Publications
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Bousquet J, Melén E, Haahtela T, et al., 2023, Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis., Allergy
Asthma, rhinitis and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease", coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitisation and multimorbidity, (iii) advances in mHealth for novel phenotype definition, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis". This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitisation patterns (mono- or pauci-sensitisation versus polysensitisation), (iii) severity of symptoms and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and auto-immune diseases.
Dramburg S, Lau S, Matricardi P, et al., 2023, Obituary: Jorg Kleine-Tebbe, ALLERGY, ISSN: 0105-4538
Layhadi J, Moya R, Tan TJ, et al., 2023, Single-cell RNA-Seq identifies precise tolerogenic cellular and molecular pathways induced by depigmented-polymerized grass pollen allergen extract, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
Background:Immunological mechanism of action of allergoids remains poorly understood. Previous models of allergenicity and immunogenicity have yielded sub-optimal knowledge of these immunotherapeutic vaccine products. Novel single-cell RNA-seq technology offers a bridge to this gap in knowledge.Objective:To identify the underpinning tolerogenic molecular and cellular mechanisms of depigmented-polymerized Phleum pratense extract.MethodsThe molecular mechanisms underlying native Phleum pratense (Phl p), depigmented Phl p (DPG-Phl p), and depigmented-polymerized (DPG-POL-Phl p) allergoid were investigated using scRNA-seq. Allergen-specific Th2A, Tfh and IL-10+ Breg cells were quantified by flow cytometry in PBMCs from 16 grass pollen allergics (GPA) and 8 non-atopic controls (NAC). The ability of Phl p, DPG-Phl p and DPG-POL-Phl p to elicit FcεRI and FcεRII-mediated IgE responses was measured by basophil activation test and IgE-FAB assay.Results:ScRNA-seq analysis revealed that DPG-POL-Phl p downregulated genes associated with Th2 signaling, induced functional Tregs exhibiting immunosuppressive roles through CD52 and Siglec-10, modulated genes encoding immunoproteasome that dysregulate the processing and presentation of antigens to T cells and promoted a shift from IgE towards an IgA1 and IgG responses. In GPA, DPG-POL-Phl p exhibited reduced capacity to elicit proliferation of Th2A, IL-4+ Tfh and IL-21+ Tfh cells whilst being the most prominent at inducing CD19+CD5hiIL-10+ and CD19+CD5hiCD38intCD24intIL-10+ Breg cell subsets compared to Phl p (all, P<.05). Furthermore, DPG-POL-Phl p demonstrated a hypoallergenic profile through basophil activation and histamine release compared to Phl p (31.54-fold, P<.001).Conclusions:ScRNA-seq provides an in-depth resolution of the mechanisms underlying the tolerogenic profile of DPG-POL-Phl p.
Poto R, Shamji M, Marone G, et al., 2022, Neutrophil Extracellular Traps in Asthma: Friends or Foes?, CELLS, Vol: 11
Sousa-Pinto B, Anto A, Berger M, et al., 2022, Real-world data using mHealth apps in rhinitis, rhinosinusitis and their multimorbidities, CLINICAL AND TRANSLATIONAL ALLERGY, Vol: 12
Durham SR, Shamji MH, 2022, Allergen immunotherapy: past, present and future, NATURE REVIEWS IMMUNOLOGY, ISSN: 1474-1733
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- Citations: 3
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, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 10, Pages: 2404-+, ISSN: 2213-2198
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- Citations: 1
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
Stoenchev K, Scadding G, Durham S, 2022, Case report: Immediate hypersensitivity to chloroxylenol and chlorocresol, Publisher: WILEY, Pages: 1011-1012, 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
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- Citations: 7
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, Vol: 12, Pages: 1503-1516, 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, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), 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
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- Citations: 8
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
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- Citations: 14
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
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- Citations: 13
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
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- Citations: 18
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
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- Citations: 32
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
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- Citations: 6
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
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- Citations: 25
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
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.
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
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- Citations: 24
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.
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