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July 2021

A population-based study on associations of stool microbiota with atopic diseases in school-age children

Chen Hu, MD, Evelien R. van Meel, MD, Carolina Medina-Gomez, PhD, Robert Kraaij, PhD, Monica Barroso, PhD, Jessica Kiefte-de Jong, MD, PhD, Djawad Radjabzadeh, MSc, Suzanne G. M. A. Pasmans, MD, PhD, Nicolette W. de Jong, PhD, Johan C. de Jongste, MD, PhD, Henriette A. Moll, MD, PhD, Tamar Nijsten, MD, PhD, Fernando Rivadeneira, MD, PhD, Luba M. Pardo, MD, PhD, and Liesbeth Duijts, MD, PhD


Background: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear. Objectives: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children.

Methods: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry.

Results: The a-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and b-diversity was associated with physician-diagnosed inhalant allergy (R2 5 0.001; P 5 .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R- 7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88- 0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed.

Conclusions: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases. (J Allergy Clin Immunol 2021;148:612-20.)

Basophil activation test: Mechanisms and considerations for use in clinical trials and clinical practice

Alexandra F. Santos, Oral Alpan, Hans-Jürgen Hoffmann


The basophil activation test (BAT) is a functional assay that measures the degree of degranulation following stimulation with allergen or controls by flow cytometry. It correlates directly with histamine release. From the dose-response curve resulting from BAT in allergic patients, basophil reactivity (%CD63+ basophils) and basophil sensitivity (EC50 or similar) are the main outcomes of the test. BAT takes into account all characteristics of IgE and allergen and thus can be more specific than sensitization tests in the diagnosis of allergic disease. BAT reduces the need for in vivo procedures, such as intradermal tests and allergen challenges, which can cause allergic reactions of unpredictable severity. As it closely reflects the patients' phenotype in most cases, it may be used to support the diagnosis of food, venom and drug allergies and chronic urticaria, to monitor the natural resolution of food allergies and to predict and monitor clinical the response to immunomodulatory treatments, such as allergen-specific immunotherapy and biologicals. Clinical application of BAT requires analytical validation, clinical validation, standardization of procedures and quality assurance to ensure reproducibility and reliability of results. Currently, efforts are ongoing to establish a platform that could be used by laboratories in Europe and in the USA for quality assurance and certification.

Breastfeeding promotes early neonatal regulatory T-cell expansion and immune tolerance of non-inherited maternal antigens

Hannah Wood; Animesh Acharjee; Hayden Pearce; Mohammed Nabil Quraishi; Richard Powell; Amanda Rossiter; Andrew Beggs; Andrew Ewer; Paul Moss; Gergely Toldi


Background: Breastfeeding is associated with long-term health benefits, such as a lower incidence of childhood infections, asthma, obesity and autoimmune disorders. However, little is known regarding how the maternal and neonatal immune systems interact after parturition when the neonate receives nutrition from maternal breast milk.

Methods: We undertook a comparative analysis of immune repertoire and function at birth and 3 weeks of age in a cohort of 38 term neonates born by caesarean section grouped according to feeding method (breast milk versus formula). We used flow cytometry to study the immune phenotype in neonatal and maternal blood samples and mixed lymphocyte reactions to establish the proliferation response of neonatal versus maternal lymphocytes and vice versa. The microbiome of neonatal stool samples was also investigated using 16S rRNA sequencing.

Results: We show that the proportion of regulatory T cells (Tregs) increases in this period and is nearly twofold higher in exclusively breastfed neonates compared with those who received formula milk only. Moreover, breastfed neonates show a specific and Treg-dependent reduction in proliferative T-cell responses to non-inherited maternal antigens (NIMA), associated with a reduction in inflammatory cytokine production. We also observed the enrichment of short chain fatty acid producing taxa (Veillonella and Gemella) in stool samples of exclusively breastfed neonates.

Conclusions: These data indicate that exposure of the neonate to maternal cells through breastfeeding acts to drive the maturation of Tregs and ‘tolerizes’ the neonate towards NIMA.

Carbohydrate epitopes currently recognized as targets for IgE antibodies

Thomas A. Platts-Mills; Christiane Hilger; Uta Jappe; Marianne van Hage; Gabriele Gadermaier; Edzard Spillner; Jonas Lidholm; Behnam Keshavarz; Rob C. Aalberse; Ronald van Ree; Richard E. Goodman; Anna Pomés


Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub-Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE-binding glycans recognized up to 2008 were considered to be “classical” cross-reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE-binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose-alpha- 1,3- galactose (alpha-gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha-gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross-reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub-Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.aller In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed.

COVID-19 risk and outcomes in adult asthmatic patients treated with biologics or systemic corticosteroids: Nationwide real-world evidence

Yochai Adir, MD, MHA, Marc Humbert, MD, PhD, and Walid Saliba, MD, MPH


Methods: We used the computerized database of Clalit Health Services, the largest health care provider in Israel, to identify all asthmatic adult patients who underwent PCR testing for SARSCoV- 2, between March 1, 2020, and December 7, 2020. A cohort approach was used to assess the association between biologics use and steroids treatment and COVID-19 severity and 90-day mortality.

Results: Overall, 8,242 of 80,602 tested asthmatic patients had positive PCR testing result for SARS-CoV-2. Both biologics and systemic corticosteroids were not associated with increased risk of SARS-CoV-2 infection. Multivariate analyses revealed that biologics were not associated with a significantly increased risk of moderate to severe COVID-19, nor with the composite end point of moderate to severe COVID-19 or all-cause mortality within 90 days. Chronic systemic corticosteroid use was associated with significantly increased risk of all tested outcome. Recent (within the previous 120 days) systemic corticosteroid use, but not former use, was significantly associated with increased risk of both moderate to severe COVID-19 and the composite of moderate to severe COVID-19 or all-cause mortality.

Conclusions: Biologics approved for asthma and systemic corticosteroids are not associated with increased risk of SARS-CoV-2 infection. In contrast, systemic corticosteroids are an independent risk factor for worst COVID-19 severity and all-cause mortality. Our findings underscore the risk of recent or current exposure to systemic corticosteroids in asthmatic patients infected with SARS-CoV-2. (J Allergy Clin Immunol 2021;148:361-7.)

Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing

Melissa Iammatteo, MD, Guillaume Lezmi, MD, PhD, Ronit Confino-Cohen, MD, Mark Tucker, MD, Moshe Ben-Shoshan, MD, and Jean-Christoph Caubet, MD


In the western world, up to 10% of the general population and more than 15% of hospitalized patients report penicillin allergy. After a comprehensive evaluation, more than 95% of patients who report a penicillin allergy can subsequently tolerate this antibiotic. Traditionally, the most widely accepted protocol to evaluate beta-lactam (BL) allergy consisted of skin testing (ST) followed by a drug provocation test (DPT) in ST-negative patients. DPT is the gold standard for proving or excluding BL allergy and is considered the final and definitive step in the evaluation. Recently, studies have been published that support the use of direct DPTs without preceding ST for both pediatric and adult patients who report a low-risk historical reaction to BLs. However, these studies use various riskstratification criteria to determine eligibility for a direct DPT. A standardized protocol for DPT is also lacking. In this review, we assess the current literature and evidence for performing direct DPT in the pediatric and adult populations. On the basis of this evidence, we also present riskbased algorithms for the evaluation of BL allergy in pediatric and adult populations based on a description of the historical reaction.  2021 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2021;9:2947-56)

Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirinexacerbated respiratory disease

Katherine N. Cahill, MD

Low-affinity but high-avidity interactions may offer an explanation for IgE-mediated allergen cross-reactivity

Xinyue Chang; Lisha Zha; Alexandra Wallimann; Mona O. Mohsen; Pascal Krenger; Xuelan Liu; Monique Vogel; Martin F. Bachmann


Background: Allergy is a global disease with overall frequencies of >20%. Symptoms vary from irritating local itching to life-threatening systemic anaphylaxis. Even though allergies are allergen-specific, there is a wide range of cross-reactivities (eg apple and latex) that remain largely unexplained. Given the abilities of low-affinity IgG antibodies to inhibit mast cells activation, here we elucidate the minimal affinity of IgE antibodies to induce type I hypersensitivity.

Methods: Three mature (high-affinity) IgE antibodies recognizing three distinct epitopes on Fel d 1, the major cat allergen, were back-mutated to germline conformation, resulting in binding to Fel d 1 with low affinity. The ability of these IgE antibodies to activate mast cells in vitro and in vivo was tested.

Results: We demonstrate that affinities as low as 10−7 M are sufficient to activate mast cells in vitro and drive allergic reactions in vivo. Low-affinity IgE antibodies are able to do so, since they bind allergens bivalently on the surface of mast cells, leading to high-avidity interactions.

Conclusions: These results suggest that the underlying mechanism of allergen cross-reactivity may be low-affinity but high-avidity binding between IgE antibodies and cross-reactive allergen.

New ideas: Food allergy stems from food quality sensing

M. Cecilia Berin, PhD

Peanut diversity and specific activity are the dominant IgE characteristics for effector cell activation in children

Oliver Hemmings, MSc, Umar Niazi, MBBS, PhD, Matthew Kwok, BSc, Louisa K. James, PhD, Gideon Lack, MBBS, FRCPCH, and Alexandra F. Santos, MD, PhD


Background: IgE mediates allergic reactions to peanut; however, peanut-specific IgE (sIgE) levels do not always equate to clinical peanut allergy. Qualitative differences between sIgE of peanut-sensitized but tolerant (PS) and peanut-allergic (PA) individuals may be important.

Objective: We sought to assess the influence of IgE characteristics on effector cell activation in peanut allergy. Methods: A cohort of 100 children was studied. The levels of IgE to peanut and peanut components were measured. Specific activity (SA) was estimated as the ratio of allergen-sIgE to total IgE. Avidity was measured by ImmunoCAP with sodium thiocyanate. IgE diversity was calculated on the basis of ImmunoCAP-Immuno Solid-phase Allergen Chip assays for 112 allergens or for 6 peanut allergens. Whole-blood basophils and mast cell line Laboratory of Allergic Diseases 2 sensitized with patients’ plasma were stimulated with peanut or controls and assessed by flow cytometry.

Results: SA to peanut (P <.001), Ara h 1 (P 5.004), Ara h 2 (P < .001), Ara h 3 (P 5.02), and Ara h 6 (P < .001) and the avidity of peanut-sIgE (P < .001) were higher in PA than in PS individuals. Diversity for peanut allergens was greater in PA individuals (P < .001). All IgE characteristics were correlated with basophil and mast cell activation. Peanut SA (R 5 0.447) and peanut diversity (R 5 0.440) had the highest standardized b-coefficients in combined multivariable regression models (0.447 and 0.440, respectively).

Conclusions: IgE specificity, SA, avidity, and peanut diversity were greater in PA than in PS individuals. IgE peanut SA and peanut diversity had the greatest influence on effector cell activation and could be used clinically. (J Allergy Clin Immunol 2021;148:495-505.)

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