Publications by authors named "Stephen R Durham"

160 Publications

Development and validation of combined symptom-medication scores for allergic rhinitis.

Allergy 2021 Dec 21. Epub 2021 Dec 21.

Section of Allergology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Background: Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air app to generate and validate hypothesis- and data-driven CSMSs.

Methods: We used MASK-air data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air , and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]).

Results: We assessed 317,176 days of MASK-air use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820).

Conclusion: The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials.
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http://dx.doi.org/10.1111/all.15199DOI Listing
December 2021

One hundred and ten years of Allergen Immunotherapy: A journey from empiric observation to evidence.

Allergy 2021 Jul 27. Epub 2021 Jul 27.

Section of Allergology and Clinical Immunology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

One hundred and ten years after Noon's first clinical report of the subcutaneous application of allergen extracts, allergen immunotherapy (AIT) has evolved as the most important pillar of the treatment of allergic patients. It is the only disease-modifying treatment option available and the evidence for its clinical efficacy and safety is broad and undisputed. Throughout recent decades, more insights into the underlying mechanisms, in particular the modulation of innate and adaptive immune responses, have been described. AIT is acknowledged by worldwide regulatory authorities, and following the regulatory guidelines for product development, AIT products are subject to a rigorous evaluation before obtaining market authorization. Knowledge and practice are anchored in international guidelines, such as the recently published series of the European Academy of Allergy and Clinical Immunology (EAACI). Innovative approaches continue to be further developed with the focus on clinical improvement by, for example, the usage of adjuvants, peptides, recombinants, modification of allergens, new routes of administration, and the concomitant use of biologicals. In addition, real-life data provide complementary and valuable information on the effectiveness and tolerability of this treatment option in the clinical routine. New mobile health technologies and big-data approaches will improve daily treatment convenience, adherence, and efficacy of AIT. However, the current coronavirus disease 2019 (COVID-19) pandemic has also had some implications for the feasibility and practicability of AIT. Taken together, AIT as the only disease-modifying therapy in allergic diseases has been broadly investigated over the past 110 years laying the path for innovations and further improvement.
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http://dx.doi.org/10.1111/all.15023DOI Listing
July 2021

Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report.

Allergy 2021 12;76(12):3589-3612

LETI Pharma, Witten, Germany.

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.
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http://dx.doi.org/10.1111/all.14957DOI Listing
December 2021

The role of allergen-specific IgE, IgG and IgA in allergic disease.

Allergy 2021 Dec 8;76(12):3627-3641. Epub 2021 Jun 8.

Wageningen University & Research, Wageningen, The Netherlands.

Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. Exposure to even minute quantities of allergens can lead to the production of IgE antibodies in atopic individuals. This is termed allergic sensitization, which occurs mainly in early childhood. Allergen-specific IgE then binds to the high (FcεRI) and low-affinity receptors (FcεRII, also called CD23) for IgE on effector cells and antigen-presenting cells. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE, even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared with IgE and do not efficiently interfere with allergen-induced inflammation. However, IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mast cells and basophils. Here, we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.
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http://dx.doi.org/10.1111/all.14908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601105PMC
December 2021

Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy.

J Allergy Clin Immunol 2021 10 2;148(4):1061-1071.e11. Epub 2021 Apr 2.

National Heart and Lung Institute, Allergy and Clinical Immunology, Imperial College NIHR Biomedical Research Centre, Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Immune Tolerance Network, Bethesda, Md.

Introduction: There is no detailed comparison of allergen-specific immunoglobulin responses following sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT).

Objective: We sought to compare nasal and systemic timothy grass pollen (TGP)-specific antibody responses during 2 years of SCIT and SLIT and 1 year after treatment discontinuation in a double-blind, double-dummy, placebo-controlled trial.

Methods: Nasal fluid and serum were obtained yearly (per-protocol population, n = 84). TGP-specific IgA, IgA, IgG, IgG, and IgE were measured in nasal fluids by ELISA. TGP-specific IgA, IgA, and Phleum pratense (Phl p)1, 2, 4, 5b, 6, 7, 11, and 12 IgE and IgG were measured in sera by ELISA and ImmunoCAP, respectively.

Results: At years 2 and 3, TGP-IgA levels in nasal fluid were elevated in SLIT compared with SCIT (4.2- and 3.0-fold for IgA, 2.0- and 1.8-fold for IgA, respectively; all P < .01). TGP-IgA level in serum was elevated in SLIT compared with SCIT at years 1, 2, and 3 (4.6-, 5.1-, and 4.7-fold, respectively; all P < .001). Serum TGP-IgG level was higher in SCIT compared with SLIT (2.8-fold) at year 2. Serum TGP-IgG level was higher in SCIT compared with SLIT at years 1, 2, and 3 (10.4-, 27.4-, and 5.1-fold, respectively; all P < .01). Serum IgG levels to Phl p1, 2, 5b, and 6 were increased at years 1, 2, and 3 in SCIT and SLIT compared with placebo (Phl p1: 11.8- and 3.9-fold; Phl p2: 31.6- and 4.4-fold; Phl p5b: 135.5- and 5.3-fold; Phl p6: 145.4- and 14.7-fold, respectively, all at year 2 when levels peaked; P < .05). IgE to TGP in nasal fluid increased in the SLIT group at year 2 but not at year 3 compared with SCIT (2.8-fold; P = .04) and placebo (3.1-fold; P = .02). IgA to TGP and IgE and IgG to TGP components stratified participants according to treatment group and clinical response.

Conclusions: The observed induction of IgA in SLIT and IgG in SCIT suggest key differences in the mechanisms of action.
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http://dx.doi.org/10.1016/j.jaci.2021.03.030DOI Listing
October 2021

Immunological Responses and Biomarkers for Allergen-Specific Immunotherapy Against Inhaled Allergens.

J Allergy Clin Immunol Pract 2021 05 27;9(5):1769-1778. Epub 2021 Mar 27.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom; Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.

Long-term efficacy that occurs with allergen immunotherapy of proven value is associated with decreases in IgE-dependent activation of mast cells and tissue eosinophilia. This suppression of type 2 immunity is accompanied by early induction of regulatory T cells, immune deviation in favor of T1 responses, and induction of local and systemic IgG, IgG, and IgA antibodies. These "protective" antibodies can inhibit allergen-IgE complex formation and consequent mast cell triggering and IgE-facilitated T2-cell activation. Recent studies have highlighted the importance of innate responses mediated by type 2 dendritic cells and innate lymphoid cells in allergic inflammation. These cell types are under the regulation of cytokines such as thymic stromal lymphopoietin and IL-33 derived from the respiratory epithelium. Novel subsets of regulatory cells induced by immunotherapy include IL-35-producing regulatory T cells, regulatory B cells, a subset of T follicular regulatory cells, and IL-10-producing group 2 innate lymphoid cells. These mechanisms point to biomarkers that require testing for their ability to predict clinical response to immunotherapy and to inform novel approaches for better efficacy, safety, and long-term tolerance.
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http://dx.doi.org/10.1016/j.jaip.2021.03.029DOI Listing
May 2021

Delayed symptoms and orthostatic intolerance following peanut challenge.

Clin Exp Allergy 2021 05 21;51(5):696-702. Epub 2021 Mar 21.

National Heart & Lung Institute, Imperial College London, London, UK.

Background: Clinical 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.

Objective: To evaluate the rate of new-onset symptoms occurring at least 1 h after stopping OFC in peanut-allergic children and adults undergoing peanut-OFC.

Methods: We 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.

Results: A 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 Relevance: Progressive 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.
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http://dx.doi.org/10.1111/cea.13865DOI Listing
May 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.

Am J Respir Crit Care Med 2021 07;204(1):23-33

Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

Sensitization to Fel d 1 ( allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Patients received REGN1908-1909 ( = 36) or a placebo ( = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo ( < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).
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http://dx.doi.org/10.1164/rccm.202011-4107OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437124PMC
July 2021

Anthony Barrington Kay 1939-2020.

Clin Exp Allergy 2021 02;51(2):206-208

MRC Clinical, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

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http://dx.doi.org/10.1111/cea.13835DOI Listing
February 2021

Innate lymphoid cells: The missing part of a puzzle in food allergy.

Allergy 2021 07 16;76(7):2002-2016. Epub 2021 Mar 16.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, UK.

Food allergy is an increasingly prevalent disease 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. Unlike lymphocytes, ILCs lack They represent a group of lymphocytes that lack specific 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 of the 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 toward inflammatory processes and regulatory mechanisms.
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http://dx.doi.org/10.1111/all.14776DOI Listing
July 2021

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

Immunity 2021 02 14;54(2):291-307.e7. Epub 2021 Jan 14.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, UK; NIHR Biomedical Research Centre, Asthma UK Centre in Allergic Mechanisms of Asthma, London, Imperial College London, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.immuni.2020.12.013DOI Listing
February 2021

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy.

Front Immunol 2020 12;11:599083. Epub 2020 Nov 12.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human experiments and in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.
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http://dx.doi.org/10.3389/fimmu.2020.599083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688745PMC
June 2021

Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy.

J Allergy Clin Immunol 2021 02 6;147(2):663-676. Epub 2020 Nov 6.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, London, United Kingdom; Asthma UK Centre in Allergic Mechanisms of Asthma, London, Imperial College London, London, United Kingdom. Electronic address:

Background: Allergen-specific immunotherapy is a disease-modifying treatment that induces long-term T-cell tolerance.

Objective: We sought to evaluate the role of circulating CXCR5PD-1 T follicular helper (cT) and T follicular regulatory (T) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape.

Methods: Phenotype and function of cT cells were initially evaluated in the grass pollen-allergic (GPA) group (n = 28) and nonatopic healthy controls (NAC, n = 13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cT and T cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cT and T cells was assessed by assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT, and SLIT groups.

Results: cT cells were shown to be distinct from T2- and T2A-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 cT-cell proliferation in the GPA group but not in the NAC group (P < .05). cT cells were higher in the GPA group compared with the NAC group and were lower in the SCIT and SLIT groups (P < .01). Time-dependent induction of IL-4, IL-21, and IL-6 was observed in nasal mucosa following intranasal allergen challenge in the GPA group but not in SCIT and SLIT groups. T and IL-10 cT cells were induced in SCIT and SLIT groups (all, P < .01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups.

Conclusions: For the first time, we showed dysregulation of cT cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of T and IL-10 cT cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cT and T cells.
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http://dx.doi.org/10.1016/j.jaci.2020.10.035DOI Listing
February 2021

Repetitive nasal allergen challenge in allergic rhinitis: Priming and Th2-type inflammation but no evidence of remodelling.

Clin Exp Allergy 2021 02 30;51(2):329-338. Epub 2020 Nov 30.

Allergy and Clinical Immunology, National Heart and Lung Institute, Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, Faculty of Medicine, Imperial College London, London, UK.

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 submucosal 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 < .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 < .01, P = .01, respectively). There was a correlation between submucosal mast cells and the early-phase clinical response (r = 0.79, P = .007) and an association between epithelial eosinophils and IL-5 concentrations in nasal secretion (r = 0.69, P = .06) in allergic rhinitis. No differences were observed after RAC with regard 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 with healthy controls.

Conclusion: Novel repetitive nasal allergen challenge in participants with severe persistent seasonal allergic rhinitis resulted in tissue eosinophilia and increases in IL-5 but no structural changes. Our data support no link between robust Th2-inflammation and development of airway remodelling in AR.
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http://dx.doi.org/10.1111/cea.13775DOI Listing
February 2021

Comparison of nasal allergen challenges with dissolved Timothy grass pollen tablets and aqueous extract.

Allergy 2021 05 6;76(5):1543-1545. Epub 2020 Oct 6.

Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College, London, UK.

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http://dx.doi.org/10.1111/all.14590DOI Listing
May 2021

Limited effect of intramuscular epinephrine on cardiovascular parameters during peanut-induced anaphylaxis: An observational cohort study.

J Allergy Clin Immunol Pract 2021 01 2;9(1):527-530.e1. Epub 2020 Sep 2.

Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1016/j.jaip.2020.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794658PMC
January 2021

Cardiovascular changes during peanut-induced allergic reactions in human subjects.

J Allergy Clin Immunol 2021 02 21;147(2):633-642. Epub 2020 Jul 21.

Section of Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, London, United Kingdom.

Background: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood.

Objective: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut.

Methods: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring.

Results: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a 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-induced 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, in which poor outcomes may occur as a result of a failure in compensatory mechanisms.
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http://dx.doi.org/10.1016/j.jaci.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858218PMC
February 2021

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice.

Allergy 2021 01 23;76(1):168-190. Epub 2020 Oct 23.

Dept of Otorhinolaryngology, Chiba University Hospital, Chiba, Japan.

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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http://dx.doi.org/10.1111/all.14422DOI Listing
January 2021

EAACI Allergen Immunotherapy User's Guide.

Pediatr Allergy Immunol 2020 05;31 Suppl 25:1-101

Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria.

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.
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http://dx.doi.org/10.1111/pai.13189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317851PMC
May 2020

Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

Allergy 2021 03;76(3):629-647

Department of Respiratory Medicine, Royal Sussex County Hospital, University of Sussex and University of Brighton, Brighton, UK.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.
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http://dx.doi.org/10.1111/all.14331DOI Listing
March 2021

Nasal allergen challenge and environmental exposure chamber challenge: A randomized trial comparing clinical and biological responses to cat allergen.

J Allergy Clin Immunol 2020 06 10;145(6):1585-1597. Epub 2020 Mar 10.

MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: The direct-instillation nasal allergen challenge (NAC) and the environmental exposure chamber (EEC) are 2 methods of conducting controlled allergen provocations. The clinical and biological comparability of these methods has not been thoroughly investigated.

Objective: We sought to compare clinical and immunologic responses to cat allergen in NAC versus EEC.

Methods: Twenty-four participants were randomized to receive either NAC followed by a 2-day challenge in an EEC or a 2-day challenge in an EEC followed by NAC. Challenges were separated by 28-day washout periods. We measured total nasal symptom scores, peak nasal inspiratory flow, nasal (0-8 hours) and serum cytokines, serum antibodies, peripheral blood antigen-specific T lymphocytes, and gene expression in nasal scrapings. The primary outcome was the total nasal symptom score area under the curve for the first 3 hours after allergen exposure in NAC or after initiation of exposure in EEC.

Results: Both challenges increased IL-5 and IL-13 in nasal fluids and serum and resulted in altered nasal cell expression of gene modules related to mucosal biology and transcriptional regulation. Changes in gene modules, more so than cytokine measurements, showed significant associations with total nasal symptom score and peak nasal inspiratory flow. Overall, EEC exposure generated larger responses and more early terminations compared with NAC. Although the 2 challenges did not correlate in symptom magnitude or temporality, striking correlations were observed in cytokine levels.

Conclusions: Although clinical outcomes of NAC and EEC were temporally different and nonequivalent in magnitude, immunologic responses were similar. Selection of a particular allergen challenge method should depend on considerations of study objectives and cost.
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http://dx.doi.org/10.1016/j.jaci.2020.02.024DOI Listing
June 2020

Is pollen-food syndrome a frequent comorbidity in adults with irritable bowel syndrome?

Allergy 2020 07 14;75(7):1780-1783. Epub 2020 Feb 14.

Department of Allergy and Clinical Immunology, Royal Brompton & Harefield NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/all.14209DOI Listing
July 2020

Allergen-specific IgG memory B cells are temporally linked to IgE memory responses.

J Allergy Clin Immunol 2020 07 27;146(1):180-191. Epub 2019 Dec 27.

ALK-Abelló A/S, Hørsholm, Denmark. Electronic address:

Background: IgE is the least abundant immunoglobulin and tightly regulated, and IgE-producing B cells are rare. The cellular origin and evolution of IgE responses are poorly understood.

Objective: The cellular and clonal origin of IgE memory responses following mucosal allergen exposure by sublingual immunotherapy (SLIT) were investigated.

Methods: In a randomized double-blind, placebo-controlled, time course SLIT study, PBMCs and nasal biopsy samples were collected from 40 adults with seasonal allergic rhinitis at baseline and at 4, 8, 16, 28, and 52 weeks. RNA was extracted from PBMCs, sorted B cells, and nasal biopsy samples for heavy chain variable gene repertoire sequencing. Moreover, mAbs were derived from single B-cell transcriptomes.

Results: Combining heavy chain variable gene repertoire sequencing and single-cell transcriptomics yielded direct evidence of a parallel boost of 2 clonally and functionally related B-cell subsets of short-lived IgE plasmablasts and IgG memory B cells. Mucosal grass pollen allergen exposure by SLIT resulted in highly diverse IgE and IgG repertoires. These were extensively mutated and appeared relatively stable as per heavy chain isotype, somatic hypermutations, and clonal composition. Single IgG memory B-cell and IgE preplasmablast transcriptomes encoded antibodies that were specific for major grass pollen allergens and able to elicit basophil activation at very low allergen concentrations.

Conclusion: For the first time, we have shown that on mucosal allergen exposure, human IgE memory resides in allergen-specific IgG memory B cells. These cells rapidly switch isotype, expand into short-lived IgE plasmablasts, and serve as a potential target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2019.11.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860973PMC
July 2020

Perspectives in allergen immunotherapy: 2019 and beyond.

Allergy 2019 12;74 Suppl 108:3-25

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
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http://dx.doi.org/10.1111/all.14077DOI Listing
December 2019

Pollen season is reflected on symptom load for grass and birch pollen-induced allergic rhinitis in different geographic areas-An EAACI Task Force Report.

Allergy 2020 05 1;75(5):1099-1106. Epub 2020 Mar 1.

German Pollen Information Service Foundation, Berlin, Germany.

Background: The effectiveness of allergen immunotherapy (AIT) in seasonal and perennial allergic rhinitis (AR) depends on the definition of pollen exposure intensity or time period. We recently evaluated pollen and symptom data from Germany to examine the new definitions of the European Academy of Allergy and Clinical Immunology (EAACI) on pollen season and peak pollen period start and end. Now, we aim to confirm the feasibility of these definitions to properly mirror symptom loads for grass and birch pollen-induced allergic rhinitis in other European geographical areas such as Austria, Finland and France, and therefore their suitability for AIT and clinical practice support.

Methods: Data from twenty-three pollen monitoring stations from three countries in Europe and for 3 years (2014-2016) were used to investigate the correlation between birch and grass pollen concentrations during the birch and grass pollen season defined via the EAACI criteria, and total nasal symptom and medication scores as reported with the aid of the patient's hay-fever diary (PHD). In addition, we conducted a statistical analysis, together with a graphical investigation, to reveal correlations and dependencies between the studied parameters.

Results: The analysis demonstrated that the definitions of pollen season as well as peak pollen period start and end as proposed by the EAACI are correlated to pollen-induced symptom loads reported by PHD users during birch and grass pollen season. A statistically significant correlation (slightly higher for birch) has been found between the Total Nasal Symptom and Medication Score (TNSMS) and the pollen concentration levels. Moreover, the maximum symptom levels occurred mostly within the peak pollen periods (PPP) following the EAACI criteria.

Conclusions: Based on our analyses, we confirm the validity of the EAACI definitions on pollen season for both birch and grass and for a variety of geographical locations for the four European countries (including Germany from a previous publication) analyzed so far. On this basis, the use of the EAACI definitions is supported in future clinical trials on AIT as well as in daily routine for optimal patient care. Further evaluation of the EAACI criteria in other European regions is recommended.
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http://dx.doi.org/10.1111/all.14111DOI Listing
May 2020

Switch-over from Pharmalgen to Alutard Bee and Wasp venom in the UK.

Clin Exp Allergy 2019 12;49(12):1645-1646

University Hospitals Birmingham NHS Foundation Trust, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.1111/cea.13529DOI Listing
December 2019

Hymenoptera Venom Allergy: How Does Venom Immunotherapy Prevent Anaphylaxis From Bee and Wasp Stings?

Front Immunol 2019 21;10:1959. Epub 2019 Aug 21.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Hymenoptera stings may cause both local and systemic allergic reactions and even life threatening anaphylaxis. Along with pharmaceutical drugs and foods, hymenoptera venom is one of the most common causes of anaphylaxis in humans. To date, no parameter has been identified that may predict which sensitized people will have a future systemic sting reaction (SSR), however some risk factors, such as mastocytosis and age >40 years are known. Venom immunotherapy (VIT) is the most effective method of treatment for people who had SSR, which is shown to be effective even after discontinuation of the therapy. Development of peripheral tolerance is the main mechanism during immunotherapy. It is mediated by the production of blocking IgG/IgG4 antibodies that may inhibit IgE dependent reactions through both high affinity (FcεRI) and low affinity (FcεRII) IgE receptors on mast cells, basophils and B cells. The generation of antigen specific regulatory T cells produces IL-10 and suppresses Th2 immunity and the immune responses shift toward a Th1-type response. B regulatory cells are also involved in the production of IL-10 and the development of long term immune tolerance. During VIT the number of effector cells in target organs also decreases, such as mast cells, basophils, innate type 2 lymphocytes and eosinophils. Several meta-analyses and randomized controlled studies have proved that VIT is effective for preventing SSR to a sting and improves the quality of life. In this review, the risk of SSR in venom allergy and how VIT changed this risk are discussed.
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http://dx.doi.org/10.3389/fimmu.2019.01959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712168PMC
October 2020

Duration of allergen immunotherapy for inhalant allergy.

Curr Opin Allergy Clin Immunol 2019 12;19(6):594-605

Allergy and Clinical Immunology, Division of Respiratory Science, Imperial College London and National Heart and Lung Institute, Royal Brompton Hospital. Dovehouse Street, London, United Kingdom.

Purpose Of Review: We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies.

Recent Findings: Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2-4 months' immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1-2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment.

Summary: Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance.
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http://dx.doi.org/10.1097/ACI.0000000000000585DOI Listing
December 2019
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