Airway Disease Research Articles

Physical Activity in Adults with Severe Asthma On-Treatment with Biological Therapies: A 1-Year Retrospective Analysis of Real-World Data.

Asthma is a complex airways disease that affects over 350-million people worldwide. It is estimated that up to 10% of adults and 2.5% of children with asthma have severe disease, which is associated with reduced physical activity. The introduction of biological therapies has revolutionised the management of severe asthma; however, it remains to be determined whether this translates into improvements in physical activity status. This 1-year retrospective study evaluated step-based physical activity (via a smartphone pedometer) in adults with severe asthma (n=20) and two matched sub-groups (n=20 mild asthma and n=20 healthy controls). The annual daily step count was significantly less in adults with severe asthma (4698±1927) versus mild asthma (7239±1815) (P=0.009) and healthy controls (8252±2115) (P=0.001). No difference in physical activity was observed between those with mild asthma and healthy controls (P>0.05). Despite long-term treatment with biological therapies, physical activity remains significantly lower in adults with severe asthma. The development of personalised evidence-based interventions to promote physical activity in people with severe asthma remains a priority.

Investigation of the mechanistic impact of CBL0137 on airway remodeling in asthma

BackgroundBronchial asthma, a chronic inflammatory airway disease, is characterized by airway remodeling, including thickening of the airway smooth muscle layer, primarily due to abnormal proliferation of airway smooth muscle cells (ASMCs). CBL0137 (Curaxin-137 hydrochloride), a histone chaperone facilitate chromatin transcription (FACT) inhibitor, has demonstrated anti-tumor properties, including inhibition of proliferation, promotion of apoptosis, and increased autophagy. However, its effects on ASMCs and airway remodeling remain unexplored.MethodsAsthma models were established using ovalbumin (OVA) in female C57BL/6 J mice, with therapeutic interventions using CBL0137 and budesonide. Lung tissues were analyzed using Hematoxylin and eosin (H&E), PAS, Masson’s trichrome, and α-SMA immunofluorescence staining. ASMCs extracted from Sprague–Dawley rats were cultured in vitro experiments, with phenotypic changes assessed via flow cytometry. Gene and protein expressions were analyzed using RT-PCR and Western blotting.ResultsCBL0137 significantly reduced airway resistance, goblet cell proliferation, alveolar collagen deposition, and airway smooth muscle layer thickening in asthmatic mice. In vitro, CBL0137 inhibited ASMC proliferation and induced apoptosis, downregulating cyclin-B1, Cdc2, and Bcl-2 while upregulating caspase-3.ConclusionsCBL0137 mitigates airway remodeling of asthmatic mice by modulating ASMC proliferation and apoptosis, presenting a potential therapeutic strategy for asthma treatment.

Type 2 inflammation, a common denominator in chronic airway disease?

This review addresses the growing understanding that a specific subset of patients with a respiratory disease, including asthma, chronic obstructive pulmonary disease (COPD), or bronchiectasis may have one thing in common: type 2 inflammation. In the era of personalized medicine, we need to refine clinical markers combined with molecular and cellular endotyping to improve patient outcomes. Recent literature reveals that type 2 markers such as blood eosinophils, fractional exhaled nitric oxide (FeNO), and immunglobulin E (IgE), can provide valuable insights into disease progression, exacerbation risk, and treatment response, but their stability remains to be investigated. Treating asthma and COPD patients with biologics to target IL-4/IL-13, IL-5, and alarmins have shown potential, although efficacy varied. In bronchiectasis, a subset of patients with type 2 inflammation may benefit from corticosteroid therapy, despite broader concerns regarding its use. This underscores the importance of improved disease endotyping to better characterize patients who may benefit from targeted therapies. In clinical practice, personalized treatment based on inflammatory profiles has been shown to improve outcomes in heterogeneous lung diseases. Future research needs to focus on validating reliable biomarkers and optimizing clinical trial designs to advance therapeutic strategies in respiratory diseases.

N-Acetylcysteine and Its Therapeutic Potential in an Animal Model of Allergic Asthma.

Background: N-acetylcysteine (NAC) is a classical mucolytic agent that, in addition to its mucolytic activity, also exhibits antioxidant activity. This could be beneficial in treating chronic inflammatory airway diseases, including asthma. Background: We evaluated the ability of NAC to modulate airway defense mechanisms, airway reactivity, inflammation, and remodeling after 10 days of administration [20 and 60 mg/(kg·d)] in an experimental guinea pig model of allergic inflammation. Methods: The concentrations of inflammatory cytokines (interleukins: IL-4, IL-5, IL-10, IL-12, and IL-13), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured in bronchoalveolar lavage fluid using a multiplex detection method. The concentration of remodeling marker transforming growth factor beta-1 (TGF-β1) was measured in lung homogenates using enzyme-linked immunosorbent assay. In vivo, changes in specific airway resistance and number of cough efforts were determined. Tracheal smooth muscle reactivity was evaluated in vitro. Ciliary beat frequency (CBF) indicated mucociliary clearance. Results: A 10-day administration of NAC at a higher dosage led to a significant decrease in the regulatory cytokines IL-4, IL-5, and GM-CSF. NAC, in both dosing schedules, decreased the levels of TGF-β1. NAC at a higher dosage reduced the number of chemically induced cough reflexes and CBF. NAC did not affect airway hyperreactivity parameters. Conclusion: NAC is a multifactorial drug, and under our experimental conditions of allergic inflammation, it showed positive effects on the levels of regulatory cytokines and growth factors, which probably led to a reduction in the intensity of airway defense mechanisms.

How I treat type 1 plasminogen deficiency.

How I treat type 1 plasminogen deficiency.

PLZF-expressing CD4+ T cells promote tissue-resident memory T cells in breaking immune tolerance in allergic asthma via IL-15/IL-15Rα signaling

BackgroundAllergic asthma is a chronic airway disease characterized by an allergic response and altered immune tolerance. CD4+ tissue-resident memory T (TRM) cells are crucial in the chronic and relapsing pathogenesis of asthma. Furthermore, promyelocytic leukemia zinc finger (PLZF) is an essential transcription factor involved in asthmatic tolerance and has been implicated in the regulation of CD4+CD44+ memory T cells. However, the role of CD4+ TRM cells in asthmatic tolerance, as well as their potential modulation by PLZF, remain unclear. Therefore, in the current study, we explore the role of CD4+ TRM cells in asthmatic immune tolerance and as well as the regulatory role of PLZF in this process.MethodsTo elucidate the role of CD4+ TRM cells in immune tolerance, asthma memory mouse models were treated with the immunomodulator FTY720. Subsequently, CD4+ T cells were isolated from the lungs and spleens and transferred to oral tolerance mouse models. To explore the regulation of PLZF in CD4+ TRM cells, asthma and oral tolerance were established in Zbtb16flox/flox CD4Cre and wild-type mice. Flow cytometry, histological analysis, and cytokine measurements were performed to characterize the immune response. The regulatory activity of PLZF on CD4+ TRM cells was analyzed through quantitative proteomics and verified in vitro and vivo.ResultsThe CD4+ TRM cell proportion positively correlated with the pathological phenotypes and molecular characteristics of asthma. Adoptive transfer of CD4+ TRM cells induced asthmatic phenotypes. This suggested that CD4+ TRM cells contributed to the pathogenesis of asthma. Conditional knockout of PLZF substantially reduced the proportion of CD4+ TRM cells, relieved asthmatic symptoms, and suppressed the interleukin (IL)-15/IL-15Rα signaling pathway. Furthermore, exposure to the IL-15Rα agonist restored asthma-related Th2 inflammation, accompanied by a markedly increased proportion of CD4+ TRM cells. Meanwhile, IL-15 and ovalbumin(OVA)-primed Beas2b supernatant co-stimulation in vitro enhanced the differentiation of pulmonary PLZF-expressing CD4+ T cells into CD4+ TRM cells. ConclusionsThis study identified CD4+ TRM cells as key mediators of immune tolerance in asthma. This process is regulated by the transcription factor PLZF in CD4+ T cells through IL-15/IL-15Rα signaling. Thus, targeting PLZF or the IL-15/IL-15Rα pathway may represent a promising therapeutic strategy for treating asthma.

Use of inhalation devices in cats with feline lower airway disease

Use of inhalation devices in cats with feline lower airway disease

Structure and function relationships of mucociliary clearance in human and rat airways

Mucociliary clearance is a vital defense mechanism of the human airways, protecting against harmful particles and infections. When this process fails, it contributes to respiratory diseases like chronic obstructive pulmonary disease (COPD) and asthma. While advances in single-cell transcriptomics have revealed the complexity of airway composition, much of what we know about how airway structure impacts clearance relies on animal studies. This limits our ability to create accurate human-based models of airway diseases. Here we show that the airways in female rats and in humans exhibit species-specific differences in the distribution of ciliated and secretory cells as well as in ciliary beat, resulting in significantly higher clearance effectiveness in humans. We further reveal that standard lab-grown cultures exhibit lower clearance effectiveness compared to human airways, and we identify the underlying structural differences. By combining diverse experiments and physics-based modeling, we establish universal benchmarks to assess human airway function, interpret preclinical models, and better understand disease-specific impairments in mucociliary clearance.

Upper and lower airway microbiota across infancy and childhood.

The upper and lower respiratory tracts feature distinct environments and responses affecting microbial colonization but investigating the relationship between them is technically challenging. We aimed to identify relationships between taxa colonizing the nasopharynx and trachea across childhood. We employed V4 16S rRNA gene sequencing to profile nasopharyngeal swabs and tracheal aspirates collected from 172 subjects between 20 weeks and 18 years of age. These samples were collected prior to elective procedures over the course of 20 weeks in 2020 from subjects enrolled in a cross-sectional study. After extraction, sequencing, and quality control, we studied the remaining 147 of 172 nasopharyngeal swabs and 95 of 172 tracheal aspirates, including 80 subject-matched pairs of samples. Sequencing data revealed that the nasopharynx is colonized by few, often highly abundant taxa, while the tracheal aspirates feature greater diversity. The patterns of colonization identified in the nasopharynx correlate with subject age across childhood. Our data suggests that there are relatively few species that colonize both the nasopharyngeal tract and the trachea. Furthermore, we observe a pattern of change in the nasopharyngeal microbiota that is correlated with age, suggesting a possible developmental progression of the nasopharyngeal microbiota across childhood. The airway microbiota in childhood plays important roles in respiratory health and immune development. In this work, we report on paired nasopharyngeal swab and tracheal aspirate samples from a cross-sectional cohort of children from infancy to 18 years. We find that the upper and lower airway microbiota are unlikely to share taxa and do not correlate in terms of diversity. We show that the composition of the upper airway microbiota is strongly correlated with age, with a stereotypic developmental trajectory during childhood and adolescence. Our results inform our understanding of airway microbiota assembly and may be used to predict airway disease in young children.

Deep Learning Estimation of Small Airways Disease from Inspiratory Chest CT: Clinical Validation, Repeatability, and Associations with Adverse Clinical Outcomes in COPD.

Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSADTLC). To evaluate an AI model for estimating fSADTLC, compare it with dual-volume parametric response mapping fSAD (fSADPRM), and assess its clinical associations and repeatability in chronic obstructive pulmonary disease (COPD). We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a randomly sampled subset (n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSADTLC in the remaining 1458 SPIROMICS participants. We compared fSADTLC with dual volume, parametric response mapping fSADPRM. We investigated univariate and multivariable associations of fSADTLC with FEV1, FEV1/FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV1 decline. The results were validated in a subset (n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV1, smoking pack years, smoking status, and percent emphysema. Inspiratory fSADTLC showed a strong correlation with fSADPRM in both SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. Higher fSADTLC levels were significantly associated with lower lung function, including lower postbronchodilator FEV1 (L) and FEV1/FVC ratio, and poorer quality of life reflected by higher total SGRQ scores, independent of percent CT emphysema. In SPIROMICS, individuals with higher fSADTLC experienced an annual decline in FEV1 of 1.156 mL (relative decrease; 95% CI: 0.613, 1.699; P < 0.001) per year for every 1% increase in fSADTLC. The rate of decline in COPDGene was slightly lower at 0.866 mL / year (relative decrease; 95% CI: 0.345, 1.386; P < 0.001) for percent increase in fSADTLC. Inspiratory fSADTLC demonstrated greater consistency between repeated measurements with a higher intraclass correlation coefficient (ICC) of 0.99 (95% CI: 0.98, 0.99) compared to fSADPRM [ICC: 0.83 (95% CI: 0.76, 0.88)]. Small airways disease can be reliably assessed from a single inspiratory CT scan using generative AI, eliminating the need for an additional expiratory CT scan. fSAD estimation from inspiratory CT correlates strongly with fSADPRM, demonstrates a significant association with FEV1 decline, and offers greater repeatability.

Longitudinal Outcomes in Pi*MZ Alpha-1 Antitrypsin Deficient Individuals with Tobacco Smoking History from the SPIROMICS Cohort.

Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT) deficient Pi*MZ heterozygotes is largely missing. We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared to Pi*MM genotype. We identified 1856 Pi*MM and 79 Pi*MZ participants with ≥20 pack-years tobacco smoking history from the SPIROMICS cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. Adjusted for age, sex, race, smoking pack-year history and smoking status, Pi*MZ participants had a lower baseline percent-predicted FEV1 (65.4% vs. 75.1%, difference 95% CI: -15.4%, -3.9%), more radiographic emphysema (<-950HU%: 12.9% vs. 7.8%, difference 95% CI: 2.8%, 7.5%) and non-significantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (-34.5mL/year vs. -34.6mL/year for Pi*MZ and Pi*MM, difference 95%CI: -16.9,17.1mL/year). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations or survival. The proportion with faster FEV1 decline (annual loss ≥40mL) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/µL, difference 95% CI: 30, 140 cells/µL). In the subgroup analysis limited to a small number of, currently smoking participants, no significant differences in longitudinal outcomes were found. Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared to Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared to Pi*MM tobacco-exposed individuals.

Geriatric nutritional risk index as a predictor of mortality in women with chronic inflammatory airway disease: evidence from NHANES 1999–2018

BackgroundThe incidence of Chronic Inflammatory Airway Diseases (CIAD) has been steadily increasing, making it a significant contributor to the global disease burden. Additionally, the risk of airway diseases in elderly women continues to rise each year, with nutritional factors playing a crucial role in the progression of CIAD. The Geriatric Nutritional Risk Index (GNRI) is a novel tool for assessing individual nutritional status. This study aims to assess the relationship between GNRI and the risk of all-cause and cardiovascular mortality in elderly women with CIAD, providing guidance for nutritional interventions to reduce mortality risk.MethodsData from elderly female patients and relevant indicators were sourced from the National Health and Nutrition Examination Survey (NHANES) database. Nutritional status was assessed using the GNRI, and patients were divided into four groups based on their GNRI quartiles. Weighted Cox proportional hazards regression models were used to examine the relationship between GNRI and all-cause as well as cardiovascular mortality in elderly women with CIAD. Additionally, restricted cubic spline (RCS) analysis was applied to explore the association between GNRI and different mortality outcomes, and subgroup analysis was conducted to further validate the robustness of the findings.ResultsA total of 1,417 elderly female CIAD patients were included in this study. During a median follow-up of 91 months, 515 deaths from all causes and 157 deaths from cardiovascular causes occurred. Multivariable-adjusted Cox proportional hazards models indicated that compared to the lowest GNRI quartile, the other quartiles showed a general decreasing trend in both all-cause and cardiovascular mortality risk (p &amp;lt; 0.05). In the fully adjusted model, the highest GNRI quartile had the lowest risks of all-cause mortality (HR = 0.40, 95% CI: 0.22–0.72, p &amp;lt; 0.05) and cardiovascular mortality (HR = 0.29, 95% CI: 0.11–0.78, p &amp;lt; 0.05).The RCS analysis demonstrated a nonlinear association between GNRI and both all-cause and cardiovascular mortality (P for nonlinearity &amp;lt;0.001).ConclusionIn elderly women with CIAD, lower GNRI levels are associated with an increased mortality risk. GNRI may serve as a potential predictive tool for both all-cause and cardiovascular mortality, providing valuable insights for nutritional interventions and clinical decision-making.

Pocket guide: biologics in upper and lower airways in adults.

The introduction of biologics for the treatment of severe upper and lower (type 2) airway inflammation has been a gamechanger in the management of these diseases. Biologics are injectable medications targeting different molecules relevant in (type 2) inflammation in patients with severe (type 2) airway diseases, like asthma, eosinophilic chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis (CRS) and those who remain uncontrolled despite regular treatment (1-3). After the phase 3 trials, showing significant impact on symptoms, quality of life and interventions like surgery (for the upper airways) and exacerbations needing hospitalisation (for the lower airways), biologics are now used in daily practice in many parts of the world (4, 5). This pocket guide is aimed at all specialists treating adult patients with severe airway disease.

Reduced Prostaglandin D2 Production by Airway Fibroblasts in Nonsteroidal Anti-inflammatory Drug- Exacerbated Airway Disease.

Reduced Prostaglandin D2 Production by Airway Fibroblasts in Nonsteroidal Anti-inflammatory Drug- Exacerbated Airway Disease.

Predicting Clinical Outcomes of Severe Bronchopulmonary Dysplasia through New Definitions and Phenotypes.

To compare the accuracy of three newly proposed definitions of bronchopulmonary dysplasia (BPD) in predicting outcomes, and to investigate the impact of large airway vs. parenchymal vs. vascular BPD phenotypes on BPD outcomes. Retrospective chart review of 100 infants with severe BPD discharged from a Children's hospital between 2020-2021. Multivariable models evaluated the associations between BPD definitions and phenotypes with tracheostomy and death at 6 months and 1 year after NICU discharge. Secondary outcomes included need of respiratory support, use of pulmonary medications and need for long-term gastrostomy feeding. NRN and BPD collaborative criteria best predicted outcomes associated with tracheostomy and/or death (p < 0.001). Among the three BPD phenotypes, large airway disease was independently associated with death or tracheostomy (OR 10.5, 95% CI 1.6, 68.1). The combination of all three phenotypes was also associated with death or tracheostomy (OR 9.8, 95% CI 1.0, 93.5). Both NRN and BPD collaborative definitions showed association with the need for respiratory support, medication use and need for long-term gastrostomy tube feeding. Among the 29 infants for whom complete information was available, 18 (62%), 20 (69%), and 18 (62%) had parenchymal, central airway and pulmonary vascular phenotype, respectively. Our results indicate that newer definitions of BPD may better predict severity of BPD and need for long-term invasive ventilation support compared to the 2001 NIH definition with BPD phenotypes impacting mortality and short-term outcomes. These data may be useful for counseling families and developing phenotype-based individualized treatment plans.

L-shaped association between leisure-time physical activity and depressive symptoms in individuals with chronic inflammatory airway disease: Data from the NHANES (2007-2018).

L-shaped association between leisure-time physical activity and depressive symptoms in individuals with chronic inflammatory airway disease: Data from the NHANES (2007-2018).

Trajectories of airflow limitation from childhood to early adulthood: an analysis of six population-based birth cohorts.

Trajectories of airflow limitation from childhood to early adulthood: an analysis of six population-based birth cohorts.

Pharmacology, toxicology and homeopathy of Luffa operculata (L.) Cogniaux (Cucurbitaceae): Integrative review.

Pharmacology, toxicology and homeopathy of Luffa operculata (L.) Cogniaux (Cucurbitaceae): Integrative review.

Small airway disease (SAD) in asthma in pregnancy evaluated by impulse oscillometry: A cross-sectional study.

Asthma is a common respiratory disease in pregnancy, with approximately 18% of cases worsening. Small airway disease (SAD) with a reported prevalence of up to 70% is now recognised as a principal indicator of poor asthma control. Impulse oscillometry (IOS) is a non-invasive, technically easier, and patient-friendly tool for detecting SAD. We aimed to assess the prevalence of SAD in pregnant women with asthma and the acceptance of the IOS across different trimesters of pregnancy. This cross-sectional study was conducted among pregnant women aged ≥18 years with clinically diagnosed asthma. All patients underwent IOS following manufacturer and European Respiratory Society guidelines. A questionnaire was used to assess their satisfaction with the technique. Out of 78 patients who underwent IOS, SAD was present in 55.1% (95% CI = 43.4 to 66.4%). Post-bronchodilator reversibility was observed in 37.2% of patients. Abnormal total (R5) and larger (R20) airway resistance were found in 79.5% and 64.1% of patients, respectively. Other IOS parameters (Fres, AX, and X5) were abnormal in 58.9%, 30.7%, and 39.7% of patients, respectively. Bivariate and multivariate logistic regression analyses indicated longer duration of asthma (OR = 1.1; 95% CI = 1.05-1.18; P < 0.001) and passive smoking (OR = 4.2; 95% CI = 1.58-11.1; P = 0.004) were significantly associated with SAD. All participants tolerated the IOS well, with a satisfaction score of 4.75 ± 0.72. The IOS is a helpful tool for the evaluation of SAD, a significant comorbidity in pregnant women with asthma. Factors such as longer disease duration and exposure to passive smoking, akin to risk factors for chronic airflow obstruction, are significantly associated with SAD. Future research should explore SAD's impact on clinical management and overall asthma outcomes.

Identifying novel therapeutic targets in cystic fibrosis through advanced single-cell transcriptomics analysis.

Identifying novel therapeutic targets in cystic fibrosis through advanced single-cell transcriptomics analysis.