BACKGROUND:Allergen-specific CD4+ T cells are a highly heterogenous population. Depletion of these cells has been proposed as essential to achieve allergen desensitization in allergen immunotherapy. OBJECTIVE:The overall aim of this study was to characterize the heterogeneity of timothy grass (Phleum pratense) allergen-specific CD4+ T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous (SCIT) immunotherapy. Correlations between frequencies of these cells with Total Nasal Symptom Score and grass-specific serum immunoglobulin were also investigated. METHODS:Mass cytometry with lanthanides-tagged peptide major histocompatibility complex class II multimers and CD154 upregulation assays were used to examine changes in the frequency and phenotype of Phl p-specific CD4+ T cells in longitudinal peripheral blood mononuclear cell samples from a randomized, double-blind, placebo-controlled trial of SLIT and SCIT. Supervised and unsupervised clustering was used for data analysis. RESULTS:Phenotypes of Phl p-specific T cells were highly heterogenous but could be categorized into two major metaclusters, CRTH2hiCD27lo and CRTH2loCD27hi, each with distinct phenotypic profiles. Weak positive correlations between Total Nasal Symptom Score and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2hiCD27lo cells, whereas SLIT depleted CRTH2loCD27hi cells. CRTH2hiCD27lo cell frequency correlated with Phl p-specific IgE and IgG4, but not IgA, levels. CONCLUSION:Unsupervised clustering revealed distinct subpopulations of allergen-specific T cells that were differentially targeted and depleted by SCIT and SLIT, suggesting that SCIT and SLIT act through overlapping but distinct immunologic pathways.

RATIONALE:Recurrent preschool wheeze accounts for most childhood hospitalizations for asthma and often responds poorly to inhaled corticosteroids (ICSs). OBJECTIVE:To relate lower airway immune cell composition in children with recurrent severe wheeze (RSW) to infection, allergic sensitization, and prescribed treatments. METHODS:Children with RSW aged 1 to 5 years underwent clinical phenotyping, bronchoscopy, multiparameter flow cytometry of blood and bronchoalveolar lavage (BAL) to characterize leukocytes, and assessments of lower airway bacterial and viral infection. An unsupervised analysis was undertaken to uncover clusters of airway inflammation. MEASUREMENTS AND MAIN RESULTS:Of 106 children (median age 36.5 months), 32% had allergic sensitization. Lower airway immune cells were similar in type and abundance in sensitized and nonsensitized children. However, significantly more nonsensitized wheezers had positive BAL bacterial culture. Bacterial infection was associated with neutrophils with low CD62L and CXCR2 expression. Children without airway bacterial infection also had up to 50% neutrophils but with high CD62L and CXCR2 expression. The data-driven analysis revealed 3 clusters: cluster 1, airway infection predominant with CD62Llo neutrophils; cluster 2, eosinophil/lymphocyte rich with CD62Lhi neutrophils; and cluster 3, low infection rate with CD62Lhi neutrophils. The clusters were independent of clinical features, prescribed ICSs, antibiotics, and allergic sensitization. CONCLUSIONS:Airway inflammation in RSW is heterogeneous. A subgroup had airway neutrophilia but with distinct neutrophil subtypes. Those with bacterial infection had CD62Llo neutrophils (cluster 1). Others had CD62Lhi neutrophils (clusters 2 and 3). Intervention trials stratifying using these clusters may provide a novel management approach.

The sense of smell, with its extensive evolutionary history, is highly prone to disorders that can have a profound impact on daily life. Anosmia affects approximately 5% of the population, with an additional 15% exhibiting reduced olfactory function. The prevalence of olfactory dysfunction (OD) varies by population and age group, and standardized testing reveals a broad range of impacts. OD includes various causes, most commonly aging, inflammation of the olfactory epithelium, upper respiratory tract infections (URTI), traumatic brain injury, and neurological conditions. The recent COVID-19 pandemic has highlighted the association between viral infections and olfactory dysfunction, with severe hyposmia/anosmia being an early marker of infection. Despite its importance, the assessment of olfactory function remains inconsistent across clinical practices. Psychophysical smell tests, while vital for diagnosis and patient management, are underutilized, especially outside of specialized centers. Standardized testing methods are crucial for objective diagnosis, but significant challenges, including test variability, lack of comparability, and healthcare reimbursement issues, persist. The European Academy of Allergy and Immunology (EAACI) advocates for improvements in the quality and standardization of chemosensory assessments. Future efforts must prioritize education, incentives for better testing, and the integration of digital tools to expand access to olfactory testing and diagnosis in remote or quarantine situations. However, office-based testing remains irreplaceable, even with advancements in telemedicine.

Pediatric immunological and allergic conditions represent a broad spectrum, ranging from highly prevalent polygenic disorders (e.g., food allergy, atopic dermatitis, asthma, and allergic rhinitis) to rarer monogenic primary atopic disorders. The management of these conditions has undergone a paradigm shift in recent years. Moving away from a "one-size-fits-all" approach, precision medicine aims to deliver the right treatment to the right patient at the right time. By integrating clinical phenotypes with molecular endotypes and using specific biomarkers and "Omics" techniques, scientists and clinicians can now employ targeted biological therapies that significantly improve patient outcomes. By identifying early therapeutic windows and specific biomarkers, pediatric specialists can implement personalized interventions that halt the atopic march and mitigate the global burden of chronic allergic diseases. By shifting the focus from symptom management to the neutralization of specific molecular pathways, it is now possible to achieve better disease control, reduce side effects associated with broad-spectrum treatments such as systemic corticosteroids, and improve the quality of life for patients with refractory allergic diseases. This review, generated during a seminar funded by the Clemens von Pirquet Foundation, aims to delineate the "rare to common" pipeline, illustrating how precision medicine tools, including multi-omics, biomarkers, and artificial intelligence methods, can connect mechanistic pathways across the immunological spectrum.

The post-COVID pandemic era has witnessed a concerning resurgence of respiratory viruses, driving a global increase in acute respiratory infections. This trend may stem from relaxed non-pharmaceutical interventions, waning herd immunity, immunological imprinting limiting heterosubtypic protection, or viral antigenic evolution. This review aims to identify and characterize risk and protective factors associated with infection, hospitalization, severe illness, and mortality, while elucidating the drivers of the rising incidence of respiratory virus infections post-pandemic. Evidence on SARS-CoV-2 sublineages, influenza, respiratory syncytial virus, rhinovirus, adenovirus, human metapneumovirus, human parainfluenza virus, human coronaviruses, and cytomegalovirus has been collected and identified. Identified risk factors include demographic characteristics such as pediatrics and older age, male sex, race (Black, Hispanic, American Indian or Alaska native), preterm birth, and HLA-DQA1, IFNAR2, ST6GAL, and B3GALT5 genetic susceptibility. Behavioral, socioeconomic (low socioeconomic status, crowded living conditions), environmental influences (cold seasons, pollution), smoking, obesity and malnutrition could also exacerbate the risk of infection and adverse outcomes. Comorbidities, such as chronic conditions and immunocompromised states, significantly increase the risk of severe disease and hospitalization. Laboratory indices linked to severe disease outcomes include neutrophilia or neutropenia, lymphopenia, eosinopenia, and elevated C-reactive protein. Viral subtypes, viral load kinetics, vaccination status, and antiviral therapies further delineate risk profiles. Epithelial barrier impairment and underlying chronic airway diseases characterized by type 2 immunity also play a detrimental role in the development and severity of respiratory viral infections. Our findings highlight the need for stratified prevention strategies, which combine universal measures targeting shared determinants with virus-specific interventions addressing unique virological and transmission dynamics. It will provide a critical framework for optimizing precision public health strategies to counter repeated respiratory threats in the evolving post-COVID-19 pandemic landscape.

BACKGROUND:Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well-justified minimal clinically important difference (MCID). METHODS:Direct patient feedback from 1071 grass-allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS0-6. Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS0-6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). RESULTS:69% of grass-allergic patients were satisfied with a 1-point-improvement (e.g., from "severe" to "moderate") in their most severe symptom. This translated into an MCID range for CSMS0-6 of -0.23 to -0.21 points or -17% to -16%. Furthermore, a -0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS0-6 of -0.21 points (-16%) was derived using RESONATE. CONCLUSIONS:Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS0-6 scale and -16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

Exposure to fire smoke has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure, with preventive and targeted interventions needed. After exposure to fire smoke, which includes PM2.5, toxic metals and perfluoroalkyl and polyfluoroalkyl substances, epidemiology-based studies have demonstrated increases in respiratory (for example, asthma exacerbation), cardiac (for example, myocardial infarction, arrhythmias), neurological (for example, stroke) and pregnancy-related (for example, low birthweight, premature birth) outcomes. However, mechanistic studies exploring how smoke exposure disrupts cellular homeostasis are lacking. Therefore, we collected blood from smoke-exposed individuals (n = 31) and age-matched and sex-matched non-smoke-exposed controls (n = 29), and investigated these complex interactions using a single-cell exposomic approach based on both methylation and mass cytometry. Overall, our data demonstrated a strong association between smoke exposure and methylation at 133 disease-relevant gene loci, while immunophenotyping showed increased homing and activation biomarkers. We developed an application of mass cytometry to analyze single-cell/metal binding and found, for example, increased levels of mercury in dead cells and cadmium in the live and dead cell populations. Moreover, mercury levels were associated with years of smoke exposure. Several epigenetic sites across multiple chromosomes were associated with individual toxic metal isotopes in single immune cells. Our methods for detecting the effect of smoke exposure at the single-cell level and the study results may help to determine the timing of exposure and identify specific molecular targets that could be modified to prevent and manage exposure to smoke.

Asthma is a complex, heterogeneous disease characterised by clinical phenotypes demonstrating distinct and overlapping immunological mechanisms, classified into type-2 high and type-2 low asthma endotypes. Both allergic and eosinophilic non-allergic asthma are driven through an underlying type-2 high-endotype, which can be targeted using therapeutic approaches such as allergen-specific immunotherapy (AIT) for allergic asthma and biologics. AIT demonstrates efficacy for the treatment of allergic asthma. Approved biologics for asthma management include using various interleukin antagonists and anti-immunoglobulin E, with Tezepelumab offering promising treatments for both type-2 high and type-2 low asthma patients. Novel therapeutic candidates, such as Itepekimab and depemokimab, have demonstrated promising results in a Phase 2 clinical trial in moderate-to-severe asthma patients.

The prevalence of allergic diseases, including allergic rhinitis, chronic rhinosinusitis, asthma, eosinophilic esophagitis, food and drug allergies, and atopic dermatitis, has been increasing globally over the past few decades. Allergic diseases are closely linked to type 2 immunity, which is characterized by the coordinated interplay between innate and adaptive immune responses. Significant advancements have been achieved in elucidating the cellular and molecular mechanisms that govern type 2 immunity, chiefly mediated by type 2 cytokines, including IL-4, IL-5, IL-9, and IL-13, which are primarily secreted by T helper 2 cells and group 2 innate lymphoid cells. In addition, a diverse array of effector cells, including mast cells, basophils, eosinophils, regulatory T cells, B lymphocytes, dendritic cells, and natural killer cells, are critically involved in orchestrating and modulating type 2 inflammatory responses. The activation of epithelial cells, secretion of alarmins and multiple chemokines, impairment of epithelial barrier integrity, and disruption of microbial dysbiosis serve as crucial mechanisms underlying not only the pathogenesis of allergic disorders but also the development of various systemic conditions. Biologic therapies targeting type 2 pathways-specifically effector functions of IL-4, IL-13, IL-5, thymic stromal lymphopoietin, and immunoglobulin E have-demonstrated promising efficacy. However, a subset of patients with severe allergic diseases remains unresponsive to these treatments, underscoring the need for deeper mechanistic insights and personalized therapeutic approaches. This review addresses the definition, evolution, cellular and molecular basis, and regulation of type 2 immunity. It then examines the common allergic diseases associated with type 2 responses and concludes by exploring the associations between inborn errors of immunity and type 2 responses.

Background Peanut allergy (PA) is one of the most prevalent food allergies with a lack of favorable safety/efficacy treatment. A cucumber mosaic virus-like particle expressing peanut allergen component Ara h 2 (VLP Peanut) has been developed as a novel therapeutic approach for PA. Objective We assessed the tolerogenic properties and reactivity of VLP Peanut. Methods Whole blood and peripheral blood mononuclear cells were collected from 6 peanut-allergic children. Modulation of dendritic cells (DCs), T cells, and B cells, stimulated with VLP Peanut, Ara h 2, and whole peanut extract in vitro, were assessed by quantitative real-time PCR and flow cytometry, respectively. Basophil and skin reactivity in response to VLP Peanut was assessed by basophil activation test and skin prick test, respectively. Results VLP Peanut showed beneficial biochemical properties, fit for use in clinical studies. VLP Peanut induced IFN-gamma(+) T(H)1 (P < .05) while having reduced capacity to elicit proliferation of T(H)2, allergen-specific T(H)2, and IL-4(+)-T follicular helper cells. Moreover, VLP Peanut is associated with upregulation of DC1-associated genes (MX1) compared to Ara h 2 and whole peanut extract. VLP Peanut was the most prominent at inducing IL-10(+) regulatory B cells (P < .05). Unbiased clustering analyses identified metaclusters of T and B cells targeted by VLP Peanut. Finally, VLP Peanut had reduced capacity to elicit high- and low-affinity IgE receptor-mediated responses compared to Ara h 2 or whole peanut extract (all P < .05). Finally, in an open-label first-in-human cohort of 6 peanut-allergic adults, administration of increasing concentration of VLP Peanut through skin prick test was tolerated and demonstrated no development of skin reactivity. Conclusions VLP Peanut displayed tolerogenic properties by modulating DCs, T cells, and B cells in vitro. Preliminary findings of skin reactivity using VLP Peanut in 6 peanut-allergic adults was safe and well tolerated in an open-label phase 1 study. Clinical Trial Identifier PROTECT, NCT 05476497

Recent advancements in genomics and "omic" technologies have ushered in a transformative era referred to as personalized or precision medicine. This innovative approach considers the unique genetic profiles of individuals, along with a range of variability factors, to devise tailored disease treatments and prevention strategies that cater to the distinct needs of each patient. Although the terms personalized medicine and precision medicine are frequently utilized interchangeably, it is essential to delineate the subtle distinctions between them. Personalized medicine concentrates on bespoke treatments and prevention strategies that are meticulously tailored for each individual. Conversely, precision medicine utilizes advanced gene sequencing and comprehensive data analytics to formulate specific treatments and prevention strategies for defined groups of individuals based on genetic, environmental, and lifestyle factors rather than focusing exclusively on individual patients. Therefore, precision medicine constitutes an extension of traditional personalized care, improving the accuracy of diagnosis, prognosis, and therapy estimations for each patient through the application of sophisticated molecular diagnostics and advanced imaging techniques enabled by recent technological innovations. The shift from personalized to precision medicine has gained considerable traction, particularly in the wake of the 2015 US Precision Medicine Initiative, which has further stimulated advancements in this domain. This review will explore multiomics approaches that have facilitated the evaluation of personalized biomarkers associated with allergen immunotherapy, particularly in the treatment of allergic diseases. By leveraging these innovative methodologies, we aspire to cultivate more effective and individualized patient care, ultimately enhancing health outcomes for individuals with allergies.