p38 MAPK expression by all leucocyte subsets of allergic subjects was associated with serum IgE levels (p ≤ 0.01), after adjusting for cell counts, age, sex, race and smoking status (p ≤ 0.04). Leucocyte expression of phos-ERK and JNK did not correlate with IgE (p = 0.09-0.99). Instead, phos-ERK expression was associated with serum IgG. When PBMC from atopic subjects were cultured for 10 days with anti-CD40/rhIL-4, IgE levels were 26.2 ± 18 ng/mL. Inclusion of SB202190 (5-20 µg/mL), a specific inhibitor of phos-p38 MAPK, in culture suppressed IgE production in dose-dependent manner, with peak suppression obtained with SB202190 at 20 µg/mL (82.1% ± 11.8) (p = 0.0001), with virtually no cytotoxicity (<5%). Different MAPK pathways may be associated with IgE (p38) and IgG (ERK) responses. Phos-p38 MAPK can be a potential anti-allergy drug target.

A randomized, double-blind, placebo-controlled trial with mannan-conjugated birch pollen allergoids.

BACKGROUND: There is still great need to develop new strategies to improve the efficacy of allergen immunotherapies with optimal safety standards for patients. A new promising approach is to couple allergoids to mannan. The objective of this phase IIa/IIb study was to identify the optimal dose of mannan-conjugated birch pollen allergoids for the short-course treatment of birch pollen-induced allergic rhinoconjunctivitis. METHODS: For this prospective, randomized, double-blind, placebo-controlled, dose-finding study, 246 birch pollen-allergic adults received 0.5 mL placebo or 1000, 3000 or 10,000 mTU/mL of mannan-conjugated birch pollen allergoids at five pre-seasonal visits. Efficacy was assessed by comparing allergic rhinoconjunctivitis symptoms and use of anti-allergic medication during the peak of the birch pollen season 2020. Immunologic, tolerability and safety effects were also analysed. RESULTS: The highest dose of mannan-conjugated birch pollen allergoids reduced the combined symptom and medication score during the peak birch pollen season by a median of 24.7% compared to placebo. The production of Bet v 1 specific IgG4 significantly increased in a dose-dependent manner (3.6- and 4.5-fold) in the 3000 and 10,000 mTU/mL groups. The Bet v 1 specific IgE/IgG4 ratio was also strongly reduced (up to -70%). No fatalities nor serious adverse events were reported, and no adrenaline was used. In total, four systemic reactions occurred (two grade I and two grade II). CONCLUSION: All doses of mannan-conjugated birch pollen allergoids can be considered as safe. Since the application of 10,000 mTU/mL resulted in the highest efficacy, this dose qualifies for further investigation.

Pharmacokinetics and Safety of Bilastine 10 mg/d in Children Aged 2 to 5 Years With Allergic Rhinoconjunctivitis or Urticaria: A Phase 3 Clinical Trial.

BACKGROUND: Bilastine is a second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis (ARC) and urticaria in adults, adolescents, and children. The pharmacokinetics and safety of oral bilastine 10 mg/d in children aged 2 to 5 years were evaluated. METHODS: This was a multicenter, open-label clinical trial in children aged 2 to 5 years with seasonal or perennial ARC or urticaria treated once daily with bilastine 10 mg orodispersible tablets. The safety evaluation included treatment-emergent adverse events (TEAEs), vital signs, and physical examination. Pharmacokinetic data were pooled with data from a prior pediatric study, and pharmacokinetic modeling was performed to assess consistency. RESULTS: A total of 37 children with ARC (81.1%), urticaria (8.1%), or both (10.8%) were included in the study, with a mean (SD) age of 3.7 (1.2) years. The highest plasma concentrations of bilastine were observed 1 hour after administration (634.91 ng/mL). Eight patients (21.6%) experienced 1 TEAE each, none of which was severe. Body weight and age were not covariates of variation in either systemic clearance or the volume of distribution in children aged 2 to 5 years and did not affect the pharmacokinetic parameters of bilastine. CONCLUSIONS: The pharmacokinetics of bilastine was linear and consistent with data from a previous trial, suggesting that a 10-mg dose may be used in children (2 to <12 years). No dose adjustments are deemed necessary. Oral once-daily bilastine 10 mg presented a good safety profile in children aged 2 to 5.

Quality of life in adolescent and adult patients with persistent allergic rhinitis after one year of subcutaneous immunotherapy with a modified mite extract.

Introduction: Allergic rhinoconjunctivitis (AR) is an IgE-mediated inflammation of nasal and ocular mucosa after environmental allergen exposure, mainly by house dust mites (HDM). AR affects more than one third of the population worldwide and it is associated with loss of quality of life (QoL). Aim: To analyse the improvement in the QoL in 50 patients with moderate-persistent AR due to house HDM before and after receiving 1 year of subcutaneous specific aeroallergen immunotherapy treatment (SAIT). Material and methods: A prospective observational study was performed based on clinical practice in 50 patients with moderate-severe persistent AR due to HDM and candidates to SAIT. Forty-one patients completed the study. Patients were evaluated with the ESPRINT short-version QoL questionnaire, a score of medication use and visual analogue scale (VAS) symptom score, prior to and 12 months after SAIT. Results: Forty-one patients (25 women, mean age 26.9 years). Mean ESPRINT values prior to the start SAIT was 3.06 (moderate-severe) and 1 year after starting subcutaneous SAIT the mean value dropped in all patients to 0.88 (mild). The VAS score symptom dropped from 8.26 to 3.68. 97.56% of patients used 3 or more drugs (oral antihistamine, ophthalmic/intranasal antihistamine, intranasal corticosteroid and/or oral antileukotrienes) prior to starting SAIT, and 1 year after it, 58.53% used one on-demand medication to control symptoms, oral antihistamine or nasal spray, and not daily use. Conclusions: Subcutaneous SAIT seems to be a valid treatment in our patients with moderate-persistent AR due to HDM, since it reduces the ESPRINT score, VAS score and the use of medication. An improvement in the quality of life and satisfaction was observed by the patients themselves.

Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy.

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

Evaluation of Safety, Efficacy, and Compliance of Intralymphatic Immunotherapy for Allergic Rhinoconjunctivitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Intralymphatic immunotherapy (ILIT) is an emerging type of allergen immunotherapy with fewer injections and shorter course for allergic rhinoconjunctivitis (ARC). The efficacy and safety have not been confirmed by informative and powerful evidence yet. METHODS: A systematic review and meta-analysis were conducted through electronic searching with PubMed, Web of Science, Embase, Scopus, and China National Knowledge Infrastructure (CNKI). The safety (incidence of adverse events [AEs]), compliance (percent of patients completing treatment), and clinical efficacy of ILIT were evaluated. Clinical efficacy could be assessed by improvement of subjective symptom and rescue medication use or the nasal tolerance to specific allergen. This study is registered with PROSPERO (CRD42022353562). RESULTS: 12 randomized controlled trials (RCTs) comparing ILIT with placebo and 3 trials (2 RCTs and one case-control study) comparing ILIT and SCIT were included in this review. Totally, 582 patients diagnosed as AR or ARC were enrolled. Almost all the AEs were mild-to-moderate reactions except 2 patients developed anaphylactic reactions at the intralymphatic injection dose 5,000 SQ-U in one study. ILIT got higher incidence of local AEs than placebo, but their incidence of systemic AEs was similar. ILIT was safer than SCIT (p < 0.05). Almost all the patients could complete ILIT treatment, and the most common reason for discontinuation of ILIT was AEs. The compliance of patients receiving ILIT seemed higher than patients receiving SCIT. ILIT could significantly ameliorate subjective allergic symptoms, especially for seasonal ARC, and increase nasal tolerance, similar to SCIT. CONCLUSION: ILIT was a safe and effective treatment for ARC and could achieve comparable clinical improvement with SCIT with shorter duration and higher compliance. Moreover, ILIT was safer than SCIT.

Knowledge mapping of immunotherapy for allergic rhinoconjunctivitis: a bibliometric study (2002-2021).

BACKGROUND: Allergic rhinoconjunctivitis (ARC) is a common chronic inflammatory disease. Numerous studies on the treatment of ARC have been published. By contrast, there are few bibliometric studies on immunotherapy for ARC. The purpose of this article is to describe the current treatments for ARC and to identify the trends in immunotherapy for ARC. METHODS: Publications were searched from the Web of Science (WOS) Core Collection on April 25, 2022. CiteSpace and Microsoft Excel software were used for further bibliometric analysis. RESULTS: A total of 969 publications on immunotherapy for ARC in English were retrieved. The number of relevant publications has been continuously increasing over the past 20 years, with many of the publications coming from Germany and the United States of America. In terms of institutions, the ALK Company in Denmark, Imperial College London in United Kingdom, and Charite-Universitatsmedizin Berlin in Germany published the most articles on immunotherapy for ARC. Meanwhile, Allergy and Journal of Allergy and Clinical Immunology published the most number of studies, and Oliver Pfaar from Germany authored the most number of articles. "Subcutaneous immunotherapy," "international consensus," "allergen immunotherapy," and "recommendation" were the most popular subjects. Thus, directions in research can be predicted as studies regarding mechanisms of ARC, clinical trials, and extracts have reported high-quality results. CONCLUSION: Over the past 20 years, the overall quality of research on immunotherapy for ARC has gradually improved, allowing the introduction of specific and targeted treatment. Currently, the main focus of ARC research is the novel routes of drug delivery and combined treatment with biological agents.

Clinical efficacy and safety of coseasonal initiation of Artemisia annua sublingual immunotherapy on patients with Artemisia-induced rhinoconjunctivitis.

PURPOSE: Patients with seasonal allergic rhinoconjunctivitis (SARC) might seek evaluation and treatment when symptoms appear during the pollen season. It is unclear whether coseasonal-initiated sublingual immunotherapy (SLIT) would be effective and safe for SARC. This study aims to identify the feasibility of initiating Artemisia annua SLIT during the pollen season. MATERIALS AND METHODS: Sixty patients with Artemisia-induced SARC were equally recruited into the SLIT and control groups during the pollen season in 2021. The SLIT group was treated with standardized Artemisia annua SLIT drops using a modified dosing schedule combined with pharmacotherapy, while the control group only received pharmacotherapy. Diary cards for clinical symptoms, rescue medication use, and adverse events (AEs) were recorded during the pollen seasons. Objective measures, including average daily combined scores of medication and rhinoconjunctivitis symptoms (CSMRS), total rhinoconjunctivitis symptom score (TRSS), total medication score (TMS), and the score of visual analog scale (VAS) were calculated to evaluate the efficacy of SLIT. Safety was assessed through the occurrence and severity of AEs. RESULTS: In total, 80.0 % (24/30) patients in the SLIT group and 86.67 % (26/30) patients in the control group completed the study. The severity of SARC, which was assessed by objective measures including CSMRS, TRSS, TMS, and VAS of the SLIT group and the control group, was generally at the same level during the 2021 pollen season, except for the medical consumption, which the score of TMS was slightly higher in the SLIT group. After one year of treatment, the scores of CSMRS, TRSS, and VAS in the SLIT group were significantly improved compared with the control group (all P < 0.001), and the difference in the TMS between the two groups disappeared (P > 0.05). Moreover, clinical improvement of the four objective measures was also observed in the SLIT group compared with the baseline value (P < 0.001). Overall, 9/24 patients in the SLIT group experienced mild local AEs, and two patients experienced mild systemic AEs during the SLIT period. CONCLUSIONS: This controlled preliminary study identified that coseasonal-initiated Artemisia annua SLIT treatment for one year was generally safe and effective in improving the symptoms of SARC patients induced by Artemisia annua pollen.

Clinical efficacy in one-year treatment with Artemisia annua-SLIT drops in monosensitized and polysensitized individuals.

PURPOSE: Seasonal allergic rhinoconjunctivitis (SARC) caused by Artemisia seriously affects patients' quality of life in northern China. This study aimed to estimate further the efficacy and safety of a one-year course of Artemisia annua-sublingual immunotherapy (SLIT) on SARC patients. MATERIALS AND METHODS: This was an open-label, randomized, controlled, single-centre study involving 150 SARC patients induced by Artemisia, randomized to SLIT group (n = 75, SLIT along with pharmacotherapy) or control group (n = 75, pharmacotherapy only). According to the skin prick test (SPT) results, the SLIT group was divided into monosensitized and polysensitized groups to analyze the influence of sensitization status on the efficacy of Artemisia annua-SLIT. The clinical indicators of this study were total rhinoconjunctivitis symptom score (TRSS), total medication score (TMS), combined scores of medication and rhinoconjunctivitis symptom (CSMRS), and score of visual analog scale (VAS). Safety was evaluated by the occurrence of adverse events (AEs). Daily administration of the drops was recorded in diaries by the patients. RESULTS: After nearly one year of treatment and follow-ups, there was a significant decline in TRSS, TMS, CSMRS, and VAS from the baseline scores in the SLIT group (p < 0.001). However, as pollen counts increased in 2022, indicators above in the control group increased significantly during the peak pollen phase (PPP) in 2022 grass pollen season (GPS) compared to the baseline. Meanwhile, we found no significant difference in TRSS, TMS, CSMRS, and VAS between the monosensitized and polysensitized groups (p > 0.05). Moreover, the result indicated that the clinical improvement in TRSS, TMS, CSMRS, and VAS was still observed in polysensitized patients who were allergic to Artemisia pollen and sensitized to house dust mite (HDM) (n = 15) in PPP of 2022, compared to the baseline value (p < 0.001). CONCLUSION: Artemisia annua-SLIT was proven effective, tolerable and safe in patients with SARC after nearly one year of treatment, whether monosensitization or polysensitization.

Clinical evaluation of subcutaneous immunotherapy with a polymerized molecular allergoid of Alt a 1 in patients with allergic rhinoconjunctivitis and/or allergic asthma caused by the mould Alternaria alternata.

Summary: This is a retrospective analysis of the clinical evolution of 14 patients diagnosed with allergic rhinoconjunctivitis (AR) and/or allergic asthma (AA) caused by Alternaria alternata, who were attended by the allergology service of Vega Baja Hospital of Orihuela (Alicante, Spain). The purpose was to assess the clinical impact and safety of 1-year of subcutaneous immunotherapy with a polymerized molecular allergoid of Alt a 1. Impact of the treatment on allergic diseases (mean number AR/AA episodes and ARIA/GINA classifications), changes in symptoms and prescribed medication, change in the global subjective clinical status of patients and satisfaction with the treatment were also evaluated. Adverse reactions were also recorded and analyzed. After 1-year of treatment, fewer AR and AA episodes (p less than 0.05) and improvements in ARIA/GINA classifications were observed. Significant improvements of symptoms (p less than 0.05) and a resulting general reduction of the medication prescribed was also detected. Improvements in the global subjective clinical status and good satisfaction rates were observed. Only 1 patient presented a local and not clinically relevant adverse reaction. The treatment showed promising effects with a significant improvement in the clinical status of all patients with a good safety profile.

Factors associated with self-assessed asthma severity.

BACKGROUND: Asthma severity can be estimated as the level of medication needed to achieve asthma control or by the patient's subjective assessment. Factors associated with self-assessed asthma severity are still incompletely explored. AIM: The aim was to study factors associated with self-assessed moderate or severe asthma. METHOD: In total, 1828 randomly selected asthma patients from primary (69%) and secondary (31%) care, completed a questionnaire including items about patient characteristics, comorbidity, the Asthma Control Test (ACT), emergency care visits and a scale for self-assessed asthma severity. Logistic regression was used to analyze associations with the dependent variable, self-assessed moderate or severe asthma in the entire study population and stratified by sex. RESULTS: Of the patients, 883 (45%) reported having moderate or severe asthma. Factors independently associated with self-assessed moderate or severe asthma were age >60 years (OR [95% CI] 1.98 [1.37-2.85]), allergic rhino-conjunctivitis (1.43 [1.05-1.95]), sinusitis (1.45 [1.09-1.93]), poor asthma control as measured by ACT <20 (5.64 [4.45-7.16]) and emergency care visits the previous year (2.52 [1.90-3.34]). Lower level of education was associated with self-assessed moderate/severe asthma in women (1.16 [1.05-2.43]) but not in men (0.90 [0.65-1.25]), p for interaction = .012. CONCLUSION: Poor asthma control, allergic rhino-conjunctivitis, recent sinusitis and older age were independently associated with self-assessed moderate or severe asthma. Important implications are that comorbid conditions of the upper airways should always be considered as part of asthma management, and that elderly patients may need extra attention.

Ragweed sublingual immunotherapy (SLIT) tablets in allergic rhinoconjunctivitis: a systematic review and meta-analysis.

PURPOSE: Ragweed allergen causes Allergic rhinoconjunctivitis and sublingual immunotherapy is one of the treatment modalities to desensitize allergic individuals. This systematic review assesses the effectiveness and safety of sublingual immunotherapy for allergic rhinoconjunctivitis caused due to Ragweed. METHODS: The databases search was done through December 2020. English-language randomized controlled trials were included if they compared sublingual immunotherapy with placebo, pharmacotherapy, or other sublingual immunotherapy regimens, and reported clinical outcomes. The strength of the evidence for each comparison and outcome was graded based on the risk of bias, consistency, magnitude of effect, and the directness of the evidence. RESULTS: The searches performed according to the protocol identified 134 abstracts of which 67 were duplicates. A total of 37 full papers were therefore reviewed of which 5 were included for the final study. Participants' ages ranged from 4 to 58 years. The risk of bias was low in most studies. The review suggests that sublingual immunotherapy improves rhinoconjunctivitis symptoms, with 4 of 4 studies reporting efficacy showed improvement in the symptom score of SLIT groups compared to placebo. Local reactions were frequent, but anaphylaxis was not reported in any of the studies. Serious adverse events were very few in all the studies. CONCLUSIONS: The overall evidence showed the effectiveness of sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis with or without asthma, but high-quality studies are still needed to answer questions regarding optimal dosing strategies.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Intralymphatic immunotherapy improves grass pollen allergic rhinoconjunctivitis: A 3-year randomized placebo-controlled trial.

BACKGROUND: Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed. OBJECTIVE: In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT). METHODS: Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). A novel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen. RESULTS: A total of 36 patients were included. Log10-transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P = .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P < .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found. CONCLUSIONS: ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. A booster injection had no additional effect.

Persistence of the clinical effect of grass allergen peptide immunotherapy after the second and third grass pollen seasons.

BACKGROUND: Grass allergen peptides are in development for the treatment of grass pollen-induced allergic rhinoconjunctivitis. A previous randomized, placebo-controlled study demonstrated that grass allergen peptides significantly improved total rhinoconjunctivitis symptom scores (TRSSs) after posttreatment challenge (PTC) to rye grass in an environmental exposure unit after 1 intervening grass pollen season (GPS1). OBJECTIVE: We sought to evaluate the efficacy/safety of 4 dosing regimens of grass allergen peptides after a second (GPS2) and third (GPS3) intervening GPS in the environmental exposure unit. METHODS: Eligible subjects who were randomized in the parent study (GPS1) during the first year of recruitment were invited to participate in GPS2 and GPS3, which took place 1 and 2 years after treatment cessation, respectively. Participants were not treated further, and both participants and study personnel remained blinded. The primary efficacy end point was the change in mean TRSS (reported every 30 minutes) from GPS1 baseline to the follow-up PTC calculated across all time points over days 2 to 4 for GPS2 and across hours 1 to 3 over days 2 to 4 for GPS3. Secondary efficacy end points and safety were also assessed. RESULTS: One hundred twenty-two and 85 participants were enrolled in GPS2 and GPS3, respectively. A numerically greater, but not statistically significant improvement from baseline in mean TRSS at PTC was observed in the group receiving one 6-nmol intradermal injection every 2 weeks for 14 weeks group compared with the placebo at GPS2 (-6.0 vs -3.6, P = .0535) and GPS3 (-6.2 vs -3.6, P = .1128). Similar findings were observed for the group receiving one 6-nmol intradermal injection every 2 weeks for 14 weeks at GPS3 (-6.4 vs -3.6, P = .0759). No adverse safety signals were detected. CONCLUSION: Treatment with grass allergen peptides led to an improvement in allergic rhinoconjunctivitis symptoms after 3 intervening GPSs, corresponding to up to 2 years off treatment.

Dietary factors during pregnancy and atopic outcomes in childhood: A systematic review from the European Academy of Allergy and Clinical Immunology.

RATIONALE: Allergic diseases are an increasing public health concern, and early life environment is critical to immune development. Maternal diet during pregnancy has been linked to offspring allergy risk. In turn, maternal diet is a potentially modifiable factor, which could be targeted as an allergy prevention strategy. In this systematic review, we focused on non-allergen-specific modifying factors of the maternal diet in pregnancy on allergy outcomes in their offspring. METHODS: We undertook a systematic review of studies investigating the association between maternal diet during pregnancy and allergic outcomes (asthma/wheeze, hay fever/allergic rhinitis/seasonal allergies, eczema/atopic dermatitis (AD), food allergies, and allergic sensitization) in offspring. Studies evaluating the effect of food allergen intake were excluded. We searched three bibliographic databases (MEDLINE, EMBASE, and Web of Science) through February 26, 2019. Evidence was critically appraised using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case-control studies and meta-analysis performed from RCTs. RESULTS: We identified 95 papers: 17 RCTs and 78 observational (case-control, cross-sectional, and cohort) studies. Observational studies varied in design and dietary intakes and often had contradictory findings. Based on our meta-analysis, RCTs showed that vitamin D supplementation (OR: 0.72; 95% CI: 0.56-0.92) is associated with a reduced risk of wheeze/asthma. A positive trend for omega-3 fatty acids was observed for asthma/wheeze, but this did not reach statistical significance (OR: 0.70; 95% CI: 0.45-1.08). Omega-3 supplementation was also associated with a non-significant decreased risk of allergic rhinitis (OR: 0.76; 95% CI: 0.56-1.04). Neither vitamin D nor omega-3 fatty acids were associated with an altered risk of AD or food allergy. CONCLUSIONS: Prenatal supplementation with vitamin D may have beneficial effects for prevention of asthma. Additional nutritional factors seem to be required for modulating the risk of skin and gastrointestinal outcomes. We found no consistent evidence regarding other dietary factors, perhaps due to differences in study design and host features that were not considered. While confirmatory studies are required, there is also a need for performing RCTs beyond single nutrients/foods.

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria.

Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and Cmax values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC0-24 and Cmax were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo.Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar.What is Known:• Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day).• An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years.What is New:• As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years.• Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo.

The SQ tree SLIT-tablet is highly effective and well tolerated: Results from a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: The SQ tree sublingual immunotherapy (SLIT)-tablet (ALK-Abelló, Hørsholm, Denmark) is developed for treatment of tree pollen-induced allergic rhinoconjunctivitis (ARC). OBJECTIVE: The aim of this pivotal phase III trial was to demonstrate the efficacy and safety of the SQ tree SLIT-tablet. METHODS: This was a randomized, double-blind, placebo-controlled trial with 634 subjects (12-65 years) with moderate-to-severe ARC despite use of symptom-relieving medication. Eligible subjects were randomized 1:1 to active or placebo treatment. The primary end point was the average daily ARC total combined score (TCS) during the birch pollen season (BPS) analyzed for subjects with diary data during the BPS. Secondary end points included average daily symptom scores (DSS) during the BPS, average TCS and DSS during the tree pollen season (TPS), and average daily medication scores (DMS) in the BPS and TPS. RESULTS: The primary and key secondary end points demonstrated statistically significant and clinically relevant effects of the SQ tree SLIT-tablet compared with placebo. For the BPS, absolute (relative) differences from placebo were 3.02 (40%) for TCS, 1.32 (37%) for DSS, and 1.58 (49%) for DMS (all P < .0001). For the TPS, absolute (relative) differences from placebo were 2.27 (37%) for TCS, 0.99 (33%) for DSS, and 1.20 (47%) for DMS (all P < .0001). Treatment was well tolerated. The most frequently reported treatment-related adverse events were mild or moderate local reactions related to sublingual administration. CONCLUSION: The trial demonstrated the efficacy and safety of the SQ tree SLIT-tablet compared with placebo during the BPS and TPS in adolescents and adults with birch pollen-induced ARC (EudraCT 2015-004821-15).