Publications
797 results found
Fokkens W, Trigg A, Lee SE, et al., 2023, Mepolizumab improvements in health-related quality of life and disease symptoms in a patient population with very severe chronic rhinosinusitis with nasal polyps: psychometric and efficacy analyses from the SYNAPSE study, Journal of Patient-Reported Outcomes, Vol: 7
Background: Although the psychometric properties of patient-reported outcome measures (e.g. the 22-item Sino-nasal Outcomes Test [SNOT-22]) in chronic rhinosinusitis with nasal polyps (CRSwNP) have been defined, these definitions have not been extensively studied in patients with very severe CRSwNP, as defined by recurrent disease despite ≥ 1 previous surgery and a current need for further surgery. Therefore, the psychometric properties of the symptoms visual analogue scales (VAS) were evaluated, and meaningful within-patient change thresholds were calculated for VAS and SNOT-22. Methods: SYNAPSE (NCT03085797), a randomized, double-blind, placebo-controlled, 52-week trial, assessed the efficacy and safety of 4-weekly mepolizumab 100 mg subcutaneously added to standard of care in very severe CRSwNP. Enrolled patients (n = 407) completed symptom VAS (six items) daily and SNOT-22 every 4 weeks from baseline until Week 52. Blinded psychometric assessment of individual and composite VAS was performed post hoc, including anchor-based thresholds for meaningful within-patient changes for VAS and SNOT-22, supported by cumulative distribution function and probability density function plots. The effect of mepolizumab versus placebo for 52 weeks on VAS and SNOT-22 scores was then determined using these thresholds using unblinded data. Results: Internal consistency was acceptable for VAS and SNOT-22 scores (Cronbach’s α-coefficients ≥ 0.70). Test–retest reliability was demonstrated for all symptom VAS (Intra-Class Correlation coefficients > 0.75). Construct validity was acceptable between individual and composite VAS and SNOT-22 total score (r = 0.461–0.598) and between individual symptom VAS and corresponding SNOT-22 items (r = 0.560–0.780), based upon pre-specified ranges. Known-groups validity assessment demonstrated generally acceptable validity based on factors associated with respiratory health, with all VAS responsive
Altman MC, Segnitz RM, Larson D, et al., 2023, Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. OBJECTIVE: The GRASS study was a randomized, double-blind, placebo-controlled trial of timothy grass allergic individuals who received 2 years of placebo (n=30), subcutaneous (SCIT) (n=27), or sublingual immunotherapy (SLIT) (n=27) and were then followed for 1 additional year. Here we used yearly biospecimens from the GRASS study to identify molecular mechanisms of response. METHODS: We utilized longitudinal transcriptomic profiling of nasal brush and peripheral blood mononuclear cell (PBMC) samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes (logFC) -0.133 to -0.640, FDRs <0.05). Interestingly, we observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (logFC 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (logFC -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and Peak Nasal Inspiratory Flow responses, indicating important links among treatment, module expression, and allergen response. CONCLUSION: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion, that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.
Kappen J, Diamant Z, Agache I, et al., 2023, Standardization of clinical outcomes used in allergen immunotherapy in allergic asthma: An EAACI position paper., Allergy
INTRODUCTION: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. METHODS: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. RESULTS: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. CONCLUSION: This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.
Spriggs K, Pfaar O, Pawankar R, et al., 2023, Is "Maintenance" a Misnomer? A Narrative Framework Setting the Right Expectations of Allergen Immunotherapy., J Allergy Clin Immunol Pract, Vol: 11, Pages: 2051-2053
Bousquet J, Melén E, Haahtela T, et al., 2023, Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis, Allergy, Vol: 78, Pages: 1169-1203, ISSN: 0105-4538
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 polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (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 sensitization patterns (mono- or pauci-sensitization versus polysensitization), (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 autoimmune 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, Vol: 151, Pages: 1357-1370.e9, 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.
Varga EM, Durham SR, 2023, Allergen Injection Immunotherapy, Inflammatory Mechanisms in Allergic Diseases, Pages: 533-549, ISBN: 9780824705404
This chapter focuses on the use of allergen injection immunotherapy for the treatment of allergy to aeroallergens and insect stings. Allergen injection immunotherapy involves subcutaneous administration of increasing doses of allergen extract to improve symptoms and requirements for medication after natural reexposure to this allergen. Allergen injection immunotherapy has been highly effective in selected patients with clear evidence of IgE-mediated diseases. Allergen injection immunotherapy profoundly influences every step of this inflammatory process. Depending on the up-dosing regimen being used, clinical efficacy of allergen injection immunotherapy becomes evident within months and is maintained during continuation of treatment. Despite that numerous studies have unanimously stated the clinical efficacy of allergen immunotherapy, the mechanisms by which it exerts its beneficial effects are still not fully understood.
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
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
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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
Cosme J, Durham SR, 2022, Allergen Immunotherapy for Allergic Diseases, Clinical Immunology: Principles and Practice, Sixth Edition, Pages: 1117-1126, ISBN: 9780702081668
Allergen immunotherapy is indicated in severe rhinoconjunctivitis with/without mild asthma. Immunotherapy, unlike anti-allergic drugs, has the potential to provide long-term clinical benefits for years after its discontinuation. Whereas subcutaneous immunotherapy has been the gold standard, the sublingual route has emerged as an effective and safer alternative for self-administration. In mite-allergic asthma, house dust mite sublingual tablets have been shown to prevent asthma exacerbations. Knowledge of mechanisms of immunotherapy has informed novel approaches and enabled the discovery of biomarkers to monitor response to treatment. Hymenoptera venom immunotherapy is highly effective and can be lifesaving. Oral immunotherapy directed against peanut and other foods have shown successful desensitization, but no long-term tolerance and a high level of side effects and is not for routine clinical use.
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
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