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The ratio of mucus-occluded bronchial compartments in 13 subjects by airway generation during asthma exacerbation and the stable phase. Mucus occlusion (mucus plug) was measured by HRCT using curved MPR software. Mucus plugs are defined as the complete occlusion of a bronchus, contiguous with patent airway lumen on longitudinal airway image. Mucus occlusions are counted per airway generation in all segments of the lung for each subject. Each point represents the ratio of mucus-occluded compartments in 13 patients for each segment. https://doi.org/10.1371/journal.pone.0229238.g004
Source publication
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...
Contexts in source publication
Context 1
... ratios of mucus-occluded bronchial compartments in 13 subjects by airway generation during asthma exacerbation and the stable phase are shown in Fig 4. Each point represents the ratio of mucus-occluded compartments in 13 patients for each segment. ...
Context 2
... the stable phase of asthma, mucus occlusion was observed in 17.9% of the fourth-generation bronchi and 18.1% in fifth-generation bronchi. Mucus plugs are most notable in the fourth-and fifth-generation bronchi and in the lower lobes (left panels of Fig 4 and Fig 5). During the exacerbation phase of asthma, mucus plugs are observed in 43.2% of the fourthgeneration bronchi and 45.9% in fifth-generation bronchi. ...
Context 3
... the exacerbation phase of asthma, mucus plugs are observed in 43.2% of the fourthgeneration bronchi and 45.9% in fifth-generation bronchi. Mucus plugs are most notable in the fourth-and fifth-generation bronchi and in the lower lobes (right panels of Fig 4 and Fig 5). Interestingly, the levels of airway where the mucus occlusion is most frequently observed are different among the lung lobes, especially during asthma exacerbation. ...
Citations
... For example, the Severe Asthma Research Program found that 58% of people with asthma exhibited airway mucus plugs (Dunican et al., 2018), and the extent of mucus plugging correlated with airflow limitation and worse control of asthma. Additionally, a small imaging study showed that individuals experiencing an asthma exacerbation had >40% of the 4 th and 5 th generation bronchi obstructed with mucus (Yoshida et al., 2020). Similar findings showing mucus obstruction of the airway due to mucus plugs and airway narrowing have been repeatedly described (Mummy et al., 2022;Tang et al., 2022). ...
Introduction: Interleukin 13 (IL-13) is an important effector molecule in allergic asthma. IL-13-mediated mucin hypersecretion requires conversion of secretoglobin-positive club cells into goblet cells through suppression of forkhead box A2 (FOXA2) and induction of SAM pointed domain containing ETS transcription factor (SPDEF). IL-13-mediated mucin hypersecretion may also include modulation of purinergic and muscarinic receptors that control basal and stimulated mucin secretion. We recently found that the transcription factor cAMP response element-binding protein (Creb1) inhibits FOXA2 and modulates mucus secretion in mice.
Methods: We tested the hypothesis that loss of club cell Creb1 mitigates the pro-mucin effects of IL-13. We challenged male and female mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-13 or vehicle. We also studied human “club cell-like” NCI-H322 cells.
Results: Loss of club cell Creb1 augmented IL-13-mediated increases in mRNA for the gel-forming mucins Muc5ac and Muc5b and prevented IL-13-mediated decreases in muscarinic 3 receptor (M3R) mRNA in male airways. In female airways, loss of club cell Creb1 reduced M3R mRNA and significantly blunted IL-13-mediated increases in purinergic receptor P2Y2 (P2ry2) mRNA but did not impact Muc5ac and Muc5b mRNA. Despite changes in mucins and secretion machinery, goblet cell density following cholinergic stimulation was not impacted by loss of club cell Creb1 in either sex. IL-13 treatment decreased basal airway resistance across sexes in mice with loss of club cell Creb1, whereas loss of club cell Creb1 augmented IL-13-mediated increases in airway elastance in response to methacholine. NCI-H322 cells displayed IL-13 signaling components, including IL-13Rα1 and IL-4Rα. Pharmacologic inhibition of CREB reduced IL-13Rα1 mRNA, whereas recombinant CREB decreased IL-4Rα mRNA. Application of IL-13 to NCI-H322 cells increased concentrations of cAMP in a delayed manner, thus linking IL-13 signaling to CREB signaling.
Conclusion: These data highlight sex-specific regulation of club cell Creb1 on IL-13-mediated mucin hypersecretion and airway mechanics.
... 10 Yoshida et al reported that airway obstruction measured as lumen diameter was significantly greater in the distal segment of the airway during an asthma attack. 11 Elliot found that airway wall thickening was related to inflammatory infiltration. 12 Li et al compared the acute attack period of asthma with the recovery period, and found ...
Objective
To explore the value of a new model based on CT radiomics in predicting the staging of patients with bronchial asthma (BA).
Methods
Patients with BA from 2018 to 2021 were retrospectively analyzed and underwent plain chest CT before treatment. According to the guidelines for the prevention and treatment of BA (2016 edition), they were divided into two groups: acute attack and non-acute attack. The images were processed as follows: using Lung Kit software for image standardization and segmentation, using AK software for image feature extraction, and using R language for data analysis and model construction (training set: test set = 7: 3). The efficacy and clinical effects of the constructed model were evaluated with ROC curve, sensitivity, specificity, calibration curve and decision curve.
Results
A total of 112 patients with BA were enrolled, including 80 patients with acute attack (range: 2–86 years old, mean: 53.89±17.306 years old, males of 33) and 32 patients with non-acute attack (range: 4–79 years old, mean: 57.38±19.223 years old, males of 18). A total of 10 imaging features are finally retained and used to construct model using multi-factor logical regression method. In the training group, the AUC, sensitivity and specificity of the model was 0.881 (95% CI:0.808–0.955), 0.804 and 0.818, separately; while in the test group, it was 0.792 (95% CI:0.608–0.976), 0.792 and 0.80, respectively.
Conclusion
The model constructed based on radiomics has a good effect on predicting the staging of patients with BA, which provides a new method for clinical diagnosis of staging in BA patients.
... Autopsy studies of asthmatic patients have demonstrated varying degrees of mucus plugging, with the highest mucus burden seen in fatal asthma [10]. Patients with a higher burden of mucus plugging seen on chest CT during exacerbation have been shown to have worsening FEV1 at the time of exacerbation and decreased responsiveness to corticosteroids and inhaled bronchodilators [11]. ...
Severe asthma exacerbations, including near-fatal asthma (NFA), have high morbidity and mortality. Mechanical ventilation of patients with severe asthma is difficult due to the complex pathophysiology resulting from severe bronchospasm and dynamic hyperinflation. Life-threatening complications of traditional ventilation strategies in asthma exacerbations include the development of systemic hypotension from hyperinflation, air trapping, and pneumothoraces. Optimizing pharmacologic techniques and ventilation strategies is crucial to treat the underlying bronchospasm. Despite optimal pharmacologic management and mechanical ventilation, the mortality rate of patients with severe asthma in intensive care units is 8%, suggesting a need for advanced non-pharmacologic therapies, including extracorporeal life support (ECLS). This review focuses on the pathophysiology of acute asthma exacerbations, ventilation management including non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV), the pharmacologic management of acute asthma, and ECLS. This review also explores additional advanced non-pharmacologic techniques and monitoring tools for the safe and effective management of critically ill adult asthmatic patients.
... Eosinophils are also the most common cell type found in the Charcot-Leyden crystals, which characterise the resulting thick, pathologic mucus that plugs the airways of patients with asthma [11,13]. Unsurprisingly, blood/ sputum eosinophil counts correlate with the severity of bronchoconstriction, mucus hypersecretion and thickening, airway inflammation and hyper-responsiveness, leading to potential airway remodelling [5,12,14,15]. Sustained or severe elevations in eosinophil count can lead to mucus plug-mediated airway obstruction, air trapping, increased exacerbation frequency, declines in lung function and even death [10,13,[15][16][17]. ...
... Unsurprisingly, blood/ sputum eosinophil counts correlate with the severity of bronchoconstriction, mucus hypersecretion and thickening, airway inflammation and hyper-responsiveness, leading to potential airway remodelling [5,12,14,15]. Sustained or severe elevations in eosinophil count can lead to mucus plug-mediated airway obstruction, air trapping, increased exacerbation frequency, declines in lung function and even death [10,13,[15][16][17]. ...
... FRI is a novel, non-invasive, quantitative method of assessing lung structure and function based on detailed, three-dimensional (3D) models of the airways of individual patients [21,31], derived from high-resolution computed tomography (HRCT) and cryo-fluorescence tomography (CFT) images [31]. FRI uses imaging equipment available at many hospitals, is not reliant on inhaled media, and allows images to be obtained at any point in the respiratory cycle [15,32]. Furthermore, segmentation algorithms can extract data from regions of interest (lobes, airways, blood vessels), permitting investigators to isolate the early stage effects of pathologies and therapies on specific systems and areas of the lungs [31]. ...
Background:
Severe eosinophilic asthma (SEA) is characterised by elevated blood/sputum eosinophil counts and airway inflammation, which can lead to mucus plug-mediated airway obstruction, increased exacerbation frequency, declines in lung function, and death. Benralizumab targets the alpha-subunit of the interleukin-5 receptor found on eosinophils, leading to rapid and near complete eosinophil depletion. This is expected to result in reduced eosinophilic inflammation, reduced mucus plugging and improved airway patency and airflow distribution.
Methods:
BURAN is an interventional, single-arm, open-label, uncontrolled, prospective, multicentre study during which participants will receive three 30 mg subcutaneous doses of benralizumab at 4-week intervals. This study will use functional respiratory imaging (FRI), a novel, quantitative method of assessing patients' lung structure and function based on detailed, three-dimensional models of the airways, with direct comparison of images taken at Weeks 0 and 13. Patients aged ≥ 18 years with established SEA who may be receiving oral corticosteroids and/or other asthma controller medications, who are inadequately controlled on inhaled corticosteroid-long-acting β2-agonist therapies and who have had ≥ 2 asthma exacerbations in the previous 12 months will be included. The objectives of BURAN are to describe changes in airway geometry and dynamics, measured by specific image-based airway volume and other FRI endpoints, following benralizumab therapy. Outcomes will be evaluated using descriptive statistics. Changes in FRI parameters, mucus plugging scores and central/peripheral ratio will be quantified as mean percent change from baseline (Week 0) to Week 13 (± 5 days) and statistical significance will be evaluated using paired t-tests. Relationships between FRI parameters/mucus plugging scores and conventional lung function measurements at baseline will be assessed with linear regression analyses for associations between outcomes, scatterplots to visualise the relationship, and correlation coefficients (Spearman's rank and Pearson's) to quantify the strength of these associations.
Conclusions:
The BURAN study will represent one of the first applications of FRI-a novel, non-invasive, highly sensitive method of assessing lung structure, function and health-in the field of biologic respiratory therapies. Findings from this study will increase understanding of cellular-level eosinophil depletion mechanisms and improvements in lung function and asthma control following benralizumab treatment. Trial registration EudraCT: 2022-000152-11 and NCT05552508.
... However, excessive mucus secretion in asthmatic patients not only blocks the airway and causes airflow limitation, but also leads to poor control of asthma and increased morbidity and mortality. Current studies have revealed that the release of inflammatory mediators will aggravate the damage to the airway in asthma, leading to increased mucin secretion and the hypersecretion of mucus will cause the weakening of airway antiinflammatory function [5,6] . The interaction between airway inflammation and airway mucus hypersecretion is the main cause of mortality in patients with severe asthma [7] . ...
Objective: To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients. Methods: From January 2020 to June 2022, 90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected. Immunohistochemistry and enzyme-linked immunosorbent assay were performed. NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected. Results: Compared to the healthy control group, the asthma group had significantly higher sputum MUC5A (20.12 ± 5 .07 versus 36.21 ± 6.13) and NLRP3 (72.31 ± 15.13 versus 119.21 ± 31.21) levels (P < 0.05) but lower MUC5B levels (1.35 ± 0.12 versus 0.53 ± 0.11, P < 0.05). Immunohistochemistry showed that NLRP3, MUC5AC, and MUC5B expressions were consistent with the sputum results. Conclusion: NLRP3 and MUC5AC levels are significantly increased in asthmatic patients, whereas MUC5B levels are reduced in these patients. They can be used as targets for the diagnosis and treatment of asthma.
... These data demonstrate that chronic mucus plugs persist over time which emphasizes the need to clear mucus plugs to improve lung function in severe asthma patients (Tang et al., 2022). To evaluate the localization of mucus plugs, Yoshida et al. used a curved, multiplanar reconstruction (MPR) technique, a newly developed technique which provides greater accuracy and visualization than standard CT images (Yoshida et al., 2020). This study showed that when subjects were in the stable phase of asthma, the fourth and fifth-generation bronchi in the lower lobes had a greater frequency of mucus plugs. ...
... However, when subjects with asthma were undergoing an exacerbation, the upper lobes had a higher frequency of mucus plus in the fifth and sixth generation bronchi. In addition, Yoshida et al. showed that over 40% of conducting airways of the lower lobes were obstructed by mucus plugs (Yoshida et al., 2020). Lastly, a study involving 44 patients with severe asthma from the SARP cohort, assessed mucus plugging on CT scans, and showed that in the same bronchopulmonary segment where there was a mucus plug present, there were greater ventilation defects (Mummy et al., 2022). ...
Asthma affects an estimated 262 million people worldwide and caused over 461,000 deaths in 2019. The disease is characterized by chronic airway inflammation, reversible bronchoconstriction, and airway remodeling. Longitudinal studies have shown that current treatments for asthma (inhaled bronchodilators and corticosteroids) can reduce the frequency of exacerbations, but do not modify disease outcomes over time. Further, longitudinal studies in children to adulthood have shown that these treatments do not improve asthma severity or fixed airflow obstruction over time. In asthma, fixed airflow obstruction is caused by remodeling of the airway wall, but such airway remodeling also significantly contributes to airway closure during bronchoconstriction in acute asthmatic episodes. The goal of the current review is to understand what is known about the heterogeneity of airway remodeling in asthma and how this contributes to the disease process. We provide an overview of the existing knowledge on airway remodeling features observed in asthma, including loss of epithelial integrity, mucous cell metaplasia, extracellular matrix remodeling in both the airways and vessels, angiogenesis, and increased smooth muscle mass. While such studies have provided extensive knowledge on different aspects of airway remodeling, they have relied on biopsy sampling or pathological assessment of lungs from fatal asthma patients, which have limitations for understanding airway heterogeneity and the entire asthma syndrome. To further understand the heterogeneity of airway remodeling in asthma, we highlight the potential of in vivo imaging tools such as computed tomography and magnetic resonance imaging. Such volumetric imaging tools provide the opportunity to assess the heterogeneity of airway remodeling within the whole lung and have led to the novel identification of heterogenous gas trapping and mucus plugging as important predictors of patient outcomes. Lastly, we summarize the current knowledge of modification of airway remodeling with available asthma therapeutics to highlight the need for future studies that use in vivo imaging tools to assess airway remodeling outcomes.
... In the present study, we included patients with NTM as a representative of chronic lower respiratory tract infections. However, NTM is caused by intracellular organisms and pathologically characterized by granulomas, which is different from most bacterial infection [18]. It remains unclear whether the results of this study can be applicable to chronic lower respiratory tract infections caused by other pathogens, such as Haemophilus influenzae and Pseudomonas aeruginosa. ...
Objective
To compare the morphological features of bronchiectasis between patients with different underlying diseases, we performed quantitative analysis of high-resolution computed tomography (HRCT) images of 14 patients with non-tuberculous mycobacteriosis (NTM) and 13 with idiopathic pulmonary fibrosis (IPF). A 3D image of the bronchial structure was made from HRCT data. Bronchiectasis was defined as abnormal dilatation of the bronchi with the diameter greater than that of the accompanying pulmonary artery. We measured the inner and outer diameters, wall area as %total airway cross sectional area (WA%), and wall thickness to airway diameter ratio (T/D) of the 4-8th generations of bronchi.
Results
In patients with IPF, the inner and outer diameters linearly decreased toward the distal bronchi. In contrast, the inner and outer diameters of NTM fluctuated. The coefficient of variation of the outer diameters of the 6-7th generations of bronchi was larger in the NTM patients than in those with IPF, whereas no significant difference was observed in the coefficient of variation of the inner diameters between the groups. In IPF patients, WA% and T/D varied between the generation of bronchi, but the coefficient of variation of WA% and T/D was relatively small in those with NTM.
... 66 Overall, mucous gland hyperplasia and excessive mucus production can lead to mucous plugging of the airway, reduced airway lumen area, and airflow obstruction. 67 Integrins have been implicated in mucous overproduction and goblet cell hyperplasia. β1 integrins have recently been shown to regulate cellular and secreted MUC5AC and MUC5B production in lung epithelial cells. ...
Airway remodeling is a complex clinical feature of asthma that involves long-term disruption and modification of airway architecture, which contributes significantly to airway hyperresponsiveness (AHR) and lung function decline. It is characterized by thickening of the airway smooth muscle layer, deposition of a matrix below the airway epithelium, resulting in subepithelial fibrosis, changes within the airway epithelium, leading to disruption of the barrier, and excessive mucous production and angiogenesis within the airway wall. Airway remodeling contributes to stiffer and less compliant airways in asthma and leads to persistent, irreversible airflow obstruction. Current asthma treatments aim to reduce airway inflammation and exacerbations but none are targeted towards airway remodeling. Inhibiting the development of airway remodeling or reversing established remodeling has the potential to dramatically improve symptoms and disease burden in asthmatic patients. Integrins are a family of transmembrane heterodimeric proteins that serve as the primary receptors for extracellular matrix (ECM) components, mediating cell-cell and cell-ECM interactions to initiate intracellular signaling cascades. Cells present within the lungs, including structural and inflammatory cells, express a wide and varying range of integrin heterodimer combinations and permutations. Integrins are emerging as an important regulator of inflammation, repair, remodeling, and fibrosis in the lung, particularly in chronic lung diseases such as asthma. Here, we provide a comprehensive summary of the current state of knowledge on integrins in the asthmatic airway and how these integrins promote the remodeling process, and emphasize their potential involvement in airway disease.
... It may be interpreted that the T2 signature in asthma is strongly linked to corticosteroids responses. 30,31 Therefore, Cluster 1 patients with the lowest T2 inflammation had the worst therapeutic responses, cluster 2 patients with moderate T2 inflammation had the moderate therapeutic responses, and cluster 3 patients with the highest T2 inflammation had the best therapeutic responses. Previous research on imaging phenotype mainly used imaging parameters of air trapping and airway structure in cluster analysis, through which clinical characteristics were generally analyzed. ...
Objective
This study aims to describe the imaging features of naïve asthma patients, defined as not receiving corticosteroids or other asthma medications for at least 1 month, and their association with therapeutic response, and to discover novel unbiased imaging phenotypes.
Methods
A total of 109 naïve asthma patients and 50 healthy controls were enrolled in this study. Clinical data and imaging indices of high-resolution computed tomography were collected. The correlation between imaging indices and clinical features was analyzed. Cluster analyses were adopted to determine three novel imaging phenotypes.
Results
Compared with healthy controls, naïve asthma patients presented higher scores of airway remodeling, bronchiectasis, and mucus plugs. Mean airway wall area (WA)% was inversely correlated with mid-expiratory flow velocity% predicted. The extent score of bronchiectasis was positively correlated with smoking history and significantly increased in the high mucus group. Mucus plugs were related to improving lung function and type 2 (T2) inflammation, as assessed by sputum and blood eosinophils and fraction of exhaled nitric oxide. Cluster 1 patients had a high proportion of emphysema, the best lung function, and the lowest T2 inflammation; cluster 2 patients had severe airway remodeling, relatively good lung function, and moderate T2 inflammation; cluster 3 patients had severe airway remodeling, mucus plugs, and bronchiectasis, and showed the worst lung function and highest T2 inflammation.
Conclusion
Naïve asthma patients had the imaging traits of airway remodeling, bronchiectasis, and mucus plugs. The unbiased imaging phenotypes had good consistency with clinical characteristics, therapeutic response, and T2 inflammation expression in naïve asthma patients.
... 22 One study collected ETTs of extubated subjects and found that secretions could cause significant pressure drop with a given air flow, compared with a control ETT, and 50% of the ETTs with secretions had resistance equivalent to one tube size smaller. 23 A recent study by Yoshida et al 24 reported that "mucus plugs occluded more than 40% of the airways." A tiny, 5 mm mucus plug on an 8.0 mm ETT would result in a 7.5 mm internal diameter and 3.75 mm radius, whereas the same mucus plug on a 7.0 mm ETT would result in a 6.5 mm diameter and a 3.25 mm radius. ...
Background:
There is limited evidence on the clinical importance of the endotracheal tube (ETT) size selection in patients with status asthmaticus who require invasive mechanical ventilation. We set out to explore the clinical outcomes of different ETT internal diameter sizes in subjects mechanically ventilated with status asthmaticus.
Methods:
This was a retrospective study of intubated and non-intubated adults admitted for status asthmaticus between 2014-2021. We examined in-hospital mortality across subgroups with different ETT sizes, as well as non-intubated subjects, using logistic and generalized linear mixed-effects models. We adjusted for demographics, Charlson comorbidities, the first Sequential Organ Failure Assessment score, intubating personnel and setting, COVID-19, and the first PaCO2 . Finally, we calculated the post-estimation predictions of mortality.
Results:
We enrolled subjects from 964 status asthmaticus admissions. The average age was 46.9 (SD 14.5) y; 63.5% of the encounters were women and 80.6% were Black. Approximately 72% of subjects (690) were not intubated. Twenty-eight percent (275) required endotracheal intubation, of which 3.3% (32) had a 7.0 mm or smaller ETT (ETT ≤ 7 group), 16.5% (159) a 7.5 mm ETT (ETT ≤ 7.5 group), and 8.6% (83) an 8.0 mm or larger ETT (ETT ≥ 8 group). The adjusted mortality was 26.7% (95% CI 13.2-40.2) for the ETT ≤ 7 group versus 14.3% ([(95% CI 6.9-21.7%], P = .04) for ETT ≤ 7.5 group and 11.0% ([95% CI 4.4-17.5], P = .02) for ETT ≥ 8 group, respectively.
Conclusions:
Intubated subjects with status asthmaticus had higher mortality than non-intubated subjects. Intubated subjects had incrementally higher observed mortality with smaller ETT sizes. Physiologic mechanisms can support this dose-response relationship.
