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Poto R, Shamji M, Marone G, et al., 2022, Neutrophil Extracellular Traps in Asthma: Friends or Foes?, CELLS, Vol: 11
Durham SR, Shamji MH, 2022, Allergen immunotherapy: past, present and future, NATURE REVIEWS IMMUNOLOGY, ISSN: 1474-1733
Dua S, Ruiz-Garcia M, Bond S, et al., 2022, Effects of Exercise and Sleep Deprivation on Reaction Severity During Oral Peanut Challenge: A Randomized Controlled Trial., J Allergy Clin Immunol Pract, Vol: 10, Pages: 2404-2413.e1
BACKGROUND: The severity of allergic reactions to foods can vary markedly. Little is known of variations in reaction severity within or between individuals or the effects of cofactors. OBJECTIVE: We examined the effects of sleep deprivation and exercise and repeat challenges on the severity and patterns of allergic reactions to peanut. METHODS: In a randomized crossover study, adults with peanut allergy underwent 3 open peanut challenges in random order: with exercise after each dose, with sleep deprivation preceding challenge, and with no intervention. The primary outcome was eliciting dose, reported elsewhere. Reaction severity was a secondary outcome, evaluated using a weighted log-transformed numerical severity score. Analyses estimated the difference in severity between nonintervention challenge and challenges with exercise or sleep deprivation, adjusting for challenge order and using the highest dose tolerated by each individual across all their challenges. Symptom pattern reproducibility was assessed by comparing symptom sequences using pairwise sequence alignment to obtain a percentage match in symptom pattern. RESULTS: Eighty-one participants (mean age 25 y) completed at least 1 postbaseline challenge. Sleep deprivation, but not exercise, significantly increased severity score by 48% (95% CI 12%-84%; P = .009) compared with no intervention. A 38% increase in severity was observed between the first and the last postbaseline challenge (95% CI 1%-75%; P = .044). The average pairwise match of symptoms within individuals was 82.4% and across individuals was 78.3%. CONCLUSIONS: A novel severity score demonstrates that sleep deprivation and repeated challenges increase reaction severity. Understanding factors affecting severity is essential for effective risk management. We also show that symptom patterns in repeat peanut challenges are similar within and between individuals.
Garcia HR, Wheeler K, Gunawardana N, et al., 2022, Optimal tests for predicting the outcome of oral food challenges to hazelnut, walnut and cashew in clinical practice, Publisher: WILEY, Pages: 1006-1006, ISSN: 0954-7894
Penagos M, Durham SR, 2022, Long-term efficacy of the sublingual and subcutaneous routes in allergen immunotherapy, ALLERGY AND ASTHMA PROCEEDINGS, Vol: 43, Pages: 292-298, ISSN: 1088-5412
Kasemsuk N, Ngaotepprutaram P, Kanjanawasee D, et al., 2022, Local nasal immunotherapy for allergic rhinitis: A systematic review and meta-analysis, INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY, ISSN: 2042-6976
Layhadi J, Lenormand M, Kirtland M, et al., 2022, Novel machine learning-led discovery of adjuvant drug candidate for allergen immunotherapy using synthetic toll-like receptor 2/6 agonist, Publisher: MOSBY-ELSEVIER, Pages: AB71-AB71, ISSN: 0091-6749
Palmer E, Layhadi J, Fedina O, et al., 2022, IL-10+regulatory B cells are dysregulated in patients with seasonal and perennial allergy, Publisher: MOSBY-ELSEVIER, Pages: AB95-AB95, ISSN: 0091-6749
Turner P, Durham S, Skypala I, et al., 2022, No apparent impact of incremental dosing on eliciting dose at double-blind, placebo-controlled peanut challenge, Allergy, Vol: 77, Pages: 667-670, ISSN: 0105-4538
Penagos M, Durham SR, 2022, Allergen immunotherapy for long-term tolerance and prevention, Journal of Allergy and Clinical Immunology, Vol: 149, ISSN: 0091-6749
Allergen immunotherapy is effective for the treatment of allergic rhinitis, allergic asthma and Hymenoptera venom allergy. In view of potential side effects, cost, and the necessary patient commitment, an important question is whether allergen immunotherapy provides persistent clinical benefits after treatment discontinuation. Here we appraise the existing evidence for long-term effects of both subcutaneous and sublingual immunotherapy in terms of clinical efficacy, immune mechanisms, prevention of asthma development and prevention of new allergen sensitisations. Evidence from large, randomised, double-blind, placebo-controlled clinical trials that include a follow-up phase after treatment cessation demonstrate long-term efficacy. The data strongly support recommendations in international guidelines that both sublingual and subcutaneous immunotherapy should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance. Grass pollen immunotherapy for seasonal rhinitis may inhibit the onset of asthma symptoms and requirements for asthma medication. Whether early intervention in infancy with mite sublingual immunotherapy may prevent asthma remains to be tested.
Sousa-Pinto B, Azevedo LF, Jutel M, et al., 2022, Development and validation of combined symptom-medication scores for allergic rhinitis*, ALLERGY, Vol: 77, Pages: 2147-2162, ISSN: 0105-4538
Pfaar O, Bergmann K-C, Bonini S, et al., 2021, Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report., Allergy, Vol: 76, Pages: 3589-3612
Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.
Layhadi JA, Lenormand MM, Sharif H, et al., 2021, Allergenicity and immunogenicity profile of depigmented-polymerized phleum pratense extract for use in allergen-specific immunotherapy treatments, Publisher: WILEY, Pages: 427-428, ISSN: 0105-4538
Shamji MH, Larson D, Eifan A, et al., 2021, Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 148, Pages: 1061-+, ISSN: 0091-6749
Han JK, Bachert C, Fokkens W, et al., 2021, Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial., Lancet Respir Med, Vol: 9, Pages: 1141-1153
BACKGROUND: Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. METHODS: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. FINDINGS: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score signi
Pfaar O, Bousquet J, Durham SR, et al., 2021, One hundred and ten years of Allergen Immunotherapy: A journey from empiric observation to evidence, ALLERGY, Vol: 77, Pages: 454-468, ISSN: 0105-4538
Shamji MH, Singh I, Layhadi JA, et al., 2021, Passive Prophylactic Administration with a Single Dose of Anti-Fel d 1 Monoclonal Antibodies REGN1908-1909 in Cat Allergen-induced Allergic Rhinitis A Randomized, Double-Blind, Placebo-controlled Clinical Trial, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 204, Pages: 23-33, ISSN: 1073-449X
Shamji MH, Valenta R, Jardetzky T, et al., 2021, The role of allergen-specific IgE, IgG and IgA in allergic disease, ALLERGY, Vol: 76, Pages: 3627-3641, ISSN: 0105-4538
Bousquet J, Pfaar O, Agache I, et al., 2021, ARIA-EAACI care pathways for allergen immunotherapy in respiratory allergy, CLINICAL AND TRANSLATIONAL ALLERGY, Vol: 11
Shamji MH, Layhadi JA, Sharif H, et al., 2021, Immunological Responses and Biomarkers for Allergen-Specific Immunotherapy Against Inhaled Allergens, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 9, Pages: 1769-1778, ISSN: 2213-2198
Turner P, Ruiz-Garcia M, Patel N, et al., 2021, Delayed symptoms and orthostatic intolerance following peanut challenge, Clinical and Experimental Allergy, Vol: 51, Pages: 696-702, ISSN: 0954-7894
BackgroundClinical reactions to Oral Food Challenge (OFC) in peanut‐allergic individuals have been well‐characterised, but rates and phenotypes of symptom recurrence beyond the first hour after objective symptoms are less well‐characterised.ObjectiveTo evaluate the rate of new‐onset symptoms occurring at least 1 h after stopping OFC in peanut‐allergic children and adults undergoing peanut‐OFC.MethodsWe prospectively collected data relating to adverse events following positive reactions at double‐blind, placebo‐controlled food challenges (DBPCFC) to peanut in children and adults evaluated for eligibility to participate in two clinical trials (NCT02149719, NCT02665793). The trials included people aged 8 to 45 with primary, IgE‐mediated peanut allergy at DBPCFC. The challenge protocol included consumption of a light meal 1 h after reaction.ResultsA total of 121 participants (64 children, 57 adults) had immediate, objective symptoms at DBPCFC, 25 (17 children, 8 adults) with anaphylaxis. Thirty‐three (27%) had progression or recurrence of symptoms ≥ 1 h after objective clinical reaction, of whom 8 developed anaphylaxis. In 23 cases, the onset of new symptoms was associated with consumption of a light meal. In eight cases, symptoms were limited to a symptomatic postural fall in blood pressure noted in preparation for discharge, without any other new features of an allergic reaction.Conclusions & Clinical RelevanceProgressive or new‐onset symptoms ≥1 h following initial allergic reaction at OFC are common and can include orthostatic hypotension. Recurrent symptoms may be temporally associated with food consumption.
Eifan A, Scadding G, Durham S, et al., 2021, Comparison of nasal allergen challenges with dissolved Timothy Grass pollen tablets and aqueous extract, Allergy, Vol: 76, Pages: 1543-1545, ISSN: 0105-4538
Pfaar O, Agache I, Bergmann K-C, et al., 2021, Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper, ALLERGY, Vol: 76, Pages: 629-647, ISSN: 0105-4538
Bousquet J, Anto JM, Czarlewski W, et al., 2021, Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19, Allergy, Vol: 76, Pages: 735-750, ISSN: 0105-4538
Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1 R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT1 R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.
Sahiner UM, Layhadi JA, Golebski K, et al., 2021, Innate Lymphoid Cells: The Missing Part Of A Puzzle In Food Allergy., Allergy
Food allergy is an increasingly prevalent disease which is mainly driven by uncontrolled type 2 immune response. Currently, knowledge about the underlying mechanisms that initiate and promote the immune response to dietary allergens is limited. Patients with food allergy are commonly sensitized through the skin in their early life, later on developing allergy symptoms within the gastrointestinal tract. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5 and IL-13 with infiltration of mast cells, eosinophils and basophils. Recent studies raised a possible role for the involvement of innate lymphoid cells (ILCs) in driving food allergy. They represent a group of lymphocytes that lack specific, recombined antigen receptors. ILCs contribute to immune responses not only by releasing cytokines and other mediators but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces ofthe airways, gut and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidence on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs towards inflammatory processes and regulatory mechanisms.
Golebski K, Layhadi JA, Sahiner U, et al., 2021, Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response., Immunity, Vol: 54, Pages: 291-307.e7, ISSN: 1074-7613
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.
Sharif H, Acharya S, Dhondalay GKR, et al., 2021, Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 663-676, ISSN: 0091-6749
BACKGROUND: Allergen-specific immunotherapy (AIT) is a disease-modifying treatment that induces long-term T cell tolerance. OBJECTIVE: To evaluate the role of circulating CXCR5+PD-1+T follicular helper (cTFH) and T follicular regulatory (TFR) cells following grass pollen subcutaneous (SCIT) and sublingual (SLIT) immunotherapy and the accompanying changes in their chromatin landscape. METHODS: Phenotype and function of cTFH cells were initially evaluated in grass pollen-allergics (GPA, n= 28) and non-atopic controls (NAC, n=13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cTFH and TFR cells were further enumerated in NAC (n=12), GPA (n=14), SCIT (n=10) and SLIT (n=8)-treated groups. Chromatin accessibility in cTFH and TFR cells was assessed by ATAC-seq to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT and SLIT. RESULTS: cTFH cells were shown to be distinct from TH2 and TH2A cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cTFH cell proliferation in GPA but not in NAC (P<.05). cTFH cells were higher in GPA compared to NAC and were lower in SCIT and SLIT (P<.01). Time-dependent induction of IL-4, IL-21 and IL-6 were observed in nasal mucosa following intranasal allergen challenge in GPA but not in SCIT and SLIT groups. TFR and IL-10+ cTFH cells were induced in SCIT and SLIT (all, P<.01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups. CONCLUSION: For the first time, we showed dysregulation of cTFH cells in GPA compared to NAC, SCIT and SLIT and induction of TFR and IL-10+ cTFH cells following SCIT and SLIT. Changes in the chromatin landscape were observed following AIT in cTFH and TFR cells.
Ruiz-Garcia M, Bartra J, Alvarez O, et al., 2021, Cardiovascular changes during peanut-induced allergic reactions in human subjects, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 633-642, ISSN: 0091-6749
Background: Food allergy is the commonest cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in non-fatal reactions remains poorly understood. Objective: To systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut. Methods: Participants underwent double-blind placebo-controlled food challenge topeanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, peripheral blood flow) and electrocardiogram during food challenges were assessed using continuous monitoring. ClinicalTrials.gov Identifier: NCT02665793 Results: 57 adults (median age 24 (IQR 20-29) years, 53% female) participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease 4.2%, 95%CI 0.8 to 7.6; p=0.03), heart rate (mean increase 11.6%, 95%CI 8.4 to 14.8; p<0.0001) and peripheral blood flow (mean increase 19.7%, 95%CI 10.8 to 28.6; p<0.0001), irrespective of reaction severity. These changes were reproduced at subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms. Conclusions: In this first detailed human study of cardiovascular changes during food-allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, where poor outcomes occur due to a failure in compensatory mechanisms.Ruiz-Garcia et al 5 Clinical Implication: Significant changes in cardiovascular function, including decreased stroke volume, occur during peanut-induced allergic reactions in adults irrespective of severit
Durham SR, Till SJ, Holgate ST, 2021, OBITUARY Anthony Barrington Kay 1939-2020, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 51, Pages: 206-208, ISSN: 0954-7894
Orban N, Jacobson MR, Nouri-Aria KT, et al., 2021, Repetitive nasal allergen challenge in allergic rhinitis: priming and Th2-type inflammation but no evidence of remodelling., Clinical and Experimental Allergy, Vol: 51, Pages: 329-338, ISSN: 0954-7894
BACKGROUND: Local tissue eosinophilia and Th2-cytokines are characteristic features of seasonal allergic rhinitis. Airway-remodelling is a feature of asthma whereas evidence for remodelling in allergic rhinitis (AR) is conflicting. OBJECTIVE: By use of a novel human repetitive nasal allergen challenge (RAC) model, we evaluated the relationship between allergic inflammation and features of remodelling in AR. METHODS: Twelve patients with moderate-severe AR underwent 5-alternate day challenges with diluent which after 4-weeks were followed by 5-alternate day challenges with grass pollen extract. Nasal symptoms, Th1/Th2 cytokines in nasal secretion and serum were evaluated. Nasal biopsies were taken 24 hours after the 1st and 5th challenges with diluent and with allergen. Sixteen healthy controls underwent a single challenge with diluent and with allergen. Using immunohistochemistry, epithelial and sub-mucosal inflammatory cells, and remodelling markers were evaluated by computed image analysis. RESULTS: There was an increase in early and late-phase symptoms after every allergen challenge compared to diluent (both p<0.05) with evidence of both clinical and immunological priming. Nasal tissue eosinophils and IL-5 in nasal secretion increased significantly after RAC compared to corresponding diluent challenges (p<0.01, p=0.01, respectively). There was a correlation between submucosal mast cells and the early-phase clinical response (r=0.79, p=0.007) and an association between epithelial eosinophils and IL-5 concentrations in nasal secretion (r=0.69, p=0.06) in allergic rhinitis. No differences were observed after RAC with regards to epithelial integrity, reticular basement membrane thickness, glandular area, expression of markers of activation of airway-remodelling including α-SMA, HSP-47, extracellular matrix (MMP7, 9 and TIMP-1), angiogenesis and lymphangiogenesis for AR compared to healthy controls. CONCLUSION: Novel repetitive nasal allergen challenge in
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