Mucus Plugs in Medium-sized Airways: A Novel Imaging Biomarker for Phenotyping Chronic Obstructive Pulmonary Disease.
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ABSTRACT:
SUBMITTER: Chassagnon G
PROVIDER: S-EPMC8048760 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceAirway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown.ObjectiveTo determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality.Design, setting, and participantsObservational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022.ExposuresMucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments.Main outcomes and measuresThe primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease.ResultsAmong the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively.Conclusions and relevanceIn participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.
| S-EPMC10201404 | biostudies-literature
Project description:BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.
| S-EPMC10967478 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with complex pathological features and largely unknown etiologies. Identification and validation of biomarkers for this disease could facilitate earlier diagnosis, appreciation of disease subtypes and/or determination of response to therapeutic intervention. To identify gene expression markers for COPD, we performed genome-wide expression profiling of lung tissue from 56 subjects using the Affymetrix U133 Plus 2.0 array. Lung function measurements from these subjects ranged from normal, un-obstructed to severely obstructed. Analysis of differential expression between cases (FEV1<70%, FEV1/FVC<0.7) and controls (FEV1>80%, FEV1/FVC>0.7) identified a set of 65 probe sets representing discrete markers associated with COPD. Correlation of gene expression with quantitative measures of airflow obstruction (FEV1 or FEV1/FVC) identified a set of 220 probe sets. A total of 31 probe sets were identified that showed evidence of significant correlation with quantitative traits and differential expression between cases and controls. Keywords: Disease state marker
2008-05-31 | GSE8581 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is localized to the lung, is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and is associated with a median survival of 3-5 years after diagnosis. A common gain-of-function MUC5B promoter variant, rs35705950, is the strongest risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF. The MUC5B promoter variant can be used to identify individuals in the preclinical phase of this progressive disease, and, in the IPF lung, we have found that MUC5B is specifically overexpressed in bronchoalveolar epithelium. Thus, MUC5B represents a key molecule to understand the mechanisms that appear to initiate the fibroproliferative process in the bronchoalveolar epithelium. Moreover, focusing on MUC5B may provide a unique opportunity to define the early molecular events that lead to, and potentially prevent, the development of IPF.
| S-EPMC6322034 | biostudies-literature
Project description:Rationale: Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality.Objectives: To correlate ex vivo parametric response mapping (PRM) analysis to in vivo lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects.Methods: Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD (n = 11 subjects) and 22 control tissue samples (n = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema.Measurements and Main Results: PRM analysis was conducted to differentiate functional small airways disease (PRMfSAD) from emphysema (PRMEmph). In COPD lungs, TB numbers were reduced (P = 0.01); surviving TBs had increased wall area percentage (P < 0.001), decreased circularity (P < 0.001), reduced cross-sectional luminal area (P < 0.001), and greater airway obstruction (P = 0.008). COPD lungs had increased airspace size (P < 0.001) and decreased alveolar surface area (P < 0.001). Regression analyses demonstrated unique correlations between PRMfSAD and TBs, with decreased circularity (P < 0.001), decreased luminal area (P < 0.001), and complete obstruction (P = 0.008). PRMEmph correlated with increased airspace size (P < 0.001), decreased alveolar surface area (P = 0.003), and fewer alveolar attachments per TB (P = 0.01).Conclusions: PRMfSAD identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.
| S-EPMC6727153 | biostudies-literature
Project description:BACKGROUND:The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS:In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS:Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ? 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION:Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION:Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING:NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.
| S-EPMC5824874 | biostudies-literature
Project description:BACKGROUND:Airway obstruction due to decreased airway diameter and increased incidence of mucus plugs has not been directly observed in asthma exacerbation. We studied the changes in the inner diameter of the airway (Din) and the frequency of mucus plugs by airway generation in patients with asthma exacerbation. We compared these patients to those in a stable phase using high-resolution computed tomography (HRCT). METHODS AND FINDINGS:Thirteen patients with asthma were studied by HRCT during asthma exacerbation and in a stable period. The HRCT study was performed on patients who could safely hold their breath for a short while in a supine position 1 hour after initial treatment for asthma exacerbation. Using a curved multiplanar reconstruction (MPR) software, we reconstructed the longitudinal airway images and the images exactly perpendicular to the airway axis to measure the Din and mucus plugs from the second- (segmental) to sixth-generation bronchi in all segments of the lungs.The ratios of Din (exacerbation/stable) were 0.91(P = 0.016), 0.88 (P = 0.002), 0.83 (P = 0.001), 0.80 (P = 0.001), and 0.87 (NS) in the second-, third-, fourth-, fifth-, and sixth-generation bronchi, respectively. The percentages of airway obstruction due to mucus plugs were notably higher in the fourth- and fifth-generation bronchi (17.9%/18.1% in stable phase and 43.2%/45.9% in the exacerbation phase, respectively) than in the other generations of bronchi. CONCLUSIONS:Among the bronchi examined, the fourth- and fifth-generation bronchi were significantly obstructed during asthma exacerbation compared with the stable phase in terms of a decreased airway diameter and mucus plugs.
| S-EPMC7046273 | biostudies-literature
Project description:BackgroundThe lower airways microbiome and host immune response in chronic pulmonary diseases are incompletely understood. We aimed to investigate possible microbiome characteristics and key antimicrobial peptides and proteins in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).Methods12 IPF patients, 12 COPD patients and 12 healthy controls were sampled with oral wash (OW), protected bronchoalveolar lavage (PBAL) and right lung protected sterile brushings (rPSB). The antimicrobial peptides and proteins (AMPs), secretory leucocyte protease inhibitor (SLPI) and human beta defensins 1 and 2 (hBD-1 & hBD-2), were measured in PBAL by enzyme linked immunosorbent assay (ELISA). The V3V4 region of the bacterial 16S rDNA gene was sequenced. Bioinformatic analyses were performed with QIIME 2.ResultshBD-1 levels in PBAL for IPF were lower compared with COPD. The predominant phyla in IPF were Firmicutes, Bacteroides and Actinobacteria; Proteobacteria were among top three in COPD. Differential abundance analysis at genus level showed significant differences between study groups for less abundant, mostly oropharyngeal, microbes. Alpha diversity was lower in IPF in PBAL compared to COPD (p = 0.03) and controls (p = 0.01), as well as in rPSB compared to COPD (p = 0.02) and controls (p = 0.04). Phylogenetic beta diversity showed significantly more similarity for IPF compared with COPD and controls. There were no significant correlations between alpha diversity and AMPs.ConclusionsIPF differed in microbial diversity from COPD and controls, accompanied by differences in antimicrobial peptides. Beta diversity similarity between OW and PBAL in IPF may indicate that microaspiration contributes to changes in its microbiome.
| S-EPMC8735599 | biostudies-literature
Project description:Preterm birth is a leading cause of neonatal mortality and lacks an effective therapy. Ascending microbial infections from the lower genital tract lead to infection of the placenta, amniotic fluid and fetus causing preterm birth or stillbirth. Directly in the path of an ascending infection is the cervical mucus plug (CMP), a dense mucoid structure in the cervical canal with potential antimicrobial properties. In this study, we aimed to define the components of CMP responsible for antimicrobial activity against a common lower genital tract organism associated with preterm birth and stillbirths, namely Group B Streptococcus (GBS). Using a quantitative proteomic approach, we identified antimicrobial factors in CMPs that were collected from healthy human pregnancies. This study aims to provide new insight into how the human CMP may limit ascending bacterial infection.
2018-02-09 | PXD008600 | Pride
Project description:Preterm birth is a leading cause of neonatal mortality and lacks an effective therapy. Ascending microbial infections from the lower genital tract lead to infection of the placenta, amniotic fluid, and fetus causing preterm birth or stillbirth. Directly in the path of an ascending infection is the cervical mucus plug (CMP), a dense mucoid structure in the cervical canal with potential antimicrobial properties. In this study, we aimed to define the components of CMP responsible for antimicrobial activity against a common lower genital tract organism associated with preterm birth and stillbirths, namely, group B streptococcus (GBS). Using a quantitative proteomic approach, we identified antimicrobial factors in CMPs that were collected from healthy human pregnancies. However, we noted that the concentration of antimicrobial peptides present in the human CMPs were insufficient to directly kill GBS, and antimicrobial activity, when observed, was due to antibiotics retained in the CMPs. Despite this insufficiency, CMP proteins were able to activate leukocytes in whole blood resulting in increased rates of bacterial killing, suggesting a role for the CMP in enhancing complement-mediated killing or leukocyte activation. This study provides new insight into how the human CMP may limit ascending bacterial infection.
| S-EPMC5913629 | biostudies-literature