BACKGROUND:Benralizumab reduces eosinophilia and improves outcomes in most, but not all, patients with asthma. We evaluated whether baseline CT imaging-derived metrics assist in clinical response prognosis after 52 weeks. RESEARCH QUESTION:Are CT imaging-derived measures prognostic of benralizumab response, assessed by exacerbation reduction, lung function, and symptom control at 52 weeks? STUDY DESIGN AND METHODS:This 2-center prospective, open-label study included patients eligible for anti-IL-5α receptor therapy who began benralizumab treatment alongside high-dose background therapy for severe eosinophilic asthma (SEA; > 300/mm3). Baseline variables included CT imaging-derived metrics (parametric response mapping [PRM] small airways disease [SAD] voxels; University of California, San Francisco, mucus plugging; and Lund-Mackay sinus score) and other potential biomarkers (blood eosinophil levels and lung function). The primary outcome was ≥ 50% reduction in exacerbation rates. The secondary outcome was a composite clinical score achieving ≥ 2 of response criteria: ≥ 50% exacerbation reduction, FEV1 increase of > 300 mL, and 5-item Asthma Control Questionnaire score improvement of > 0.5. RESULTS:Of 59 enrolled patients, 47 patients (60% female; median age, 54 years) completed the study with high-quality paired inspiratory and expiratory spirometrically gated CT scans. Forty-two of 47 patients achieved ≥ 50% exacerbation reduction, for which no prognostic factor could be identified. Thirty-five of 47 patients achieved the secondary outcome. Receiver operating characteristic (ROC) curve analyses indicated that PRM SAD voxels (area under the ROC curve [AUC], 0.693; 95% CI, 0.513-0.873) and sinus score (AUC, 0.714; 95% CI, 0.501-0.928) were robust prognostic factors of responder status, both outperforming blood eosinophil count (AUC, 0.630; 95% CI, 0.428-0.832). INTERPRETATION:Our results show that the CT imaging-derived metrics, PRM SAD voxels, and sinus score were associated with benralizumab response as defined by a composite clinical end point and could be valuable biomarkers for response prognosis in patients with SEA. The high rate of exacerbation reduction limited discrimination of the primary end point. These findings support incorporating CT imaging phenotyping into precision management of SEA and warrant validation in larger cohorts. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03976310; URL: www. CLINICALTRIALS:gov.

INTRODUCTION:Post-infectious bronchiolitis obliterans (PIBO) is a rare and severe chronic lung disease. Our goal was to characterize respiratory epithelium in children with PIBO, which remains unexplored, using an ex vivo model culture. METHODS:Proximal bronchial biopsies from children with PIBO and reconstituted bronchial epithelium from PIBO patients (n = 3) and controls (n = 17) were analyzed using an air-liquid interface culture model. Epithelial cell composition, barrier integrity, and mediator production, including mucins, inflammatory and antiviral responses, were assessed in this pathological and functional approach. RESULTS:Epithelial thickness was assessed in PIBO biopsies. Ex vivo reconstituted PIBO epithelia appeared to exhibit comparable cohesion and cell composition to controls. Mucin expression and secretion were likewise similar between groups. PIBO epithelial might have displayed reduced IL-33 transcript levels and decreased TSLP secretion, whereas IFN-λ1, IFN-λ2-3 and IFN-β secretion could have been elevated. No differences were detected in remodeling markers (MMP-9 and YKL-40). CONCLUSIONS:In summary, ex vivo model of PIBO epithelia suggested that the epithelium may preserve structural characteristics and mucin production, without evidence of remodeling. However, PIBO epithelial cells may have a distinct immune profile, with lower alarmin expression and higher interferon secretion. This could indicate a tendency toward enhanced antiviral response rather than structural changes. These preliminary results need to be confirmed in larger cohorts.

BACKGROUND:Obesity-related asthma (OBA) is a distinct asthma phenotype, with increased severity. Adipokine release from excessive adipose tissue is suggested to be a key feature of OBA pathophysiology. However, it is unclear how the clinical characteristics of severe asthma associate with adipokine mediators. We examined systemic adipokine levels and evaluated relationships with disease severity, weight, sex, and steroid treatment in asthma. METHODS:A multiplex immunoassay for nine adipokines with proposed involvement in obesity-related inflammation (adiponectin, adipsin, BAFF, chemerin, FGF-21, leptin, lipocalin-2/NGAL, osteonectin and resistin) was designed. Plasma adipokines were measured in 127 patients with mild-to-moderate asthma (MMA) or severe asthma (SA) from the European BIOAIR cohort at baseline and after a controlled 2-week oral corticosteroid (OCS) intervention. RESULTS:Leptin and chemerin were significantly increased in patients with SA vs. MMA. Leptin, adiponectin, adipsin, and NGAL were affected by sex, whereas leptin and adipsin were strongly affected by weight. OCS increased leptin and adiponectin, decreased adipsin and BAFF, and did not affect osteonectin, resistin, or chemerin. No adipokines showed positive associations with exhaled NO, blood or sputum eosinophils, although certain correlations with serum CRP, blood, and sputum neutrophils were observed. CONCLUSIONS:Overall, we observe variable relationships between the nine adipokines, obesity and asthma severity. There were no relationships between adipokine levels and type-2 airway inflammation, yet associations with systemic neutrophilic inflammation were seen. Although one adipokine, chemerin, was independently associated with asthma severity, deciphering the role of adipokines in OBA is complex due to the influence of sex, BMI, and OCS.

Abstract:This scoping review summarises the effects of pollen exposure during exercise on health and exercise performance in athletic individuals and examines how pollen allergies influence physical activity and sports participation. Primary studies reporting health or performance outcomes in individuals exercising under pollen exposure were included, while reviews and guidelines were excluded. Searches were conducted in PubMed, Scopus, Web of Science, and SportDiscus in January 2025 following Joanna Briggs Institute methodology and PRISMA-ScR guidelines. Of 3,345 records, 18 studies met the inclusion criteria. Most participants were children or young adults with rhinitis or asthma, and most studies were conducted in northern Europe and North America. Seasonal pollen exposure was associated with reduced post-exercise lung function, lower sports participation, decreased perceived training capacity, and impaired quality of life. Major research gaps remain, including the absence of objective performance outcomes and the limited investigation of potential side effects of anti-allergic medications.

Post-infectious bronchiolitis obliterans (PIBO) is a rare but severe pulmonary disease in children, often associated with adenovirus infection. Risk factors include male sex, hypoxemia, and mechanical ventilation. Diagnosis is based on clinical history, bronchialobstruction, and radiological abnormalities. PIBO is characterized by chronic inflammation leading to tissue remodeling and bronchiolar fibrosis. Airway epithelial lesions, potentially linked to viral infection, are considered key mechanisms of PIBO. In the absence of specific treatments, research efforts aim to better understand mechanisms of PIBO, identify biomarkers, and improve management strategies. (c) 2025 SPLF. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Oral corticosteroids (OCS) have been used for both maintenance and burst treatment of asthma since the 1950s owing to their beneficial effect on symptoms and exacerbations coupled with a historical lack of alternative therapies. Despite the current availability of well-tolerated and effective treatment with biologics, chronic OCS use remains high. This is of great concern because evidence suggests that a lifetime cumulative exposure even as low as 0.5 to 1.0 g prednisolone equivalent (about three to four bursts of OCS) significantly increases the risk of a wide range of acute and long-term adverse effects, some of which may not be fully reversible. Conversely, biologics have demonstrated a more favorable benefit-risk profile compared with OCS, while reducing exacerbations and improving symptom control. Here, we review the current situation, highlight the need for improved stewardship of OCS use, describe the cumulative and potentially irreversible toxicity seen with even short bursts of OCS, and discuss the role of biologics in minimizing their use. Finally, we provide our opinion on how maintenance OCS therapy in asthma can be relegated to history, with early patient risk evaluation to identify and measure biomarkers and/or clinical traits that may predict risk of future exacerbations, enabling proactive preventative intervention.

Background: Bronchiolitis obliterans syndrome (BOS) is a late-onset noninfectious pulmonary complication of allogeneic hematopoietic cell transplant (HCT) that is often diagnosed at an advanced stage with severe lung impairment. Increasing use of HCT for the treatment of hematologic diseases worldwide translates to an increasing burden of BOS, particularly for the community pulmonologist. Early recognition of BOS, which offers the best opportunity to mitigate morbidity and mortality, is hampered by incomplete knowledge of the clinical course and disease process. The goal of this research statement is to survey our current understanding of BOS and to define the research agenda for the early detection of BOS. Methods: We convened a multidisciplinary panel that included community representatives for an in-depth survey of the published literature followed by an online workshop. Results: Major knowledge gaps were identified within interrelated themes of natural history and pathogenesis, risk factors, and the clinical diagnostic approach. Conclusions: This statement reflects the detailed assessment of identified knowledge gaps with associated key research questions, as well as a proposed research road map to stimulate cross-disciplinary collaborations from preclinical to clinical investigations.

Respiratory diseases are major causes of chronic disorders and death worldwide, involving inflammatory, tumoral or infectious processes. It has been proven that vascular mechanisms are key contributors to the pathogenesis of these diseases. For that purpose, it is essential to describe and validate new biomarkers and/or therapeutic targets responsible for lung vascularisation and/or angiogenesis. CD146 is an endothelial cell adhesion molecule also expressed on mesenchymal stem cells, epithelial cells and T-helper 17 lymphocytes. A soluble form of CD146 exists, sCD146, which can be detected in blood and biological samples, including the bronchoalveolar lavage fluid. CD146/sCD146 are involved in angiogenesis and inflammation and are associated with many inflammatory diseases. Recent studies have reported both protective and detrimental roles of CD146/sCD146 in lung diseases. In the present review, we will describe the potential role of CD146 and sCD146 in the pathogenesis of respiratory diseases in order to use them as key mechanistic biomarkers or new therapeutical targets to treat or even cure these pathologies.

BACKGROUND:The SOURCE phase 3 oral corticosteroid (OCS)-sparing study of tezepelumab indicated an OCS-sparing effect with tezepelumab versus placebo in patients with OCS-dependent asthma and baseline blood eosinophil counts (BECs) of at least 150 cells per μL. The WAYFINDER study aimed to further evaluate the ability of tezepelumab to reduce or discontinue OCS use in a larger cohort of patients with OCS-dependent severe, uncontrolled asthma. METHODS:WAYFINDER was a phase 3b, multicentre, single-arm, open-label, OCS-sparing study. Adults (aged 18-80 years) with severe, uncontrolled asthma receiving a maintenance OCS dose of 5-40 mg per day (or equivalent) of prednisone or prednisolone were recruited from 68 clinical centres across 11 countries (Argentina, Belgium, Bulgaria, France, Germany, Latvia, Mexico, Poland, Spain, UK, and USA). Participants received tezepelumab 210 mg subcutaneously once every 4 weeks for up to 52 weeks. The co-primary endpoints, assessed at weeks 28 and 52, were the proportion of participants who reduced their prescribed maintenance OCS dose to 5 mg per day or less without loss of asthma control and the proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to below 5 mg per day were contingent on participants demonstrating preserved adrenal function. This completed study was registered with ClinicalTrials.gov (NCT05274815). FINDINGS:WAYFINDER was conducted between May 17, 2022, and Sept 9, 2024. Overall, 382 participants were enrolled and 298 participants (206 female [69·1%]) received tezepelumab and were included in the efficacy and safety analyses. The mean baseline maintenance OCS dose was 10·8 (SD 6·5) mg per day. The proportion of participants who had a maintenance OCS dose of 5 mg per day or less without loss of asthma control was 265 of 298 (88·9% [95% CI 84·8-92·3]) at week 28 and 268 of 298 (89·9% [85·9-93·1]) at week 52. The proportion of participants who discontinued OCS without loss of asthma control was 96 of 298 (32·2% [26·9-37·8]) at week 28 and 150 of 298 (50·3% [44·5-56·2]) at week 52. OCS reduction and discontinuation were achieved across pre-specified subgroups based on baseline BEC, fractional exhaled nitric oxide level, or allergy status. Serious adverse events were reported in 28 (9·4%) of 298 participants (asthma [13 participants] and pneumonia [three participants] were the most common), and four participants (1·3%) had adverse events leading to tezepelumab discontinuation. Two participants died during the study but neither death was considered to be causally related to tezepelumab treatment. INTERPRETATION:After 52 weeks of open-label tezepelumab treatment, nearly 90% of patients with OCS-dependent severe, uncontrolled asthma had a maintenance OCS dose of 5 mg per day or less and more than 50% completely discontinued OCS, while maintaining asthma control. These findings indicate that tezepelumab treatment can help enable patients with severe asthma to reduce their OCS use and its associated burden, with broad applicability across patient phenotypes. FUNDING:AstraZeneca and Amgen.

Rationale: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP) activity. In the phase 3 oral corticosteroid (OCS)-sparing SOURCE study in patients with OCS-dependent asthma (n=150; NCT03406078), the primary endpoint was not met. However, a daily maintenance OCS (mOCS) dose reduction was achieved in tezepelumab versus placebo recipients with baseline blood eosinophil counts of ≥150 cells/μL. In the phase 3b WAYFINDER study (NCT05274815), the ability of tezepelumab to reduce or discontinue OCS use without loss of asthma control was investigated over 52 weeks in a larger cohort of OCS-dependent patients with severe asthma. Methods: WAYFINDER was an open-label, single-arm, OCS-sparing study in adults with severe asthma (across baseline blood eosinophil counts) receiving OCS (prednisone/prednisolone 5-40 mg/day or equivalent) for ≥3 months before study entry. Participants received tezepelumab 210 mg subcutaneously every 4 weeks for up to 52 weeks. After a 4-week induction phase on a stable OCS dose, participants entered a 48-week OCS reduction and maintenance phase. Co-primary endpoints, assessed at weeks 28 and 52, were 1) proportion of participants who reduced their daily prescribed mOCS dose to ≤5 mg/day without loss of asthma control; and 2) proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to <5 mg/day were contingent on participants retaining adrenal function, assessed via an initial morning cortisol test and then either adrenocorticotropic hormone stimulation tests or repeated morning serum cortisol tests. Results: Overall, 298 patients started tezepelumab treatment and 273 completed the study. The mean (SD) baseline mOCS dose was 10.8 (6.5) mg/day. The proportion of participants who had an mOCS dose of ≤5 mg/day was 88.9% at week 28 and 89.9% at week 52 (Figure). The proportion of participants who discontinued OCS was 32.2% at week 28 and 50.3% at week 52 (Figure). 82.2% of participants had an mOCS dose of ≤5 mg/day without loss of asthma control at week 52 when the reason for systemic corticosteroid treatment was related to adrenal insufficiency (post hoc analysis; details in Figure). The safety profile of tezepelumab was consistent with previous studies. Conclusions: Most patients in this broad severe asthma population treated with tezepelumab achieved clinically meaningful reductions in mOCS dose to ≤5 mg/day or completely discontinued OCS, while maintaining asthma control. Over 80% of patients were able to reduce their mOCS dose to ≤5 mg/day when the reason for systemic corticosteroid treatment was related to adrenal insufficiency.

Remission is emerging as a feasible treatment goal in moderate-to-severe asthma, driven by the success of biologic therapies in controlling inflammation and reducing exacerbations. Yet current definitions of remission-focused on symptom control, lung function, and corticosteroid reduction-lack precision, can only be ascertained retrospectively, and do not reflect the underlying mechanisms and pathology that drive disease progression. This gap limits the clinical applicability of these definitions and might obscure opportunities for early, disease-modifying intervention. In this Series paper, we propose a refined framework for understanding and reaching remission, centred on distinguishing modifiable disease activity from irreversible remodelling and comorbidity-related factors that contribute to disease burden. We introduce the concept of at-risk asthma as a crucial phase characterised by high disease activity and immune dysregulation, in which timely intervention might prevent irreversible airway and extrapulmonary damage and support long-term disease modification. We examine how symptoms, lung function impairment, and exacerbations can arise from distinct and overlapping mechanisms, underscoring the need for careful attribution in clinical assessment. We also outline four key pathophysiological domains-airway hyper-responsiveness, immune hyper-responsiveness, immune remodelling, and structural remodelling-and describe their temporal evolution and implications for treatment responsiveness. Finally, we present a domain-based strategy for assessment and intervention, linking targeted therapies to underlying mechanisms. This approach supports more personalised treatment decisions and redefines remission, not simply as the absence of symptoms, but as stabilisation of disease biology. As the field advances towards earlier intervention and more tailored application of biologics in at-risk asthma, such a framework could be essential to improve long-term outcomes and prevent overtreatment of irreversible disease.

BACKGROUND:Lung quantitative computed tomography (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways, using radiomultiomics, integrating qCT, multiomics and machine learning/artificial intelligence. METHODS:We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterise radiomultiomic-associated clusters (RACs). RESULTS:qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated body mass index, mild airflow limitation, decreased CT lung volume and increased lung density and upregulation of the complement pathway. RAC2 (n=34) subjects had airway wall thickness and a mild degree of airflow limitation, with upregulation of proliferative pathways including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B, and downregulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signalling and signalling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. CONCLUSIONS:U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent a novel strategy to identify new molecular pathways in asthma pathobiology.

INTRODUCTION:There are no validated decision-making algorithms concerning severe asthma (SA) management. Future risks are crucial factors and can be derived from SA trajectories. AREAS COVERED:The future severe asthma-decision trees should revisit current knowledge and gaps. A focused literature search has been conducted. EXPERT OPINION:Asthma severity is currently defined a priori, thereby precluding a role for early interventions aiming to prevent outcomes such as exacerbations (systemic corticosteroids exposure) and lung function decline. Asthma 'at-risk' might represent the ultimate paradigm but merits longitudinal studies considering modern interventions. Real exacerbations, severe airway hyperresponsiveness, excessive T2-related biomarkers, noxious environments and patient behaviors, harms of OCS and high-doses inhaled corticosteroids (ICS), and low adherence-to-effectiveness ratios of ICS-containing inhalers are predictors of future risks. New tools such as imaging, genetic, and epigenetic signatures should be used. Logical and numerical artificial intelligence may be used to generate a consistent risk score. A pragmatic definition of response to treatments will allow development of a validated and applicable algorithm. Biologics have the best potential to minimize the risks, but cost remains an issue. We propose a simplified six-step algorithm for decision-making that is ultimately aiming to achieve asthma remission.

IntroductionDespite the new biologics to treat inflammation in severe asthma, targeting persistent obstruction of the airways remains challenging. Galectin-10 eosinophil derived crystals, also known as Charcot-Leyden crystals (CLCs) have been described to be present in the mucus plugs in the airways of patients with severe asthma. However, a direct role for CLCs in mucus production has not been established. We hypothesize that plugged airways constitute a unique niche where type 2 immune cells communicate with structural cells to perpetuate disease. We aimed to set up a new model using induced pluripotent stem cells (iPSCs).MethodsThree human iPSCs lines from type 2 severe asthma patients have been derived (MOSAIC study, University Hospital of Montpellier, NCT05616338) and differentiated into airway epithelium in air–liquid interface (i-ALI). The healthy iPSC line UHOMi002-A was used as a control. At day 21 of ALI culture, iPSC derived-airway epithelia were stimulated at the apical side with either IL-13 every two days (10ng/mL) during one week, acute stimulation (24h) with recombinant Gal10 crystals (100ng/mL), both IL-13 and Gal10 crystals or PBS (vehicle). We aimed to evaluate the effect on i-ALI differentiation at day 30.ResultsWe successfully differentiated the iPSC lines generated from the T2 severe asthma patients, and achieving a high purity rate at each developmental stages. The mean cell purity at the definitive endoderm for each cell line was>80% assessed by flow cytometry quantification of C-X-C Motif Chemokine Receptor 4 (CXCR4)/c-KIT double positive cells and immunolabelling of Forkhead Box A2 (FOXA2)+/SRY-box transcription factor 17 (SOX17)+. Purity for ventral anterior foregut endoderm (vAFE) stage was evaluated at 70%, through Transcription Factor NK2 Homeobox 1 (NKX2.1) expression, Carboxy Peptidase M (CPM) by flow cytometry. vAFE cells from the hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions. Chronic IL-13 challenging and CLC were both able to induce an increasing of MUC5AC+ cells and also an increase of neuroendocrine cells in asthmatic iPSC lines.ConclusioniALI bronchial epithelium can recapitulate T2 severe asthma features in vitro, and highlighted a possible direct effect of the CLC on the airway epithelium.