Causal inference analysis of the radiologic progression in the chronic obstructive pulmonary disease.

There is limited evidence regarding the causal inference of emphysema and functional small airway disease in the subsequent progression of chronic obstructive pulmonary disease (COPD). Patients consisting of two independent cohorts diagnosed with COPD and underwent two serial chest CT scans were included. Total percent emphysema (PRMEmph) and fSAD (PRMfSAD) was quantified via PRM. To investigate the progression of emphysema, we divided COPD patients with PRMEmph < 10% into low and high PRMfSADgroup, matched with similar baseline characteristics, and conducted nonparametric hypothesis tests based on randomization inference using Wilcoxon signed rank test and Huber's M statistics. In patients with baseline PRMEmph < 10%, there were 26 and 16 patients in the low PRMfSA group and 52 and 64 patients in the high PRMfSA in the derivation and validation cohorts, respectively. In the both low and high PRMfSAD groups, there were 0.11 and 1.43 percentage point increases (Huber's M statistic p = 0.016) and 0.58 and 2.09 percentage point increases (p = 0.038) in the proportion of emphysema in the derivation and validation cohorts, respectively. On the contrary, among patients with baseline PRMfSAD < 20%, there was no significant differences in the interval changes of PRMfSAD between the low and high PRMEmph groups in both cohorts. In COPD patients with low emphysema, group with baseline high PRMfSAD showed greater change of PRMEmph than those with low PRMfSAD in both the derivation and validation cohorts. Imaging-based longitudinal quantitative analysis may provide important evidence that small airway disease precedes emphysema in CT-based early COPD patients.

Non-communicable airway disease and air pollution in three African Countries: Benin, Cameroon and The Gambia.

BACKGROUND: Air pollution exposure can increase the risk of development and exacerbation of chronic airway disease (CAD). We set out to assess CAD patients in Benin, Cameroon and The Gambia and to compare their measured exposures to air pollution. METHODOLOGY: We recruited patients with a diagnosis of CAD from four clinics in the three countries. We collected epidemiological, spirometric and home air pollution data. RESULTS: Of the 98 adults recruited, 56 were men; the mean age was 51.6 years (standard deviation ±17.5). Most (69%) patients resided in cities and ever smoking was highest in Cameroon (23.0%). Cough, wheeze and shortness of breath were reported across the countries. A diagnosis of asthma was present in 74.0%; 16.3% had chronic obstructive pulmonary disease and 4.1% had chronic bronchitis. Prevalence of airflow obstruction was respectively 77.1%, 54.0% and 64.0% in Benin, Cameroon, and Gambia. Across the sites, 18.0% reported >5 exacerbations. The median home particulate matter less than 2.5 µm in diameter (PM2.5) was respectively 13.0 µg/m3, 5.0 µg/m3 and 4.4 µg/m3. The median home carbon monoxide (CO) exposures were respectively 1.6 parts per million (ppm), 0.3 ppm and 0.4 ppm. Home PM2.5 differed significantly between the three countries (P < 0.001) while home CO did not. CONCLUSION: Based on these results, preventive programmes should focus on ensuring proper spirometric diagnosis, good disease control and reduction in air pollution exposure.

CONTEXTE: L'exposition à la pollution de l'air peut accroître le risque de développement et d'aggravation des maladies chroniques des voies respiratoires (CAD). Nous avons entrepris d'évaluer les patients atteints de CAD au Bénin, au Cameroun et en Gambie et de comparer les niveaux d'exposition à la pollution de l'air qu'ils ont subis. MÉTHODOLOGIE: Nous avons sélectionné des patients ayant reçu un diagnostic de CAD dans quatre cliniques de ces trois pays. Nous avons collecté des informations épidémiologiques, des mesures spirométriques ainsi que des données sur la pollution de l'air à leur domicile. RÉSULTATS: En total, 98 individus adultes ont été sélectionnés pour cette étude. Parmi eux, 56 étaient de sexe masculin. L'âge moyen de ces participants était de 51,6 ans, avec un écart-type de ±17,5. La majorité des patients (69%) résidaient en milieu urbain, tandis que le taux de tabagisme le plus élevé était observé au Cameroun (23,0%). Les symptômes de toux, de respiration sifflante et d'essoufflement ont été rapportés dans tous les pays. Parmi les patients, 74% ont reçu un diagnostic d'asthme, 16,3% souffraient de maladie pulmonaire obstructive chronique et 4,1% de bronchite chronique. L'obstruction des voies respiratoires était présente respectivement chez 77,1%, 54,0% et 64,0% des cas au Bénin, au Cameroun et en Gambie. Sur l'ensemble des sites, 18,0% ont signalé plus de cinq exacerbations. La médiane des PM2.5 à domicile était de 13,0 µg/m3, 5,0 µg/m3 et 4,4 µg/m3, respectivement. Les expositions médianes au monoxyde de carbone (CO) à domicile étaient de 1,6 ppm, 0,3 ppm et 0,4 ppm respectivement. Les PM2,5 à domicile présentaient des différences significatives entre les trois pays (P < 0,001), contrairement au CO à domicile. CONCLUSION: En se basant sur ces résultats, il est recommandé que les programmes de prévention se focalisent sur un dépistage spirométrique adéquat, une gestion efficace de la maladie et une diminution de l'exposition à la pollution atmosphérique.

The role of Sodium-Glucose Transporter-2 Inhibitors (SGLT-2i) in preventing chronic obstructive disease exacerbation in patients with diabetes and COPD: An electronic health database analysis.

BACKGROUND: Sodium Glucose Transporter 2 inhibitor (SGLT-2i) medications reduce inflammation, improve glycemic control, and impart weight loss, all of which may play a role in chronic obstructive pulmonary disease (COPD) pathophysiology. OBJECTIVES: The primary objective of our study was to explore the incidence of COPD exacerbation in patients with diabetes and COPD on SGLT-2i medications. The secondary objective was to assess the impact of SGLT-2i medications on COPD exacerbations needing hospitalization, ICU admission, and mechanical ventilation. METHODS: This was a retrospective cohort analysis of COPD patients with diabetes enrolled in the COPD registry at a Mid-west Tertiary care teaching hospital from January 1, 2022, to December 31, 2022. We used Slicer-Dicer, a self-service cohort exploration tool embedded in EPIC for data extraction. RESULTS: We had 31,411 patients registered with the COPD registry during the study period. Of these, 18,713 had diabetes, and 1295 patients were on SGLT-2i medication. The incidence of COPD exacerbation, including severe COPD exacerbation needing hospitalization, was significantly lower in the SGLT-2i medication group (3.16% vs 18.3%, p < 0.05; 1.2% vs 5.04%, p < 0.05). Also, there was a non-significant trend suggesting that the incidence of COPD exacerbation needing intensive care unit admission and intubation was lower in the SGLT-2i medication group (0.07% vs 3.4%; 0 vs 0.04%). SGLT-2i medication use was associated with reduced incidence of COPD exacerbation irrespective of underlying control of diabetes. CONCLUSIONS: Our study suggests possible role of SGLT-2i in preventing COPD exacerbation. Randomized trials are needed in the future to confirm or refute these findings.

Small airways disease in chronic obstructive pulmonary disease.

INTRODUCTION: Small airway disease (SAD) represents a common and critical feature of Chronic Obstructive Pulmonary Disease (COPD). Introduced in the '60s, SAD has gradually gained increasing interest as assessment methodologies have improved. Chronic exposure to smoking and noxious particles or gases induces inflammation and remodeling, leading to airway obstruction and SAD, eventually resulting in complete airway loss. AREAS COVERED: A literature search up to June 2024 was performed in PubMed to identify articles on SAD and airway diseases mainly COPD, but also to the extent that it seemed relevant in the uncontrolled/severe asthma field, where SAD is better studied. We provide clinicians and translational scientists with a comprehensive analysis of the existing literature on SAD in COPD, concentrating on the underlying pathophysiological mechanisms, diagnostic techniques, and current pharmacological approaches targeting airflow obstruction in small airways. EXPERT OPINION: Small airways are the primary site for the onset and progression of airflow obstruction in patients with COPD, with significant clinical consequences associated with poor lung function, hyperinflation, and impaired quality of life. The early identification of individuals with subclinical SAD may allow us to prevent its further progress from airway loss and potential development of emphysema and choose the appropriate therapeutic approach.

Aerodynamic Simulation of Small Airway Resistance: A New Imaging Biomarker for Chronic Obstructive Pulmonary Disease.

Purpose: To develop a novel method for calculating small airway resistance using computational fluid dynamics (CFD) based on CT data and evaluate its value to identify COPD. Patients and Methods: 24 subjects who underwent chest CT scans and pulmonary function tests between August 2020 and December 2020 were enrolled retrospectively. Subjects were divided into three groups: normal (10), high-risk (6), and COPD (8). The airway from the trachea down to the sixth generation of bronchioles was reconstructed by a 3D slicer. The small airway resistance (RSA) and RSA as a percentage of total airway resistance (RSA%) were calculated by CFD combined with airway resistance and FEV1 measured by pulmonary function test. A correlation analysis was conducted between RSA and pulmonary function parameters, including FEV1/FVC, FEV1% predicted, MEF50% predicted, MEF75% predicted and MMEF75/25% predicted. Results: The RSA and RSA% were significantly different among the three groups (p<0.05) and related to FEV1/FVC (r = -0.70, p < 0.001; r = -0.67, p < 0.001), FEV1% predicted (r = -0.60, p = 0.002; r = -0.57, p = 0.004), MEF50% predicted (r = -0.64, p = 0.001; r = -0.64, p = 0.001), MEF75% predicted (r = -0.71, p < 0.001; r = -0.60, p = 0.002) and MMEF 75/25% predicted (r = -0.64, p = 0.001; r = -0.64, p = 0.001). Conclusion: Airway CFD is a valuable method for estimating the small airway resistance, where the derived RSA will aid in the early diagnosis of COPD.

Time to re-set our thinking about airways disease: lessons from history, the resurgence of chronic bronchitis / PBB and modern concepts in microbiology.

In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary disease' (COPD) has minimally changed in recent decades while 'the incidence of bronchiectasis' is on the rise. The current focus on producing guidelines for these two airway 'diseases' has hindered progress in both treatment and prevention. The elephant in the room is that neither COPD nor bronchiectasis is a disease but rather a consequence of progressive untreated airway inflammation. To make this case, it is important to review the evolution of our understanding of airway disease and how a pathological appearance (bronchiectasis) and an arbitrary physiological marker of impaired airways (COPD) came to be labelled as 'diseases'. Valuable insights into the natural history of airway disease can be obtained from the pre-antibiotic era. The dramatic impacts of antibiotics on the prevalence of significant airway disease, especially in childhood and early adult life, have largely been forgotten and will be revisited as will the misinterpretation of trials undertaken in those with chronic (bacterial) bronchitis. In the past decades, paediatricians have observed a progressive increase in what is termed 'persistent bacterial bronchitis' (PBB). This condition shares all the same characteristics as 'chronic bronchitis', which is prevalent in young children during the pre-antibiotic era. Additionally, the radiological appearance of bronchiectasis is once again becoming more common in children and, more recently, in adults. Adult physicians remain sceptical about the existence of PBB; however, in one study aimed at assessing the efficacy of antibiotics in adults with persistent symptoms, researchers discovered that the majority of patients exhibiting symptoms of PBB were already on long-term macrolides. In recent decades, there has been a growing recognition of the importance of the respiratory microbiome and an understanding of the ability of bacteria to persist in potentially hostile environments through strategies such as biofilms, intracellular communities, and persister bacteria. This is a challenging field that will likely require new approaches to diagnosis and treatment; however, it needs to be embraced if real progress is to be made.

The Modulation of Respiratory Epithelial Cell Differentiation by the Thickness of an Electrospun Poly-ε-Carprolactone Mesh Mimicking the Basement Membrane.

The topology of the basement membrane (BM) affects cell physiology and pathology, and BM thickening is associated with various chronic lung diseases. In addition, the topology of commercially available poly (ethylene terephthalate) (PET) membranes, which are used in preclinical in vitro models, differs from that of the human BM, which has a fibrous and elastic structure. In this study, we verified the effect of BM thickness on the differentiation of normal human bronchial epithelial (NHBE) cells. To evaluate whether the thickness of poly-ε-carprolactone (PCL) mesh affects the differentiation of NHBE cells, cells were grown on thin- (6-layer) and thick-layer (80-layer) meshes consisting of electrospun PCL nanofibers using an air-liquid interface (ALI) cell culture system. It was found that the NHBE cells formed a normal pseudostratified epithelium composed of ciliated, goblet, and basal cells on the thin-layer PCL mesh; however, goblet cell hyperplasia was observed on the thick-layer PCL mesh. Differentiated NHBE cells cultured on the thick-layer PCL mesh also demonstrated increased epithelial-mesenchymal transition (EMT) compared to those cultured on the thin-layer PCL mesh. In addition, expression of Sox9, nuclear factor (NF)-κB, and oxidative stress-related markers, which are also associated with goblet cell hyperplasia, was increased in the differentiated NHBE cells cultured on the thick-layer PCL mesh. Thus, the use of thick electrospun PCL mesh led to NHBE cells differentiating into hyperplastic goblet cells via EMT and the oxidative stress-related signaling pathway. Therefore, the topology of the BM, for example, thickness, may affect the differentiation direction of human bronchial epithelial cells.

Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: Associations with airflow limitation, health-related independence and mortality.

BACKGROUND AND OBJECTIVE: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema. METHODS: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT. RESULTS: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality. CONCLUSION: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD.

Clinical efficacy of bronchoalveolar lavage in the treatment of small airway diseases in children.

Objective: This study aimed to evaluate the efficacy of bronchoalveolar lavage (BAL) in the treatment of children with small airway diseases. Methods: Children [n = 112; boys: 76, girls: 36 (ratio 2.1:1); age range: 1 month-10 years; median age: 12 months] with small airway diseases diagnosed by high-resolution computed tomography (HRCT) were enrolled in this study. The patients were assigned to either the BAL group (BAL and conventional therapy) or the control group (conventional therapy only). The duration of cough, fever, wheezing, hospitalization duration, disease course before admission, treatment cost, HRCT recovery time, and re-hospitalization rate were compared between the two groups. Results: The median disease course before admission of the BAL group patients was longer than that of the controls (p = 0.006). The duration of cough and wheezing in the BAL group was significantly longer than that in the control group (p = 0.012 and p = 0.001, respectively). The recovery time of cough, the re-hospitalization rate, and the total expenditure incurred for the BAL group were lower than those for the control group (p = 0.027, p = 0.026, and p = 0.000, respectively). At 2 months after discharge, the small airway lesions were found to be absorbed in 86.2% of BAL group patients vs. 64.1% of control group patients. At 6 months after discharge, the lesions were not fully absorbed in 3.4% of the BAL group patients compared to 20.5% in the control group patients. Conclusion: BAL is suitable for patients with a long disease course before admission, a long duration of coughing, and recurrent wheezing. BAL treatment of small airway diseases in children can promote the disappearance of clinical symptoms, accelerate the improvement of imaging, reduce the rate of re-hospitalization, and reduce the cost of treatment.

Multistrain probiotics fail to modulate the asthmatic phenotype, respiratory microbiota, and immune responses in cats.

OBJECTIVE: To determine if multistrain probiotics administered to asthmatic cats treated with anti-inflammatory glucocorticoids would attenuate the asthmatic phenotype and beneficially alter respiratory, blood, and oropharyngeal (OP) microbial communities and immune parameters versus placebo. ANIMALS: 13 client-owned asthmatic cats. METHODS: A randomized, blinded, placebo-controlled clinical trial of asthmatic cats receiving anti-inflammatory glucocorticoids with oral multistrain probiotics or placebo assessed owner-perceived improvement and airway eosinophilia at baseline and after 2 weeks of treatment. Bronchoalveolar lavage fluid (BALF), blood, OP, and rectal microbial communities were compared using 16S rRNA amplicon sequencing. Real-time PCR for transcription factors, activation markers and cytokines, and IgA ELISAs were evaluated. Statistical analyses used 2-way repeated-measures ANOVA or permutational ANOVA (significance, P < .05). RESULTS: After treatment, there were no significant differences in owner-perceived clinical signs or mean ± SEM BALF eosinophils between groups. There was a significant decrease in rectal α-diversity but not in α- or ß-diversity in BALF, blood, or OP between groups or over time. There were no significant differences in CD25, FoxP3, GATA, Helios, IL-4, IL-5, IL-10, IL-13, IL-17, IFN-γ mRNA, or serum or BALF IgA between groups or over time. CLINICAL RELEVANCE: In asthmatic cats, oral multistrain probiotics failed to improve owner-perceived signs, reduce airway eosinophilia, modify microbial community composition, or alter assessed immune responses versus placebo or over time. Longer treatment, different probiotic composition or delivery (eg, aerosolized), or larger number of cats would represent the next stages of study.

Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection.

The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including Pseudomonas aeruginosa, which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic tolerance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacy in vitro. We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance of P. aeruginosa. Our results demonstrate that polymer concentration and molecular weight affect P. aeruginosa survival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardized in vitro model for recapitulating the ex vivo antibiotic tolerance of P. aeruginosa observed in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolved P. aeruginosa populations. IMPORTANCE: Antibiotic treatment failure in Pseudomonas aeruginosa chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors in vitro, is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant in vitro condition that recapitulates antibiotic tolerance observed in ex vivo treated sputum. Ultimately, this study revealed a dominant effect of in vivo evolved bacterial populations in defining inter-subject ex vivo antibiotic tolerance and establishes a robust and translatable in vitro model for therapeutic development.

Unilateral pulmonary agenesis with ipsilateral facial congenital anomalies in an adult with obstructive airway disease.

Pulmonary agenesis is a rare congenital anomaly which can be isolated or co-exist with other developmental defects. Boyden et al has described three degrees of mal development of lung which include agenesis, hypoplasia and aplasia. Almost all the reported cases are in paediatric age group patients while, adults with pulmonary developmental abnormalities are sparsely documented in the literature. Interestingly, adult with coexisting hemifacial anomaly and pulmonary agenesis has not been reported in the medical literature. Here, we describe a middle-aged female who initially presented with bronchial asthma and her chest radiography showed absent left lung which was later confirmed with enhanced CT imaging. Furthermore, she had ipsilateral hemi facial microsomia, microtia, facial nerve palsy and mixed sensory loss, left side large café au lait patch, splenicule and hemangioma in segment V/VI of the liver.

Exploratory Study on COPD Phenotypes and their Progression: Integrating SPECT and qCT Imaging Analysis.

Background: The objective of this study is to understand chronic obstructive pulmonary disease (COPD) phenotypes and their progressions by quantifying heterogeneities of lung ventilation from the single photon emission computed tomography (SPECT) images and establishing associations with the quantitative computed tomography (qCT) imaging-based clusters and variables. Methods: Eight COPD patients completed a longitudinal study of three visits with intervals of about a year. CT scans of these subjects at residual volume, functional residual capacity, and total lung capacity were taken for all visits. The functional and structural qCT-based variables were derived, and the subjects were classified into the qCT-based clusters. In addition, the SPECT variables were derived to quantify the heterogeneity of lung ventilation. The correlations between the key qCT-based variables and SPECT-based variables were examined. Results: The SPECT-based coefficient of variation (CVTotal), a measure of ventilation heterogeneity, showed strong correlations (|r| ≥ 0.7) with the qCT-based functional small airway disease percentage (fSAD%Total) and emphysematous tissue percentage (Emph%Total) in the total lung on cross-sectional data. As for the two-year changes, the SPECT-based maximum tracer concentration (TCmax), a measure of hot spots, exhibited strong negative correlations with fSAD%Total, Emph%Total, average airway diameter in the left upper lobe, and airflow distribution in the middle and lower lobes. Conclusion: Small airway disease is highly associated with the heterogeneity of ventilation in COPD lungs. TCmax is a more sensitive functional biomarker for COPD progression than CVTotal. Besides fSAD%Total and Emph%Total, segmental airways narrowing and imbalanced ventilation between upper and lower lobes may contribute to the development of hot spots over time.

Impact of Isolated Exercise-Induced Small Airway Dysfunction on Exercise Performance in Professional Male Cyclists.

BACKGROUND: Professional cycling puts significant demands on the respiratory system. Exercise-induced bronchoconstriction (EIB) is a common problem in professional athletes. Small airways may be affected in isolation or in combination with a reduction in forced expiratory volume at the first second (FEV1). This study aimed to investigate isolated exercise-induced small airway dysfunction (SAD) in professional cyclists and assess the impact of this phenomenon on exercise capacity in this population. MATERIALS AND METHODS: This research was conducted on professional cyclists with no history of asthma or atopy. Anthropometric characteristics were recorded, the training age was determined, and spirometry and specific markers, such as fractional exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), were measured for all participants. All of the cyclists underwent cardiopulmonary exercise testing (CPET) followed by spirometry. RESULTS: Compared with the controls, 1-FEV3/FVC (the fraction of the FVC that was not expired during the first 3 s of the FVC) was greater in athletes with EIB, but also in those with isolated exercise-induced SAD. The exercise capacity was lower in cyclists with isolated exercise-induced SAD than in the controls, but was similar to that in cyclists with EIB. This phenomenon appeared to be associated with a worse ventilatory reserve (VE/MVV%). CONCLUSIONS: According to our data, it appears that professional cyclists may experience no beneficial impacts on their respiratory system. Strenuous endurance exercise can induce airway injury, which is followed by a restorative process. The repeated cycle of injury and repair can trigger the release of pro-inflammatory mediators, the disruption of the airway epithelial barrier, and plasma exudation, which gradually give rise to airway hyper-responsiveness, exercise-induced bronchoconstriction, intrabronchial inflammation, peribronchial fibrosis, and respiratory symptoms. The small airways may be affected in isolation or in combination with a reduction in FEV1. Cyclists with isolated exercise-induced SAD had lower exercise capacity than those in the control group.

Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis.

Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 (WFDC2) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.

"Air That Once Was Breath" Part 2: Wildfire Smoke and Airway Disease - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Population growth and climate change have led to more frequent and larger wildfires, increasing the exposure of individuals to wildfire smoke. Notably, asthma exacerbations and allergic airway sensitization are prominent outcomes of such exposure. SUMMARY: Key research questions relate to determining the precise impact on individuals with asthma, including the severity, duration, and long-term consequences of exacerbations. Identifying specific risk factors contributing to vulnerability, such as age, genetics, comorbidities, or environmental factors, is crucial. Additionally, reliable biomarkers for predicting severe exacerbations need exploration. Understanding the long-term health effects of repeated wildfire smoke exposures in individuals with asthma and addressing healthcare disparities are important research areas. KEY MESSAGES: This review discusses the need for comprehensive research efforts to better grasp wildfire smoke-induced respiratory health, particularly in vulnerable populations such as farmworkers, firefighters, pregnant women, children, the elderly, and marginalized communities. Effective mitigation would require addressing the current limitations we face by supporting research aimed at a better understanding of wildfire smoke-induced airway disease.

Capturing COPD heterogeneity: anomaly detection and parametric response mapping comparison for phenotyping on chest computed tomography.

Background: Chronic obstructive pulmonary disease (COPD) poses a substantial global health burden, demanding advanced diagnostic tools for early detection and accurate phenotyping. In this line, this study seeks to enhance COPD characterization on chest computed tomography (CT) by comparing the spatial and quantitative relationships between traditional parametric response mapping (PRM) and a novel self-supervised anomaly detection approach, and to unveil potential additional insights into the dynamic transitional stages of COPD. Methods: Non-contrast inspiratory and expiratory CT of 1,310 never-smoker and GOLD 0 individuals and COPD patients (GOLD 1-4) from the COPDGene dataset were retrospectively evaluated. A novel self-supervised anomaly detection approach was applied to quantify lung abnormalities associated with COPD, as regional deviations. These regional anomaly scores were qualitatively and quantitatively compared, per GOLD class, to PRM volumes (emphysema: PRMEmph, functional small-airway disease: PRMfSAD) and to a Principal Component Analysis (PCA) and Clustering, applied on the self-supervised latent space. Its relationships to pulmonary function tests (PFTs) were also evaluated. Results: Initial t-Distributed Stochastic Neighbor Embedding (t-SNE) visualization of the self-supervised latent space highlighted distinct spatial patterns, revealing clear separations between regions with and without emphysema and air trapping. Four stable clusters were identified among this latent space by the PCA and Cluster Analysis. As the GOLD stage increased, PRMEmph, PRMfSAD, anomaly score, and Cluster 3 volumes exhibited escalating trends, contrasting with a decline in Cluster 2. The patient-wise anomaly scores significantly differed across GOLD stages (p < 0.01), except for never-smokers and GOLD 0 patients. In contrast, PRMEmph, PRMfSAD, and cluster classes showed fewer significant differences. Pearson correlation coefficients revealed moderate anomaly score correlations to PFTs (0.41-0.68), except for the functional residual capacity and smoking duration. The anomaly score was correlated with PRMEmph (r = 0.66, p < 0.01) and PRMfSAD (r = 0.61, p < 0.01). Anomaly scores significantly improved fitting of PRM-adjusted multivariate models for predicting clinical parameters (p < 0.001). Bland-Altman plots revealed that volume agreement between PRM-derived volumes and clusters was not constant across the range of measurements. Conclusion: Our study highlights the synergistic utility of the anomaly detection approach and traditional PRM in capturing the nuanced heterogeneity of COPD. The observed disparities in spatial patterns, cluster dynamics, and correlations with PFTs underscore the distinct - yet complementary - strengths of these methods. Integrating anomaly detection and PRM offers a promising avenue for understanding of COPD pathophysiology, potentially informing more tailored diagnostic and intervention approaches to improve patient outcomes.

Downregulation of protein phosphatase 2Aα in asthmatic airway smooth muscle.

Airway smooth muscle cell (ASM) is renowned for its involvement in airway hyperresponsiveness through impaired ASM relaxation and bronchoconstriction in asthma, which poses a significant challenge in the field. Recent studies have explored different targets in ASM to alleviate airway hyperresponsiveness, however, a sizeable portion of patients with asthma still experience poor control. In our study, we explored protein phosphatase 2 A (PP2A) in ASM as it has been reported to regulate cellular contractility by controlling intracellular calcium ([Ca2+]i), ion channels, and respective regulatory proteins. We obtained human ASM cells and lung tissues from healthy and patients with asthma and evaluated PP2A expression using RNA-Seq data, immunofluorescence, and immunoblotting. We further investigated the functional importance of PP2A by determining its role in bronchoconstriction using mouse bronchus and human ASM cell [Ca2+]i regulation. We found robust expression of PP2A isoforms in human ASM cells with PP2Aα being highly expressed. Interestingly, PP2Aα was significantly downregulated in asthmatic tissue and human ASM cells exposed to proinflammatory cytokines. Functionally, FTY720 (PP2A agonist) inhibited acetylcholine- or methacholine-induced bronchial contraction in mouse bronchus and further potentiated isoproterenol-induced bronchial relaxation. Mechanistically, FTY720 inhibited histamine-evoked [Ca2+]i response and myosin light chain (MLC) phosphorylation in the presence of interleukin-13 (IL-13) in human ASM cells. To conclude, we for the first time established PP2A signaling in ASM, which can be further explored to develop novel therapeutics to alleviate airway hyperresponsiveness in asthma.NEW & NOTEWORTHY This novel study deciphered the expression and function of protein phosphatase 2Aα (PP2Aα) in airway smooth muscle (ASM) during asthma and/or inflammation. We showed robust expression of PP2Aα in human ASM while its downregulation in asthmatic ASM. Similarly, we demonstrated reduced PP2Aα expression in ASM exposed to proinflammatory cytokines. PP2Aα activation inhibited bronchoconstriction of isolated mouse bronchi. In addition, we unveiled that PP2Aα activation inhibits the intracellular calcium release and myosin light chain phosphorylation in human ASM.

Airway Diseases Related to the Use of Cleaning Agents in Occupational Settings.

Exposure to disinfectants and cleaning products (DCPs) is now a well-established risk factor for work-related asthma (WRA). However, questions remain on the specific causal agents and pathophysiological mechanisms. Few studies have also reported an association between DCPs and rhinitis or chronic obstructive pulmonary disease. This review discusses the recent evidence pertaining to airway diseases attributable to occupational exposure to DCPs. In contrast to other agents, the incidence of WRA due to DCPs has increased over time. The use of DCPs in spray form has clearly been identified as an added risk factor. The mechanisms for WRA associated with DCPs remain poorly studied; however, both allergic and nonallergic responses have been described, with irritant mechanisms thought to play a major role. An early diagnostic workup based on clinical assessment accompanied by evaluation of lung function and immunological and airway inflammatory markers is important to guide optimal care and exposure avoidance to the implicated agent. Future research should focus on the effects of "green" products, pathophysiological mechanisms, and quantitative exposure assessment including the use of barcode-based methods to identify specific agents. There is an urgent need to strengthen preventive measures and interventions to reduce the burden of airway diseases associated with DCPs.