Background The phenotypic nature of multimorbidity in severe asthma is poorly understood. Our aims in this study were to define multimorbidity phenotypes and their characteristics in severe asthma across Europe by identifying and characterising co-aggregation of comorbidities. Methods Cross-sectional patient data were analysed from the pan-European Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) Central database of national severe asthma registries. Patients were grouped by four European regions (North, South, East, and West). Hierarchical clustering of comorbidities was applied to characterise the correlation structure of the ten commonest comorbidities within these geographical regions. Subsequent multimorbidity phenotypes (MMP) and their clinical features were then defined. Findings Data were available for 2690 severe asthma patients and 23 comorbidities from 11 countries. Three comorbidity clusters were consistently seen across the four European regions: 1) osteoporosis plus steroid-induced weight gain, 2) eczema plus rhinitis, and 3) chronic sinusitis plus nasal polyps. Four further comorbidities (obesity, bronchiectasis, gastro-oesophageal reflux disease, psychological factors) showed variable clustering. Multimorbidity was ubiquitous. Patients were assigned multimorbidity phenotypes (MMP) according to comorbidity cluster alignment. MMP sn (sinonasal-associated) and MMP u (no specific cluster alignment) were commonest. MMP ster (steroid-associated multimorbidity) had highest maintenance oral steroid (m-OCS) use, and Body Mass Index, plus worst lung function, asthma control, and asthma exacerbation frequency. MMP max (maximal multimorbidity) showed high prevalence of variably assigned comorbidities, higher m-OCS and biologic treatment needs. Interpretation Multimorbidity is common in severe asthma and can be classified into replicable novel phenotypes with characteristic clinical traits and outcomes. Recognising these phenotypes can guide better care of the ‘whole patient’ with severe asthma. Future clinical guidance should promote such understanding in order to support delivery of more effective personalised asthma care. Funding European Respiratory Society, pharmaceutical industry partners (Sanofi, TEVA, Novartis, GlaxoSmithKline, Chiesi).

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.

A bioengineered 3D-organoid model for respiratory disease. A hybrid protein-polymer matrix hydrogel with dynamic light-control of stiffness mimics the disease mechano-microenvironment and enables time-resolved investigation of lung mechanobiology.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) represents a leading cause of global morbidity and mortality. Genome-wide association studies (GWAS) have implicated numerous genetic variants in lung function impairment, yet confidently identifying the underlying genes and pathways, and translating these findings into mechanistic insight, remains a significant challenge. Objectives To leverage the genetic amenability and high-throughput screening capability of Drosophila melanogaster to determine the role of candidate causal genes in epithelial cell homeostasis. Methods We performed a loss-of-function analysis of 60 prioritised lung function candidate causal genes implicated from GWAS in two distinct epithelia: the dorsal thorax and trachea. Results We identified 57/60 tested candidate genes that alter at least one aspect of epithelial morphology and behaviour upon knockdown. With a focus on junctional integrity, cell delamination and tissue growth, we identified 11 genes for further study: Sec6, RpS26, pAbp, Arf102f, Riok1, Sra-1, Inpp5e, CG31759, ssh, eIF6 and Rtf1 . Further characterisation found a significant reduction in junctional E-Cadherin levels following Arf102F , Rtf1 , RioK1 and Sra-1 knockdown. Following a secondary screen in the Drosophila tracheal system for priority candidates, Sec6 and RpS26 were associated with significant airway defects and a reduction in larval body size. 8/11 priority genes exhibited differential lung gene expression between controls and patients with COPD. Conclusions These data demonstrate the amenability of Drosophila melanogaster to perform in vivo functional analyses of candidate causal genes at scale. Initial findings implicate several genes in epithelial homeostasis and integrity, providing new mechanistic understanding and potential therapeutic targets for COPD. Graphical Abstract

Artificial intelligence (AI), first defined in 1955 by John McCarthy, has transformed daily life across industries through applications such as chatbots, autonomous vehicles, and navigation systems. The 2022 release of ChatGPT marked a pivotal moment, highlighting AI’s rapidly expanding potential. The health care industry is increasingly embracing AI-enabled tools across oncology, pathology, and radiology to augment disease screening and clinical workflows. Ambient listening technologies support clinical documentation, reduce administrative burden, and improve patient-physician interactions. Large language models combined with natural language processing are being evaluated for generating clinical summaries managing patient portal messaging and converting freehand notes to electronic health records, while also uncovering patterns in patient data to support more personalized treatments. Forward-thinking health systems are establishing informatics departments to optimize these models. Notably, with 1 in 6 adults sourcing health information from AI, rising to nearly one-quarter among individuals younger than 30 years, there is a growing need to ensure that these technologies provide accurate and reliable information to safeguard patient safety and support appropriate clinical use. PRACTALL, a collaboration between the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy & Clinical Immunology, aims to equip allergist-immunologists with essential AI insights highlighting tools for clinical practice, education, and research. By addressing potential pitfalls and biases, PRACTALL illustrates how AI can enhance efficiency, improve patient care, and alleviate administrative burdens in health care.

Background:Multimorbidity refers to the presence of multiple coexisting conditions, but is often underappreciated in the context of severe asthma (SA) management. We sought to identify differences in approaches to multimorbidity management in SA, variability in access to multidisciplinary team (MDT) resources, and whether physician perspectives on multimorbidity differ between SA specialists and general respiratory physicians. Methods:The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration circulated an online physician survey via European national respiratory societies to assess 1) available resources to address multimorbidity and 2) physician perspectives on multimorbidity in SA. Results:495 responses from 25 European countries included 48% SA specialists and 52% general respiratory physicians. SA specialists had more experience with SA patients (20% were seeing >60 patients per month) compared to general respiratory physicians. SA specialists had greater access to multidisciplinary care - including better access to MDTs, allied health professionals and referrals to external specialists, and therefore more routinely assessed comorbidities and considered them greater influences on their practice. They also considered multimorbidity to a greater degree and rated its impact on their patients' asthma outcomes (and general health outcomes) as more substantial. Conclusions:Alongside more experience of treating SA, SA specialists have increased awareness of multimorbidity and better resources to manage it. However, access to MDTs remains a significant gap for both SA specialists and general respiratory physicians. Furthermore, both groups identified a high need for further education and training about multimorbidity. These findings highlight key areas for improvement in clinical practice, resources and training.

BACKGROUND:Early identification of children at risk of asthma attacks is important for optimizing treatment strategies. We aimed to integrate salivary microbiome and serum inflammatory mediator profiles with asthma attacks history to develop a comprehensive predictive model for future attacks. METHODS:This study contained a discovery (SysPharmPediA) and a replication phase (U-BIOPRED). School-aged children with asthma were classified into at risk and no-risk groups, based on the presence or absence of one or more severe attacks during one-year follow-up. Prediction models were developed using random forest on the training set (70%) with data on past asthma attacks, microbiome composition, serum inflammatory mediator levels, and their combinations and then tested on the rest of the population (30%). Outcomes were replicated in a subset of children with severe asthma from U-BIOPRED. RESULTS:Complete data were available for 154 children (SysPharmPediA = 121, U-BIOPRED = 33). In discovery, the model based on past attacks resulted in an area under the receiving characteristic curve (AUROCC) ~ 0.7. Models including six salivary bacteria or six inflammatory mediators achieved similar results. The combined model incorporating seven features, past asthma attacks, Capnocytophaga, Corynebacterium, and Cardiobacterium, TIMP-4, VEGF, and MIP-3β achieved the highest accuracy with AUROCC ~0.87. The combined model in the U-BIOPRED limited to available inflammatory mediators (VEGF), and incorporating past asthma attacks, Capnocytophaga, Corynebacterium, and Cardiobacterium, resulted in an AUROCC of 0.84. CONCLUSION:Serum inflammatory mediators and salivary microbiome complement asthma attacks history for predicting future attacks. These results highlight the imperative for continued investigation into oral microbiota and its interaction with the immune system.

IntroductionNeutrophilic asthma has been suggested to be a clinically distinct phenotype characterised by more severe airflow obstruction and higher exacerbation risk. However, this has only been assessed in few and smaller studies, using different cut-offs to define neutrophilia, and with conflicting results. We used data from ATLANTIS, an observational longitudinal study including a large number of patients with asthma and healthy controls. The aim of the present study was to examine whether neutrophilic inflammation, either in sputum or blood, is more prevalent in asthma and whether it correlates with disease severity.MethodsATLANTIS included 773 asthma patients, with blood collected from 767 (99%) and sputum from 228 patients (30%). Data were available from 244 healthy controls, all providing blood and 126 (52%) providing sputum. Asthma patients were characterised, including parameters of large and small airways disease at baseline and after 6 and 12 months of follow-up. Sputum and blood neutrophilia were defined as values exceeding the upper quartile in asthma patients.ResultsThe prevalence of sputum neutrophilia did not differ between asthma patients and healthy controls. Asthma patients with sputum neutrophilia did not display more severe symptoms, large or small airways disease or more frequent exacerbations. Blood neutrophilia was more common in asthma and was associated with higher body mass index, female sex, current smoking and systemic corticosteroid use. Patients with blood neutrophilia had a statistically significant, but small, increase in residual volume/total lung capacity. Blood neutrophilia was not associated with large or small airways disease or exacerbation risk.ConclusionSputum and blood neutrophilia do not define a distinct clinical phenotype in asthma.

ABSTRACTBackgroundAirway remodelling is a feature of severe asthma with airway epithelial damage observed frequently. We evaluated the role of WNT5a and TGF‐β1 in asthmatic airway biopsies and in sputum and bronchial brushings assessed their role in remodelling.MethodsWNT5a and TGF‐β1 protein expression were assessed in the lamina propria epithelium of people with asthma (GINA 1–3, n‐8 and GINA 4–5, n‐14) and healthy subjects (n‐9), alongside relevant remodelling markers. The effects of WNT5a and TGF‐β1 on BEAS‐2B epithelial cell wound healing and differentiation were assessed in vitro. Replication was performed in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U‐BIOPRED) study in sputum (n = 120) and bronchial brushes (n = 147).ResultsWNT5a and TGF‐β1 protein expression were significantly increased in the airway epithelium and lamina propria in asthma patients with concurrent airflow limitation or severe disease. Furthermore, WNT5a protein expression in the lamina propria correlated with tissue eosinophils and vascular remodelling. Airway epithelial WNT5a was co‐localised predominantly to airway basal cells and correlated with Th17 gene expression (r = 0.40, p = 0.025) and both the % intact (rs = 0.54, p = 0.001) and % denuded epithelium (rs = −0.39, p = 0.003). Experiments in BEAS‐2B cells confirmed that WNT5a at maximal physiological concentrations (1 μg/mL), promoted epithelial wound healing, independently of TGF‐β1, as well as induction of EMT‐like morphology. WNT5a mRNA was associated with severe asthma, airflow limitation, sputum eosinophilia and Th2, and Th17 and neutrophil activation transcriptomes in sputum in U‐BIOPRED.ConclusionWNT5a is associated with both airway remodelling and severe asthma.Trial RegistrationClinicalTrials.gov identifier: NCT01982162

Background Eosinophils are crucial in allergic inflammation, and their correlation with asthma severity has made them a focal point in predicting treatment outcomes. Blood eosinophil count is a commonly utilized marker. However, its limitations have prompted alternative biomarker exploration, such as eosinophil-derived neurotoxin (EDN). Objective This research was conducted over 24 weeks on 56 patients with severe asthma treated with mepolizumab, reslizumab, and dupilumab. We aimed to evaluate the clinical significance of blood eosinophil count and their potential, including those of blood EDN levels and urine EDN values as biomarkers for predicting treatment response. Methods The analysis encompassed examining correlations between biomarkers and clinical features, including exacerbation rates and lung function, through ELISA assays and subsequent statistical analyses. The study protocol is registered at ClinicalTrials.gov (NCT05164939). Results The findings underscore strong correlations between serum EDN levels, blood eosinophil counts, and treatment responses, with EDN demonstrating comparable predictive capabilities to blood eosinophil counts to determine treatment responses. Different biologics exhibited varying efficacy regarding baseline eosinophil counts and EDN levels. Conclusions Blood eosinophil counts and EDN levels show potential as predictive markers for treatment responses in patients with severe asthma undergoing biologic therapies. However, further comprehensive studies are warranted to enhance the reliability and applicability of EDN as an effective asthma treatment biomarker.

Vitronectin (VTN) is an important extracellular matrix protein in tissue remodeling, but its role in chronic obstructive pulmonary disease (COPD) is unknown. We show that VTN regulates tissue remodeling through urokinase plasminogen activator (uPA) signaling pathway in COPD. In human COPD airways and bronchoepithelial cells and the airways of mice with cigarette smoke (CS)-induced experimental COPD, VTN protein was not changed, but downstream uPA signaling was altered (increased plasminogen activator inhibitor-1) that induced collagen and airway remodeling. In the parenchyma, VTN levels were decreased, uPA signaling pathway differentially altered and collagen reduced in lung fibroblasts from human and lung parenchyma in experimental COPD. Vtn inhibition with siRNA in mouse fibroblasts altered uPA signaling increased matrix metalloproteinase-12, and reduced collagen, whereas over-expression restored collagen production after CS extract challenge. Vtn-/- and Vtn small interfering RNA- treated mice had exaggerated inflammation, emphysema, and impaired lung function compared with controls with CS- induced COPD. Restoration of VTN in the parenchyma may be a therapeutic option for emphysema and COPD.

Background:The relationship between pre-treatment levels of blood eosinophil count (BEC), fractional exhaled nitric oxide (F ENO) and sputum eosinophils (Sp-EOS) and treatment response to monoclonal antibodies (mAbs) in severe eosinophilic asthma (SEA) remains unclear. We evaluated pre-treatment levels of BEC, F ENO, Sp-EOS and their combinations as predictors of treatment responses in patients with SEA undergoing anti-interleukin (IL)-5/IL-5Rα or anti-IL-4Rα antibody therapies. Methods:The study included 153 adult patients with SEA (59 anti-IL-5/IL-5Rα and 94 anti-IL-4Rα users). Logistic regression models were used to evaluate the association between predictors and 12-month treatment responses and clinical remission across four domains: exacerbation rate, maintenance of oral corticosteroid dose, forced expiratory volume in 1 s (FEV1) and asthma control test (ACT) improvement. Results:Pre-treatment BEC and Sp-EOS were not associated with treatment responses in either mAb group. For combined data from anti-IL-5/IL-5Rα and anti-IL-4Rα users, the adjusted odds ratios (95% confidence intervals) for a 1-unit increase in log-transformed F ENO were 1.8 (1.21-2.74) for FEV1 response and 2.15 (1.29-3.75) for ACT response. For anti-IL-4Rα users, these values were 2.34 (1.39-4.17) and 3.6 (1.73-8.84), respectively. No significant association between F ENO and treatment response was found among anti-IL-5/IL-5Rα users. Additionally, no associations were observed between BEC, Sp-EOS or F ENO and clinical remission across mAb categories. Combining biomarkers did not significantly enhance predictive ability. Conclusion:In patients with SEA treated with anti-IL-4Rα antibodies, pre-treatment F ENO may be a good predictor for certain treatment response domains.

Background:Asthma exacerbations are episodes of symptom worsening requiring increased therapy, which affect patients across all asthma severities. Potential genetic associations with asthma exacerbations in an understudied population were investigated. Objective:We sought to perform a genome-wide association study on severe asthma exacerbations in an admixed adult population with varying asthma severities and to explore potential epigenetic roles. Methods:A genome-wide association study was conducted in 727 Brazilian patients (mean age, 43 years; 20% male; and 55% with exacerbations) from the Programa de Controle da Asma na Bahia study, analyzing 12 million variants. Severe exacerbation was defined as systemic corticosteroid use for 3 or more days, emergency room visits, or hospital admissions within the past year. Analyses were adjusted for age, sex, asthma severity, and genotype principal components. Replication was sought in the cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (UBIOPRED) study, the Genes-environments and Admixture in Latino Americans II study, and the Study of African Americans, Asthma, Genes, and Environments using the same methodology. Epigenetic effects were assessed in silico via PhenoScanner v2. Results:Five intergenic variants (rs55670125, rs10854420, rs68160941, rs11910414, and rs35834033) in complete linkage disequilibrium reached genome-wide significance (odds ratio [OR], 2.5; P = 3.47 × 10-8), located between the CXADR and LOC105372741 genes on chromosome 21. Although not replicated, rs35834033 showed a nonsignificant trend (OR, 1.79; P = .17). Four variants were associated with H3K4me1 histone modification, linked to asthma pathogenesis. In addition, 88 suggestive variants were found; rs17697822 in FOXP1 was negatively associated with exacerbations (OR, 0.44; P = 4.03 × 10-6). Conclusions:The CXADR is highlighted as a potential novel susceptibility locus for asthma exacerbations, possibly tied to viral respiratory infections. Further replication and validation are needed.