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May 2021

2020 Updated Asthma Guidelines: Bronchial thermoplasty in the management of asthma

Mario Castro, MD, MPH and Geoffrey Chupp, MD

Anaphylaxis to drugs: Overcoming mast cell unresponsiveness by fake antigens

Werner J. Pichler


Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are (a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. (b) Some noncovalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-protein adducts. Such drug-protein complexes represent so-called “fake antigens,” as they are unable to induce immunity, but may react with and cross-link preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. (c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE-mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.

Asthma and viruses: A focus on rhinoviruses and SARS-CoV-2

Yorissa Padayachee, MBChB, Tasnim Shahridan Faiez, MSc, Aran Singanayagam, PhD, Patrick Mallia, PhD, and Sebastian Lennox Johnston, PhD

Basophil activation test: A diagnostic, predictive and monitoring assay for allergen immunotherapy

The Editors

Butyrate as a bioactive human milk protective component against food allergy

Lorella Paparo; Rita Nocerino; Elena Ciaglia; Carmen Di Scala; Carmen De Caro; Roberto Russo; Giovanna Trinchese; Rosita Aitoro; Antonio Amoroso; Cristina Bruno; Margherita Di Costanzo; Annalisa Passariello; Francesco Messina; Annalisa Agangi; Marcello Napolitano; Luana Voto; Giusy Della Gatta; Laura Pisapia; Francesco Montella; Maria Pina Mollica; Antonio Calignano; Annibale Puca; Roberto Berni Canani


Background: Food allergy (FA) is a growing health problem worldwide. Effective strategies are advocated to limit the disease burden. Human milk (HM) could be considered as a protective factor against FA, but its mechanisms remain unclear. Butyrate is a gut microbiota-derived metabolite able to exert several immunomodulatory functions. We aimed to define the butyrate concentration in HM, and to see whether the butyrate concentration detected in HM is able to modulate the mechanisms of immune tolerance.
Methods: HM butyrate concentration from 109 healthy women was assessed by GSMS. The effect of HM butyrate on tolerogenic mechanisms was assessed in in vivo and in vitro models.
Results: The median butyrate concentration in mature HM was 0.75 mM. This butyrate concentration was responsible for the maximum modulatory effects observed in all experimental models evaluated in this study. Data from mouse model show that in basal condition, butyrate up-regulated the expression of several biomarkers of gut barrier integrity, and of tolerogenic cytokines. Pretreatment with butyrate significantly reduced allergic response in three animal models of FA, with a stimulation of tolerogenic cytokines, inhibition of Th2 cytokines production and a modulation of oxidative stress. Data from human cell models show that butyrate stimulated human beta defensin-3, mucus components and tight junctions expression in human enterocytes, and IL-10, IFN-γ and FoxP3 expression through epigenetic mechanisms in PBMCs from FA children. Furthermore, it promoted the precursors of M2 macrophages, DCs and regulatory T cells.
Conclusion: The study's findings suggest the importance of butyrate as a pivotal HM compound able to protect against FA.

Predicting food allergy: The value of patient history reinforced

Sarah A. Lyons; André C. Knulst; Peter G. J. Burney; Montserrat Fernandez-Rivas; Barbara K. Ballmer-Weber; Laura Barreales; Christian Bieli; Michael Clausen; Ruta Dubakiene; Cristina Fernandez-Perez; Monika Jedrzejczak-Czechowicz; Marek L. Kowalski; Ischa Kummeling; Tanya Kralimarkova; Tihomir B. Mustakov; Harmieke van Os-Medendorp; Nikolaos G. Papadopoulos; Todor A. Popov; James Potts; Serge A. Versteeg; Paraskevi Xepapadaki; Paco M. J. Welsing; Clare Mills; Ronald van Ree; Thuy-My Le


Background: EAACI guidelines emphasize the importance of patient history in diagnosing food allergy (FA) and the need for studies investigating its value using standardized allergy-focused questionnaires.
Objective: To determine the contribution of reaction characteristics, allergic comorbidities and demographics to prediction of FA in individuals experiencing food-related adverse reactions.
Methods: Adult and school-age participants in the standardized EuroPrevall population surveys, with self-reported FA, were included. Penalized multivariable regression was used to assess the association of patient history determinants with “probable” FA, defined as a food-specific case history supported by relevant IgE sensitization.
Results: In adults (N = 844), reproducibility of reaction (OR 1.35 [95% CI 1.29-1.41]), oral allergy symptoms (OAS) (4.46 [4.19-4.75]), allergic rhinitis (AR) comorbidity (2.82 [2.68-2.95]), asthma comorbidity (1.38 [1.30-1.46]) and male sex (1.50 [1.41-1.59]) were positively associated with probable FA. Gastrointestinal symptoms (0.88 [0.85- 0.91]) made probable FA less likely. The AUC of a model combining all selected predictors was 0.85 after cross-validation. In children (N = 670), OAS (2.26 [2.09-2.44]) and AR comorbidity (1.47 [CI 1.39-1.55]) contributed most to prediction of probable FA, with a combined cross-validation-based AUC of 0.73. When focusing on plant foods, the dominant source of FA in adults, the pediatric model also included gastrointestinal symptoms (inverse association), and the AUC increased to 0.81.
Conclusions: In both adults and school-age children from the general population, reporting of OAS and of AR comorbidity appear to be the strongest predictors of probable FA. Patient history particularly allows for good discrimination between presence and absence of probable plant FA.

Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s

Kathleen R. Bartemes, PhD and Hirohito Kita, MD

Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy

Andrzej Eljaszewicz, PhD; Fiorella Ruchti, MSc; Urszula Radzikowska, MSc; Anna Globinska, PhD; Tadech Boonpiyathad, MD, PhD; Anna Gschwend, MD, PhD; Hideaki Morita, MD, PhD; Arthur Helbling, MD, PhD; Stefania Arasi, MD, PhD; Helga Kahlert, PhD; Nadine Berek, PhD; Andreas Nandy, PhD; M€ubeccel Akdis, MD, PhD; Christoph Willers, MD, PhD; Marcin Moniuszko, MD, PhD; Cezmi A. Akdis, MD; and Milena Sokolowska, MD, PhD


Background: Despite the efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated.
Objective: Here, we have performed a comprehensive longitudinal analysis of the systemic innate immune cell repertoire during the course of AIT.
Methods: Patients with allergy received standard preseasonal subcutaneous AIT with allergoids to birch and/or grass. Healthy controls were monitored without any intervention. Flow cytometry of innate lymphoid cell (ILC), natural killer cell, monocyte cell, and dendritic cell (DC) subsets was performed at baseline, 3 months (birch season), 6 months (grass seasons), and 12 months after the therapy in patients or at similar seasonal time points in controls. Additional analyses were performed in the third-year birch and grass season.
Results: We observed a durable decrease in group 2 ILCs and an increase of group 1 ILCs after AIT, with dynamic changes in their composition. We found that an expansion of CD1271CD2511 clusters caused observed shifts in the heterogeneity of group 1 ILCs. In addition, we observed development of CD1271CD2511c-Kit1 group 3 ILC clusters. Moreover, we found an increase in the number of intermediate monocytes in parallel with a reduction in nonclassical monocytes during the first year after AIT. Classical and intermediate monocytes presented significant heterogeneity in patients with allergy, but AIT reduced the HLA-DR11 clusters. Finally, an increase in plasmacytoid DCs and CD1411 myeloid DCs was observed in individuals with allergy, whereas the number of CD1c1 myeloid DCs was reduced during the first year of AIT.
Conclusion: AIT induces changes in the composition and heterogeneity of circulating innate immune cells and brings them to the level observed in healthy individuals. Monitoring of ILCs, monocytes, and DCs during AIT might serve as a novel biomarker strategy. (J Allergy Clin Immunol 2021;147:1865- 77.)

Update on food allergy

Rachel L. Peters; Marta Krawiec; Jennifer J. Koplin; Alexandra F. Santos


Food allergy is a major public health issue with growing prevalence in the urbanized world and significant impact on the lives of allergic patients and their families. Research into the risk factors that have contributed to this increase and their underlying immune mechanisms could lead us to definitive ways for treatment and prevention of food allergy. For the time being, introduction of peanut and other allergenic foods in the diet at the time of weaning seems to be an effective way to prevent the development of food allergy. Improved diagnosis and appropriate management and support of food allergic patients are central to patient care with food immunotherapy and biologics making the transition to clinical practice. With the new available treatments, it is becoming increasingly important to include patients' and family preferences to provide a management plan tailored to their needs.

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