Severe asthma (SA) is a heterogeneous disease that remains uncontrolled despite optimized, high-dose inhaled therapy. It is also associated with substantial morbidity, corticosteroid exposure, and a significant healthcare burden. The advent of targeted biologic therapies has transformed SA management, making accurate biomarker-guided phenotyping essential. Fractional exhaled nitric oxide (FeNO), a noninvasive biomarker of IL-4/IL-13-driven airway inflammation, is widely used in asthma; however, interpreting its levels in SA is complex. This narrative review provides a biology-driven analysis of FeNO in SA, focusing on mechanistic foundations, interpretive limitations, and biologic-specific behavior. Chronic exposure to high-dose inhaled or systemic corticosteroids, overlap with reference ranges in healthy populations, and common SA comorbidities, such as obesity, chronic rhinosinusitis with nasal polyps, and bronchiectasis, can substantially modify FeNO levels. This limits the usefulness of fixed cutoffs. We summarize the available evidence on FeNO dynamics across biologic classes, highlighting the rapid and pronounced suppression observed with anti-IL-4Rα and anti-TSLP therapies. This is in contrast to the variable and often modest changes seen with anti-IL-5/IL-5R agents. We also review data linking baseline FeNO values and early FeNO trajectories to clinical outcomes and asthma remission. FeNO should be integrated with blood eosinophils, IgE, sputum cytology, and clinical features to guide biologic selection and longitudinal monitoring, rather tham being used in isolation. Key evidence gaps include the need for prospective FeNO-guided biologic trials, harmonized SA-specific FeNO thresholds, and integration with multi-omics approaches to fully realize the full potential of FeNO as a precision biomarker in SA.

Donor cell-derived haematological neoplasms (DDHN) are rare disorders and currently do not have standardised diagnostic criteria and therapeutic management. International experts in allogeneic transplantation and haematological malignancies from Europe, the Americas, and Australia worked together on behalf of the EBMT Practice Harmonisation and Guidelines Committee to delineate a pragmatic diagnostic framework and issue guidance for downstream clinical management for DDHN. The team met on Sept 18-19, 2025, in Berlin, Germany, to discuss the definition, molecular insights, treatments, and donor outcomes for DDHN after an intensive review of the literature. In this Review, we present the epidemiology and clinical definitions of DDHN, provide guidance on diagnosis and prevention, address therapeutic considerations, and outline recommendations for donor management.

Non-cystic fibrosis bronchiectasis is increasingly recognized as a major cause of chronic respiratory morbidity, particularly among older adults. Its rising prevalence is largely attributable to improved diagnostic imaging and heightened clinical awareness, with epidemiological data consistently demonstrating a marked age-related increase in disease burden. Older patients represent the majority of contemporary cases and exhibit a distinct clinical phenotype characterized by multimorbidity, frailty, and worse outcomes. Pathophysiologically, bronchiectasis is driven by a 'vicious vortex’ of airway inflammation, impaired mucociliary clearance, chronic infection, and structural lung damage. In older individuals, this process is amplified by immunosenescence, inflammaging, and age-related structural and functional lung changes, which together promote persistent infection and progressive airway injury. Additional contributors, such as microaspiration, cumulative environmental exposures, and coexisting conditions, including chronic obstructive pulmonary disease and gastroesophageal reflux disease, further exacerbate disease progression. Diagnosis in older adults with bronchiectasis is frequently delayed due to atypical presentations and clinical overlap with other chronic conditions, resulting in more advanced disease at the time of recognition. Microbiologically, older patients show a shift toward more virulent and resistant pathogens, particularly Pseudomonas aeruginosa and Enterobacteriaceae, with important implications for management. Prognosis is poorer in this population, with higher mortality, increased healthcare utilization, and reduced quality of life, largely driven by frailty and comorbidities rather than by disease severity alone. These findings highlight the need for a comprehensive, geriatric-informed approach integrating respiratory care with systematic assessment of functional status, comorbidities, and patient-centered outcomes to optimize management in older patients with bronchiectasis.

Severe eosinophilic asthma is driven by interleukin (IL)-5-mediated type 2 inflammation and frequently requires long-term biologic therapy. Depemokimab was designed to achieve sustained IL-5 neutralization with a twiceyearly dosing schedule, addressing key unmet needs related to treatment burden and adherence. This review summarizes the molecular design, preclinical pharmacology, model-informed drug development (MIDD) strategy, Phase I-III clinical trial program, and regulatory approvals of depemokimab in asthma and chronic rhinosinusitis with nasal polyps. Depemokimab exemplifies how rational antibody engineering, including Fc modification and high-affinity IL-5 binding, can enable sustained pharmacodynamic activity and ultra-longacting cytokine inhibition. A twice-yearly dosing regimen may offer advantages in terms of treatment adherence, patient convenience, and long-term disease control. The application of MIDD approaches facilitated efficient clinical development and supported the progression of pivotal trials, potentially shortening development timelines by approximately two to three years. Although efficacy and safety data are encouraging, longer-term real-world evidence will be necessary to better define immunogenicity, rare adverse events, and adherence patterns. Comparative effectiveness studies of depemokimab versus other approved anti-IL-5 therapies and type 2-targeted biologics will be critical to establish its relative clinical value. Further investigation into additional eosinophilic diseases, pediatric populations, and diverse healthcare settings may expand its therapeutic utility, positioning depemokimab as a representative example of next-generation long-acting biologics that target cytokine-mediated inflammatory diseases.

Comparison of SF3B1-mutated MDS with del(5q) to subclonal SF3B1-mutated MDS without del(5q). (A-F) No significant differences in baseline clinical demographics or SF3B1 VAF were observed between cases with vs. without del(5q). (G,H) Whilst survival was superior in patients with clonal SF3B1 mutations, no significant difference in leukemia-free or overall survival was identified between cases of SF3B1-mutated MDS with del(5q) vs. subclonal SF3B1-mutated MDS without del(5q), suggesting survival outcomes in such cases are influenced by alternative molecular driver events. Reported p-values utilized the cox model Wald test.

The U.S. Food and Drug Administration’s proposal to adopt a single randomized controlled trial (RCT) as the default evidentiary standard for drug approval marks a substantial change in regulatory philosophy. Although advances in mechanistic science, biomarkers, and statistical methods may justify this approach for conditions with significant, biologically coherent treatment effects, applying it to chronic obstructive pulmonary disease (COPD) raises substantial concerns. COPD is a heterogeneous, multifactorial syndrome with variable disease trajectories, modest treatment effects, and limited validated biomarkers. In this context, reliance on a single trial increases inferential fragility, risks type I error, and limits generalizability due to restrictive eligibility criteria and contextual variability. Although biomarker- and trait-based strategies are promising, they remain insufficiently validated to ensure robust estimation of treatment effects across populations. Similarly, the modest effect sizes and endpoint variability in COPD trials amplify the risk of false-positive or context-specific findings. Replication across independent studies primarily serves to test the consistency and robustness of observed effects under varying conditions, rather than to increase statistical power. We discuss a conceptual regulatory framework in which a single RCT may be acceptable only if it meets strict criteria, including large effect sizes, strong biological plausibility, a low risk of bias, and consistent subgroup effects. However, for highly heterogeneous conditions such as COPD, at least two independent studies remain preferable. Alternatively, if a single robust RCT is conducted, equivalent post-marketing validation is required. Ultimately, regulatory standards should be calibrated to biological and methodological uncertainty, balancing timely patient access with evidentiary reliability.

Cardiovascular disease (CVD) is a major comorbidity in asthma and chronic obstructive pulmonary disease (COPD), yet the contribution of artificial intelligence (AI) and machine learning (ML) to CVD risk assessment and management in these conditions remains insufficiently characterized. This scoping review identified the main original full-text studies applying AI/ML to the overlap between CVD and asthma or COPD for prediction, phenotyping or clinical decision support. Among the eleven identified studies, only one specifically addressed asthma, developing ML-based CVD risk prediction models from electronic health records that achieved good short-term discrimination but lacked external validation. The remaining studies focused on COPD and CVD, employing supervised learning, deep-learning survival analysis, natural language processing, unsupervised clustering and AI-enabled clinical decision support. Across these investigations, COPD and related comorbidities consistently emerged as strong predictors of CVD events, mortality and adverse clinical trajectories. Unsupervised clustering revealed COPD-dominant heart failure phenotypes with particularly poor outcomes, while AI-derived risk models frequently provided superior discrimination and calibration compared with traditional statistical approaches. However, most studies were retrospective, largely reliant on structured data, limited in generalizability and rarely implemented in routine care. Overall, current evidence indicates substantial potential for AI/ML to enhance CVD risk stratification, phenotyping and management in COPD, whereas applications in asthma are strikingly scarce. These findings underscore a critical need for large-scale, prospectively evaluated and clinically integrated AI/ML strategies to improve detection, risk stratification and personalized management of CVD in patients with asthma or COPD.

INTRODUCTION:Chronic airway diseases, such as asthma and COPD, are major contributors to global morbidity and the healthcare burden. Due to their heterogeneity and sensitivity to environmental factors, including air pollution, tobacco smoke, and occupational exposures, they are critical models for examining how the environment shapes disease biology and treatment response. AREAS COVERED:This expert narrative review integrates mechanistic, clinical, and epidemiological evidence on the impact of environmental exposures on the biology of airway disease and therapeutic outcomes. A structured literature search was performed, prioritizing mechanistic studies, large cohorts, randomized trials, and high-quality reviews relevant to asthma and COPD endotypes, phenotypes, and environment-adaptive therapies. The evidence indicates that environmental exposures modulate inflammatory pathways, oxidative stress, and drug responsiveness. These exposures often account for variability in clinical outcomes and apparent treatment resistance. EXPERT OPINION:Environmental exposures should be recognized as core biological modifiers that directly impact therapeutic efficacy, dosing requirements, and safety. Incorporating a systematic approach to environmental assessment into precision respiratory medicine allows for environment-adaptive therapies, optimizes pharmacological interventions, and reduces the risk of overtreatment. Future research and clinical protocols should integrate exposure metrics to personalize therapy, improve symptom control, and enhance long-term outcomes for patients with asthma and COPD.

Severe asthma is a heterogeneous disorder characterized by persistent symptoms, frequent exacerbations, and corticosteroid dependence despite optimized therapy. Seven monoclonal antibodies are currently approved, targeting immunoglobulin E (IgE; omalizumab), interleukin (IL)-5 or IL-5 receptor α (mepolizumab, reslizumab, depemokimab, benralizumab), IL-4 receptor α (dupilumab), and the epithelial alarmin thymic stromal lymphopoietin (TSLP; tezepelumab). These therapies have demonstrated substantial reductions in exacerbation rates and oral corticosteroid use, along with improvements in lung function and patient-reported outcomes. Safety profiles are generally favorable across populations. Key predictors of response include blood eosinophil counts, fractional exhaled nitric oxide, and phenotype-specific biomarkers. Despite these advances, unmet needs remain. Current biologics only partially address type 2-low, neutrophilic, and mixed granulocytic phenotypes, as well as airway remodeling and persistent exacerbations in type 2-high patients. Emerging strategies aim to overcome these limitations by targeting upstream alarmins (TSLP and IL-33), dual or trispecific cytokine pathways, and IgE-producing B cells. Novel Fc-engineered and dual-receptor anti-IgE monoclonal antibodies enhance the magnitude and durability of IgE suppression. Multi-target constructs, including bispecific and trispecific agents, simultaneously block overlapping type 2 and non-type 2 pathways, which could improve outcomes in heterogeneous and refractory populations. Preclinical and early-phase clinical studies suggest that these approaches may provide disease-modifying effects and support biomarker-guided personalized therapy. This review summarizes the current landscape of approved biologics and the rationale for next-generation therapies in severe asthma. It highlights mechanistic insights, clinical efficacy, and future directions for precision-targeted treatment strategies.

The 2026 report from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) introduces substantial conceptual and practical updates to the management of chronic obstructive pulmonary disease. While maintaining the established spirometric definition, the report emphasizes early diagnosis, multi-dimensional assessment, and personalized treatment strategies that move beyond a spirometry-centric approach. Key innovations include formally recognizing disease activity as a therapeutic target, refining the ABE classification with a lower threshold for patients prone to exacerbations (Group E), and integrating blood eosinophil counts to guide inhaled corticosteroid therapy. Nonpharmacologic interventions, such as pulmonary rehabilitation, vaccination, smoking cessation, structured self-management, and post-exacerbation care, are elevated to core disease-modifying strategies. Pharmacological escalation is structured around dual bronchodilation as the preferred initial step, with further intensification to biomarker-guided triple therapy, including inhaled corticosteroids or other anti-inflammatory agents, reserved for selected patients who remain symptomatic or experience exacerbations despite optimized dual therapy. GOLD 2026 also introduces biologics, dupilumab and mepolizumab, as an add-on therapy for exacerbation-prone eosinophilic chronic obstructive pulmonary disease. However, it also highlights ongoing limitations in efficacy, cost effectiveness, and generalizability. Artificial intelligence and emerging digital technologies are recognized as promising adjuncts in the management of chronic obstructive pulmonary disease, though their clinical implementation remains preliminary. Overall, GOLD 2026 advances precision medicine in chronic obstructive pulmonary disease by combining structured individualized assessments with early targeted interventions. However, significant uncertainties remain, including biological variability of biomarkers, limited evidence for emerging therapies, and barriers to equitable access to nonpharmacologic and advanced interventions. Careful context-sensitive application and continued validation are essential.

Purpose: Pulmonary hypertension (PH) is a serious complication of COPD associated with worse outcomes. Reliable circulating biomarkers of pulmonary vascular involvement are lacking. Angiopoietin-1 (ANGP-1) and angiopoietin-2 (ANGP-2) regulate endothelial homeostasis, but their relationship with echocardiographically estimated pulmonary pressure in COPD remains uncertain. Methods: This prospective cross-sectional study included 70 consecutively recruited adults with COPD, stratified using a study-specific echocardiographic threshold into the COPD PH group (mPAP > 20 mmHg; n = 46) and the COPD without PH (mPAP < 20 mmHg; n = 24), together with 20 additional controls. This non-invasive stratification was not considered equivalent to PH confirmed by right heart catheterization. Serum ANGP-1 and ANGP-2 were measured using ELISA. Group differences and associations with e-mPAP and right atrial pressure (RAP) were assessed. Results: Median ANGP-1 was higher in the elevated e-mPAP group [8780.06 (IQR 7955.29-9902.88) pg/mL] than in the lower e-mPAP group [3065.14 (1170.69-6200.41)] and controls [2997.19 (1292.13-3278.18); p < 0.001]. ANGP-2 showed a similar pattern [6152.92 (5380.27-8652.50), 2669.77 (1802.18-4744.00), and 2405.54 (1779.73-3751.76) pg/mL; p < 0.001]. Among COPD participants, ANGP-1 and ANGP-2 correlated with e-mPAP (r = 0.64 and r = 0.54) and RAP (r = 0.54 and r = 0.52; all Holm-adjusted p < 0.001). In multivariable models, e-mPAP and RAP were independently associated with ANGP-1, whereas RAP was independently associated with ANGP-2. Conclusions: Higher circulating ANGP-1 and ANGP-2 were associated with an elevated echo-estimated pulmonary-pressure phenotype in COPD. These findings are exploratory and require validation in larger cohorts using direct hemodynamic assessment.

WHO 2016 classification of included patients with mutated SF3B1

Molecular characteristics of SF3B1-mutated MDS. (A) Mixed violin/boxplot depicting the VAF of SF3B1 in patients with clonal vs. subclonal SF3B1 mutations. Box and whisker plot demonstrates median (solid bar), interquartile range, minimum, and maximum VAF values. (B) The number of cases based on the count of co-occurring mutations between SF3B1low vs. SF3B1high MDS. (C) Distribution of identified amino acid variants within the SF3B1 protein. Variant frequency is represented as Log2 values. Location of variants displayed within HEAT domains, conserved regions (1–20) of tandem repeats within the SF3B1 protein. Canonical MDS mutations are commonly associated with domains 4 to 7 (yellow highlight). (D) Barplot depicting clonality of SF3B1low vs. SF3B1high MDS cases. (E) Barplot depicting differences in canonical and non-canonical variants between SF3B1low vs. SF3B1high MDS. (F) Alternative SF3B1 variants identified in SF3B1low vs. SF3B1high MDS. VAF: variant allele frequency. Asterisk indicates Fisher’s exact p-value <0.05.

WHO 2016 classification of included patients with NPM1-mutated myeloid neoplasms (MN)

Chronic airway diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis, are increasingly recognized as heterogeneous disorders characterized by overlapping pathophysiological mechanisms. Among these, abnormalities in mucus production, composition, and clearance have been identified as clinically significant contributors to symptoms, airflow limitation, exacerbations, and disease progression. Within the "treatable traits" framework, mucus-related abnormalities represent a distinct, modifiable phenotype that supports personalized management strategies. This narrative review explores mucus as a treatable trait across chronic airways diseases, integrating mechanistic insights with clinical assessment, biomarkers, and current and emerging therapeutic approaches. We discuss the role of mucus in disease phenotyping, its impact on morbidity, and the potential of targeted interventions to improve outcomes. Recognizing mucus as a treatable trait aligns with the principles of precision medicine and offers a pathway toward individualized therapy beyond traditional diagnostic labels.

Comparison of SF3B1-mutated MDS groups with SF3B1a and SF3B1b subgroups. (A) Patients with SF3B1low and subclonal SF3B1 mutations were more frequently assigned to the SF3B1b subgroup (defined as having a co-occurring mutation in any gene including BCOR, BCORL1, NRAS, RUNX1, SRSF2, or STAG2) compared to patients with SF3B1high or clonal SF3B1 mutations, who were more frequently assigned to the SF3B1a group (defined as having any other co-mutation with SF3B1). (B,C) Leukemia-free and overall survival was shorter in patients with SF3B1b vs. SF3B1a mutations. (D) When comparing groups stratified based on SF3B1 VAF, significant survival differences were observed (E). Multivariable analysis demonstrating differences in outcomes based on SF3B1a and SF3B1b designation, clinical parameters, and SF3B1 VAF. Reported p-values utilized the cox model Wald test.

This review describes the eosinophil journey through the various physiological and pathophysiological phases, from production, maturation, and activation by chemokines and cytokines [especially eotaxin, interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF)], to interaction with the innate and adaptive immune system and tissue homing. Excessive production and activation of eosinophils lead to the release of granule proteins, such as major basic protein, eosinophil cationic protein, eosinophil peroxidase, and others, resulting in inflammation, cell cytotoxicity, and oxidative stress. The pathogenesis, clinical features, diagnostic processes, and the latest therapeutic approaches to the resulting diseases—which affect the upper and lower airways, gastrointestinal tract, skin, myocardium, and may occur systemically—are discussed.

Density plot depicting Bradley-Terry modeling of the estimated order of mutation acquisition in AML samples from the UKNCRI and AMLSG cohorts. Mutations in genes classified as MR mutations (SRSF2, ASXL1, RUNX1, U2AF1, ZRSR2, EZH2, STAG2, BCOR, SF3B1) tended to occur as earlier events relative to mutations in NPM1. VAF: Variant allele frequency