Background: Food-induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen-food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. Methods: Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests (SPTs) were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. Results: Seventy-eight patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in %16.7 of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). Conclusions: Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE.

Background: Food allergy affects up to 8% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS). Methods: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0-24h. Distribution of relevant cell subsets was confirmed using single cell nuclear sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed. Results: PCIS viability was maintained for 24h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction. Conclusion: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.

Biologic Pathways For Chronic Spontaneous Urticaria And Their Regulation By Benralizumab

Background: From early life, respiratory viruses are implicated in the development, exacerbation and persistence of respiratory conditions such as asthma. Complex dynamics between microbial communities and host immune responses, shape immune maturation and homeostasis, influencing health outcomes. We evaluated the hypothesis that the respiratory virome is linked to systemic immune responses, using peripheral blood and nasopharyngeal swab samples from preschool-age children in the PreDicta cohort. Methods: Peripheral blood mononuclear cells from 51 children (32 asthmatics, 19 healthy controls), participating in the 2-year multinational PreDicta cohort were cultured with bacterial (Bacterial-DNA, LPS) or viral (R848, Poly:IC, RV) stimuli. Supernatants were analyzed by Luminex for the presence of 22 relevant cytokines. Virome composition was obtained using untargeted high troughput sequencing of nasopharyngeal samples. The metagenomic data were used for the characterization of virome profiles and the presence of key viral families (Picornaviridae, Anelloviridae, Siphoviridae). These were correlated to cytokine secretion patterns, identified through hierarchical clustering and principal component analysis. Results: High spontaneous cytokine release was associated with increased presence of Prokaryotic virome profiles and reduced presence of Eukaryotic and Anellovirus profiles. Antibacterial responses did not correlate with specific viral families or virome profile, however, low antiviral responders had more Prokaryotic and less Eukaryotic virome profiles. Anelloviruses and Anellovirus-dominated profiles were equally distributed amongst immune response clusters. The presence of Picornaviridae and Siphoviridae was associated with low interferon-λ responses. Asthma or allergy did not modify these correlations. Conclusions: Antiviral cytokines responses at a systemic level reflect the upper airway virome composition. Individuals with low innate interferon responses have higher abundance of Picornaviruses (mostly Rhinoviruses) and bacteriophages. Bacteriophages, particularly Siphoviridae appear to be sensitive sensors of host antimicrobial capacity, while Anelloviruses are not affected by TLR-induced immune responses.

Article type: Editorial

Title: Sputum transcriptome analysis of co-regulated genes related to arachidonic acid metabolism in N-ERDShort title: Cluster analysis of sputum transcriptome in N-ERD

Adolescence is a critical stage of rapid biological, emotional and social change and development. Adolescents and young adults (AYA) with asthma and allergies need to develop the knowledge and skills to self-manage their health independently. Healthcare professionals (HCP), parents and their wider network play an essential role in supporting AYA in this process. Previous work showed significant limitations in transition care across Europe. In 2020, the first evidence-based guideline on effective transition for AYA with asthma and allergies was published by EAACI. We herein summarize practical resources to support this guideline’s implementation in clinical practice. For this purpose, multi-stakeholder Task Force members searched for resources in peer review journals and grey literature. These resources were included if relevant and of good quality, and were pragmatically rated for their evidence-basis and user friendliness. Resources identified covered a range of topics and targeted healthcare professionals, AYA, parents/carers, schools, workplace, and wider community. Most resources were in English, web-based and had limited evidence-basis. This position paper provides a valuable selection of practical resources for all stakeholders to support effective transitional care for AYA with asthma and allergies. Future research should focus on developing validated, patient-centred tools to further assist evidence-based transition care.

Allergy, Editorial

Background: Randomized controlled trials (RCTs) are the gold-standard for benefit-risk assessments during drug approval processes. Real-word data (RWD) and the resulting real-world evidence (RWE) are becoming increasingly important for assessing the effectiveness of drug products after marketing authorization showing how RCT results are transferred into real life care. The effectiveness of allergen immunotherapy (AIT) has been assessed in several RWE studies based on large prescription databases. Methods: We performed a literature search for retrospective cohort assessments of prescription databases in Europe to provide an overview on the methodology, long-term effectiveness outcomes and adherence to AIT. Results: 13 respective publications were selected. AIT was more effective in reducing the progression of allergic rhinitis (AR) compared to a non-AIT control group receiving only symptomatic treatment for AR for up to 6 years. The development and progression of asthma was hampered for most endpoints in patients treated with most preparations compared to the non-AIT group, receiving only anti-asthmatic medication. The results for “time to onset” of asthma were inconsistent. Adherence to AIT decreased during the recommended 3-years treatment period, however in most studies higher adherence to subcutaneous than to sublingual AIT was shown. Conclusion: The analysis of long-term effectiveness outcomes of the RWE studies based on prescription databases confirms the long-term efficacy of AIT demonstrated in RCTs. Progression of rhinitis and asthma symptoms as well as delayed onset of asthma triggered by different allergens, real life adherence to the treatment shows differences in particular application routes.

Article Type: Letter to the EditorTitle : The impact of maternal-fetal omalizumab transfer on peanut-specific responses in an ex vivo placental perfusion model

Allergic diseases are allergen-induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T-cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate-like lymphoid cells, alarmins, IL-4, IL-5, IL-9, IL-13 and IL-17).

Immune-inflammatory proteome of elite ice hockey players before and after SARS-CoV-2 infection

Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a “fixed” bronchial obstruction due to structural changes unresponsive to current therapies, from a “reversible” one as demonstrated by lung function normalization during biological therapies not previously obtained even with high dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent tissue-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert “fixed” remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.

LetterDelta or Omicron BA.1/2-neutralizing antibody levels and T-cell reactivity after triple-vaccination or infectionTo the editor,In Germany, SARS-CoV-2 infections in fall 2021 were caused by the Delta variant of concern (VOC B.1.617.2), which was completely replaced by the Omicron VOC (BA.1, B.1.529.1/BA.2, B.1.529.2) in winter. Meanwhile, the BA.2 sublineage dominates, apparently having a selection advantage1.We studied the kinetics of anti-spike (S) protein IgG and Delta neutralizing antibodies (NA) as well as the release of interferon-gamma (IFN-γ) from SARS-CoV-2-specific T-cells in 152 individuals (117 women, 35 men, median age 41 years) who received two doses of vector vaccine (AstraZeneca, AZD, N=34), mRNA vaccine (BioNTech or Moderna, mRNA, N=62), or a combination of both (N=56) followed by an mRNA vaccine boost (N=81). In a subset of 15 age- and gender-matched vaccinees and in ten triple-vaccinated and two unvaccinated patients with previous BA.1 infection, the Delta- and Omicron BA.1/BA.2 NAs and T-cell reactivity were examined. For comparison, variant-specific antibody responses of unvaccinated patients after infection with Alpha- (N=10) or Beta VOCs (N=1) were included.Within 279 days after the second vaccination, a decrease in anti-S IgG concentrations (Figures S 1A-C) and Delta NA titers (Figure 1A) was measured regardless of the immunization regimen. The booster vaccination led to a significant increase of anti-S IgG concentrations (Figures S1 D-F) and of Delta NA titers (Figure 1B). The IgG levels and Delta NAs reached four weeks after the mRNA vaccine booster were 1.3 - 1.7-fold higher than after the second mRNA dose, but this difference was significant only for IgG (Figures 1A, C; Figures S 1A-C, G-I). The release of IFN-γ as a measure of SARS-CoV-2 T-cell reactivity was demonstrated for months after second vaccination. In contrast to the Delta NA levels, IFN-γ concentrations were independent of the underlying vaccination schedule and increased slightly after the third immunization (Figures 1D, E). The parameters of humoral and cellular immunity decreased again after the booster vaccination (Figures 1C, F; Figures S 1G-I).As reported by others 1-4, NAs to Omicron BA.1 were induced by the mRNA vaccine booster, but also against the predominant BA.2 sublineage, which was previously unclear. The BA.2 NA geometric mean titer (GMT) was higher than the BA.1 NA GMT (Figure 2A). With respect to the results presented in Figures 1C and 2B, we suspect that NAs against the Omicron VOC will decline rapidly after booster vaccination alone. High NA titers against Omicron BA.1/BA.2 and against Delta VOC were exclusively observed in triple-vaccinated individuals two to three weeks after Omicron breakthrough infection (Figure 2A). This indicates broadened immunity covering additional viral variants and may also explain why few BA.2 infections have occurred in this group of individuals to date 5. Because Omicron is a distinct serotype 6, only NAs against this VOC were detectable in two unvaccinated BA.1-infected individuals (Figure 2A), while unvaccinated Alpha- and Beta VOC patients developed isolated NAs against the antigenically more related Delta VOC (Figure S 2A). Accordingly, both BA.1 patients had very low IgG levels against the receptor-binding domain (RBD) of a Wuhan-like virus (Figure S 2B), whereas IgGs against the higher preserved nucleocapsidprotein were barely affected (Figures S 2C, D). The results of a surrogate neutralization assay confirmed very limited humoral immunity after Omicron infection alone (Figure S 2E).The increase of IFN-γ release by mRNA booster vaccination was moderate (Figures 1D, E), while the breakthrough infection insignificantly increased IFN-γ release by a factor of 1.9 - 2.6 (Figure 2C).In conclusion, the importance of pre-existing vaccine-induced immunity is clearly demonstrated. The booster vaccination with the conventional mRNA vaccine resulted in measurable BA.1/BA.2 NAs. However, a multivalent vaccine could induce higher titers, which could provide better protection.

A potential immunological silver bullet for COVID-19: the trivalent chimpanzee adenoviral serotype-68 vector (Tri:ChAd)

Background: Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. Methods: We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. Results: A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared to pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared to pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. Conclusion: We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings have implications for future vaccination strategies and possibly cross-reactive T cell immunity.

Humans inhale, ingest and touch thousands of fungi each day. The ubiquity and diversity of the fungal kingdom are in sharp contrast with their complex and relatively blurred taxonomy and scarce knowledge about their distribution, pathogenic effects, and effective interventions at the environmental and individual levels. Here, we present an overview of salient features of fungi as permanent players of the human exposome and key determinants of human health. Improved understanding of the fungal exposome sheds new light on the epidemiology of fungal-related diseases, their immunological substratum, the currently available methods, and biomarkers for environmental and medical fungi. Unmet needs are described and potential approaches are highlighted as perspectives.

A document by Sergio Bonini. Click on the document to view its contents.