Systemic glucocorticoid therapy for acute lung injury (ALI) is frequently limited by poor pulmonary targeting and severe systemic side effects. To address these challenges, we developed a bio-inspired, inhalable nanoplatform using naturally derived nanovesicles from the medicinal plant Polygonum cuspidatum (PcDNs) to actively deliver dexamethasone (PcDNs@Dex) via nebulization.

We assessed the post-nebulization stability of the nanosystem and evaluated its therapeutic efficacy in vitro and in vivo. In vitro, we investigated macrophage polarization (M1/M2) and the associated signaling pathways. Untargeted metabolomics was employed to analyze metabolic reprogramming. In vivo, a murine lipopolysaccharide (LPS)-induced ALI model was utilized to assess pulmonary targeting, alveolar damage, vascular permeability, and cytokine production.

Unlike conventional inert synthetic carriers, PcDNs function as intrinsic synergistic therapeutics. PcDNs@Dex maintained robust structural and functional stability post-nebulization, ensuring efficient targeted pulmonary delivery. In vitro, PcDNs@Dex exerted superior anti-inflammatory and cytoprotective effects by actively reprogramming macrophages from a pro-inflammatory M1 to a pro-resolving M2 phenotype, synergistically mediated through the coordinated inhibition of NF-κB and JAK-STAT signaling pathways. Crucially, untargeted metabolomics unveiled a novel immunometabolic mechanism: PcDNs inherently act as bioactive modulators that restore glycerophospholipid metabolic homeostasis, thereby stabilizing cell membranes and restricting pro-inflammatory mediator production at the metabolic level. In an LPS-induced ALI model, nebulized PcDNs@Dex precisely targeted the pulmonary niche, significantly attenuating alveolar damage, reducing vascular permeability, and suppressing the local cytokine storm.

This dual intervention effectively promoted a reparative immune microenvironment while exhibiting excellent systemic safety. These results establish PcDNs@Dex as a promising, multi-target strategy that integrates targeted delivery with synergistic bioactivity for managing inflammatory lung diseases.

Asthma is a common chronic respiratory disease that imposes a heavy burden of morbidity and mortality in most countries. Eosinophils have become major therapeutic targets for severe eosinophilic asthma and other eosinophil-associated diseases. This study investigated the role of eosinophils in asthma through three complementary approaches: (i) Mendelian randomization to test causal associations, (ii) single-cell transcriptomic analysis to explore potential biological mechanisms underlying elevated blood eosinophil counts, and (iii) clinical data analysis and machine learning modelling to evaluate their predictive value in clinical practice. These analyses demonstrated the potential value of eosinophils in clinical applications.

We conducted three complementary but methodologically independent analyses in adult asthma patients. First, a two-sample Mendelian randomization analysis using publicly available GWAS summary statistics was performed to assess whether genetically predicted eosinophil count and eosinophil percentage are causally associated with asthma susceptibility. Second, a publicly available peripheral blood mononuclear cell scRNA-seq dataset (GSE248688), which contrasts asthma patients with healthy controls, was used to characterize transcriptomic differences and intercellular communication in the potential biological mechanisms for increased blood eosinophil counts in adult asthma. Third, using retrospectively collected data from two adult asthma cohorts (SWMU, n = 370, training/internal validation; Chongqing, n = 180, external validation), we developed and externally validated machine learning models for 12-month exacerbation risk. All predictors were measured at a clinically stable baseline visit preceding the 12-month outcome window.

The Mendelian randomization analysis provided genetic evidence that eosinophil count is causally associated with asthma susceptibility (IVW: OR 1.005, 95% CI 1.002-1.008, P < 0.001), whereas the signal for eosinophil percentage was small and borderline (IVW: OR 0.984, 95% CI 0.970-0.998, P = 0.027) and directionally inconsistent with the clinical data, most plausibly reflecting the compositional nature of a percentage measurement. Overall, eotaxins and type 2 inflammation provide a plausible explanation for increased blood eosinophil counts in asthma patients. Further analysis revealed that the platelet subcluster in the asthma group highly expressed CCL26 (eotaxin-3). Upregulated transcriptional activity of GATA3 and MAF was observed in CD14⁺ monocytes. Cell-cell communication analysis indicated network remodeling. Specifically, three cell types-CD14⁺ monocytes, platelets, and hematopoietic stem and progenitor cells (HSPCs)-simultaneously showed upregulated sender activity for MIF signaling. The five machine learning models achieved external-cohort AUCs ranging from 0.718 to 0.769 (RF 0.763, XGBoost 0.769, LR 0.755, SVM-RBF 0.905, KNN 0.733), with substantially overlapping 95% CIs; a parsimonious three-variable benchmark model achieved a comparable AUC of 0.892.

Peripheral blood eosinophils may play an important role in asthma. They are especially promising as potential clinical predictors of asthma exacerbation. However, the mechanisms underlying their increase are complex. We speculate that three pathways may be involved: bone marrow release, peripheral survival, and peripheral activation. Therefore, both the clinical utility and the specific biological mechanisms of peripheral blood eosinophils still require further validation.

This study aimed to determine frailty prevalence among patients aged ≥65 diagnosed with Chronic Obstructive Pulmonary Disease (COPD) and investigate its relationship with disease severity, hospitalization rates, and acute exacerbation frequency.

This cross-sectional study evaluated 112 elderly patients with COPD. Patient records, pulmonary function tests, Modified Medical Research Council (mMRC) dyspnea scores, COPD Assessment Test (CAT) scores, and the previous year's exacerbations and hospitalizations were analyzed. Frailty was assessed using the FRAIL scale.

Frailty prevalence was 49.1% (55/112). A significant negative correlation was found between FRAIL and FEV1% values (r _s : -0.695, 95% CI: -0.782 to -0.581, p <0.001). Conversely, FRAIL scores correlated positively with CAT (r _s : 0.840, 95% CI: 0.773 to 0.888, p <0.001) and mMRC values (r _s : 0.733, 95% CI: 0.631 to 0.811, p <0.001). Significant differences in CAT, mMRC, and FEV1% were observed between high and low frailty groups. COPD exacerbations and hospitalizations were significantly higher in patients with higher FRAIL scores (p <0.001).

The FRAIL scale is strongly associated with higher rates of exacerbations and hospitalizations in elderly COPD patients, reflecting increased disease severity and poorer clinical outcomes.

Chronic pulmonary infections caused by multidrug-resistant (MDR) bacteria are a growing global health problem, and the declining effectiveness of conventional antibiotics increases the need for alternative antimicrobial strategies. Unlike broad-spectrum antibiotics, bacteriophages are highly specific, and their use therefore offers not only antibacterial activity but also the possibility of reshaping the airway microbial ecosystem in a targeted manner. In this review, we reframe phage therapy as a precision microbiome-modulating strategy for chronic pulmonary infections. We first review precision pathogen identification and phage-host matching, then discuss formulation engineering for pulmonary delivery, and then examine the interactions between phages and host immune barriers. We further analyze how phage therapy may selectively deplete MDR pathogens while sparing the commensal microbiota and how it may remodel the airway microbial ecosystem, and we critically evaluate the clinical evidence, distinguishing preclinical data, case-based evidence, observational studies, and controlled trials. By integrating these dimensions, we identify the main scientific and technical challenges and evidence gaps that currently limit clinical implementation, and we discuss strategies that could support the development of safe, effective, and clinically applicable phage-based therapies for chronic pulmonary infections.

Patients with inflammatory rheumatic diseases (IRDs) may be at increased risk for adverse COVID-19 outcomes because of immune dysregulation, comorbidities, and immunomodulatory treatments. However, the effects of specific rheumatic disease subsets, treatment patterns, and vaccine types remain incompletely understood.

To evaluate clinical characteristics and factors associated with COVID-19 infection and hospitalization among patients with IRDs.

This retrospective observational cohort study included 1,024 adult patients with IRDs followed between March 2020 and January 2023. Demographic characteristics, rheumatic disease subtypes, treatments, vaccination status, COVID-19 infection, hospitalization, radiologic findings, and recovery duration were analyzed.

Among all patients, 347 (33.9%) developed COVID-19 infection. Patients with COVID-19 were younger than those without COVID-19 (49.1 ± 13.4 vs. 51.5 ± 14.5 years, p = 0.007). Vaccination before infection was significantly more frequent in the COVID-19-negative group (92.3% vs. 23.9%, p < 0.001). Spondyloarthritis frequency was higher among COVID-19-positive patients (25.9% vs. 20.1%, p = 0.030), whereas methotrexate use was lower (14.4% vs. 22.6%, p = 0.002). Among COVID-19-positive patients, 40 (11.5%) required hospitalization. Hospitalized patients were older, had more frequent lung disease, longer rheumatic disease duration, increased radiologic involvement, and prolonged recovery duration (all p < 0.05). In univariate analyses, FMF, colchicine use, and BNT162b2 vaccination were associated with lower hospitalization rates; however, these associations were not retained after multivariable adjustment.

Older age, pulmonary comorbidity, longer disease duration, and radiologic involvement were associated with COVID-19-related hospitalization in IRDs. In contrast, FMF, colchicine use, and BNT162b2 vaccination were associated with lower hospitalization rates.

The detection of Aspergillus in the lower respiratory tract complicates the clinical course of viral pneumonia and is linked to poor outcomes, but prior evidence is confined to the intensive care unit (ICU) or single-virus settings (e.g., influenza or SARS-CoV-2). Whether its frequency and prognostic significance differ across viral etiologies in hospitalized adults remains unknown.

This multicenter retrospective cohort study included adults with community-acquired viral pneumonia at seven tertiary hospitals in China (2017-2025). Patients were categorized into SARS-CoV-2, influenza, or other viral groups. The exposure was lower respiratory tract Aspergillus detection (via using culture, real-time PCR, or metagenomic next-generation sequencing). The primary outcome was in-hospital all-cause mortality.

Among 929 patients, Aspergillus was detected in 175 (18.8%). The detection rates differed significantly across viral etiologies (33.2% in patients with influenza, 14.6% in those with SARS-CoV-2, and 7.4% in those with other viruses; P < 0.001). In the fully adjusted model, Aspergillus detection was independently associated with increased overall mortality (aOR = 2.99; 95% CI 1.60-5.58; P < 0.001), but the association varied markedly by viral etiology. Virus-stratified analyses revealed that in influenza, Aspergillus detection remained independently associated with mortality after multivariable adjustment, and the association was consistently observed across prespecified subgroups, including non-ventilated patients, whereas in SARS-CoV-2, the association was largely confined to ventilated patients.

Lower respiratory tract Aspergillus detection differed substantially by viral etiology and was most frequent in patients with influenza pneumonia. It was independently associated with increased mortality across all influenza subgroups, including non-ventilated patients, whereas in SARS-CoV-2 pneumonia this association was largely confined to mechanical ventilation patients. These findings support a virus-stratified approach to fungal surveillance and warrant prospective validation.

Acute mountain sickness (AMS) poses formidable challenges for individuals venturing into high-altitude (HA) environments. Early and precise prediction of AMS is crucial for the timely identification of high-risk individuals and the development of effective treatment strategies. We sought to develop and validate an interpretable Acute Mountain Sickness Four-Task Ensemble (AMS-FTE) model for predicting AMS occurrence and severity according to the old and new LLS definitions.

This study enrolled 330 healthy subjects who underwent rapid exposure to HA. Questionnaire surveys utilizing the Lake Louise Score for AMS were administered upon arrival. Five machine learning (ML) algorithms were evaluated independently for each prediction task, after which RF, AdaBoost, and LightGBM were combined to construct the AMS-FTE framework. To enhance interpretability, the SHapley Additive exPlanation method illuminated feature importance. The area under the receiver operating characteristic curve and decision curve analysis were evaluated to calculate predictive power and assess the model's clinical applicability.

Following algorithm comparison, AMS-FTE model was constructed to provide unified predictions for the four AMS-related tasks. Based on feature importance rankings, interpretable final model was developed for each task using the top 5 contributing features, which were associated with baseline cardiopulmonary fitness (post-exercise heart rate, post-exercise SpO₂, AT-RCP time, peak VO₂, and ΔVO₂ AT-RCP). This model demonstrated robust predictive accuracy for AMS, and showed significant clinical net benefit probability ranges, demonstrating strong clinical applicability.

The predictive value of baseline cardiorespiratory fitness parameters proved valuable in distinguishing AMS and non-AMS subjects, as revealed through an interpretable ML model and a support system. This will enable earlier diagnosis for AMS, and more targeted interventions for acute altitude illness.

The treatable traits approach involves the identification of traits that are measurable and clinically relevant to the patient, which informs an individualized management plan. While improved quality of life and health outcomes have been demonstrated, the acceptability of this approach to people with bronchiectasis has not been explored. The aim of our study was to explore the acceptability of the treatable traits approach to people with bronchiectasis in a regional setting.

An exploratory qualitative study. Interviews were conducted with adults who first attended an outpatient bronchiectasis clinic in regional Australia, which had implemented the treatable traits approach. The interview guide was developed to explore the seven components of the theoretical framework of acceptability. Engagement with the transcripts occurred using the six phases of thematic analysis to develop key themes.

Ten participants were included (age 37-82 years; female sex, 70%; Bronchiectasis Severity Index, mild, 20%; moderate, 50%; and severe, 30%). This study reports three themes. 'A tool kit to support my health' explores the contribution of individualized and multifaceted interventions to a perceived improvement in respiratory health. 'Better health, better self' captures the patient-reported impact of improved respiratory health on quality of life. 'Some things don't change' describes the ongoing challenges for people living with bronchiectasis that are not impacted by the clinic interventions.

People with bronchiectasis from a single regional Australian clinic described a highly valued and acceptable clinic experience, with perceived improvements in respiratory health and overall well-being despite significant ongoing impacts on daily life.

This study was registered in the Australian and New Zealand Clinical Trials Registry (https://www.anzctr.org.au/, ACTRN12620000377932).

Dupilumab reduced exacerbations in patients with COPD and type 2 inflammation in clinical trials; however, multicenter real-world data remain limited.

We performed a multicenter analysis of patients with COPD treated with dupilumab across centers in Germany. Patients with comorbid asthma were included to compare outcomes between COPD-only patients and those with comorbid asthma, as well as between patients with and without chronic bronchitis (CB). The primary endpoint was change in the annualized rate of moderate-to-severe exacerbations. Changes in lung function and CAT score were also assessed.

A total of 99 patients were included (60% male, mean age 66 years, FEV₁ 37% predicted, DLCO 41% predicted, 45% comorbid asthma, 58% CB, 7% current smokers). Over a median follow-up of 11 months [IQR 8-14], dupilumab reduced the annualized moderate-to-severe exacerbation rate from 3.52 (95% CI 2.94-4.09) at baseline to 1.04 (95% CI 0.71-1.37) during follow-up, corresponding to a 70% reduction. Reductions in exacerbation rates were consistent irrespective of exacerbation severity, comorbid asthma, CB, or emphysema severity. CAT improved by a mean of 4.5 points. FEV₁ improved by 50 mL (p = 0.077), while greater improvements were observed for residual volume (- 150 mL; p = 0.071) and total airway resistance (- 12.6%; p < 0.001). Eight patients were non-responders and had no reduction in exacerbation under treatment.

In this real-world multicenter cohort, dupilumab effectively reduced exacerbation burden in patients with COPD and type 2 inflammation. Exploratory subgroup analyses suggested consistent treatment effects across different clinical phenotypes, although these findings require confirmation in larger studies. The high baseline exacerbation burden may partly explain the marked treatment response.

The optimal management of enteral nutrition before tracheostomy in mechanically ventilated patients in the intensive care unit (ICU) remains uncertain, and pre-procedural fasting is widely practiced in clinical settings to reduce the risk of aspiration. However, interruption of enteral nutrition (EN) may adversely affect metabolic stability and caloric intake in critically ill patients. This study aimed to prospectively evaluate whether continuation of EN before tracheostomy increases aspiration risk or influences clinical outcomes in mechanically ventilated ICU patients.

This prospective observational study was conducted in the anesthesiology and resuscitation intensive care units of a tertiary care center. Adult mechanically ventilated patients scheduled for elective percutaneous tracheostomy were included. Patients were divided into two groups according to the enteral nutrition strategy applied before the procedure: the continuous feeding group and the fasting group. The primary endpoint was the incidence of aspiration pneumonia within 72 h after tracheostomy. Secondary endpoints included respiratory parameters, arterial blood gas measurements, delta (Δ) changes in physiological variables, procedure-related complications, and ICU and hospital outcomes.

A total of 110 patients were assessed for eligibility, and 91 patients were included in the final analysis (continuous feeding group n = 45; fasting group n = 46). Baseline demographic characteristics, disease severity scores, and pre-tracheostomy respiratory parameters were comparable between groups. The incidence of aspiration pneumonia was 6.7% in the continuous feeding group and 4.4% in the fasting group, corresponding to an absolute risk difference of 2.3% (95% CI, - 6.6 to 11.2) and a crude odds ratio of 1.57 (95% CI, 0.25-9.88). Post-tracheostomy FiO₂ requirements were higher in the fasting group (p = 0.005), while other respiratory and arterial blood gas parameters were similar. Delta analyses showed greater increases in PaO₂ and more stable lactate levels in the continuous feeding group (p = 0.024 and p = 0.033). ICU and hospital length of stay, complication rates, and mortality were comparable.

Continuation of EN before tracheostomy with passive nasogastric drainage was not associated with a statistically significant increase in aspiration pneumonia or adverse outcomes compared with conventional fasting. However, the small number of events and wide confidence intervals indicate that clinically relevant differences cannot be excluded. Larger, adequately powered studies are needed to confirm safety and clarify the clinical implications of pre-tracheostomy feeding strategies.

ClinicalTrials.gov, NCT07508293. Registered on March 21, 2026, retrospectively registered.