The effect of disease and respiration on airway shape in patients with moderate persistent asthma

Choi

et al. 2021

Preprint

Background: Asthma comprises heterogeneous inflammatory airway disorders whose classification has not been established. Quantitative computed tomography (QCT) methods can differentiate lung disease using accurate assessment of location, extent, and severity of the disease. This study aimed to identify heterogeneous asthmatic groups by QCT metrics of airway and parenchymal structure, which is associated with radiologists’ visual analysis and bronchodilator responses in a prospective design.Methods: Using the input from QCT-based metrics, including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph), a cluster analysis was performed and compared with grouping based on site of airway involvement and remodeling evaluated by radiologists.Results: 61 asthmatics were grouped into four clusters with different clinical severities. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbation in 5-year follow-up were observed. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthma, which had reserved bronchodilator responses of proximal airways. C3 and C4 presented severe asthmatics that exhibited reduced Dh of proximal airway and its bronchodilator responsiveness; C3 was severe allergic asthma without fSAD, while C4 was ex-smokers with significantly high fSAD% and Emph%. These clusters were correlated with the grouping by radiologists and their clinical outcomes.Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and may serve as complementary tools for predicting future asthma outcomes.

Section: Discussionmentioning

confidence: 99%

Phenotypic Clusters On Computed Tomography Reflects Asthma Heterogeneity And Severity

Choi

et al. 2021

Preprint

Journal of Engineering and Science in Medical Diagnostics and Therapy

“…4 of this review, a single value of ASM strain cannot be attributed to a DI. This is because many procedural and biological confounders contribute to the variability between individuals and between airways within the same individual, as well as to the temporal variability of any given airway of a given individual [96]. At this point, it seems more appropriate to provide a rough estimated range of strains that is physiologically relevant.…”

Section: Discussionmentioning

confidence: 99%

“…It is also important to mention that considerable regional differences in P L exist within the lungs. During the same breathing maneuvers, the airways in lower lobes are more strained than airways of the same generation in the apical lobes [87,88,92,96]. The estimated strain ASM undergoes is thus highly influenced by the region of the lungs in which the airways are embedded.…”

Section: Confoundersmentioning

confidence: 99%

The Strain on Airway Smooth Muscle During a Deep Inspiration to Total Lung Capacity

Bossé

2019

The deep inspiration (DI) maneuver entices a great deal of interest because of its ability to temporarily ease the flow of air into the lungs. This salutary effect of a DI is proposed to be mediated, at least partially, by momentarily increasing the operating length of airway smooth muscle (ASM). Concerningly, this premise is largely derived from a growing body of in vitro studies investigating the effect of stretching ASM by different magnitudes on its contractility. The relevance of these in vitro findings remains uncertain, as the real range of strains ASM undergoes in vivo during a DI is somewhat elusive. In order to understand the regulation of ASM contractility by a DI and to infer on its putative contribution to the bronchodilator effect of a DI, it is imperative that in vitro studies incorporate levels of strains that are physiologically relevant. This review summarizes the methods that may be used in vivo in humans to estimate the strain experienced by ASM during a DI from functional residual capacity (FRC) to total lung capacity (TLC). The strengths and limitations of each method, as well as the potential confounders, are also discussed. A rough estimated range of ASM strains is provided for the purpose of guiding future in vitro studies that aim at quantifying the regulatory effect of DI on ASM contractility. However, it is emphasized that, owing to the many limitations and confounders, more studies will be needed to reach conclusive statements.

“…When introducing clinically appropriate enhancements, users should be aware that the modified measurement apparatuses retain fixed dimensions, whereas the airways of the lungs are flexible with variable diameters and length and possibly changing angles of bifurcation upon inhalation (54). Furthermore, obstructive lung disease has an influence on airway morphology (55). In consequence, the predictive capability for such CI-based measurements with the modifications suggested by Mitchell and Suggett (26) for the purpose of correlating in vitro with in vivo outcomes will likely still be limited (56).…”

Section: Enhancements the CI Methods To Support The Clinical Programmentioning

confidence: 99%

Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs

Mitchell¹,

Doub³

et al. 2019

AAPS PharmSciTech

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.