BACKGROUND: Information 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. METHODS: CT 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. RESULTS: The 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. CONCLUSION: Persistent 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 REGISTRATION: Clinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915. FUNDING: AstraZeneca, 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.

This study aimed to introduce a one-dimensional (1D) computational fluid dynamics (CFD) model for airway resistance and lung compliance to examine the relationship between airway resistance, pressure, and regional flow distribution. We employed five healthy and five asthmatic subjects who had dynamic computed tomography (CT) scans (4D CT) along with two static scans at total lung capacity and functional residual capacity. Fractional air-volume change ($\Delta {\text{V}}_{\text{air}}^{\text{f}}$ ) from 4D CT was used for a validation of the 1D CFD model. We extracted the diameter ratio from existing data sets of 61 healthy subjects for computing mean and standard deviation (SD) of airway constriction/dilation in CT-resolved airways. The lobar mean (SD) of airway constriction/dilation was used to determine diameters of CT-unresolved airways. A 1D isothermal energy balance equation was solved, and pressure boundary conditions were imposed at the acinar region (model A) or at the pleural region (model B). A static compliance model was only applied for model B to link acinar and pleural regions. The values of 1D CFD-derived $\Delta {\text{V}}_{\text{air}}^{\text{f}}$ for model B demonstrated better correlation with 4D CT-derived $\Delta {\text{V}}_{\text{air}}^{\text{f}}$ than model A. In both inspiration and expiration, asthmatic subjects with airway constriction show much greater pressure drop than healthy subjects without airway constriction. This increased transpulmonary pressures in the asthmatic subjects, leading to an increased workload (hysteresis). The 1D CFD model was found to be useful in investigating flow structure, lung hysteresis, and pressure distribution for healthy and asthmatic subjects. The derived flow distribution could be used for imposing boundary conditions of 3D CFD. NEW & NOTEWORTHY A one-dimensional (1D) computational fluid dynamics (CFD) model for airway resistance and lung compliance was introduced to examine the relationship between airway resistance, pressure, and regional flow distribution. The 1D CFD model investigated differences of flow structure, lung hysteresis, and pressure distribution for healthy and asthmatic subjects. The derived flow distribution could be used for imposing boundary conditions of three-dimensional CFD.

Image registration-based local displacement analysis enables evaluation of respiratory motion between two computed tomography-captured lung volumes. The objective of this study was to compare diaphragm movement among emphysema, idiopathic pulmonary fibrosis (IPF) and normal subjects. 29 normal, 50 emphysema, and 51 IPF subjects were included. A mass preserving image registration technique was used to compute displacement vectors of local lung regions at an acinar scale. Movement of the diaphragm was assumed to be equivalent to movement of the basal lung within 5 mm from the diaphragm. Magnitudes and directions of displacement vectors were compared between the groups. Three-dimensional (3D) and apico-basal displacements were smaller in emphysema than normal subjects (P = 0.003, P = 0.002). Low lung attenuation area on expiration scan showed significant correlations with decreased 3D and apico-basal displacements (r = − 0.546, P < 0.0001; r = − 0.521, P < 0.0001) in emphysema patients. Dorsal–ventral displacement was smaller in IPF than normal subjects (P < 0.0001). The standard deviation of the displacement angle was greater in both emphysema and IPF patients than normal subjects (P < 0.0001). In conclusion, apico-basal movement of the diaphragm is reduced in emphysema while dorsal–ventral movement is reduced in IPF. Image registration technique to multi-volume CT scans provides insight into the pathophysiology of limited diaphragmatic motion in emphysema and IPF.

Rheumatoid arthritis (RA) affects roughly 1% of the population and commonly involves the lungs. Of lung involvement in RA, interstitial lung disease (ILD) is well known; however, airways disease in RA is relatively understudied. What are the baseline airways abnormalities in a prospective cohort of patients with RA based on pulmonary function testing (PFT) results, high-resolution CT (HRCT) scans, and computational imaging analysis and are there associations between these abnormalities and respiratory symptoms? In this single-center study, 188 patients with RA without a clinical diagnosis of ILD underwent HRCT imaging and PFT. Radiologists assessed HRCT scans for airway abnormalities. Computational imaging via VIDA Vision software and in-house quantitative CT imaging analysis was applied to 147 HRCT scans to quantify airway abnormalities. Airways obstruction (FEV₁ to FVC ratio < 0.7) was present in 20.7% of patients and was associated with older age, male sex, and higher smoking rate. Radiologists identified airway abnormalities in 61% of patients: 55% had bronchial wall thickening, 12% had bronchiectasis, and 5% had mosaic attenuation. These airways findings were associated with older age; male sex; lower FEV₁, FVC, and FEV₁ to FVC ratio; and higher rates of rheumatoid factor positivity. Prespecified quantitative CT scan metrics (wall thickening percentage and emphysema percentage) correlated with obstruction in PFT results and more severe respiratory symptoms, including shortness of breath and cough. High rates of airways abnormalities were found in this prospective RA cohort based on three methods of detection. Significant associations were identified between quantitative CT scan measures and respiratory symptoms. Airways disease may be an underrecognized extra-articular manifestation of RA and quantitative CT imaging may be a sensitive method to detect the clinical impact on respiratory symptoms.

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.