Mechanistic study of inspiratory training in childhood Asthma: Rationale and methods of a pediatric clinical trial.

Gender-specific association between household cooking oil fumes exposure and small airway dysfunction in China: a national cross-sectional study.

Automated quantification of ciliary beat frequency and area as functional endpoints in ALI-differentiated human airway epithelial models.

Enhanced MSC spheroid adhesion on 3D-printed leaf-stacked scaffolds for functional tracheal regeneration.

Innate defenses of the respiratory epithelium are the first barrier against incoming respiratory viruses. To understand the contribution of both basal (tonic) and induced interferon (IFN) to antiviral defenses in a physiologically relevant system, we established air-liquid interface (ALI) cultures of primary human bronchial epithelium (HBE) and small airway epithelium (HSE). Via an organoid intermediate stage, the limited healthy donor material was expanded while preserving stemness, and subsequently differentiated. Characterization by immunofluorescent profiling and transcriptomic analyses showed that the cellular diversity and architecture of our ALI cultures were comparable to native human lung epithelium. Infection with human rhinovirus (HRV16) induced a strong and early IFN response, whereas human coronavirus (HCoV-229E and HCoV-NL63) infection caused a more subdued and delayed response. HRV16, but not HCoV-229E, infection was eventually cleared from the cultures after more than 30 days. Depletion of tonic or early type I/III IFNs using neutralizing antibodies or scavengers increased infectious HRV production by ~10- or ~1,000-fold, respectively, suggesting a role of IFNs in clearance. Taken together, we present a method for generating primary lung epithelial air-liquid interface cultures that retain effective IFN responses, demonstrate clearance of HRV by innate defenses, and highlight the importance of tonic and early IFN.IMPORTANCEMild respiratory viral infections, for example, with human common cold coronaviruses or rhinoviruses, are a massive cause of human morbidity. The respiratory tract is the primary entry route for these viruses and also the contact site for initial innate immune defenses. Here, we show that primary human lung epithelial cell-derived air-liquid interface cultures mimic the architecture and cell composition of native human lung epithelium, and retain both induced and tonic interferon (IFN) responses. Notably, our data show that the model's innate immune defense, characterized by rapid and robust IFN responses, are sufficient to clear human rhinovirus (HRV) infections but not human coronavirus 229E. Finally, depletion of induced or tonic IFNs led to a marked increase in HRV infection. Thus, our data suggest that tonic low levels of IFNs contribute to the epithelial defense against viruses, maintaining the tissue's immune readiness.

Corticosteroid treatment has no effect in patients without sputum eosinophilia. Sputum neutrophils and lymphocytes contribute to chronic cough hypersensitivity. The characteristics of chronic cough patients without sputum eosinophilia have not been investigated. This study included a total of 1061 patients at the First Affiliated Hospital of Guangzhou Medical University between July 2021 and June 2024 (Approval number: ES-2024-K117-02). We analyzed clinical characteristics, sputum cell profiles, spirometry, and pulmonary lesions across four groups: chronic cough patients with normal sputum (n = 180), lymphocytotic sputum (n = 270), neutrophilic sputum (n = 349), and mixed leukocytotic sputum (n = 262). Gastroesophageal reflux cough was the most prevalent disease in chronic cough patients with normal sputum. Atopic cough was more common in patients with lymphocytotic sputum. COPD and bronchiectasis were more prevalent in both neutrophilic and leukocytotic sputum groups. Advanced age was a characteristic of patients with neutrophilic or leukocytotic sputum. Patients with neutrophilic sputum had a higher prevalence of smoking history and a longer smoking duration. Pulmonary lesions were less severe in patients with lymphocytotic sputum but more severe in those with neutrophilic or leukocytotic sputum. Compared to patients with normal sputum, both neutrophilic and leukocytotic sputum groups exhibited marked reductions in overall lung function (FVC% of predicted, FEV1% of predicted, FEV1/FVC% of predicted, and PEF% of predicted) and small airway function (MMEF% of predicted, FEF75% of predicted, and FEF50% of predicted). Associations were observed among age, smoking history, sputum neutrophil percentages, pulmonary lesions, and declined lung functions. Elevated sputum neutrophils were independently associated with reduced lung function across multiple parameters (FVC% of predicted, FEV1/FVC% predicted, FEV1/VCmax% predicted, PEF% predicted, MMEF% of predicted, and FEF50% of predicted), despite robust adjustment for age and the presence of COPD, bronchiectasis, and interstitial lung disease. Advanced age and smoking history are risk factors for elevated sputum neutrophils in chronic cough patients. Neutrophil-mediated airway inflammation is associated with pulmonary lesions and declined lung functions in chronic cough patients.

Lophomonas blattarum (L. blattarum) is an emerging protozoan increasingly reported in respiratory specimens. This study aimed to characterize the clinical and radiological features of adult patients with L. blattarum detected in bronchial lavage samples. This retrospective observational study included adult patients diagnosed at a tertiary care center between January 1, 2024 and January 1, 2026. Demographic data, comorbidities, clinical presentation, laboratory findings, radiological features, treatment approaches, and outcomes were analyzed descriptively. Fifty-one patients were included (mean age 59.0 ± 14.8 years; 51.0% male). Symptoms were predominantly chronic, with 73.3% reporting duration > 8 weeks. The most common symptoms were cough (73.3%), sputum (46.7%), and dyspnea (45.7%); fever was uncommon (6.5%). Frequent comorbidities included diabetes mellitus (31.9%), hypertension (29.8%), cardiovascular disease (23.4%), prior tuberculosis (25.0%), malignancy (26.0%), and immunosuppression (21.3%). More than half were never-smokers (52.2%). The mean leukocyte count was 9.02 ± 3.39 × 10⁹/L, and the median C-reactive protein level was 12.70mg/L (IQR: 3.38-42.88). Chest CT findings were heterogeneous. Nodules were most frequent (38.3%), followed by ground-glass opacities (29.8%) and small airway signs (27.7%). Consolidation was observed in 16.3% and mediastinal or hilar lymphadenopathy was present in 48.9%. Metronidazole was administered to 54.9% of patients; radiological improvement was observed in 21.7%. Microscopy-based detection of L. blattarum-like organisms in bronchial lavage was mainly observed in patients with chronic respiratory symptoms, heterogeneous and non-specific CT findings, and substantial comorbidity burden. Further prospective controlled studies with molecular confirmation are needed to clarify its clinical significance.

Small airway dysfunction is an early and clinically important feature of many respiratory diseases but remains difficult to detect using conventional physiological tests. Multiple-breath washout (MBW) is widely used to assess ventilation heterogeneity; however, its sensitivity to the specific location and severity of airway narrowing is not fully understood. Nitrogen MBW was simulated using a physiologically realistic computational airway model reconstructed from high-resolution chest CT imaging. Sixty-four airway constriction scenarios were examined, varying systematically by airway generation, constriction ratio, and constricted branch ratio. Standard MBW indices (LCI, Sacin, and Scond) were evaluated alongside a novel intrapulmonary reverse flow (RF) metric. Sensitivity to airway structural changes was assessed using Spearman's rank correlation and multiple linear regression analyses. MBW indices were predominantly sensitive to severe proximal constriction (Gen 5-9, ≥ 75% severity) with minimal changes observed in distal scenarios. RF showed strong correlations with all MBW indices, particularly Sacin (ρ = 0.93, p < 0.0001), and consistently increased with constriction at any given airway location. Notably, while Sacin has long been regarded as a marker of peripheral convective-diffusive heterogeneity at the acinar level, our findings demonstrate that convective heterogeneities arising from more proximal airway constrictions generate significant RF, which in turn influences the Sacin signal. In multivariable regression, RF emerged as the most sensitive marker of ventilation heterogeneity arising from airway structural alterations, explaining the greatest proportion of variance (Adj. R2 = 0.933, p < 0.001), exceeding that of Sacin (0.826), LCI (0.732), and Scond (0.564). In simulations, RF was sensitive to ventilation abnormalities arising from mild and distal airway narrowing. As a physiologically interpretable, flow-based marker, RF offers a novel and complementary means of enhancing the sensitivity of MBW for the early detection and motivates further experimental and clinical validation. Importantly, by identifying RF as a convective link between central airway narrowing and peripheral washout behaviour, our study suggests that Sacin reflects a broader spectrum of ventilation disturbances than previously assumed, providing a new mechanistic basis for interpreting MBW indices.

Abstract Rationale Small airway disease is a hallmark of COPD and recent work has defined distinct small airway lesions, that emerge with disease progression, and include “web”, “occlusion”, and “collapse” (Geudens et al., AJRCCM, 2025). However, despite a growing appreciation of the structural heterogeneity of small airway disease, the cellular microenvironments and underlying biology that drive these lesions is unknown. Objective To define the cellular pathology underlying structurally distinct small airway lesions in COPD. Methods We performed an integrated radiological and molecular analysis combining microCT, spatial transcriptomics, and single-nuclear RNA sequencing (snRNA-seq) on inflated and frozen lung tissue cylinders from nine human lungs: three control donor lungs without emphysema, three lungs with emphysema (5-20% based on radiologist assessment), and three COPD GOLD IV explants. A 10-µm-resolution microCT scan was used to map distinct small-airway lesions, after which individual lesions were sectioned, allowing precise isolation of both diseased and normal small airways. Airways were profiled using Xenium spatial transcriptomics with a 480-gene custom panel; data underwent quality control and were analyzed with Seurat v5.1. Results MicroCT identified 45 individual small airways: normal (n = 14), web (n = 9), occlusion (n = 4), and collapse (n = 18) lesions. Small airways were confirmed histopathologically and registered to spatial transcriptomic maps (28.071.607 transcripts and 659.051 cells) (Fig. 1a-c). Across compartments, we identified 53 distinct canonical cell types and previously validated cell states (Zhang et al., Nature Genetics, in press), including fibroblast/perivascular (n = 6), endothelial (n = 11), epithelial (n = 12), myeloid (n = 8), and lymphoid/dendritic (n = 12) populations. In addition to the tissue, also associated mucus plugs were profiled and found to consist predominantly of accumulated macrophages and epithelial cells (Fig. 1d). Across samples, we identified distinct lesion-specific patterns of cellular co-occurrence and an evolution from web to occlusion to collapse. Conclusions This study establishes a proof of concept for integrating microCT-based lesion mapping, precision microdissection and spatial transcriptomics to define the cellular architecture of small airway disease. Together with ongoing snRNA-seq analyses from the same samples, these data will refine our understanding of lesion subtypes in early-stage COPD and may ultimately guide the development of targeted interventions to prevent disease progression. This abstract is funded by: DOD

The clinical, functional and imaging landscape of lung involvement in Sjögren Disease: a potential link between interstitial lung disease and small airways dysfunction.

ObjectiveAmbient air pollution is a leading global environmental health risk, significantly contributing to the burden of chronic respiratory diseases and premature mortality worldwide. Despite being a major industrial and agricultural hub, the specific impact of long-term exposure to urban and industrial pollutants on pulmonary function in the Central Anatolian region remains insufficiently characterized. This study aimed to evaluate the subclinical respiratory effects of air pollution on healthy adults in Konya, Turkey, with a particular focus on the cumulative impact of industrial proximity.MethodsThis prospective, cross-sectional comparative study involving 455 participants collected data on sociodemographic characteristics, smoking history, and respiratory symptoms. Lung function was measured via portable spirometry. Individualized exposure scores were calculated from 1-year and 4-year air quality data. Industrial proximity was categorized using a 10-km threshold for both residence and workplace.ResultsPulmonary function test values were significantly lower in smoking individuals and in those with respiratory diseases (p < 0.05). Nonsmoking healthy individuals living and working within 10 km of industrial zones showed significantly lower forced expiratory volume in 1 second/forced vital capacity (79.17% vs. 82.71%, p < 0.001) and small airway parameters ( forced expiratory flow between 25% and 75% of vital capacity, maximal expiratory flow at 25% of vital capacity, maximal expiratory flow at 50% of vital capacity, and maximal expiratory flow at 75% of vital capacity; p < 0.005) than in those living farther away. Notably, nonsmoking individuals living near industrial zones had lower small airway flow rates than smoking individuals living far from industrial areas (p < 0.05). The Karatay district, demonstrating the highest levels of particulate matter ≤10 µm in diameter, showed the lowest maximal expiratory flow at 25% of vital capacity values (p = 0.049).ConclusionsIndustrial proximity and smoking are independent risk factors for airway obstruction. Continuous industrial exposure may cause more pronounced small airway damage than tobacco consumption, thereby highlighting the need for air quality management in urban planning.

There is a need for a patient-centered tool that can quantitatively identify acute exacerbations of COPD. This study aims to develop and validate a digital tool that enables such care by providing a quantifiable severity score. A total of 161 AECOPD patients and 130 stable COPD patients from Henan Provincial People's Hospital were enrolled. Demographics, clinical symptoms, pulmonary function parameters and admission laboratory data for patients were collected. The COPD Exacerbation Recognition Tool (CERT) was quantified using a 4-point Likert scale (0-3) to derive the Quantitative-CERT (Q-CERT) score. Effectiveness of the CERT and Q-CERT in identifying AECOPD was assessed. The CERT demonstrated strong diagnostic performance for recognizing AECOPD, with a sensitivity of 85.7%, specificity of 80.8%, and accuracy of 83.5%. The quantitative Q-CERT score further optimized diagnostic accuracy. At a cutoff of 5 points, the Q-CERT provided optimal sensitivity (89.4%) and specificity (83.8%) combination, with an AUC of 0.956 (95% CI: 0.937-0.976, P< 0.001). Q-CERT scores were significantly higher in patients with AECOPD than in those with stable COPD (8 vs. 0 points, P< 0.001). Furthermore, elevated Q-CERT scores correlated negatively with pulmonary function parameters, including FEV1%pred, FEV1/FVC, MEF75%pred, MEF50%pred, and MMEF%pred (r = -0.406 to -0.358, all P < 0.001), with the strongest associations observed in small airway metrics. Conversely, higher Q-CERT scores showed positive correlations with the neutrophil-to-lymphocyte ratio (NLR) (r = 0.181, P<0.05) and platelet-to-lymphocyte ratio (PLR) (r = 0.245, P<0.05). Q-CERT enhanced the original CERT's ability to identify AECOPD. And total score was correlated with pulmonary function impairment and systemic inflammation, making it an efficient and reliable tool for clinical practice.

Abstract Rationale Acute exacerbations (AECOPD) are the primary contributor to COPD-associated morbidity and mortality and are associated with accelerated lung function decline and impaired quality of life (QoL). Approximately 50% of AECOPD are caused by rhinovirus (RV) infection, for which there is no vaccine or treatment. We examined the efficacy of Vapendavir (VPV), an oral potent and specific RV capsid inhibitor, in experimental RV-A16 infection of COPD patients. Methods 52 participants with GOLD stage II COPD were enrolled, 44 were inoculated intranasally with RV-A16, and 40 developed symptoms and were randomized. Upon reporting a cold or an increase of ≥ 2 points above baseline upper or lower respiratory symptom scores (URSS/LRSS), participants were dosed orally with placebo (n = 20) or VPV (n = 20) for 7 days. Participants were followed up for 42 days post-infection. Outputs included participant reported symptom scores, QoL, pulmonary function tests and virus load. Results Vapendavir treatment was well tolerated with no evident safety concerns. VPV reduced RV-induced worsening of QoL assessed by the St George’s Respiratory Questionnaire (SGRQ) (VPV median -5.52 [95%CI -11.47-0.420], placebo 4.12 [-2.05-10.29], p=0.04) and responder analysis of numbers of participants with clinically significant (≥4 point) worsenings was fewer with VPV n = 5 [25%] vs. placebo 11 [58%], p=0.036. SGRQ domains including symptoms (difference in favor of VPV=-6.39), activity (-10.44), and impact (-11.70) all favoured VPV. Symptoms measured by EXACT-RS area under the curve [AUC] were significantly improved in patients treated with VPV (p = 0.018). ER-S domains including breathlessness (AUCDay21 -12.66), cough/sputum (AUCDay21 -16.56), and chest symptoms (AUCDay21 -11.53) all favored VPV. Spirometry was not significantly different between groups. Oscillometry however revealed improved ventilation inhomogeneity in VPV-treated participants (AUC AX VPV -163.99 [-434.25-106.27], placebo 287.69 [32.92-542.47], p=0.018) and a trend towards reduced worsening in small airways function (AUC R5-R20 VPV -1.87 [-11.39-7.65], placebo 8.71 [-0.25-17.67], p = 0.11). VPV significantly reduced RV-A16 peak and AUC virus load in nasal swabs vs placebo (peak -1.3 Log10 copies/mL, p=0.03, AUC -25 Log10 copies/mL*days, p=0.04) with a trend (p=0.074) towards reduced peak virus load in nasal lavage samples. VPV reduced the duration of virus shedding in nasal swabs (VPV 5 days, placebo 11 days, p = 0.04). Conclusions Vapendavir reduced upper and lower respiratory symptoms and accelerated virus clearance and symptom resolution following experimental RV-A16 infection in individuals with COPD, supporting its progression into further clinical trials in patients with COPD and other chronic lung diseases. This abstract is funded by: Altesa BioSciences Inc

Clinical relevance of extrapulmonary chest computed tomography findings in COPD and asthma: A narrative review of established evidence in COPD and emerging insights in asthma.

Inflammation-induced cysts mimic honeycombing on high-resolution computed tomography in rheumatoid arthritis-associated usual interstitial pneumonia.

Poor discriminative abilities of age, duration and pack-years smoking exposure for diagnosing small airways dysfunction.

Abstract Introduction Maritime occupational medicine spirometric profiles (SP) protects the seafarers health.The main objective was to describe the spirometric profiles of seafarers previously examined between 2016 and 2018. in the Analakininina University Hospital of Toamasina, a big harbor located on the Madagascar East Coast.Spirometry pulmonary functional test (PFT), according to the global lung function initiative ( GLI ) recommendations, was performed for assessing lung capacity and screening respiratory disorders. Methodology This was a cross-sectional, descriptive observational study of 1005 spirometry records of seafarers. Each subject underwent a pre-departure medical examination including usual spirometric parameters between 2016 and 2018., Results Our study population was predominantly male (86.7%) with a mean age of 40.5 ± 7.5 years. The mean BMI was 25.6 ± 4.0 kg/m². Smoking prevalence was 13%, with a mean consumption of 4.5 pack-years. Spirometric profiles showed that 81.4% were normal and 18.6% showed abnormalities including 10.5% with small airways obstructive syndrome and only 1.99% with obstructive ventilatory impairment. A statistically significant correlation was observed between smoking and spirometric values abnormalities, with a p-value &amp;lt; 0.05. 0.0001 and an OR of 12.26. Overweight and obesity were also associated with increased severity of the observed obstructive disorders, with a p-value of 0.01. Conclusion Spirometry is an essential and useful diagnostic and preventive tool in maritime medicine for the early detection of respiratory illness and for the fitness assessment for seafaring. This abstract is funded by: none

Small airways dysfunction (SAD) is an important treatable trait in asthma that is often under-recognised. It can be assessed through spirometry as forced expiratory flow between 25% and 75% of vital capacity however this is limited due to being both effort and volume dependent. Forced oscillometry technique is effort independent and showing to be more sensitive for SAD. We reviewed patients with severe uncontrolled asthma prior to commencing biologic therapy to identify the incidence of abnormal SAD defining values. SAD was identified in 63% of patients. Of the 31 patients with preserved spirometry (normal FEV1 and FEV1/FVC), only 6% had an impaired FEF25-75 while 29% had impaired oscillometry. This result highlights SAD is a common finding in severe uncontrolled asthma and that oscillometry is more sensitive than spirometry at identifying SAD, particularly when spirometry is preserved.

Childhood cancer survivors (CCS) are at risk for long-term pulmonary complications from treatment-related toxicity. Nitrogen multiple-breath washout (N2MBW) may detect small airway dysfunction earlier than standard pulmonary function tests (PFTs), but its value in CCS remains uncertain. To determine the prevalence of ventilation inhomogeneity measured by N2MBW in CCS, evaluate whether it detects abnormalities beyond spirometry and diffusion capacity for carbon monoxide (DLCO), and explore associations with treatment exposures. In this prospective multicenter study (Bern, Basel, Geneva), we measured lung function in all CCS aged 6-21 years who were undergoing routine follow-up. We stratified participants into high-risk (pulmotoxic chemotherapy [busulfan, bleomycin, nitrosoureas], thoracic surgery, radiotherapy, or hematopoietic stem cell transplantation [HSCT]) and standard-risk (other systemic anticancer treatments). PFTs included N2MBW (lung clearance index [LCI], acinar [SACIN] and conductive [SCOND] inhomogeneity), spirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC]), and DLCO. Abnormal values were defined as z-score < -1.645 or > 1.645, calculated using the Global Lung Initiative references. We quantified the proportion of participants with isolated elevated LCI and analyzed associations with treatment exposures using multivariable linear regression. We included 191 CCS (median 7 years post-diagnosis). Mean LCI was 6.27 (95%CI 6.17-6.37), with 7% of participants showing abnormal values. N2MBW results did not differ between high- and standard-risk groups, but allogeneic HSCT survivors had the highest mean LCI (7.18, 95%CI 5.88-8.37), with 33% abnormal. Survivors had mildly impaired mean FEV1, FVC, and DLCO z-scores (-0.21, -0.34, 0.23), more pronounced in high-risk CCS (-0.67, -0.85, -0.05). Isolated LCI impairment, without abnormalities in spirometry or DLCO, occurred in only 3%. Among treatment exposures, only allogeneic HSCT was associated with higher LCI (1.40, 95%CI 0.57-2.33) and SACIN (1.24, 95%CI 0.20-2.28). Most pediatric CCS had normal lung function. N2MBW abnormalities were rare, occurring mainly in allogeneic HSCT survivors. Overall, N2MBW added little beyond standard PFTs, suggesting it may not be needed for routine follow-up at this stage, except after allogeneic HSCT. Larger, longitudinal studies should clarify the onset, progression, and prognostic significance of N2MBW abnormalities and their potential role in risk-adapted follow-up care.

Establishment and characterization of air-liquid interface cultures of human small airway epithelial cells from two commercial sources.