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Changes in airway diameter and mucus plugs in patients with asthma exacerbation.

ABSTRACT: 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.

SUBMITTER: Yoshida Y

PROVIDER: S-EPMC7046273 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Changes in airway diameter and mucus plugs in patients with asthma exacerbation.

Yoshida Yuki Y Takaku Yotaro Y Nakamoto Yasuo Y Takayanagi Noboru N Yanagisawa Tsutomu T Takizawa Hajime H Kurashima Kazuyoshi K

PloS one 20200227 2

<h4>Background</h4>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).<h4>Methods and findings</h4>Thirteen patients with asthma were studied by ...[more]

PMID: 32106233

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Project description:BackgroundThe 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.MethodsIn 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.ResultsMucus 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.ConclusionMucus 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 registrationClinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915.FundingNIH 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.

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.

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.

Project description:Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Project description:BackgroundIn infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development.ObjectiveWe hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes.MethodsNasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses.ResultsSix nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species-dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species-dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species-dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested.ConclusionDistinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season.

Project description:IntroductionAsthma with airway mucus hypersecretion is an inadequately characterized variant of asthma. While several studies have reported that hypersecreting patients may carry genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of those studies have been questioned for their numerous limitations and contradictory results.Objectives(1) To determine the presence of genetic variants of the CFTR gene in patients with asthma with and without airway mucus hypersecretion. (2) To identify the clinical, inflammatory and functional characteristics of the asthma phenotype with airway mucus hypersecretion.MethodComparative multicentre cross-sectional descriptive study that included 100 patients with asthma (39 hypersecretors and 61 non-hypersecretors). Asthmatic hypersecretion was defined as the presence of cough productive of sputum on most days for at least 3 months in 2 successive years. The patients were tested for fractional exhaled nitric oxide, spirometry, induced sputum cell count, total immunoglobulin E (IgE), peripheral blood eosinophil count, C-reactive protein, blood fibrinogen and blood albumin and underwent a skin prick test. Asthma control and quality of life were assessed by the Asthma Control Test and Mini Asthma Quality of Life questionnaires, respectively. Blood DNA samples were collected from the patients and next-generation sequencing using a MiSeq sequencer and the Illumina platform was used for the CFTR gene analysis.ResultsGenetic differences were observed in the c.1680-870T>A polymorphism of the CFTR gene, significantly more evident in hypersecretors than in non-hypersecretors: 78.94% vs. 59.32% in the majority allele and 21.05% vs. 40.67% in the minority allele (p = 0.036). Clinically, asthma hypersecretors compared to non-hypersecretors were older (57.4 years vs. 49.4 years; p = 0.004); had greater asthma severity (58.9% vs. 23.7%; p = 0.005); experienced greater airway obstruction (FEV1/FVC% 64.3 vs. 69.5; p = 0.041); had poorer asthma control (60% vs. 29%; p = 0.021); had lower IgE levels (126.4 IU/mL vs. 407.6 IU/mL; p = 0.003); and were less likely to have a positive prick test (37.5% vs. 68.85%; p = 0.011).ConclusionThe results suggest that patients with asthma and with mucus hypersecretion (1) may have a different phenotype and disease mechanism produced by an intronic polymorphism in the CFTR gene (NM_000492.3:c.1680-870T>A), and (2) may have a poorer clinical outcome characterized by severe disease and poorer asthma control with a non-allergic inflammatory phenotype.

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Changes in airway diameter and mucus plugs in patients with asthma exacerbation.

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Changes in airway diameter and mucus plugs in patients with asthma exacerbation.

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