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Introduction: Eosinophil‐derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non‐invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma. Method s : We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)‐adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression. Results: uEDN/uCr values were higher in atopic versus non‐atopic preschool‐aged subjects (p =.035) and associated with the sum of allergen‐specific IgE in younger (r = 0.24, p =.003), and older subjects (r = 0.23, p =.043). uEDN/uCr was marginally a good determinant for atopy (p =.078, for subjects aged <6 years, and p =.058 for subjects ≥6 years). Children with the T2‐high phenotype had higher uEDN/uCr (p <.001) versus T2‐low—irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z‐scores: r = −0.30, p =.007, and FEV1/FVC z‐scores: r = −0.24, p =.038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p =.038), and to a lesser extent, FEV1/FVC (p =.080). Conclusions: uEDN/uCr may serve as a non‐invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays. [ABSTRACT FROM AUTHOR]

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0–20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels. Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype–dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels. Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions. The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT 02496468). [ABSTRACT FROM AUTHOR]

Understanding antigen-specific T-cell responses, for example, following virus infections or allergen exposure, is of high relevance for the development of vaccines and therapeutics. We aimed on optimizing immunophenotyping of T cells after antigen stimulation by improving staining procedures for flow and mass cytometry. Our method can be used for primary cells of both mouse and human origin for the detection of low-frequency T-cell response using a dualbarcoding system for individual samples and conditions. First, live-cell barcoding was performed using anti-CD45 antibodies prior to an in vitro T-cell stimulation assay. Second, to discriminate between stimulation conditions and prevent cell loss, sample barcoding was combined with a commercial barcoding solution. This dual-barcoding approach is cell sparing and, therefore, particularly relevant for samples with low cell numbers. To further reduce cell loss and to increase debarcoding efficiency of multiplexed samples, we combined our dualbarcoding approach with a new centrifugation-free washing system by laminar flow (Curiox™). Finally, to demonstrate the benefits of our established protocol, we assayed virus-specific T-cell response in SARS-CoV-2-vaccinated and SARSCoV-2-infected patients and compared with healthy non-exposed individuals by a high-parameter CyTOF analysis. We could reveal a heterogeneity of phenotypes among responding CD4, CD8, and gd-T cells following antigenspecific stimulations. Our protocol allows to assay antigen-specific responses of minute populations of T cells to virus-derived peptides, allergens, or other antigens from the same donor sample, in order to investigate qualitative and quantitative differences. [ABSTRACT FROM AUTHOR]

The prevalence and complexity of allergic diseases have increased in recent decades, leading to a significant burden for patients and their families. However, training in Allergy and Clinical Immunology (ACI) varies worldwide, with significant heterogeneity between countries. This variability may limit the number of healthcare professionals and researchers undergoing ACI training in the future. To address this, the European Academy of Allergy and Clinical Immunology (EAACI) has developed a mentorship program to support young professionals in enhancing their skills and network. The program has been successful and may serve as a model for other scientific organizations in the ACI field. [Extracted from the article]

Rationale: Fungal exposure has been associated with predisposing and protective effects on the development of childhood asthma. Objectives: To study whether early-life house dust mycobiota composition is associated with the development of asthma. Methods: Mycobiota were determined by amplicon sequencing from 382 dust samples collected from living room floors 2 months after birth in homes of the LUKAS cohort. Asthma status by 10.5 years of age was defined from questionnaires and assigned as ever asthma (n = 68) or current asthma (n = 27). Inhalant atopy was clinically determined at the same age. b-composition was analyzed using PERMANOVA-S, and asthma and atopy analyses were performed using discrete time hazard models and logistic regression, respectively. Results: The house dust mycobiota composition based on Bray-Curtis distance was different in the homes of children who later did or did not develop asthma. The first and the fourth axes scores of principal coordinates analysis based on Bray-Curtis were associated with ever asthma. Of the genera with the strongest correlation with these axes, the relative abundance of Boeremia, Cladosporium, Microdochium, Mycosphaerella, and Pyrenochaetopsis showed protective associations with asthma. None of these associations remained significant after mutual adjustment among the five genera or when mutually adjusted for other microbial cell wall markers and previously identified asthma-protective bacterial indices. Neither fungal a-diversity nor load was associated with asthma in the whole population, but higher fungal richness was a risk factor among children on farms. Higher fungal loads (measured via quantitative polymerase chain reaction) in house dust were associated with the risk of inhalant atopy. Conclusions: The results of our analyses from this wellcharacterized birth cohort suggest that the early-life house dust mycobiota in Finnish homes, characterized via DNA amplicon sequencing, do not have strong predisposing or protective effects on asthma development. [ABSTRACT FROM AUTHOR]

The circulating nucleocapsid (NCP) antigen of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is detectable in coronavirus disease‐2019 (COVID‐19) patients. To better understand the biology of disease severity, we investigated NCP clearance kinetics in hospitalized COVID‐19 patients. Serum NCP was quantified using a commercial NCP‐specific enzyme‐linked immunoassay in hospitalized COVID‐19 patients (n = 63) during their hospital stay. Results were correlated to COVID‐19 disease severity, inflammation parameters, antibody response, and results of SARS‐CoV‐2 PCR from nasopharyngeal swabs. We demonstrate that NCP antigen levels in serum remained elevated in 21/45 (46.7%) samples from patients in intensive care units (ICU) after >8 days postdiagnosis. The proportion of ICU patients with detectable antigenemia declined only gradually from 84.6% to 25.0% over several weeks. This was in contrast to complete NCP clearance in all non‐ICU patients after 8 days, and also in contrast to mucosal clearance of the virus as measured by PCR. Antigen clearance was associated with higher IgG against S1 but not NCP. Clearance of NCP antigenemia is delayed in >40% of severely ill COVID‐19 patients. Thus, NCP antigenemia detected after 8 days post COVID‐19 diagnosis is a characteristic of patients requiring intensive care. Prospective trials should further investigate NCP antigen clearance kinetics as a mechanistic biomarker. [ABSTRACT FROM AUTHOR]

Heat waves are increasing in intensity, frequency, and duration causing significant heat stress in all living organisms. Heat stress has multiple negative effects on plants affecting photosynthesis, respiration, growth, development, and reproduction. It also impacts animals leading to physiological and behavioral alterations, such as reduced caloric intake, increased water intake, and decreased reproduction and growth. In humans, epidemiological studies have shown that heat waves are associated with increased morbidity and mortality. There are many biological effects of heat stress (structural changes, enzyme function disruption, damage through reactive oxygen or nitrogen species). While plants and animals can mitigate some of these effects through adaptive mechanisms such as the generation of heat shock proteins, antioxidants, stress granules, and others, these mechanisms may likely be inadequate with further global warming. This review summarizes the effects of heat stress on plants and animals and the adaptative mechanisms that have evolved to counteract this stress. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta‐analysis was to critically assess the published literature related to community‐acquired viral co‐infections and COVID‐19 and to evaluate the prevalence, most identified co‐pathogens, and relevant risk factors. Furthermore, we aimed to examine the clinical features and outcomes of co‐infected compared to mono‐infected COVID‐19 patients. We systematically searched PubMed, Web of Science, Embase, Scopus, and The Cochrane Library for studies published from 1 November 2019 to 13 August 2021. We included patients of all ages and any COVID‐19 severity who were screened for respiratory viral co‐infection within 48 h of COVID‐19 diagnosis. The main outcome was the proportion of patients with a respiratory viral co‐infection. The systematic review was registered to PROSPERO (CRD42021272235). Out of 6053 initially retrieved studies, 59 studies with a total of 16,643 SARS‐CoV‐2 positive patients were included. The global pooled prevalence was 5.01% (95% CI 3.34%–7.27%; I2 = 95%) based on a random‐effects model, with Influenza Viruses (1.54%) and Enteroviruses (1.32%) being the most prevalent pathogens. Subgroup analyses showed that co‐infection was significantly higher in paediatric (9.39%) than adult (3.51%) patients (p‐value = 0.02). Furthermore, co‐infected patients were more likely to be dyspnoeic and the odds of fatality (OR = 1.66) were increased. Although a relatively low proportion of COVID‐19 patients have a respiratory viral co‐infection, our findings show that multiplex viral panel testing may be advisable in patients with compatible symptoms. Indeed, respiratory virus co‐infections may be associated with adverse clinical outcomes and therefore have therapeutic and prognostic implications. [ABSTRACT FROM AUTHOR]

The global epidemiology of asthma among patients with coronavirus disease 2019 (COVID-19) presents striking geographic differences, defining prevalence zones of high and low co-occurrence of asthma and COVID-19. We aimed to compare asthma prevalence among hospitalized patients with COVID-19 in major global hubs across the world by applying common inclusion criteria and definitions. We built a network of 6 academic hospitals in Stanford (Stanford University)/the United States; Frankfurt (Goethe University), Giessen (Justus Liebig University), and Marburg (Philipps University)/Germany; and Moscow (Clinical Hospital 52 in collaboration with Sechenov University)/Russia. We collected clinical and laboratory data for patients hospitalized due to COVID-19. Asthmatic individuals were overrepresented among hospitalized patients with COVID-19 in Stanford and underrepresented in Moscow and Germany as compared with their prevalence among adults in the local community. Asthma prevalence was similar among patients hospitalized in an intensive care unit and patients hospitalized in other than an intensive care unit, which implied that the risk for development of severe COVID-19 was not higher among asthmatic patients. The numbers of males and comorbidities were higher among patients with COVID-19 in the Stanford cohort, and the most frequent comorbidities among these patients with asthma were other chronic inflammatory airway disorders such as chronic obstructive pulmonary disease. The observed disparity in COVID-19–associated risk among asthmatic patients across countries and continents is connected to the varying prevalence of underlying comorbidities, particularly chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Vitamin D supplementation and its impact on immunoregulation are widely investigated. We aimed to assess the prevention and treatment efficiency of vitamin D supplementation in the context of coronavirus disease 2019 (COVID-19) and any disease-related complications. For this systematic review and meta-analysis, we searched databases (PubMed, Embase, Scopus, Web of Science, The Cochrane Library, medRxiv, Cochrane COVID-19 Study Register, and ClinicalTrial.gov) for studies published between 1 November 2019 and 17 September 2021. We considered randomized trials (RCTs) as potentially eligible when patients were tested for SARS-CoV-2 infection and received vitamin D supplementation versus a placebo or standard-of-care control. A random-effects model was implemented to obtain pooled odds ratios for the effect of vitamin D supplementation on the main outcome of mortality as well as clinical outcomes. We identified a total of 5,733 articles, of which eight RCTs (657 patients) met the eligibility criteria. Although no statistically significant effects were reached, the use of vitamin D supplementation showed a trend for reduced mortality [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.32-1.71, p = 0.48] compared with the control group, with even stronger effects, when vitamin D was administered repeatedly (OR 0.33, 95% CI 0.1-1.14). The mean difference for the length of hospitalization was -0.28 (95% CI -0.60 to 0.04), and the ORs were 0.41 (95% CI 0.15-1.12) and 0.52 (95% CI 0.27-1.02) for ICU admission and mechanical ventilation, respectively. In conclusion, vitamin D supplementation did not improve the clinical outcomes in COVID-19 patients, but trends of beneficial effects were observed. Further investigations are required, especially studies focusing on the daily administration of vitamin D. [ABSTRACT FROM AUTHOR]